WO2024003558A1 - Prodrugs of lysyl oxidase inhibitors - Google Patents

Prodrugs of lysyl oxidase inhibitors Download PDF

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Publication number
WO2024003558A1
WO2024003558A1 PCT/GB2023/051702 GB2023051702W WO2024003558A1 WO 2024003558 A1 WO2024003558 A1 WO 2024003558A1 GB 2023051702 W GB2023051702 W GB 2023051702W WO 2024003558 A1 WO2024003558 A1 WO 2024003558A1
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cancer
compound
solvate
disease
salt
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PCT/GB2023/051702
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French (fr)
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Deborah SMITHEN
Leo Leung
Dan Niculescu-Duvaz
Richard Marais
Caroline Springer
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The Institute Of Cancer Research: Royal Cancer Hospital
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Publication of WO2024003558A1 publication Critical patent/WO2024003558A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms

Definitions

  • the present disclosure relates to prodrugs of lysyl oxidase (LOX) inhibitors as defined by Formula I herein. Also, disclosed are pharmaceutical compositions comprising said prodrugs and methods of therapy comprising the administeration of said prodrugs.
  • the prodrugs are for use in the treatment of a range of conditions, including conditions mediated by LOX, such as cancer and fibrotic disease.
  • LOX is part of a protein family consisting of five paralogues, LOX, LOX-like 1 [LOXL1], LOX-like 2 [LOXL2], LOX-like 3 [LOXL3] and LOX-like 4 [LOXL4]), all containing a conserved catalytic region.
  • LOX enzymes play a crucial role in maintaining extracellular matrix (ECM) stability, by initiating and regulating the crosslinking of collagens and elastin within the ECM.
  • ECM extracellular matrix
  • LOX In addition to its role in tissue remodelling, LOX also plays a critical role in primary cancer and metastasis. Studies have shown that LOX plays a fundamental role in the growth of primary tumours in colorectal and lung cancer (Gao, Xiao et al. 2010, Baker, Cox et al. 2011) and glioblastoma (Mammoto, Jiang et al. 2013). Tumour growth of PDAC KRAS mut /p53 wt cells engineered to express high levels of human LOX in murine allograft models is increased significantly compared to cells with endogenous LOX level (Miller, Morton et al. 2015). Lysyl oxidase activity also contributes to primary tumor growth in an aggressive pancreatic ductal adenocarcinoma (PDAC) model by impacting senescence (Wiel, Augert et al. 2013).
  • PDAC pancreatic ductal adenocarcinoma
  • LOX is elevated in more than 70 % of breast cancer patients with Estrogen Receptor negative disease, in 80 % of head and neck cancer patients, in 33 % of primary colorectal carcinomas (CRC) and 48 % of metastatic tissues from patients with CRC (Baker, Cox et al. 2011), and in cirrhotic hepatocellular carcinoma (HCC) patients with a history of alcoholism (Huang, Ho et al. 2013).
  • LOX is also overexpressed in lung adenocarcinoma (Wilgus, Borczuk et al. 2011), LKB1-mutant lung cancer (Gao, Xiao et al.
  • Elevated LOX expression is associated with metastasis and decreased patient survival (Baker, Cox et al. 2011 , Wilgus, Borczuk et al. 2011).
  • LOX acts remotely to pre-condition the niche at future sites of metastasis. T umour cell metastasis is facilitated by these “premetastatic niches” formed in destination organs (Erler, Bennewith et al. 2009).
  • Increased LOX expression is associated with disease grade, increased distant metastasis and lower overall survival in gastric cancer (Kasashima, Yashiro et al. 2015), hepatocellular carcinoma (Zhu, Huang et al.
  • LOX inhibition counteracted the metastasis-promoting, ECM-related effects of paclitaxel (Haj-Shomaly et al. 2022).
  • Nerve growth factor promotes LOX-dependent chondrosarcoma metastasis (Tzeng et al. 2021).
  • higher LOX expression leads to the FAK pathway activation and increased pulmonary metastases in vivo (Chen et al, 2022).
  • Desmoplasia and increased fibrosis have been associated with progression of several cancers such as breast, pancreatic, colorectal, gastric and hepatocellular (Barker, Cox et al. 2012). Desmoplasia is also an intrinsic mechanism of resistance to immunotherapy in stromally-rich tumours (Zhao and Subramanian, 2017). LOX and LOX family members have an essential role in extracellular matrix remodelling and desmoplasia (Levental, 2009; Xiao, 2012).
  • Lysyl oxidase family members expression is associated with tumour ECM, tumour stroma or tumour-associated vasculature of several cancers, such as colorectal, pancreatic, breast, laryngeal, endometrial, testicular, hepatocellular, renal (reviewed in Barker et al (Barker, Cox et al. 2012)), gastric cancer (Kasashima, Yashiro et al. 2014).
  • LOXL2 expression is upregulated in breast, gastric, colon, esophageal, head and neck, lung and laryngeal carcinomas (Barker, Cox et al. 2012) and in renal cells carcinoma (Hase, Jingushi et al. 2014) (Nishikawa, Chiyomaru et al. 2015).
  • High LOXL2 expression is associated with poor prognosis in patients with squamous cell carcinoma, laryngeal, oesophagus and breast cancer, increased metastases in colon and breast cancer, as well as drug resistance in pancreatic cancer cells (Barker, Cox et al.
  • L0XL2 up-regulation increases the invasiveness of otherwise non-invasive breast cancer cells (Akiri, Sabo et al. 2003).
  • LOXL2 and LOXL4 are required for metastatic niche formation in a breast orthotopic mouse model (Wong et al, 2011).
  • LOXL2 expression is associated with lymph node metastasis, histological grades and poor prognosis in cholangiocarcinoma, and knockdown of LOXL2 reduces invasion and metastasis (Xu, Li et al. 2014).
  • HCC metastasis relies on LOXL2, which is overexpressed in tumor tissues and sera of HCC patients (Wong, Tse et al. 2014).
  • LOXL2 is upregulated in glioma, correlates with WHO grade and poor prognosis in patients, promotes glioma cells proliferation and invasion, and reduces their sensitivity to temozolomide (Zhang et al, 2020).
  • LOX and LOXL2 enhanced invasion and migration of cervical cancer cells can be inhibited by BAPN or LOXL2 inhibitors (Yang, Li et al. 2013; Peng et al, 2022).
  • LOX and LOXL2 do not compensate one another; manipulation of LOX expression did not affect LOXL2 levels in a colorectal cancer model (Baker, Cox et al. 2011). While LOX and LOXL2 are involved in similar extra-cellular processes, it appears that they have distinct roles.
  • LOXL1 is overexpressed in metastatic non-small cells lung cancer (NSCLC), and the metastatic phenotype can be reduced by inhibition with LOXL1 siRNA (Lee, Kim et al. 2011).
  • Treatment with the pan-LOX inhibitor BAPN and silencing of LOXL1 expression decrease tumor growth, invasion, and metastasis in invasive lobular carcinoma, (Sflomos et al. 2021).
  • LOXL3 mRNA is expressed in Hs578T highly invasive breast cancer cells, but not in poorly invasive and non-metastatic breast cancer cells MCF7 and T47D (Kirschmann, Seftor et al. 2002).
  • Overexpression of LOXL3 in MDCK epithelial cells induces an epithelial- mesenchymal transition (EMT) process, which is a key step in the progression of metastasis (Peinado, Del Carmen Iglesias-de la Cruz et al. 2005).
  • EMT epithelial- mesenchymal transition
  • Knockdown of LOXL3 with siRNA reduces invasiveness of glioma cells (Laurentino et al., 2021).
  • LOXL4 High expression of mRNA levels of LOXL4 was detected in 71% of all head and neck squamous cell carcinomas, and only in 9% of the healthy mucosa samples, (Scola and Gorogh 2010).
  • LOXL4 expression is upregulated in invasive HNC and significantly correlated with local lymph node metastases and higher tumour stages (Goeroegh, Shoes et al. 2007).
  • LOXL4 promotes metastasis in gastric cancer (Li, Zhao et al. 2015).
  • LOXL4 together with LOXL2 is required for metastatic niche formation in a breast orthotopic mouse model (Wong, Gilkes et al. 2011).
  • LOXL4 is enhanced in keratocystic odontogenic tumors (KCOT) stromal tissues and primary KCOT stromal fibroblasts (Jiang, Sima et al. 2014).
  • KCOT keratocystic odontogenic tumors
  • LOX and LOXL are implicated in fibrotic diseases, such as liver fibrosis, lung fibrosis, kidney fibrosis, cardiac fibrosis, myelofibrosis and schleroderma. Both LOX and LOXL are highly expressed in fibrotic areas, in surrounding myofibroblasts and in serum of patients with fibrotic conditions (Kagan 1994) (Kim, Peyrol et al. 1999) (Siegel, Chen et al.
  • LOX family inhibitors include a number of fibrotic conditions: myelofibrosis (Primary myelofibrosis, Post Polycythemia Vera or Post Essential Thrombocythemia Myelofibrosis), idiopathic pulmonary fibrosis (IPF), liver fibrosis due to non-alcoholic steatohepatitis (NASH), HIV and/or Hepatitis C- infection or primary sclerosing cholangitis (PSC) and compensated liver cirrhosis due to NASH.
  • myelofibrosis Primary myelofibrosis, Post Polycythemia Vera or Post Essential Thrombocythemia Myelofibrosis
  • IPF idiopathic pulmonary fibrosis
  • NASH non-alcoholic steatohepatitis
  • PSC Hepatitis C- infection or primary sclerosing cholang
  • LOX has been implicated in the pathogenesis of renal fibrosis and its inhibition with the alleviation of the symptoms (Di Donato, Ghiggeri et al. 1997, Haase 2009, Chen, Lin et al. 2015), including renal disfunctions associated with Alport syndrome (Cosgrove et al, 2018).
  • Hyperuricemia results in hypertension, intrarenal vascular disease, and renal injury and is associated with increased expression of lysyl oxidase (LOX) in kidneys (Yang, Wang et al. 2010).
  • Increased LOX activity has been linked to delayed graft failure after renal transplant, potentially due to increased local fibrosis (Zhi, 2017).
  • Calcineurin inhibitors such as Cyclosporin (CsA) used in anti-rejection therapy in solid organ transplants can paradoxically induce progressive nephropathy characterised by renal dysfunction and interstitial fibrosis.
  • CsA Cyclosporin
  • LOX and LOXL2 inhibitors can attenuate CsA induced nephropathy (Nguyen et al, 2021).
  • LOX and LOXL2 are involved in liver fibrosis (Kagan 1994, Marshall and Smith 2011) (Ricard-Blum, Bresson-Hadni et al. 1996) (Smith and Van Vlasselaer 2011) (Georges, Hui et al. 2007), liver cirrhosis (the last stage of liver fibrosis) (Kagan 1994) and related diseases such as Wilson’s disease and primary biliary cirrhosis (Vadasz, Kessler et al. 2005).
  • LOXL1 plays an important role in the progression of non-alcoholic fatty liver disease (NAFLD) to NASH, in particular in non-obese patients (Aiting et al. 2021).
  • NAFLD non-alcoholic fatty liver disease
  • LOX expression is increased in hypoxic lymphatic endothelial cells, which might be responsible for fibrosis associated with lymphedema (Becker et al. 2021). Fibrotic changes in clubfoot-contracted tissue are associated with increased collagen deposition and LOX- mediated crosslinking and can be reduced by treatment with a LOX inhibitor indicated potential for the treatment of relapsed and resistant clubfeet (Knitlova et al. 2022). LOX inhibition is a potential treatment for intestinal fibrosis in Crohn's disease (de Bruyn et al. 2018).
  • LOX inhibitors assist in collagen remodeling and re-establishment of collagen architecture in human Dupuytren's, keloid and scar fibroblasts (Priyanka, 2016).
  • Topical application of LOX inhibitor reduces scarring in rodent and non-rodent models (Hamprecht, Zhou et al. 2021).
  • LOXL1 silencing inhibited TGF-pi induced ECM deposition of hypertrophic scar fibroblasts, and inhibitors could be effective in treating hypertrophic scarring (Ying et al. 2021).
  • LOX is also implicated in cardiovascular disease. BAPN treatment reduces myocardial fibrosis in a mouse model, therefore LOX inhibition is useful as potential therapeutic targeting of collagen regulation and thereby age-related myocardial fibrosis (Rosin, Sopel et al. 2015). Increased expression of LOX is associated with myocardial fibrosis and cardiac dysfunction (Zibadi, Vazquez et al. 2010) (Gao, Xiao et al. 2010) (Lopez, Gonzalez et al. 2010). Left atrial myocardium of patients with atrial fibrillation express higher levels of lysyl oxidase and fibronectin expression as well as collagen crosslinking.
  • Fibronectin upregulation is mediated by LOX in cardiac fibroblasts (Adam, Theobald et al. 2011). Inhibition of LOX with a blocking antibody reduced cardiac fibrosis and infarct expansion in a mouse model (Gonzalez- Santamaria, 2016). Lysyl oxidases play a causal role in experimental pulmonary hypertension and inhibition with BAPN reduces the symptoms (Nave, Mizikova et al. 2014). LOX facilitate the formation of crosslinked and therefore insoluble collagen and the subsequent left ventricle stiffness and systolic dysfunction in patients with hypertensive heart disease (HHD) and heart failure (HF) of hypertensive origin (Lopez, Gonzalez et al.
