Solid Forms of Heterocyclic Amides as IRAK4 Inhibitors

Abstract

This specification relates to novel physical forms of indazole-5-carboxamide derivatives, as well as solvates and salt forms of the same compounds. Also provided are processes for preparing the compounds and uses of the novel physical forms thereof.

Description

Technical Field

[0001] This specification relates to polymorphic forms, salt forms, co-crystal forms and solvate forms of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (Compound (I)), pharmaceutical compositions containing them, and their use in therapy. This specification also relates to the chemical process for the manufacture of Compound (I). Compound (I) has been discovered to be a highly active IRAK4 inhibitor and as a result has potential utility as an agent for the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), cancer, inflammatory diseases, and autoinflammatory / autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjögren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis and psoriasis.

Background Art

[0002] Interleukin-1 receptor (IL-1R)-associated kinase 4 (IRAK4) is an important regulator of immune signaling. IRAK4 is expressed by multiple cell types and mediates signal transduction from Toll-like receptors (TLRs) and receptors of the interleukin-1 (IL-1) family such as IL-1R, IL-18R, and IL-33 receptor ST2. TLRs recognize and respond to microbial-derived ligands such as lipopolysaccharide (LPS) or microbial RNA or DNA, while receptors of the IL-1 family can be activated by endogenous ligands (IL-1β and IL-18) produced by cells activated by TLRs or by endogenous ligands (IL-1α and IL-33) produced by tissue damage. When these ligands activate TLRs or IL-1 receptors, the adapter protein myeloid differentiation primary response 88 (MyD88) is recruited to the receptor and forms a multimeric protein complex called the "midbody" together with proteins of the IRAK family (IRAK1, IRAK2, and IRAK4). The midbody functions as a signal transduction platform that induces the nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signal transduction pathways, resulting in the activation of the transcription factors NF-κB, activator protein 1 (AP1), c-AMP response element-binding protein (CREB), and interferon regulatory factor 5 (IRF5), and driving the transcription of inflammatory cytokines and chemokines. Mice lacking IRAK4 are viable but lack an inflammatory cytokine response to IL-1β, IL-18, and LPS. Humans presenting loss-of-function mutations in IRAK4 show an immunodeficiency phenotype, and these immune cells show suppression of cytokine responses to TLR agonists and IL-1 receptor ligands.

[0003] IRAK4 is characterized by an N-terminal death domain that mediates interaction with MyD88 and a centrally located kinase domain. Midbody formation promotes autophosphorylation of IRAK4, which regulates midbody stability and downstream signaling. The kinase activity of IRAK4 is required for cytokine induction by TLR and IL-1R, as shown by studies in knock-in mice expressing kinase-dead IRAK4 and studies using small molecule IRAK4 kinase inhibitors.

[0004] Given its important role in triggering the inflammatory response, IRAK4 is a target for drugs that exert anti-inflammatory effects.

[0005] Asthma and COPD (Chronic Obstructive Pulmonary Disease) are chronic lung diseases that represent a serious unmet medical need worldwide. Asthma and COPD are characterized by chronic airway inflammation associated with abnormal cytokine release, dysregulation of immune cell activation, and airway remodeling. In asthma, airway assaults such as allergic, viral, and bacterial invasions activate TLR receptors via pathogen-associated molecular patterns (PAMPs), through the release of alarmins including IL-33 and IL-1α, and by IL-1β released during inflammasome activation, activating IL-1R and ST2 receptors. TLR and IL-1 family receptors are present in multiple cell types within the airway, including macrophages, dendritic cells, mast cells, monocytes, and epithelial cells, and respond to their ligands by releasing inflammatory cytokines (TNF-α, IL-6, IL-8, GM-CSF, IL-5), leading to airway inflammation, recruitment of inflammatory cells such as neutrophils and eosinophils, airway hyperresponsiveness, and mucus production. Inhibiting IRAK4 may suppress these inflammatory pathways in the airway. Gene expression analysis of lung samples from patients with asthma and COPD has revealed increased expression of genes related to the IL-1R inflammatory pathway and TLR2 / 4 inflammatory pathway in a subset of severe patients. To the inventors' knowledge, IRAK4 inhibitors have not been clinically investigated for the treatment of respiratory diseases, but preclinical data from several research groups indicate that airway inflammation is attenuated by interfering with the regulatory pathway by IRAK4 in animal models of both asthma and COPD. For example, mice lacking MyD88, a central component of the midbody, are protected from airway inflammation induced by allergen or IL-33, as are mice treated with small molecule mimics that block the interaction between IRAK2 and IRAK4. In a mouse model of steroid-resistant asthma, blocking IL-1β with a monoclonal antibody has also been shown to suppress airway inflammation induced by allergen and bacteria. Furthermore, in a mouse model of allergic asthma, treating mice with anakinra, an IL-1R antagonist, at the time of allergen challenge improves asthma-like symptoms.Chronic exposure to tobacco smoke is a major cause of the development of COPD. In mice exposed to tobacco smoke, IL-1 signaling is central in mediating neutrophilic airway inflammation, and blocking IL-1 signaling with antibodies against IL-1α, IL-1β, or IL-1R in mice exposed to tobacco smoke can improve pulmonary neutrophilic inflammation and reduce exacerbations induced by bacteria or viruses. In summary, inhibition of IRAK4 has the potential to provide a broad anti-inflammatory effect in inflammatory respiratory diseases by simultaneously blocking signaling pathways associated with several diseases.

