Patent Description:
Various protein kinases are present in vivo, and are known to be involved in a wide range of functional regulations. RET is a receptor tyrosine kinase identified as one of the protooncogenes. RET binds to the glial cell line-derived neurotrophic factor (GDNF) and GDNF receptor to form a complex, which enables RET to perform physiological functions through intracellular phosphorylation signaling. ) Some studies indicate that in cancers, such as lung cancer, thyroid cancer, breast cancer, pancreas cancer, and prostate cancer, the translocation, mutation, and overexpression of RET enhances its activation to thereby contribute to cell growth, tumor formation, or tissue infiltration. (<NPL>); <NPL>);<NPL>); <NPL>); <NPL>); and <NPL>)). In addition, RET is known to be a poor prognostic factor of cancer, as indicated in some reports that the translocation of RET and its enhanced activation level are also inversely correlated with prognosis in cancer (<NPL>); <NPL>); <NPL>); and<NPL>)). Therefore, an inhibitor capable of inhibiting RET activity is thought to be useful as a therapeutic agent for diseases associated with abnormally enhanced RET signaling pathways, including cancers.

Furthermore, many cancers can lead to a metastatic brain tumor. Symptomatic metastatic brain tumors have been reported to occur in <NUM> to <NUM>% of cancer patients, and there is also a report that, in lung cancer, brain metastasis has been reported at a frequency of <NUM> to <NUM>% according to autopsy. (<NPL>); <NPL>); <NPL>)). Accordingly, it is desirable to find treatments that effectively treat cancer, including brain metastasis of the cancer.

Even more desirable is that the treatment can be administered in a form that is easily absorbed by the body and also shelf stable. The pharmaceutically active substance used to prepare the treatment should be as pure as possible and its stability on long-term storage should be guaranteed under various environmental conditions. These properties are useful to prevent the appearance of unintended degradation products in pharmaceutical compositions, which degradation products may be potentially toxic or result simply in reducing the potency of the composition.

A primary concern for the large-scale manufacture of pharmaceutical compounds is that the active substance should have a stable crystalline morphology to ensure consistent processing parameters and pharmaceutical quality. If an unstable crystalline form is used, crystal morphology may change during manufacture and/or storage resulting in quality control problems and formulation irregularities. Such a change may affect the reproducibility of the manufacturing process and thus lead to final formulations which do not meet the high quality and stringent requirements imposed on formulations of pharmaceutical compositions. In this regard, it should be generally borne in mind that any change to the solid state of a pharmaceutical composition which can improve its physical and chemical stability gives a significant advantage over less stable forms of the same drug.

When a compound crystallizes from a solution or slurry, it may crystallize with different spatial lattice arrangements, a property referred to as "polymorphism. " Each of the crystal forms is a "polymorph. " While polymorphs of a given substance have the same chemical composition, they may differ from each other with respect to one or more physical properties, such as solubility, dissociation, true density, dissolution, melting point, crystal shape, compaction behavior, flow properties, and/or solid state stability.

RET inhibitor <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide (also known as HM06 or TAS0953) is reported in <CIT>. The molecular formula of the free base form of HM06/TAS0953 is C<NUM>H<NUM>N<NUM>O<NUM>, the molecular weight is <NUM>, and the structural formula of the free base is:
<CHM>.

However, crystalline forms of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide have not been heretofore disclosed.

Accordingly, disclosed herein are substantially crystalline forms of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide free base, HCl salt forms, processes for making said crystalline forms, and methods for using said forms.

The present disclosure relates to substantially crystalline forms of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide. In one aspect of the present disclosure, the crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide is a free base. In one aspect of the present disclosure, the crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide is an HCl salt, for example a <NUM>:<NUM> or <NUM>:<NUM> HCl salt.

The present disclosure also relates to a pharmaceutical composition comprising at least one substantially crystalline form as described herein and a pharmaceutically acceptable excipient.

The present disclosure further relates to a method of treating cancer in a human patient in need thereof comprising administering to the patient an effective amount of a substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide.

Additional objects and advantages will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice. The objects and advantages will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claims.

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate one (several) embodiment(s) and together with the description, serve to explain the principles described herein.

As summarized above, and as set forth in detail below, the present disclosure relates to crystalline forms of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide (also referred to as HM06 or TAS953). The present disclosure also relates to methods of making the crystalline free base forms and HCl salt forms thereof, such as a dichloride (or <NUM>:<NUM>) HCl salt:
<CHM>.

Also disclosed herein are methods of using the crystalline forms for therapeutic treatment such as for cancer.

The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.

The present disclosure relates to substantially crystalline forms of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide. In at least one aspect of the present disclosure, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide is a free base.

In some embodiments of the present disclosure the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide free base is Form <NUM>. In at least one embodiment the <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide free base Form <NUM> is characterized by an XRPD pattern substantially the same as <FIG>. In at least one embodiment the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide free base Form <NUM> is characterized by an XRPD pattern comprising one or more peaks chosen from peaks at about <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, and <NUM>°2θ.

In some embodiments of the present disclosure, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide free base is Form <NUM>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide free base Form <NUM> is characterized by an XRPD pattern substantially the same as <FIG>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide free base Form <NUM> is characterized by an XRPD pattern comprising one or more peaks chosen from peaks at about <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, and <NUM>°2θ.

In some embodiments of the present disclosure, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide free base is Form <NUM>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide free base Form <NUM> is characterized by an XRPD pattern substantially the same as <FIG>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide free base Form <NUM> is characterized by an XRPD pattern comprising one or more peaks chosen from peaks at about <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, and <NUM>°2θ.