  • HHD hypertensive heart disease
  • HF heart failure
  • Lysyl oxidase inhibition has been proposed as a therapeutic method for decreasing or preventing recurrent restenosis (Nuthakki, Fleser et al. 2004) (Brasselet, Durand et al. 2005).
  • LOX activity is increased in atherosclerosis (Kagan, Raghavan et al. 1981).
  • LOX is overexpressed in pathologies associated with increased thrombosis, such as myeloproliferative neoplasms, chronic kidney disease and arterial stenosis and enhances platelets aggregation (Shinobu et al, 2016).
  • LOX inhibition attenuates arterial medial calcification, a form of vascular calcification (VC).
  • VC increases cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD), particularly those on dialysis, with diabetes, and senile patients, because it causes ischemic cardiovascular disease and cerebrovascular disease (llto et al. 2021).
  • CKD chronic kidney disease
  • LOX inhibition improves venous adaptation after arteriovenous fistula (Hernandez et al. 2021). Therefore, LOX inhibition may prove beneficial in the treatment or prevention of cardiovascular conditions, including hypertensive heart disease, heart failure, cardiac hypertrophy and atherosclerosis.
  • LOX is associated with the amyloid-beta (Ap) related pathological hallmarks (such as cerebral amyloid angiopathy and senile plaques) of both Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D) pathogenesis (Wilhelmus, Bol et al. 2013).
  • LOX activity is increased in the hippocampal samples of Alzheimer’s disease and in non-Alzheimer’s dementia (Gilad, Kagan et al. 2005).
  • LOX is increased at the site of brain injury (Gilad, Kagan et al.
  • LOXLs are implicated in pulmonary diseases.
  • LOXL2 and LOXL3 are likely to have a role in Primary Alveolar Proteinosis (PAP) since both are expressed in PAP tissue, but not normal lung tissue (Neufeld and Brekhman 2009).
  • PAP Primary Alveolar Proteinosis
  • Excessive lysyl oxidase activity was linked to the pathologic pulmonary features of bronchopulmonary dysplasia (Kumarasamy, Schmitt et al. 2009).
  • Abnormal vascular permeability such as present in diseases such as pulmonary edema and acute respiratory distress syndrome (ARDS) or endotoxin-induced lung injury can be normalised by LOX inhibition (Mammoto, Mammoto et al.
  • LOXL2 inhibition reduces key features of airway remodelling, in an ovalbumin mouse model of asthma, suggesting that LOXL2 inhibition is a potential therapy to reduce remodelling of the airways in severe asthma (Ramis et al. 2022).
  • LOX inhibition may be beneficial in the treatment of various ocular conditions. Inhibition of LOX or LOXL2 prevents neovascularization and fibrosis following laser-induced choroidal neovascularization (CNV). Therefore LOX and LOXL inhibitors can be useful in the treatment of conditions characterized by neovascularization, such as age-related macular degeneration (AMD), diabetic retinopathy and retinopathy of prematurity (Stalmans, Marshall et al. 2010).
  • AMD age-related macular degeneration
  • D diabetic retinopathy
  • retinopathy of prematurity Talmans, Marshall et al. 2010.
  • LOXL2 levels have been associated with failure following glaucoma surgery and treatment with a L0XL2 antibody reduced pathological angiogenesis, inflammation, and ocular fibrosis (Park, Kim et al. 2014) (Van Bergen, Marshall et al. 2013)(Stalmans, Van Bergen et al. 2011).
  • LOXL1 expression is increased in the initial stages of abnormal fibrogenesis in pseudoexfoliation syndrome/glaucoma tissues (Zenkel, Krysta et al. 2011) (Schlotzer- Schrehardt, Pasutto et al. 2008).
  • LOX is implicated in inflammatory conditions and may be useful in the treatment of acute respiratory distress syndrome (ARDS) (Mambetsariev, Tian et al. 2014).
  • LOX and LOXL1 reduction and collagen crosslinking reduction are associated with decreased inflammation in an Angiotensin II induced model of hypertension (Gonzalez, Rhaleb et al. 2014).
  • LOXL3 plays a significant role in the pathogenesis of leptin-associated osteoarthritis; its knock-down reduces apoptosis in chondrocyte, a prime factor involved in the pathogenesis of osteoarthritis (Wei et al., 2022).
  • LOX is the main isoenzyme expressed in human adipose tissue and that its expression is strongly upregulated in samples from obese patients.
  • BAPN reduces body weight gain and improves the metabolic profile in diet-induced obesity in rats (Miana, Galan et al. 2015) and reduces local adipose tissue inflammation (Halberg, Khan et al. 2009) and obesity-induced fibrosis (Liu et al. 2022).
  • LOX inhibition stimulate transdifferentiation of storage white adipocytes into thermogenic beige adipocytes, leading to increased cellular energy expenditure and reduced adiposity. Therefore targeting Lox to expand beige fat may be useful for treating obesity and metabolic diseases (Xing et al. 2020).
  • LOX may be useful in treating bacterial infections and subsequent fibrotic complications.
  • LOX is upregulated in infections with Staphylococcus Aureus and inhibition with BAPN influences resulting abscesses morphology and collagenisation (Beerlage, Greb et al. 2013).
  • LOX is implicated also in some parasitic diseases: LOX and LOXLs are upregulated in the early stages of liver granuloma development in schistosomiasis (Decitre, Gleyzal et al. 1998), and BAPN inhibition reduces the size of the granulomas and reduces the egg load in combination with antiparasitic drug PZQ compared to PZQ alone (Giboda, Zenka et al. 1992).
  • LOX is upregulated in endometriosis and may be implicated in the establishment and progression of endometriotic lesions (Ruiz, Dutil et al. 2011) (Dentillo, Meola et al. 2010).
  • Certain LOX inhibitors are known. These include p-aminopropionitrile (BAPN), haloamines, 1 ,2-diamines, allyl and propargyl amines, hydrazines, semicarbazide and thiolactones, benzylamines, mercaptopyridine and pyridazinone compounds (Pinnell and Martin 1968) (Tang, Simpson et al.
  • LOX inhibitors containing hydrazine and hydrazide groups Boke et al, 2017
  • LOXL2 inhibitors derivatives of haloallylamine (Chang et al, 2017), pyridines (Rowbottom et al, 2016a; Rowbottom et al, 2016b), pyrimidines (Rowbottom & Hutchinson, 2017a) and chromenones (Rowbottom & Hutchinson, 2017b).
  • the compounds of the present invention demonstrate improved intestinal permeability, oral exposure and/or oral bioavailability, particularly in higher species such as dog.
  • ester prodrugs of LOX inhibitors demonstrate enhanced intestinal permeability in comparison to the parent carboxylic acid compounds as well as providing advantageous improvements in one or more pharmacokinetic parameter in vivo, such as improvements in Cmax, exposure (e.g. AUG) and oral bioavailability (F%) compared to other similar ester prodrugs.
  • the present invention provides a compound of Formula I as defined herein, and/or a salt or solvate thereof.
  • the present invention provides a pharmaceutical composition which comprises a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.
  • the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.
  • the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a disease or medical condition mediated by lysyl oxidase (LOX).
  • LOX lysyl oxidase
  • the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a proliferative disease.
  • the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of cancer.
  • the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a fibrotic disorder.
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a disease or medical condition mediated by lysyl oxidase (LOX).
  • LOX lysyl oxidase
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a proliferative disease.
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of cancer.
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a fibrotic disorder.
  • the present invention provides a method of treating or preventing a disease or medical condition mediated by lysyl oxidase (LOX), said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
  • LOX lysyl oxidase
  • the present invention provides a method of treating or preventing a proliferative disease, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method of treating or preventing cancer, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • the present invention provides a method of treating or preventing a fibrotic disorder, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • the present invention provides a combination comprising a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, with one or more additional therapeutic agents.
  • Figure 1 shows percent (%) conversion of the compound of Example 1 to its free carboxylic acid parent compound by rat, dog and human liver microsomes at 0, 15 and 30 minutes.
  • (Ca-b)alkyl indicates an alkyl moiety having the integer “a” to the integer “b” number of carbon atoms, inclusive.
  • Certain moieties may also be described according to the minimum and maximum number of members with or without specific reference to a particular atom or overall structure.
  • the terms “a to b membered ring” or “having between a to b members” refer to a moiety having the integer “a” to the integer “b” number of atoms, inclusive.
  • alkyl and alkyl group refer to a branched or unbranched saturated hydrocarbon chain. Unless specified otherwise, alkyl groups typically contain 1-10 carbon atoms, such as 1-6 carbon atoms or 1-4 carbon atoms or 1-3 carbon atoms, and can be substituted or unsubstituted.
  • Representative examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, tert-butyl, isobutyl, etc.
  • alkoxy and alkoxy group refer to O-alkyl groups. Representative examples include, but are not limited to, -OMe, -OEt, -O-'Pr and O-'Bu. Alkoxy groups can be substituted or unsubstituted unless indicated otherwise.
  • alkenyl and “alkenyl group” refer to a branched or unbranched hydrocarbon chain containing at least one double bond.
  • alkenyl groups typically contain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and can be substituted or unsubstituted.
  • Representative examples include, but are not limited to, ethenyl, 3-buten-1-yl, 2-ethenylbutyl, and 3-hexen-1-yl.
  • alkynyl and alkynyl group refer to a branched or unbranched hydrocarbon chain containing at least one triple bond. Unless specified otherwise, alkynyl groups typically contain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, and 3-pentyn-1-yl.
  • aromatic refers to monocyclic and polycyclic ring systems containing 4n+2 pi electrons, where n is an integer.
  • Aromatic should be understood as referring to and including ring systems that contain only carbon atoms (i.e. “aryl”) as well as ring systems that contain at least one heteroatom selected from N, O or S (i.e. “heteroaromatic” or “heteroaryl”).
  • An aromatic ring system can be substituted or unsubstituted.
  • non-aromatic refers to a monocyclic or polycyclic ring system having at least one double bond that is not part of an extended conjugated pi system.
  • non-aromatic refers to and includes ring systems that contain only carbon atoms as well as ring systems that contain at least one heteroatom selected from N, O or S.
  • a non-aromatic ring system can be substituted or unsubstituted.
  • aryl and aryl group refer to phenyl and 7-15 membered bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro, and/or fused ring systems, in which at least one of the rings is aromatic.
  • Aryl groups can be substituted or unsubstituted. Unless specified otherwise, an aryl group may contain 6 ring atoms (i.e., phenyl) or a ring system containing 9 to 15 atoms, such as 9 to 11 ring atoms, or 9 or 10 ring atoms.
  • Representative examples include, but are not limited to, naphthyl, indanyl, 1 ,2,3,4-tetrahydronaphthalenyl, 6,7,8,9-tetrahydro-5H- benzocycloheptenyl, and 6,7,8,9-tetrahydro-5H-benzocycloheptenyl.
  • an aryl group is phenyl and naphthyl, suitably phenyl.
  • Carbocyclic group and “carbocycle” refer to monocyclic and polycyclic ring systems that contain only carbon atoms in the ring(s), i.e., hydrocarbon ring systems, without regard or reference to aromaticity or degree of unsaturation.
  • carbocyclic group should be understood as referring to and including ring systems that are fully saturated (such as, for example, a cyclohexyl group), ring systems that are aromatic (such as, for example, a phenyl group), as well as ring systems having fully saturated, aromatic and/or unsaturated portions (such as, for example, cyclohexenyl, 2,3-dihydro-indenyl, and 1 ,2,3,4-tetrahydro- naphthalenyl).
  • the terms carbocyclic and carbocycle further include bridged, fused, and spirocyclic ring systems.
  • cycloalkyl and cycloalkyl group refer to a non-aromatic carbocyclic ring system, that may be monocyclic, bicyclic, or tricyclic, saturated or unsaturated, and may be bridged, spiro, and/or fused.
  • a cycloalkyl group may be substituted or unsubstituted. Unless specified otherwise, a cycloalkyl group typically contains from 3 to 12 ring atoms.
  • a cycloalkyl group may contain 4 to 10 ring atoms (e.g., 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, etc.).
  • Representative examples include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl, norbornenyl, bicyclo[2.2.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[3.3.2]decane.
  • haloalkyl and “haloalkyl group” refer to alkyl groups in which one or more hydrogen atoms are replaced by halogen atoms.
  • Haloalkyl includes both saturated alkyl groups as well as unsaturated alkenyl and alkynyl groups.
  • Haloalkyl groups can be substituted or unsubstituted.
  • a haloalkyl group is selected from CHF 2 and CF3, suitably CF3.
  • haloalkoxy and haloalkoxy group refer to alkoxy groups (i.e. O-alkyl groups) in which one or more hydrogen atoms are replaced by halogen atoms.
  • Haloalkoxy includes both saturated alkoxy groups as well as unsaturated alkenyl and alkynyl groups.
  • Haloalkoxy groups can be substituted or unsubstituted.
  • a haloalkyoxy group is selected from -OCHF2 and -OCF3, suitably - OCF 3 .
  • halo and halogen include fluorine, chlorine, bromine and iodine atoms and substituents.
  • heteroaryl and heteroaryl group refer to (a) 5 and 6 membered monocyclic aromatic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and (b) 7 to15 membered bicyclic and tricyclic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and in which at least one of the rings is aromatic.
  • a heteroaryl group can contain two or more heteroatoms, which may be the same or different.
  • Heteroaryl groups can be substituted or unsubstituted, and may be bridged, spiro, and/or fused.
  • a heteroaryl group may contain 5, 6, or 8 to 15 ring atoms.
  • a heteroaryl group may contain 5 to 10 ring atoms, such as 5, 6, 9, or 10 ring atoms.
