Solid forms of heterocyclyl amides as 1RAK4 inhibitors

Abstract

The present specification relates to novel physical forms of indazole-5-carboxamide derivatives as well as solvate and salt forms of the compounds. A process for preparing the compound and uses of these novel physical forms are also provided.

Description

[0001] The present invention relates to polymorphs, salts, co-crystals and solvate forms of N-(imidazo[1,2-b]pyridazine-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide (compound (I)), pharmaceutical compositions containing the same and their use in therapy. The present invention also relates to a chemical method for producing compound (I). It has been found that compound (I) is a highly active inhibitor of IRAK4 and therefore has potential utility as a drug for treating 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.

[0002] Interleukin-1 receptor (IL-1R)-associated kinase 4 (IRAK4) is a key regulator of immune signaling. IRAK4 is expressed by a variety of cell types and mediates signal transduction from Toll-like receptors (TLRs) and receptors of the interleukin-1 (IL-1) family, including IL-1R, IL-18R, and IL-33 receptor ST2. TLRs recognize and respond to ligands derived from microorganisms, such as lipopolysaccharide (LPS) or microbial RNA or DNA, while receptors of the IL-1 family can be activated by endogenous ligands produced by TLR-activated cells (IL-1β and IL-18) or by tissue injury (IL-1α and IL-33). Upon activation of TLRs or IL-1 receptors by their ligands, the adaptor protein myeloid differentiation primary response 88 (MyD88) is recruited to the receptors and, together with proteins of the IRAK family (IRAK1, IRAK2, and IRAK4), forms a multimeric protein complex known as the "Myddosome." Myddosome acts as a signaling platform to induce nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, ending with the activation of transcription factors NF-κB, activator protein 1 (AP1), c-AMP response element binding protein (CREB), and interferon regulatory factor 5 (IRF5), thereby driving the transcription of inflammatory cytokines and chemokines. Mice lacking IRAK4 are viable but lack inflammatory cytokine responses to IL-1β, IL-18, and LPS. Humans presenting loss-of-function mutations in IRAK4 display an immunocompromised phenotype, and their immune cells show abrogated 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. Myddosome formation promotes IRAK4 autophosphorylation, which regulates Myddosome stability and downstream signaling. Cytokine induction through TLRs and IL-1R requires the kinase activity of IRAK4, as shown by studies in knock-in mice expressing IRAK4 with loss of kinase activity and studies using small molecule IRAK4 kinase inhibitors.

[0004] Given its critical role in resolving inflammatory responses, IRAK4 constitutes a target for drugs that exert anti-inflammatory effects.

[0005] Asthma and COPD (chronic obstructive pulmonary disease) are chronic lung diseases that constitute unmet medical needs worldwide. Asthma and COPD are characterized by chronic airway inflammation, involving abnormal cytokine release, dysregulated immune cell activation and airway remodeling. In asthma, airway stimulation (such as allergic, viral and bacterial stimulation) activates TLR receptors via pathogen-associated molecular patterns (PAMPs), and activates IL-1R and ST2 receptors via the release of alarmins (including IL-33 and IL-1α) and IL-1β released during inflammasome activation. TLR and IL-1 family receptors are present in a variety of cell types in 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), resulting in airway inflammation, recruitment of inflammatory cells (such as neutrophils and eosinophils), airway hyperresponsiveness and mucus production. IRAK4 inhibition has the potential to inhibit these inflammatory pathways in the airway. Gene expression analysis of lung samples from patients with asthma and COPD has revealed upregulation of gene expression associated with IL-1R and TLR2 / 4 inflammatory pathways in a subset of critically ill patients. To our knowledge, although IRAK4 inhibitors have not been explored in the clinic for the treatment of respiratory diseases, preclinical data from several research groups indicate that interference with IRAK4-regulated pathways reduces airway inflammation in animal models of both asthma and COPD. For example, mice lacking MyD88 (an important component of myddosome) are protected from airway inflammation induced by allergens or IL-33, such as mice treated with small molecule mimics that block the interaction between IRAK2 and IRAK4. It has also been found that blocking IL-1β with a monoclonal antibody inhibits airway inflammation induced by allergens and bacteria in a steroid-resistant mouse model of asthma. In addition, treating mice with the IL-1R antagonist anakinra during allergen attack improves asthma-like symptoms in a mouse model of allergic asthma. Long-term exposure to cigarette smoke is a major factor in the development of COPD. In mice exposed to cigarette smoke, IL-1 signaling is important in mediating neutrophilic airway inflammation, and blocking IL-1 signaling with antibodies against IL-1α, IL-1β, or IL-1R can improve neutrophilic inflammation in the lung and reduce bacterial or viral-induced exacerbations in mice exposed to cigarette smoke. Taken together, IRAK4 inhibition has the potential to provide a broad anti-inflammatory effect in inflammatory respiratory diseases by simultaneously blocking several disease-related signaling pathways.

[0006] As an important regulator of Myddosome, 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, WO2017207386 and WO 2015150995). In SLE, immune complexes composed of autoantibodies and autoantigens can drive TLR-dependent pathological signaling. In the pathogenesis of SLE, it is reported that IRAK4 inhibits the release of type I interferons and proinflammatory cytokines mediated by TLR7 and TLR9 activation in plasmacytoid dendritic cells. Mice expressing IRAK4 kinase activity loss mutants or treated with IRAK4 kinase inhibitor compounds tolerate experimentally induced arthritis and lupus (see, for example, WO 2017207386). The approved 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 upregulated in PBMCs (peripheral blood mononuclear cells), and salivary gland and TLR activation can stimulate the release of interferons and other inflammatory cytokines, indicating its involvement in the pathogenesis of Sjögren's syndrome. MyD88 knockout mice also show reduced disease manifestations in experimental mouse models of Sjögren's syndrome. Systemic sclerosis is a severe autoimmune disorder in which IL-1R, TLR4, TLR8, and ST2 signaling can drive pathogenic mechanisms, including microvascular damage and fibrosis. Inhibition of IRAK4 as a treatment for systemic sclerosis will therefore simultaneously block multiple disease-related pathways. In myositis, high levels of IL-1α and IL-1β may promote muscle cell inflammation. Myositis patients are also characterized as high type I interferon gene markers, which can be driven in part by TLR7 / 9 activation, and the relevance of IL-1R signaling is supported by the improved clinical results of myositis patients treated with anakinra in a smaller mechanical clinical trial. As an important regulator of the IL-1R pathway, IRAK4 is also a promising target for the treatment of gout. Monosodium urate crystals characteristically formed in gout patients can trigger the activation of inflammasomes and the release of IL-1β. Both canakinumab (a kind of anti-IL-1β monoclonal antibody) or anakinra have been used to demonstrate clinical efficacy in the treatment of gout attacks. High levels of IL-1β and IL-33 have also been found in patients with endometriosis. The importance of IRAK4 in the disease process of endometriosis is shown in a mouse model in which oral administration of IRAK4 inhibitors inhibits lesion formation. MyD88 knockout mice are also protected from suffering from endometriosis in the same mouse model.IL-33 / ST2 signal transduction is a key mechanism in atopic dermatitis, which is related to the regulation of skin inflammation, epithelial barrier integrity and eosinophil recruitment. IL-33 can trigger eczema and dermatitis in mice in a MyD88-dependent manner. As an important component of the regulator of ST2 signal transduction and myddosome, IRAK4 has the potential to suppress pathogenic IL-33 / ST2 signal transduction in atopic dermatitis. Both TLR7 and IL-1R-mediated mechanisms show that psoriasis is involved. Imiquimod (TLR / 8 agonist) can induce psoriasis-like disease in mice in a MyD88-dependent manner. IL-1 β is upregulated in psoriasis lesions and has been shown that IL-1 β / IL-1R axis contributes to skin inflammation and regulates the generation of IL-17 (a key cytokine released from TH17 cells) in the pathogenesis of psoriasis. It has been further shown that IRAK4 kinase activity is required for regulating TH17 differentiation and TH17-mediated diseases in vivo.

