Pyrazoloquinazoline compound and salt form and crystal form thereof

Abstract

Provided are a free base or pharmaceutically acceptable salt of a pyrazoloquinazoline compound of formula (I), which can be used as a PLK1 inhibitor, optionally in a crystalline form, and a solvate or hydrate thereof, wherein the pharmaceutically acceptable salt comprises a hydrochloride, sulfate, phosphate, maleate, fumarate, L-tartrate, citrate, L-aspartate, hippurate, L-glutamate, L-malate, adipate, glutarate, p-toluenesulfonate, and methanesulfonate of the pyrazoloquinazoline compound of formula (I), and also provided is a pharmaceutical composition comprising same, and a use thereof in the treatment of diseases and conditions caused by dysregulated activity of PLK1 and / or diseases and conditions related to PLK1, such as cancer.

Description

A pyrazoloquinazoline compound and its salt forms and crystalline forms

[0001] Cross reference to related applications

[0002] This application claims priority to Chinese patent application No. CN 202410947409.8, filed on July 15, 2024, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0003] The present disclosure relates to the field of medicinal chemistry, in particular to pyrazoloquinazoline compounds of Formula (I) and their salt forms and crystalline forms useful as PLK1 inhibitors. The present disclosure also relates to pharmaceutical compositions comprising the pyrazoloquinazoline compounds of Formula (I) and their salt forms and crystalline forms, and their use in the treatment of diseases and conditions resulting from dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1, such as cancer. BACKGROUND

[0004] Mammalian polo-like kinases (PLKs) consist of a family of five serine / threonine kinases (PLKs 1-5) with distinct functions and expression patterns in mammalian cells. Most PLKs have a C-terminal polo-box domain (PBD) that recognizes substrates, and an N-terminal kinase domain that phosphorylates substrates. Among the PLKs, PLK1 is the most extensively studied family member and has a key function in cell cycle progression, especially at the G2-M checkpoint, mitosis, and cytokinesis. PLK1 activity is tightly regulated during cell cycle progression through binding to other phosphorylated scaffolding proteins.

[0005] PLK1 has been extensively studied as an attractive target for cancer therapy, and several small molecule PLK1 inhibitors have been developed over the past decade. Both liquid tumors such as leukemia and lymphoma, and solid tumors such as pancreatic cancer, breast cancer, and prostate cancer. However, although PLK1 inhibitors have shown anti-tumor effects in preclinical cancer models and have also shown promising results in clinical trials, they have not yet achieved satisfactory therapeutic effects due to dose-limiting toxicity (Translational Oncology Volume 16, February 2022, 101332). Among the PLK1-targeted ATP-competitive inhibitors under clinical development, onvansertib (NMS-P937, NMS1286937) has high selectivity and good prospects for clinical development. However, most of the onvansertib derivatives (Bioorg Med Chem Lett. 2011 May 15; 21(10): 2969-74, Bioorg Med Chem Lett. 2010 Nov 15; 20(22): 6489-94) have very poor oral absorption and bioavailability in mice, and the literature (Mol Cancer Ther; 11(4) April 2012, Supplementary table S4) discloses that onvansertib also has very different absorption and bioavailability in different species, which is not regular and poses a challenge for the development of selective PLK1 inhibitors.

[0006] The present inventors have found that deuterium-modified compounds of onvansertib are effective polo-like kinase inhibitors suitable for targeting PLK1 and can be used to treat diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1:

[0007] Therefore, there is a need in therapy to provide water-soluble salts of the compounds and crystalline forms thereof having good and reproducible physicochemical and bulk properties, such as high stability, high solubility, low hygroscopicity, and advantageous solid morphology, thus enabling good drug preservation and safe and effective drug administration. SUMMARY

[0008] Through a series of innovative research and in-depth experimental exploration, the inventors have successfully discovered a free base crystal form of a compound of formula (I) (which can also be referred to herein as "Compound 012" equally) and a novel water-soluble salt thereof and a crystal form thereof, which have excellent physical and chemical properties. These free base crystal forms and the novel water-soluble salt thereof and the crystal form thereof have outstanding performance in terms of physical and chemical properties such as stability, solubility, hygroscopicity and solid morphology, and are more suitable for preparation into a drug for administration to a patient to achieve more excellent therapeutic effect, thereby solving the above technical problems.

[0009] In one aspect, the present disclosure relates to a free base or a pharmaceutically acceptable salt of a compound of formula (I), and solvates, hydrates thereof:

[0010] The pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, phosphate, maleate, fumarate, L-tartrate, citrate, L-aspartate, hippurate, L-glutamate, L-malate, adipate, glutarate, p-toluenesulfonate and methanesulfonate.

[0011] In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, phosphate, maleate, fumarate, L-tartrate, citrate, L-malate, glutarate, p-toluenesulfonate and methanesulfonate.

[0012] In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, phosphate, maleate, fumarate, L-tartrate and L-malate.

[0013] In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, maleate and fumarate.

[0014] In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of monohydrochloride, monophosphate, monomaleate, monofumarate, hemi-L-tartrate and mono-L-malate.

[0015] In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of monohydrochloride, monomaleate and monofumarate.

[0016] In some embodiments, the free base or the pharmaceutically acceptable salt of a compound of formula (I) and solvates, hydrates thereof according to the present disclosure are in a crystalline form.

[0017] In some embodiments, the free base or pharmaceutically acceptable salt of the compound of formula (I) and solvates, hydrates thereof, according to the present disclosure, in crystalline form, wherein the X-ray powder diffraction (XRPD) pattern of the free base Form A of the compound of formula (I) has characteristic diffraction peaks expressed in degrees 2Q ± 0.2° at the following 2Q angles: 3.34, 6.66, 9.10, 9.55, 9.98, 11.15, 12.22, 16.06, 17.47, 18.00, 18.24, and / or 21.41.

[0018] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the free base Form A of the compound of formula (I) according to the present disclosure is as shown in Figure 1.

[0019] In some embodiments, the free base or pharmaceutically acceptable salt of the compound of formula (I) and solvates, hydrates thereof, according to the present disclosure, in crystalline form, wherein the pharmaceutically acceptable salt of the compound of formula (I) in the crystalline form is a hydrochloride salt, preferably a monohydrochloride salt, has a X-ray powder diffraction (XRPD) pattern of Form B of the Cu-Ka radiation expressed in degrees 2Q ± 0.2° at the following 2Q angles: 2.53, 5.05, 8.78, 10.09, 11.80, 18.78, 18.99, 20.50, and / or 25.32.

[0020] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the monohydrochloride Form B of the compound of formula (I) according to the present disclosure is as shown in Figure 5.

[0021] In some embodiments, the free base or pharmaceutically acceptable salt of the compound of formula (I) and solvates, hydrates thereof, according to the present disclosure, in crystalline form, is a monohydrochloride hydrate of the compound of formula (I).

[0022] In some embodiments, the free base or pharmaceutically acceptable salt of the compound of formula (I) and solvates, hydrates thereof, according to the present disclosure, in crystalline form, wherein the pharmaceutically acceptable salt of the compound of formula (I) in the crystalline form is a maleate salt, preferably a monomaleate salt, has a X-ray powder diffraction (XRPD) pattern of Form A of the Cu-Ka radiation expressed in degrees 2Q ± 0.2° at the following 2Q angles: 6.83, 8.13, 11.15, 13.66, 16.51, 17.67, 19.05, 20.52, 23.26, 23.85, 26.77, and / or 27.47.

[0023] In some embodiments, the Cu-Ka X-ray powder diffraction (XRPD) pattern of the monomaleate salt Form A of the compound of formula (I) according to the present disclosure is shown in Figure 9.

[0024] In some embodiments, the free base or pharmaceutically acceptable salt of the compound of formula (I) and solvates, hydrates thereof according to the present disclosure is a monomaleate salt hydrate of the compound of formula (I) in crystalline form.

[0025] In some embodiments, the free base or pharmaceutically acceptable salt of the compound of formula (I) and solvates, hydrates thereof according to the present disclosure is in crystalline form, wherein the pharmaceutically acceptable salt of the compound of formula (I) in crystalline form is a fumarate salt, preferably a monofumarate salt, having a Cu-Ka X-ray powder diffraction (XRPD) pattern with characteristic diffraction peaks expressed in degrees 2Q ± 0.2° at the following 2Q angles: 6.20, 12.39, 14.34, 15.33, 18.62, 20.09, 21.57, 22.94, 24.04, 24.90, and / or 26.79.