In some embodiments of the present disclosure, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide free base is Form <NUM>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide free base Form <NUM> is characterized by an XRPD pattern substantially the same as <FIG>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide free base Form <NUM> is characterized by an XRPD pattern comprising one or more peaks chosen from peaks at about <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, and <NUM>°2θ.

In some embodiments of the present disclosure, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide is a mixture of free base forms.

In some embodiments, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide is an HCl salt Form A. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide HCl salt Form A is characterized by an XRPD pattern substantially the same as <FIG>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide HCl salt Form A is characterized by an XRPD pattern comprising one or more peaks chosen from peaks at about <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, and <NUM>°2θ.

In some embodiments of the present disclosure, the substantially crystalline form is <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt is Form <NUM>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM> is characterized by an XRPD pattern substantially the same as <FIG>, <FIG>, or <FIG>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl Form <NUM> is characterized by an XRPD pattern comprising one or more peaks chosen from peaks at about <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, and <NUM>°2θ. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM> -morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl Form <NUM> has at least one characteristic chosen from a DSC thermogram substantially the same as <FIG> and a TGA profile substantially the same as <FIG>.

In some embodiments of the present disclosure, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide is a mixture of HCl Form A and <NUM>:<NUM> HCl Form <NUM>.

In some embodiments, the substantially crystalline form is <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt.

In some embodiments, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt is Form <NUM>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM> is characterized by an XRPD pattern substantially the same as <FIG>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl Form <NUM> is characterized by an XRPD pattern comprising one or more peaks chosen from peaks at about <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, and <NUM>°2θ. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl Form <NUM> has at least one characteristic chosen from a DSC thermogram substantially the same as <FIG> and a TGA profile substantially the same as <FIG>.

In some embodiments, the substantially crystalline form is <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt is Form <NUM>-bis. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM>-bis is characterized by an XRPD pattern substantially the same as <FIG> or <FIG>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM>-bis is characterized by an XRPD pattern comprising one or more peaks chosen from peaks at about <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, and <NUM>°2θ.

In some embodiments of the present disclosure, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt is a mixture of Form <NUM> and Form <NUM>-bis.

In some embodiments of the present disclosure, the substantially crystalline form <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt is Form <NUM>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM> is characterized by an XRPD pattern substantially the same as <FIG>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM> is characterized by an XRPD pattern comprising one or more peaks chosen from peaks at about <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, and <NUM>°2θ. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM> has at least one characteristic chosen from a DSC thermogram substantially the same as <FIG> and a TGA profile substantially the same as <FIG>.

In some embodiments of the present disclosure, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt is a mixture of Form <NUM> and Form <NUM>.

In some embodiments of the present disclosure, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt is Form <NUM>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM> is characterized by an XRPD pattern substantially the same as <FIG>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM> is characterized by an XRPD pattern comprising one or more peaks chosen from peaks at about <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, and <NUM>°2θ. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM> has at least one characteristic chosen from a DSC thermogram substantially the same as <FIG> and a TGA profile substantially the same as <FIG>.

In some embodiments of the present disclosure, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt is Form <NUM>-bis. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM>-bis is characterized by an XRPD pattern substantially the same as <FIG>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM>-bis is characterized by an XRPD pattern comprising one or more peaks chosen from peaks at about <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>, and <NUM>°2θ.

In some embodiments of the present disclosure, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt is Form <NUM>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM> is characterized by an XRPD pattern substantially the same as <FIG>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM> is characterized by an XRPD pattern comprising one or more peaks chosen from peaks at about <NUM>°2θ. <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, and <NUM>°2θ.

In some embodiments of the present disclosure, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt is a mixture of Form <NUM>-bis and Form <NUM>.

In some embodiments of the present disclosure, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt is Form <NUM>-bis. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM>-bis is characterized by an XRPD pattern substantially the same as <FIG>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM>-bis is characterized by an XRPD pattern comprising one or more peaks chosen from peaks at about <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, and <NUM>°2θ.

In some embodiments of the present disclosure, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt is Form <NUM>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM> is characterized by an XRPD pattern substantially the same as <FIG>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM>-bis is characterized by an XRPD pattern comprising one or more peaks chosen from peaks at about <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, and <NUM>°2θ. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM> has at least one characteristic chosen from a DSC thermogram substantially the same as <FIG> and a TGA profile substantially the same as <FIG>.

In some embodiments of the present disclosure, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt is Form <NUM>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM> is characterized by an XRPD pattern substantially the same as <FIG>. In at least one embodiment, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt Form <NUM> is characterized by an XRPD pattern comprising one or more peaks chosen from peaks at about <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, and <NUM>°2θ.

In some embodiments of the present disclosure, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt is a mixture of Form <NUM>, Form <NUM>, and Form <NUM>.

In some embodiments of the present disclosure, the substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt is a mixture of at least one form chosen from Form <NUM>, Form <NUM>-bis, Form <NUM>, Form <NUM>, Form <NUM>-bis, Form <NUM>, Form <NUM>-bis, Form <NUM>, and Form <NUM>.

The substantially crystalline forms disclosed herein can be in at least <NUM>% crystalline form, such as at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, or <NUM>% crystalline.

The present disclosure also relates to pharmaceutical compositions comprising at least one substantially crystalline form as disclosed herein and a pharmaceutically acceptable excipient. For example, in some embodiments, the pharmaceutical compositions can comprise the substantially crystalline forms of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt.

The present disclosure still further relates to a method of treating cancer in a human patient in need thereof comprising administering to the patient an effective amount of a substantially crystalline form of <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide. In at least one embodiment, the substantially crystalline form is <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide free base Form <NUM>. In at least one embodiment, the substantially crystalline form is <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl Form <NUM>. In at least one embodiment, the substantially crystalline form is <NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl Form <NUM>.