  • Representative examples include, but are not limited to, 2,3-dihydrobenzofuranyl, 1 ,2-dihydroquinolinyl, 3,4-dihydroisoquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, 1 ,2,3,4-tetrahydroquinolinyl, benzoxazinyl, benzthiazinyl, chromanyl, furanyl, 2-furanyl, 3-furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl, 2-, 4-, or 5-pyrimidinyl, pyrazolyl, pyrrolyl, 2- or 3-pyrrolyl, pyrazinyl, pyridazinyl, 3- or 4-pyridazinyl, 2-pyrazinyl,
  • heterocyclic group and “heterocycle” refer to monocyclic and polycyclic ring systems that contain carbon atoms and at least one heteroatom selected from nitrogen, oxygen, sulfur or phosphorus in the ring(s), without regard or reference to aromaticity or degree of unsaturation.
  • heterocyclic group should be understood as referring to and including ring systems that are fully saturated (such as, for example, a piperidinyl group), ring systems that are aromatic (such as, for example, a pyridinyl group), as well as ring systems having fully saturated, aromatic and/or unsaturated portions (such as, for example, 1 , 2,3,6- tetrahydropyridinyl and 6,8-dihydro-5H-[1 ,2,4]triazolo[4,3-a]pyrizinyl).
  • the terms heterocyclic and heterocycle further include bridged, fused, and spirocyclic ring systems.
  • heterocycloalkyl and “heterocycloalkyl group” refer to 3 to15 membered monocyclic, bicyclic, and tricyclic non-aromatic ring systems, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen, sulfur or phosphorus. Heterocycloalkyl groups may be fully saturated or contain unsaturated portions and may be bridged, spiro, and/or fused ring systems. In some instances a heterocycloalkyl group may contain at least two or heteroatoms, which may be the same or different. Heterocycloalkyl groups can be substituted or unsubstituted.
  • a heterocycloalkyl group may contain from 3 to 10 ring atoms or from 3 to 7 ring atoms or from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms.
  • Representative examples include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl, homopiperazinyl, thiomorpholinyl-5-oxide, thiomorpholinyl-S,S-dioxide, pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridin
  • a heterocyclylalkyl group as defined herein is a monocyclic, bicyclic or spiro heterocyclyl group comprising one, two or three heteroatoms selected from N, O or S.
  • “pharmaceutically acceptable” refers to materials that are generally chemically and/or physically compatible with other ingredients (such as, for example, with reference to a formulation), and/or is generally physiologically compatible with the recipient (such as, for example, a subject) thereof.
  • composition refers to a composition that can be used to treat a disease, condition, or disorder in a subject, including a human.
  • stable and “chemically stable” refer to a compound that is sufficiently robust to be isolated from a reaction mixture with a useful degree of purity.
  • the present application is directed solely to the preparation of stable compounds.
  • substituents include members which, owing to valency requirements, chemical stability, or other reasons, cannot be used to substitute a particular group, the list is intended to be read in context to include those members of the list that are suitable for substituting the particular group. For example, when considering the degree of optional substitution of a particular moiety, it should be understood that the number of substituents does not exceed the valency appropriate for that moiety.
  • subject(s) and “patient(s)” refer to mammals, in particular humans.
  • substituted indicates that a hydrogen atom on a molecule has been replaced with a different atom or group of atoms and the atom or group of atoms replacing the hydrogen atom is a “substituent.” It should be understood that the terms “substituent”, “substituents”, “moiety”, “moieties”, “group”, or “groups” refer to substituent(s).
  • terapéutica refers to an amount a compound, composition or medicament that (a) inhibits or causes an improvement in a particular disease, condition or disorder; (b) attenuates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder. It should be understood that the terms “therapeutic” and “therapeutically effective” encompass any one of the aforementioned effects (a)-(b), either alone or in combination with any of the others (a)-(b).
  • a therapeutically effective amount in, for example, a human or other mammal, can be determined experimentally in a laboratory or clinical setting, or a therapeutically effective amount may be the amount required by the guidelines of the United States Food and Drug Administration (FDA) or equivalent foreign regulatory body, for the particular disease and subject being treated. It should be appreciated that determination of proper dosage forms, dosage amounts, and routes of administration is within the level of ordinary skill in the pharmaceutical and medical arts.
  • FDA United States Food and Drug Administration
  • treating refers to and include ameliorative, palliative, and curative uses and results.
  • the terms “treating”, “treated”, and “treatment” refer to curative uses and results as well as uses and results that diminish or reduce the severity of a particular condition, characteristic, symptom, disorder, or disease described herein.
  • treatment can include diminishment of several symptoms of a condition or disorder or complete eradication of said condition or disorder.
  • the terms “prevent”, “preventative” or “prevention”, refers to diminishing the likelihood, or delaying the onset, of one or more symptoms of a particular disease, condition or disorder described herein. It should be understood that the terms “prevent”, “preventative” or “prevention” are not necessarily used in an absolute sense, but also refers to uses and results where the administration of a compound or composition diminishes the likelihood or seriousness of a condition, symptom, or disease state, and/or delays the onset of a condition, symptom, or disease state for a period of time.
  • a ’’therapeutic agent or “therapeutically active agent”, whether used alone or in conjunction with another term or terms, refers to any compound, i.e. a drug, that has been found to be useful in the treatment of a disease, disorder or condition and is not described by Formula I. It should be understood that a therapeutic agent may or may not be approved by the FDA or an equivalent foreign regulatory body.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject or patient to be treated.
  • a bond terminating in a “ ” represents that the bond is connected to another atom that is not shown in the structure.
  • a bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be variably connected to atoms in the ring structure where allowed by valency unless otherwise defined.
  • the present invention relates to a compound, or a salt or solvate thereof, according to formula I: wherein,
  • X is selected from the group consisting of S, NR 1 and O;
  • R 1 is selected from hydrogen and C1.4 alkyl
  • Y is selected from N and CR 4 ;
  • R 4 is selected from hydrogen, halogen and C1.4 alkyl; one of W and Z is carbon and is bonded to the sulfone moiety, , and the other of W and Z is N or CH;
  • R 2 is selected from a phenyl, 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl group, each of which may be optionally substituted by one or more R 3 groups;
  • R 3 is selected from the group consisting of halogen, oxo, R A3 , -OR B3 , -NR B3 R C3 , -SR B3 , -CN, -NO 2 , -NR B3 C(O)R C3 , -C(O)NR B3 R C3 , -NR B3 C(O)OR C3 , -OC(O)NR B3 R C3 , -NR B3 SO 2 R C3 , - SC>2NR B3 R C3 , -SC>2R B3 , -C(O)R B3 , -C(O)OR B3 , 3-7 membered heterocycloalkyl optionally substituted with one or more R D3 and C3-6 cycloalkyl optionally substituted with one or more R D3 ; where R A3 is selected from the group consisting of Ci-e alkyl, Ci-e alkenyl, C2-6 alkynyl, Ci-e
  • the compounds of Formula I and sub-formulae thereof are pro-drugs which are broken down in the human or animal body to release a parent compound.
  • the compounds of Formula I and sub-formulae thereof include an in vivo cleavable ethyl ester group which is metabolically cleaved after administration to a subject to give the corresponding free carboxy group (i.e. parent acid).
  • R 1 is selected from hydrogen, methyl or ethyl.
  • R 1 is hydrogen.
  • R 4 is selected from hydrogen, chloro, methyl and ethyl.
  • R 4 is hydrogen, methyl or ethyl. More suitably, R 4 is hydrogen.
  • X is selected from the group consisting of S, NH, NMe and O.
  • X is S or O. In another embodiment, X is S.
  • Y is N or CH.
  • Y is N.
  • W is carbon and is bonded to the sulfone moiety.
  • Z is carbon and is bonded to the sulfone moiety.
  • W is carbon and is bonded to the sulfone moiety and Z is CH.
  • Z is carbon and is bonded to the sulfone moiety and W is CH.
  • X is S and Y is N. In another embodiment, X is S and Y is CH.
  • X is S, Y is N and W is carbon and is bonded to the sulfone moiety. In another embodiment, X is S, Y is CH and W is carbon and is bonded to the sulfone moiety.
  • X is S, Y is N and Z is carbon and is bonded to the sulfone moiety. In another embodiment, X is S, Y is CH and Z is carbon and is bonded to the sulfone moiety.
  • the compound of formula I is a compound according to one of sub-formula la to Ig:
  • the compound of formula I is a compound according to one of subformula la, lb or Ic. In another embodiment, the compound of formula I is a compound according to sub-formula la. In another embodiment, the compound of formula I is a compound according to sub-formula lb. In another embodiment, the compound of formula I is a compound according to sub-formula Ic.
  • R 2 is selected from a phenyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl and piperazinyl group, each of which may be optionally substituted by one or more R 3 groups.
  • R 2 is selected from a phenyl, imidazolyl, pyrazolyl, triazolyl, pyridyl and pyrimidinyl, each of which may be optionally substituted by one or more R 3 groups.
  • R 2 is selected from a phenyl, pyrrolidinyl, pyrazolyl and pyridyl group, each of which may be optionally substituted by one or more R 3 groups.
  • R 2 is a phenyl or pyrazolyl group, each of which may be optionally substituted by one or more R 3 groups.
  • R 2 is selected from: each of which may be optionally substituted by one or more R 3 groups.
  • R 2 is selected from:
  • R 3 is selected from the group consisting of halogen, R A3 , - OR B3 , -NR B3 R C3 , -CN, -NR B3 C(O)R C3 , -C(O)NR B3 R C3 , -NR B3 C(O)OR C3 , -NR B3 SO 2 R C3 , - SC>2NR B3 R C3 , -SC>2R B3 , -C(O)R B3 , -C(O)OR B3 , 3-7 membered heterocycloalkyl optionally substituted with one or more R D3 and C3-6 cycloalkyl optionally substituted with one or more R D3 .
  • R 3 is selected from the group consisting of halogen, R A3 , - OR B3 , -C(O)NR B3 R C3 , -C(O)R B3 , 3-7 membered heterocycloalkyl optionally substituted with one or more R D3 and C3-6 cycloalkyl optionally substituted with one or more R D3 .
  • R 3 is selected from the group consisting of halogen, R A3 , - OR B3 , - 3-7 membered heterocycloalkyl optionally substituted with one or more R D3 and C3-6 cycloalkyl optionally substituted with one or more R D3 .
  • R 3 is selected from the group consisting of halogen, R A3 , - OR B3 and C3-6 cycloalkyl optionally substituted with one or more R D3 .
  • R 3 is selected from the group consisting of halogen, R A3 and -OR B3 .
  • R 3 is R A3 or -OR B3 .
  • R A3 is selected from the group consisting of Ci-e alkyl, C2- 6 alkynyl and Ci-e haloalkyl, each of which may be optionally substituted with a substituent selected from the group consisting of C1.4 alkoxy, hydroxy, -NH2, NHMe and NMe2.
  • R A3 is Ci-e alkyl optionally substituted with a substituent selected from the group consisting of C1.4 alkoxy, hydroxy, -NH2, NHMe and NMe2.
  • R B3 and R C3 are independently selected from hydrogen and C1.4 alkyl, each of which may be optionally substituted with a substituent selected from the group consisting of C1.4 alkoxy, phenyl and hydroxy.
  • R D3 and R E3 are independently selected from the group consisting of C1.4 alkyl, C1.4 haloalkyl, C1.4 alkoxy and hydroxy. In another embodiment, R D3 and R E3 are independently selected from C1.4 alkyl or C1.4 alkoxy.
  • X is selected from the group consisting of: S, NR 1 and O;
  • R 1 is selected from hydrogen and C1.4 alkyl
  • Y is selected from N and CR 4 ;
  • R 4 is selected from hydrogen, halogen and C1.4 alkyl; one of W and Z is carbon and is bonded to the sulfone moiety, , and the other of W and Z is N or CH;
  • R 2 is selected from a phenyl, 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl group, each of which may be optionally substituted by one or more R 3 groups;
  • R 3 is selected from the group consisting of halogen, oxo, R A3 , -OR B3 , -NR B3 R C3 , -SR B3 , -CN, -NO 2 , -NR B3 C(O)R C3 , -C(O)NR B3 R C3 , -NR B3 C(O)OR C3 , -OC(O)NR B3 R C3 , -NR B3 SO 2 R C3 , - SC>2NR B3 R C3 , -SC>2R B3 , -C(O)R B3 , -C(O)OR B3 , 3-7 membered heterocycloalkyl optionally substituted with one or more R D3 and C3-6 cycloalkyl optionally substituted with one or more R D3 ; where R A3 is selected from the group consisting of Ci-e alkyl, Ci-e alkenyl, C2-6 alkynyl, Ci-e
  • R 2 is selected from a phenyl or 5-6 membered heteroaryl, each of which may be optionally substituted by one or more R 3 groups.
  • R 2 is selected from a phenyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl group, each of which may be optionally substituted by one or more R 3 groups.
  • R 2 is selected from a phenyl, imidazolyl, pyrazolyl, triazolyl, pyridyl and pyrimidinyl, each of which may be optionally substituted by one or more R 3 groups.
  • R 2 is a phenyl, pyrrolidinyl, pyrazolyl and pyridyl group, each of which may be optionally substituted by one or more R 3 groups.
  • R 2 is a phenyl or pyrazolyl group, each of which may be optionally substituted by one or more R 3 groups.