[0006] As a central regulator of the midbody, IRAK4 is also a promising therapeutic target in other inflammatory diseases driven by mechanisms mediated by IL-1R, TLR, or ST2. As previously disclosed, IRAK4 plays a role in autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus (SLE) (see, for example, Patent Document 1 and Patent Document 2). In SLE, immune complexes composed of autoantibodies and autoantigens can drive TLR-dependent pathological signaling. In the pathogenesis of SLE, inhibition of IRAK4 has been reported to block the release of type I interferon and inflammatory cytokines mediated by the activation of TLR7 and TLR9 in plasmacytoid dendritic cells. Mice expressing a kinase-dead mutant of IRAK4, or mice treated with an IRAK4 kinase inhibitor compound, are resistant to experimentally induced arthritis and lupus (see, for example, Patent Document 1). The approval of the use of anakinra (an IL-1 receptor antagonist) for the treatment of rheumatoid arthritis also supports the role of pathogenic IL-1R signaling in this disease. In Sjögren's syndrome, TLRs are increased in peripheral blood mononuclear cells (PBMCs) and salivary glands, and activation of TLRs can stimulate the release of interferons and other inflammatory cytokines that have been suggested to be involved in the pathogenesis of Sjögren's. MyD88 knockout mice also show a reduction in disease symptoms in an experimental mouse model of Sjögren's syndrome. Systemic sclerosis is a severe autoimmune disorder, and signaling through IL-1R, TLR4, TLR8, and ST2 can drive pathogenic mechanisms such as microvascular damage and fibrosis. Thus, inhibition of IRAK4 as a treatment for systemic sclerosis blocks multiple disease-related pathways simultaneously. In myositis, elevated levels of IL-1α and IL-1β can contribute to inflammation of muscle tissue. Myositis patients are also characterized by a high expression of the gene signature of type I interferon, which can be partially driven by TLR7 / 9 activation, and the relevance of IL-1R signaling is supported by the improvement in clinical outcomes in myositis patients treated with anakinra in a smaller mechanistic clinical trial.As a central regulator of the IL-1R pathway, IRAK4 is a promising target in the treatment of gout. Monosodium urate crystals, which characteristically form in patients with gout, can induce inflammasome activation and the release of IL-1β. The use of both canakinumab, an anti-IL-1β monoclonal antibody, and anakinra has demonstrated clinical efficacy in the treatment of gout inflammation. In patients with endometriosis, elevated levels of IL-1β and IL-33 have also been observed. The importance of IRAK4 in the disease process of endometriosis was shown in a mouse model in which oral administration of an IRAK4 inhibitor suppressed lesion formation. MyD88 knockout mice were also protected against the development of endometriosis in the same mouse model. IL-33 / ST2 signaling is an important mechanism in atopic dermatitis and is involved in the control of skin inflammation, epithelial barrier integrity, and eosinophil recruitment. IL-33 can induce eczema and dermatitis in mice in a MyD88-dependent manner. As a regulator of ST2 signaling and a central component of the midbody, inhibition of IRAK4 has the potential to inhibit pathogenic IL-33 / ST2 signaling in atopic dermatitis. Mechanisms mediated by both TLR7 and IL-1R have been suggested to be involved in psoriasis. Imiquimod (a TLR / 8 agonist) can induce psoriasis-like disease in mice in a MyD88-dependent manner. IL-1β is increased in psoriatic skin lesions, and the IL-1β / IL-1R axis has been suggested to contribute to skin inflammation and to control the production of IL-17, a highly important cytokine released from TH17 cells in the pathogenesis of psoriasis. IRAK4 kinase activity has been further shown to be required for TH17 differentiation and the control of TH17-mediated diseases in vivo.

[0007] Multiple IRAK4 kinase inhibitors are known and have been developed mainly for use in oncology or inflammatory diseases (see, for example, Patent Documents 2, 1, 3, 4, 5). Multiple clinical trials are underway to investigate the therapeutic utility of IRAK4 inhibitors.

[0008] N-(Imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide has its activity as an inhibitor of IRAK4 enzyme (IC 50 0.2 nM) and IRAK4 activity in Karpas-299 cells (IC 50 5 nM), and is disclosed in Patent Document 6. In order to test the therapeutic potential of this compound, it is desirable to have a solid form of this compound with properties suitable for pharmaceutical development. The present application describes novel polymorphic forms, salt forms and solvate forms of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide. This compound is structurally different from previously known IRAK4 inhibitors.

[0009] In the formulation of the drug substance, it is important that the drug substance (active compound) is in a form that can be easily handled and processed. This is important not only from the perspective of obtaining a commercially viable manufacturing process for the drug substance itself, but also from the perspective of the subsequent manufacture of pharmaceutical formulations containing the active compound and appropriate additives. The chemical and physical stability of the active compound are important factors in determining the suitability of the solid form for use in the development of pharmaceutical formulations. The active compound and the formulations containing it must be able to be effectively stored for a reasonable period of time without any significant changes in the physicochemical properties (e.g., chemical composition, density, hygroscopicity and solubility) of the active compound. The object of the present specification is to provide a solid form suitable for pharmaceutical development of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide. For a further object, the present specification provides a rapid route for manufacturing N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide.

Prior Art Documents

Patent Documents

[0010]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Summary of the Invention

Problems to be Solved by the Invention

[0011] This application relates to a crystalline form of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (hereinafter referred to as "Compound (I)"). The structure of Compound (I) is shown below.

Chemical Formula

[0012] This application also relates to a process for producing Compound (I) and important synthetic intermediates.

Means for Solving the Problems

[0013] The inventors have discovered that Compound (I) can exist in multiple crystalline forms and salt forms.

[0014] One aspect provides a crystalline form of Compound (I).

[0015] In a further aspect, there is provided Form A, a physical form of compound (I). "Form A" presents an X-ray diffraction pattern substantially shown in FIG. 1. Form A is an anhydrous crystalline form of compound (I). Form A is the most thermodynamically stable anhydrous crystalline form of compound A identified to date and is stable against long-term storage under accelerated aging conditions (40 °C and 75% relative humidity).

[0016] In a further aspect, there is provided Form B, a physical form of compound (I). "Form B" presents an X-ray diffraction pattern substantially shown in FIG. 2. Form B is a trihydrate crystalline form of compound (I).

[0017] A metastable dihydrate crystalline form of compound (I) is also described. "Form C" presents an X-ray diffraction pattern substantially shown in FIG. 3. Form B is a dihydrate crystalline form of compound (I).

[0018] In a further aspect, there is provided a crystalline solvate form of compound (I).

[0019] In a further aspect, there is provided a crystalline hydrate form of compound (I), such as a trihydrate form.

[0020] In a further aspect, there is provided a crystalline oxalate form of compound (I).

[0021] In a further aspect, there is provided a crystalline form comprising compound (I) and 3-hydroxybenzoic acid, which is referred to herein as the 3-hydroxybenzoic acid form of compound (I) or 3-hydroxybenzoic acid of compound (I).

[0022] In a further aspect, there is provided a crystalline form of compound (I) for use in the manufacture of a pharmaceutical.

[0023] In a further aspect, there is provided a crystalline form of compound (I) for use in the manufacture of a medicament for the prevention or treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD).

[0024] In a further aspect, there is provided a crystalline form of compound (I) for use in the manufacture of a medicament for the prevention or treatment of hematological malignancies selected from cancer, such as Waldenström macroglobulinemia (WM), non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), primary central nervous system lymphoma (PCNSL), splenic marginal zone lymphoma (SMZL), small lymphocytic lymphoma (SLL), leukemia (chronic lymphocytic leukemia (CLL)), and monoclonal gammopathy of undetermined significance (MGUS-IgM+).

[0025] In a further aspect, there is provided a crystalline form of compound (I) for use in the manufacture of a medicament for the prevention or treatment of inflammatory diseases and autoinflammatory / autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjögren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis, and psoriasis.

[0026] Aspects of the present specification regarding the medicament include aspects where the medicament is intended for use in humans.

[0027] In a further aspect, there is a process for preparing compound (I), the process comprising

Chemical formula

[0028] In a further aspect, the present specification provides N-((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)-N-methylacetamide

Chemical formula

[0029] For the present specification to be fully understood, the following description of the drawings is provided.

Brief Description of the Drawings

[0030]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Mode for Carrying Out the Invention

[0031] In the first embodiment, this specification provides the crystalline form of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (Compound (I)):

Chemical formula

[0032] In an embodiment, the crystalline form of Compound (I) is an anhydrous crystalline form. In such an embodiment, the crystalline form is Form A of Compound (I), and it is characterized by presenting at least one of the following 2θ values measured using Cu K α irradiation: 4.9° and 23.4°. Further characteristics of Form A are described hereinbelow.

