WO2024189184A1

WO2024189184A1 - N-[3-(5-(2-aminopyrimidin-4-yl)-2-(tert-butyl)thiazol-4-yl)-2-fluorophenyl]-2,6-difluorobenzenesulfonamide or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of cerebral cavernous malformation

Info

Publication number: WO2024189184A1
Application number: PCT/EP2024/056929
Authority: WO
Inventors: Hua Huang; Peetra MAGNUSSON; Maximiliano ARCE
Original assignee: Individual
Current assignee: Individual
Priority date: 2023-03-16
Filing date: 2024-03-15
Publication date: 2024-09-19
Anticipated expiration: 2025-09-16

Abstract

The disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of cerebral cavernous malformation (CCM). Further, the disclosure provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable excipient, carrier and/or diluent for use in the treatment and/or prevention of cerebral cavernous malformation (CCM).

Description

N-[3-(5-(2-AMINOPYRIMIDIN-4-YL)-2-(TERT-BUTYL)THIAZOL-4-YL)-2- FLUOROPHENYL]-2,6-DIFLUOROBENZENESULFONAMIDE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF FOR USE IN THE TREATMENT AND/OR PREVENTION OF CEREBRAL CAVERNOUS MALFORMATION Technical field The present disclosure relates to the compound N-[3-(5-(2-aminopyrimidin-4-yl)-2- (tert-butyl)thiazol-4-yl)-2-fluorophenyl]-2,6-difluorobenzenesulfonamide, or a pharmaceutically acceptable salt thereof, and uses thereof. More specifically, the present disclosure relates to N-[3-(5-(2-aminopyrimidin-4-yl)-2-(tert-butyl)thiazol-4- yl)-2-fluorophenyl]-2,6-difluorobenzenesulfonamide, or a pharmaceutically acceptable salt thereof, for use in the treatment and prevention of Cerebral Cavernous Malformation (CCM). Background Cerebral cavernous malformation, which is commonly abbreviated as CCM, is a neurological disorder characterised by vascular lesions comprised of clusters of dilated, tightly packed veins in the central nervous system (CNS). Cerebral cavernous malformation may also be denominated Cerebral cavernoma, Cerebral cavernous angioma, Cerebral cavernous haemangioma, Central nervous system cavernous malformation, Central nervous system cavernous angioma, Central nervous system cavernous haemangioma, Familial cerebral cavernous malformation, Familial cerebral cavernous angioma, Familial cerebral cavernous haemangioma, Cerebral cavernous venous malformation, Intracerebral cavernous malformation, Intracerebral cavernous angioma or Intracerebral cavernous haemangioma. There are two forms of CCM: familial and sporadic. Familial CCM is reported to be hereditary and caused by mutations in any one of the three genes CCM1 (or KRIT1), CCM2 (or Malcavernin) and CCM3 (or PDCD10). CCM proteins form functional protein complex. CCMs proteins are important in maintaining junctions and vascular barriers. Loss of function of the CCM genes leads to vascular leakage. These genes are understood to encode three cytoplasmic proteins, CCM1-3. Individuals affected by familial CCM typically have multiple lesions. In contrast, those affected by the sporadic forms have no family history of the disorder. Typically, those affected by sporadic CCM have only one lesion. The CCM lesions, which are commonly detected via magnetic resonance imaging (MRI), range in size from a few millimetres to several centimetres, depending on the number of blood vessels involved. CCMs may exist without apparent symptoms. However, the thin, dilated vascular walls of the lesions are susceptible to bleeding, which may lead to haemorrhagic stroke, seizures, various neurological symptoms such as headache and/or focal neurological deficits such as problems associated with speech, vision or hearing. Repeat bleeding from a CCM is common, occurs unpredictably, and can progressively worsen neurological problems. Familial CCM is a rare disorder affecting only a small percentage of the population. It is estimated that about 16 to 50 per 10,000 people worldwide are affected by CCMs, with an increasing prevalence of detection at older ages. CCMs are one of several types of vascular malformations (VMs), which are characterised by abnormal vessels. VMs are divided into four groups: simple malformations, combined malformations, malformations of major named vessels, and malformations associated with other anomalies. Simple malformations are composed of only one type of vessel, i.e., capillary, lymphatic and venous malformations, except for arteriovenous malformations (AVMs), which contain arteries, veins, and capillaries. In combined vascular malformations, two or more VMs are associated in one lesion. Malformations of major named vessels consist of anomalies in the origin, course, number, length, diameter or valves of large veins, arteries, or lymphatics. Malformations associated with other anomalies occur when VMs (simple and/or of major named vessels) are associated with anomalies of bone, soft tissue or viscera. VMs can be categorised into two groups based on flow characteristics: high-flow and low-flow. Low-flow malformations involve interconnections between abnormal capillaries, lymphatics, or veins (i.e., capillary, lymphatic and venous malformations), whilst high-flow malformations involve direct complex interconnections between arteries and veins (i.e., AVMs). Thus, there is a large amount of heterogeneity between the several types of VMs, which represent a broad spectrum of disorders from a simple “birthmark” to life-threatening structures. As clusters of dilated, tightly packed veins in the CNS, CCMs fall under the category of venous malformations. Vemurafenib is a cancer drug used for the treatment of late-stage melanoma associated with a mutated version of the gene BRAF and acts as an inhibitor of the associated enzyme B-Raf. Vemurafenib has been shown to be an effective treatment for AVMs. J. Clin. Invest. 2018, 128(4), pp. 1496–1508 discloses that mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy. Multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF and MAP2K1, a pathway commonly activated in cancer and responsible for the germ- line RAS-opathies, are described. The variants were more frequent in high-flow than low-flow VMs. Treatment of AVM-BRAF mutant zebrafish having AVM with vemurafenib restored blood flow in AVM. It is stated that the findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalised medical treatment by repurposing existing cancer therapies. Interventional Neuroradiology 2021, 27(4), pp. 539–546 discloses findings that support a high prevalence of somatic activating mutations in KRAS and, less commonly, BRAF in the overwhelmingly majority of brain AVMs. It is stated that this pathway homogeneity in CNS arteriovenous malformations also supports the development of targeted therapies with RAS/RAF pathway inhibitors. BRAIN 2019, 142, pp. 23-34 discloses that a high prevalence of KRAS/BRAF somatic mutations are found in brain and spinal arteriovenous malformations (BAVMs/SAVMs), with no other replicated tumour-related mutations. The findings support a causative role of somatic activating mutations in KRAS/BRAF in the overwhelming majority of BAVMs and SAVMs. This pathway homogeneity and high prevalence are stated to imply the development of targeted therapies with RAS/RAF pathway inhibitors without the necessity of tissue genetic diagnoses. WO 2009/137391 discloses dabrafenib and pharmaceutically acceptable salts thereof, including dabrafenib mesylate. The use of dabrafenib for treating and/or preventing CCM is not disclosed. Currently, there are no direct therapeutic approaches for CCM other than surgery. The decision to remove the lesion is made based on its location and the associated risks of complication. Individuals with CCM encounter a diagnosis that imparts risk of multiple, unpredictable haemorrhages with no option for preventative therapy except surgical removal. Thus, there is a need for a therapeutic agent allowing for treating and/or preventing CCM. Summary It is an object of the present disclosure to overcome or at least mitigate some of the problems associated with the treatment and/or prevention of cerebral cavernous malformation (CCM). Further, it is an object of the present disclosure to provide aspects and/or advantages not provided by hitherto known techniques. The present disclosure provides a compound of Formula I:

Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of cerebral cavernous malformation (CCM). There is also provided a pharmaceutical composition comprising a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable excipient, carrier and/or diluent for use in the treatment and/or prevention of CCM. The present disclosure also provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for the manufacture of a medicament for use in the treatment and/or prevention of CCM. The present disclosure also provides a method for the treatment and/or prevention of CCM, said method comprising administering to a mammal, such as a human or an animal, in need thereof, an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Brief description of the drawings Figure 1 shows the chemical structure of the pharmaceutical drug vemurafenib. Figure 2A shows a confocal microscopy image of cultured shScramble control human brain endothelial cells in relation to dabrafenib. Figure 2B shows a confocal microscopy image of cultured CCM3-deficient human brain endothelial cells in relation to dabrafenib. Figure 2C shows cell eccentricity in shScramble cells and cultured CCM3-deficient human brain endothelial cells analysed by CellProfiler. Figure 2D shows the quantification of Ki67 staining of cultured CCM3-deficient human brain endothelial cells using Ki67 antibodies. Figure 2E shows the protein level of the pathogenic transcription factor marker KLF4 in CCM3-deficient human brain endothelial cells KLF4 protein levels analysed by Western blot. Figure 2F shows a confocal microscopy image of cultured CCM3-deficient human brain endothelial cells in relation to vemurafenib. Figure 3A shows the dabrafenib treatment schedule in the acute CCM3 mouse model. Figure 3B shows brain lesions after sectioning in the acute CCM3 mouse model for dabrafenib and vehicle, respectively. Figure 3C shows the quantification of the lesion area in the cerebellum of the acute CCM3 mouse model for dabrafenib and vehicle, respectively. Figure 3D shows the quantification of the lesion number in the cerebellum of the acute CCM3 mouse model for dabrafenib and vehicle, respectively. Figure 3E shows the quantification of immunoglobulin G (IgG) in the brain parenchyma of the acute CCM3 mouse model for dabrafenib and vehicle, respectively. Figure 3F shows the quantification of the IgG mean intensity in the brain parenchyma of the acute CCM3 mouse model for dabrafenib and vehicle, respectively. Figure 3G shows KLF4 expression in lesion vessels marked by collagen IV for dabrafenib and vehicle, respectively. Figure 4A shows the dabrafenib treatment schedule in the chronic CCM3 mouse model. Figure 4B shows the brain lesions after sectioning in the chronic CCM3 mouse model for dabrafenib and vehicle, respectively. Figure 4C shows the quantification of the lesion area in the cerebellum of the chronic CCM3 mouse model for dabrafenib and vehicle, respectively. Figure 5A shows the vemurafenib treatment schedule in the comparative acute CCM3 mouse model. Figure 5B shows brain lesions after sectioning in the comparative acute CCM3 mouse model for vemurafenib and vehicle, respectively. Figure 5C shows the quantification of the lesion area in the cerebellum of the comparative acute CCM3 mouse model for vemurafenib and vehicle, respectively. Figure 5D shows the quantification of the lesion number in the cerebellum of the comparative acute CCM3 mouse model for vemurafenib and vehicle, respectively. Figure 5E shows the quantification of immunoglobulin G (IgG) in the brain parenchyma of the comparative acute CCM3 mouse model for vemurafenib and vehicle, respectively. Figure 5F shows the quantification of the IgG mean intensity in the brain parenchyma of the comparative acute CCM3 mouse model for vemurafenib and vehicle, respectively. Description The present disclosure provides a compound of Formula I:

Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of cerebral cavernous malformation (CCM). Further, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable excipient, carrier and/or diluent for use in the treatment and/or prevention of cerebral cavernous malformation (CCM). Unexpectedly, the present inventors have found that the compound of Formula I may be used in the treatment and/or prevention of CCM. In particular, it has been found that the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, allows for inhibiting lesion expansion, stabilising the lesion vasculature, reducing the size of existing lesions and/or reducing vascular leakage. The compound of Formula I is a drug used for the treatment of cancers associated with a mutated version of the gene BRAF and has the International Nonproprietary Name (INN) dabrafenib. However, the inventors of the present invention have found that the beneficial effect provided by the compound of Formula I in the treatment and/or prevention of CCM is associated with a mechanism of action other than the inhibition of the BRAF. The chemical name of the compound of Formula I may be N-(3-(5-(2- aminopyrimidin-4-yl)-2-(tert-butyl)thiazol-4-yl)-2-fluorophenyl)-2,6- difluorobenzenesulfonamide, N-[3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)- 4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide or N-(3-(5-(2- aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl)-2-fluorophenyl)-2,6- difluorobenzenesulfonamide. In this document, the terms compound of Formula I, dabrafenib, N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tert-butyl)thiazol-4-yl)-2- fluorophenyl)-2,6-difluorobenzenesulfonamide, N-[3-[5-(2-amino-4-pyrimidinyl)-2- (1,1-dimethylethyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide and N-(3-(5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl)-2-fluorophenyl)-2,6- difluorobenzenesulfonamide are used interchangeably. The present disclosure also provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for the manufacture of a medicament for use in the treatment and/or prevention of CCM. Further, the present disclosure provides a method for the treatment and/or prevention of CCM, said method comprising administering to a mammal, such as a human or an animal, in need thereof, an effective amount such as a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. The pharmaceutical composition described herein may be an oral pharmaceutical composition. For example, the oral pharmaceutical composition may be provided as a liquid such as a syrup. Alternatively, the oral pharmaceutical composition may be provided as a solid such as a tablet, capsule or lozenge. In a further example, the pharmaceutical composition described herein may be a pharmaceutical composition for intravenous administration. For example, the pharmaceutical composition for intravenous administration may be a solution such as an aqueous solution comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof. The compound of Formula I, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition may be provided in a therapeutically effective amount, i.e., an amount allowing for achieving a desired therapeutic effect. For example, the therapeutically effective amount may be adjusted to provide curing and/or relief of symptoms. Further, it will be appreciated that the therapeutically effective amount may be adjusted depending on the administration route such as oral or intravenous administration. Moreover, the compound of Formula I, or pharmaceutically acceptable salt thereof, or pharmaceutical composition described herein may be administered an appropriate number of times with a frequency suitable to achieve the desired therapeutic effect. For instance, the compound of Formula I, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition may be administered daily such as once daily. Moreover, the compound of Formula I, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein may be administered during a suitable period of time such as a time sufficient to cure the CCM. Additionally or alternatively, the compound of Formula I, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein may be administered during a suitable period of time such as a time sufficient to remove or alleviate the symptoms associated with the CCM. Surprisingly, it has been found that administration of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a subject suffering from CCM inhibits lesion expansion, stabilises the lesion vasculature and/or reduces the size of existing lesions. This is in contrast to e.g. the BRAF inhibitor vemurafenib which has been found by the present inventors not to have a beneficial impact on the treatment of CCM. It will be appreciated that the compound of Formula I described herein may be provided as a pharmaceutically acceptable salt such as an acid addition salt. For example, the pharmaceutically acceptable salt may be a combination of the compound of Formula I and an acid such as a combination of the compound of Formula I and the acid in a ratio of 1:n, i.e. the ratio of the compound of Formula I to the acid, wherein n is an integer such as 1 or 0.5. The acid may be an organic acid or an inorganic acid. Pharmaceutically acceptable salts of the compound of Formula I may include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, ethanol amine, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate (methanesulfonate), methyl bromide, methyl nitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N- methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate (methylbenzenesulfonate), triethiodide, trimethylammonium and valerate. For example, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment and/or prevention of CCM wherein the pharmaceutically acceptable salt is selected from the group consisting of a mesylate, sulfate, hydrochloride and sodium salt. In particular, the pharmaceutically acceptable salt may be a mesylate salt. For instance, the mesylate salt may comprise the compound of Formula I and methanesulfonic acid in a ratio of 1:1 thereby providing a salt of Formula Ia:

