A new form of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide hydrochloride

Abstract

The present invention relates to a new form of inhibitor of Axl / Mer receptor tyrosine kinase and CSF1R (colony stimulating factor 1 receptor), and in particular to a new form of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoro-ethoxy)-1H-pyrazole-3-carboxamide hydrochloride.

Description

[Technical field]

[0001] The present invention relates to a new form of inhibitor of Axl / Mer receptor tyrosine kinase and CSF1R (colony stimulating factor 1 receptor), and in particular to a new form of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoro-ethoxy)-1H-pyrazole-3-carboxamide hydrochloride. [Background technology]

[0002] Axl / Mer receptor tyrosine kinase (Axl / Mer RTK) is a member of the TAM (tyrosine, Axl, Mer) receptor tyrosine kinases. Such TAM receptor tyrosine kinases are characterized by an extracellular domain consisting of two immunoglobulin-like domains followed by two fibronectin type 3-like domains. Activation of the Axl / Mer pathway is triggered by its cognate protein ligands, namely, growth arrest specific 6 (Gas6) and protein S (Pros1), respectively.

[0003] Many inhibitors of TAM receptor tyrosine kinases, such as Myers et al., 2019, Mol. Cancer, 18, 94; https: / / doi.org / 10.1186 / s12943-019-1022-2 It is described in.

[0004] CSF1R is known to control the differentiation of bone marrow progenitor cells into heterogeneous populations of monocytes, macrophages, dendritic cells (DCs) and bone-resorbing osteoclasts. Furthermore, activated CSF1R promotes the survival, proliferation, differentiation and chemotaxis of differentiated macrophages (Geissmann F et al., Science. 2010 Feb 5; 327(5966):656-61).

[0005] Based on the role of CSF1R in immune cells, various approaches targeting either CSF1R or its ligands for immunotherapy and cancer have been developed and are currently in the clinical stage.

[0006] A number of such inhibitors are described in WO 2019 / 229251, including the compound N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide, also known as "Q702."

[0007] There is a continuing need in the art to find improved and suitable inhibitors of Axl / Mer receptor tyrosine kinase and CSF1R that provide high bioavailability, good solubility, and good stability.

[0008] These objects are the compound N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide hydrochloride, of formula

[0009] [ka]

[0010] having and having at least one or several peaks from a first set of peaks in an X-ray powder diffraction (XRPD) spectrum obtained by irradiation with Cu-Kα-radiation (Cu-Kα), the first set of peaks being: 8.2° 2θ, 9.9° 2θ, 11.4° 2θ, 15.2° 2θ, 15.4° 2θ, 19.9° 2θ, 21.4° 2θ, 21.7° 2θ, 22.9° 2θ, 23.3° 2θ, 25.5° 2θ, 25.7° 2θ, 25.9° 2θ, 28.2° 2θ, and 28.7° 2θ, ±0.2° 2θ; Preferably, the compound herein is resolved by a compound having at least two peaks, at least three peaks, at least four peaks, at least five peaks, at least six peaks or more peaks from the first set of peaks, such a compound also being designated herein as "Form A" of (N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide hydrochloride).

[0011] In one embodiment, the compound has at least two peaks from a second set of peaks in an X-ray powder diffraction (XRPD) spectrum obtained by irradiation with Cu-Kα-radiation (Cu-Kα), the second set of peaks being: 3.8° 2θ, 7.6° 2θ, 10.7° 2θ, 12.9° 2θ, 16.5° 2θ, 17.2° 2θ, 24.6° 2θ, 24.8° 2θ, 29.5° 2θ, 29.9° 2θ, and 31.1° 2θ, ± 0.2° 2θ; wherein preferably the compound has at least three peaks or at least four peaks from the second set of peaks, such compound also being designated herein as "Form A" of (N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide hydrochloride).

[0012] In one embodiment, the compound has all of the peaks from the first peak set and / or the second peak set, such compound is also designated herein as "Form A" of (N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide hydrochloride).

[0013] In one embodiment, the compound is obtained by irradiation with Cu-Kα-radiation (Cu-Kα) and has the XRPD spectrum shown below:

[0014] [ka]

[0015] Such compounds are also designated herein as "Form A" of (N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide hydrochloride).

[0016] In one embodiment, the compound has a differential scanning calorimetry (DSC) thermogram in the range of 115°C to 150°C, preferably in the range of 135°C to 148°C, more preferably in the range of 135°C to 146°C, even more preferably in the range of 140°C to 146°C, even more preferably in the range of 144°C to 146°C, even more preferably about 145°C, and most preferably about 145.8°C.

[0017] In one embodiment, the compound has a differential scanning calorimetry (DSC) thermogram as shown below:

[0018] [ka]

[0019] In one embodiment, the compound is prepared by a method comprising the steps of: - providing, in any order, a defined amount of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide free base and a defined amount of hydrochloric acid, such that a 1:1 stoichiometric ratio of said free base to said hydrochloric acid is provided; - dissolving the free base in a suitable solvent or mixture of solvents selected from methanol, ethanol, tetrahydrofuran (THF), acetone, water and mixtures of water with any of methanol, ethanol, tetrahydrofuran (THF) and acetone; and, optionally, adding 1-5 reaction volumes of water; - adding about half of the specified amount of hydrochloric acid; - adding a seeding amount of Form A of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide hydrochloride (such Form A being as defined herein, e.g. in any of claims 1 to 4); thereby promoting the formation and precipitation of Form A; adding the remaining half of the specified amount of hydrochloric acid over a period of 30 minutes to 5 hours; - stirring for a defined period of time ranging from 30 min to 2 h, preferably from 30 min to 1 h; - adding water in an amount of 5 to 15 reaction volumes, preferably about 10 reaction volumes, over a period of 1 to 20 h, preferably over a period of 2 to 10 h; Optionally isolating the precipitated Form A, preferably by filtration, sieving or solvent evaporation.

[0020] In a further aspect, the present invention also relates to a method for preparing a compound as defined herein, comprising the steps of: - providing, in any order, a defined amount of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide free base and a defined amount of hydrochloric acid, such that a 1:1 stoichiometric ratio of said free base to said hydrochloric acid is provided; - dissolving the free base in a suitable solvent or mixture of solvents selected from methanol, ethanol, tetrahydrofuran (THF), acetone, water and mixtures of water with any of methanol, ethanol, tetrahydrofuran (THF) and acetone; and, optionally, adding 1-5 reaction volumes of water; - adding about half of the specified amount of hydrochloric acid; - adding a seeding amount of Form A of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide hydrochloride (such Form A being as defined herein, e.g. in any of claims 1 to 4); thereby promoting the formation and precipitation of Form A; adding the remaining half of the specified amount of hydrochloric acid over a period of 30 minutes to 5 hours; - stirring for a defined period of time ranging from 30 min to 2 h, preferably from 30 min to 1 h; - adding water in an amount of 5 to 15 reaction volumes, preferably about 10 reaction volumes, over a period of 1 to 20 h, preferably over a period of 2 to 10 h; Optionally isolating the precipitated Form A, preferably by filtration, sieving or solvent evaporation.

[0021] In a further aspect, the present invention also relates to a pharmaceutical composition comprising at least one compound as defined herein, together with at least one pharma- ceutically acceptable carrier, excipient and / or diluent.

[0022] In one embodiment of the pharmaceutical composition, it further comprises at least one other pharma- ceutical active agent.

[0023] In a further aspect, the present invention also relates to a compound or a pharmaceutical composition as defined herein for use in the treatment of a disease selected from a hyperproliferative disease, an inflammatory disease and a neurodegenerative disease.