  • R 3 is selected from the group consisting of halogen, R A3 , -OR B3 , - NR B3 R C3 , -CN, -NR B3 C(O)R C3 , -C(O)NR B3 R C3 , -NR B3 C(O)OR C3 , -NR B3 SO 2 R C3 , -SO 2 NR B3 R C3 , - SO 2 R B3 , -C(O)R B3 , -C(O)OR B3 , 3-7 membered heterocycloalkyl optionally substituted with one or more R D3 and C3-6 cycloalkyl optionally substituted with one or more R D3 .
  • R 3 is selected from the group consisting of halogen, R A3 , -OR B3 , - C(O)NR B3 R C3 , -C(O)R B3 , 3-7 membered heterocycloalkyl optionally substituted with one or more R D3 and C3-6 cycloalkyl optionally substituted with one or more R D3 .
  • R 3 is selected from the group consisting of halogen, R A3 , -OR B3 , - 3-7 membered heterocycloalkyl optionally substituted with one or more R D3 and C3-6 cycloalkyl optionally substituted with one or more R D3 .
  • R 3 is selected from the group consisting of halogen, R A3 , -OR B3 and C3-6 cycloalkyl optionally substituted with one or more R D3 .
  • R 3 is selected from the group consisting of R A3 and -OR B3 and C3-6 cycloalkyl optionally substituted with one or more R D3 .
  • R A3 is selected from the group consisting of Ci-e alkyl, C2-6 alkynyl and C1.6 haloalkyl, each of which may be optionally substituted with a substituent selected from the group consisting of C1.4 alkoxy, hydroxy, -NH2, NHMe and NMe2.
  • R A3 is Ci-e alkyl optionally substituted with a substituent selected from the group consisting of C1.4 alkoxy, hydroxy, -NH2, NHMe and NMe2.
  • R B3 and R C3 are independently selected from hydrogen and C1.4 alkyl, each of which may be optionally substituted with a substituent selected from the group consisting of C1.4 alkoxy, phenyl and hydroxy.
  • R D3 and R E3 are independently selected from the group consisting of Ci- 4 alkyl, C1.4 haloalkyl, C1.4 alkoxy and hydroxy.
  • R D3 and R E3 are independently C1.4 alkyl or C1.4 alkoxy.
  • the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.
  • the present invention excludes any individual compounds not possessing the biological activity defined herein.
  • the compounds (including final products and intermediates) described herein may be isolated and used per se or may be isolated in the form of a salt, suitably pharmaceutically acceptable salts.
  • salt(s) and salt form(s) used by themselves or in conjunction with another term or terms encompasses all inorganic and organic salts, including industrially acceptable salts, as defined herein, and pharmaceutically acceptable salts, as defined herein, unless otherwise specified.
  • industrially acceptable salts are salts that are generally suitable for manufacturing and/or processing (including purification) as well as for shipping and storage, but may not be salts that are typically administered for clinical or therapeutic use.
  • Industrially acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more.
  • Pharmaceutically acceptable salts are salts that are generally chemically and/or physically compatible with the other ingredients comprising a formulation, and/or are generally physiologically compatible with the recipient thereof.
  • Pharmaceutically acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more. It should be understood that pharmaceutically acceptable salts are not limited to salts that are typically administered or approved by the FDA or equivalent foreign regulatory body for clinical or therapeutic use in humans. A practitioner of ordinary skill will readily appreciate that some salts are both industrially acceptable as well as pharmaceutically acceptable salts. It should be understood that all such salts, including mixed salt forms, are within the scope of the application.
  • the compounds of Formula I and sub-formulae thereof are isolated as pharmaceutically acceptable salts.
  • a suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation
  • a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxye
  • salts of the present application can be prepared in situ during the isolation and/or purification of a compound (including intermediates), or by separately reacting the compound (or intermediate) with a suitable organic or inorganic acid or base (as appropriate) and isolating the salt thus formed.
  • the degree of ionisation in the salt may vary from completely ionised to almost non-ionised.
  • the various salts may be precipitated (with or without the addition of one or more co-solvents and/or anti-solvents) and collected by filtration or the salts may be recovered by evaporation of solvent(s).
  • Salts of the present application may also be formed via a “salt switch” or ion exchange/double displacement reaction, i.e. reaction in which one ion is replaced (wholly or in part) with another ion having the same charge.
  • salts may be prepared and/or isolated using a single method or a combination of methods.
  • Representative salts include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate and the like.
  • salts include alkali or alkaline earth metal cations such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzathine, choline, tromethamine, diolamine, glycine, meglumine, olamine and the like.
  • N-oxides Compounds of the Formula I and sub-formulae thereof containing an amine function may also form N-oxides.
  • a reference herein to a compound of the Formula I and sub-formulae thereof that contains an amine function also includes the N-oxide.
  • one or more than one nitrogen atom may be oxidised to form an N-oxide.
  • Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g.
  • N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.
  • mCPBA m-chloroperoxybenzoic acid
  • keto-, enol-, and enolate-forms examples include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), pyrimidone/hydroxypyrimidine, imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
  • keto enol enolate examples include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), pyrimidone/hydroxypyrimidine, imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
  • Isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • Certain compounds of Formula I and sub-formulae thereof may have one or more asymmetric centres and therefore can exist in a number of stereoisomeric configurations. Consequently, such compounds can be synthesized and/or isolated as mixtures of enantiomers and/or as individual (pure) enantiomers, and, in the case of two or more asymmetric centres, single diastereomers and/or mixtures of diastereomers. It should be understood that the present application includes all such enantiomers and diastereomers and mixtures thereof in all ratios.
  • the compounds of the present invention are described herein using structural formulas that do not specifically recite the mass numbers or the isotope ratios of the constituent atoms. As such it is intended that the present application includes compounds in which the constituent atoms are present in any ratio of isotope forms. For example, carbon atoms may be present in any ratio of 12 C, 13 C, and 14 C; hydrogen atoms may be present in any ratio of 1 H, 2 H, and 3 H; etc.
  • the constituent atoms in the compounds of the present invention are present in their naturally occurring ratios of isotope forms.
  • compositions of the invention which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • the compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs).
  • the compositions of the invention are solid dosage forms for oral use (for example as tablets, lozenges, hard or soft capsules).
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more disintegrant, lubricant, glidant, filler, colouring, sweetening, flavouring and/or preservative agent.
  • An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
  • dosages and dosing regimens may vary with the type and severity of the condition to be alleviated, and may include the administration of single or multiple doses, i.e. QD (once daily), BID (twice daily), etc., over a particular period of time (days or hours). It is to be further understood that for any particular subject or patient, specific dosage regimens may need to be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the pharmaceutical compositions. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values.
  • the present application encompasses intrapatient dose-escalation as determined by the person skilled in the art.
  • Procedures and processes for determining the appropriate dosage(s) and dosing regimen(s) are well-known in the relevant art and would readily be ascertained by the skilled artisan.
  • dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the pharmaceutical compositions described herein.
  • a daily dose in the range for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
  • Oral administration may also be suitable, particularly in tablet form.
  • unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
  • the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.
  • the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a disease or medical condition mediated by lysyl oxidase (LOX).
  • LOX lysyl oxidase
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a disease or medical condition mediated by lysyl oxidase (LOX).
  • LOX lysyl oxidase
  • the present invention provides a method of treating or preventing a disease or medical condition mediated by lysyl oxidase (LOX), said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
  • LOX lysyl oxidase
  • LOX disease or medical condition mediated by LOX
  • the disease or medical condition mediated by LOX may be any of the diseases or medical conditions listed in this application.
  • LOX is known to mediate a variety of diseases or medical conditions, for instance, proliferative diseases, cancer, fibrotic diseases, cardiovascular disease, neurological disorders, pulmonary diseases, ocular conditions, inflammatory conditions, metabolic disease, bacterial infections and endometriosis.
  • a further aspect of the invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a proliferative disease.
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a proliferative disease.
  • the present invention provides a method of treating or preventing a proliferative disease, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the proliferative disease may be malignant or non-malignant.
  • the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of cancer.
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of cancer.
  • the present invention provides a method of treating or preventing cancer, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • the compound of the invention, or a pharmaceutically acceptable salt thereof is for use in the treatment of metastatic cancer in a subject.
  • a compound of the invention, or a pharmaceutically acceptable salt thereof may be for use as an inhibitor of the motility of tumour cells.
  • the compound of the invention, or a pharmaceutically acceptable salt thereof may be for use as an inhibitor of the dissemination and invasiveness of mammalian cancer cells leading to inhibition of metastatic tumour growth.
  • a compound of the invention, or a pharmaceutically acceptable salt thereof may be for use as an anti-invasive agent for use in the containment and/or treatment of solid tumour disease.
  • the compound of the invention, or a pharmaceutically acceptable salt thereof may be for use in the treatment of a cancer, which may be a solid tumour or a haematological (“liquid”) cancer.
  • a cancer which may be a solid tumour or a haematological (“liquid”) cancer.
  • the cancer is selected from:
  • Carcinoma including for example tumours derived from stratified squamous epithelia (squamous cell carcinomas) and tumours arising within organs or glands (adenocarcinomas).
  • squamous cell carcinomas stratified squamous epithelia
  • adenocarcinomas derived from stratified squamous epithelia (squamous cell carcinomas) and tumours arising within organs or glands.
  • squamous cell carcinoma include breast, colon, lung, prostate, ovary, esophageal carcinoma (including, but not limited to, esophageal adenocarcinoma and squamous cell carcinoma), basal-like breast carcinoma, basal cell carcinoma (a form of skin cancer), squamous cell carcinoma (various tissues), head and neck carcinoma (including, but not limited to, squamous cell carcinomas), stomach carcinoma (including, but not limited to, stomach adenocarcinoma, gastrointestinal stromal tumor), signet
  • Sarcomas including: osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesothelial sarcoma and mesothelioma (membranous lining of body cavities); fibrosarcoma (fibrous tissue); angiosarcoma and hemangioendothelioma (blood vessels); liposarcoma (adipose tissue); glioma and astrocytoma (neurogenic connective tissue found in the brain); myxosarcoma (primitive embryonic connective tissue); chordoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, Ewing's sarcoma, mesenchymous and mixed mesodermal tumor (mixed connective
  • Hematopoietic tumours including: myelogenous and granulocytic leukemia (malignancy of the myeloid and granulocytic white blood cell series); lymphatic, lymphocytic, and lymphoblastic leukemia (malignancy of the lymphoid and lymphocytic blood cell series); polycythemia vera and erythremia (malignancy of various blood cell products, but with red cells predominating); myelofibrosis.
  • myelogenous and granulocytic leukemia malignancy of the myeloid and granulocytic white blood cell series
  • lymphatic, lymphocytic, and lymphoblastic leukemia malignancy of the lymphoid and lymphocytic blood cell series
  • polycythemia vera and erythremia malignancy of various blood cell products, but with red cells predominating
  • Lymphomas including: Hodgkin and Non-Hodgkin lymphomas;
  • Solid tumors of the nervous system including medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma and schwannoma;
  • Melanoma uveal melanoma and retinoblastoma
  • Mixed Types including, e.g., adenosquamous carcinoma, mixed mesodermal tumor, carcinosarcoma or teratocarcinoma.
  • the cancer is selected from anus cancer, bile duct cancer, bladder cancer, blood cancer, brain cancer, breast cancer, uterine cervix cancer, colon cancer, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, head and neck cancer, hypopharyngeal cancer, pancreatic cancer, pharyngeal cancer, lip and oral cancer, liver cancer, lung cancer, melanoma, mesothelioma, multiple myeloma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, stomach cancer, testicular cancer and thyroid gland cancer.
  • the cancer is selected from bladder cancer, blood cancer, brain cancer, breast cancer, colon cancer, esophageal cancer, head and neck cancer, pancreatic cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, stomach cancer, testicular cancer and thyroid gland cancer.
  • the cancer is wherein the cancer is selected from pancreatic cancer, colon cancer, breast cancer and lung cancer.
  • LOX and LOXL are implicated in fibrotic diseases. Accordingly, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a fibrotic disorder.
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a fibrotic disorder.
  • the present invention provides a method of treating or preventing a fibrotic disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • the fibrotic disorder may be a disorder characterised by excess fibrosis, e.g., an excess of fibrous connective tissue in a tissue or organ, e.g., triggered by a reparative or reactive process, e.g., in response to injury (e.g., scarring, healing, radiotherapy) or excess fibrotic tissue arising from a single cell line (e.g., fibroma).
  • excess fibrosis e.g., an excess of fibrous connective tissue in a tissue or organ, e.g., triggered by a reparative or reactive process, e.g., in response to injury (e.g., scarring, healing, radiotherapy) or excess fibrotic tissue arising from a single cell line (e.g., fibroma).