Formula Ia Moreover, it will be appreciated that the compound of Formula I described herein may be provided as a solvate or as a solvate of a pharmaceutically acceptable salt of the compound of Formula I. The CCM described herein may be familial CCM or sporadic CCM. For example, the CCM may be familial CCM. Alternatively, the CCM may be sporadic CCM. It will be appreciated that familial CCM is the hereditary form of the CCM disorder and may be associated with multiple lesions. Further, sporadic CCM is considered not to be hereditary and may be associated with a single lesion. Thus, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment and/or prevention of sporadic CCM. Moreover, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment and/or prevention of familial CCM. The CCM(s) described herein can form anywhere in the body such as the human body. For example, the CCM(s) may form in the brain, retina, spinal cord and/or in the skin. In particular, the CCM(s) may form in the brain and/or the spinal cord. CCM may be asymptomatic CCM, i.e., the CCM may occur without symptoms such as without apparent symptoms. Alternatively, CCM may be symptomatic CCM, i.e., the CCM may involve symptom(s). The symptom(s) may be one or more symptom(s) with different size, location, and/or number of lesions. The CCM described herein may be asymptomatic CCM or symptomatic CCM. For example, the CCM may be asymptomatic CCM. Alternatively, the CCM may be symptomatic CCM. Accordingly, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment of asymptomatic CCM. Moreover, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment of symptomatic CCM. The symptoms may comprise or consist of one or more focal neurological deficits. For example, the focal neurological deficit(s) may be one or more of the following: headache, seizure, weakness, paralysis, numbness, thinking problem(s), memory problem(s), vision problem(s), hearing problem(s), speech problem(s), balance problem(s), attention problem(s). For instance, the symptoms may comprise or consist of headache, speech problem(s), seizure. It will be appreciated that the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment and/or prevention of CCM wherein the treatment and/or prevention comprises or consists of alleviation of one or more of the following symptoms: headache, seizure, weakness, paralysis, numbness, thinking problem(s), memory problem(s), vision problem(s), hearing problem(s), speech problem(s), balance problem(s), attention problem(s). Further, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, for use in the treatment and/or prevention of CCM wherein the treatment and/or prevention comprises or consists of alleviation of one or more of the following symptoms: headache, speech problem(s), seizure. It will be appreciated that for the treatment and/or prevention of headache as described herein the compound of Formula I, or a pharmaceutically acceptable salt thereof, may be administered in combination with acetylsalicylic acid to further enhance the alleviation of the headache. Thus, there is provided a combination comprising: (i) a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, (ii) acetylsalicylic acid, and (iii) optionally instructions for use. The components (i) and (ii) may be administered separately, sequentially or simultaneously. The instructions for use may include instructions for separate, sequential or simultaneous administration. The combination may be provided as a kit of parts or a single composition. The CCM described herein may comprise or consist of bleeding such as microbleeding and/or haemorrhage. Thus, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment of CCM wherein the CCM comprises or consists of bleeding such as microbleeding and/or haemorrhage. Further, it will be appreciated that the bleeding such as microbleeding and/or haemorrhage may occur as a singular or recurring event. The CCM described herein may comprise or consist of thrombosis. Thus, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment of CCM wherein the CCM comprises or consists of thrombosis. Further, it will be appreciated that the thrombosis described herein may occur as a singular or recurring event. The CCM may occur in subjects such as human beings of all ages. For example, the compound of Formula I, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition may be administered to a patient aged 18 or older. Additionally or alternatively, the compound of Formula I, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition may be administered to a patient who is a child or teenager under the age of 18. The compound of Formula I, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition may be administrated in conjunction with surgery to remove the CCM(s). Alternatively, the compound of Formula I, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition may be administered as an alternative to surgery. Monitoring of the CCM may take place prior to, during and after the administration. For example, Magnetic Resonance Imaging (MRI) may be used to monitor the CCM. Salts In this document, the chemical structure of the salt of Formula Ia comprising a combination of the compound of Formula I and methanesulfonic acid has been drawn as a complex wherein the acidic proton(s) of the acid is attached to said acid. However, the skilled person understands that the acidic proton(s) of the acid may be attached to a nitrogen atom of the compound of Formula I and/or shared between the nitrogen atom of the compound of Formula I and the acid. For instance, the salt of Formula Ia being a 1:1 combination of the compound of Formula I and methanesulfonic acid may also be represented as:

Formula Ia It is understood that also for other salts of the compound of Formula I the acidic proton(s) of the acid may be attached to the nitrogen atom of the compound of Formula I and/or shared between the nitrogen atom of the compound of Formula I and the acid. Isotopes The compound of Formula I of the present disclosure may contain an atomic isotope at one or more of the atoms that constitute said compounds, i.e., said compound may be labelled with an isotope. For example, the compound of Formula I may be labelled with one or more isotopes, such as for example tritium (³H), deuterium (²H) or carbon- 14 (¹⁴C). Polymorphs The compound of the present disclosure may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. Thus, it is to be understood that all polymorphs, such as mixtures of different polymorphs, are included within the scope of the claimed compounds. The disclosure further provides the following items. Item 1 Use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein for the manufacture of a medicament for use in the treatment and/or prevention of cerebral cavernous malformation (CCM). Item 2 Use of a pharmaceutical composition comprising a compound of Formula I as defined in item 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable excipient, carrier and/or diluent for the manufacture of a medicament for use in the treatment and/or prevention of cerebral cavernous malformation (CCM). The use according to item 1 or 2, wherein the pharmaceutically acceptable salt is a mesylate salt. Item 4 The use according to any one of items 1-3, wherein the cerebral cavernous malformation is sporadic cerebral cavernous malformation. The use according to any one of items 1-3, wherein the cerebral cavernous malformation is familial cerebral cavernous malformation. The use according to any one of items 1-5, wherein the cerebral cavernous malformation is symptomatic cerebral cavernous malformation. Item 7 The use according to item 6, wherein the cerebral cavernous malformation comprises bleeding, stroke and/or thrombosis. The use according to item 6 or 7, wherein the treatment and/or prevention comprises alleviation of one or more focal neurological deficits. The use according to any one of items 6-8, wherein the treatment and/or prevention comprises alleviation of one or more of the following symptoms: headache, speech problem(s), seizure. The use according to any one of items 1-5, wherein the cerebral cavernous malformation is asymptomatic cerebral cavernous malformation. Item 11 The use according to any one of items 1-10, wherein the compound of Formula I, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered to a patient aged 18 or older. Item 12 The use according to any one of items 1-10, wherein the compound of Formula I, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered to a patient who is a child or teenager under the age of 18. Item 13 A method for the treatment and/or prevention of cerebral cavernous malformation (CCM), said method comprising administering to a mammal, such as a human or an animal, in need thereof, an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein. Item 14 A method for the treatment and/or prevention of cerebral cavernous malformation (CCM), said method comprising administering to a mammal, such as a human or an animal, in need thereof, an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein. Item 15 The method according to item 13 or 14, wherein the pharmaceutically acceptable salt is a mesylate salt. Item 16 The method according to any one of items 13-15, wherein the cerebral cavernous malformation is sporadic cerebral cavernous malformation. Item 17 The method according to any one of items 13-15, wherein the cerebral cavernous malformation is familial cerebral cavernous malformation. Item 18 The method according to any one of items 13-17, wherein the cerebral cavernous malformation is symptomatic cerebral cavernous malformation. Item 19 The method according to item 18, wherein the cerebral cavernous malformation comprises bleeding, stroke and/or thrombosis. Item 20 The method according to item 18 or 19, wherein the treatment and/or prevention comprises alleviation of one or more focal neurological deficits. Item 21 The method according to any one of items 18-20, wherein the treatment and/or prevention comprises alleviation of one or more of the following symptoms: headache, speech problem(s), seizure. Item 22 The method according to any one of items 13-17, wherein the cerebral cavernous malformation is asymptomatic cerebral cavernous malformation. Item 23 The method according to any one of items 13-22, wherein the compound of Formula I, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered to a patient aged 18 or older. Item 24 The method according to any one of items 13-22, wherein the compound of Formula I, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is administered to a patient who is a child or teenager under the age of 18. The invention will be further described by reference to the following examples, which are not intended to limit the scope of the invention. Examples In this document, unless otherwise stated, the drawings of the compounds have been made using the software package Chem Draw Ultra version 12.0.21076. If the drawing and the chemical name are inconsistent, the chemical structure shall be considered to be correct. Further, the chemical name of the compound of Formula I has been generated with Chem Draw Ultra version 12.0.21076 is N-(3-(5-(2-aminopyrimidin-4- yl)-2-(tert-butyl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide. General Dabrafenib was purchased from Selleckchem (GSK2118436, catalogue number S2807, lot number S208708), and prepared in stock solution at 10 mM concentration in DMSO and stored at -80 °C for later treatment assessment. Tamoxifen (CAS number 10540- 29-1) was purchased from Sigma-Aldrich and Merck. Abbreviations AVM arteriovenous malformation CCM Cerebral Cavernous Malformation CCM3 Cerebral Cavernous Malformation 3 CNS central nervous system DAPI ^Ļ^^-diamidino-2-phenylindole DMSO dimethyl sulfoxide F-actin filamentous actin GAPDH Glyceraldehyde 3-phosphate dehydrogenase HBMVEC(s) Human Brain Microvascular Endothelial Cell(s) kg kilogram(s) KLF4 Krüppel-like factor 4 mg milligram(s) mM millimolar mL millilitre(s) MRI Magnetic Resonance Imaging Tween 80 Polysorbate 80 Pg microgram(s) PL microlitre(s) Pm micrometre(s) PM micromolar PFA paraformaldehyde PBS phosphate-buffer saline RNA ribonucleic acid w/v weight in volume VE-cadherin Vascular Endothelial Cadherin VM vascular malformation shCCM3 Short Hairpin CCM3 PDCD10 Programmed cell death 10 KRIT1 Krev1 interaction trapped gene 1 Example 1 A CCM3 in vitro cell model was achieved using primary human brain microvascular endothelial cells (i.e., HBMVECs, purchased from iXCells catalogue number 10HU- 051) transduced with lentivirus containing short hairpin RNA against CCM3 mRNA (i.e., shCCM3; 5´- GATCCGGATATAGCTAGTGCAATATTCAAGAGATATTGCACTAGCTATATCC-3´and 5´- GATCCCAACCGACTAATTCATCAATTCAAGAGATTGATGAATTAGTCGGTTG-3´). HBMVECs transduced with 3^rd generation lentiviral vectors containing scrambled shRNA were used as a control (denominated shScramble; 5´- CCTAAGGTTAAGTCGCCCTCGCTCGAGCGAGGGCGACTTAACCTTAGG-3´). Cells were transduced in low passage 3 or 4, and selection of transduced cells was performed with 2 μg/mL of puromycin to ensure successful transduction. The puromycin had CAS number 58-58-2. Freshly transduced cells were seeded with high density in collagen-I