[0007] A variety of IRAK4 kinase inhibitors are known and have been developed in principle for oncology or inflammatory diseases (see, for example, WO 2015150995, WO 2017207386, WO 2017009806, WO2016174183, WO2018234342). Many clinical trials exploring the therapeutic utility of IRAK4 inhibitors are ongoing.

[0008] PCT / EP2021 / 084916 discloses N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide and its activity as an IRAK4 enzyme inhibitor (IC 50 0.2 nM) and IRAK4 activity in Karpas-299 cells (IC 50 5nM). In order to study the therapeutic potential of this compound, it is desirable to have a solid form of the compound with properties suitable for drug development. The present application describes novel polymorphs, salts and solvates of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide. The compound is structurally different from previously known IRAK4 inhibitors.

[0009] In the formulation of drug substances, 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 point of view of obtaining a commercially viable manufacturing method for the drug substance itself, but also from the point of view of subsequently manufacturing a drug formulation containing an active compound and a suitable excipient. The chemical stability and physical stability of the active compound are important factors that determine the suitability of the solid form for use in the development of drug formulations. The active compound and the formulation containing it should be able to be effectively stored over a considerable period of time without showing any significant changes in the physicochemical characteristics (such as chemical composition, density, hygroscopicity and solubility) of the active compound. The purpose of this specification is to provide a solid form of N-(imidazo[1,2-b]pyridazine-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide suitable for drug development. In another object, the present description provides a fast route for producing N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide.

[0010] The present application relates to a crystalline form of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide (hereinafter, "Compound (I)"). The structure of Compound (I) is shown below:

[0011]

[0012] The present application also relates to a method for producing compound (I) and key synthetic intermediates.

[0013] We have found that compound (I) can exist in a number of crystalline and salt forms.

[0014] In one aspect there is provided a crystalline form of Compound (I).

[0015] In another aspect, there is provided a physical form of Compound (I), Form A. "Form A" provides substantially Figure 1 X-ray diffraction pattern shown in . 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 for extended storage under accelerated aging conditions (40° C. and 75% relative humidity).

[0016] In another aspect, there is provided a physical form of Compound (I), Form B. "Form B" provides substantially Figure 2X-ray diffraction pattern shown in. Form B is a trihydrate crystalline form of Compound (I).

[0017] A metastable dihydrate crystalline form of Compound (I) is also described. "Form C" provides substantially Figure 3 X-ray diffraction pattern shown in. 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), for example the trihydrate form.

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

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

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

[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, a crystalline form of compound (I) is provided for use in the manufacture of a medicament for preventing or treating the following diseases: cancer, e.g., a hematological malignancy selected from the group consisting of Waldenstrom's macroglobulinemia (WM), non-Hodgkin's 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, a crystalline form of Compound (I) is provided 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 relating to a medicament include those aspects wherein the medicament is intended for human use.

[0027] In another aspect, there is provided a method for producing compound (I), the method comprising:

[0028]

[0029] The reaction is carried out in the presence of carbon monoxide and a catalyst, wherein the group X is selected from Br, Cl, I, OTf and OSO2Me.

[0030] In another aspect, the present specification provides N-((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)-N-methylacetamide

[0031]

[0032] In order that the present specification may be more fully understood, reference is made to the following drawings.

[0033] Figure 1 X-ray powder diffraction pattern of the anhydrous physical form of Compound (I) Form A, N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide.

[0034] Figure 2 X-ray powder diffraction pattern of Compound (I) Form B, the trihydrate physical form of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide.

[0035] Figure 3 X-ray powder diffraction pattern of Compound (I) Form C, dihydrate physical form of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide.

[0036] Figure 4 X-ray powder diffraction pattern of the physical form of compound (I) oxalate form, N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide.

[0037] Figure 5 X-ray powder diffraction pattern of the physical form of compound (I) 3-hydroxybenzoic acid form, N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide.

[0038] Figure 6 Thermogravimetric analysis / differential scanning calorimetry of trihydrate Form B reveals that controlled heating causes dehydration to an amorphous anhydrous form which, upon further heating, continues to crystallize to anhydrous Form D. Continued heating of Form D results in conversion to Form A. The solid and dashed lines represent differential scanning calorimetry and thermogravimetric analysis, respectively.

[0039] In the first embodiment, the present specification provides a crystalline form of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide (Compound (I)) or a pharmaceutically acceptable salt or solvate thereof:

[0040]

[0041] In an embodiment, the crystalline form of Compound (I) is an anhydrous crystalline form. In one such embodiment, the crystalline form is Compound (I) Form A, and is characterized in that the use of CuK α At least one of the following 2θ values ​​measured radiometrically: 4.9° and 23.4°. Additional features of Form A are described below.

[0042] In an embodiment, the crystalline form of Compound (I) is a hydrate crystalline form. In one such embodiment, the crystalline form is Compound (I) trihydrate Form B, and is characterized in that the use of Cu K α At least one of the following 2θ values ​​measured radiometrically: 17.2° and 26.1°. Additional features of Form B are described below.

[0043] In an embodiment, a salt form of compound (I) is provided. In one such embodiment, an oxalate form of compound (I) is provided, which is characterized in that the use of CuK α A crystalline form having at least one of the following 2θ values ​​measured radiometrically: 11.2° and 27.2°. Additional features of the oxalate salt form of Compound (I) are described below.

[0044] In an embodiment, a co-crystal form of compound (I) is provided. In one such embodiment, a 3-hydroxybenzoic acid crystalline form of compound (I) is provided, characterized in that the co-crystal form of compound (I) is provided using CuK α At least one of the following 2θ values ​​measured radiometrically: 10.8° and 16.5°. Additional characteristics of the physical form of Compound (I) 3-hydroxybenzoic acid are described below.

[0045] In an embodiment of the present specification, a method for manufacturing compound (I) is provided, the method comprising reacting a compound with formula (A), imidazo[1,2-b]pyridazine-3-amine dissolved in a suitable solvent with carbon monoxide. The group X in the compound with formula (A) is a leaving group, for example, a leaving group selected from Br, Cl, I, OSO2R, wherein R is methyl, trifluoromethyl or tolyl. The reaction is conveniently carried out with a palladium catalyst (e.g., palladium (II) catalyst). The palladium (II) catalyst can be a palladium (II) catalyst characterized by a diphosphine ligand, such as Pd(dppf)Cl2.

[0046]

[0047] Form A

[0048] Compound (I) Form A, an anhydrous physical form of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide, characterized by providing a α At least one of the following 2θ values ​​measured by irradiation: 4.9° and 23.4°. Compound (I) Form A is characterized by providing substantially Figure 1 The X-ray powder diffraction pattern of is shown in . The ten most significant peaks are shown in Table 1:

[0049] Table 1 The ten most prominent peaks of the X-ray powder diffraction pattern of Compound (I) Form A.