[0033] In an embodiment, the crystalline form of Compound (I) is a hydrate crystalline form. In such an embodiment, the crystalline form is Trihydrate Form B of Compound (I), and it is characterized by presenting at least one of the following 2θ values measured using Cu K α irradiation: 17.2° and 26.1°. Further characteristics of Form B are described hereinbelow.

[0034] In an embodiment, a salt form of Compound (I) is provided. In such an embodiment, using Cu K αProvided is an oxalate form of compound (I) having a crystalline form characterized by presenting at least one of the following 2θ values measured using irradiation: 11.2° and 27.2°. Further properties of the oxalate form of compound (I) are described hereinbelow.

[0035] In an embodiment, a cocrystal form of compound (I) is provided. In such an embodiment, Cu K α Provided is a 3-hydroxybenzoic acid crystal form of compound (I) characterized by presenting at least one of the following 2θ values measured using irradiation: 10.8° and 16.5°. Further properties of the physical form of 3-hydroxybenzoic acid of compound (I) are described hereinbelow.

[0036] In an embodiment of the present specification, provided is a process for preparing compound (I) comprising the step of reacting a compound of formula (A), namely imidazo[1,2-b]pyridazin-3-amine, dissolved in a suitable solvent, with carbon monoxide. The X group of the compound of formula (A) is a leaving group, for example, a leaving group selected from Br, Cl, I, OSO2R, and R is methyl, trifluoromethyl or tolyl. The reaction is conveniently carried out using a palladium catalyst, for example, a palladium(II) catalyst. The palladium(II) catalyst can be a palladium(II) catalyst characterized by a diphosphine ligand such as Pd(dppf)Cl2.

Chemical formula

[0037] Form A The physical form of form A of compound (I), namely the anhydride of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide, is Cu K αCharacterized by presenting at least one of the following 2θ values measured using irradiation: 4.9° and 23.4°. Polymorph A of compound (I) is characterized by presenting an X-ray powder diffraction pattern substantially shown in Figure 1. The ten most prominent peaks are shown in Table 1.

Table 1

[0038] According to the present specification, there is provided polymorph A of compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing at least one specific peak at about 2-theta = 4.9°.

[0039] According to the present specification, there is provided polymorph A of compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing at least one specific peak at about 2-theta = 23.4°.

[0040] According to the present specification, there is provided polymorph A of compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing at least two specific peaks at about 2-theta = 4.9 and 23.4°.

[0041] According to the present specification, there is provided polymorph A of compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing specific peaks at about 2-theta = 4.9, 12.5, 16.7, 18.8, and 23.4°.

[0042] According to the present specification, there is provided polymorph A of compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing specific peaks at about 2-theta = 4.9, 9.7, 12.5, 16.7, 18.8, 19.5, 20.7, 23.4, 25.1, and 27.4°.

[0043] According to the present specification, there is provided polymorph A of compound (I) having an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in Figure 1.

[0044] According to the present specification, there is provided Form A of Compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing at least one specific peak at 2-theta = 4.9° plus or minus 0.2° 2-theta.

[0045] According to the present specification, there is provided Form A of Compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing at least one specific peak at 2-theta = 23.4° plus or minus 0.2° 2-theta.

[0046] According to the present specification, there is provided Form A of Compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing at least two specific peaks at 2-theta = 4.9 and 23.4° (the said values may be plus or minus 0.2° 2-theta).

[0047] According to the present specification, there is provided Form A of Compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing specific peaks at about 2-theta = 4.9, 12.5, 16.7, 18.8, and 23.4° plus or minus 0.2° 2-theta.

[0048] According to the present specification, there is provided Form A of Compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing specific peaks at about 2-theta = 4.9, 9.7, 12.5, 16.7, 18.8, 19.5, 20.7, 23.4, 25.1, and 27.4° plus or minus 0.2° 2-theta.

[0049] When the present specification states that it relates to Form A which is a crystalline form of Compound (I), the crystallinity is preferably more than about 60%, more preferably more than about 80%, preferably more than about 90%, more preferably more than about 95%. Most preferably, the crystallinity is more than about 98%.

[0050] Form A of compound (I) exhibits an X-ray powder diffraction pattern that is substantially the same as the X-ray powder diffraction pattern shown in Figure 1 and has the substantially most prominent 10 peaks (2-theta angle values) shown in Table 1. Of course, the 2-theta values of the X-ray powder diffraction pattern may vary slightly depending on the machine or the sample, and therefore, the cited values should not be construed as absolute.

[0051] It is known that depending on the measurement conditions (e.g., the apparatus or machine used), an X-ray powder diffraction pattern with one or more measurement errors may be obtained. In particular, it is generally known that the intensity in the X-ray powder diffraction pattern may vary depending on the measurement conditions. Therefore, of course, form A of compound (I) herein is not limited to crystals that exhibit an X-ray powder diffraction pattern identical to the X-ray powder diffraction pattern shown in Figure 1, and any crystal that exhibits an X-ray powder diffraction pattern substantially the same as that shown in Figure 1 falls within the scope of this specification. Those skilled in X-ray powder diffraction can determine the substantial identity of the X-ray powder diffraction patterns.

[0052] Form B The physical form of form B of compound (I), namely the trihydrate of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide, is characterized by presenting at least one of the following 2θ values measured using Cu K α irradiation: 17.2° and 26.1°. Form B of compound (I) is characterized by presenting an X-ray powder diffraction pattern substantially shown in Figure 2. The most prominent 10 peaks are shown in Table 2.

Table 2

[0053] According to the present specification, there is provided Form B of Compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing at least one specific peak at about 2-theta = 17.2°.

[0054] According to the present specification, there is provided Form B of Compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing at least one specific peak at about 2-theta = 26.1°.

[0055] According to the present specification, there is provided Form B of Compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing at least two specific peaks at about 2-theta = 17.2° and 26.1°.

[0056] According to the present specification, there is provided Form B of Compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing specific peaks at about 2-theta = 6.7, 11.3, 11.9, 17.2, and 26.1°.

[0057] According to the present specification, there is provided Form B of Compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing specific peaks at about 2-theta = 6.7, 11.3, 11.9, 12.3, 15.7, 17.2, 22.7, 26.1, 27.2, and 28.5°.

[0058] According to the present specification, there is provided Form B of Compound (I), which has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in Figure 2.

[0059] According to the present specification, there is provided Form B of Compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing at least one specific peak at 2-theta = 17.2° plus or minus 0.2° 2-theta.

[0060] According to the present specification, there is provided Form B of Compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing at least one specific peak at 2-theta = 26.1° plus or minus 0.2° 2-theta.

[0061] According to the present specification, there is provided Form B of Compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing at least two specific peaks at 2-theta = 17.2° and 26.1° (the said values may be 2-theta plus or minus 0.2°).

[0062] According to the present specification, there is provided Form B of Compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing specific peaks at about 2-theta = 6.7, 11.3, 11.9, 17.2, 26.1° plus or minus 0.2° 2-theta.