Unless otherwise specified, following instruments and parameters were used for the physical characterization of the crystalline forms disclosed herein.

X-Ray Powder Diffraction (XRPD) Analysis.

DSC analysis was carried out using a DSC Mettler Toledo DSC1.

The sample was weighed in an aluminum pan hermetically sealed with an aluminum cover. The analysis was performed heating the sample from <NUM> to <NUM> at <NUM>/min.

TG analysis was carried out using the Mettler Toledo TGA/DSC1.

The sample was weighed in an aluminum pan hermetically sealed with an aluminum pierced cover. The analysis was performed heating the sample from <NUM> to <NUM> at <NUM>/min.

HM06 free base Form <NUM> was prepared using a Sonogashira cross-coupling reaction mediated by Pd(PPh<NUM>)<NUM>Cl<NUM> and CuI in ACN. More specifically, <NUM>-amino-<NUM>-bromo-N-(<NUM>-(methoxymethyl)phenyl)-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>,<NUM>-dihydro-<NUM>H-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide (<NUM>) (which can be prepared according to known methods, such as Example <NUM> of <CIT>) was added to a reaction vessel at room temperature and the following reagents were added: CuI (<NUM>), Pd(PPh<NUM>)<NUM>Cl<NUM> (<NUM>) and CH<NUM>CN (<NUM>). <NUM>-(prop-<NUM>-yn-<NUM>-yl)morpholine (<NUM>) was added to the mass. TEA (<NUM>) was added. The mass was inerted with vacuum and N<NUM> five times (<NUM> mbar/<NUM> mbar). The mass was heated to Tj <NUM> (Ti: <NUM>) under N<NUM> and it was stirred for <NUM> hours at Tj <NUM> to obtain a solution, and then cooled to Ti <NUM>-<NUM>. THF (<NUM>) was added and the mixture was warmed to Ti <NUM>. The warmed mixture was filtered through a <NUM>-<NUM> mesh filter (PTFE) by applying just pressure (at least <NUM> bars). The filtered mix was cooled to Ti <NUM>-<NUM>. The mixture was then passed through a plug of resin (ISOLUTE® Si-Thiol; Ti <NUM>-<NUM> mix by applying RATE: <NUM>/h). The reaction vessel, the filter, and the resin cake were washed with THF (<NUM>). The wet resin was discarded. The solvent was distilled at Tj: <NUM> under vacuum until applying Vmax (by stopping stirring when needed). MeTHF (<NUM>) was added to the residue and stirred at room temperature to obtain a homogeneous suspension.

To the organic suspension <NUM> solution of N-acetylcysteine (<NUM>) in water (<NUM>) was added. The mass was heated to Tj: <NUM> (Ti: <NUM>-<NUM>) and stirred for <NUM> hours. The stirring was then stopped, and the phases were allowed to separate for at least <NUM> minutes. After phases separation, the aqueous layer was back-extracted with MeTHF (<NUM>) at Ti <NUM>-<NUM>. The mixture was stirred for <NUM> minutes and then the stirring was stopped, and the layers were allowed to separate for at least <NUM> minutes at Ti:<NUM>-<NUM>. The layers were then separated, and the aqueous layer was disposed of. The two organic layers were combined and then NaCl <NUM>% (<NUM>) was added at Ti:<NUM>-<NUM>. The mixture was stirred for <NUM> minutes and then stirring was stopped, and the phases were allowed to separate for at least <NUM> minutes. The aqueous layer was removed and disposed of. Water (<NUM>) was added to the organic layer at Ti:<NUM>-<NUM>. The mixture was stirred for <NUM> minutes at the same temperature and then stirring was stopped and the phases were allowed to separate for at least <NUM> minutes. The aqueous layer was again removed and discarded.

The organic layer was distilled to residue at Tj: <NUM> under vacuum until applying Vmax. The residue was stripped overnight at Tj: <NUM> under Vmax without stirring. Acetone was added (<NUM>) to the residue at Tj: <NUM> and then heated to Ti: <NUM> (Tj: <NUM>). The mixture was stirred for at least <NUM> hour to obtain a homogeneous suspension. The suspension was cooled to Ti: -<NUM> (Tj: -<NUM>) over at least <NUM> hours. The product was then isolated by filtration using a <NUM> mesh filter at Tj: -<NUM> by applying vacuum and pressure (at least <NUM> bars). The filter cake was washed with pre-cooled acetone (<NUM>; Ti: -<NUM>) by applying pressure (at least <NUM> bars) and vacuum until no more deliquoring was observed. The solid was dried at Tj: <NUM> for at least <NUM> hours to obtain the final product (<NUM>). The product was stored at Tj: <NUM>-<NUM>.

<FIG> shows an XRPD pattern of HM06 crystalline free base Form <NUM> obtained using CuKα radiation. Peaks identified in <FIG> include those set forth in Table <NUM>:.

Five (<NUM>) new crystalline phases for the free base, and an HCl crystalline salt form, were observed after selected re-crystallization experiments using the solvents listed in the Table <NUM>.

<FIG> shows an XRPD pattern of an HM06 HCl salt Form A obtained using CuKα radiation. Peaks identified in <FIG> include those set forth in Table <NUM>:.

<FIG> shows an overlay of XRPD patterns of five HM06 crystalline free base forms and an HM06 HCl salt Form A obtained using CuKα radiation.