[0024] In one embodiment of the compound or pharmaceutical composition for such use, the hyperproliferative disease is cancer, preferably adenocarcinoma, acoustic neuroma, acute lymphocytic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, ampullary carcinoma, basal cell carcinoma, bile duct carcinoma, bladder cancer, bone cancer, osteosarcoma and malignant fibrous histiocytoma, brain stem glioma, brain tumor, central nervous system atypical teratoid / rhabdoid tumor, craniopharyngioma, ependymoblastoma, ependymoma, medulloblastoma, medulloepithelioma, pineal parenchymal tumor of intermediate differentiation, supratentorial primitive neuroectodermal tumor, Tumors and pineoblastoma, brain and spinal cord tumors, breast cancer, urachal tumors, Burkitt's lymphoma, carcinoid tumors, choroidal melanoma, gastrointestinal cancer, central nervous system lymphoma, cervical cancer, body cancer, chordoma, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, desmoid tumors, mycosis fungoides, endometrial cancer, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma family tumors, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, ear tumors, intraocular melanoma, retinoblastoma, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumors, gastrointestinal ductal stromal tumors, gastrointestinal stromal cell tumors, gynecological tumors, ovarian germ cell tumors, gestational trophoblastic tumors, gliomas, gallbladder cancer, hairy cell leukemia, head and neck cancer, cardiac cancer, hepatocellular carcinoma, histiocytosis, hypopharyngeal cancer, hematological tumors, pancreatic islet cell tumors (endocrine pancreas), renal cell carcinoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, non-small cell lung cancer, small intestinal tumors, small cell lung cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, primary central nervous system lymphoma, macroglobulinemia, malignant fibrous histiocytoma and osteosarcoma of bone, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cervical Cancer Occult Primary, Spinal Cord Tumors, Multiple Endocrine Neoplasia Syndromes, Myelodysplastic Syndromes, Myelodysplastic / Myeloproliferative Neoplasms, Myeloid Leukemia, Multiple Myeloma, Myeloproliferative Disorders, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Oral Cavity Cancer, Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer, Ovarian Epithelial Cancer, Ovarian Low-Grade Tumor, Oligodendroglioma, Plasmacytoma, Pancreatic Cancer, Papillomatosis, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pituitary Tumors, Plasmacytoma / Multiple Myeloma, Pleuropulmonary Blastoma, Prostate Cancer, Rectal Cancer, Renal Cell Carcinoma, Transitional Cell Carcinoma, Respiratory Tract Cancer, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma, Skin Testicular Cancer, Ewing's Sarcoma,Kaposi's sarcoma, uterine sarcoma, non-melanoma skin cancer, melanoma skin cancer, skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous cell cervical cancer, gastric cancer, soft tissue tumors, testicular cancer, pharyngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, testicular cancer, pregnancy cancer, urinary tract tumors, ureter and renal pelvis cancer, urethral cancer, urothelial carcinoma, uterine cancer, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia and Wilms' tumor, tumors causing effusion in potential body spaces, pleural effusion, pericardial effusion, ascites (also known as ascites), giant cell tumor (GCT), GCT of bone, pigmented villonodular synovitis (PVNS), tenosynovial giant cell tumor (TGCT), TGCT of tendon sheath (TGCT-TS),

[0025] In one embodiment of the compound or pharmaceutical composition for such use, the inflammatory disease is selected from osteoarthritis, inflammatory bowel syndrome, transplant rejection, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease, emphysema, Kawasaki disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, atherosclerosis, primary progressive multiple sclerosis, Tensie, type I diabetes, type II diabetes, insulin resistance, hyperglycemia, obesity, lipolysis, hypocreocinoic hyperplasia, osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e.g., osteomyelitis), periprosthetic or wear debris-mediated osteolysis, endometriosis, inflammatory pain, chronic pain, and bone pain.

[0026] In one embodiment of the compound or pharmaceutical composition for such use, the neurodegenerative disease is selected from Binswanger dementia, prosencephaly, microcephaly, cerebral palsy, congenital hydrocephalus, ascites, progressive supranuclear palsy, glaucoma, Wilson's disease, Alzheimer's disease and other dementias, Parkinson's disease (PD) and PD-related diseases, multi-infarct dementia, frontotemporal dementia, pseudo-dementia, prion diseases, motor neuron diseases, Huntington's disease, spinocerebellar ataxia, and spinal muscular atrophy.

[0027] In one embodiment of the compound or pharmaceutical composition for such use, the use is in combination with other pharma- ceutical active drugs or treatments, in particular radiation therapy, chemotherapeutic agents, targeted drugs and immune checkpoint inhibitors.

[0028] In a still further aspect, the present invention relates to a method for the treatment of a disease selected from a hyperproliferative disease, an inflammatory disease and / or a neurodegenerative disease, comprising the administration of a compound as defined herein or a pharmaceutical composition as defined herein.

[0029] In a still further aspect, the present invention relates to the use of a compound as defined herein for the manufacture of a medicament for the treatment of a disease selected from a hyperproliferative disease, an inflammatory disease and / or a neurodegenerative disease.

[0030] In both of the above aspects, the disease selected from a hyperproliferative disease, an inflammatory disease and / or a neurodegenerative disease, the compound and the pharmaceutical composition are as defined herein.

[0031] As used herein, the term "Q702" refers to the compound N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide. Similarly, as used herein, the terms "Q702 salt" or "Q702 HCl" or "Q702 HCl salt" refer to the common salt or HCl form or HCl salt of such compound, respectively.

[0032] As used herein, the term "Q702 HCl Form A" refers to a particular crystalline form of Q702 HCl defined by various peaks in an XRPD spectrum, or its overall XRPD spectrum. Such peaks and spectrum of such Form A are outlined and described herein, e.g., in any of claims 1-4, or in FIG. 8.

[0033] As used herein, the term "seed amount" or "seed amount of form A" is meant to refer to any amount of Q702 form A suitable and sufficient to act as nucleation sites or points for the crystallization of Q702 HCl form A or to promote the growth of more crystals of Q702 HCl form A.

[0034] A person skilled in the art will be able to determine and specify such amounts, taking into account the reaction conditions and reaction scale selected in each case. Seeding crystallisation is described, for example, in Parambil, 2017, “ Engineering Crystallography: From Molecule to Crystal to Functional Form (pp.235-245) “ (DOI: 10.1007 / 978-94-024-1117-1_13 )

[0035] Further, see the attached figures. [Brief description of the drawings]