coated 18-well plates (purchased from ibidi), and treated with 5 μM dabrafenib or vemurafenib for 48 hours in full endothelial cell growth medium MV2 media (purchased from PromoCell GmbH). Afterwards, the cells were fixed with 4% PFA for 20 minutes at room temperature and washed with PBS. Fixed cells were permeabilised with 0.1% non-ionic surfactant Triton-X100 (CAS number 9036-19-5) in PBS for 5 minutes, and subsequently visualised for adherence junction VE-cadherin and F-actin stress fiber by antibody staining as follows. Antibody against VE-cadherin (catalogue number #2500, Cell Signaling Technology) was incubated with the fixed cells in PBS supplemented with 3% (w/v) BSA overnight at 4 °C. The day after, the cells were washed 3 times with PBS, and secondary antibodies donkey-anti-rabbit AlexaFluor 488 (catalogue number 711-545-152, Jackson Immunology Research) and donkey-anti-rat AlexaFluor 568 (A10037, Life Technologies) were incubated in combination with the peptide dye phalloidin-AlexaFluor 647 (catalogue number A22287, Life Technologies) for 1 hour at room temperature. After staining the cell nuclei with DAPI, the cells were mounted using the mounting medium Fluoromount-G (catalogue number 00-4958-02, Fisher Scientific), and representative images were taken using confocal microscopy on a Leica DMi8 microscope. Figure 2A shows a confocal microscopy image of cultured shScramble control human brain endothelial cells when the experiment was performed with dabrafenib. Figure 2B shows a confocal microscopy image of cultured CCM3-deficient human brain endothelial cells when the experiment was performed with dabrafenib. It was observed that the compound dabrafenib effectively restored VE-cadherin junctional location. Further, it was observed that the compound dabrafenib reduced the excessive F-actin stress fiber formation in CCM3-knockdown cells without affecting control shScramble HBMVECs. The lowest dabrafenib concentration tested and shown to be effective in restoring adherens junction VE-cadherin and F-actin stress fiber was 0.1 μM in the shCCM3 HBMVEC model. Figure 2C shows cell eccentricity analysed using the open-source software CellProfiler (https://cellprofiler.org). Cultured CCM3-knockdown cells have an elongated cell shape. Dabrafenib at a concentration of 5 μM restored the cell shape of shCCM3 HBMVECs as revealed by the cell eccentricity analysis showing that the shCCM3 HBMVECs became cobblestone-like, similar to control cells. Figure 2D shows the result of Ki67 staining of CCM3-knockdown cells using an anti- Ki67 antibody (catalogue number 14-5798-82, Thermo Fisher Scientific) following the same protocol as described above. It was observed that dabrafenib at a concentration of 5 μM reduced cell proliferation significantly. Figure 2E shows KLF4 protein levels analysed by Western blot using an anti-KLF4 antibody (catalogue number AF3640, R&D Systems). As described in EMBO Mol. Med. 2016, vol 8(1), p. 6-24, KLF4 is a pathogenic transcription factor marker in CCM. An increased KLF4 protein level was observed in the shCCM3 HBMVEC model. As shown in Figure 2E, dabrafenib at a concentration of 5 μM significantly decreased the KLF4 protein level in CCM3-knockdown cells. KLF4 relative protein levels were normalised to GAPDH, which was detected using an anti-GAPDH antibody (catalogue number ab181602, Abcam) levels using open source image analysing software ImageJ (https://imagej.nih.gov/ij/) and analysed using statistical program GraphPad Prism 9 (GraphPad Software Inc., San Diego, California). Figure 2E shows that vemurafenib reduced the expression of pathogenic marker KLF4 protein level in CCM3-knockdown human brain endothelial cells (shCCM3 HBMVECs), similar (but to a lesser extent) to dabrafenib. Figure 2F shows a confocal microscopy image of cultured CCM3-deficient human brain endothelial cells when the experiment was performed with vemurafenib. A comparison of Figure 2F with Figure 2B shows that dabrafenib had a better effect in remodeling VE-cadherin junctions and in reducing F-actin stress fibers. Thus, as evidenced by the CCM3-deficient human brain endothelial cell model, the compound dabrafenib effectively inhibited the CCM phenotype. Further, it was concluded that dabrafenib had a better effect than that exhibited by vemurafenib. Example 2 The effect of compound dabrafenib was further assessed in the mouse model Cdh5(PAC)-CreER^T2/Ccm3^fl/fl (Ccm3-iECKO) as described in Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8421-6. In this model, mice were injected intragastrically (i.g.) with tamoxifen (60 μg/30μL) dissolved in corn oil on postnatal day 1 (P1) to induce endothelial specific knockout of the Ccm3 gene. It will be appreciated that the Ccm3 gene may also be denominated Pdcd10. CCM lesion onset begins at P4 and peaks at P8. Figure 3A shows the dabrafenib treatment schedule in the acute CCM3 mouse model. As used herein, postnatal day is abbreviated P followed by the number of the postnatal day. For example, postnatal day 4 is abbreviated P4. Mice were treated with dabrafenib through daily intraperitoneal (i.p.) injections starting at P4 and continuing for four days at a dose of 20 mg/kg/day. Dabrafenib solution was first prepared as a 100 mg/mL stock solution in DMSO. The dabrafenib/DMSO stock solution was further diluted by adding 5 μL stock solution to 500 μL vehicle solution (0.2% Tween 80, 0.5% hydroxymethylcellulose in saline (i.e. 0.9% NaCl in water), ILOWHUHG^WKURXJK^D^^^^^ǋP^ILOWHU^^^7KH^FRQWURO^JURXS^UHFHLYHG^WKH^YHKLFOH^VROXWLRQ^^$W^3^^^ mice were anesthetised and euthanised with an i.p injection of 100 μL anesthetic solution (40% ketamine + 10% xylazine in PBS) and perfused first with 10 mL PBS followed by 10 mL 1% PFA perfusion through the heart. Brains were dissected and post-fixed in 4% PFA overnight at 4 °C. The following day, the brains were transferred to PBS and prepared for sectioning for further lesion assessment and lesion characteristic analysis. The comparison was performed using the same mouse litter to avoid variations coming from the genetic background. IgG leakage was measured by staining sectioned brain tissue using an antibody, anti- mouse-AlexaFluor568 diluted in PBS-0.1% Triton X-100 containing 5% donkey serum and incubated with the brain tissue sections overnight. The following day the brain sections were washed three times with PBS and mounted in Fluoromount-G. The staining was imaged by epifluorescence microscopy (Leica DMi8). Positive signal area of IgG staining was measured under a defined threshold for the detectable signals. IgG leakage was assessed by the percentage of positive IgG signal area normalized to the cerebellum parenchymal area and the mean gray value of the IgG positive signal from the whole cerebellum parenchymal tissue using ImageJ software. Figure 3B shows the brain lesions of the vehicle-treated and dabrafenib-treated mice, respectively, after sectioning. Figure 3C shows the quantification of the lesion area in the cerebellum of the vehicle-treated and dabrafenib-treated mice. Figure 3D shows the quantification of the lesion number in the cerebellum of the vehicle-treated and dabrafenib-treated mice. It was observed that after four days of treatment, the mouse group receiving dabrafenib had a significant reduction in lesion area and lesion number compared to the vehicle-treated group. CCM lesions are characterised by thin vessel walls and disrupted junctions and blood components are prone to leak to the brain parenchyma. Figure 3E shows the