[0026] In some embodiments, the Cu-Ka X-ray powder diffraction (XRPD) pattern of the monofumarate salt Form A of the compound of formula (I) according to the present disclosure is shown in Figure 13.

[0027] In some embodiments, the free base or pharmaceutically acceptable salt of the compound of formula (I) and solvates, hydrates thereof according to the present disclosure is a monofumarate salt anhydrate of the compound of formula (I) in crystalline form.

[0028] In yet another aspect, the present disclosure relates to a pharmaceutical composition comprising the free base or pharmaceutically acceptable salt of the compound of formula (I) and solvates, hydrates thereof according to the present disclosure, and a pharmaceutically acceptable carrier or excipient.

[0029] In yet another aspect, the present disclosure relates to a method of treating a disease and condition caused by dysregulation of PLK1 activity and / or a disease and condition associated with PLK1 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the free base or pharmaceutically acceptable salt of the compound of formula (I) and solvates, hydrates thereof according to the present disclosure.

[0030] In yet another aspect, the present disclosure relates to the free base or pharmaceutically acceptable salt of the compound of formula (I) and solvates, hydrates thereof according to the present disclosure for use in the treatment of a disease and condition caused by dysregulation of PLK1 activity and / or a disease and condition associated with PLK1.

[0031] In yet another aspect, the present disclosure relates to use of a free base or pharmaceutically acceptable salt of a compound of formula (I) as described herein, and solvates, hydrates thereof, for the preparation of a medicament for the treatment of diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1.

[0032] In yet another aspect, the present disclosure relates to a kit for the treatment of diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1, comprising: a free base or pharmaceutically acceptable salt of a compound of formula (I) as described herein, and solvates, hydrates thereof, or a pharmaceutical composition as described herein, and a container and optionally a package insert or label instructing the treatment.

[0033] In the present disclosure, the diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1 include, but are not limited to, leukemia, lymphoma, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, colorectal cancer, liver cancer, gastric cancer, esophageal cancer, melanoma, multiple myeloma, and sepsis, etc. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 shows the XRPD pattern of Compound 012 free base Pattern A.

[0035] Figure 2 shows the DSC pattern of Compound 012 free base Pattern A.

[0036] Figure 3 shows the TGA pattern of Compound 012 free base Pattern A.

[0037] Figure 4 shows the 1 H-NMR pattern of Compound 012 free base Pattern A.

[0038] Figure 5 shows the XRPD pattern of Compound 012 monohydrochloride salt Pattern B.

[0039] Figure 6 shows the DSC pattern of Compound 012 monohydrochloride salt Pattern B.

[0040] Figure 7 shows the TGA pattern of Compound 012 monohydrochloride salt Pattern B.

[0041] Figure 8 shows the 1 H-NMR pattern of Compound 012 monohydrochloride salt Pattern B.

[0042] Figure 9 shows the XRPD pattern of Compound 012 monomaleate salt Pattern A.

[0043] Figure 10 shows the DSC pattern of Compound 012 monomaleate Pattern A.

[0044] Figure 11 shows the TGA pattern of Compound 012 monomaleate Pattern A.

[0045] Figure 12 shows the XRPD pattern of Compound 012 monomaleate Pattern A. 1 H-NMR pattern.

[0046] Figure 13 shows the XRPD pattern of Compound 012 monofumarate Pattern A.

[0047] Figure 14 shows the DSC pattern of Compound 012 monofumarate Pattern A.

[0048] Figure 15 shows the TGA pattern of Compound 012 monofumarate Pattern A.

[0049] Figure 16 shows the H-NMR pattern of Compound 012 monofumarate Pattern A. 1 H-NMR pattern.

[0050] Figure 17 shows the PLM photograph of Compound 012 free form Pattern A.

[0051] Figure 18 shows the PLM photograph of Compound 012 monohydrochloride Pattern B.

[0052] Figure 19 shows the PLM photograph of Compound 012 monofumarate Pattern A.

[0053] Figure 20 shows the PLM photograph of Compound 012 monomaleate Pattern A. DETAILED DESCRIPTION

[0054] Certain embodiments will now be described in detail in the specific embodiments described herein. While the described embodiments are intended to be illustrative only, it will be understood that the disclosure is not limited to these embodiments. Rather, this disclosure is intended to cover all alternatives, modifications, and equivalents that can be included within the scope of the disclosure as defined by the claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many alternatives to the specific embodiments described herein. The disclosure is therefore to be understood in an illustrative sense rather than a limiting sense.

[0055] It is understood that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable

[0056] As used in the claims and specification, the terms "including," "containing," and "having," or any variation thereof, shall be construed as indicating an open-ended group that can include other elements not specified. The terms "at least one" and "one or more" can be used interchangeably. The term "single" is applied to indicate one and only one. Similarly, other specific integer values will be used where so desired, such as "two." The terms "preferably," "preferred," "prefer," "optionally," "may," and similar terms are used to indicate optional features, that is, features that are not essential to the practice of the embodiments. Unless otherwise stated, ranges described as "between a and b" include "a" and "b."

[0057] While various improvements have been described herein with reference to particular embodiments of the disclosure, it is to be understood that such description is merely illustrative of the ways in which the disclosure can be practiced. It is therefore not to be construed that any requirements of the invention are limited to the specific embodiments discussed herein. Accordingly, the scope and content of any claimed disclosure will be limited only by the terms of the appended claims in their current form or as modified in the course of prosecution, or as practiced in any continuation application. Furthermore, it is to be understood that features of any of the specific embodiments discussed herein can be combined with one or more features of any one or more of the embodiments otherwise discussed or considered herein, unless otherwise stated.

[0058] Definitions of certain functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, and specific functional moieties and reactivity are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEd., John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rdEd., Cambridge University Press, Cambridge, 1987.

[0059] All ranges recited herein include the range itself.

[0060] Terms used herein but not defined have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. However, the following definitions apply regardless of the number of occurrences.

[0061] Free base and pharmaceutically acceptable salts

[0062] As used herein, the term “free base” generally refers to the non-salt form of a compound, i.e., it is not in salt form with an acid or other proton source, and the term “free base” can be replaced equivalently with “free base,” “free form,” herein.

[0063] As used herein, the term "pharmaceutically acceptable salt" includes salts that retain the biological effectiveness and none of the properties that are undesirable of the free acids / bases forms of specific compounds and are not biologically or otherwise undesirable. Pharmaceutically acceptable salts can include salts with inorganic or organic bases and acids. The compounds of Formula (I) of the present disclosure contain one or more basic groups, for example, groups that can be protonated, can exist in the form of a salt, and can be used according to the present disclosure in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, maleic acid, fumaric acid, L-tartaric acid, citric acid, L-aspartic acid, hippuric acid, L-glutamic acid, L-malic acid, adipic acid, glutaric acid, p-toluenesulfonic acid, methanesulfonic acid, and others known to those skilled in the art. The salts formed are, inter alia, hydrochlorides, sulfates, phosphates, maleates, fumarates, L-tartrates, citrates, L-aspartates, hippurates, L-glutamates, L-malates, adipates, glutarates, p-toluenesulfonates, and methanesulfonates, and the like. The stoichiometry of the salts formed from the compounds of Formula (I) of the present disclosure can be an integer multiple of 1 or a non-integer multiple.

[0064] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) of the present disclosure is selected from the group consisting of a hydrochloride, a sulfate, a phosphate, a maleate, a fumarate, a L-tartrate, a citrate, a L-malate, a glutarate, a p-toluenesulfonate, and a methanesulfonate.

[0065] In some embodiments, the pharmaceutically acceptable salt is selected from a hydrochloride, a phosphate, a maleate, a fumarate, a L-tartrate, and a L-malate. More specifically, the pharmaceutically acceptable salt is selected from a monohydrochloride, a monophosphate, a monomaleate, a monofumarate, a hemi-L-tartrate, and a mono-L-malate.

[0066] In some embodiments, the pharmaceutically acceptable salt is selected from a hydrochloride, a maleate, and a fumarate. More specifically, the pharmaceutically acceptable salt is selected from a monohydrochloride, a monomaleate, and a monofumarate.