[0050] 2θ,° Relative Strength 4.9 Very strong 9.7 powerful 12.5 Very strong 16.7 Very strong 18.8 Very strong 19.5 Very strong 20.7 Very strong 23.4 Very strong 25.1 Very strong 27.4 Very strong

[0051] According to the present description, there is provided a crystalline form, Compound (I) Form A, having an X-ray powder diffraction pattern having at least one characteristic peak at about 2-θ=4.9°.

[0052] According to the present description, there is provided a crystalline form, Compound (I) Form A, having an X-ray powder diffraction pattern having at least one characteristic peak at about 2-θ=23.4°.

[0053] According to the present description, there is provided a crystalline form, Compound (I) Form A, having an X-ray powder diffraction pattern with at least two characteristic peaks at about 2-θ=4.9° and 23.4°.

[0054] According to the present description, there is provided a crystalline form, Compound (I) Form A, having an X-ray powder diffraction pattern with characteristic peaks at about 2-θ=4.9°, 12.5°, 16.7°, 18.8° and 23.4°.

[0055] According to the present description, there is provided a crystalline form, Compound (I) Form A, having an X-ray powder diffraction pattern having characteristic peaks at approximately 2-θ=4.9°, 9.7°, 12.5°, 16.7°, 18.8°, 19.5°, 20.7°, 23.4°, 25.1° and 27.4°.

[0056] According to the present description, there is provided a compound (I) form A having Figure 1 The X-ray powder diffraction pattern shown in is substantially the same as the X-ray powder diffraction pattern shown in.

[0057] According to the present description, there is provided a crystalline form, Compound (I) Form A, wherein the crystalline form has an X-ray powder diffraction pattern having at least one characteristic peak at 2-θ=4.9°±0.2° 2-θ.

[0058] According to the present description, there is provided a crystalline form, Compound (I) Form A, wherein the crystalline form has an X-ray powder diffraction pattern having at least one characteristic peak at 2-θ=23.4°±0.2° 2-θ.

[0059] According to the present description, there is provided a crystalline form, Compound (I) Form A, wherein the crystalline form has an X-ray powder diffraction pattern having at least two characteristic peaks at 2-θ=4.9° and 23.4°, wherein the value may be ±0.2° 2-θ.

[0060] According to the present description, there is provided a crystalline form, Compound (I) Form A, wherein the crystalline form has an X-ray powder diffraction pattern having characteristic peaks at about 2-θ=4.9°, 12.5°, 16.7°, 18.8° and 23.4°±0.2° 2-θ.

[0061] According to the present description, there is provided a crystalline form, Compound (I) Form A, wherein the crystalline form has an X-ray powder diffraction pattern having characteristic peaks at about 2-θ=4.9°, 9.7°, 12.5°, 16.7°, 18.8°, 19.5°, 20.7°, 23.4°, 25.1° and 27.4°±0.2° 2-θ.

[0062] When stating that the specification refers to the crystalline form of Compound (I) Form A, the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, preferably greater than about 90% and more preferably greater than about 95%. Most preferably, the degree of crystallinity is greater than about 98%.

[0063] Compound (I) Form A provides Figure 1The X-ray powder diffraction pattern of the present invention is substantially the same as that shown in Table 1, and has substantially the ten most significant peaks (angle 2-θ values) shown in Table 1. It will be understood that the 2-θ values ​​of an X-ray powder diffraction pattern may vary slightly from one machine to another or from one sample to another, and therefore the quoted values ​​are not to be construed as being absolute.

[0064] It is known that, depending on the measurement conditions (such as the equipment 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 an X-ray powder diffraction pattern may fluctuate depending on the measurement conditions. Therefore, it should be understood that the Compound (I) Form A of the present specification is not limited to providing Figure 1 The crystals having the same X-ray powder diffraction pattern as shown in Figure 1 Crystals having X-ray powder diffraction patterns substantially identical to those shown in the foregoing fall within the scope of the present specification. A person skilled in the art of X-ray powder diffraction is able to judge the substantial identity of the X-ray powder diffraction patterns.

[0065] Form B

[0066] Compound (I) Form B, a trihydrate physical form of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide, characterized by providing a α At least one of the following 2θ values ​​measured by irradiation: 17.2° and 26.1°. Compound (I) Form B is characterized by providing substantially Figure 2 The X-ray powder diffraction pattern of is shown in . The ten most significant peaks are shown in Table 2:

[0067] Table 1 The ten most prominent peaks of the X-ray powder diffraction pattern of Compound (I) Form B.

[0068] 2θ,° Relative Strength 6.7 Very strong 11.3 Very strong 11.9 Very strong 12.3 powerful 15.7 powerful 17.2 Very strong 22.7 powerful 26.1 Very strong 27.2 powerful 28.5 powerful

[0069] According to the present description, there is provided a crystalline form, Compound (I) Form B, having an X-ray powder diffraction pattern having at least one characteristic peak at about 2-θ=17.2°.

[0070] According to the present description, there is provided a crystalline form, Compound (I) Form B, having an X-ray powder diffraction pattern having at least one characteristic peak at about 2-θ=26.1°.

[0071] According to the present description, there is provided a crystalline form, Compound (I) Form B, having an X-ray powder diffraction pattern with at least two characteristic peaks at about 2-θ=17.2° and 26.1°.

[0072] According to the present description, there is provided a crystalline form, Compound (I) Form B, having an X-ray powder diffraction pattern with characteristic peaks at about 2-θ=6.7°, 11.3°, 11.9°, 17.2° and 26.1°.

[0073] According to the present description, there is provided a crystalline form, Compound (I) Form B, having an X-ray powder diffraction pattern having characteristic peaks at approximately 2-θ=6.7°, 11.3°, 11.9°, 12.3°, 15.7°, 17.2°, 22.7°, 26.1°, 27.2° and 28.5°.

[0074] According to the present description, there is provided a compound (I) form B having Figure 2 The X-ray powder diffraction pattern shown in is substantially the same as the X-ray powder diffraction pattern shown in.

[0075] According to the present description, there is provided a crystalline form, Compound (I) Form B, wherein the crystalline form has an X-ray powder diffraction pattern having at least one characteristic peak at 2-θ=17.2°±0.2° 2-θ.

[0076] According to the present description, there is provided a crystalline form, Compound (I) Form B, wherein the crystalline form has an X-ray powder diffraction pattern having at least one characteristic peak at 2-θ=26.1°±0.2° 2-θ.

[0077] According to the present description, there is provided a crystalline form, Compound (I) Form B, wherein the crystalline form has an X-ray powder diffraction pattern having at least two characteristic peaks at 2-θ=17.2° and 26.1°, wherein the value may be ±0.2° 2-θ.

[0078] According to the present description, there is provided a crystalline form, Compound (I) Form B, wherein the crystalline form has an X-ray powder diffraction pattern having characteristic peaks at about 2-θ=6.7°, 11.3°, 11.9°, 17.2°, 26.1°±0.2° 2-θ.

[0079] According to the present description, there is provided a crystalline form, Compound (I) Form B, wherein the crystalline form has an X-ray powder diffraction pattern having characteristic peaks at about 2-θ=6.7°, 11.3°, 11.9°, 12.3°, 15.7°, 17.2°, 22.7°, 26.1°, 27.2° and 28.5°±0.2° 2-θ.

[0080] When stating that the specification refers to the crystalline form of Compound (I) Form B, the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, preferably greater than about 90% and more preferably greater than about 95%. Most preferably, the degree of crystallinity is greater than about 98%.