[0063] According to the present specification, there is provided Form B of Compound (I), which is a crystalline form having an X-ray powder diffraction pattern showing specific peaks at about 2-theta = 6.7, 11.3, 11.9, 12.3, 15.7, 17.2, 22.7, 26.1, 27.2, and 28.5° plus or minus 0.2° 2-theta.

[0064] When it is stated that the present specification relates to Form B which is a crystalline form of Compound (I), the crystallinity is preferably more than about 60%, more preferably more than about 80%, preferably more than about 90%, more preferably more than about 95%. Most preferably, the crystallinity is more than about 98%.

[0065] Form B of Compound (I) presents an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in Figure 2 and has substantially the 10 most prominent peaks (2-theta angle values) shown in Table 1. Naturally, the 2-theta values of the X-ray powder diffraction pattern may vary slightly depending on the machine or the sample, and therefore, the cited values should not be construed as absolute.

[0066] It is known that depending on the measurement conditions (for example, the apparatus or machine used), an X-ray powder diffraction pattern with one or more measurement errors may be obtained. In particular, it is generally known that the intensity in the X-ray powder diffraction pattern may vary depending on the measurement conditions. Therefore, naturally, Form B of the compound (I) herein is not limited to crystals presenting an X-ray powder diffraction pattern identical to that shown in FIG. 2, and any crystal presenting an X-ray powder diffraction pattern substantially the same as that shown in FIG. 2 falls within the scope of this specification. Those skilled in X-ray powder diffraction can determine the substantial identity of the X-ray powder diffraction patterns.

[0067] Form C Form C, a further crystalline form of compound (I), i.e., the metastable dihydrate form of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide, was also obtained. Form C of compound (I) presents an X-ray powder diffraction pattern substantially the same as that shown in FIG. 3.

[0068] The oxalate form of compound (I) The oxalate crystal form of compound (I) is a crystal salt form containing N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide and oxalic acid in a 1:1 ratio, characterized by presenting at least one of the following 2θ values measured using Cu K α irradiation: 11.2° and 27.2°. The oxalate crystal form of compound (I) is characterized by presenting an X-ray powder diffraction pattern substantially shown in FIG. 4. The most prominent 10 peaks are shown in Table 3.

Table 3

[0069] According to the present specification, there is provided an oxalate form of compound (I) which is a crystalline form having an X-ray powder diffraction pattern showing at least one specific peak at about 2-theta = 11.2°.

[0070] According to the present specification, there is provided an oxalate form of compound (I) which is a crystalline form having an X-ray powder diffraction pattern showing at least one specific peak at about 2-theta = 27.2°.

[0071] According to the present specification, there is provided an oxalate form of compound (I) which is a crystalline form having an X-ray powder diffraction pattern showing at least two specific peaks at about 2-theta = 11.2 and 27.2°.

[0072] According to the present specification, there is provided an oxalate form of compound (I) which is a crystalline form having an X-ray powder diffraction pattern showing specific peaks at about 2-theta = 11.2, 27.2, 3.6, 22.6 and 26.5°.

[0073] According to the present specification, there is provided an oxalate form of compound (I) which is a crystalline form having an X-ray powder diffraction pattern showing specific peaks at about 2-theta = 11.2, 27.2, 3.6, 22.6, 26.5, 15.0, 13.9, 15.7, 14.6 and 18.1°.

[0074] According to the present specification, there is provided an oxalate form of compound (I) having an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 4.

[0075] According to the present specification, there is provided an oxalate form of compound (I) which is a crystalline form having an X-ray powder diffraction pattern showing at least one specific peak at 2-theta = 11.2° plus or minus 0.2° 2-theta.

[0076] According to the present specification, there is provided an oxalate form of compound (I) which is a crystalline form having an X-ray powder diffraction pattern showing at least one specific peak at 2-theta = 27.2° plus or minus 0.2° 2-theta.

[0077] According to the present specification, there is provided an oxalate form of compound (I) which is a crystalline form having an X-ray powder diffraction pattern showing at least two specific peaks at 2-theta = 11.2 and 27.2° (the said values may be plus or minus 0.2° 2-theta).

[0078] According to the present specification, there is provided an oxalate form of compound (I) which is a crystalline form having an X-ray powder diffraction pattern showing specific peaks at about 2-theta = 11.2, 27.2, 3.6, 22.6 and 26.5° plus or minus 0.2° 2-theta.

[0079] According to the present specification, there is provided an oxalate form of compound (I) which is a crystalline form having an X-ray powder diffraction pattern showing specific peaks at about 2-theta = 11.2, 27.2, 3.6, 22.6, 26.5, 15.0, 13.9, 15.7, 14.6 and 18.1° plus or minus 0.2° 2-theta.

[0080] When the present specification states that it relates to an oxalate form which is a crystalline form of compound (I), the crystallinity is preferably more than about 60%, more preferably more than about 80%, preferably more than about 90%, more preferably more than about 95%. Most preferably, the crystallinity is more than about 98%.

[0081] The oxalate form of compound (I) presents an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in Figure 4 and has substantially the 10 most prominent peaks (2-theta angle values) shown in the table. Of course, the 2-theta values of the X-ray powder diffraction pattern may vary slightly depending on the machine or the sample, and thus the cited values should not be construed as absolute.

[0082] It is known that X-ray powder diffraction patterns with one or more measurement errors may be obtained depending on the measurement conditions (for example, the apparatus or machine used). In particular, it is generally known that the intensity in an X-ray powder diffraction pattern may vary depending on the measurement conditions. Therefore, it goes without saying that the oxalate form of the compound (I) herein is not limited to crystals presenting an X-ray powder diffraction pattern identical to that shown in FIG. 4, and any crystal presenting an X-ray powder diffraction pattern substantially the same as that shown in FIG. 4 falls within the scope herein. Those skilled in X-ray powder diffraction can determine the substantial identity of X-ray powder diffraction patterns.

[0083] 3-Hydroxybenzoic acid form of compound (I) The 3-hydroxybenzoic acid crystal form of compound (I) is a co-crystalline form containing N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide and 3-hydroxybenzoic acid in a 1:1 ratio, and is characterized by presenting at least one of the following 2θ values measured using Cu K α irradiation: 10.8° and 16.5°. The 3-hydroxybenzoic acid form of compound (I) is characterized by presenting an X-ray powder diffraction pattern substantially shown in FIG. 5. The most prominent 10 peaks are shown in Table 1. It is possible to make this co-crystalline form into a salt form, but this has not been formally determined. [Table 4]

[0084] According to the present specification, there is provided a 3-hydroxybenzoic acid of compound (I) in a crystalline form having an X-ray powder diffraction pattern showing at least one specific peak at about 2-theta = 10.8°.

[0085] According to the present specification, there is provided 3-hydroxybenzoic acid of compound (I) in a crystalline form having an X-ray powder diffraction pattern showing at least one specific peak at about 2-theta = 16.5°.

[0086] According to the present specification, there is provided 3-hydroxybenzoic acid of compound (I) in a crystalline form having an X-ray powder diffraction pattern showing at least two specific peaks at about 2-theta = 10.8° and 16.5°.