[0067] The free base or pharmaceutically acceptable salt of the compound of Formula (I) can exist in non-solvated and solvated forms. As used herein, the term "solvate" refers to a molecular complex comprising the free base of the compound of Formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solvent molecules. The term "hydrate" is used when the solvent is water.

[0068] Unless otherwise specified, the present application intends to include stoichiometric and non-stoichiometric "solvates" and "hydrates" when referring to "solvates" and "hydrates".

[0069] Accordingly, herein the expression "free base or pharmaceutically acceptable salt of a compound of Formula (I), and solvates, hydrates thereof" is intended to include the free base of a compound of Formula (I), solvates / hydrates formed from the free base of a compound of Formula (I) and one or more pharmaceutically acceptable solvent molecules / water; and pharmaceutically acceptable salts of a compound of Formula (I), solvates / hydrates of a pharmaceutically acceptable salt of a compound of Formula (I) and one or more pharmaceutically acceptable solvent molecules / water.

[0070] A stoichiometric solvate has a fixed ratio of solvent molecules to compound molecules. This is typically due to a bonding interaction between the solvent and the compound molecules. In a non-stoichiometric solvate, the solvent is not present in a fixed ratio to the compound molecules and often can vary. In a non-stoichiometric solvate, the solvent often resides in interstitial spaces or channels within the lattice. A stoichiometric hydrate has a fixed ratio of water molecules to compound molecules. This is typically due to a bonding interaction between the water and the compound molecules. In a non-stoichiometric hydrate, the water is not present in a fixed ratio to the compound molecules and often can vary. In a non-stoichiometric hydrate, the water often resides in interstitial spaces or channels within the lattice.

[0071] In some embodiments, the present disclosure provides anhydrous forms of the free base of a compound of Formula (I).

[0072] In some embodiments, the present disclosure provides anhydrous forms of the pharmaceutically acceptable salt of a compound of Formula (I), e.g., monofumarate anhydrous forms.

[0073] In some embodiments, the present disclosure provides hydrates of the pharmaceutically acceptable salt of a compound of Formula (I), e.g., monohydrochloride hydrates, monomaleate hydrates.

[0074] Crystalline forms and polymorphs

[0075] As used herein, the term "crystalline form" generally refers to a solid state existence form of a compound in which atoms, ions, or molecules are arranged in a specific, ordered pattern. This ordered arrangement imparts specific geometric shape and repeating internal structure to the crystal, which can be analyzed and characterized by techniques such as X-ray diffraction.

[0076] As used herein, the term "polymorph" generally refers to different crystalline forms in which the same compound can exist in the solid state. Each polymorph has a unique crystal structure and physicochemical properties, such as melting point, solubility, density, and optical properties. Differences in polymorphs often affect the bioavailability, stability, and manufacturing process of a drug.

[0077] As used herein, the term "polymorphism" generally refers to the phenomenon that a compound is able to form two or more different crystal forms. These different crystal forms have different physical and chemical properties due to different ways of arrangement of the molecules in the crystal lattice, but the same chemical composition.

[0078] Provided in the present disclosure are free base or pharmaceutically acceptable salts of the compound of Formula (I), and solvates, hydrates thereof:

[0079] wherein the free base, pharmaceutically acceptable salts, solvates, hydrates are as defined herein.

[0080] In some embodiments, the free base or pharmaceutically acceptable salts of the compound of Formula (I), and solvates, hydrates thereof can be in amorphous form, can be in crystalline form. In some embodiments, the free base or pharmaceutically acceptable salts of the compound of Formula (I), and solvates, hydrates thereof are in crystalline form.

[0081] 1. a free base of the compound of Formula (I) in crystalline form

[0082] In some embodiments, the present disclosure provides a free base of the compound of Formula (I) in crystalline form. In some embodiments, the free base of the compound of Formula (I) in crystalline form has Form A, which can also be referred to herein as "Form A of the free base of the compound of Formula (I)" or "Compound 012 Freebase Pattern A" and the like.

[0083] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the Form A of the free base of the compound of Formula (I) includes any one or more of the following characteristic diffraction peaks expressed in degrees 2theta ± 0.2° at 2theta angles of 3.34, 6.66, 9.10, 9.55, 9.98, 11.15, 12.22, 16.06, 17.47, 18.00, 18.24, and / or 21.41.

[0084] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the Form A of the free base of the compound of Formula (I) further includes any one or more of the following characteristic diffraction peaks expressed in degrees 2theta ± 0.2° at 2theta angles of 18.95, 20.44, 23.47, 24.51, and 27.50.

[0085] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the free base crystalline Form A of the compound of Formula (I) further comprises any one or more of the following characteristic diffraction peaks expressed in degrees 2-theta ± 0.2° at the following 2-theta angles: 7.04, 13.08, 13.34, 16.69, 20.05, 22.34, 25.68, 26.75, 27.25, 28.29, 30.20, 31.87, and 39.56.

[0086] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the free base crystalline Form A of the compound of Formula (I) comprises the following characteristic diffraction peaks expressed in degrees 2-theta ± 0.2° at the following 2-theta angles: 3.34, 6.66, 7.04, 9.10, 9.55, 9.98, 11.15, 12.22, 13.34, 16.06, 17.47, 18.00, 18.24, 18.95, 20.44, 21.41, 22.34, 23.47, 24.51, 26.75, and 27.50.

[0087] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the free base crystalline Form A of the compound of Formula (I) comprises the following characteristic diffraction peaks expressed in degrees 2-theta ± 0.2° at the following 2-theta angles: 3.34, 6.66, 7.04, 9.10, 9.55, 9.98, 11.15, 12.22, 13.08, 13.34, 16.06, 16.69, 17.47, 18.00, 18.24, 18.95, 20.05, 20.44, 21.41, 22.34, 23.47, 24.51, 25.68, 26.75, 27.25, 27.50, 28.29, 30.20, 31.87, and 39.56.

[0088] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the free base crystalline Form A of the compound of Formula (I) is as shown in FIG. 1.

[0089] In some embodiments, the differential scanning calorimetry pattern of the free base crystalline Form A of the compound of Formula (I) exhibits an exothermic peak at about 120.2 ± 3.0 °C, and / or an endothermic peak at about 246.2 ± 3.0 °C. In reference to the “±” range in temperature when referring to the differential scanning calorimetry pattern herein, it can be “± 3.0 °C,” “± 2.0 °C,” “± 1.0 °C,” or “± 0.5 °C.”

[0090] In some embodiments, the differential scanning calorimetry pattern of the free base crystalline Form A of the compound of Formula (I) is as shown in FIG. 2.

[0091] In some embodiments, the thermal gravimetric analysis pattern of the free base crystalline Form A of the compound of Formula (I) shows a weight loss of about 0.7 ± 0.2% at 100 °C, and / or a weight loss of about 0.3 ± 0.2% between 100 °C and 220 °C. In this context, when referring to the “±” range for the weight loss percentage in the thermal gravimetric analysis pattern, it can be “± 0.2%” or “± 0.1%”.

[0092] In some embodiments, the thermal gravimetric analysis pattern of the free base crystalline Form A of the compound of Formula (I) is shown in Figure 3.

[0093] 2. A hydrochloride salt of the compound of Formula (I) in a crystalline form

[0094] In some embodiments, the present disclosure provides a hydrochloride salt of the compound of Formula (I) in a crystalline form, preferably a monohydrochloride salt. In some embodiments, the present disclosure provides a hydrochloride salt hydrate of the compound of Formula (I) in a crystalline form, preferably a monohydrochloride salt hydrate. In some embodiments, the hydrochloride salt of the compound of Formula (I) in a crystalline form has Form B, which can also be referred to herein equally as “monohydrochloride salt Form B of the compound of Formula (I)” or “Compound 012 monohydrochloride salt Pattern B” and the like.

[0095] In some embodiments, the Cu-Ka ray X-ray powder diffraction (XRPD) pattern of the monohydrochloride salt Form B of the compound of Formula (I) includes any one or more of the following characteristic diffraction peaks expressed in degrees 2q ± 0.2° at 2q angles of: 2.53, 5.05, 8.78, 10.09, 11.80, 18.78, 18.99, 20.50, and 25.32.