[0081] Compound (I) Form B provides Figure 2 The X-ray powder diffraction pattern of the present invention is substantially the same as that shown in Table 1, and has substantially the ten most significant peaks (angle 2-θ values) shown in Table 1. It will be understood that the 2-θ values ​​of an X-ray powder diffraction pattern may vary slightly from one machine to another or from one sample to another, and therefore the quoted values ​​are not to be construed as being absolute.

[0082] It is known that, depending on the measurement conditions (such as the equipment 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 an X-ray powder diffraction pattern may fluctuate depending on the measurement conditions. Therefore, it should be understood that the Compound (I) Form B of the present specification is not limited to providing Figure 2 The crystals having the same X-ray powder diffraction pattern as shown in Figure 2 Crystals having X-ray powder diffraction patterns substantially identical to those shown in the foregoing fall within the scope of the present specification. A person skilled in the art of X-ray powder diffraction is able to judge the substantial identity of the X-ray powder diffraction patterns.

[0083] Form C

[0084] Another crystalline form of compound (I) is also obtained, namely the metastable dihydrate form of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide, Form C. Form C of compound (I) provides Figure 3 The X-ray powder diffraction pattern shown in is substantially the same as the X-ray powder diffraction pattern shown in.

[0085] Compound (I) oxalate form

[0086] Compound (I) oxalate crystalline form is a crystalline salt form comprising N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide and oxalic acid in a 1:1 ratio, characterized in that a Cu K α At least one of the following 2θ values ​​measured by irradiation: 11.2° and 27.2°. The crystalline form of the oxalate salt of Compound (I) is characterized by providing substantially Figure 4The X-ray powder diffraction pattern of is shown in . The ten most significant peaks are shown in Table 3:

[0087] Table 3 The ten most prominent peaks of the X-ray powder diffraction pattern of the crystalline form of Compound (I) oxalate.

[0088]

[0089]

[0090] According to the present description, there is provided a crystalline form, Compound (I) oxalate salt form, having an X-ray powder diffraction pattern having at least one characteristic peak at about 2-θ=11.2°.

[0091] According to the present description, there is provided a crystalline form, Compound (I) oxalate salt form, having an X-ray powder diffraction pattern having at least one characteristic peak at about 2-θ=27.2°.

[0092] According to the present description, there is provided a crystalline form, Compound (I) oxalate salt form, having an X-ray powder diffraction pattern having at least two characteristic peaks at about 2-θ=11.2° and 27.2°.

[0093] According to the present description, there is provided a crystalline form, Compound (I) oxalate salt form, having an X-ray powder diffraction pattern with characteristic peaks at about 2-θ=11.2°, 27.2°, 3.6°, 22.6° and 26.5°.

[0094] According to the present description, there is provided a crystalline form, the oxalate form of compound (I), which has an X-ray powder diffraction pattern having characteristic peaks at about 2-θ=11.2°, 27.2°, 3.6°, 22.6°, 26.5°, 15.0°, 13.9°, 15.7°, 14.6° and 18.1°.

[0095] According to the present description, there is provided a compound (I) oxalate form having Figure 4 The X-ray powder diffraction pattern shown in is substantially the same as the X-ray powder diffraction pattern shown in.

[0096] According to the present description, there is provided a crystalline form, Compound (I) oxalate form, wherein the crystalline form has an X-ray powder diffraction pattern having at least one characteristic peak at 2-θ=11.2°±0.2°2-θ.

[0097] According to the present description, there is provided a crystalline form, Compound (I) oxalate form, wherein the crystalline form has an X-ray powder diffraction pattern having at least one characteristic peak at 2-θ=27.2°±0.2° 2-θ.

[0098] According to the present description, there is provided a crystalline form, the oxalate form of compound (I), wherein the crystalline form has an X-ray powder diffraction pattern having at least two characteristic peaks at 2-θ=11.2° and 27.2°, wherein the value may be ±0.2° 2-θ.

[0099] According to the present description, there is provided a crystalline form, the oxalate form of compound (I), wherein the crystalline form has an X-ray powder diffraction pattern having characteristic peaks at about 2-θ=11.2°, 27.2°, 3.6°, 22.6° and 26.5°±0.2° 2-θ.

[0100] According to the present description, there is provided a crystalline form, the oxalate form of compound (I), wherein the crystalline form has an X-ray powder diffraction pattern having characteristic peaks at about 2-θ=11.2°, 27.2°, 3.6°, 22.6°, 26.5°, 15.0°, 13.9°, 15.7°, 14.6° and 18.1°±0.2° 2-θ.

[0101] When stating that the specification refers to the crystalline form of the oxalate salt form of Compound (I), the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, preferably greater than about 90% and more preferably greater than about 95%. Most preferably, the degree of crystallinity is greater than about 98%.

[0102] Compound (I) in the form of an oxalate provides Figure 4 The X-ray powder diffraction pattern shown in the table is substantially the same as the X-ray powder diffraction pattern shown in the table, and has substantially the ten most significant peaks (angle 2-θ values) shown in the table. It will be understood that the 2-θ values ​​of the X-ray powder diffraction pattern can vary slightly from one machine to another or from one sample to another, and therefore the quoted values ​​are not to be interpreted as being absolute.

[0103] It is known that, depending on the measurement conditions (such as the equipment 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 an X-ray powder diffraction pattern may fluctuate depending on the measurement conditions. Therefore, it should be understood that the oxalate form of compound (I) of the present specification is not limited to providing Figure 4 The crystals having the same X-ray powder diffraction pattern as shown in Figure 4 Crystals having X-ray powder diffraction patterns substantially identical to those shown in the foregoing fall within the scope of the present specification. A person skilled in the art of X-ray powder diffraction is able to judge the substantial identity of the X-ray powder diffraction patterns.

[0104] Compound (I) 3-Hydroxybenzoic acid form

[0105] Compound (I) 3-hydroxybenzoic acid crystalline form is a co-crystal form, which contains N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide and 3-hydroxybenzoic acid in a 1:1 ratio, characterized in that the use of CuK α At least one of the following 2θ values ​​measured by radiation: 10.8° and 16.5°. Compound (I) in 3-hydroxybenzoic acid form is characterized by providing substantially Figure 5 The X-ray powder diffraction pattern is shown in . The ten most significant peaks are shown in Table 1. It is possible that this co-crystal form is a salt form, but this has not been formally determined.

[0106] Table 4 The ten most prominent peaks in the X-ray powder diffraction pattern of compound (I) 3-hydroxybenzoic acid.

[0107] 2θ,° Relative Strength 3.4 Very strong 10.8 Very strong 13.3 Very strong 13.9 powerful 16.5 Very strong 17.8 Very strong 18.4 Very strong 23.4 Very strong 24.9 Very strong 27.1 Very strong

[0108] According to the present description, there is provided a crystalline form, Compound (I) 3-hydroxybenzoic acid, having an X-ray powder diffraction pattern having at least one characteristic peak at about 2-θ=10.8°.

[0109] According to the present description, there is provided a crystalline form, Compound (I) 3-hydroxybenzoic acid, having an X-ray powder diffraction pattern having at least one characteristic peak at about 2-θ=16.5°.

[0110] According to the present description, there is provided a crystalline form, Compound (I) 3-hydroxybenzoic acid, having an X-ray powder diffraction pattern having at least two characteristic peaks at about 2-θ=10.8° and 16.5°.