quantification of immunoglobulin G (IgG) in the brain parenchyma of the vehicle- treated and dabrafenib-treated mice. Figure 3F shows the quantification of the IgG mean intensity in the brain parenchyma of the vehicle-treated and dabrafenib-treated mice. Dabrafenib treatment significantly reduced perilesional leakage of the macromolecule IgG to the brain parenchyma, as assessed by the IgG staining of the brain sections collected from the mice. KLF4 expression was assessed by an anti-KLF4 antibody (purchased from R&D Systems) incubation on the brain sections overnight at 4 °C, followed by a specific secondary antibody incubation. KLF4 staining was visualised using confocal microscopy on a Leica DMi8 microscope. Figure 3G shows KLF4 expression in lesion vessels marked by using an anti-collagen IV antibody with the same method as the KLF4 detection described above (purchased from AbD Serotec, catalogue number 2150-1470). It was observed that dabrafenib treatment reduced the pathogenic marker KLF4 expression in the lesion vessels in comparison to the vehicle-treated mice. Thus, as evidenced by the acute CCM mouse model, the compound dabrafenib effectively decreases CCM lesion burden. Example 3 The effect of dabrafenib on pre-existing lesions was assessed in a chronic CCM mouse model using Cdh5(PAC)-CreER^T2/Ccm3^fl/fl (Ccm3-iECKO) mice. In this model, mice were injected intragastrically (i.g.) with tamoxifen (5 μg/30μL) dissolved in corn oil on P1. CCM lesions establish at P8, further progress by growing in size until P14, and eventually, the disease severity peaks at P28-P30 (Nat Commun., 2019, vol. 10, p. 2761). Figure 4A shows the dabrafenib treatment schedule in the chronic CCM3 mouse model. Mice were treated with dabrafenib daily through oral gavage at a dose of 5 mg/kg/day, starting from P14 to P28. A dabrafenib stock solution was prepared following the same procedure as described for the acute CCM mouse model. The treatment dose for the mice was calculated to correspond to a dose used in a clinical trial for paediatric glioma patients (Clin. Cancer Res., 2019, vol. 25, p. 7303-7311). The control group received a corresponding vehicle solution (i.e. .2% Tween 80, 0.5% hydroxymethylcellulose in water^^ILOWHUHG^WKURXJK^D^^^^^ǋP^ILOWHUV^. The CCM lesions were assessed at P29 following the same procedure as described for the acute CCM mouse model. Figure 4B shows the brain lesions of the vehicle-treated and dabrafenib-treated mice, respectively, after sectioning. Figure 4C shows the quantification of the lesion area in the cerebellum of the vehicle-treated and dabrafenib-treated mice. The mouse group receiving dabrafenib had a significantly reduced cerebellar CCM lesion area compared to the vehicle-treated group. Thus, as evidenced by the chronic CCM mouse model, the compound dabrafenib effectively reduces the size of pre-existing established lesions. Comparative Example The effect of compound vemurafenib was assessed in a comparative acute mouse model to directly compare the effects of two compounds that have been reported to be BRAF inhibitors, vemurafenib and dabrafenib (as described in Example 2). The effect of compound vemurafenib was assessed in the mouse model Cdh5(PAC)- CreER^T2/Ccm3^fl/fl (Ccm3-iECKO) as described in Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8421-6. In this model, mice were injected intragastrically (i.g.) with tamoxifen (60 μg/30μL) dissolved in corn oil on postnatal day 1 (P1) to induce endothelial specific knockout of the Ccm3 gene. CCM lesion onset begins at P4 and peaks at P8. Figure 5A shows the vemurafenib treatment schedule in the acute CCM3 mouse model. As used herein, postnatal day is abbreviated P followed by the number of the postnatal day. For example, postnatal day 4 is abbreviated P4. Mice were treated with vemurafenib through daily intraperitoneal (i.p.) injections starting at P4 and continuing for four days at a dose of 20 mg/kg/day. Vemurafenib solution was first prepared as a 100 mg/mL stock solution in DMSO. The vemurafenib/DMSO stock solution was further diluted by adding 5 μL stock solution to 500 μL vehicle solution (0.2% Tween 80, 0.5% hydroxymethylcellulose in saline, filtered through a 0.2 ǋm filter). The control group received the vehicle solution. At P8, mice were anesthetised and euthanised with an i.p injection of 100 μL anesthetic solution (40% ketamine + 10% xylazine in PBS) and perfused first with 10 mL PBS followed by 10 mL 1% PFA perfusion through the heart. Brains were dissected and post-fixed in 4% PFA overnight at 4 °C. The following day, the brains were transferred to PBS and prepared for sectioning for further lesion assessment and lesion characteristic analysis. The comparison was performed using the same mouse litter to avoid variations coming from the genetic background. IgG leakage was measured by staining sectioned brain tissue using an antibody, anti- mouse-AlexaFluor568 diluted in PBS-0.1% Triton X-100 containing 5% donkey serum and incubated with the brain tissue sections overnight. The following day the brain sections were washed three times with PBS and mounted in Fluoromount-G. The staining was imaged by epifluorescence microscopy (Leica DMi8). Positive signal area of IgG staining was measured under a defined threshold for the detectable signals. IgG leakage was assessed by the percentage of positive IgG signal area normalized to the cerebellum parenchymal area and the mean gray value of the IgG positive signal from the whole cerebellum parenchymal tissue using ImageJ software. Figure 5B shows the brain lesions of the vehicle-treated and vemurafenib-treated mice, respectively, after sectioning. Figure 5C shows the quantification of the lesion area in the cerebellum of the vehicle-treated and vemurafenib-treated mice. Figure 5D shows the quantification of the lesion number in the cerebellum of the vehicle-treated and vemurafenib-treated mice. It was observed that after four days of treatment, the mouse group receiving vemurafenib showed no significant reduction in lesion area or lesion number compared to the vehicle-treated group. Figure 5E shows the quantification of immunoglobulin G (IgG) in the brain parenchyma of the vehicle-treated and vemurafenib-treated mice. Figure 5F shows the quantification of the IgG mean intensity in the brain parenchyma of the vehicle- treated and vemurafenib-treated mice. Vemurafenib treatment did not reduce perilesional leakage of the macromolecule IgG to the brain parenchyma, as assessed by the IgG staining of the brain sections collected from the mice included in the study. Thus, as evidenced by the comparative acute CCM mouse model, the compound vemurafenib does not decrease CCM lesion burden. This is in contrast to the compound dabrafenib which decreased CCM lesion burden in the comparative acute CCM mouse model as shown in Example 2. Vemurafenib and dabrafenib have both been reported to be BRAF inhibitors. However, as shown in this comparative example, only dabrafenib had a beneficial impact on treating CCM. References 1. Al-Olabi L., et al., J. Clin. Invest. 2018, 128(4), pp. 1496–1508. 2. Bameri O., et al., Interventional Neuroradiology 2021, 27(4), pp. 539–546. 3. Hong T., et al., BRAIN 2019, 142, pp. 23-34. 4. Cuttano R., et al., EMBO Mol. Med. 2016, vol 8(1), p. 6-24. 5. Orsenigo F., et al., eLife 2020, 9:e61413. 6. Malinverno M. et al., Nat Commun., 2019, vol. 10, p. 2761. 7. Hargrave D. R., Clin. Cancer Res., 2019, vol. 25, p. 7303-7311. 8. Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8421-6.