[0096] In some embodiments, the Cu-Ka ray X-ray powder diffraction (XRPD) pattern of the monohydrochloride salt Form B of the compound of Formula (I) further includes any one or more of the following characteristic diffraction peaks expressed in degrees 2q ± 0.2° at 2q angles of: 8.09, 17.75, 19.61, 20.24, 22.76, 23.50, 25.67, 25.95, 26.58, 26.82, 27.66, 32.33, and 32.51.

[0097] In some embodiments, the Cu-Ka ray X-ray powder diffraction (XRPD) pattern of the monohydrochloride salt Form B of the compound of Formula (I) further comprises any one or more of the following characteristic diffraction peaks, in degrees 2Θ ± 0.2°, at 2Θ angles of 4.15, 7.56, 12.66, 13.15, 13.82, 14.38, 15.64, 15.79, 16.18, 17.98, 21.30, 23.99, 29.03, 29.60, 30.25, 30.50, 31.80, and 33.68.

[0098] In some embodiments, the Cu-Ka ray X-ray powder diffraction (XRPD) pattern of the monohydrochloride salt Form B of the compound of Formula (I) comprises the following characteristic diffraction peaks, in degrees 2Θ ± 0.2°, at 2Θ angles of 2.53, 4.15, 5.05, 7.56, 8.09, 8.78, 10.09, 11.80, 13.82, 15.64, 15.79, 16.18, 17.75, 17.98, 18.78, 18.99, 19.61, 20.24, 20.50, 21.30, 22.76, 23.50, 23.99, 25.32, 25.67, 25.95, 26.58, 26.82, 27.66, 30.50, 32.33, 32.51, and 33.68.

[0099] In some embodiments, the Cu-Ka ray X-ray powder diffraction (XRPD) pattern of the monohydrochloride salt Form B of the compound of Formula (I) comprises the following characteristic diffraction peaks, in degrees 2Θ ± 0.2°, at 2Θ angles of 2.53, 4.15, 5.05, 7.56, 8.09, 8.78, 10.09, 11.80, 12.66, 13.15, 13.82, 14.38, 15.64, 15.79, 16.18, 17.75, 17.98, 18.78, 18.99, 19.61, 20.24, 20.50, 21.30, 22.76, 23.50, 23.99, 25.32, 25.67, 25.95, 26.58, 26.82, 27.66, 29.03, 29.60, 30.25, 30.50, 31.80, 32.33, 32.51, and 33.68.

[0100] In some embodiments, the Cu-Ka ray X-ray powder diffraction (XRPD) pattern of the monohydrochloride salt Form B of the compound of Formula (I) is as shown in Figure 5.

[0101] In some embodiments, the differential scanning calorimetry pattern of the monohydrochloride salt Form B of the compound of formula (I) exhibits an endothermic peak at about 16.9 ± 3.0 °C, about 87.1 ± 3.0 °C, and / or about 195.2 ± 3.0 °C.

[0102] In some embodiments, the differential scanning calorimetry pattern of the monohydrochloride salt Form B of the compound of formula (I) is as shown in Figure 6.

[0103] In some embodiments, the thermogravimetric analysis pattern of the monohydrochloride salt Form B of the compound of formula (I) exhibits a weight loss of about 4.3 ± 0.2% at 85 °C, and / or a weight loss of about 0.4 ± 0.2% between 85 °C and 160 °C.

[0104] In some embodiments, the thermogravimetric analysis pattern of the monohydrochloride salt Form B of the compound of formula (I) is as shown in Figure 7.

[0105] 3. A maleate salt of the compound of formula (I) in crystalline form

[0106] In some embodiments, the present disclosure provides a maleate salt of the compound of formula (I), preferably a monomaleate salt, in crystalline form. In some embodiments, the present disclosure provides a maleate salt hydrate of the compound of formula (I), preferably a monomaleate salt hydrate, in crystalline form. In some embodiments, the maleate salt of the compound of formula (I) in crystalline form has Form A, which can also be referred to herein as “monomaleate salt Form A of the compound of formula (I)” or “Compound 012 monomaleate salt Pattern A” and the like.

[0107] In some embodiments, the Cu-Ka ray X-ray powder diffraction (XRPD) pattern of the monomaleate salt Form A of the compound of formula (I) includes any one or more of the following characteristic diffraction peaks expressed in degrees 2-theta ± 0.2° at 2-theta angles of 6.83, 8.13, 11.15, 13.66, 16.51, 17.67, 19.05, 20.52, 23.26, 23.85, 26.77, and 27.47.

[0108] In some embodiments, the Cu-Ka ray X-ray powder diffraction (XRPD) pattern of the monomaleate salt Form A of the compound of formula (I) includes any one or more of the following characteristic diffraction peaks expressed in degrees 2-theta ± 0.2° at 2-theta angles of 14.35, 22.39, 22.84, 24.90, 25.59, and 27.14.

[0109] In some embodiments, the Cu-Ka radiation X-ray powder diffraction (XRPD) pattern of the monomaleate salt Form A of the compound of Formula (I) further comprises any one or more of the following characteristic diffraction peaks expressed in degrees 2-theta ± 0.2° at 2-theta angles of 8.82, 9.47, 14.91, 15.45, 17.44, 17.90, 18.21, 18.65, 19.54, 20.05, 20.73, 21.04, 21.51, 24.43, 26.38, 27.87, 28.26, 28.88, 30.66, 32.64, and 34.52.

[0110] In some embodiments, the Cu-Ka radiation X-ray powder diffraction (XRPD) pattern of the monomaleate salt Form A of the compound of Formula (I) comprises the following characteristic diffraction peaks expressed in degrees 2-theta ± 0.2° at 2-theta angles of 6.83, 8.13, 11.15, 13.66, 14.35, 16.51, 17.44, 17.67, 17.90, 18.21, 19.05, 20.05, 20.52, 20.73, 21.51, 22.39, 22.84, 23.26, 23.85, 24.43, 24.90, 25.59, 26.38, 26.77, 27.14, 27.47, 27.87, 28.26, and 28.88.

[0111] In some embodiments, the Cu-Ka radiation X-ray powder diffraction (XRPD) pattern of the monomaleate salt Form A of the compound of Formula (I) comprises the following characteristic diffraction peaks expressed in degrees 2-theta ± 0.2° at 2-theta angles of 6.83, 8.13, 8.82, 9.47, 11.15, 13.66, 14.35, 14.91, 15.45, 16.51, 17.44, 17.67, 17.90, 18.21, 18.65, 19.05, 19.54, 20.05, 20.52, 20.73, 21.04, 21.51, 22.39, 22.84, 23.26, 23.85, 24.43, 24.90, 25.59, 26.38, 26.77, 27.14, 27.47, 27.87, 28.26, 28.88, 30.66, 32.64, and 34.52.

[0112] In some embodiments, the Cu-Ka radiation X-ray powder diffraction (XRPD) pattern of the monomaleate salt Form A of the compound of Formula (I) is as shown in Figure 9.

[0113] In some embodiments, the differential scanning calorimetry pattern of the monomaleate salt Form A of the compound of formula (I) exhibits an endothermic peak at about 30.4 ± 3.0 °C, and / or about 219.3 ± 3.0 °C.

[0114] In some embodiments, the differential scanning calorimetry pattern of the monomaleate salt Form A of the compound of formula (I) is as shown in Figure 10.

[0115] In some embodiments, the thermogravimetric analysis pattern of the monomaleate salt Form A of the compound of formula (I) exhibits a weight loss of about 1.5 ± 0.2% at 100 °C, and / or a weight loss of about 0.7 ± 0.2% between 100 °C and 180 °C.

[0116] In some embodiments, the thermogravimetric analysis pattern of the monomaleate salt Form A of the compound of formula (I) is as shown in Figure 11.

[0117] 4. A fumarate salt of the compound of formula (I) in crystalline form

[0118] In some embodiments, the present disclosure provides a fumarate salt of the compound of formula (I) in crystalline form, preferably a monofumarate salt. In some embodiments, the fumarate salt of the compound of formula (I) in crystalline form has Form A, which can also be referred to herein as “monofumarate salt Form A of the compound of formula (I)” or “Compound 012 monofumarate salt Pattern A” and the like.