[0111] According to the present specification, there is provided a crystalline form, Compound (I) 3-hydroxybenzoic acid, having an X-ray powder diffraction pattern with characteristic peaks at about 2-θ=10.8°, 16.5°, 27.1°, 18.4° and 3.4°.

[0112] According to the present description, there is provided a crystalline form, compound (I) 3-hydroxybenzoic acid, having an X-ray powder diffraction pattern with characteristic peaks at about 2-θ=10.8°, 16.5°, 27.1°, 18.4°, 3.4°, 23.4°, 13.3°, 24.9°, 17.8° and 13.9°.

[0113] According to the present description, there is provided a compound (I) 3-hydroxybenzoic acid having Figure 5 The X-ray powder diffraction pattern shown in is substantially the same as the X-ray powder diffraction pattern shown in.

[0114] According to the present description, there is provided a crystalline form, Compound (I) 3-hydroxybenzoic acid, wherein the crystalline form has an X-ray powder diffraction pattern having at least one characteristic peak at 2-θ=10.8°±0.2°2-θ.

[0115] According to the present description, there is provided a crystalline form, Compound (I) 3-hydroxybenzoic acid, wherein the crystalline form has an X-ray powder diffraction pattern having at least one characteristic peak at 2-θ=16.5°±0.2°2-θ.

[0116] According to the present description, a crystalline form is provided, compound (I) 3-hydroxybenzoic acid, wherein the crystalline form has an X-ray powder diffraction pattern having at least two characteristic peaks at 2-θ=10.8° and 16.5°, wherein the value may be ±0.2° 2-θ.

[0117] According to the present description, there is provided a crystalline form, Compound (I) 3-hydroxybenzoic acid, wherein the crystalline form has an X-ray powder diffraction pattern having characteristic peaks at about 2-θ=10.8°, 16.5°, 27.1°, 18.4° and 3.4°±0.2° 2-θ.

[0118] According to the present description, there is provided a crystalline form, compound (I) 3-hydroxybenzoic acid, wherein the crystalline form has an X-ray powder diffraction pattern having characteristic peaks at about 2-θ=10.8°, 16.5°, 27.1°, 18.4°, 3.4°, 23.4°, 13.3°, 24.9°, 17.8° and 13.9°±0.2° 2-θ.

[0119] When stating that the specification refers to a crystalline form of compound (I) 3-hydroxybenzoic acid, the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, preferably greater than about 90% and more preferably greater than about 95%. Most preferably, the degree of crystallinity is greater than about 98%.

[0120] Compound (I) 3-hydroxybenzoic acid provides Figure 5 The X-ray powder diffraction pattern of the present invention is substantially the same as that shown in Table 1, and has substantially the ten most significant peaks (angle 2-θ values) shown in Table 1. It will be understood that the 2-θ values ​​of an X-ray powder diffraction pattern may vary slightly from one machine to another or from one sample to another, and therefore the quoted values ​​are not to be construed as being absolute.

[0121] It is known that, depending on the measurement conditions (such as the equipment 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 an X-ray powder diffraction pattern may fluctuate depending on the measurement conditions. Therefore, it should be understood that the compound (I) 3-hydroxybenzoic acid of the present specification is not limited to providing Figure 5 The crystals having the same X-ray powder diffraction pattern as shown in Figure 5 Crystals having X-ray powder diffraction patterns substantially identical to those shown in the foregoing fall within the scope of the present specification. A person skilled in the art of X-ray powder diffraction is able to judge the substantial identity of the X-ray powder diffraction patterns.

[0122] Anhydrous form D

[0123] A sample of the trihydrate Form B was subjected to thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and the results are presented in Figure 6 In brief, TGA and DSC measurements were performed using TGDiscovery550 (TA Instruments, Germany) and DSCDiscovery2500 (TA Instruments, Germany), respectively. Approximately 5 mg of sample (for TGA) and 2-3 mg of sample (for DSC) were weighed into an aluminum pan. Then, the sample was heated from room temperature to 350°C (for TGA) and from -50°C to 300°C (for DSC) at a heating rate of 3°C / min under a nitrogen purge of 100 mL / min. An empty aluminum pan was used as a reference for DSC. For TGA and DSC measurements, open pans and closed pans were used, respectively. For DSC measurements, a modulation mode was used, in which the modulation temperature amplitude and modulation period were set to 1°C and 60s, respectively.

[0124] In the TGA (dashed line in the figure, TGA scale on the right), a weight loss of 10.13% was observed in the temperature range from below 25°C to about 120°C. This weight loss is due to dehydration, and the 10.13% weight loss is equivalent to 2.89 water molecules per molecule of API. This is consistent with the formal designation of Form B as a trihydrate. The dehydration was carried out from relatively low temperatures (i.e., below 25°C). DSC measurements (solid line, DSC scale on the left) were carried out starting from -50°C. As shown from Figure 6 As can be seen in Figure 5, the dehydration ends at about 120°C. After dehydration, an exotherm starting at about 130°C is observed, indicating crystallization, and the new anhydrous Form D is produced. Another exotherm starting at 160°C is observed, indicating crystallization to Form A.

[0125] In situ characterization of Form D

[0126] To learn more about the characteristics of Form D, in situ characterization was performed using a SmartLab X-ray diffractometer (Rigaku, Japan) equipped with a DSC accessory. A sample of Form B was placed on a flat aluminum DSC pan. PXRD patterns were collected from 2θ = 5° to 38° with a step size and scan speed of 0.01° and 10° min, respectively. -1 The heating rate of DSC was set at 1 °C min -1 A CuKα source was used with the X-ray power set at 40 kV, 50 mA. The heating process was continued until Form B was completely dehydrated to an amorphous form and subsequently crystallized, as indicated by the appearance of diffraction peaks. The heating process was stopped immediately after obtaining the second PXRD pattern of the crystalline material (at about 111°C). -1 The furnace was cooled to room temperature at a ramp rate of 1.5 s. The material was then 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 RigakuHyPix-ED detector optimized for operation in a Micro-ED experimental setup. A total of two data sets were collected and merged to obtain a comprehensive data set with a resolution limit of Form D was determined to crystallize in triclinic space group P-1 with the following lattice parameters: α=71.25(10)°, β=85.46(10)°, γ=89.23(9), It is found that Z and Z' are 2 and 1 respectively.

[0127] X-ray powder diffraction analysis

[0128] X-ray powder diffraction analysis is performed according to standard methods, which can be found in, for example, Kitaigorodsky, AI (1973), Molecular Crystals and Molecules, Academic Press, New York; Bunn, CW (1948), Chemical Crystallography, Clarendon Press, London, London; or Klug, HP and Alexander, LE (1974), X-ray Diffraction Procedures, John Wiley & Sons, New York.

[0129] Those skilled in the art of X-ray powder diffraction will appreciate that the relative intensity of the peaks can be affected by grains, for example, that are larger than 30 microns and have non-uniform aspect ratios, which can affect the analysis of the sample. The technician will also appreciate that the reflection position can be affected by the precise height at which the sample is located in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also have a subtle effect. Therefore, the diffraction pattern data presented cannot be used as absolute values. (Jenkins, R and Snyder, RL 'Introduction to X-Ray Powder Diffractometry' John Wiley & Sons 1996; Bunn, CW (1948), Chemical Crystallography, Clarendon Press, London; Klug, HP and Alexander, LE (1974), X-Ray Diffraction Procedures).