[0036] [Figure 1] FIG. 1 shows the XRPD spectra of the different Q702 HCl salt forms identified in the course of this invention, namely, forms A through F (top to bottom) in FIG. 1a, forms G through L (top to bottom) in FIG. 1b, and forms M through R (top to bottom) in FIG. 1c. [Diagram 2] FIG. 2 shows the XRPD spectrum of amorphous Q702 HCl prepared by rotary evaporation and freeze drying. [Diagram 3] FIG. 3 shows the XRPD spectrum of Q702 HCl salt form C. [Figure 4] FIG. 4 shows the TGA analysis data for Q702 HCl salt Form C (open pan). [Diagram 5] FIG. 5 shows the TGA analysis data for Q702 HCl salt Form C (closed pan). [Figure 6] FIG. 6 shows the 1H NMR spectrum of Q702 HCl salt form C. [Figure 7] FIG. 7 shows the DVS data for Q702 HCl salt form C. [Figure 8]FIG. 8 shows the XRPD spectrum of Q702 HCl salt form A. [Figure 9] FIG. 9 shows the TGA analysis data for Q702 HCl salt Form A (closed pan). [Figure 10] FIG. 10 shows the TGA analysis data for Q702 HCl salt Form A (open pan). [Figure 11] FIG. 11 shows the 1H NMR spectrum of Q702 HCl salt form A. [Figure 12] FIG. 12 shows the DVS data for Q702 HCl salt form A. [Figure 13] FIG. 13 shows the DVS kinetic plot of Q702 HCl salt form A. [Figure 14] FIG. 14 shows the XRPD spectra of Q702 HCl salt Form A before (top) and after (bottom) DVS analysis. [Figure 15] FIG. 15 shows the XRPD spectrum of Q702 HCl salt Form A before (top) and after (bottom) exposure to 40° C. and 75% RH. [Figure 16] FIG. 16 shows the 1H NMR spectrum of Q702 HCl salt Form A after 15 days of exposure to 40° C. and 75% RH. [Figure 17] FIG. 17 shows the results of crystallization run 1 of Example 3, where the top four traces show XRPD-spectra at different stages of the reaction, and the bottom trace (labeled "PS02379-129-NP.brmi") is a reference trace of Form A of Q702. [Figure 18] FIG. 18 shows the results of crystallization run 2 of Example 3, where the top four traces show XRPD-spectra at different stages of the reaction, and the bottom trace (labeled "PS02379-129-NP.brmi") is a reference trace of Form A of Q702. [Figure 19] FIG. 19 shows the results of crystallization run 3 of Example 3, where the top four traces show XRPD-spectra at different stages of the reaction, and the bottom trace (labeled "PS02379-129-NP.brmi") is a reference trace of Form A of Q702. [Figure 20] FIG. 20 shows the results of crystallization run 3 of Example 3, where the top four traces show XRPD-spectra at different stages of the reaction, and the bottom trace (labeled "PS02379-129-NP.brmi") is a reference trace of Form A of Q702. [Figure 21] FIG. 21 shows the results of crystallization run 3 of Example 3, where the top four traces show the XRPD-spectra of different stages of the reaction, and the bottom trace (labeled "HCl Pat C.txt") is a reference trace of Form A of Q702. [Figure 22] FIG. 22 shows the results of crystallization experiments 6-9 of Example 3, with the top four traces showing XRPD-spectra at different stages of the described experiment, and the bottom trace showing the reference trace of Form A, labeled "PS02379-129-NP.brmi." [Figure 23] FIG. 23 shows an overlay of the XRPD spectra of Q702 HCl salt form A after 24 months of exposure to 25° C. and 60% RH, where the top four traces show the XRPD-spectra at 24 months of exposure to 25° C. and 60% RH, and the middle trace (labeled "C18051198-N (C18051198-N18001M)") is the reference trace of Q702 form A, and the bottom trace shows Q702 form A as originally prepared, i.e., without 24 months of exposure. [Figure 24] FIG. 24 shows an overlay of the XRPD spectra of Q702 HCl salt form A after 6 months of exposure to 40° C. and 75% RH, with the top trace showing the XRPD-spectrum upon 24 months of exposure to 25° C. and 60% RH, and the bottom trace showing Q702 form A as originally prepared, i.e., without the 6 months of exposure. [Diagram 25] FIG. 25 shows an overlay of the mean plasma concentrations of Q702 in mice following oral administration of Q702 HCl Form A and Q702 free base, both at 30.0 mg / kg. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] In addition, reference is made to the following examples, which are provided by way of illustration and not by way of limitation.

[0038] Working Example Example 1 Screening for the best salt The compound N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide ("Q702") was prepared as described in WO 2019 / 229251.

[0039] This was used to identify stable crystalline salts for development as therapeutic drug forms. This approach produced solids under a wide and diverse range of nucleation conditions designed to mimic the process conditions and solvents used during development and formulation. To this end, solvent-based experiments were performed, specifically evaporation experiments, steam stress experiments (room temperature and 40 °C), and slurry experiments (room temperature and 40 °C). All solids from these experiments were analyzed by XRPD and the resulting patterns / morphologies were compared to those exhibited by the starting material. When sufficient material was available, further analysis (e.g., by NMR or thermogravimetric analysis (TGA)) was performed on solids with new XRPD patterns / morphologies. Additionally, the salts were tested for their solubility in various solvents and aqueous solutions.

[0040] More specifically, the following screening methods were performed: Salt Screening Method Experiments were performed at a 1:1 stoichiometry (salt former:free acid) on a .about.30 mg scale.

[0041] evaporation Solutions of Q702 were prepared in each solvent and filtered through a 0.2 μm PTFE filter. The filtered solutions were allowed to evaporate in vials covered with perforated aluminum foil at room temperature in a fume hood. The resulting solids were analyzed by XRPD.

[0042] Slurry Experiments Sufficient Q702 salt (amorphous / disordered salt) was added to a given solvent at the desired temperature (20 or 40 °C) until undissolved solids remained. The vial was sealed and the slurry was maintained at the selected temperature and agitated by magnetic stirring for 1 to 11 days. The solids were isolated by centrifugation and air-dried before analysis by XRPD.

[0043] Steam Stress Approximately 30 mg of Q702 salt (amorphous / disordered salt) was added to a vial and placed unsealed in a larger sealed container containing 1 mL of the selected solvent. After 1-6 days, samples were removed and analyzed by XRPD. Vapor stress was performed at room temperature and at 40°C.

[0044] In addition, the following techniques for analysis were used: Techniques for the analysis of produced salt. X-ray powder diffraction (XRPD) XRPD analysis was performed using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray tube and a Pixcel detector system. Isothermal samples were analyzed in transmission mode and held between low density polyethylene films. The default XRPD program was used (range 3-40°2θ, step size 0.013°, count time 22 s, ~5 min run time as well as longer runs at (count time 46 s, ~11 min run time), (count time 97 s, ~22 min run time) and (count time 591 s, ~2 h run time). XRPD forms were filtered, manipulated and indexed using HighScore Plus 2.2c software.

[0045] Differential Scanning Calorimetry (DSC) DSC analysis was performed on a Perkin Elmer Jade Differential Scanning Calorimeter. Accurately weighed samples were placed in crimped aluminum pans (i.e., sealed but not airtight). Each sample was heated under nitrogen at a rate of 10°C / min up to 300°C. Indium metal was used as the calibration standard. Temperatures were reported to the nearest 0.01 degree at the onset of the transition.

[0046] Thermogravimetric differential thermal analysis (TG / DTA) Thermogravimetric analysis was performed on a Mettler Toledo TGA / DSC1 STARe. Calibration standards were indium and tin. Samples were placed in aluminum sample pans, inserted into the TG furnace, and accurately weighed. The heat flow signal was allowed to stabilize at 30°C for 1 minute, then heated to 300°C at a rate of 10°C / min in a stream of nitrogen.

[0047] Dynamic Vapor Sorption (DVS) Dynamic vapor sorption (DVS) was performed using a Hiden Analytical Instruments IGAsorp Vapour Sorption Balance. Approximately 30 mg of sample was placed in a wire mesh vapor sorption pan and placed on the IGAsorp vapor sorption balance held at 25°C ± 0.1°C. Samples were subjected to a step profile of 10% increments from 0 to 90% RH, followed by desorption in 10% increments from 90% RH to 0% RH. Equilibrium criteria were set at 99.0% step completion within a minimum of 60 minutes and a maximum of 5 hours for each increment. Weight change was monitored during the adsorption cycle to determine the hygroscopicity of the sample. Data collection intervals were in seconds.

[0048] 1 H / 13 C nuclear magnetic resonance spectroscopy (NMR) NMR analyses were performed on a Bruker 500 MHz instrument in methanol-d4 or DMSO-d6, and instrumental parameters are given in the relevant spectral plots.

[0049] Solubility measurement Solubility was determined by a) solubility estimation by aliquot addition and b) HPLC: a) Estimation of solubility by adding aliquots Aliquots of test solvent were added to accurately weighed samples (~20 mg) of Q702 material, e.g., a particular Q702 salt, such as the isethionate or hydrochloride salt of Q702, at room temperature. Aliquot volumes were typically 100-1000 μL. Complete dissolution of the test material was determined by visual inspection. Solubility was estimated from these experiments based on the total amount of solvent used to provide complete dissolution.

[0050] If dissolution had not occurred after addition of the final aliquot of solvent (usually ∼50 volumes of solvent), the sample was subjected to two cycles of the following temperature cycling regime in a Clarity crystallization station: Heat from 20°C to within 3°C of the boiling point of the solvent (or 100°C, whichever is lower) at 0.5°C / min. Cool down to 20℃ at 0.2℃ / min. ·Agitation speed 600 rpm.