Claims

Claims 1. A compound of Formula I:

Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of cerebral cavernous malformation (CCM).

2. A pharmaceutical composition comprising a compound of Formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable excipient, carrier and/or diluent for use in the treatment and/or prevention of cerebral cavernous malformation (CCM).

3. The compound of Formula I, or pharmaceutically acceptable salt thereof, for use according to claim 1, or the pharmaceutical composition for use according to claim 2, wherein the pharmaceutically acceptable salt is a mesylate salt.

4. The compound of Formula I, or a pharmaceutically acceptable salt thereof, for use according to claim 1 or 3, or the pharmaceutical composition for use according to claim 2 or 3, wherein the cerebral cavernous malformation is sporadic cerebral cavernous malformation.

5. The compound of Formula I, or a pharmaceutically acceptable salt thereof, for use according to claim 1 or 3, or the pharmaceutical composition for use according to claim 2 or 3, wherein the cerebral cavernous malformation is familial cerebral cavernous malformation.

6. The compound of Formula I, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 or 3-5, or the pharmaceutical composition for use according to any one of claims 2-5, wherein the cerebral cavernous malformation is symptomatic cerebral cavernous malformation.

7. The compound of Formula I, or a pharmaceutically acceptable salt thereof, for use according to claim 6, or the pharmaceutical composition for use according to claim 6, wherein the symptomatic cerebral cavernous malformation comprises bleeding, stroke and/or thrombosis.

8. The compound of Formula I, or a pharmaceutically acceptable salt thereof, for use according to claim 6 or 7, or the pharmaceutical composition for use according to claim 6 or 7, wherein the treatment and/or prevention comprises alleviation of one or more focal neurological deficits.

9. The compound of Formula I, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 6-8, or the pharmaceutical composition for use according to any one of claims 6-8, wherein the treatment and/or prevention comprises alleviation of one or more of the following symptoms: headache, speech problem(s), seizure.

10. The compound of Formula I, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 or 3-5, or the pharmaceutical composition for use according to any one of claims 2-5, wherein the cerebral cavernous malformation is asymptomatic cerebral cavernous malformation.

11. The compound of Formula I, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 or 3-10, or the pharmaceutical composition for use according to any one of claims 2-10, wherein the compound of Formula I, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered to a patient aged 18 or older.

12. The compound of Formula I, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 or 3-10, or the pharmaceutical composition for use according to any one of claims 2-10, wherein the compound of Formula I, or pharmaceutically acceptable salt thereof, the pharmaceutical composition, or is administered to a patient who is a child or teenager under the age of 18.