[0130] Typically, the measurement error of the diffraction angle in the X-ray powder diffraction pattern is about 5% or less, especially ±0.2° 2-θ, and when considering Figure 1 , Figure 2 , Figure 3 , Figure 4 and Figure 5 Such a degree of measurement error should be taken into account when looking at the X-ray powder diffraction patterns in Table 1, Table 2, Table 3 and Table 4. In addition, it should be understood that the intensity may fluctuate depending on the experimental conditions and sample preparation (preferred orientation). The definition of relative intensity is described in Table 3.

[0131] X-ray powder diffraction data were measured using Corundum as an internal reference. X-ray powder diffraction (referred to herein as XRPD) patterns were determined by mounting the sample on a zero background holder single crystal silicon and spreading the sample into a thin layer.

[0132] The X-ray wavelength was 2.37 nm and 1.5 nm, respectively, using a Rigaku Miniflex 600 equipped with a D / Tex Ultra detector. Nickel-filtered CuK α Powder X-ray diffraction was recorded with a θ-2θ scanning axis and one-dimensional scanning (radiation, 40 kV, 15 mA). An automatic variable anti-scattering slit was used and the sample was rotated at 30 revolutions per minute during the measurement. The sample was scanned from 3°-50° 2-θ using a step width and scanning speed of 0.01° and 1° / min, respectively.

[0133] X-ray powder diffraction analysis is performed according to standard methods, which can be found in, for example, Kitaigorodsky, AI (1973), Molecular Crystals and Molecules, Academic Press, New York; Bunn, CW (1948), Chemical Crystallography, Clarendon Press, London, London; or Klug, HP and Alexander, LE (1974), X-ray diffraction procedures for polycrystalline and amorphous materials, John Wiley, New York, London.

[0134] Table 2 Definition of relative strength

[0135] %Relative Strength* definition 25-100 vs (very strong) 10-25 s(strong) 3-10 m(Medium) 1-3 w(weak)

[0136] *Relative intensities derived from diffraction patterns measured with fixed slits

[0137] Those skilled in the art will appreciate that the value or range of values ​​observed in a DSC thermogram of a particular compound will show variation between batches of varying purity. Thus, while the range may be small for one compound, it may be quite large for other compounds. Typically, the measurement error of the diffraction angle in a DSC thermal event is about ±5°C, and this degree of measurement error should be taken into account when considering the DSC data contained therein.

[0138] In the methods described herein, crystallization of the desired form can be assisted by seeding with crystals of the desired form. Seeds can be obtained using one of the methods described in the examples. The use of seeding is particularly advantageous in large-scale manufacturing.

[0139] In this specification, where a compound is described as having an "X-ray powder diffraction pattern having at least one characteristic peak at about 2θ = ...", the XRPD of the compound may contain one or more of the listed 2θ values. For example, one or more of the 2θ values, 2 or more of the 2θ values, or 3 or more of the 2θ values ​​are listed.

[0140] In the preceding paragraphs defining the X-ray powder diffraction peaks of the crystalline form of Compound (I), the use of the term "about =" in the expression "at 2θ about =" to indicate that the exact position of the peak (i.e. the 2-θ angle value recited) should not be interpreted as an absolute value, because, as will be appreciated by those skilled in the art, the exact position of the peak may vary slightly between one measuring device and another, from one sample to another, or due to slight changes in the measurement conditions used. It is also noted in the preceding paragraphs that the crystalline form of Compound (I) provides a peak similar to Figure 1 'substantially' the same X-ray powder diffraction pattern as shown in , having substantially the most significant peaks (2-θ angle values) shown in Table 1. It should be understood that the use of the term 'substantially' in this context is also intended to indicate that the 2-θ angle values ​​of the X-ray powder diffraction pattern may vary slightly from one apparatus to another, from one sample to another, or due to slight changes in the measurement conditions used, so that the peak positions shown in the figures or quoted in the tables are no longer to be interpreted as absolute values.

[0141] Those skilled in the art of X-ray powder diffraction will appreciate that the relative intensity of a peak can be affected by grains having a size of, for example, more than about 30 microns and non-uniform aspect ratios, which may affect the analysis of a sample. In addition, it should be understood that the intensity may fluctuate according to experimental conditions and sample preparation, such as the preferred orientation of particles in the sample. The use of automatic or fixed divergent slits will also affect relative intensity calculations. Those skilled in the art can handle such influences when comparing diffraction patterns.

[0142] Those skilled in the art of X-ray powder diffraction will also be aware that small shifts in the 2θ position may occur due to differences in sample height and calibration errors in the detector position. Typically, a deviation of ±0.1° from a given value is considered correct.

[0143] The forms of Compound (I) described herein may also be characterized and / or distinguished from other physical forms using other suitable analytical techniques (eg, NIR spectroscopy or solid-state nuclear magnetic resonance spectroscopy).

[0144] The chemical structure of the Compound (I) forms described herein can be confirmed by conventional methods such as proton nuclear magnetic resonance (NMR) analysis.

[0145] Compound (I) Forms may be prepared as described in the Examples below.

[0146] method

[0147] A synthesis of compound (I) is described in PCT / EP2021 / 084916.

[0148] The present specification provides a method for manufacturing compound (I), which comprises reacting a compound of formula (A) dissolved in a suitable solvent, imidazo[1,2-b]pyridazine-3-amine with a suitable catalyst under a carbon monoxide atmosphere. The reaction can be carried out under a high pressure of carbon monoxide, such as 5 atmospheres or higher, such as 15 atmospheres. The group X in the compound of formula (A) is a leaving group, such as a leaving group selected from Br, Cl, I, OSO2R, wherein R is methyl, trifluoromethyl or tolyl. In an embodiment, the group X is Br. The reaction is conveniently carried out with a palladium catalyst (e.g., 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), such as Pd(dppf)Cl2. Other suitable palladium (II) catalyst systems may be used, such as those featuring ligands such as Xantphos ((9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)), BINAP ((2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)) or dppp (1,3-bis(diphenylphosphino)propane). The catalyst may be preformed or may be 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 on palladium-catalyzed carbonylations are provided, for example, in Brennfuhrer et al., Angew. Chem. Int. Ed [Applied Chemistry International Edition] 2009, 48, 4114-33. The solvent may be acetonitrile. Other solvents or mixtures of solvents may also be used.

[0149] Scheme 1: Synthesis of compound (I) via aminocarbonylation reaction

[0150]

[0151] In one practical example, the reaction is carried out using N-((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)-N-methylacetamide

[0152]

[0153] Medical and pharmaceutical uses

[0154] The crystalline form of compound (I) can be used to prevent or treat respiratory diseases in mammals, especially humans, 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.

[0155] Combination therapy

[0156] The crystalline form of Compound (I) may also be administered in combination with other compounds useful in treating the above conditions.

[0157] 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 in admixture for the treatment of one or more of the above listed conditions. This combination may be used in combination with one or more additional active ingredients.

[0158] Application

[0159] A method of treating a disorder in which inhibition of IRAK4 is required is provided, the method comprising administering to a human suffering from or susceptible to such a disorder a therapeutically effective amount of a crystalline form of Compound (I).

[0160] The crystalline form of compound (I) will generally be administered via oral, parenteral, intravenous, intramuscular, subcutaneous or other injectable means, buccal, rectal, vaginal, transdermal and / or nasal routes and / or via inhalation, in the form of a pharmaceutical preparation comprising the active ingredient, in a pharmaceutically acceptable dosage form. Depending on the disorder and patient to be treated and the route of administration, these compositions can be administered at different doses.