[0051] From the infrared (IR) transmission data of the sample vials, dissolution and precipitation events were recorded as the points of complete IR transmission and the onset of IR turbidity, respectively.

[0052] Samples were kept at room temperature for 18 hours to maximize the possibility of precipitation. Any recoverable solids were analyzed by XRPD. Solubility values ​​for Q702 materials are expressed as ranges and rounded to the nearest whole number.

[0053] b) HPLC for determination of equilibrium solubility The HPLC method used to determine the equilibrium solubility in various solvents is outlined. The retention time of Q702 was typically 18.4±0.143 minutes. A phenomenex Kinetex column with a particle size of 2.6 μm was used.

[0054] result Solubility of different Q702 salts in water / aqueous solutions Regarding solubility, the various salts formed exhibited the following solubility values ​​in aqueous solution, as summarized in Table 1:

[0055] [Table 1]

[0056] 1. The crystalline salt was slurried overnight in deionized water (pH = 6.8) and the pH of the solution was measured. 2. The crystalline salt was slurried in deionized water (pH = 6.8) overnight and the solid was filtered and analyzed by XRPD. 3. The solution was crushed after filtration and redissolved in DMSO and CHCl. ​​The precipitation may be due to the formation of less soluble salt forms, such as hydrates.

[0057] As can be seen from Table 1, the isethionate salt showed the highest solubility in aqueous solution, but it was not possible to reproduce such salts, especially for XRPD analysis, much less on a scale suitable for manufacturing purposes. The same applies to the ketoglutarate and ethanesulfonate salts ("esylate salts"). The phosphate, citrate, ethanedisulfonate and oxalate salts have substantially reduced aqueous solubility, and the sulfate and tosylate salts are among the least aqueous soluble salts, while the hydrochloride salt showed a solubility of 1.95 mg / mL, which is by far the best of all the salts produced. Exactly why this is the case remains to be elucidated. The fact that the hydrochloride salt is so much superior to, for example, the sulfate (0.27 mg / mL) and tosylate (0.026 mg / mL) salts, which have the lowest aqueous solubility, was quite surprising and could not be expected from other systems such as albendazole, where the HCl, sulfate and tosylate salts have rather similar aqueous solubility values ​​(Paulekuhn et al, 2013, Pharmazie, volume 68, pages 555-5).

[0058] Example 2 Q702 HCl salt polymorphism screen Based on the surprising findings of Example 1, the inventors further investigated the hydrochloride salt of Q702 to understand whether different polymorphic forms exist and to identify stable forms with suitable properties. To this end, crystallization experiments were performed and the resulting solids were analyzed by XRPD with the pattern / morphology compared to that exhibited by the starting material. To identify different forms of the HCl salt of Q702, the following screening method was performed:

[0059] Screening Methods Temperature Cycling Test solvent (1 mL) was added to a sample of Q702 HCl salt (~20 mg) at room temperature and the following temperature program was cycled twice using a Clarity crystallization station: - Heat from 20°C to 50-80°C (depending on the boiling point of the solvent) at 1°C / min Cool to 20°C at -1°C / min - Stirring speed - 600 rpm

[0060] Slow evaporation Solutions of Q702 HCl salt were prepared in each solvent and filtered through a 0.2 μm PTFE filter. The filtered solutions were allowed to evaporate in a vial covered with perforated aluminum foil at room temperature in a fume hood. The resulting solids were analyzed by XRPD.

[0061] Slurry Experiments Sufficient Q702 HCl salt (crystalline and / or amorphous) was added to a given solvent at the desired temperature (5, 20, 40 or 50 °C) until undissolved solids remained. The vial was sealed and the slurry was maintained at the selected temperature and agitated by magnetic stirring for 5-8 days. The solids were isolated by centrifugation and dried in air before analysis by XRPD.

[0062] Vapor diffusion The solution of Q702 HCl salt was filtered through a 0.2 μm PTFE filter into a clean vial. The vial was placed unsealed within a larger vial containing an aliquot of antisolvent. The larger vial was sealed and left undisturbed under ambient conditions. The samples did not form solids and therefore they were allowed to evaporate in air prior to analysis by XRPD.

[0063] Sonication of Pastes Q702 HCl salt (~20 mg) was added to a vial along with 50-150 μL of the chosen solvent to form a paste. The mixture was sonicated at 70% intensity using a Cole-Parmer 130W ultrasonic processor using a pulse program. When the solid had dissolved at room temperature, the sample was left uncapped to evaporate. The wet paste recovered from these experiments was analyzed using XRPD.

[0064] Steam Stress Approximately 20 mg (crystalline and / or amorphous) was added to a vial and placed unsealed in a larger sealed container containing 1 mL of the selected solvent. After 7-8 days, the sample was removed and analyzed by XRPD.

[0065] Moisture stress using crystalline materials Approximately 25 mg of Q702 HCl salt was added to four individual vials and placed, unsealed, in the following relative humidity chamber (a closed cabinet in which relative humidity conditions are controlled by a supersaturated salt solution) for 8 days prior to analysis by XRPD: -Chamber 1 - 23% relative humidity - Chamber 2 - 59% relative humidity - Chamber 3 - 75% relative humidity - Chamber 4 - 98% relative humidity

[0066] Moisture stress using amorphous materials Approximately 20 mg of amorphous Q702 HCl salt was added to two separate vials and placed, unsealed, in the following relative humidity chamber (a closed cabinet in which relative humidity conditions are controlled by a supersaturated salt solution) for 6 days prior to analysis by XRPD: -Chamber 1 - 59% relative humidity - Chamber 2 - 40°C and 75% relative humidity

[0067] Thermal Stress Approximately 20 mg of amorphous Q702 HCl salt was added to the vial, flushed with nitrogen, sealed, and placed in a heater block at 50° C. for 7 days prior to analysis.

[0068] compression Q702 HCl salt (50 mg) was added to a KBr pellet die and compressed overnight at ∼740 MPa using a hydraulic press The resulting solid disk was removed from the press and immediately analyzed by XRPD.

[0069] Crushing Approximately 50 mg of Q702 HCl salt was added to the grinding chamber equipped with agate grinding balls. The material was ground for 3 x 2 minutes at a frequency of 25 Hz using a Retsch MM200 mixer mill. Periodically, grinding was stopped and the powder adhering to the grinding chamber was scraped off. The resulting ground material was analyzed using XRPD.

[0070] Desolvation experiments The samples were heated to 100-116 °C on a hot plate and held under a nitrogen flow for 20-40 min. The samples were cooled to room temperature and immediately analyzed by XRPD.

[0071] Techniques for the analysis of produced salt. For the analysis of the different forms, X-Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC), Thermogravimetry / Differential Calorimetry (TG / DTA), all as described in Example 1, 1 H / 13A variety of analytical techniques were used, including C nuclear magnetic resonance spectroscopy (NMR), dynamic vapor sorption (DVS), solubility estimation by aliquot addition, and equilibrium solubility measurements by HPLC.

[0072] In addition, the following additional analytical techniques were used: Volumetric Karl Fischer (KF) analysis for moisture content Volumetric KF analysis was performed using a Mettler Toledo V30 KF titrator. A measured amount of solvent was added to the KF cell via syringe. The solution was stirred and then the water content of the sample was determined by automatic titration against a standard KF reagent titrant.

[0073] result 1. Solubility of Q702 HCl salt in different solvents Regarding solubility in different solvents, the solubility of Q702 HCl salt was estimated in nine solvent systems using the aliquot addition method. Q702 HCl salt had a solubility of >20 mg / mL in four solvents at room temperature. The solubility data obtained is shown in Table 2. From these data and the solubility screen, the solvents were classified into three groups outlined in the following table to define the scope of the screening experiments.