  • the compound of the invention or a pharmaceutically acceptable salt thereof may be for use in the treatment of a fibrotic disorder selected from:
  • a fibrotic condition affecting the lungs for example pulmonary fibrosis secondary to cystic fibrosis; idiopathic pulmonary fibrosis; coal worker’s progressive massive fibrosis; cryptogenic fibrosing alveolitis, chronic fibrosing interstitial pneumonia, interstitial lung disease (ILD), diffuse parenchymal lung disease (DPLD), emphysema and chronic obstructive pulmonary disease (COPD), or chronic asthma; or
  • a fibrotic condition affecting the liver for example cirrhosis, and associated conditions such as chronic viral hepatitis B or C, Wilson’s disease, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), biliary cirrhosis or autoimmune hepatitis; or
  • a fibrotic condition affecting the kidneys for example diabetic nephropathy, vesicoureteral reflux, tubulointerstitial renal fibrosis; glomerulonephritis or glomerular nephritis, including focal segmental glomerulosclerosis and membranous glomerulonephritis or mesangiocapillary glomerular nephritis;
  • a fibrotic condition affecting the heart or vascular system for example endomyocardial fibrosis; old myocardial infarction; atrial fibrosis; congestive heart failure, cardiomyopathy, hypertensive heart disease (HHD), hypertension (for example pulmonary hypertension) and fibrosis associated with hypertension, atherosclerosis, restenosis (e.g. coronary, carotid, and cerebral lesions), and heart disease associated with cardiac ischemic events; or
  • HHD hypertensive heart disease
  • a fibrotic condition affecting the mediastinum for example mediastinal fibrosis
  • a fibrotic condition affecting bone for example myelofibrosis, including primary myelofibrosis, post polycythemia vera or post essential thrombocythemia myelofibrosis; or
  • a fibrotic condition affecting the retroperitoneum for example retroperitoneal fibrosis skin
  • a fibrotic condition affecting the skin for example nephrogenic systemic fibrosis, keloid formation and scarring, systemic sclerosis, scleroderma, hypertrophic scarring, scleredema (Buschke disease), systemic amyloidosis, lipodermatosclerosis, progeroid disorders, stiff skin syndrome, Dupuytren's contracture, nephrogenic fibrosing dermopathy (NFD), mixed connective tissue disease, scleromyxedema, graft-versus-host disease (GVHD), Peyronie’s disease and eosinophilic fasciitis; or
  • a fibrotic condition affecting the Gl tract for example a fibrotic intestinal disorder, inflammatory bowel disease, ulcerative colitis or Crohn’s disease; or
  • fibrotic condition affecting connective tissue, for example arthrofibrosis; or capsulitis; or
  • a fibrotic condition affecting the eye for example ocular scarring, ocular fibrosis following surgery or pseudoexfoliation syndrome glaucoma.
  • a fibrotic condition induced by radiation such as fibrosis following radiotherapy.
  • the fibrotic condition induced by radiation may occur in any tissue treated by radiotherapy, for instance, the skin and subcutaneous tissue, lungs, breast, gastrointestinal and genitourinary tracts, muscles, and other organs.
  • LOX and LOXL are implicated in cardiovascular disease. Accordingly, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a cardiovascular disease.
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a cardiovascular disease.
  • the present invention provides a method of treating or preventing a cardiovascular disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • the cardiovascular disease is selected from hypertensive heart disease (HHD), heart failure, cardiac hypertrophy and atherosclerosis.
  • HHD hypertensive heart disease
  • heart failure heart failure
  • cardiac hypertrophy cardiac hypertrophy
  • atherosclerosis atherosclerosis
  • LOX and LOXL are implicated in neurological disorders. Accordingly, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a neurological disorder.
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a neurological disorder.
  • the present invention provides a method of treating or preventing a neurological disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • the neurological disorder is selected from bipolar disorder (BD), schizophrenia, Alzheimer’s disease and non-Alzheimer’s dementia.
  • LOX and LOXL are implicated in pulmonary diseases. Accordingly, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a pulmonary disease.
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a pulmonary disease.
  • the present invention provides a method of treating or preventing a pulmonary disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • the pulmonary disease is selected from pulmonary edema, acute respiratory distress syndrome (ARDS), endotoxin-induced lung injury and asthma.
  • ARDS acute respiratory distress syndrome
  • endotoxin-induced lung injury and asthma.
  • LOX and LOXL are implicated in ocular conditions. Accordingly, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of an ocular condition.
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of an ocular condition.
  • the present invention provides a method of treating or preventing an ocular condition, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • the ocular condition is glaucoma.
  • LOX and LOXL are implicated in inflammatory conditions. Accordingly, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of an inflammatory condition.
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of an inflammatory condition.
  • the present invention provides a method of treating or preventing an inflammatory condition, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • the inflammatory condition is arthritis, such as osteoarthritis or rheumatoid arthritis.
  • LOX and LOXL are implicated in metabolic diseases. Accordingly, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a metabolic disease.
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a metabolic disease.
  • the present invention provides a method of treating or preventing a metabolic disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • LOX and LOXL are implicated in bacterial infections. Accordingly, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a bacterial infection.
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a bacterial infection.
  • the present invention provides a method of treating or preventing a bacterial infection, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • LOX and LOXL are implicated in endometriosis. Accordingly, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of endometriosis.
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of endometriosis.
  • the present invention provides a method of treating or preventing endometriosis, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • the compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, sub
  • the compounds of the invention or pharmaceutical compositions comprising these compounds are for oral administration.
  • LOX inhibition can be a useful method for improving the efficacy of other drugs or addressing resistance to drug treatment through a number of mechanisms. Interfering with collagen stabilization by inhibition of lysyl oxidases significantly enhanced response to chemotherapy in various tumor models (Rossow et al. 2018). Specific inhibition of LOX with siRNA can induce apoptosis of laryngeal cancer Hep-2 cells and enhance the sensitivity of Hep-2 cells to chemotherapeutic drugs such as cisplatin (Dong, Lu et al. 2014) and to radiation (Dong, Xin et al. 2014).
  • chemotherapeutic drugs such as cisplatin (Dong, Lu et al. 2014) and to radiation (Dong, Xin et al. 2014).
  • LOX and LOXL2 inhibition can alter vascular permeability or normalise vasculature in a tumour environment, which can enhance the delivery or effectiveness of drugs (Ingber and Mammoto 2014) (Marshall, Spangler et al. 2012), for example improved efficacy of treatment in ovarian xenograft and lung allograft mice models with chemotherapeutic agents such as taxol (Zaffryar-Eilot, Marshall et al. 2013) or triple negative breast cancer models with doxorubicin (Saatchi et al. 2020) or epirubicin-loaded nanoparticles (De Vita et al. 2021).
  • chemotherapeutic agents such as taxol (Zaffryar-Eilot, Marshall et al. 2013) or triple negative breast cancer models with doxorubicin (Saatchi et al. 2020) or epirubicin-loaded nanoparticles (De Vita et al. 2021).
  • LOX inhibition synergized with gemcitabine to kill tumors and significantly prolonged tumor-free survival in a pancreatic mouse model.
  • LOX inhibition reduces ECM content and tumor stiffness leading to improved T cell migration and increased efficacy of anti-PD-1 blockade in murine models (Nicolas-Boluda, Donnadieu et al. 2021).
  • the combined use of LOX inhibitors and ICIs can therefore improve patient’s response rate to immunotherapy.
  • LOX-expression and secretion is increased in response to ionizing radiation (IR) and hypoxia, suggesting that LOX may contribute towards an IR-induced migratory phenotype in sub lethally-irradiated tumor cells and tumor progression; therefore LOX inhibitors can be used in combination with radiotherapy to reduce side effects in surrounding tissues receiving a reduced radiation dose (Shen, Sharma et al. 2014), including in breast cancer cells that becomes resistant to radiotherapy (Ko et al, 2020).
  • IR ionizing radiation
  • hypoxia ionizing radiation
  • LOX inhibitors can be used in combination with radiotherapy to reduce side effects in surrounding tissues receiving a reduced radiation dose (Shen, Sharma et al. 2014), including in breast cancer cells that becomes resistant to radiotherapy (Ko et al, 2020).
  • Pre-exisiting lung diseases such as I PF are a major risk factor for radiation-induced lung fibrosis (RIF) (Kong, Wang 2015; I PF - Kim et al. 2019). Therefore LOX inhibitors can be used in combination with RT to reduce side effects in surrounding tissues as well as to improve radiotherapy efficacy.
  • RAF radiation-induced lung fibrosis
  • LOX activity inhibition or depletion reduces lung metastasis after surgery and increases survival. Therefore LOX inhibitors have utility in combination with surgery to reduce the risk of subsequent metastasis (Rahman-Tzemah et al, 2017).
  • the compounds of the invention may be used alone to provide a therapeutic effect.
  • the compounds of the invention may also be used in combination with one or more additional therapeutic agents or methods.
  • the present invention provides a compound of formula I as defined herein in combination with an anti-cancer agent and/or radiotherapy.
  • the anti-cancer agent may be selected from one or more of the following:
  • antiproliferative/antineoplastic drugs and combinations thereof such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustin, melphalan, chlorambucil, chlormethine, busulphan, temozolamide, nitrosoureas, ifosamide, melphalan, pipobroman, triethylene-melamine, triethylenethiophoporamine, carmustine, lomustine, stroptozocin, temozolomide and dacarbazine); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, leucovorin, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopur
  • cytostatic agents such as antiestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride; and navelbene, CPT-II, anastrazole, letrazole, capecitabine, reloxafme and droloxafine; and abiraterone, Enzalutamide; analogues
  • anti-invasion agents for example dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase;
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies, for example anti-erbB2 antibodies trastuzumab, margetuximab, the anti-HER2 antibody pertuzumab; the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family: gefitinib, erlotinib, , afatinib, vandetanib, osimertinib and rociletinib); erbB2 tyrosine kinase inhibitors such as lapatinib, neratinib, mobocertinib, tucatinib and antibodies to costimulatory molecules such as CTLA-4, 4-IBB and PD-1 , or antibodies to cytokines (IL-IO, TGF-beta); inhibitors of the IL-IO, TGF-bet
  • aurora kinase inhibitors and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors or CDK4/CDK6 inhibitors such as palbociclib, abemaciclib, ribociclib; CCR2, CCR4 or CCR6 antagonists; mTOR kinase inhibitors such as Everolimus; Janus kinase family inhibitors such as ruxolitinib; Brunton’s tyrosine kinase inhibitors such as Ibrutinib, zanubrutinib; anaplastic lymphoma kinase - ALK - such as ceritinib, crizotinib, alectinib, lorlatinib, brigatinib; c-Met kinase inhibitors such as cabozantinib, tepotinib, cap
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, for example bevacizumab (AvastinTM), anti-VEGF2 antibody ramucirumab; recombinant fusion protein ziv-aflibercept]; thalidomide; pomalidomide; lenalidomide; and for example, a VEGF receptor tyrosine kinase inhibitor such as regorafenib, vandetanib, vatalanib, sunitinib, axitinib, pazopanib, lenvatinib, tivozanib;
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2; oncolytic viruses such as talimogene laherparepvec; CAR-T cells based therapies such as ciltacabtagene autoleucel, brexucabtagene autoleucel
  • immunotherapy approaches including for example antibody therapy such as denosumab, obinutuzumab, blinatomumab, dinutuximab, idarucizumab, daratumumab, necitumumab, elotuzumab, olaratumab, alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®), isatuximab, avelumab, tafasitamab, naxitamab and ofatumumab; interferons such as interferon a, peginterferon alpha-2b; interleukins such as IL-2 (aldesleukin); interleukin inhibitors for example IRAK4 inhibitors; cancer vaccines including prophylactic and treatment vaccines such as HPV vaccines, for example Gardasil, Cervarix, Oncophage and Sipuleucel- T (Provenge);
  • cytotoxic agents for example fludaribine (fludara), cladribine, pentostatin (NipentTM);
  • SMAC second mitochondria-derived activator of caspases
  • IAP Apoptosis Proteins
  • SMAC second mitochondria-derived activator of caspases
  • IAP Apoptosis Proteins
  • XIAP XIAP
  • clAP1 and clAP2 Birinapant
  • LCL161 Novartis
  • UPS ubiquitin proteasome system
  • bortezomib, ixazomib, carfilzomib and marizomib DNA repair inhibitors
  • DNA repair inhibitors such as Olaparib, rucaparib, niraparib
  • antiapoptotic BCL proteins family inhibitors such as venetoclax.
  • the present invention provides a compound of formula I as defined herein in combination with an anti-fibrotic agent.
  • the anti-fibrotic agent may be selected from one or more of the following:
  • Antifibrotic agents such as pirfenidone, nintedanib; CTFG antibody inhibitors such as pamrevlumab; recombinant human pentraxin-2 (PRM-151); anti-inflammatory agents such as corticosteroids, interferon-gamma; cardiovascular drugs such as pentoxifylline; ROS scavengers such as Vitamin E, superoxide dismutase.
  • Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within a therapeutically effective dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • the amount of the compound of the invention and the amount of the other pharmaceutically active agent(s) are, when combined, therapeutically effective to treat a targeted disorder in the patient.
  • the combined amounts are “therapeutically effective amount” if they are, when combined, sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder; cure the disorder; reverse, completely stop, or slow the progress of the disorder; or reduce the risk of the disorder getting worse.
  • such amounts may be determined by one skilled in the art by, for example, starting with the dosage range described in this specification for the compound of the invention and an approved or otherwise published dosage range(s) of the other pharmaceutically active compound(s).
  • a compound of the invention as defined hereinbefore and an additional anti-cancer agent as defined hereinbefore for use in the conjoint treatment of cancer.
  • a pharmaceutical product comprising a compound of the invention as defined hereinbefore and an additional anti-cancer agent as defined hereinbefore for the conjoint treatment of cancer.
  • a method of treatment of a human or animal subject suffering from a cancer comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with an additional anticancer agent as defined hereinbefore.
  • a compound of the invention for use simultaneously, sequentially or separately with an additional anti-cancer agent as defined hereinbefore, in the treatment of a cancer.
  • the compound of the invention may also be used be used in combination with radiotherapy.
  • Suitable radiotherapy treatments include, for example X-ray therapy, proton beam therapy or electron beam therapies.
  • Radiotherapy may also encompass the use of radionuclide agents, for example 131 1, 32 P, 90 Y, 89 Sr, 153 Sm or 223 Ra.