[0119] In some embodiments, the Cu-Ka ray X-ray powder diffraction (XRPD) pattern of the monofumarate salt Form A of the compound of formula (I) comprises any one or more of the following characteristic diffraction peaks expressed in degrees 2theta ± 0.2° at 2theta angles of 6.20, 12.39, 14.34, 15.33, 18.62, 20.09, 21.57, 22.94, 24.04, 24.90, and 26.79.

[0120] In some embodiments, the Cu-Ka ray X-ray powder diffraction (XRPD) pattern of the monofumarate salt Form A of the compound of formula (I) further comprises any one or more of the following characteristic diffraction peaks expressed in degrees 2theta ± 0.2° at 2theta angles of 14.87, 18.12, 18.49, 21.14, 24.77, and 31.26.

[0121] In some embodiments, the Cu-Ka ray X-ray powder diffraction (XRPD) pattern of the monofumarate salt Form A of the compound of formula (I) further comprises any one or more of the following characteristic diffraction peaks, in degrees 2-theta ± 0.2°, at the following 2-theta angles: 7.17, 11.19, 14.00, 15.93, 17.73, 21.30, 22.12, 23.87, 24.54, 25.57, 27.05, 28.46, 36.32, and 37.72.

[0122] In some embodiments, the Cu-Ka ray X-ray powder diffraction (XRPD) pattern of the monofumarate salt Form A of the compound of formula (I) further comprises any one or more of the following characteristic diffraction peaks, in degrees 2-theta ± 0.2°, at the following 2-theta angles: 9.23, 9.72, 12.10, 13.45, 16.28, 16.62, 19.62, 23.46, 24.42, 26.30, 29.19, 29.51, 32.14, 35.85, 36.57, and 38.12.

[0123] In some embodiments, the Cu-Ka ray X-ray powder diffraction (XRPD) pattern of the monofumarate salt Form A of the compound of formula (I) comprises the following characteristic diffraction peaks, in degrees 2-theta ± 0.2°, at the following 2-theta angles: 6.20, 7.17, 11.19, 12.39, 14.00, 14.34, 14.87, 15.33, 15.93, 17.73, 18.12, 18.49, 18.62, 20.09, 21.14, 21.30, 21.57, 22.12, 22.94, 23.87, 24.04, 24.54, 24.77, 24.90, 25.57, 26.30, 26.79, 27.05, 28.46, 31.26, 36.32, and 37.72.

[0124] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the monofumarate salt Form A of the compound of Formula (I) comprises characteristic diffraction peaks, expressed in degrees two-theta ± 0.2°, at the following 2 theta angles: 6.20, 7.17, 9.23, 9.72, 11.19, 12.10, 12.39, 13.45, 14.00, 14.34, 14.87, 15.33, 15.93, 16.28, 16.62, 17.73, 18.12, 18.49, 18.62, 19.62, 20.09, 21.14, 21.30, 21.57, 22.12, 22.94, 23.46, 23.87, 24.04, 24.42, 24.54, 24.77, 24.90, 25.57, 26.30, 26.79, 27.05, 28.46, 29.19, 29.51, 31.26, 32.14, 35.85, 36.32, 36.57, 37.72, and 38.12.

[0125] In some embodiments, the X-ray powder diffraction (XRPD) pattern of the monofumarate salt Form A of the compound of Formula (I) is as shown in Figure 13.

[0126] In some embodiments, the differential scanning calorimetry pattern of the monofumarate salt Form A of the compound of Formula (I) exhibits an endothermic peak at about 19.1 ± 3.0 °C, and / or about 260.4 ± 3.0 °C.

[0127] In some embodiments, the differential scanning calorimetry pattern of the monofumarate salt Form A of the compound of Formula (I) is as shown in Figure 14.

[0128] In some embodiments, the thermogravimetric analysis pattern of the monofumarate salt Form A of the compound of Formula (I) exhibits a weight loss of about 0.7 ± 0.2% at 100 °C, and / or a weight loss of about 2.0 ± 0.2% between 100 °C and 220 °C.

[0129] In some embodiments, the thermogravimetric analysis pattern of the monofumarate salt Form A of the compound of Formula (I) is as shown in Figure 15.

[0130] In this document, the free base or pharmaceutically acceptable salts of the compound of Formula (I) and solvates, hydrates thereof in crystalline form are substantially pure crystalline forms. The term "substantially pure" means that the crystalline forms of the present disclosure have at least 90% purity. More preferably, the crystalline forms of the present disclosure have at least 95% purity, most preferably at least 99% by weight of the crystalline form of the free base or pharmaceutically acceptable salts of the compound of Formula (I) and solvates, hydrates thereof are present in the crystalline form as described in the present disclosure.

[0131] Use and Administration

[0132] The free base or pharmaceutically acceptable salts of the compounds of Formula (I) of the present disclosure, optionally in crystalline form, and solvates, hydrates thereof, can be used as medicaments. They were found to exhibit pharmacological activity in inhibiting PLK1. It is hypothesized that by this activity, the free base or pharmaceutically acceptable salts of the compounds of Formula (I) of the present disclosure, optionally in crystalline form, and solvates, hydrates thereof, can prevent or reverse the dysregulation of PLK1 activity. By preventing the dysregulation of its PLK1 activity, it can be able to exert its role as a tumor suppressor. In addition to preventing or reversing the dysregulation of PLK1 activity, the pharmacological activity of the free base or pharmaceutically acceptable salts of the compounds of Formula (I) of the present disclosure, optionally in crystalline form, and solvates, hydrates thereof, can also be useful in inhibiting PLK1 in other pathophysiological situations that would be beneficial.

[0133] Thus, the free base or pharmaceutically acceptable salts of the compounds of Formula (I) of the present disclosure, optionally in crystalline form, and solvates, hydrates thereof, as PLK1 inhibitors are particularly useful in the treatment of diseases and conditions resulting from dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1, such as cancer, including but not limited to the following: cancers such as leukemia, lymphoma, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, colorectal cancer, liver cancer, gastric cancer, esophageal cancer, melanoma, multiple myeloma, and sepsis, etc. Without wishing to commit to any particular theory or explanation, it can be hypothesized that these compounds can be able to achieve this by acting directly on cancer cells and / or indirectly by modulating the response of the immune system to the tumor.

[0134] The free base or pharmaceutically acceptable salts of the compounds of Formula (I) of the present disclosure, optionally in crystalline form, and solvates, hydrates thereof, can be administered in an amount effective to treat the diseases or conditions described herein. For administration and dosing purposes, the free base or pharmaceutically acceptable salts of the compounds of Formula (I) of the present disclosure, optionally in crystalline form, and solvates, hydrates thereof, can be referred to herein sometimes simply as the salt forms of the present disclosure and their crystalline forms.

[0135] The salt forms of the present disclosure and their crystalline forms are administered by any suitable route, in the form of pharmaceutical compositions adapted to such route, and in a dose effective for the intended treatment. The salt forms of the present disclosure and their crystalline forms can be administered orally, rectally, vaginally, parenterally, or topically.

[0136] As used herein, the term "administering" means absorbing, taking up, injecting, inhaling, implanting, or otherwise introducing a compound of the disclosure or a pharmaceutical composition thereof. The term "treating" means reversing, alleviating, delaying the onset of, or inhibiting the progress of a "pathological condition" (e.g., a disease, disorder, or condition, or one or more signs or symptoms thereof) described herein. In certain embodiments, treatment can be administered after one or more signs or symptoms of the disease or condition have developed or have been observed. In other embodiments, treatment can be administered in the absence of signs or symptoms of the disease or condition. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment can also continue after symptoms have resolved, for example to delay or prevent recurrence. As used herein, the terms "disease," "disorder," "condition," and "pathological condition" are used interchangeably.

[0137] A person of skill in the art can determine the dosage level of administration by routine experimentation. Dosage regimes for the salt forms of the disclosure and their crystalline forms and / or compositions comprising the same are based on a variety of factors, including the type, age, weight, sex, and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, dosage regimes can vary widely. For example, dosage levels of the salt forms of the disclosure and their crystalline forms can range from about 0.001 to about 100 mg / kg (i.e., mg / kg body weight) per day. In certain embodiments, the total daily dose per day of the salt forms of the disclosure and their crystalline forms, administered in single or divided doses, can range from about 0.001 to about 10 mg / kg. It is not uncommon for administration of the salt forms of the disclosure and their crystalline forms to be repeated several times a day.