[0074] [Table 2]

[0075] [Table 3]

[0076] 2. Polymorphism Screening The inventors attempted to generate solids under a wide and diverse range of nucleation conditions designed to mimic the process conditions and solvents used during development and formulation.

[0077] All solids obtained from crystallization experiments were analyzed by XRPD, and the resulting patterns / forms were compared to those exhibited by the starting materials. New XRPD patterns / forms were assigned alphabetical descriptors in the order of discovery (Form B, Form C, etc.). If sufficient material was available, further analysis (e.g., NMR or TGA) was performed on solids with new XRPD patterns / forms to tentatively assign the new patterns / forms as polymorphs, solvates, hydrates, degradants, or mixtures thereof.

[0078] Formation of amorphous materials The primary goal of the experimental program was to obtain amorphous materials for screening, since the inventors believe that such solids have no "memory" and that subsequent stresses will maximize the chances of discovering new crystalline forms. In cases where amorphous materials are highly unstable at room temperature, disordered (less crystalline) materials can be used instead.

[0079] Amorphous material was isolated by lyophilization. A solution of Q702 free base material (7.5 g batch) in a 50:50 mixture of acetonitrile (ACN):water containing 0.5M HCl acid was prepared, frozen in liquid nitrogen, and dried under vacuum. A white material was obtained, which was shown to be amorphous by XRPD (Figure 2). 1 The 1 H NMR spectrum (data not shown) was consistent with the molecular structure and no solvent was detected.

[0080] Solvent-Based Screening Techniques Solvent-based experiments were performed on a scale of approximately 20 mg in glass vials. The methods used are described in more detail above. We believe that varying the nucleation conditions in this way maximizes the chances of discovering new forms and also maximizes the frequency of occurrence of these forms under the prevailing processing conditions. Different patterns / forms emerged from the different experiments and were classified into 18 different forms A-R by analysis obtained by XRPD.

[0081] A total of 18 unique crystalline solids (summarized in Table 4) were obtained during this study and designated Forms A–R based on the XRPD patterns / morphologies shown in Figures 1a–1c. Amorphous material was also produced from lyophilization of Q702 free base in ACN:water containing 0.5M HCl.

[0082] [Table 4]

[0083] More specifically, in generating these various forms, the following screening techniques were employed:

[0084] Temperature Cycling The samples were subjected to the temperature cycling program further outlined above and the results are shown in Table 5. Three new solids were obtained, designated Forms F, G and H. HCl Form F was isolated from EtOAc, Form G was isolated from acetone and Form H was isolated as a mixture from ACN.

[0085] [Table 5]

[0086] Evaporation in the vial Slow evaporation of the Q702 HCl salt solution was performed as further described above. The results are shown in Table 6. Two new solids were obtained, designated Forms E and G. Form E was isolated twice using both EtOH and MeOH, while Form G, with additional peaks at 7.9 and 8.9° 2θ, was isolated using acetone. Amorphous material was obtained from DMSO, while a mixture of amorphous and HCl Form C material was obtained from DCM.

[0087] Vapor diffusion experiments at room temperature did not produce any solid material and were allowed to evaporate in air for several days (see Table 7). Two new solids were obtained, designated Form L and Form P. Disordered Form L was isolated from experiments in EtOH using MTBE as the anti-solvent, while Form P was isolated from experiments in DMSO using MTBE as the anti-solvent.

[0088] Vapor diffusion experiments at 40° C. did not produce any solid material and were allowed to evaporate in air for several days (see Table 8). One experiment in EtOH using water as the anti-solvent produced Form B material minus the peak at 9.8° 2θ. One new solid, designated Form O, was isolated from DMSO using water as the anti-solvent. An experiment in MeOH using water as the anti-solvent gave disordered Form C with an additional peak at 8.0° 2θ.

[0089] [Table 6]

[0090] [Table 7]

[0091] [Table 8]

[0092] Slurry experiment at 5°C Suspensions of amorphous Q702 HCl salt in various solvents were slurried at 5°C for 7-8 days and then isolated and analyzed by XRPD (see Table 9). Two runs, one in MTBE and one in a 5:45 mixture of DCM:heptane, produced amorphous material. Three other runs in a 5:45 mixture of ethanol:water, a 5:45 mixture of acetone:water and a 5:45 mixture of THF:water contained Form B material with additional peaks. The run in acetone gave Form G material, while Form F was isolated three times in EtOAc, MEK (methyl ethyl ketone) and iPrOAc (isopropyl acetate).

[0093] [Table 9]

[0094] Slurry experiment at 20℃ Suspensions of Q702 free base material in various concentrations of acid stock solutions were stirred at 20° C. for 5 days, then isolated and analyzed by XRPD (see Table 10).

[0095] [Table 10]

[0096] Slurry experiments at 40°C and 50°C Suspensions of Q702 HCl salt in various solvents were stirred at 50° C. for 6 days before being isolated and analyzed by XRPD (see Table 11). One new solid, designated Form K, was isolated from a 1:3 mixture of DMSO:MTBE. Form A was isolated from two experiments, a 1:3 mixture of EtOH:water and a 1:3 mixture of MeOH:water. Form C was obtained from two experiments in MTBE and MIBK, while Form H was isolated from ACN. One experiment in acetone at 40° C. yielded disordered Form G material.

[0097] [Table 11]

[0098] Vapor diffusion Vapor diffusion experiments were performed as described further above, however, none of the experiments produced any solid material.

[0099] Vapor diffusion at 40°C Vapor diffusion experiments were carried out at 40° C. as further described above, however all experiments did not produce any solid material.

[0100] Sonication Suspensions of amorphous Q702 HCl salt were prepared in various solvents and subjected to the pulse program as outlined above. Samples were stored at 5° C. prior to isolation and analysis by XRPD (see Table 12). For two experiments, one in a 20:80 mixture of acetone:MTBE and one in DCM, the sample remained amorphous material. Disordered forms C, F and H were isolated from iPrOAc, ACN and EtOAc. One experiment in THF yielded form C material. Two new solids, designated form I and form M, were obtained. Form I with amorphous content was isolated from ethanol, while form M was isolated from dioxane.

[0101] [Table 12]

[0102] 1. The experiment was dissolved in solution and refrigerated. The solid that formed was then analyzed by XRPD.

[0103] Solid-State Screening Techniques Non-solvent-based (solid state) screening methods include ball milling, compression heat, steam and moisture stress (see further above). These techniques mimic conditions that may be encountered in large-scale processing, for example on hot reactor walls and during drying and tabletting operations. The inventors believe that varying the nucleation conditions in this way maximizes the chances of discovering new morphologies, and also maximizes the frequency of occurrence of these morphologies under typical processing conditions.

[0104] compression A die press was used to mimic the uniaxial stresses that occur during tablet compression, which can reach up to 300 MPa. To limit possible morphological changes at 1 bar pressure, samples were analyzed immediately after depressurization (see Table 13). Diffractograms (not shown) show that the samples consist of disordered HCl C material.

[0105] [Table 13]

[0106] Crushing A ball mill was used to mimic the effects of milling that occurs during formulation processes such as dry blending and wet granulation. Milling was performed on a sample of the Q702 HCl salt to limit the possibility of further changes in morphology (see Table 14). Samples were analyzed immediately after milling was completed. The resulting XRPD (not shown) reveals that the HCl Form C material becomes more disordered when dry milled.

[0107] [Table 14]

[0108] Desolvation Desolvation of solvates or hydrates can be a useful method for screening for novel solid forms. Samples were heated to the desired temperature for 20-40 minutes under a nitrogen flow. The results are shown in the table below. Q702 HCl Form C material remained in Form C, while Q702 HCl Form A+C remained in Form A+C.

[0109] [Table 15]

[0110] Thermal Stress The amorphous Q702 HCl salt was heat stressed at 50° C. under nitrogen in a sealed vial for 7 days and analyzed by XRPD. As shown in Table 16, the sample remained amorphous.