In a <NUM> single-neck round-bottom flask, <NUM> (I. ) of HCl solution <NUM> in water was added to l g of HM06 free base. <NUM> of tetrahydrofuran was charged and the suspension was allowed to stir (<NUM> rpm) at room temperature (<NUM>) for two days.

A sampling was collected, filtered, and analyzed by XRPD. The remaining suspension was recovered by suction, dried under vacuum (<NUM> mbar) at <NUM> for one day. The dried sample was analyzed by XRPD.

<FIG> shows an XRPD pattern of crystalline HM06 <NUM>:<NUM> HCl Form <NUM> obtained using CuKα radiation. <FIG> and <FIG> also show XRPD patterns of crystalline HM06 <NUM>:<NUM> HCl Form <NUM> obtained using CuKα radiation. Peaks identified in <FIG> for crystalline HM06 <NUM>:<NUM> HCl include those set forth in Table <NUM>:.

The DSC profile of HM06 <NUM>:<NUM> HCl Form <NUM> recorded in a sealed pan showed an event after <NUM> ascribable to sample melt and degradation. <FIG> is a DSC thermogram of HM06 <NUM>:<NUM> HCl Form <NUM>. The lack of the signal in the DSC profile related to solvent release and the change in the baseline was probably due to the sealed pan used combined with the effect due to solvent release.

The TGA profile of HM06 <NUM>:<NUM> HCl Form <NUM> showed a weight loss of <NUM>% in the range of <NUM>°-<NUM> consistent with water evolution as recorded by EGA. Degradation occurred after <NUM>. <FIG> provides the TGA profile of HM06 <NUM>:<NUM> HCl Form <NUM>. The heat-flow recorded in TGA showed a broad and large event that took place in the range of water loss and a signal after <NUM> ascribable to melt, then degradation occurred.

<NUM> of HM06 free base was weighed and transferred in a <NUM> reactor equipped with a magnetic stirring bar. <NUM> of ethanol were then added and the resulting mixture was heated until complete dissolution of the solid (T = <NUM>). When no solid material was observed, the solution was cooled to <NUM>. <NUM>µL (<NUM> eq. ) of HCl <NUM>% were slowly added into the reactor. The formation of a solid was immediately observed. The mixture was cooled to <NUM> in <NUM> minutes and then stirred for additional <NUM> hour. After this time, the formed solid was isolated by vacuum filtration, washed with ethanol and dried at <NUM> and <NUM> mbar for <NUM> hours. <NUM> of product was recovered as white solid in nearly quantitative yield.

<NUM> of HM06 free base were weighed and transferred in a <NUM> reactor equipped with a magnetic stirring bar. <NUM> of ethanol were then added and the resulting mixture was heated until complete dissolution of the solid (T = <NUM>). When no solid material was observed, the solution was cooled at <NUM>. Precipitation of a small amount of solid was observed, so the solution was heated again until complete dissolution and then cooled to <NUM>. At this temperature, no formation of precipitate was observed. <NUM> (<NUM> eq. ) of HCl <NUM>% were then dissolved in <NUM> of ethanol and the obtained solution was slowly added in the reactor. The formation of a solid was immediately observed. The mixture was cooled at <NUM> in <NUM> minutes, and then stirred for additional <NUM> hour. After this time, the formed solid was isolated by vacuum filtration, washed with ethanol and dried at <NUM> and <NUM> mbar for <NUM> hours. <NUM> of product was recovered as a white solid in nearly quantitative yield.

<NUM> of HM06 free base were weighed and transferred into a <NUM> reactor equipped with a magnetic stirring bar. <NUM> of ethanol were then added and the resulting mixture was heated until complete dissolution of the solid (T = <NUM>). When no solid material was observed, the solution was cooled at <NUM>. <NUM> (<NUM> eq. ) of anhydrous HCl <NUM> in ethanol were mixed with <NUM> of ethanol and the resulting solution was slowly added into the reactor. The formation of a solid was immediately observed. The mixture was cooled to <NUM> in <NUM> minutes, and then stirred for additional <NUM> hour. After this time, the formed solid was isolated by vacuum filtration, washed with additional <NUM> of ethanol and then collected and dried at <NUM> and <NUM> mbar for <NUM> hours. The solid was further dried at <NUM> and <NUM> mbar for additional <NUM> hours. TG/EG analysis confirmed the recovery of an anhydrous compound. <NUM> of product is recovered as a white solid in nearly quantitative yield.

To determine the stoichiometry of the salt, chloride analysis was performed by ionic chromatography. A solution of HM06 <NUM>:<NUM> HCl was prepared by dissolving <NUM> of powder in a volumetric flask (<NUM>) with water (HPLC grade). Based on the TGA analysis performed on the batch just before the chloride determination, (weight loss associated to water content of <NUM>%) the amount of dosed anhydrous salt was considered to be <NUM> (<NUM>%).

Assuming a stoichiometry of <NUM>:<NUM> (HM06:HCl), the molecular weight of the anhydrous salt is <NUM>/mol that corresponds to a concentration of <NUM> mmol/mL of HM06 in the prepared solution. The chloride concentration determined by ionic chromatography was found to be <NUM> mmol/mL corresponding to a chlorides/HM06 molar ratio of <NUM>, confirming the HM06:HCl stoichiometry of <NUM>:<NUM>.