[0087] According to the present specification, there is provided 3-hydroxybenzoic acid of compound (I) in a crystalline form having an X-ray powder diffraction pattern showing specific peaks at about 2-theta = 10.8, 16.5, 27.1, 18.4 and 3.4°.

[0088] According to the present specification, there is provided 3-hydroxybenzoic acid of compound (I) in a crystalline form having an X-ray powder diffraction pattern showing specific peaks at about 2-theta = 10.8, 16.5, 27.1, 18.4, 3.4, 23.4, 13.3, 24.9, 17.8 and 13.9°.

[0089] According to the present specification, there is provided 3-hydroxybenzoic acid of compound (I) having an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 5.

[0090] According to the present specification, there is provided 3-hydroxybenzoic acid of compound (I) in a crystalline form having an X-ray powder diffraction pattern showing at least one specific peak at 2-theta = 10.8° plus or minus 0.2° 2-theta.

[0091] According to the present specification, there is provided 3-hydroxybenzoic acid of compound (I) in a crystalline form having an X-ray powder diffraction pattern showing at least one specific peak at 2-theta = 16.5° plus or minus 0.2° 2-theta.

[0092] According to the present specification, there is provided 3-hydroxybenzoic acid of compound (I) in a crystalline form having an X-ray powder diffraction pattern showing at least two specific peaks at 2-theta = 10.8° and 16.5° (the said values may be 2-theta with plus or minus 0.2°).

[0093] According to the present specification, there is provided 3-hydroxybenzoic acid of compound (I) in a crystalline form having an X-ray powder diffraction pattern showing specific peaks at about 2-theta = 10.8, 16.5, 27.1, 18.4 and 3.4° plus or minus 0.2° 2-theta.

[0094] According to the present specification, there is provided 3-hydroxybenzoic acid of compound (I) in a crystalline form having an X-ray powder diffraction pattern showing specific peaks at about 2-theta = 10.8, 16.5, 27.1, 18.4, 3.4, 23.4, 13.3, 24.9, 17.8 and 13.9° plus or minus 0.2° 2-theta.

[0095] When the present specification is described as relating to 3-hydroxybenzoic acid which is a crystalline form of compound (I), the crystallinity is advantageously more than about 60%, more advantageously more than about 80%, preferably more than about 90%, more preferably more than about 95%. Most preferably, the crystallinity is more than about 98%.

[0096] 3-Hydroxybenzoic acid of compound (I) presents an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in Figure 5 and has substantially the 10 most prominent peaks (2-theta angle values) shown in Table 1. Naturally, the 2-theta values of the X-ray powder diffraction pattern may vary slightly depending on the machine or the sample, and therefore, the cited values should not be construed as absolute.

[0097] It is known that X-ray powder diffraction patterns with one or more measurement errors may be obtained depending on the measurement conditions (for example, the apparatus or machine used). In particular, it is generally known that the intensity in an X-ray powder diffraction pattern may vary depending on the measurement conditions. Therefore, naturally, the 3-hydroxybenzoic acid of compound (I) herein is not limited to crystals presenting an X-ray powder diffraction pattern identical to that shown in Figure 5, and any crystal presenting an X-ray powder diffraction pattern substantially the same as that shown in Figure 5 falls within the scope herein. Those skilled in X-ray powder diffraction can determine the substantial identity of X-ray powder diffraction patterns.

[0098] Anhydrous form D A sample of the trihydrate form B was subjected to thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), and the results are shown in Figure 6. Briefly, the TGA and DSC measurements were carried out using TG Discovery 550 (TA instruments, Germany) and DSC Discovery 2500 (TA instruments, Germany), respectively. Samples of approximately 5 mg for TGA and 2 - 3 mg for DSC were weighed and placed in aluminum pans. The samples were then heated at a heating rate of 3 °C / min under a nitrogen purge of 100 mL / min, from room temperature to 350 °C for TGA and from -50 °C to 300 °C for DSC. An empty aluminum pan was used as a reference for DSC. For the TGA and DSC measurements, an uncovered pan and a covered pan were used, respectively. A modulation mode was used for the DSC measurement, and the modulation temperature amplitude and modulation period were set to 1 °C and 60 seconds, respectively.

[0099] In TGA (dashed lines in the figure, TGA scale on the right), a weight loss of 10.13% was observed over the temperature range from below 25 °C to around 120 °C. This weight loss is due to dehydration, and the 10.13% weight loss corresponds to 2.89 water molecules per molecule of the API. This is consistent with the designation in the form of the trihydrate of polymorph B. The dehydration proceeds at a relatively low temperature, i.e., below 25 °C. The DSC measurement (solid line, DSC scale on the left) was carried out starting from -50 °C. As can be seen from Figure 6, the dehydration ends around 120 °C. After dehydration, an exotherm was observed to start around 130 °C, which indicates crystallization and a new anhydrous form D was obtained. Another exothermic curve was observed to start at 160 °C. This indicates crystallization to form A.

[0100] In-situ Characterization of Polymorph D To further understand the properties of polymorph D, in-situ characterization was performed using a SmartLab X-ray diffractometer (Rigaku Corporation, Japan) equipped with a DSC attachment. A sample of polymorph B was placed in a flat aluminum DSC pan. The PXRD pattern was collected from 2θ = 5° to 38° with a step width and a scanning speed of 0.01° and 10° min -1 respectively. The heating rate of DSC was set at 1 °C min -1 . Using a Cu Kα source, the X-ray output was set at 40 kV and 50 mA. The heating process was continued until polymorph B was fully dehydrated to an amorphous form and then crystallization occurred as indicated by the appearance of diffraction peaks. The heating process was stopped immediately after the second PXRD pattern of the crystalline material was obtained (at about 111 °C). Subsequently, the ramping rate was 10 °C min -1The furnace was cooled to room temperature. Subsequently, the material was analyzed by electron diffraction to determine the crystal structure. Electron diffraction measurements were collected using a Rigaku Synergy-ED (Rigaku Corporation, Japan) equipped with a Rigaku HyPix-ED detector optimized for operation in a Micro-ED experimental setup. A total of two data sets were collected and integrated to obtain a combined data set with a resolution limit of 1.05 Å. Form D was determined to be crystallized with the following lattice parameters in the triclinic space group P-1: a = 6.995(7) Å, b = 11.416(12) Å, c = 15.90(2) Å, α = 71.25(10)°, β = 85.46(10)°, γ = 89.23(9), V = 1198(2) Å 3 It was found that Z and Z’ are 2 and 1, respectively.

[0101] X-ray powder diffraction analysis X-ray powder diffraction analysis was performed according to standard methods that can be found, for example, in Kitaigorodsky, A.I. (1973), Molecular Crystals and Molecules, Academic Press, New York; Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H.P. & Alexander, L.E. (1974), X-ray Diffraction Procedures, John Wiley & Sons, New York.