[0111] [Table 16]

[0112] Steam Stress X-ray amorphous material produced from freeze-drying was analyzed by XRPD after exposure to air saturated with solvent vapor for 7-8 days. Because amorphous material has lost long-range order, it is in a high-energy state. Exposure to vapor plasticizes the solid, allowing restricted molecular mobility, and is therefore a useful method of producing metastable solvates and hydrates.

[0113] For the steam stress experiments performed with the amorphous material, two experiments yielded disordered Form C material. Two experiments, one in a 20:80 mixture of EtOH:ethyl acetate and one in EtOAc, produced Form F material. Form G material was isolated from MEK while disordered Form G material was isolated from THF. One experiment in a 50:50 mixture of EtOH:MTBE produced disordered Form I+A material. Form L material was obtained from a 50:50 mixture of MeOH:THF. One new solid designated Form N was isolated from a 20:80 mixture of DMSO:water. The results are shown in Table 17.

[0114] Steam stress experiments were also performed at room temperature using Q702 HCl salt. One experiment was performed using Q702 free base material. The results are shown in Table 18. Form I material was isolated from ethanol while disordered Form H material was isolated from ACN. One experiment in a 13:1 mixture of THF:water produced disordered Form C material while an experiment in MTBE produced Form C with amorphous inclusions. One experiment was performed using Q702 free base material with 0.5M HCl in water. MeOH was used as the solvent and produced Form L material.

[0115] [Table 17]

[0116] [Table 18]

[0117] Moisture Stress The X-ray amorphous material produced from freeze drying was exposed to various controlled humidity conditions for 6 days prior to analysis by XRPD. The results are shown in Table 19. Both samples remained amorphous material. A weight gain of 6.13% was observed for the sample stressed at 40° C. / 75% RH (see Table 20), suggesting that the material is hygroscopic.

[0118] Humidity stress experiments were also performed using crystalline Q702 HCl Form C material and stressed for 8 days. The results are shown in Table 21. All samples remained as Q702 HCl Form C material. A weight gain of 2.99% was observed for samples stressed at 98% RH (see Table 22). A weight loss of 11.05% was observed for samples stressed at 75% RH stress, while a weight loss of 1.96% was observed at 40° C. / 75% RH.

[0119] [Table 19]

[0120] [Table 20]

[0121] [Table 21]

[0122] [Table 22]

[0123] Conclusions from polymorphism screening Approximately 80 experiments were performed using solvent and non-solvent based techniques. During this work, 18 unique crystalline solids (see Table 4) were observed and designated Forms A through R. Amorphous material was also produced from lyophilization of Q702 free base in ACN:water with 0.5M HCl.

[0124] Using all of the methodologies described herein, 18 different patterns / morphologies were identified and prepared using different techniques, as summarized in Table 23.

[0125] [Table 23]

[0126] The amorphous form of the HCl salt of Q702 represents the starting point for various other crystalline forms. However, ultimately, except for forms A, B, C, D, E, Q and R, all other forms produced in this example are solvates. Furthermore, the unsolvated forms B, D, E, Q and R have low crystallinity; therefore, the two most promising crystalline patterns / forms were the unsolvated forms A and C.

[0127] Example 3 Q702 Comparison of HCl salt forms A and C Q702 Preparation of HCl salt form C Preparation of samples with Form C Q702 free base (~500 mg) was weighed into a glass vial. 0.5M HCl (1.883 mL) was added to inhibitor-free THF (9.38 mL). The sample was evaporated to dryness under nitrogen. Once crystallization began, it was seeded with HCl Form C material. The material was allowed to dry in air. After drying, it was analyzed by XRPD: Forms B+C.

[0128] A 20:80 mixture of acetone:water (3333 μL) was added to the sample and stirred at 40° C. for 2 days. The sample was centrifuged for 3 minutes and the liquid was decanted. The sample was allowed to dry in air and then analyzed by XRPD: HCl C material.

[0129] Q702 Characterization of HCl Salt Form C Material Q702 HCl salt Form C material was analyzed by XRPD, TGA, DSC, 1 H NMR, 13 It was characterized by a variety of analytical techniques including C NMR, PLM, DVS, FT-IR, UV-vis, IDR and CHN elemental analysis. XRPD data showed that the material was crystalline but disordered and contained some amorphous inclusions even after attempts to improve the crystallinity (see Figure 3).

[0130] Different batches of Form C material were analyzed by TGA using open pan and / or closed pan configurations to better understand the nature of the material.

[0131] Using an open pan with a lid, the sample lost 8% weight during TG analysis from 30 to 167 °C (see Figure 4), followed by an additional 8% weight loss from 167 to 257 °C. The total weight loss is equivalent to 6 molar equivalents of water. The HCl content of the 1:1 salt is 6.4%, so the weight loss is too large for HCl loss. This suggests that the HCl salt Form C material is likely hydrated. Another sample lost 5.7% weight from 30 to 166 °C, and then an additional 6.1% weight loss from 167 to 236 °C. The total weight loss is equivalent to 4 molar equivalents of water. The difference in weight loss may be due to the samples not being completely dried.

[0132] Much smaller weight losses were seen in the closed pan configuration because the pan lid retarded evaporation. One sample (see Figure 5) showed a 4.8% weight loss from 74 to 175 °C, and a further 6.3% weight loss from 178 to 279 °C. Another sample showed a 3% weight loss from 30 to 90 °C during TG analysis, followed by a 22% weight loss from 90 to 120 °C, likely due to moisture loss (up to 3 molar equivalents). However, this may be due to the sample being wet.

[0133] Hygroscopicity was assessed by DVS analysis (see Figure 7). The isothermal plot shows that the total weight gain between 40 and 80% RH was 0.7% w / w, and based on the European Pharmacopoeia classification, the sample is slightly hygroscopic. XRPD analysis of the sample after DVS (data not shown) was consistent with that of HCl Form C, and no physical changes in the sample were detected.

[0134] HCl Form C was stressed at 40° C. / 75% relative humidity for 15 days. XRPD analysis showed that it remained as the HCl salt Form C. 1 1 H NMR spectrum showed that the sample conformed to the molecular structure and no solvent was detected (data not shown).

[0135] HCl Form C was desolvated on a hot plate under a nitrogen stream at 100° C. XRPD analysis indicated that the sample remained as HCl C material (data not shown).

[0136] Preparation of Form A of the HCl salt of Q702 Q702 HCl salt form A substance Form A material was produced from several different experiments as described in Table 24, although two samples were mixtures that also contained Form C material. Form A material was crystalline by XRPD analysis (see Figure 8).

[0137] [Table 24]

[0138] TG analysis of HCl Form A using a closed pan showed a continuous gradual weight loss from 60°C (see Figure 9). The large endotherm is likely due to melting with an onset temperature of 139°C. A weight loss of 4.2% was seen between 69 and 171°C and is equivalent to 1.4 molar equivalents of water. A second weight loss of 7.3% was seen between 171 and 279°C.

[0139] TG / DSC analysis of HCl Form A using an open pan showed a weight loss of 6.8% from 30 to 145 °C, equivalent to 2 molar equivalents of water (see Figure 10). A second weight loss of 6.9% was seen from 151 to 239 °C, likely due to melting. An onset was observed at 142 °C.

[0140] Form A material 1 The H NMR spectrum showed that the sample conformed to the molecular structure (see FIG. 11). No solvent was detected. A peak shift was observed compared to the spectrum of Q702 free base, suggesting that salt formation had occurred.

[0141] Hygroscopicity was assessed by DVS analysis (see Figures 12 and 13). The isothermal plot showed that the total weight gain between 40 and 80% RH was 0.5% w / w and based on the European Pharmacopoeia classification, the sample was slightly hygroscopic. XRPD analysis of the sample after DVS (see Figure 14) was consistent with that of HCl Form A and no physical changes in the sample were detected.