HM06 free base (<NUM>) was added to hot ethanol (<NUM>) and the mass was heated at Ti: <NUM> with stirring until the solid completely dissolved. The solution then underwent polishing filtration over a <NUM> cartridge (PP or PTFE). A mixture of HCl <NUM>% (<NUM>) and EtOH (<NUM>) was added over at least <NUM> hr to the pre-filtered solution with stirring while maintaining a temperature of Ti: <NUM>-<NUM> (target <NUM>). The mass was then cooled to Ti: <NUM>-<NUM> over at least <NUM> and then stirred at Ti: <NUM>-<NUM> for at least <NUM> hour. The mixture was then isolated by filtration on a <NUM> mesh filter by applying pressure (at least <NUM> bars) and vacuum until no more deliquoring was observed. The filter cake was washed twice with EtOH (<NUM> × <NUM>) by applying pressure (at least <NUM> bars) and vacuum until no more deliquoring was observed. The wet product was dried at Tj: <NUM> for at least <NUM> hours. The product HM06 <NUM>:<NUM> HCl Form <NUM> was obtained (<NUM>). The product was stored at Tj: <NUM>-<NUM>.

<FIG> shows an XRPD pattern the crystalline HM06 <NUM>:<NUM> HCl Form <NUM> obtained using CuKα radiation. Peaks identified in <FIG> include those set forth in Table <NUM>:.

Thermal analysis was performed after <NUM> months of storage at low temperature (<NUM>-<NUM>) in a sealed container. <FIG> provides the TGA profile of HM06 <NUM>:<NUM> HCl Form <NUM>. A weight loss of <NUM>% was observed in the range <NUM>-<NUM> ascribable to water release as confirmed by EGA. Above approx. <NUM>, degradation took place. TGA showed a further weight loss ascribable to methanol release as confirmed by EGA. <FIG> is a DSC thermogram of HM06 <NUM>:<NUM> HCl Form <NUM>. As shown in the figure, the DSC showed a broad endothermic event ascribable to water release starting at <NUM> and lasting up to approx. The following endothermic peak at <NUM> (onset <NUM>) was associated to sample melting.

Crystals of HM06 <NUM>:<NUM> HCl Form <NUM> were obtained by slow evaporation. The crystals were big enough for single crystal diffraction, but all were affected by non-merohedry twinning, which means that two crystals grow together to form the same macroscopic sample. It was not possible to separate the two crystals and collected data clearly showed the presence of two reciprocal lattices (see <FIG>). The solution and refinement of the structure was influenced by this situation.

Two data sets were collected of two different crystals. Both cases were twinned crystals and the second lattice was obtained by the rotation of <NUM>° along b* of the first lattice. In the first case, the crystal was made of two almost equal components, and the non-merohedry twinning affected badly the data and did not allow one to refine the structure to obtain good R values. The second data collection was characterized by one dominant component and a second weaker component. In this case, the refinement was acceptable.

The HM06 <NUM>:2HCl Form <NUM> crystallizes as monoclinic in space group P2<NUM>\c and parameters a= <NUM>(<NUM>) Å, b= <NUM>(<NUM>) Å, c= <NUM>(<NUM>) Å , β= <NUM>(<NUM>)° and V= <NUM>(<NUM>)<NUM>. The asymmetric unit consists of one HM06 diprotonated, two chloride ions, and <NUM> water molecules located in two position (see <FIG>). The chloride ion labelled Cl2 is disordered over three positions with occupancy <NUM>, <NUM> and <NUM> respecitvley for Cl2A, Cl2B, Cl2C. Probably the position of the Cl2 depends on the number of water molecules in the cell, since the Cl- and the oxygen in the water molecule may be repelling each other.

The HM06 molecules form columns along the b axis which present short contacts (molecules distance of <NUM>. 4Å) ascribible to the presence of π-stack interactions. The columns have a kind of cross section, which propbably prevents collapse of the structure upon the removal of water molecules (see Error! Reference source not found. 4A and 4B).

To determine the hydrate/anhydrous nature of HM06 <NUM>:<NUM> HCl Form <NUM>, and to define the exact amount of water present in the crystal lattice, a set of preliminary dehydration/drying experiments were performed, which led to the discovery of Form <NUM>-bis.

<FIG> shows an XRPD pattern of crystalline HM06 <NUM>:<NUM> HCl Form <NUM>-bis obtained using CuKα radiation. Peaks identified in <FIG> include those set forth in Table <NUM>:.

VP-XRPD measurements were performed on the Panalytical X'pert equipped with the Anton Paar TTK450 chamber which allowed for measurement of the powder in-situ at controlled temperature and/or under vacuum.

The first measurement was collected at RT and atmospheric pressure. The sample was then left for <NUM> minutes under vacuum (<NUM> mbar). <FIG> shows an XRPD pattern of HM06 <NUM>:<NUM> HCl crystalline Form <NUM>-bis obtained using CuKα radiation. As shown in <FIG>, the second pattern labelled Form <NUM>-bis is different with respect to the pattern of the starting material (Form <NUM>) since the vacuum leads to the dehydration of the sample.

It can be noted that some peaks do not change their position, while others clearly shift to higher theta values; probably the release of the water molecules affects some crystallographic planes while the structure does not dramatically change. Based on the structure determination by SC-XRD, Form <NUM>-bis was supposed to be a very unstable anhydrous form not drastically different from Form <NUM>. This behavior allows the easy uptake of the water molecule in short time.

The uptake of water by Form <NUM>-bis was observed via XRPD by following the difference in the pattern in the range 2θ= <NUM>°- <NUM>-<NUM>° (see <FIG>). Under vacuum the highest peak is the peak at 2θ = <NUM>° while after exposure of the sample in air <NUM> minutes the highest is at 2θ= <NUM>°. The peak at 2θ = <NUM>° moves to 2θ= <NUM>° in <NUM> minutes. HM06 <NUM>:<NUM> HCl crystalline Form <NUM>-bis uptakes the water from the atmosphere as soon as the powder is exposed to the air, and it reachs the diffraction pattern of the starting material in <NUM> minutes (see Error! Reference source not found. This experiment was done in ambient condition with RH% of the room about at <NUM>%.