[0102] Those skilled in X-ray powder diffraction will understand that the relative intensity of peaks can be affected, for example, by particles with a size exceeding 30 microns and non-unitarity of the aspect ratio, which can affect the analysis of the sample. Those skilled in the art will also recognize that the position of the reflection can be affected by the exact height at which the sample is positioned on the diffractometer and the zero-point calibration of the diffractometer. The flatness of the surface of the sample may also have a slight effect. Therefore, the presented diffraction pattern data should not be regarded as absolute values (Jenkins, R & Snyder, R.L. ‘Introduction to X-Ray Powder Diffractometry’ John Wiley & Sons 1996; Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London; Klug, H.P. & Alexander, L.E. (1974), X-Ray Diffraction Procedures).

[0103] Generally, the measurement error of the diffraction angle in an X-ray powder diffractogram is about 5% or less, especially plus or minus 0.2° 2-theta. When examining the X-ray powder diffraction patterns in Figures 1, 2, 3, 4 and 5, and when reading Tables 1, 2, 3 and 4, such a degree of measurement error should be taken into account. Furthermore, as a matter of course, the intensity can vary depending on the experimental conditions and sample preparation (preferred orientation). The definition of relative intensity is described in Table 3.

[0104] The X-ray powder diffraction data were measured using corundum as an internal standard. The X-ray powder diffraction (referred to as XRPD in this specification) pattern was determined by placing the sample on a single-crystal silicon holder with zero background and spreading the sample into a thin layer.

[0105] Powder X-ray diffraction was performed using a theta-2 theta scanning axis on a Rigaku Miniflex 600 equipped with a D / Tex Ultra detector (X-ray wavelength 1.5418 Å, through a nickel filter, Cu K αIt was recorded in a one-dimensional scan using irradiation (40 kV, 15 mA). An automatic variable anti-scattering slit was used, and during the measurement, the sample was rotated 30 times per minute. The sample was scanned from 3 to 50° 2-theta using step widths of 0.01° and 1° / min scanning speed respectively.

[0106] X-ray powder diffraction analysis was performed according to standard methods that can be found, for example, in Kitaigorodsky, A.I. (1973), Molecular Crystals and Molecules, Academic Press, New York; Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H.P. & Alexander, L.E. (1974), X-ray diffraction procedures for polycrystalline and amorphous materials, John Wiley, New York, London.

[0107]

Table 5

[0108] Those skilled in the art understand that the values or ranges of values observed in the DSC thermograms of specific compounds vary between batches of different purities. Thus, there are compounds for which the range can be small, and there are compounds for which the range can be quite large. Generally, the measurement error of the diffraction angle in the thermal events of DSC is approximately plus or minus 5 °C, and such a degree of measurement error should be considered when examining the DSC data included in this specification.

[0109] The desired form of crystallization in the processes described herein can be promoted by seeding with crystals of the desired form. The seed crystals can be obtained using one of the methods described in the examples. The use of seeding is particularly advantageous in larger scale manufacturing.

[0110] In this specification, when a compound is described as having an "X-ray powder diffraction pattern showing at least one specific peak at 2θ of about =....", the XRPD of the compound may contain one or more of the listed 2θ values. For example, one or more of the 2θ values, two or more of the 2θ values, or three or more of the listed 2θ values.

[0111] In the foregoing paragraph defining the X-ray powder diffraction peaks of the crystalline form of compound (I), the term "about =" is used in the expression "... at 2θ of about =..." to indicate that the exact position of the peak (i.e., the listed 2-theta angle value) should not be interpreted as an absolute value. This is because, as recognized by those skilled in the art, the exact position of the peak may vary slightly between measuring devices, by the sample, or as a result of minor variations in the measurement conditions utilized. The crystalline form of compound (I) also presents an X-ray powder diffraction pattern that is "substantially" the same as the X-ray powder diffraction pattern shown in Figure 1 and has the substantially most prominent peaks (2-theta angle values) shown in Table 1, as also stated in the foregoing paragraph. Of course, the use of the term "substantially" in this context also indicates that the 2-theta angle values of the X-ray powder diffraction pattern may vary slightly as a result of variations in the device, by the sample, or in the measurement conditions utilized, and therefore the peak positions shown in the figure or cited in the table should not be interpreted as absolute values either.

[0112] Those skilled in the art of X-ray powder diffraction will understand that the relative intensity of the peaks may be affected, for example, by particles with a size exceeding approximately 30 micrometers and non-unitary aspect ratios, and this can affect the analysis of the sample. Furthermore, of course, the intensity can vary depending on the experimental conditions and sample preparation, such as the preferred orientation of the particles in the sample, etc. The use of an automatic or fixed divergence slit also affects the calculation of the relative intensity. Those skilled in the art can handle such effects when comparing diffraction patterns.

[0113] Those skilled in X-ray powder diffraction will also recognize that due to differences in sample height and errors in detector position calibration, a slight shift may occur in the 2θ position. Generally, a difference of ±0.1° from a given value should be considered correct.

[0114] Each form of compound (I) described herein can also be characterized and / or distinguished from other physical forms using other suitable analytical techniques, such as NIR spectroscopy or solid-state nuclear magnetic resonance spectroscopy.

[0115] The chemical structure of each form of compound (I) described herein can be confirmed by conventional methods, such as proton nuclear magnetic resonance (NMR) analysis.

[0116] Each form of compound (I) can be prepared as described in the following examples.

[0117] Process One synthesis of compound (I) is described in the specification of International Application PCT / EP2021 / 084916.

[0118] This specification provides a process for preparing compound (I) that includes reacting a compound of formula (A), i.e., imidazo[1,2-b]pyridazin-3-amine, dissolved in a suitable solvent, with a suitable catalyst in a carbon monoxide atmosphere. The reaction can be carried out under high-pressure carbon monoxide, for example, at a pressure of 5 atm or more, for example, 15 atm. The X group of the compound of formula (A) is a leaving group, for example, a leaving group selected from Br, Cl, I, OSO2R, where R is methyl, trifluoromethyl, or tolyl. In an embodiment, the X group is Br. The reaction is conveniently carried out using a palladium catalyst, for example, a palladium(II) catalyst. The palladium(II) catalyst can be a palladium(II) catalyst characterized by a diphosphine ligand such as dppf (1,1’-bis(diphenylphosphino)ferrocene), for example, Pd(dppf)Cl2. Other suitable palladium(II) catalyst systems, for example, those characterized by ligands such as xantphos ((9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)), BINAP ((2,2’-bis(diphenylphosphino)-1,1’-binaphthyl)), or dppp (1,3-bis(diphenylphosphino)propane) can be used. The catalyst may be pre-formed or generated in situ by stirring a palladium(II) source such as palladium(II) acetate or palladium(II) chloride and a suitable ligand in a suitable solvent. Details of carbonylation with palladium catalysts are described, for example, in Brennfuhrer et al, Angew.Chem.Int.Ed 2009, 48, 4114-33. The solvent can be acetonitrile. Other solvents or mixtures of solvents can be used as well.

[0119] Scheme 1 Synthesis of Compound (I) by Aminocarbonylation Reaction

Chemical Formula

[0120] Medical and pharmaceutical uses The crystalline form of compound (I) may be useful for the prevention or treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), cancer, inflammatory diseases, and autoinflammatory / autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjögren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis, and psoriasis in mammals, particularly humans.

[0121] Combination therapy The crystalline form of compound (I) can also be administered in combination with other compounds used for the treatment of the above-mentioned conditions.