  • radionuclide therapies are well known and commercially available.
  • a method of treatment of a human or animal subject suffering from a cancer comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with radiotherapy.
  • a compound of the invention as defined hereinbefore and an additional anti-fibrotic agent as defined hereinbefore for use in the conjoint treatment of a fibrotic disorder.
  • a pharmaceutical product comprising a compound of the invention as defined hereinbefore and an additional anti-fibrotic agent as defined hereinbefore for the conjoint treatment of a fibrotic disorder.
  • a method of treatment of a human or animal subject suffering from a fibrotic disorder comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with an additional anti-fibrotic agent as defined hereinbefore.
  • a compound of the invention for use simultaneously, sequentially or separately with an additional anti-fibrotic agent as defined hereinbefore, in the treatment of a fibrotic disorder.
  • the compounds of the invention may be prepared using synthetic techniques that are known in the art (as illustrated by the examples herein).
  • Flash chromatography was performed on a Biotage Isolera or Combiflash Rf + UV-vis flash purification system using prepacked silica gel cartridges with HPLC grade solvents.
  • Thin layer chromatography (TLC) analysis was performed using silica gel 60 F- 254 thin layer plates and visualized using UV light (254 nm) and/or developed with vanillin stain.
  • LCMS and HRMS analyses of chemical compounds were performed on an Agilent 1200 series HPLC and diode array detector coupled to an Agilent 6210 time-of-flight mass spectrometer with a multimode ESI source; or a Waters Acquity LIPLC or l-class LIPLC with a diode array detector coupled to a Waters G2 QToF, SQD, or QDa mass spectrometer fitted with a multimode ESI/APCI source.
  • Example 1 The compound of Example 1 at 10 pM final concentration was incubated with rat (RLM), dog (DLM) or human (HLM) liver microsomes for 0, 15, and 30 min. Control samples containing no microsomes and no cofactors were also assessed at 0 and 30 min. Samples were extracted by protein precipitation and centrifugation for 20 min in a refrigerated centrifuge (4 °C) at 3700 rpm. The supernatant was analyzed by LCMS/MS for the free acid parent, 5- ((2-(aminomethyl)thiazol-5-yl)sulfonyl)-[1 , 1 '-biphenyl]-3-carboxylic acid.
  • Caco-2 cells were seeded onto Millicell 96 well plates (Millipore, MA, USA) at 1 x 10 5 cells/cm 2 .
  • the cells were cultured in DMEM (37°C, 5% CO2, relative humidity 95%) and media was changed every two or three days for 20 days for confluent cell monolayer formation.
  • the monolayers were prepared by rinsing both apical and basolateral surfaces twice with HBSS.
  • Cells were incubated with Hanks Balanced Salt Solution (HBSS, supplemented with 25mM HEPES and 4.45 mM glucose and the pH adjusted to 7.4) in both apical and basolateral compartments for 40 minutes to stabilise physiological parameters.
  • HBSS Hanks Balanced Salt Solution
  • the dosing solutions were prepared by diluting test compound with HBSS to give a final test compound concentration of 10 pM (final DMSO concentration of 1 % v/v).
  • the fluorescent integrity marker lucifer yellow (PromoCell) was also included in the dosing solution.
  • HBSS was removed from the apical compartment and replaced with test compound dosing solution.
  • the apical compartment insert was then placed into a companion plate containing fresh buffer (containing 1 % v/v DMSO). At 120 minutes the apical compartment inserts and the companion plates were separated and apical and basolateral samples diluted for analysis.
  • Test compounds were quantified by LC/MS/MS analysis using a 7 point calibration with appropriate dilution of the samples. The integrity of the monolayer throughout the experiment was checked by monitoring lucifer yellow permeation using fluorimetric analysis. The final receiver concentration (FRC) is the concentration of test compound at the basolateral compartment at 120 minutes.
  • the prodrugs of Examples 1 to 3 deliver a much higher concentration of drug through a monolayer of human colon epithelial cells (Caco2).
  • the prodrug of Example 1 delivers approximately 17-fold higher concentration of parent drug across Caco2 cells compared to treatment with the free carboxylic acid parent.
  • the ethyl prodrug of Example 2 delivers approximately 24-fold higher concentration of parent drug compared with the free carboxylic acid parent.
  • the prodrug of Example 3 delivers approximately 11-fold higher concentration of parent drug compared with the free carboxylic acid parent. This data indicates an advantage for the prodrugs compared to parent drugs for treatment of patients via oral administration.
  • mice Male - female CD1 , NcR, FVB or C57/BI6 mice (Charles River Laboratories) at 6 weeks of age were used for the PK analyses. The mice were dosed orally by gavage (50 mg/kg in dimethyl sulfoxide (DMSO)/water 1 :19 v/v) or by intravenous injection (2 or 10 mg/kg in DMSO/tween/saline 10:1 :89 v/v/v). Two groups of three mice were used.
  • DMSO dimethyl sulfoxide
  • Plasma samples were taken from the tail vein of each group into K2EDTA or heparinised syringes at four time points, alternated at: group 1) 5, 30 minutes, 2 and 6 hours; and group 2) 15 min, 1 , 4 and 8 or 24 hours. Plasma samples were snap-frozen in liquid nitrogen and then stored at -80 °C prior to LC-MS/MS analysis.
  • Rat (performed by Evotec Ltd) - 2 female Sprague Dawley rats were dosed orally by gavage (20 mg/kg in DMSO/water 1 :19 v/v) or by intravenous injection (4 mg/kg in DMSO/tween/saline 10:1 :89 v/v/v).
  • Blood samples were taken from the tail vein into K2EDTA or heparinised syringes at 8 time points: 15, 30, 45 minutes, 1 , 2, 4, 8 and 24 hours. Plasma samples were snap-frozen in liquid nitrogen and then stored at -80 °C prior to LC-MS/MS analysis.
  • Dog (performed by Covance Ltd) - 3 female Beagle dogs were dosed orally by gavage (5 mg/kg in DMSO/water 1 :19 v/v) or intravenous injection (2 mg/kg in DMSO/tween/saline 10:1 :89 v/v/v).
  • Blood samples were taken from the jugular vein into heparinised syringes at 8 time points: 15, 30, 45 minutes, 1 , 2, 4, 8 and 24 hours. Plasma samples were snap-frozen in liquid nitrogen and then stored at -80 °C prior to LC-MS/MS analysis.
  • Test compound solutions (1 mg/mL in DMSO) were used to make stock Standard Curve (SC) and Quality Control (QC) solutions at appropriate concentrations. Blank plasma was spiked with stock solutions to produce a 9-point standard curve ranging from 1.5- 10,000 pg/mL; with 2 QC concentrations within this range and where the DMSO concentration was 10% of the plasma volume.
  • Plasma PK samples, Standards and QC’s were added to individual Eppendorf tubes and DMSO (10% of plasma volume) was added to the plasma PK samples. SC, QC and plasma samples were extracted with methanol (100 pL) containing internal standard. Following protein precipitation, the samples were centrifuged for 10 minutes in a refrigerated centrifuge (4°C) at 14000 rpm.
  • AUC area under curve
  • Cmax maximal concentration
  • F bioavailability
  • rat ethyl ester prodrug (Example 1) has superior PK properties compared to the isopropyl ester prodrug (Reference Example 2), with a Cmax for released drug >5-fold higher, and with superior AUC of > 3-fold higher.
  • Example 1 In a non-rodent species (dog), the ethyl ester prodrug (Example 1) is superior to free carboxylic acid having approximately 4-fold increase in Cmax, approximately 2-fold increase in AUC and approximately 2-fold better oral bioavailability. Both rat and dog are species of preclinical development for drug candidates and used to predict human pharmacokinetics, therefore Example 1 is surprisingly better than the free carboxylic acid parent and closely related ester prodrugs (Reference Examples 1 and 2) in terms of preclinical pharmacokinetics and developability.
  • AUC area under curve
  • Cmax maximal concentration
  • F bioavailability
  • the PK profile of the ethyl ester prodrug of Example 2 is superior in mouse to the corresponding parent drug, with approximately 7-fold increase in Cmax and approximately 4-fold improvements in AUC and F%.
  • MTV-PyMT (Guy et al, 1992) (FVB) female mice were selected randomly for LOX inhibitor treatments from day 70 post-birth, when animals had no detectable tumour. Mice were treated daily with LOX inhibitor in vehicle, or daily vehicle (5% DMSO/2.5% Tween20 in water) by oral gavage. Mammary tumours and lungs were collected when the primary tumours reached ethical limits.
  • T/C ratio of average tumour volume between compound treated and vehicle control treated
  • Reduction in tumour volume in the compound treated group compared to vehicle-treated control group results in T/C ⁇ 1.
  • the efficacy of LOX inhibitors described in this invention, as measured by T/C in breast cancer models is shown in Table 4 and is significant (p ⁇ 0.05) for all the data presented.
  • Tumour growth inhibition assessment - CD-1 female mice at 6-7 weeks old from Charles River were injected into the third upper nipple mammary fat pad with cells dissociated from the PyMT tumours (6 x10 5 in 100ul PBS). When tumours reached a mean volume of 20 mm 3 the animals were allocated in groups of 8. LOX inhibitor (100 mg/kg) or vehicle (5% DMSO in water) was then administrated by oral gavage dosing, at 0.2ml/20g bodyweight once daily for up to 21 consecutive days. Tumours and weights were measured twice weekly using calipers. At the end of the study the animals were culled, and samples taken, fixed in 10% formalin or snap frozen in liquid nitrogen. Frozen samples were kept at - 80 degree centigrade until being analysed and the fixed samples stained according to the desired marker.
  • the ethyl ester prodrug (Example 1) is at least as effective as the parent drug in reducing breast cancer growth in a GEMM model, in agreement with mouse PK data; the ethyl ester prodrug also reduces significantly metastasis formation in an orthotopic breast cancer model.
  • LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling. Proceedings of the National Academy of Sciences 107(44): 18892-18897.
  • Knitlova J., et al. (2021). "Increased Collagen Crosslinking in Stiff Clubfoot Tissue: Implications for the Improvement of Therapeutic Strategies" International Journal of Molecular Sciences, 22(21), 11903
  • LEOXL4 Lysyl oxidase-like 4
  • Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proceedings of the National Academy of Sciences 108(39): 16369-16374.

Abstract

Provided is a compound, or a salt or solvate thereof, according to formula I: as defined herein, and pharmaceutical compositions and combinations comprising said compounds. Also described are said compounds for use in therapy, in particular for use in methods of treating or preventing proliferative disorders, such as cancer, and fibrotic disorders.

Description

PRODRUGS OF LYSYL OXIDASE INHIBITORS
INTRODUCTION
[001] The present disclosure relates to prodrugs of lysyl oxidase (LOX) inhibitors as defined by Formula I herein. Also, disclosed are pharmaceutical compositions comprising said prodrugs and methods of therapy comprising the administeration of said prodrugs. The prodrugs are for use in the treatment of a range of conditions, including conditions mediated by LOX, such as cancer and fibrotic disease.
BACKGROUND OF THE INVENTION
[002] LOX is part of a protein family consisting of five paralogues, LOX, LOX-like 1 [LOXL1], LOX-like 2 [LOXL2], LOX-like 3 [LOXL3] and LOX-like 4 [LOXL4]), all containing a conserved catalytic region. LOX enzymes play a crucial role in maintaining extracellular matrix (ECM) stability, by initiating and regulating the crosslinking of collagens and elastin within the ECM. LOX expression decreases during ageing indicating that its activity is especially important during development.
[003] In addition to its role in tissue remodelling, LOX also plays a critical role in primary cancer and metastasis. Studies have shown that LOX plays a fundamental role in the growth of primary tumours in colorectal and lung cancer (Gao, Xiao et al. 2010, Baker, Cox et al. 2011) and glioblastoma (Mammoto, Jiang et al. 2013). Tumour growth of PDAC KRASmut/p53wt cells engineered to express high levels of human LOX in murine allograft models is increased significantly compared to cells with endogenous LOX level (Miller, Morton et al. 2015). Lysyl oxidase activity also contributes to primary tumor growth in an aggressive pancreatic ductal adenocarcinoma (PDAC) model by impacting senescence (Wiel, Augert et al. 2013).
[004] Expression of LOX is elevated in more than 70 % of breast cancer patients with Estrogen Receptor negative disease, in 80 % of head and neck cancer patients, in 33 % of primary colorectal carcinomas (CRC) and 48 % of metastatic tissues from patients with CRC (Baker, Cox et al. 2011), and in cirrhotic hepatocellular carcinoma (HCC) patients with a history of alcoholism (Huang, Ho et al. 2013). LOX is also overexpressed in lung adenocarcinoma (Wilgus, Borczuk et al. 2011), LKB1-mutant lung cancer (Gao, Xiao et al. 2010), aggressive prostate adenocarcinoma (Stewart, Gray et al. 2008), uveal melanoma (Abourbih, Di Cesare et al. 2010), oral and oropharyngeal squamous carcinoma (Albinger- Hegyi, Stoeckli et al. 2010), thyroid cancer (Boufraqech, Nilubol et al. 2015), myeloproliferative neoplasms, especially myelofibrosis (Papadantonakis, Matsuura et al. 2012, Tadmor, Bejar et al. 2013, Leiva et al. 2019), mesothelioma (Perryman et al, 2022) and pancreatic cancer (Sansom 2012, Miller, Morton et al. 2015).