HM06 <NUM>:<NUM> HCl Form <NUM> was observed in mixture with Form <NUM> from a high temperature (<NUM>) slurry experiment using ethanol. <NUM> of HM06 <NUM>:<NUM> HCl Form <NUM> was suspended in <NUM> of ethanol and allowed to stir at <NUM> for three days. After this time, the suspension was filtered under vacuum under approx. <NUM>-<NUM> %RH and analyzed by XRPD. Its diffraction pattern is reported in <FIG> as the top pattern, compared with XRPD patterns for Form <NUM> and a standard pattern for Form <NUM> (bottom two lines).

The crystallization procedure was reproduced twice. Reproduction R01 lead to HM06 <NUM>:<NUM> HCl Form <NUM> affected with minor traces of Form <NUM>, while pure Form <NUM> was recovered from reproduction R02. For both the experiments, the filtration step and the preparation of the plate for the XRPD analysis were conducted under <NUM>% RH. The XRPD measurement was performed using a Kapton film. A summary of the obtained results and the relative XRPD patterns are reported in Table <NUM>.

The XRPD patterns of the results of R01 and R02, as compared to standard reference patterns of Form <NUM> and Form <NUM>, are shown in <FIG>.

Different micro scale-up procedures were attempted to obtain enough powder to be used for further tests and to probe the process feasibility. The first trial was carried out on <NUM> of HM06 <NUM>:<NUM> HCl Form <NUM>. The powder was suspended in <NUM> of ethanol (<NUM>/mL) and allowed to stir at <NUM> for four days. After this time, the suspension was filtered under vacuum under <NUM>% RH conditions and the preparation of the XRPD plate covered with Kapton film was conducted under the same % RH conditions. HM06 <NUM>:<NUM> HCl Form <NUM> was isolated and the collected XRPD pattern was used as standard (STD) reference pattern of Form <NUM>.

This procedure was reproduced twice, and the isolation step performed after five days under <NUM>% RH conditions. The first reproduction (R01) resulted in HM06 <NUM>:<NUM> HCl Form <NUM> affected by some traces of Form <NUM>, while the second reproduction (R02) resulted in Form <NUM> with one signal at <NUM>° 2Theta, which was ascribable to Form <NUM>.

Taking into account this data, a further procedure was attempted. <NUM> of HM06 <NUM>:<NUM> HCl Form <NUM> was suspended in <NUM> of ethanol (<NUM>/mL) and left to stir at <NUM> for ten days. From this procedure, Form <NUM> was isolated with a small signal at <NUM>°<NUM> theta from Form <NUM>.

A summary of the obtained results are reported in Table <NUM>.

<FIG> shows the XRPD pattern of HM06 <NUM>:<NUM> HCl Form <NUM> collected after <NUM>-days slurry experiments from ethanol scaled on <NUM> obtained using CuKα radiation, and used as STD reference. Peaks identified in <FIG> include those set forth in Table <NUM>:.

<FIG> is a DSC thermogram of HM06 <NUM>:<NUM> HCl Form <NUM>, which showed an endothermic event at <NUM> (onset at <NUM>) consistent with sample melting. Above approx. <NUM>, degradation took place.

<FIG> provides the TGA profile of HM06 <NUM>:<NUM> HCl Form <NUM>, which showed no weight loss. The sample can be considered anhydrous. The methanol and HCl release was detected during degradation.

<FIG> and <FIG> show the relative XRPD patterns from the Example <NUM> micro scale ups obtained using CuKα radiation.

<NUM> of HM06 <NUM>:<NUM> HCl Form <NUM> was suspended in <NUM> of acetonitrile and it was allowed to stir at <NUM> degree for three days. After this time, the suspension was filtered under vacuum under approx. <NUM>-<NUM> %RH and analyzed by XRPD. <FIG> shows an XRPD pattern overlay of crystalline HM06 <NUM>:<NUM> HCl Form <NUM> obtained after HT (<NUM>) slurry experiments from acetonitrile (top line), and the standard reference patterns of Form <NUM> (black line,) Form <NUM> (bottom line), and Form <NUM> (pink line) obtained using CuKα radiation.

The crystallization procedure was reproduced twice, extending the time up to nine days and treating the recovered powder at <NUM>% RH condition. Kapton film was used to prepare the XRPD plate. Reproduction R01 led to a phase in which some traces of Form <NUM> were observed. Reproduction R02 lead to Form <NUM> and some further unassigned peaks.

Since pure Form <NUM> was collected from a fast precipitation experiment using <NUM>-propanol and used as the standard reference pattern, additional reproductions were attempted. All three fast gradient trials were prepared as follows. To <NUM> of HM06 <NUM>:<NUM> HCl Form <NUM> was added <NUM> of <NUM>-propanol. The suspension was heated up to the solvent's boiling point for few minutes. A clear solution was immediately observed. It was crash cooled to <NUM> using an ice bath. The precipitation occurred immediately. The powder was recovered by under vacuum filtration and the XRPD plate was prepared using a Kapton film. All these experiments were treated under controlled <NUM>-<NUM>% RH conditions.

Different micro scale-up procedures were attempted to obtain enough powder to be used for further tests and to probe the process feasibility. All the trials were treated under controlled %RH conditions between <NUM>-<NUM>% values both for the isolation step and the preparation of the XRPD sample plate for which a Kapton film was used.