[0122] In another embodiment, there is a combination therapy in which the crystalline form of compound (I) and a second active ingredient are administered simultaneously, sequentially, or mixed for the treatment of one or more of the above-mentioned conditions. Such combinations can be used in combination with one or more additional active ingredients.

[0123] Administration There is provided a method for treating a condition that requires inhibition of IRAK4, the method comprising administering a therapeutically effective amount of the crystalline form of compound (I) to a person suffering from or susceptible to such a condition.

[0124] The crystalline form of compound (I) will typically be administered in the form of a pharmaceutical preparation containing the active ingredient in a pharmaceutically acceptable dosage form, by oral, parenteral, intravenous, intramuscular, subcutaneous, or other injectable means, by buccal, rectal, vaginal, transdermal, and / or nasal routes, and / or by inhalation. Depending on the disorder to be treated, the patient, and the route of administration, the composition can be administered in various dosages.

[0125] Dosage forms suitable for oral use form one aspect of the present specification.

[0126] The compositions of the present specification can be obtained by conventional procedures using conventional pharmaceutical additives well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents and / or preservatives.

[0127] Pharmaceutically acceptable additives suitable for tablet formulations include, for example, inert diluents such as lactose, granulating and disintegrating agents such as corn starch, binding agents such as starch, and lubricants such as magnesium stearate. Tablet formulations may or may not be coated, or may be coated using conventional coating agents and procedures well known in the art.

[0128] For further information on formulations, the reader is referred to Chapter 25.2, Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

[0129] The amount of active ingredient combined with one or more additives to create a single dosage form will necessarily vary depending on the host to be treated and the particular route of administration.

[0130] A suitable daily dose of the crystalline form of compound (I) is about 0.0001 - 100 mg / kg body weight in the therapeutic treatment of humans.

[0131] Oral formulations, particularly tablets or capsules formulated in a manner known to those skilled in the art to provide a dosage of the active compound in the range of 0.1 mg to 1000 mg, are preferred.

[0132] For further information regarding the route of administration and dosing schedule, the reader is referred to Chapter 25.3, Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

[0133] Accordingly, in a further aspect, there is provided a pharmaceutical composition comprising a crystalline form of compound (I) admixed with a pharmaceutically acceptable adjuvant, diluent and / or carrier.

Example

[0134] The abbreviations used in the analytical data are in accordance with the general usage in the art (see J Med Chem Standard Abbreviations and Acronyms http: / / pubsapp.acs.org / paragonplus / submission / jmcmar / jmcmar_abbreviations.pdf?). The compound names described below are generated using PerkinElmer ChemDraw Professional, version 20.0.2.51. Where there is uncertainty regarding the absolute stereochemistry, the relative stereochemistry is specified as far as possible.

[0135] Preparation of Form A of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide 5-Bromo-4-fluoro-2-nitrobenzaldehyde

Chemical formula

[0136] 5-Bromo-4-methoxy-2-nitrobenzaldehyde

Chemical formula

[0137] N-((1r,4r)-4-(5-Bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)acetamide

Chemical formula

[0138] N-((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)-N-methylacetamide [Chemical formula] A mixture of N-((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)acetamide (4.60 kg, 12.56 mol) in THF (46 L) was added with MeI (3.39 kg, 23.86 mol) at 0 °C, and then tert-butoxide potassium (23.94 mol in THF, volume 13.3 L) was added dropwise, and the mixture was stirred at 0 °C for 3 hours. The reaction of this mixture was quenched while maintaining the temperature between 0 and 10 °C using acetic acid (907.9 g, 15.12 mol). Then cyclopentyl methyl ether was added (23 L), the mixture was concentrated, and then cyclopentyl methyl ether (23 L) was added further. The resulting mixture was heated to 100 °C, stirred for 2 hours, and then cooled to 20 °C over 4 hours. The solid was filtered, and the filter cake was washed with cyclopentyl methyl ether (9.2 L). The isolated solid was dried in a vacuum oven at 40 °C to obtain N-((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)-N-methylacetamide (4.41 kg, 11.60 mol).

[0139] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamide)cyclohexyl)-2H-indazole-5-carboxamide

Chemical Structure

[0140] A suspension of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (6.03 kg, 13.0 mol) was added to methanol (47.8 L), and the mixture was stirred and heated to 50 °C. To this was added a mixture of methanesulfonic acid (1.25 kg, 13.0 mol) in methanol (3 L), and the solution was stirred at 50 °C for 2 hours. Then N-methylmorpholine (0.131 kg, 1.30 mol) was gradually added as a solution in methanol (0.6 L), and then a seed crystal of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (54.3 g) taken from a 6.27 kg batch of the solid prepared immediately above was added. The resulting mixture was stirred at 50 °C overnight, treated with a further portion of a solution of N-methylmorpholine (1.18 kg, 11.7 mol) in methanol (4.26 kg), and then stirred at 50 °C overnight. The resulting solid was filtered, the cake was washed with methanol (2 × 4.74 kg), and dried to obtain Form A (5.78 kg, 12.4 mol) of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide as a yellow solid. The XRPD of this Form A material is shown in Figure 1. 1H NMR (500 MHz, CDCl3) δ ppm 1.7 (qd, J = 12.7, 3.2 Hz, 2H) 1.8 - 2.0 (m, 2H) 2.1 - 2.2 (m, 2H) 2.1 (s, 3H) 2.4 - 2.4 (m, 2H) 2.9 (s, 3H) 4.2 - 4.2 (m, 3H) 4.3 - 4.4 (m, 1H) 4.6 - 4.7 (m, 1H) 6.9 - 7.0 (m, 1H) 7.2 (s, 1H) 7.9 (dd, J = 9.1, 1.4 Hz, 1H) 8.1 (s, 1H) 8.3 - 8.4 (m, 1H) 8.4 (s, 1H) 8.8 (s, 1H) 11.2 (s, 1H).

[0141] Crystallization test Formation of amorphous material Form A of the 3g compound (I) was dissolved by stirring in 60 mL of trifluoroethanol / water (50:50) at 50 °C for 0.5 h. The resulting solution was immersed in a liquid N2 bath and frozen, and then freeze-dried in a freeze dryer (see Christ Alpha2-4 LD, www.martinchrist.de) to produce the amorphous compound (I). The amorphous nature of the recovered solid was confirmed by XRPD analysis. A mass recovery rate of 91% was obtained.

[0142] Form A The amorphous compound (I) (20 mg) was suspended in 2-propanol (800 μL) and stirred at room temperature for 2 weeks. The resulting solid was collected by filtration. After drying at ambient temperature, XRPD analysis of the material revealed that the solid was Form A, the anhydrous form of compound (I) (see the diffractogram in Figure 1). The solid of Form A was exposed to accelerated aging conditions (40 °C, 75% relative humidity) for 2 days and re-analyzed by XRPD, and it was found that Form A was stable under the accelerated aging conditions.