[0138] Pharmaceutical compositions

[0139] In some aspects, the disclosure relates to a pharmaceutical composition comprising a free base or a pharmaceutically acceptable salt of a compound of Formula (I), as provided herein, optionally in crystalline form, and solvates, hydrates thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0140] As used herein, the term "pharmaceutically acceptable carrier or adjuvant" means a carrier or adjuvant that can be used in preparing a pharmaceutical composition typically is safe, non-toxic, and neither biologically nor otherwise undesirable, and includes a carrier or adjuvant that is acceptable for veterinary use as well as human pharmaceutical use. A pharmaceutically acceptable carrier or adjuvant as used herein includes one and more than one such carrier or adjuvant. The specific carrier or adjuvant employed will depend on the means and purpose of the application of the compounds of the disclosure. Suitable carriers and adjuvants are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C, et al. Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. One or more of buffering agents, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, flavors, sweeteners, perfuming agents, trace elements, and other known additives, such as those described in Remington: The Science and Practice of Pharmacy, 22nd Edition, Philadelphia, PA: Mack Publishing Company, 2012, Chapter 82, can also be included, as desired, to provide a precise presentation or to enhance the production of a pharmaceutical product.

[0141] The compositions of the present disclosure can be formulated into various forms. These include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, suppositories, and the like. The form is dependent on the intended means of administration and therapeutic application.

[0142] Pharmaceutical compositions of the present disclosure can be prepared by any of the well-known pharmaceutical techniques, e.g., effective formulation and administration procedures. The above considerations regarding effective formulation and administration procedures are well known in the art and are described in standard textbooks. For example, formulation of pharmaceutical products is discussed in Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients, 3rdEd., American Pharmaceutical Association, Washington, 1999.

[0143] In yet another aspect, the present disclosure relates to a kit for treating a disease and a condition caused by dysregulation of PLK1 activity and / or a disease and a condition associated with PLK1, comprising a free base or a pharmaceutically acceptable salt of a compound of Formula (I), optionally in crystalline form, and solvates, hydrates thereof, as provided herein, or a pharmaceutical composition comprising a free base or a pharmaceutically acceptable salt of a compound of Formula (I), optionally in crystalline form, and solvates, hydrates thereof, as provided herein, a container, and optionally a package insert or label instructing the treatment.

[0144] Method of treatment

[0145] In yet another aspect, the present disclosure relates to a method of treating a disease and a condition caused by dysregulation of PLK1 activity and / or a disease and a condition associated with PLK1 in a subject in need thereof, due to the PLK1 inhibitory activity of the salt form and its crystalline forms of the present disclosure, comprising administering to the subject a therapeutically effective amount of a free base or a pharmaceutically acceptable salt of a compound of Formula (I), optionally in crystalline form, and solvates, hydrates thereof, as provided herein.

[0146] As used herein, the term “a subject in need thereof’ is a subject who has a disease and a condition caused by dysregulation of PLK1 activity and / or a disease and a condition associated with PLK1, or a subject who has an increased risk of developing a PLK1 -associated disease or condition relative to the general population. In certain embodiments, the subject is a warm-blooded animal. In certain embodiments, the warm-blooded animal is a mammal. In certain embodiments, the warm-blooded animal is a human.

[0147] As used herein, the term "diseases and conditions resulting from dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1" refers to any pathophysiological situation in which inhibition of PLK1 would be beneficial. In certain embodiments, the diseases and conditions resulting from dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1 are cancer. In certain embodiments, the diseases and conditions resulting from dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1 are diseases and conditions selected from the group consisting of leukemia, lymphoma, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, colorectal cancer, liver cancer, gastric cancer, esophageal cancer, melanoma, multiple myeloma, and sepsis.

[0148] In yet another aspect, the present disclosure relates to the use of a compound of Formula (I), as provided herein, optionally in crystalline form, as a free base or a pharmaceutically acceptable salt, and solvates, hydrates thereof, for the preparation of a medicament for the treatment of diseases and conditions resulting from dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1.

[0149] In yet another aspect, the present disclosure relates to the use of a compound of Formula (I), as provided herein, optionally in crystalline form, as a free base or a pharmaceutically acceptable salt, and solvates, hydrates thereof, for the preparation of a medicament for the treatment of diseases and conditions resulting from dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1.

[0150] Synthesis

[0151] The compounds of the present disclosure can be prepared by the general and specific methods described below using the general knowledge of a person skilled in the art of synthetic organic chemistry. Such general knowledge can be found in standard reference books, for example, Barton and Ollis (Eds.), Comprehensive Organic Chemistry, Elsevier; Richard Larock, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, John Wiley and Sons; and Organic Syntheses Methods, Vols. I-XII, Wiley-Interscience.

[0152] The schemes described below are intended to provide a general description of the methods used to prepare the compounds of the present disclosure. Some of the compounds of the present disclosure can contain a single or multiple chiral centers with stereochemical designation (R) or (S). It will be apparent to one skilled in the art that all synthetic transformations can be carried out in an analogous manner, whether the material is enantiomerically enriched or racemic. In addition, resolution of the desired optically active material can be achieved using well-known methods, such as those described herein and in the chemical literature, at any desired point in the sequence.

[0153] Examples

[0154] To describe the disclosure in further detail, the following examples are presented. The examples described herein serve to illustrate the compounds, methods, and compositions provided herein and should not be construed to limit the scope thereof in any way.

[0155] During synthesis, it can be necessary and / or desirable to protect sensitive or reactive groups of any of the molecules involved. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene and P. G. M. Wutts, Protective Groups in Organic Synthesis, 4th ed., John Wiley and Sons. The protecting groups are optionally removed at a convenient subsequent stage using methods well known from the art.

[0156] The compounds of the present disclosure can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents, and conventional synthetic procedures. Variations of the reactions outlined in these reaction schemes can also be used to prepare the compounds of the present disclosure, as will be apparent to a skilled person. In addition, other methods of preparing the compounds of the present disclosure according to the reaction schemes and examples described herein will be readily apparent to a skilled person. Unless otherwise indicated, all variables are as defined above. Generally speaking, in the chemical procedures, all reagents and starting materials are either commercially available or can be readily prepared by one skilled in the art.

[0157] Terminology Abbreviations

[0158] Instruments and Methods

[0159] Example 1. Synthesis of compound 012 of formula (I)

[0160] The synthetic route is shown below:

[0161] First step, synthesis of A2

[0162] 5-Bromo-2-trifluoromethoxyaniline A1 (10.0 g, 39.0 mmol) was dissolved in EtOH (30 mL), a solution containing cyanamide (3.28 g, 78 mmol), EtOH (10 mL), and H2O (2 mL) was added dropwise, a mixture of 37% HCl (6.5 mL) and EtOH (20 mL) was added dropwise to the mixture, refluxed for 5 days, the reaction was cooled to room temperature, concentrated and diluted with water; 1 N NaOH was added to the reaction until it was basic, extracted with ethyl acetate several times, dried over sodium sulfate and concentrated to give A2 (3.2 g, 27%).

[0163] Second step, synthesis of intermediate INT-1

[0164] A2 (29.3 g, 98.3 mmol, 1.2 eq) was dissolved in DMF (400 mL), and a DMF solution (200 mL) of intermediate INT-A (24 g, 81.9 mmol, 1.0 eq) was added. The reaction was reacted at 110 °C for 16 h, cooled to room temperature, poured into ice water, and the insoluble matter was filtered to obtain white solid compound INT-1 (21.2 g, 50%). LCMS: 528.2, 530.2 ([M+H] + ).

[0165] Step 3, synthesis of intermediate compound INT-2

[0166] Compound INT-1 (21.2 g, 40.1 mmol, 1.0 eq) was dissolved in THF (500 mL), and NH4Cl (6.44 g, 120 mmol, 3.0 eq) and LiHMDS (240 mmol, 6.0 eq) were added, and stirred at room temperature for 30 min. The solvent was removed by rotary evaporation, and the residue was washed with water and dried to obtain white solid compound INT-2 (16.8 g, 81.8%). LCMS: 513.1, 515.1 ([M+H] + ).