The first trial was carried out on <NUM> of HM06 <NUM>:<NUM> HCl Form <NUM>. The powder was suspended in <NUM> of acetonitrile (<NUM>/mL) and allowed to stir at <NUM> for four days. After this time, the suspension was filtered under vacuum and analyzed by XRPD. A mixture of Form <NUM> and Form <NUM> was recovered. To try to reach pure Form <NUM>, a first reproduction R01 was planned, extending the slurry time up to twelve days. In parallel, the same experiment tested on a concentration of <NUM>/mL was also prepared. From reproduction R01, Form <NUM> was gathered, while the other trial led to a mixture of Form <NUM> and Form <NUM> with the observation of an unassigned peak at <NUM>° 2theta.

Since pure Form <NUM> was achieved from a fast gradient precipitation from <NUM>-propanol performed on <NUM> and in spite of the reproductions did not lead to Form <NUM>, a micro scale-up procedure was pursued. <NUM> of HM06 <NUM>:<NUM> HCl Form <NUM> was suspended in <NUM> of <NUM>-propanol. It was heated up to the solvent's boiling point. After few minutes, the obtained clear solution was crash cooled at <NUM> and left under magnetic stirring for <NUM> minutes. Then the powder was isolated by filtration and analyzed by XRPD. Pure Form <NUM> was achieved and its XRPD pattern was used as standard reference. A very minor signal at <NUM>° 2theta, probably attributable to Form <NUM>, was observed. The filtration step and the preparation of the XRPD sample plate covered with Kapton film was performed at <NUM>% RH.

Reproduction R01 was conducted following the procedure noted in Table <NUM> and a drying process was applied. A sampling was analyzed by XRPD. Form <NUM> was attained so the entire wet cake was treated at <NUM>/<NUM> mbar for three hours and then re-measured. Form <NUM> was achieved although a minor signal at <NUM>° 2theta ascribable to Form <NUM> was detected.

Two further reproductions (R02 and R03) were carried out according to the same procedure. Form <NUM> was collected although a minor signal at <NUM>° 2theta ascribable to Form <NUM> was detected. No additional drying step was applied for R03. Reproduction R02 was instead subjected to two dying steps followed both by TGA-EGA analysis. The low crystallinity degree showed by R02 was due to the low amount used for the XRPD analysis.

Based on these results, fast gradient precipitation from <NUM>-propanol can be considered as a suitable procedure to obtain Form <NUM>.

A summary of the obtained results is reported in Table <NUM>.

<FIG> shows an XRPD pattern of HM06 <NUM>:<NUM> HCl Form <NUM> collected after fast gradient precipitation from <NUM>-propanol scaled on <NUM> obtained using CuKα radiation. Peaks from HM06 <NUM>:<NUM> HCl Form <NUM> identified in <FIG> include those set forth in Table <NUM>:.

<FIG> is a DSC thermogram of HM06 <NUM>:<NUM> HCl Form <NUM>, which showed an endothermic event at <NUM> (onset at <NUM>) ascribable to sample melting. Above approx. <NUM>, degradation took place.

<FIG> provides the TGA profile of HM06 <NUM>:<NUM> HCl Form <NUM>, which showed a very mild weight loss of <NUM>% up to <NUM>. During degradation methanol and HCl evolution was detected by EGA.

Form <NUM>-bis was collected after evaporation experiment from methanol at <NUM> under low pressure according to the following procedure:.

A saturated solution of HM06 <NUM>:<NUM> HCl Form <NUM> in methanol approx. <NUM>/mL was prepared and allowed to stir at room temperature overnight (<NUM> hours). After this time, it was filtered and left to evaporate at <NUM>/<NUM> mbar. The preparation of the sample plate sealed with Kapton film was performed under <NUM>-<NUM>% RH. The collected XRPD pattern compared with Form <NUM> is reported in <FIG>. Some very minor signals of Form <NUM> were present.

The experiment was reproduced four times following the procedure reported above (reproductions R01-R04). The preparation of the XRPD sample plate sealed with Kapton film was performed under <NUM>-<NUM>% RH. In all the trials, Form <NUM> was recovered. This procedure was attempted another four times, but in this case the sample was isolated under controlled % RH with values between <NUM>-<NUM>% RH. In all the analyzed samples, a new pattern labelled as Form <NUM>, affected by signals of Form <NUM>, was observed. From a qualitative point of view, reproduction R05 showed the lowest amount of Form <NUM>. Table <NUM> sets forth the reproduction procedures and results.

<FIG> shows an XRPD pattern of HM06 <NUM>:<NUM> HCl Form <NUM>-bis. Peaks identified in <FIG> for HM06 <NUM>:<NUM> HCl Form <NUM>-bis include those set forth in Table <NUM>:.

The stability of Form <NUM>-bis was assessed after seven days of storage in a sealed vial. It showed a complete conversion into Form <NUM> as shown in <FIG>.

As described in the previous Section, HM06 <NUM>:<NUM> HCl Form <NUM> was isolated in mixture with Form <NUM> from the reproduction experiments that were performed in an attempt to achieve Form <NUM>-bis.

As described in the previous Section and in Table <NUM>, Form <NUM> was recovered from all the four reproduction experiments performed (R05-R08). Reproduction R05 seemed to have the lowest amount of Form <NUM> from a qualitative point of view.

<FIG> shows an XRPD pattern of HM06 <NUM>:<NUM> HCl Form <NUM> obtained using CuKα radiation. Peaks identified in <FIG> of HM06 <NUM>:<NUM> HCl Form <NUM> include those set forth in Table <NUM>:.

HM06 <NUM>:<NUM> HCl Form <NUM> exposed powder was stored overnight at room temperature under <NUM>% RH. No significant modifications were observed as shown in <FIG>.