[0143] In similar experiments using ethers (1,2-dimethoxyethane, diethyl ether, THF, t-butyl methyl ether, anisole), esters (ethyl acetate, ethyl formate, isopropyl acetate), alcohols (methanol, ethanol, 1-propanol), ketones (acetone, methyl isobutyl ketone), acetonitrile and DMSO, Form A of compound (I) was obtained in all cases.

[0144] The physical and chemical stabilities of Form A of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide were further evaluated according to a standard protocol over 21 days under stress conditions (high temperature (70 °C), low relative humidity (11%) and high relative humidity (75%)). Briefly, samples of the Form A material were weighed and placed into sample vials, which were then placed into separate jars each containing a MadgeTech temperature and humidity logger, and into the separate vials was placed a saturated solution of either lithium chloride (to impart 11% relative humidity) or sodium chloride (to impart 75% relative humidity). The two jars (low / high humidity) were then sealed and placed in an oven calibrated to 70 °C for 21 days. During the test period, control samples were placed in sealed vials and maintained in a refrigerator.

[0145] Analysis of the samples by UHPLC revealed that no organic impurities were generated in the samples stored at 70 °C for 21 days at low or high relative humidity. Furthermore, it was confirmed by XRPD that the physical form of the material did not change over the test period. Thus, it can be concluded that neither chemical decomposition nor change in the physical form of the sample occurred even when stored under stress conditions. Therefore, the suitability of Form A of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide for further development of pharmaceutical formulations was established.

[0146] Form B The amorphous compound (I) (19.6 mg) was dissolved in 700 μL of THF / water / 1,1,1,3,3,3 - hexafluoro - 2 - propanol (ratio 38.6:25.7:35.7) at room temperature (RT). The resulting solution was treated with a defined volume of cyclopropyl methyl ether (700 μL) at RT until precipitation occurred. The precipitated solid was separated from the liquid phase by centrifugation and then dried under ambient conditions (Amb.) and analyzed by HT - XRPD. Analysis revealed that this material was in the trihydrate crystalline form, i.e., Form B presenting the XRPD shown in Figure 2.

[0147] Form C The amorphous compound (I) (1.012 g) was dissolved in a 50 / 50 mixture of trifluorethanol / water (15.4 mL), then frozen (liquid N2 bath) and dried overnight (in a freeze - dryer Christ Alpha2 - 4 LD). The resulting amorphous material was incubated at 40 °C and 75% relative humidity for 2 days to obtain Form C of compound (I).

[0148] The oxalate form of compound (I) Form A of compound (I) (1 g, 1 equivalent) and oxalic acid dihydrate (273 mg, 1 equivalent) were slurried in 5 ml of ethyl acetate at ambient temperature for 4 days. Then, another 10 ml of ethyl acetate was added and slurrying was continued at ambient temperature for a further 4 days. The solid obtained at this stage was collected by filtration. The resulting sample of the oxalate of compound (I) was dried at ambient temperature and then subjected to XRPD analysis.

[0149] The 3 - hydroxybenzoic acid form of compound (I) Form A of compound (I) (1 g, 1 equivalent) and 3 - hydroxybenzoic acid (299 mg, 1 equivalent) were slurried in 5 ml of dichloromethane / methanol (1:1) at ambient temperature for 4 days. The solid obtained at this stage was collected by filtration. The resulting sample of the 3 - hydroxybenzoic acid form of compound (I) was dried at ambient temperature and then subjected to XRPD analysis.

Claims

1. N-(imidazo[1,2-b]pyridazine-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamide)cyclohexyl)-2H-indazole-5-carboxamide: 【Chemistry 1】 The crystalline form of or a pharmaceutically acceptable salt or solvate thereof.

2. The crystalline form according to claim 1, characterized by having an X-ray powder diffraction pattern showing specific peaks at approximately 2-theta = 4.9, 12.5, 16.7, 18.8, and 23.4°, which is an anhydrous form of form A.

3. The crystal form according to claim 1, characterized in that it is an anhydrous form of form A, having an X-ray powder diffraction pattern showing specific peaks at approximately 2-theta = 4.9, 9.7, 12.5, 16.7, 18.8, 19.5, 20.7, 23.4, 25.1, and 27.4°.

4. When measured using CuKα irradiation, Figure 1 【Chemistry 2】 The crystal morphology according to claim 1, characterized by having an X-ray powder diffraction pattern substantially shown therein.

5. The crystalline form of the trihydrate form of form B according to claim 1, characterized by having an X-ray powder diffraction pattern showing specific peaks at approximately 2-theta = 6.7, 11.3, 11.9, 17.2, and 26.1°.

6. When measured using CuKα irradiation, Figure 2 【Transformation 3】 The crystal morphology according to claim 1, characterized by having an X-ray powder diffraction pattern substantially shown therein.

7. The crystalline form according to claim 1, characterized by having an X-ray powder diffraction pattern showing specific peaks at approximately 2-theta = 11.2, 27.2, 3.6, 22.6 and 26.5°, being a 1:1 acid addition salt of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamide)cyclohexyl)-2H-indazole-5-carboxamide and oxalic acid.

8. When measured using CuKα irradiation, Figure 4 【Chemistry 4】 The crystal morphology according to claim 1, characterized by having an X-ray powder diffraction pattern substantially shown therein.

9. The crystalline form according to claim 1, characterized by having an X-ray powder diffraction pattern showing specific peaks at approximately 2-theta = 10.8, 16.5, 27.1, 18.4 and 3.4°, and being a 1:1 cocrystal of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamide)cyclohexyl)-2H-indazole-5-carboxamide and 3-hydroxybenzoic acid.

10. When measured using CuKα irradiation, Figure 5 【Transformation 5】 The crystal morphology according to claim 1, characterized by having an X-ray powder diffraction pattern substantially shown therein.

11. A pharmaceutical preparation comprising a crystalline form according to any one of claims 1 to 10 and at least one pharmaceutically acceptable additive such as a diluent or granulator.

12. The pharmaceutical composition according to claim 11 for the prevention or treatment of respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), cancer, inflammatory diseases, or autoinflammatory / autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjögren's syndrome, systemic scleroderma, gout, endometriosis, atopic dermatitis, and psoriasis.

13. The pharmaceutical composition according to claim 11 for use in the treatment of hematological malignancies selected from cancers, for example, Waldenström macroglobulinemia (WM), non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), primary central nervous system lymphoma (PCNSL), splenic marginal zone lymphoma (SMZL), small lymphocytic lymphoma (SLL), leukemia (chronic lymphocytic leukemia (CLL)), and monoclonal hypergammaglobulinemia of unspecified significance (MGUS-IgM+).

14. A pharmaceutical product comprising the crystalline form of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamide)cyclohexyl)-2H-indazole-5-carboxamide as an active ingredient, according to any one of claims 1 to 10.

15. A method for producing N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamide)cyclohexyl)-2H-indazole-5-carboxamide, wherein the method is 【Transformation 6】 The step involves reacting the X group in the presence of carbon monoxide and a catalyst, wherein the X group is Br, Cl, I, OTf, or OSO ２ A method selected from Me.

16. Compound N-((1r,4r)-4-(5-bromo-6-methoxy-2H-indazole-2-yl)cyclohexyl)-N-methylacetamide. 【Transformation 7】

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