[0167] Step 4, synthesis of compound 012 (CPD012)

[0168] A mixture of compound INT-2 (2.0 g, 3.9 mmol), 1.0 eq), N-methylpiperazine-2,2,3,3,5,5,6,6-D8 hydrochloride (1.13 g, 6.25 mmol, 1.6 eq), Pd2(dba)3 (285 mg, 0.312 mmol, 0.08 eq), and Davephos (123 mg, 0.312 mmol, 0.08 eq) was added to THF (100 mL) and LiHMDS (40 mL, 40 mmol). The mixture was reacted at 100 °C for 2 h, and the reaction was quenched by adding water, and the reaction liquid was extracted with EtOAc (50 mL x 3), and the combined organic phases were rotary evaporated to remove the solvent, and the residue was purified by silica gel column chromatography to obtain the target product white solid CPD012 (1 g, 47.4%). LCMS: 541.3 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.92 (s, 1H), 8.34 (s, 1H), 7.45 (bs, 1H), 7.27-7.21 (m, 3H), 6.80 (dd, 1H), 4.62 (q, 3H), 3.62 (q, 2H), 2.97 (t, 2H), 2.79 (t, 2H), 2.49-2.32 (m, 3H).

[0169] Example 2. Preparation of salt forms of compound 012 of formula (I)

[0170] The term "salt forms of compound 012 of formula (I)" as used herein refers to one or more forms of pharmaceutically acceptable salts of compound 012 of formula (I), and in this example, a plurality of pharmaceutically acceptable salts of compound 012 of formula (I) were prepared, as described below.

[0171] Compound 012 prepared in Example 1 is a small molecule compound with a molecular weight of 540.58. In this example, salt forms of compound 012 were prepared starting from the free form Pattern A (free base Pattern A) of compound 012 and polymorphs thereof.

[0172] The free form Pattern A of compound 012 is an anhydrate and has the material characterization shown in the table below.

[0173] Table 1. Material characterization of the free form Pattern A of compound 012

[0174] The counterions used to prepare the salt forms of compound 012 are shown in the table below

[0175] Table 2. Counterions used to prepare the salt forms of compound 012

[0176] Approximately 20 mg of compound 012 free form Pattern A was weighed into a 2 mL glass vial with 1.0 equivalent of the counterion and a screening solvent (acetonitrile / water (95 / 5, v / v), tetrahydrofuran, and methanol) was added to perform the preparation screening experiment in suspension. The resulting sample was suspended at 50 °C for 2 hours, after which it was allowed to cool to 25 °C and was suspended at 25 °C for 3 days.

[0177] The resulting suspension was centrifuged at 14,000 rpm through a 0.45 μιη nylon filter membrane and the resulting solid was vacuum dried at 50 °C for 2 hours before being characterized by XRPD. Samples that showed changes in the XRPD and had high crystallinity were further characterized by 1 H-NMR and IC characterization to confirm stoichiometry, and additional HPLC and DSC characterization for solid state physical form for some samples. The salt forms of compound 012 that were successfully obtained using the counterions described above are shown in the table below.

[0178] Table 3. Salt forms of compound 012

[0179] Example 3. Scale-up preparation of salt forms of compound 012 of formula (I)

[0180] Single hydrochloride salt Pattern B, single fumarate salt Pattern A and single maleate salt Pattern A were selected for scale-up preparation, which were prepared according to the following detailed description.

[0181] 3.1 Scale-up of single hydrochloride salt Pattern B

[0182] Single hydrochloride salt Pattern B was prepared according to the following procedure.

[0183] • 0.25 g of free Pattern A was weighed into an 8 mL glass vial. 1.2 mL of methanol and ~1.1 equivalent of HCl (0.41 mL; 37% w / w concentrated HCl diluted 10 times with methanol) were added, and about 2 mg of single hydrochloride salt Pattern B seed crystals were added to the suspension, which was stirred at 50 °C for 2 hours to obtain a suspension;

[0184] • The suspension was transferred to 25 °C, and about 2 mg of single hydrochloride salt Pattern B seed crystals were added again to the suspension, which was stirred at 25 °C for 4 days;

[0185] • ~0.2 equivalent of HCl (0.075 mL; 37% w / w concentrated HCl diluted 10 times with methanol) was added to the system, which was continued to be stirred at 25 °C for 0.5 days;

[0186] • After 12 hours of stirring, the suspension was centrifuged to separate the solid part, which was dried at 50 °C under vacuum for about 2 hours, and then at 35 °C under vacuum for about 16 hours;

[0187] • A total of 173 mg of single hydrochloride salt Pattern B was obtained as white powder, with a yield of about 61%.

[0188] • The solid was characterized by XRPD, DSC, TGA, IC, HPLC, PLM and 1 H-NMR, and the results are listed in Table 4.

[0189] 3.2 Scale-up of single fumarate salt Pattern A

[0190] Single fumarate salt Pattern A was prepared according to the following procedure.

[0191] • 0.25 g of free Pattern A and 1.0 equivalent of fumaric acid were weighed into an 8 mL glass vial. 1.2 mL of methanol was added, and about 2 mg of single fumarate salt Pattern A seed crystals were added to the suspension, which was stirred at 50 °C for 2 hours to obtain a suspension;

[0192] • The suspension was transferred to 25 °C and to the above suspension was added again about 2 mg of the monofumarate Pattern A seed crystals at 25 °C and stirred for 4 days at 25 °C;

[0193] • The suspension was centrifuged through a filter and the solid part obtained was dried at 50 °C under vacuum for about 2 hours and continued at 35 °C under vacuum for about 16 hours;

[0194] • A total of 246 mg of white powder of monofumarate Pattern A was obtained with a yield of about 79%.

[0195] • The solid was characterized by XRPD, DSC, TGA, HPLC, PLM and 1 H-NMR characterization, the results are shown in Table 4.

[0196] 3.3 Scale-up of monomaleate Pattern A

[0197] The monomaleate Pattern A was prepared according to the following procedure.

[0198] • 0.25 g of free Pattern A and 1.0 equivalent of maleic acid were weighed in an 8 mL glass vial. 2.0 mL of acetonitrile / water (95 / 5, v / v) were added and to the above suspension was added about 2 mg of monomaleate Pattern A seed crystals and stirred for 2 hours at 50 °C to obtain a suspension;

[0199] • The suspension was transferred to 25 °C and to the above suspension was added again 2 mg of monomaleate Pattern A seed crystals at 25 °C and stirred for 4 days at 25 °C;

[0200] • To the above system was added ~0.15 equivalent of maleic acid and continued to stir for 1 day at 25 °C;

[0201] • The suspension was centrifuged through a filter and the solid part obtained was dried at 50 °C under vacuum for about 2 hours and continued at 35 °C under vacuum for about 16 hours;

[0202] • A total of 266 mg of white powder of monomaleate Pattern A was obtained with a yield of about 86%.

[0203] • The solid was characterized by XRPD, DSC, TGA, HPLC, PLM and 1 H-NMR characterization, the results are shown in Table 4.

[0204] The salts prepared in this example were characterized by XRPD, DSC, TGA, 1 H-NMR, IC, HPLC and PLM (Table 4).

[0205] Table 4 Characterization of salt forms prepared at scale

[0206] The characterization data showed that the monohydrochloride Pattern B, the monofumarate Pattern A and the monomaleate Pattern A exhibited good basic properties such as high crystallinity, high melting point, reasonable stoichiometry and counterion safety.

[0207] Example 4. Comparison of free base and pharmaceutically acceptable salts of compound 012 of formula (I)

[0208] The pharmaceutically acceptable salts of compound 012 of formula (I) prepared in Example 3 were comprehensively evaluated and compared to the free Pattern A of compound 012 of formula (I) in terms of stability, solubility, hygroscopicity and solid morphology.

[0209] 4.1 Solid stability

[0210] Open containers with free sample and 3 candidate salt form samples were placed at 25 °C / 92% RH for 1 week. Closed containers with free sample and 3 candidate salt form samples were placed at 60 °C for 1 week. The chemical purity change was investigated by HPLC, the crystal form change was investigated by XRPD, and the sample color change was observed. The monohydrochloride Pattern B was additionally characterized by IC (Table 5).

[0211] The monofumarate Pattern A and the monomaleate Pattern A were continued to be placed under the original experimental conditions for 3 weeks after 1 week sampling. The chemical purity change was investigated by HPLC, the crystal form change was investigated by XRPD, and the sample color change was observed (Table 6).