[0142] Form A was stressed at 40° C. / 75% for 15 days. XRPD analysis after stress showed that the material remained as Form A (see FIG. 15). 1 The H NMR spectrum showed that the sample conformed to the molecular structure (see FIG. 16). No solvent was detected. Therefore, this form was found to be absolutely stable under these conditions.

[0143] The A-form is the most stable of all forms studied and can be reproducibly produced on a large scale: Small scale preparation of Q702 HCl salt A slurry of Q702 in acetone and HCl / water was prepared by dissolving 10.0 g of Q702 free base in acetone and adding HCl solution in the specified amount shown below in Table 25. After filtration and drying, the crystal pattern / morphology changed to Form A.

[0144] [Table 25]

[0145] Preparation of Q702 HCl salt on medium scale A slurry of Q702 in acetone and HCl / water was prepared by dissolving 72 g of Q702 free base in acetone and adding HCl solution in the specified amount shown in Table 26. XRPD of the wet cake showed that Form C was obtained. After filtration and drying, 69.3 g of Q702 HCl salt was obtained as Form C with 99.8% HPLC purity and 88.3% assay yield.

[0146] [Table 26]

[0147] Thus, there appears to be scale-related or other factors that favor one form over the other. Therefore, we speculated that there may be a change in crystal form during the crystallization process, or that there may be some interconversion between the two forms, which may depend on various factors such as the rate of addition of the HCl solution. To test this further, we performed various crystallization experiments in different conditions, as outlined below.

[0148] Experiment A: Tracking the changes in crystal shape during the crystallization process In the crystallization experiments, 5 g of each of the five lots of Q702 free base was used to prepare the corresponding HCl salt, and the formation and / or change of each crystal form was followed in the crystallization experiments. For this, the addition time of aq. HCl was extended to 6 hours. During the addition of aq. HCl, the product Q702 HCl salt precipitated in a specific form, which was confirmed by XRPD. During the crystallization, in various experiments, seed crystals of Form A were added to the reaction to confirm whether such intermediate addition / seeding of Form A had any effect on the final form achieved. The various experiments, reaction conditions and results are summarized in Table 27 below.

[0149] [Table 27-1]

[0150] [Table 27-2]

[0151] [Table 27-3]

[0152] XRPD spectra at various stages of Runs 1-5 are shown in Figures 17-21. The traces shown in Figures 17-20 show various stages of Runs 1-4, respectively, in Table 27, with an additional reference trace of the reference XRPD spectrum of Form A (labeled "PS02379-129-NP.brml") in the bottom trace of each of Figures 17-20. In Figure 21, the corresponding reference trace of the reference XRPD spectrum of Form C (labeled "HCl Pat C.txt") is also displayed in the bottom trace of this Figure 21. On this scale, it can be seen that under the reaction conditions shown, Form A appears to be favored in Runs 1-4. In Run 5, Form C was favored and appears to have been present earlier in the reaction.

[0153] Experiment B: Investigating the interconversion of Forms A and C To test whether there is any interconversion between the different crystalline forms, the interconversion of the crystalline forms was studied by stirring 50 mg of Form A and 50 mg of Form C in mother liquor (Lot 1 in Form A mother liquor; Lot 2 in Form C mother liquor). Both gave the target Form A, and it can be concluded that Form A is more stable under these conditions (PS03606-51-N-1-P / Exp. 6, PS03606-51-N-2-P / Exp. 7).

[0154] Furthermore, two additional experiments were performed to evaluate whether form C could be converted to form A: in the first experiment, form C was subjected to recrystallization by dissolving it in acetone / H2O=1:1 (14 V) and adding water (21 V) to precipitate the solid at 20-25 °C (PS03606-52-N-1-P / experiment 8). In the second experiment, form C was prepared as a hot slurry in acetone / H2O=2:8 (10 V) at 40 °C (PS03606-52-N-2-P / experiment 9). XRPD of both experiments showed that the target form A was the result in both experiments (Figure 22).

[0155] In FIG. 22, the corresponding reference trace of the reference XRPD spectrum of Form A (labeled "PS02379-129-NP.brml") is also shown as the bottom trace in this FIG.

[0156] Form A of the Q702 HCl salt was tested for long term stability for 24 months. XRPD results showed that Form A was stable for up to 24 months (Table 28).

[0157] [Table 28]

[0158] Example 4 Pharmacokinetic studies In this example, a pharmacokinetic study is carried out by using Form A of the HCl-salt of Q702 and its free base (FB) in plasma after oral administration of such Form A and the free base to male SD rats.

[0159] The appropriate amount of Q702 HCl form A or free base was accurately weighed and mixed with the appropriate amount of vehicle (water) to obtain a clear solution or homogenous suspension. Male SD rats were administered a nominal dose of 30 mg / kg body weight. After dosing, 0.2 mL of blood was collected per time point at 0 h, 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h. For such blood collections, blood was collected from the jugular vein or other appropriate site of each animal into pre-chilled plastic microcentrifuge tubes containing 5 μL of 1000 IU heparin Na as an anticoagulant. Blood samples were processed to plasma by centrifugation at 3200 g for 10 min at approximately 4°C. Plasma was collected and transferred to pre-labeled polypropylene tubes, flash frozen on dry ice, and stored at or below -60°C until LC-MS / MS analysis. The LC-MS / MS method was performed using a calibration curve containing at least six non-zero calibration standards.

[0160] Plasma concentration versus time was plotted and analyzed by a noncompartmental approach using the Phoenix WinNonlin 6.3 software program. Relevant pharmacokinetic parameters, e.g., C for oral administration, max , T max , T 1 / 2 , AUC (0-t) was calculated according to route of administration (shown in Table 29 and Figure 25).

[0161] [Table 29]

[0162] Looking at the mean AUC-values, Form A of the HCl-salt of Q702 appears to have a plasma exposure level that is 33% higher than that of the free base.

[0163] Using relative bioavailability, this is: Relative bioavailability (%) = (AUC_test / AUC_ref) x (dose_ref / dose_test) x 100 where test = HCl-salt form A and ref = the free base of Q702 It is calculated as:

[0164] The relative bioavailability of Form A of the HCl-salt of Q702 is found to be 144.2% of that of the free base. This large difference in bioavailability is quite surprising.

Claims

1. The compound N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide hydrochloride has the formula 【Chemistry 1】 having and having at least one or several peaks from a first set of peaks in an X-ray powder diffraction (XRPD) spectrum obtained by irradiation with Cu-Kα-radiation (Cu-Kα), the first set of peaks being: 8.2° 2θ, 9.9° 2θ, 11.4° 2θ, 15.2° 2θ, 15.4° 2θ, 19.9° 2θ, 21.4° 2θ, 21.7° 2θ, 22.9° 2θ, 23.3° 2θ, 25.5° 2θ, 25.7° 2θ, 25.9° 2θ, 28.2° 2θ, and 28.7° 2θ, ±0.2° 2θ; wherein, preferably, the compound has at least two peaks, at least three peaks, at least four peaks, at least five peaks, at least six peaks or more peaks from the first set of peaks ("Form A" of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide hydrochloride).

2. having at least two peaks from a second set of peaks in an X-ray powder diffraction (XRPD) spectrum obtained by irradiation with Cu-Kα-radiation (Cu-Kα), the second set of peaks being: 3.8° 2θ, 7.6° 2θ, 10.7° 2θ, 12.9° 2θ, 16.5° 2θ, 17.2° 2θ, 24.6° 2θ, 24.8° 2θ, 29.5° 2θ, 29.9° 2θ, and 31.1° 2θ, ±0.2° 2θ; Preferably, the compound has at least three peaks or at least four peaks from the second set of peaks ("Form A" of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide hydrochloride) according to claim 1 .

3. The compound of any one of claims 1 to 2 ("Form A" of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide hydrochloride), wherein the compound has all peaks from the first peak set and / or the second peak set.