An evaporation experiment of HM06 <NUM>:<NUM> HCl Form <NUM> in a mixture of <NUM>/<NUM> water/dimethylformamide at <NUM> led to the isolation of a new XRPD pattern in which some signals from Form <NUM> were observed. Because of the similarity, it was labelled as Form <NUM>-bis. The treatment of the sample was performed under <NUM>-<NUM>% RH condition.

<FIG> shows the XRPD pattern of HM06 <NUM>:<NUM> HCl Form <NUM>-bis compared with Form <NUM>.

The evaporation experiment was reproduced twice and an orange-colored powder was collected. Both samples were analyzed by XRPD and presented the diffraction pattern of Form <NUM>, with some minor signals probably associated with Form <NUM>-bis and further unassigned, in particular one at <NUM>° 2theta with a discrete intensity. Based on these results Form <NUM>-bis was considered as not reproducible.

The stability of the HM06 <NUM>:<NUM> HCl Form <NUM>-bis sample was assessed after <NUM> hours exposed to air and after one week in a sealed vial, both at room temperature.

Form <NUM>-bis was measured after <NUM> hours exposed powder at room temperature. The %RH was approx. Its XRPD pattern displayed some modifications: e.g., lack of signals at <NUM>° and <NUM>° 2theta and the rising of a peak at <NUM>° 2theta.

These changes could not be associated with conversion into one of the other isolated polymorphs observed during this study: thus, the sample was considered not stable. <FIG> shows the XRPD pattern of Form <NUM>-bis (blue top pattern) and the same sample analyzed after <NUM> hrs exposed (bottom red pattern).

HM06 <NUM>:<NUM> HCl Form <NUM>-bis was measured after seven days at room temperature in a sealed vial. As shown in <FIG>, the sample started to convert into Form <NUM>.

An evaporation experiment of HM06 <NUM>:2HCl Form <NUM> in dimethyl sulfoxide at <NUM> gave Form <NUM> with further unassigned signals. To better understand the nature of these few new signals, the re-crystallization procedure was reproduced twice: R01 and R02. Both samples showed a dark brown color and while R02 was completely vitreous, few powders from R01 were able to be recovered. The powders from R01 were analyzed by XRPD and showed a diffraction pattern with a low crystallinity degree that was labelled as Form <NUM>.

<FIG> shows the XRPD pattern of HM06 <NUM>:<NUM> HCl Form <NUM> obtained using CuKα radiation. Peaks identified in <FIG> for HM06 <NUM>:<NUM> HCl Form <NUM> include those set forth in Table <NUM>:.

<FIG> is a DSC thermogram of HM06 <NUM>:<NUM> HCl Form <NUM>, which showed an endothermic broad event between <NUM>-<NUM> ascribable to solvent release as was also observed in TGA-EGA. Two consecutive endothermic events at <NUM> (onset at <NUM>) and <NUM> (onset at <NUM>) were also observed.

<FIG> provides the TGA profile of HM06 <NUM>:<NUM> HCl Form <NUM>, which showed a weight loss of water up to <NUM>. It was not possible to clearly ascribe the evolution of water to dehydration or adsorbed water release. Above <NUM>, degradation took place. The EGA did not detect the HCl evolution as observed for the other isolated forms. The formation of a salt with a lower HCl content might not be excluded; the stoichiometry of the salt in Form <NUM> was not determined definitively.

Form <NUM> was collected after evaporation of HM06 <NUM>:<NUM> HCl Form <NUM> in a <NUM>:<NUM> acetonitrile/water solution at room temperature under low pressure. After <NUM> days of storage under these conditions, conversion into Form <NUM> was observed. Since the batch showed an orange color and because of its phase instability, no further analysis was performed.

<FIG> shows an XRPD pattern of HM06 <NUM>:<NUM> HCl Form <NUM> using CuKα radiation. Peaks identified in <FIG> for HM06 <NUM>:<NUM> HCl Form <NUM> include those set forth in Table <NUM>:.

<FIG> reports an overlay of XRPD patterns of all isolated forms of HM06 <NUM>:<NUM> HCl.

Samples of HM06 <NUM>:<NUM> HCl Form <NUM> were subjected to accelerated storage conditions and long-term storage. The results demonstrated that HM06 <NUM>:<NUM> HCl Form <NUM> remained stable and crystalline.

Samples of HM06 <NUM>:<NUM> HCl Form <NUM> from the same lot were stored at <NUM> and <NUM>% relative humidity for <NUM> months with testing at regular intervals. Table <NUM> sets forth the sample analysis at times <NUM>, <NUM> month, <NUM> months, and <NUM> months.

Samples of HM06 <NUM>:<NUM> HCl Form <NUM> from the same lot were stored at <NUM> and <NUM>% relative humidity for six months with testing at regular intervals. Table <NUM> sets forth the sample analysis at times <NUM>, <NUM> months, <NUM> months, <NUM> months, <NUM> months, <NUM> months, and <NUM> months.

The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the embodiments. The foregoing description and Examples detail certain embodiments and describes the best mode contemplated by the inventors. It will be appreciated, however, that no matter how detailed the foregoing may appear in text, the embodiment may be practiced in many ways and should be construed in accordance with the appended claims and any equivalents thereof.

Claim 1:
<NUM>-amino-N-[<NUM>-(methoxymethyl)phenyl]-<NUM>-(<NUM>-methylcyclopropyl)-<NUM>-(<NUM>-morpholinoprop-<NUM>-yn-<NUM>-yl)-<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidine-<NUM>-carboxamide <NUM>:<NUM> HCl salt, in crystalline form <NUM>, characterized by an XRPD pattern comprising peaks at about <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, <NUM>°2θ, and <NUM>°2θ.