[0212] Table 5 Solid stability: purity and appearance - 1

[0213] Note A: no color change; B: slight discoloration

[0214] C: moderate discoloration; D: severe discoloration

[0215] Table 6 Solid stability: purity and appearance - 2

[0216] Note A: no color change; B: slight discoloration

[0217] C: moderate discoloration; D: severe discoloration

[0218] 4.2 Solubility

[0219] The free form Pattern A, monohydrochloride Pattern B, monofumarate Pattern A and monomaleate Pattern A, each in an amount equivalent to 8 mg of anhydrous free form, were accurately weighed into 8 mL glass vials, and 4 mL of the respective solvent was added to each. The resulting suspensions / clarified solutions were stirred at 37°C at 400 rpm, and samples were taken at 0.5 and 2 hours, respectively. The samples were centrifuged at 14,000 rpm for 5 min at 37°C. The supernatant concentrations were determined by HPLC and the pH of the supernatant was determined by a pH meter. The residual solids (wet) after 2 hours were examined for polymorphic change by XRPD. The results are shown in Table 7.

[0220] 4.3 Hygroscopicity

[0221] 4.4 Solid morphology

[0222] Table 9 Solid morphology

[0223] The characterization data show that monohydrochloride Pattern B, monofumarate Pattern A and monomaleate Pattern A exhibit better solubility, solid morphology and physicochemical properties, in particular:

[0224] Better solubility: The three salt forms / polymorphs of this example show significant improvement in solubility in pure water and FaSSIF-vl (pH 6.5).

[0225] Solid morphology: The three salt forms / polymorphs of this example are solid particles with suitable particle size, and have good flowability, which is beneficial for production and granulation. In comparison, the free base is rod-like or needle-like, and the flowability can be relatively poor.

[0226] Basic physicochemical properties: The three salt forms / polymorphs of this example have better basic physicochemical properties, such as higher melting point.

[0227] In addition, it can be seen from the characterization data that monofumarate Form A (monofumarate Pattern A) in particular has good physicochemical properties, high crystallinity, high melting point, stable solid properties, almost no hygroscopicity and many other advantages, and is therefore very suitable for use in the preparation of drugs.

[0228] The foregoing description is considered as illustrative only of the principles of the disclosure. Further, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the disclosure to the exact construction and process as described above. Accordingly, all suitable modifications and equivalents can be considered as falling within the scope of the disclosure as defined by the claims that follow.

[0229] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety into the present disclosure.

Claims

1. A free base or a pharmaceutically acceptable salt of a compound of formula (I), and solvates, hydrates thereof: ###00001### (I) ​ the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, phosphate, maleate, fumarate, L-tartrate, citrate, L-aspartate, hippurate, L-glutamate, L-malate, adipate, glutarate, p-toluenesulfonate and methanesulfonate; Preferably, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, phosphate, maleate, fumarate, L-tartrate, citrate, L-malate, glutarate, p-toluenesulfonate and methanesulfonate; More preferably, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, maleate and fumarate. More preferably, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, maleate and fumarate.

2. The free base or pharmaceutically acceptable salt of the compound of formula (I) and solvates, hydrates thereof according to claim 1, wherein, the pharmaceutically acceptable salt is selected from the group consisting of monohydrochloride, monophosphate, monomaleate, monofumarate, hemi-L-tartrate and mono-L-malate; Preferably, the pharmaceutically acceptable salt is selected from the group consisting of monohydrochloride, monomaleate and monofumarate.

3. The free base or a pharmaceutically acceptable salt of the compound of formula (I) according to claim 1 or 2, and solvates, hydrates thereof, in crystalline form.

4. The free base or pharmaceutically acceptable salt of the compound of formula (I) and solvates, hydrates thereof, in crystalline form according to any one of claims 1-3, wherein, The X-ray powder diffraction (XRPD) pattern of crystalline Form A of the free base of the compound of formula (I) has characteristic diffraction peaks expressed in degrees 2theta ± 0.2° at the following 2theta angles: 3.34, 6.66, 9.10, 9.55, 9.98, 11.15, 12.22, 16.06, 17.47, 18.00, 18.24, and / or 21.

41.

5. The free base or pharmaceutically acceptable salt of the compound of formula (I) according to any one of claims 1 to 3, and solvates, hydrates thereof, in crystalline form, wherein, The pharmaceutically acceptable salt of the compound of formula (I) in crystalline form is a hydrochloride, preferably a monohydrochloride, the X-ray powder diffraction (XRPD) pattern of crystalline Form B of which has characteristic diffraction peaks expressed in degrees 2theta ± 0.2° at the following 2theta angles: 2.53, 5.05, 8.78, 10.09, 11.80, 18.78, 18.99, 20.50, and / or 25.

32.

6. The free base or a pharmaceutically acceptable salt of the compound of formula (I) according to claim 5, and solvates, hydrates thereof, which is a monohydrochloride hydrate of the compound of formula (I) in crystalline form.

7. The free base or pharmaceutically acceptable salt of the compound of formula (I) according to any one of claims 1 to 3, and solvates, hydrates thereof, in crystalline form, wherein, The pharmaceutically acceptable salt of the compound of formula (I) in crystalline form is a maleate, preferably a monomaleate, the X-ray powder diffraction (XRPD) pattern of crystalline Form A of which has characteristic diffraction peaks expressed in degrees 2theta ± 0.2° at the following 2theta angles: 6.83, 8.13, 11.15, 13.66, 16.51, 17.67, 19.05, 20.52, 23.26, 23.85, 26.77, and / or 27.

47.

8. The free base or pharmaceutically acceptable salt of the compound of formula (I) and solvates, hydrates thereof according to claim 7, which is a monomaleate hydrate of the compound of formula (I) in crystalline form.

9. The free base or pharmaceutically acceptable salt of the compound of formula (I) according to any one of claims 1 to 3, and solvates, hydrates thereof, in crystalline form, wherein, The pharmaceutically acceptable salt of the compound of formula (I) in crystalline form is a fumarate salt, preferably a monofumarate salt, which has a Cu-Ka ray X-ray powder diffraction (XRPD) pattern of the crystalline Form A with characteristic diffraction peaks expressed in degrees 2q ± 0.2° at the following 2q angles: 6.20, 12.39, 14.34, 15.33, 18.62, 20.09, 21.57, 22.94, 24.04, 24.90, and / or 26.

79.

10. The free base or pharmaceutically acceptable salt of the compound of formula (I) and solvates, hydrates thereof according to claim 9, which is a monofumarate anhydrate of the compound of formula (I) in crystalline form.

11. A pharmaceutical composition comprising the free base or pharmaceutically acceptable salt of the compound of formula (I) and solvates, hydrates thereof according to any one of claims 1-10, and a pharmaceutically acceptable carrier or excipient.

12. A method of treating a disease and condition caused by dysregulation of PLK1 activity and / or a disease and condition associated with PLK1 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the free base or pharmaceutically acceptable salt of the compound of formula (I) and solvates, hydrates thereof according to any one of claims 1-10.

13. The free base or pharmaceutically acceptable salt of the compound of formula (I) and solvates, hydrates thereof according to any one of claims 1-10 for use in the treatment of a disease and condition caused by dysregulation of PLK1 activity and / or a disease and condition associated with PLK1.

14. Use of the free base or pharmaceutically acceptable salt of the compound of formula (I) and solvates, hydrates thereof according to any one of claims 1-10 in the manufacture of a medicament for the treatment of a disease and condition caused by dysregulation of PLK1 activity and / or a disease and condition associated with PLK1.

15. A kit for use in the treatment of a disease and condition caused by dysregulation of PLK1 activity and / or a disease and condition associated with PLK1, the kit comprising: the free base or pharmaceutically acceptable salt of the compound of formula (I) and solvates, hydrates thereof according to any one of claims 1-10, or a pharmaceutical composition according to claim 11, and a container and optionally a package insert or label instructing treatment.

16. The method according to claim 12, the use according to claim 13, or the kit according to claim 15, wherein, The disease and condition caused by dysregulation of PLK1 activity and / or a disease and condition associated with PLK1 include, but are not limited to, leukemia, lymphoma, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, colorectal cancer, liver cancer, gastric cancer, esophageal cancer, melanoma, multiple myeloma, and sepsis, etc.

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