[005] Elevated LOX expression is associated with metastasis and decreased patient survival (Baker, Cox et al. 2011 , Wilgus, Borczuk et al. 2011). LOX acts remotely to pre-condition the niche at future sites of metastasis. T umour cell metastasis is facilitated by these “premetastatic niches” formed in destination organs (Erler, Bennewith et al. 2009). Increased LOX expression is associated with disease grade, increased distant metastasis and lower overall survival in gastric cancer (Kasashima, Yashiro et al. 2015), hepatocellular carcinoma (Zhu, Huang et al. 2015), non-small cells lung cancer (Liu, Ping et al. 2014), astrocytomas (da Silva, Uno et al. 2015) and laryngeal cancer (Se, 2017). High expression of LOX in primary breast tumours leads to osteolytic lesion formation; silencing or inhibition of LOX activity abrogates tumour- driven bone metastases (Cox, Rumney et al. 2015). LOX inhibition with BAPN and CCT365623 significantly reduce metastatic lung tumour burden in a mouse model of spontaneous breast cancer that metastasizes to the lungs (Tang et al, 2017). In a metastatic breast carcinoma model, LOX inhibition counteracted the metastasis-promoting, ECM-related effects of paclitaxel (Haj-Shomaly et al. 2022). Nerve growth factor promotes LOX-dependent chondrosarcoma metastasis (Tzeng et al. 2021). In osteosarcoma, higher LOX expression leads to the FAK pathway activation and increased pulmonary metastases in vivo (Chen et al, 2022).
[006] Desmoplasia and increased fibrosis have been associated with progression of several cancers such as breast, pancreatic, colorectal, gastric and hepatocellular (Barker, Cox et al. 2012). Desmoplasia is also an intrinsic mechanism of resistance to immunotherapy in stromally-rich tumours (Zhao and Subramanian, 2017). LOX and LOX family members have an essential role in extracellular matrix remodelling and desmoplasia (Levental, 2009; Xiao, 2012). Lysyl oxidase family members expression, either secreted by cancer cells or by activated fibroblasts, is associated with tumour ECM, tumour stroma or tumour-associated vasculature of several cancers, such as colorectal, pancreatic, breast, laryngeal, endometrial, testicular, hepatocellular, renal (reviewed in Barker et al (Barker, Cox et al. 2012)), gastric cancer (Kasashima, Yashiro et al. 2014).
[007] Other members of the LOX family are also implicated in proliferative diseases such as cancer. LOXL2 expression is upregulated in breast, gastric, colon, esophageal, head and neck, lung and laryngeal carcinomas (Barker, Cox et al. 2012) and in renal cells carcinoma (Hase, Jingushi et al. 2014) (Nishikawa, Chiyomaru et al. 2015). High LOXL2 expression is associated with poor prognosis in patients with squamous cell carcinoma, laryngeal, oesophagus and breast cancer, increased metastases in colon and breast cancer, as well as drug resistance in pancreatic cancer cells (Barker, Cox et al. 2012). L0XL2 up-regulation increases the invasiveness of otherwise non-invasive breast cancer cells (Akiri, Sabo et al. 2003). LOXL2 and LOXL4 are required for metastatic niche formation in a breast orthotopic mouse model (Wong et al, 2011). LOXL2 expression is associated with lymph node metastasis, histological grades and poor prognosis in cholangiocarcinoma, and knockdown of LOXL2 reduces invasion and metastasis (Xu, Li et al. 2014). HCC metastasis relies on LOXL2, which is overexpressed in tumor tissues and sera of HCC patients (Wong, Tse et al. 2014). LOXL2 is upregulated in glioma, correlates with WHO grade and poor prognosis in patients, promotes glioma cells proliferation and invasion, and reduces their sensitivity to temozolomide (Zhang et al, 2020). LOX and LOXL2 enhanced invasion and migration of cervical cancer cells can be inhibited by BAPN or LOXL2 inhibitors (Yang, Li et al. 2013; Peng et al, 2022).
[008] LOX and LOXL2 do not compensate one another; manipulation of LOX expression did not affect LOXL2 levels in a colorectal cancer model (Baker, Cox et al. 2011). While LOX and LOXL2 are involved in similar extra-cellular processes, it appears that they have distinct roles.
[009] LOXL1 is overexpressed in metastatic non-small cells lung cancer (NSCLC), and the metastatic phenotype can be reduced by inhibition with LOXL1 siRNA (Lee, Kim et al. 2011). Treatment with the pan-LOX inhibitor BAPN and silencing of LOXL1 expression decrease tumor growth, invasion, and metastasis in invasive lobular carcinoma, (Sflomos et al. 2021).
[0010] LOXL3 mRNA is expressed in Hs578T highly invasive breast cancer cells, but not in poorly invasive and non-metastatic breast cancer cells MCF7 and T47D (Kirschmann, Seftor et al. 2002). Overexpression of LOXL3 in MDCK epithelial cells induces an epithelial- mesenchymal transition (EMT) process, which is a key step in the progression of metastasis (Peinado, Del Carmen Iglesias-de la Cruz et al. 2005). Knockdown of LOXL3 with siRNA reduces invasiveness of glioma cells (Laurentino et al., 2021).
[0011] High expression of mRNA levels of LOXL4 was detected in 71% of all head and neck squamous cell carcinomas, and only in 9% of the healthy mucosa samples, (Scola and Gorogh 2010). LOXL4 expression is upregulated in invasive HNC and significantly correlated with local lymph node metastases and higher tumour stages (Goeroegh, Weise et al. 2007). LOXL4 promotes metastasis in gastric cancer (Li, Zhao et al. 2015). LOXL4 together with LOXL2 is required for metastatic niche formation in a breast orthotopic mouse model (Wong, Gilkes et al. 2011). Expression of LOXL4 is enhanced in keratocystic odontogenic tumors (KCOT) stromal tissues and primary KCOT stromal fibroblasts (Jiang, Sima et al. 2014). [0012] LOX and LOXL are implicated in fibrotic diseases, such as liver fibrosis, lung fibrosis, kidney fibrosis, cardiac fibrosis, myelofibrosis and schleroderma. Both LOX and LOXL are highly expressed in fibrotic areas, in surrounding myofibroblasts and in serum of patients with fibrotic conditions (Kagan 1994) (Kim, Peyrol et al. 1999) (Siegel, Chen et al. 1978) (Jourdan- Le Saux, Gleyzal et al. 1994) (Murawaki, Kusakabe et al. 1991). Therapeutic indications for LOX family inhibitors include a number of fibrotic conditions: myelofibrosis (Primary myelofibrosis, Post Polycythemia Vera or Post Essential Thrombocythemia Myelofibrosis), idiopathic pulmonary fibrosis (IPF), liver fibrosis due to non-alcoholic steatohepatitis (NASH), HIV and/or Hepatitis C- infection or primary sclerosing cholangitis (PSC) and compensated liver cirrhosis due to NASH. Levels of lysyl oxidase are increased in patients with scleroderma and systemic sclerosis (Chanoki, Ishii et al. 1995) (Rimar, Rosner et al. 2014).
[0013] LOX has been implicated in the pathogenesis of renal fibrosis and its inhibition with the alleviation of the symptoms (Di Donato, Ghiggeri et al. 1997, Haase 2009, Chen, Lin et al. 2015), including renal disfunctions associated with Alport syndrome (Cosgrove et al, 2018). Hyperuricemia results in hypertension, intrarenal vascular disease, and renal injury and is associated with increased expression of lysyl oxidase (LOX) in kidneys (Yang, Wang et al. 2010). Increased LOX activity has been linked to delayed graft failure after renal transplant, potentially due to increased local fibrosis (Zhi, 2017). Calcineurin inhibitors, such as Cyclosporin (CsA) used in anti-rejection therapy in solid organ transplants can paradoxically induce progressive nephropathy characterised by renal dysfunction and interstitial fibrosis. LOX and LOXL2 inhibitors can attenuate CsA induced nephropathy (Nguyen et al, 2021).
[0014] Similar involvement of LOX or LOXL2 in the pathology of disease and reduction in symptoms with LOX family inhibitors has been demonstrated for lung fibrosis (Barry-Hamilton, Spangler et al. 2010) (Haase 2009, Cox, Bird et al. 2013, Chien, Richards et al. 2014). Inhibition of LOX activity alleviates fibrosis by limiting fibrillar collagen cross-linking, thereby potentially impeding the formation of a pathological microenvironment in IPF (Tjin et al., 2017).
[0015] LOX and LOXL2 are involved in liver fibrosis (Kagan 1994, Marshall and Smith 2011) (Ricard-Blum, Bresson-Hadni et al. 1996) (Smith and Van Vlasselaer 2011) (Georges, Hui et al. 2007), liver cirrhosis (the last stage of liver fibrosis) (Kagan 1994) and related diseases such as Wilson’s disease and primary biliary cirrhosis (Vadasz, Kessler et al. 2005). LOXL1 plays an important role in the progression of non-alcoholic fatty liver disease (NAFLD) to NASH, in particular in non-obese patients (Aiting et al. 2021).
[0016] LOX expression is increased in hypoxic lymphatic endothelial cells, which might be responsible for fibrosis associated with lymphedema (Becker et al. 2021). Fibrotic changes in clubfoot-contracted tissue are associated with increased collagen deposition and LOX- mediated crosslinking and can be reduced by treatment with a LOX inhibitor indicated potential for the treatment of relapsed and resistant clubfeet (Knitlova et al. 2022). LOX inhibition is a potential treatment for intestinal fibrosis in Crohn's disease (de Bruyn et al. 2018).
[0017] LOX inhibitors assist in collagen remodeling and re-establishment of collagen architecture in human Dupuytren's, keloid and scar fibroblasts (Priyanka, 2016). Topical application of LOX inhibitor reduces scarring in rodent and non-rodent models (Hamprecht, Zhou et al. 2021). LOXL1 silencing inhibited TGF-pi induced ECM deposition of hypertrophic scar fibroblasts, and inhibitors could be effective in treating hypertrophic scarring (Ying et al. 2021).
[0018] LOX is also implicated in cardiovascular disease. BAPN treatment reduces myocardial fibrosis in a mouse model, therefore LOX inhibition is useful as potential therapeutic targeting of collagen regulation and thereby age-related myocardial fibrosis (Rosin, Sopel et al. 2015). Increased expression of LOX is associated with myocardial fibrosis and cardiac dysfunction (Zibadi, Vazquez et al. 2010) (Gao, Xiao et al. 2010) (Lopez, Gonzalez et al. 2010). Left atrial myocardium of patients with atrial fibrillation express higher levels of lysyl oxidase and fibronectin expression as well as collagen crosslinking. Fibronectin upregulation is mediated by LOX in cardiac fibroblasts (Adam, Theobald et al. 2011). Inhibition of LOX with a blocking antibody reduced cardiac fibrosis and infarct expansion in a mouse model (Gonzalez- Santamaria, 2016). Lysyl oxidases play a causal role in experimental pulmonary hypertension and inhibition with BAPN reduces the symptoms (Nave, Mizikova et al. 2014). LOX facilitate the formation of crosslinked and therefore insoluble collagen and the subsequent left ventricle stiffness and systolic dysfunction in patients with hypertensive heart disease (HHD) and heart failure (HF) of hypertensive origin (Lopez, Gonzalez et al. 2013) (Lopez, Querejeta et al. 2012). A role for LOXL1 has been suggested in cardiac hypertrophy and BAPN administration inhibits angiotensin Il-induced cardiac hypertrophy in vivo (Ohmura, Yasukawa et al. 2012). LOX knockdown attenuates cardiac and vascular fibrosis in high fat diet induced obesity (Martinez-Martinez, 2016).
[0019] Lysyl oxidase inhibition has been proposed as a therapeutic method for decreasing or preventing recurrent restenosis (Nuthakki, Fleser et al. 2004) (Brasselet, Durand et al. 2005). LOX activity is increased in atherosclerosis (Kagan, Raghavan et al. 1981). LOX is overexpressed in pathologies associated with increased thrombosis, such as myeloproliferative neoplasms, chronic kidney disease and arterial stenosis and enhances platelets aggregation (Shinobu et al, 2016). Arterial stiffness and cardiac dysfunction, hallmarks of Hutchinson-Gilford Progeria Syndrome, is improved by treatment with a LOX inhibitor (von Kleeck et al. 2021). LOX inhibition attenuates arterial medial calcification, a form of vascular calcification (VC). VC increases cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD), particularly those on dialysis, with diabetes, and senile patients, because it causes ischemic cardiovascular disease and cerebrovascular disease (llto et al. 2021). LOX inhibition improves venous adaptation after arteriovenous fistula (Hernandez et al. 2021). Therefore, LOX inhibition may prove beneficial in the treatment or prevention of cardiovascular conditions, including hypertensive heart disease, heart failure, cardiac hypertrophy and atherosclerosis.
[0020] LOX is associated with the amyloid-beta (Ap) related pathological hallmarks (such as cerebral amyloid angiopathy and senile plaques) of both Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D) pathogenesis (Wilhelmus, Bol et al. 2013). LOX activity is increased in the hippocampal samples of Alzheimer’s disease and in non-Alzheimer’s dementia (Gilad, Kagan et al. 2005). LOX is increased at the site of brain injury (Gilad, Kagan et al. 2001) and spinal cord injury and its inhibition lead to accelerated functional recovery in an unilateral spinal cord dissection model (Gilad and Gilad 2001). Pharmacogenomic analyses placed LOX at the centre of ECM remodelling networks associated with bipolar disorder (BD), schizophrenia and Alzheimer disease, and inhibition of LOX had striking morphogenic effects on astrocytes, equivalent to lithium, an approved mood stabiliser treatment of BD, in an ex vivo model (Rivera, Butt 2019).