[0161] Dosage forms suitable for oral use form one aspect of the present description.

[0162] The compositions of the present specification can be obtained by conventional procedures well known in the art using conventional pharmaceutical excipients. Therefore, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0163] Suitable pharmaceutically acceptable excipients for tablet formulations include, for example, inert diluents such as lactose; granulating agents and disintegrants such as corn starch; binders such as starch; lubricants such as magnesium stearate. Tablet formulations can be uncoated or coated using conventional coating agents and procedures well known in the art.

[0164] For additional information on formulations, the reader is referred to Chapter 25.2 of Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board) (Pergamon Press 1990).

[0165] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.

[0166] In therapeutic treatment of humans, a suitable daily dosage of the crystalline form of Compound (I) is about 0.0001-100 mg / kg body weight.

[0167] Oral formulations are preferred, particularly tablets or capsules, which can be formulated by methods known to those skilled in the art to provide a dose of active compound in the range of 0.1 mg to 1000 mg.

[0168] For additional information on routes of administration and dosage regimens, the reader is referred to Chapter 25.3 of Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board) (Pergamon Press 1990).

[0169] According to a further aspect, there is therefore provided a pharmaceutical composition comprising a crystalline form of Compound (I) in admixture with a pharmaceutically acceptable adjuvant, diluent and / or carrier.

[0170] Examples

[0171] Abbreviations used for analytical data are consistent with common usage in the art (see J Med Chem Standard Abbreviations and Acronyms). http: / / pubsapp.acs.org / paragonplus / submission / jmcmar / jmcmar_abbreviati ons.pdf ? ). The compound names provided below were generated using PerkinElmer ChemDraw Professional, version 20.0.2.51. In cases where there is uncertainty about the absolute stereochemistry, relative stereochemistry was assigned whenever possible.

[0172] Preparation of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide Form A

[0173] 5-Bromo-4-fluoro-2-nitrobenzaldehyde

[0174]

[0175] A solution of 3-bromo-4-fluorobenzaldehyde (18 kg, 88.6 mol) in concentrated sulfuric acid (54 L) at 0° C. and concentrated nitric acid (17.18 kg, 177.3 mol, 65 w / w%) at room temperature (rt) were flowed into a reaction tube at 45° C. for 15 minutes. The mixture was quenched in ice water (180 L) and extracted with toluene (90 L), the organic phase was washed with 5% aqueous K3PO4 solution (54 L), and then with saturated sodium chloride solution (54 L) to give 5-bromo-4-fluoro-2-nitrobenzaldehyde as a solution in toluene, which was used in the next step without purification.

[0176] 5-Bromo-4-methoxy-2-nitrobenzaldehyde

[0177]

[0178] At room temperature, a solution of 5-bromo-4-fluoro-2-nitrobenzaldehyde in toluene (105.3 kg) and sodium methoxide (17.31 kg, 96 mol, 30 w / w%) in methanol (110 L) were flowed into a reaction tube at 50° C. for 15 minutes to give 5-bromo-4-methoxy-2-nitrobenzaldehyde as a solution in toluene / methanol, which was used in the next step without purification.

[0179] N-((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)acetamide

[0180]

[0181] To a solution of 5-bromo-4-methoxy-2-nitrobenzaldehyde in toluene / methanol (61.47 kg) were added N-[(1R, 4R)-4-aminocyclohexyl]acetamide trifluoroacetate (3.27 kg, 12.1 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (2.81 kg, 18.4 mol), the mixture was stirred at 45° C. for 16 hours, and then cooled to room temperature. Tributylphosphine (8.17 kg, 40.38 mol) was added, and the mixture was stirred at 65° C. for 16 hours, and then allowed to cool to room temperature, concentrated, and water (30 L) was added, followed by extraction with dichloromethane (2×30 L), the organic phase was separated, and then concentrated. A solvent exchange was performed to isopropanol (IPA) and n-heptane was added to give a slurry when cooled to 0 °C, the solid was filtered and the filter cake was washed with IPA / n-heptane (1:2), dried under vacuum at 50 °C to give N-((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)acetamide (2.19 kg, 5.98 mol).

[0182] N-((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)-N-methylacetamide

[0183]

[0184] To 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) at 0°C was added MeI (3.39 kg, 23.86 mol) followed by potassium tert-butoxide (23.94 mol in THF, volume 13.3 L) dropwise and stirred at 0°C for 3 hours. The mixture was quenched with acetic acid (907.9 g, 15.12 mol) while maintaining the temperature between 0°C and 10°C. Cyclopentyl methyl ether (23 L) was then added and the mixture was concentrated before further addition of cyclopentyl methyl ether (23 L). The resulting mixture was heated to 100°C and stirred for 2 hours before being cooled to 20°C over 4 hours before 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 give N-((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)-N-methylacetamide (4.41 kg, 11.60 mol).

[0185] N-(Imidazolo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide

[0186]

[0187] N-((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)-N-methylacetamide (3.5 kg, 9.20 mol), imidazo[1,2-b]pyridazin-3-amine (1.47 kg, 10.96 mol) and triethylamine (1.86 kg, 18.38 mol) were charged into an autoclave and mixed with acetonitrile (27.3 kg) under nitrogen, stirred for 10 minutes and then treated with Pd(dppf)Cl2 (0.20 kg, 0.27 mol). The autoclave was sealed and heated at 95°C for 18 hours under a CO atmosphere at 0.1-0.8 MPa, allowed to cool and filtered, and the filter cake was washed with acetonitrile (8.19 kg). (This reaction was repeated on the same scale and the solids were combined after filtration). The combined solids were stirred in a mixture of methanol (5.37 kg) and dichloromethane (81.4 kg) and then treated with activated carbon (0.68 kg) and 3-mercaptopropyl ethyl sulfide silica (0.68 kg), stirred at room temperature for 18 hours, then filtered through celite (3.4 kg) and the filter cake washed with a 10% mixture of methanol and dichloromethane (34.82 kg). The filtrate was filtered through a 0.2 μm filter and then concentrated, diluted with methanol (37.6 kg) when all the dichloromethane had been removed, then heated to 50° C. for 2 hours, then slowly cooled to 25° C., then centrifuged, the filter cake washed with methanol (16.12 kg), and dried in a vacuum oven at 50° C. to give N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide (6.27 kg, 13.60 mol). A sample of the material was retained for seeding purposes in the crystallization described immediately below.

[0188] To a suspension of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide (6.03 kg, 13.0 mol) was added methanol (47.8 L), and the mixture was stirred and heated to 50° C. A mixture of methanesulfonic acid (1.25 kg, 13.0 mol) in methanol (3 L) was added thereto, and the solution was stirred at 50° C. for 2 hours. A solution of N-methylmorpholine (0.131 kg, 1.30 mol) in methanol (0.6 L) was then gradually added, followed by seeding with a sample of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide (54.3 g) taken from a 6.27 kg solid batch prepared directly above. The resulting mixture was stirred at 50° C. overnight, treated with another portion 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 and the filter cake was washed with methanol (2 x 4.74 kg) and dried to afford N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide Form A (5.78 kg, 12.4 mol) as a yellow solid. The XRPD of this Form A material is shown at Figure 1 middle.

[0189] 1H NMR (500MHz, CDCl3) δppm 1.7(qd,J=12.7,3.2Hz,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=9.1,1.4Hz,1H)8.1(s,1H)8.3-8.4(m,1H)8.4(s,1H)8.8(s,1H)11.2(s,1H).