4. A compound according to any of the preceding claims ("Form A" of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide hydrochloride), obtained by irradiation with Cu-Kα-radiation (Cu-Kα) and having the XRPD spectrum shown below: 【Chemistry 2】

5. 13. A compound according to any preceding claim, having a Differential Scanning Calorimetry (DSC) thermogram exhibiting an endotherm with an onset temperature in the range of 115°C to 150°C, preferably in the range of 135°C to 148°C, more preferably in the range of 135°C to 146°C, even more preferably in the range of 140°C to 146°C, even more preferably in the range of 144°C to 146°C, even more preferably at about 145°C, and most preferably at about 145.8°C.

6. The compound of claim 5 having a differential scanning calorimetry (DSC) thermogram as shown below: 【Chemistry 3】

7. 2. A compound according to any of the preceding claims, prepared by a process comprising the steps of: - providing, in any order, a defined amount of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide free base and a defined amount of hydrochloric acid, such that a 1:1 stoichiometric ratio of said free base to said hydrochloric acid is provided; - dissolving the free base in a suitable solvent or mixture of solvents selected from methanol, ethanol, tetrahydrofuran (THF), acetone, water and mixtures of water with any of methanol, ethanol, tetrahydrofuran (THF) and acetone; and, if necessary, adding 1 to 5 reaction volumes of water; - adding about half of the specified amount of hydrochloric acid; - adding a seed amount of Form A of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide hydrochloride as defined in any one of claims 1 to 4, thereby promoting the formation and precipitation of Form A; - adding the remaining half of the amount of hydrochloric acid over a period of 30 minutes to 5 hours; - stirring for a defined period of time ranging from 30 min to 2 h, preferably from 30 min to 1 h; - adding water in an amount of 5 to 15 reaction volumes, preferably about 10 reaction volumes, over a period of 1 to 20 h, preferably over a period of 2 to 10 h; Optionally isolating the precipitated Form A, preferably by filtration, sieving or solvent evaporation.

8. A method for preparing a compound as defined in any one of claims 1 to 7, comprising the steps of: - providing, in any order, a defined amount of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide free base and a defined amount of hydrochloric acid, such that a 1:1 stoichiometric ratio of said free base to said hydrochloric acid is provided; - dissolving the free base in a suitable solvent or mixture of solvents selected from methanol, ethanol, tetrahydrofuran (THF), acetone, water and mixtures of water with any of methanol, ethanol, tetrahydrofuran (THF) and acetone; and, if necessary, adding 1 to 5 reaction volumes of water; - adding about half of the specified amount of hydrochloric acid; - adding a seed amount of Form A of N-(5-((6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-propyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxamide hydrochloride as defined in any one of claims 1 to 4, thereby promoting the formation and precipitation of Form A; - adding the remaining half of the amount of hydrochloric acid over a period of 30 minutes to 5 hours; - stirring for a defined period of time ranging from 30 min to 2 h, preferably from 30 min to 1 h; - adding water in an amount of 5 to 15 reaction volumes, preferably about 10 reaction volumes, over a period of 1 to 20 h, preferably over a period of 2 to 10 h; - optionally isolating the precipitated Form A, preferably by filtration, sieving or solvent evaporation.

9. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 7, together with at least one pharma- ceutically acceptable carrier, excipient and / or diluent.

10. 10. The pharmaceutical composition of claim 9, further comprising at least one other pharma- ceutical active agent.

11. A compound according to any one of claims 1 to 7 or a pharmaceutical composition according to any one of claims 9 to 10 for use in the treatment of a disease selected from a hyperproliferative disease, an inflammatory disease and a neurodegenerative disease.

12. The hyperproliferative disease is cancer, preferably adenocarcinoma, acoustic neuroma, acute lymphocytic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, ampullary carcinoma, basal cell carcinoma, bile duct carcinoma, bladder cancer, bone cancer, osteosarcoma and malignant fibrous histiocytoma, brain stem glioma, brain tumor, central nervous system atypical teratoid / rhabdoid tumor, craniopharyngioma, ependymoblastoma, ependymoma, medulloblastoma, medulloepithelioma, pineal parenchymal tumor of intermediate differentiation, supratentorial primitive neuroectodermal tumor and pineoblastoma, brain and spinal cord tumor, breast cancer, urachal tumor, Burkitt's disease, Lymphoma, carcinoid tumor, choroidal melanoma, gastrointestinal cancer, central nervous system lymphoma, cervical cancer, body cancer, chordoma, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disease, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, desmoid tumor, mycosis fungoides, endometrial cancer, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma family tumors, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, ear tumor, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gastrointestinal stromal cell tumor, gynecological tumor, ovarian germ cell tumor, gestational trophoblastic tumor Cancer of the head and neck, cardiac cancer, hepatocellular carcinoma, histiocytosis, hypopharyngeal cancer, hematological tumors, islet cell tumors (endocrine pancreas), renal cell carcinoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, non-small cell lung cancer, small intestinal tumors, small cell lung cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, primary central nervous system lymphoma, macroglobulinemia, malignant fibrous histiocytoma and osteosarcoma of bone, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell neck cancer occult primary, spinal cord tumors, multiple endocrine neoplasia syndrome, myelodysplastic syndrome, Myelodysplastic / myeloproliferative neoplasms, myeloid leukemia, multiple myeloma, myeloproliferative disorders, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cavity cancer, oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian low-grade malignant tumor, oligodendroglioma, plasmacytoma, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal cell carcinoma, transitional cell carcinoma, respiratory tract cancer, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin testicular cancer, Ewing's sarcoma, Kaposi's sarcoma, uterine sarcoma, non-melanoma skin cancer, melanoma skin cancer, skin cancer, small intestine cancer,The compound or pharmaceutical composition for use according to claim 11, wherein the cancer is selected from soft tissue sarcoma, squamous cell carcinoma, squamous cell cervical carcinoma, gastric cancer, soft tissue tumors, testicular cancer, pharyngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, testicular cancer, pregnancy cancer, urological tumors, ureter and renal pelvis cancer, urethral cancer, urothelial carcinoma, uterine cancer, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia and Wilms' tumor, tumors causing effusion in potential spaces of the body, pleural effusion, pericardial effusion, ascites (also known as ascites), giant cell tumor (GCT), GCT of bone, pigmented villonodular synovitis (PVNS), tenosynovial giant cell tumor (TGCT), TGCT of tendon sheath (TGCT-TS).

13. The compound or pharmaceutical composition for use according to claim 11, wherein the inflammatory disease is selected from osteoarthritis, inflammatory bowel syndrome, transplant rejection, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease, emphysema, Kawasaki disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, atherosclerosis, primary progressive multiple sclerosis, tenesmus, type I diabetes, type II diabetes, insulin resistance, hyperglycemia, obesity, lipolysis, hypocreocinoic hyperplasia, osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e.g. osteomyelitis), periprosthetic or wear debris-mediated osteolysis, endometriosis, inflammatory pain, chronic pain, and bone pain.

14. 12. The compound or pharmaceutical composition for use according to claim 11, wherein the neurodegenerative disease is selected from Binswanger dementia, prosencephaly, microcephaly, cerebral palsy, congenital hydrocephalus, ascites, progressive supranuclear palsy, glaucoma, Wilson's disease, Alzheimer's disease and other dementias, Parkinson's disease (PD) and PD-related diseases, multi-infarct dementia, frontotemporal dementia, pseudo-dementia, prion diseases, motor neuron diseases, Huntington's disease, spinocerebellar ataxia, and spinal muscular atrophy.

15. The compound or pharmaceutical composition for use according to any of claims 11 to 14, wherein said use is in combination with other pharma- ceutically active drugs or treatments, in particular radiotherapy, chemotherapeutic agents, targeted drugs and immune checkpoint inhibitors.

16. A method for the treatment of a disease selected from a hyperproliferative disease, an inflammatory disease and / or a neurodegenerative disease, comprising the administration of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to any one of claims 9 to 10.

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