[0190] Crystallization studies

[0191] Production of amorphous materials

[0192] Amorphous Compound (I) was produced by dissolving 3 g of Compound (I) Form A in 60 mL of trifluoroethanol / water (50:50) by stirring at 50 °C for 0.5 h, freezing the resulting solution by inserting into a liquid N2 bath, and then freezing in a freeze dryer (Christ Alpha2-4 LD, see www.martinchrist.de ). The amorphous nature of the recovered solid was confirmed by XRPD analysis. A mass recovery of 91% was obtained.

[0193] Form A

[0194] 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 Figure 1 The Form A solid was exposed to accelerated aging conditions (40° C., 75% relative humidity) for 2 days and reanalyzed by XRPD, which showed that Form A was stable under accelerated aging conditions.

[0195] Similar experiments were performed with ethers (1,2-dimethoxyethane, diethyl ether, THF, tert-butyl methyl ether, anisole), esters (ethyl acetate, ethyl formate, isopropyl acetate), alcohols (methanol, ethanol, 1-propanol), ketones (acetone, methyl isobutyl ketone), acetonitrile and DMSO, all of which gave Compound (I) Form A.

[0196] The physical and chemical stability of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide Form A was further evaluated under stress conditions (high temperature (70°C), at low relative humidity (11%) and high relative humidity (75%)) for a period of 21 days according to standard protocols. Briefly, samples of Form A material were weighed into sample vials, which were placed in separate jars each containing a MadgeTech temperature and humidity recorder and, in a separate vial, a saturated solution of lithium chloride (to give 11% relative humidity) or a saturated solution of sodium chloride (to give 75% relative humidity). Both jars (low / high humidity) were then sealed and placed in a calibrated oven at a temperature of 70°C for a period of 21 days. Control samples were kept in sealed vials in a refrigerator for the duration of the study.

[0197] Analysis of the samples by UHPLC revealed that no organic impurities were present in the samples stored at 70°C for 21 days at low or high relative humidity. In addition, XRPD confirmed that the physical form of the material did not change during the study. It can therefore be concluded that the samples did not undergo chemical degradation or changes in their physical form when stored under stress conditions. Therefore, the suitability of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide Form A for further development of pharmaceutical formulations was established.

[0198] Form B

[0199] 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 an equal portion of cyclopropyl methyl ether (700 μL) at room temperature until precipitation occurred. The precipitated solid was separated from the liquid phase by centrifugation, then dried under ambient conditions (Amb.) and analyzed by HT-XRPD. Analysis revealed that this material was a trihydrate crystalline form, Form B, with Figure 2 XRPD shown in .

[0200] Form C

[0201] Amorphous Compound (I) (1.012 g) was dissolved in a 50 / 50 mixture of trifluoroethanol / water (15.4 mL) and then frozen (liquid N2 bath) and dried (in a freeze dryer Christ Alpha 2-4LD) overnight. The resulting amorphous material was incubated at 40°C and 75% relative humidity for 2 days to obtain Compound (I) Form C.

[0202] Compound (I) oxalate form

[0203] Compound (I) Form A (1 g, 1 eq) and oxalic acid dihydrate (273 mg, 1 eq) were slurried in 5 ml of ethyl acetate at ambient temperature for 4 days. An additional 10 ml of ethyl acetate was then added and the slurry was continued at ambient temperature for another 4 days, at which stage the resulting solid was collected by filtration. The resulting Compound (I) oxalate sample was then dried at ambient temperature prior to XRPD analysis.

[0204] Compound (I) 3-Hydroxybenzoic acid form

[0205] Compound (I) Form A (1 g, 1 eq) and 3-hydroxybenzoic acid (299 mg, 1 eq) were slurried in 5 ml of dichloromethane / methanol (1:1) at ambient temperature for 4 days, at which stage the resulting solid was collected by filtration. A sample of the resulting Compound (I) 3-hydroxybenzoic acid form was then dried at ambient temperature prior to XRPD analysis.

Claims

1. A crystalline form of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide: or a pharmaceutically acceptable salt or solvate thereof.

2. The crystalline form according to claim 1, which is a Form A anhydrous form, characterized in that The crystalline form has an X-ray powder diffraction pattern having characteristic peaks at about 2-θ = 4.9°, 12.5°, 16.7°, 18.8° and 23.4°.

3. The crystalline form according to claim 1, which is a Form A anhydrous form, characterized in that The crystalline form has an X-ray powder diffraction pattern having characteristic peaks at about 2-θ = 4.9°, 9.7°, 12.5°, 16.7°, 18.8°, 19.5°, 20.7°, 23.4°, 25.1° and 27.4°.

4. The crystalline form according to claim 1, characterized in that The crystalline form has an X-ray powder diffraction pattern substantially as shown in Figure 1 when measured using CuKa radiation.

5. The crystalline form of claim 1, which is in the form of Form B trihydrate, characterized in that: The crystalline form has an X-ray powder diffraction pattern having characteristic peaks at about 2-θ = 6.7°, 11.3°, 11.9°, 17.2° and 26.1°.

6. The crystalline form according to claim 1, characterized in that The crystalline form has an X-ray powder diffraction pattern substantially as shown in Figure 2 when measured using CuKa radiation.

7. The crystalline form according to claim 1, which is a 1:1 acid addition salt of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide and oxalic acid, characterized in that The crystalline form has an X-ray powder diffraction pattern having characteristic peaks at about 2-θ = 11.2°, 27.2°, 3.6°, 22.6° and 26.5°.

8. The crystalline form according to claim 1, characterized in that The crystalline form has an X-ray powder diffraction pattern substantially as shown in Figure 4 when measured using CuKa radiation.

9. The crystalline form of claim 1, which is a co-crystal of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide and 3-hydroxybenzoic acid in a 1:1 ratio, characterized in that The crystalline form has an X-ray powder diffraction pattern having characteristic peaks at about 2-θ = 10.8°, 16.5°, 27.1°, 18.4° and 3.4°.

10. The crystalline form according to claim 1, characterized in that The crystalline form has an X-ray powder diffraction pattern substantially as shown in Figure 5 when measured using CuKa radiation.

11. A pharmaceutical formulation comprising a crystalline form according to any preceding claim and at least one pharmaceutically acceptable excipient such as a diluent or granulating agent.

12. The crystalline form according to any one of claims 1 to 10 for use as a medicament or for use in a method of treatment comprising administering the crystalline form according to any one of claims 1 to 10 or the composition according to claim 11 to a patient in need thereof.

13. The use or method according to claim 12 or the pharmaceutical composition according to claim 11 for preventing or treating 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 sclerosis, gout, endometriosis, atopic dermatitis and psoriasis.

14. The use or method according to claim 12 or the pharmaceutical composition according to claim 11 for treating cancer, for example a hematological malignancy selected from the group consisting of Waldenstrom's macroglobulinemia (WM), non-Hodgkin's 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+).

15. A crystalline form of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide according to any one of claims 1 to 10 for use in the manufacture of a medicament.

16. A method for producing N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetylamino)cyclohexyl)-2H-indazole-5-carboxamide, the method comprising: The reaction is carried out in the presence of carbon monoxide and a catalyst, and wherein the group X is selected from Br, Cl, I, OTf or OSO2Me.

17. A compound N-((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)-N-methylacetamide

Images