[0021] LOXLs are implicated in pulmonary diseases. LOXL2 and LOXL3 are likely to have a role in Primary Alveolar Proteinosis (PAP) since both are expressed in PAP tissue, but not normal lung tissue (Neufeld and Brekhman 2009). Excessive lysyl oxidase activity was linked to the pathologic pulmonary features of bronchopulmonary dysplasia (Kumarasamy, Schmitt et al. 2009). Abnormal vascular permeability, such as present in diseases such as pulmonary edema and acute respiratory distress syndrome (ARDS) or endotoxin-induced lung injury can be normalised by LOX inhibition (Mammoto, Mammoto et al. 2013) (Ingber and Mammoto 2014). LOXL2 inhibition reduces key features of airway remodelling, in an ovalbumin mouse model of asthma, suggesting that LOXL2 inhibition is a potential therapy to reduce remodelling of the airways in severe asthma (Ramis et al. 2022).
[0022] LOX inhibition may be beneficial in the treatment of various ocular conditions. Inhibition of LOX or LOXL2 prevents neovascularization and fibrosis following laser-induced choroidal neovascularization (CNV). Therefore LOX and LOXL inhibitors can be useful in the treatment of conditions characterized by neovascularization, such as age-related macular degeneration (AMD), diabetic retinopathy and retinopathy of prematurity (Stalmans, Marshall et al. 2010). Increased LOXL2 levels have been associated with failure following glaucoma surgery and treatment with a L0XL2 antibody reduced pathological angiogenesis, inflammation, and ocular fibrosis (Park, Kim et al. 2014) (Van Bergen, Marshall et al. 2013)(Stalmans, Van Bergen et al. 2011). LOXL1 expression is increased in the initial stages of abnormal fibrogenesis in pseudoexfoliation syndrome/glaucoma tissues (Zenkel, Krysta et al. 2011) (Schlotzer- Schrehardt, Pasutto et al. 2008).
[0023] LOX is implicated in inflammatory conditions and may be useful in the treatment of acute respiratory distress syndrome (ARDS) (Mambetsariev, Tian et al. 2014). LOX and LOXL1 reduction and collagen crosslinking reduction are associated with decreased inflammation in an Angiotensin II induced model of hypertension (Gonzalez, Rhaleb et al. 2014). LOXL3 plays a significant role in the pathogenesis of leptin-associated osteoarthritis; its knock-down reduces apoptosis in chondrocyte, a prime factor involved in the pathogenesis of osteoarthritis (Wei et al., 2022). Inhibition of LOX with BAPN attenuates inflammation, synovial hyperplasia, angiogenesis and expression of MMP-2 and MMP-9 in a type II collagen- induced arthritis rat model suggesting that LOX may be a potential therapeutic target for rheumatoid arthritis (Wang et al. 2017).
[0024] LOX is the main isoenzyme expressed in human adipose tissue and that its expression is strongly upregulated in samples from obese patients. BAPN reduces body weight gain and improves the metabolic profile in diet-induced obesity in rats (Miana, Galan et al. 2015) and reduces local adipose tissue inflammation (Halberg, Khan et al. 2009) and obesity-induced fibrosis (Liu et al. 2022). LOX inhibition stimulate transdifferentiation of storage white adipocytes into thermogenic beige adipocytes, leading to increased cellular energy expenditure and reduced adiposity. Therefore targeting Lox to expand beige fat may be useful for treating obesity and metabolic diseases (Xing et al. 2020).
[0025] LOX may be useful in treating bacterial infections and subsequent fibrotic complications. LOX is upregulated in infections with Staphylococcus Aureus and inhibition with BAPN influences resulting abscesses morphology and collagenisation (Beerlage, Greb et al. 2013). LOX is implicated also in some parasitic diseases: LOX and LOXLs are upregulated in the early stages of liver granuloma development in schistosomiasis (Decitre, Gleyzal et al. 1998), and BAPN inhibition reduces the size of the granulomas and reduces the egg load in combination with antiparasitic drug PZQ compared to PZQ alone (Giboda, Zenka et al. 1992).
[0026] LOX is upregulated in endometriosis and may be implicated in the establishment and progression of endometriotic lesions (Ruiz, Dutil et al. 2011) (Dentillo, Meola et al. 2010). [0027] Certain LOX inhibitors are known. These include p-aminopropionitrile (BAPN), haloamines, 1 ,2-diamines, allyl and propargyl amines, hydrazines, semicarbazide and thiolactones, benzylamines, mercaptopyridine and pyridazinone compounds (Pinnell and Martin 1968) (Tang, Simpson et al. 1984) (Palfreyman, McDonald et al. 1989) (Sayre 2007) (Carrington, Bird et al. 1984) (Levene, Sharman et al. 1992) (Liu, Nellaiappan et al. 1997) (Williamson and Kagan 1987) (Anderson, Bartlett et al. 2007) (Schohe-Loop, Burchardt et al. 2003) (Burchardt 2006; Aslam, Miele et al. 2015). However, in general these compounds are either non-selective, lack potency or are unsuitable for use in patients.
[0028] More recent LOX and LOXL2 inhibitors have been described: LOX inhibitors containing hydrazine and hydrazide groups (Burke et al, 2017); LOXL2 inhibitors: derivatives of haloallylamine (Chang et al, 2017), pyridines (Rowbottom et al, 2016a; Rowbottom et al, 2016b), pyrimidines (Rowbottom & Hutchinson, 2017a) and chromenones (Rowbottom & Hutchinson, 2017b).
[0029] Small molecule methylamine derivatives have recently been shown to be inhibitors of LOX and paralogues thereof (WO 2017/141049 A1).
[0030] However, there remains a need for further compounds capable of inhibiting LOX or paralogues thereof. In particular, provided herein are compounds which demonstrate differentiated potency and/or pharmacokinetics to existing LOX inhibitors.
[0031] Suitably, the compounds of the present invention demonstrate improved intestinal permeability, oral exposure and/or oral bioavailability, particularly in higher species such as dog.
SUMMARY OF THE INVENTION
[0032] Described herein are ester prodrugs of LOX inhibitors. The ester prodrugs of Formula I demonstrate enhanced intestinal permeability in comparison to the parent carboxylic acid compounds as well as providing advantageous improvements in one or more pharmacokinetic parameter in vivo, such as improvements in Cmax, exposure (e.g. AUG) and oral bioavailability (F%) compared to other similar ester prodrugs.
[0033] In one aspect, the present invention provides a compound of Formula I as defined herein, and/or a salt or solvate thereof. [0034] In another aspect, the present invention provides a pharmaceutical composition which comprises a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.
[0035] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.
[0036] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a disease or medical condition mediated by lysyl oxidase (LOX).
[0037] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a proliferative disease.
[0038] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of cancer.
[0039] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a fibrotic disorder.
[0040] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a disease or medical condition mediated by lysyl oxidase (LOX).
[0041] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a proliferative disease.
[0042] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of cancer. [0043] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a fibrotic disorder.
[0044] In another aspect, the present invention provides a method of treating or preventing a disease or medical condition mediated by lysyl oxidase (LOX), said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
[0045] In another aspect, the present invention provides a method of treating or preventing a proliferative disease, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
[0046] In another aspect, the present invention provides a method of treating or preventing cancer, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
[0047] In another aspect, the present invention provides a method of treating or preventing a fibrotic disorder, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
[0048] In another aspect, the present invention provides a combination comprising a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, with one or more additional therapeutic agents.
[0049] Preferred, suitable, and optional features of any one particular aspect of the present invention are also preferred, suitable, and optional features of any other aspect.
BRIEF DESCRIPTION OF THE DRA WINGS
[0050] Figure 1 shows percent (%) conversion of the compound of Example 1 to its free carboxylic acid parent compound by rat, dog and human liver microsomes at 0, 15 and 30 minutes.
DETAILED DESCRIPTION OF THE INVENTION
Definitions [0051] The compounds and intermediates described herein may be named according to either the IIIPAC (International Union for Pure and Applied Chemistry) or CAS (Chemical Abstracts Service) nomenclature systems. It should be understood that unless expressly stated to the contrary, the terms “compounds of Formula I” and the more general term “compounds” refer to and include any and all compounds described by and/or with reference to Formula I. It should also be understood that these terms encompasses all isomers, such as geometric i.e. cis and trans isomers, as well as optical isomers, i.e. R and S enantiomers, of such compounds, in substantially pure form and/or any mixtures of the foregoing in any ratio. This understanding extends to pharmaceutical compositions and methods of treatment that employ or comprise one or more compounds of the Formula I, either by themselves or in combination with additional agents.
[0052] The various hydrocarbon-containing moieties provided herein may be described using a prefix designating the minimum and maximum number of carbon atoms in the moiety, e.g. “(Ca-b)” or “Ca-Cb” or “(a-b)C”. For example, (Ca-b)alkyl indicates an alkyl moiety having the integer “a” to the integer “b” number of carbon atoms, inclusive. Certain moieties may also be described according to the minimum and maximum number of members with or without specific reference to a particular atom or overall structure. For example, the terms “a to b membered ring” or “having between a to b members” refer to a moiety having the integer “a” to the integer “b” number of atoms, inclusive.
[0053] "About" when used herein in conjunction with a measurable value such as, for example, an amount or a period of time and the like, is meant to encompass reasonable variations of the value, for instance, to allow for experimental error in the measurement of said value.
[0054] As used herein by themselves or in conjunction with another term or terms, "alkyl" and “alkyl group” refer to a branched or unbranched saturated hydrocarbon chain. Unless specified otherwise, alkyl groups typically contain 1-10 carbon atoms, such as 1-6 carbon atoms or 1-4 carbon atoms or 1-3 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, tert-butyl, isobutyl, etc.
[0055] As used herein by themselves or in conjunction with another term or terms, “alkoxy” and “alkoxy group” refer to O-alkyl groups. Representative examples include, but are not limited to, -OMe, -OEt, -O-'Pr and O-'Bu. Alkoxy groups can be substituted or unsubstituted unless indicated otherwise. [0056] As used herein by themselves or in conjunction with another term or terms, “alkenyl” and “alkenyl group” refer to a branched or unbranched hydrocarbon chain containing at least one double bond. Unless specified otherwise, alkenyl groups typically contain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, ethenyl, 3-buten-1-yl, 2-ethenylbutyl, and 3-hexen-1-yl.
[0057] As used herein by themselves or in conjunction with another term or terms, “alkynyl” and “alkynyl group” refer to a branched or unbranched hydrocarbon chain containing at least one triple bond. Unless specified otherwise, alkynyl groups typically contain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, and 3-pentyn-1-yl.
[0058] As used herein by itself or in conjunction with another term or terms, “aromatic” refers to monocyclic and polycyclic ring systems containing 4n+2 pi electrons, where n is an integer. Aromatic should be understood as referring to and including ring systems that contain only carbon atoms (i.e. “aryl”) as well as ring systems that contain at least one heteroatom selected from N, O or S (i.e. “heteroaromatic” or “heteroaryl”). An aromatic ring system can be substituted or unsubstituted.
[0059] As used herein by itself or in conjunction with another term or terms, “non-aromatic” refers to a monocyclic or polycyclic ring system having at least one double bond that is not part of an extended conjugated pi system. As used herein, non-aromatic refers to and includes ring systems that contain only carbon atoms as well as ring systems that contain at least one heteroatom selected from N, O or S. A non-aromatic ring system can be substituted or unsubstituted.
[0060] As used herein by themselves or in conjunction with another term or terms, “aryl” and “aryl group” refer to phenyl and 7-15 membered bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro, and/or fused ring systems, in which at least one of the rings is aromatic. Aryl groups can be substituted or unsubstituted. Unless specified otherwise, an aryl group may contain 6 ring atoms (i.e., phenyl) or a ring system containing 9 to 15 atoms, such as 9 to 11 ring atoms, or 9 or 10 ring atoms. Representative examples include, but are not limited to, naphthyl, indanyl, 1 ,2,3,4-tetrahydronaphthalenyl, 6,7,8,9-tetrahydro-5H- benzocycloheptenyl, and 6,7,8,9-tetrahydro-5H-benzocycloheptenyl. Suitably an aryl group is phenyl and naphthyl, suitably phenyl. [0061] As used herein by themselves or in conjunction with another term or terms, “carbocyclic group” and “carbocycle” refer to monocyclic and polycyclic ring systems that contain only carbon atoms in the ring(s), i.e., hydrocarbon ring systems, without regard or reference to aromaticity or degree of unsaturation. Thus, carbocyclic group should be understood as referring to and including ring systems that are fully saturated (such as, for example, a cyclohexyl group), ring systems that are aromatic (such as, for example, a phenyl group), as well as ring systems having fully saturated, aromatic and/or unsaturated portions (such as, for example, cyclohexenyl, 2,3-dihydro-indenyl, and 1 ,2,3,4-tetrahydro- naphthalenyl). The terms carbocyclic and carbocycle further include bridged, fused, and spirocyclic ring systems.
[0062] As used herein by themselves or in conjunction with another term or terms, “cycloalkyl” and “cycloalkyl group” refer to a non-aromatic carbocyclic ring system, that may be monocyclic, bicyclic, or tricyclic, saturated or unsaturated, and may be bridged, spiro, and/or fused. A cycloalkyl group may be substituted or unsubstituted. Unless specified otherwise, a cycloalkyl group typically contains from 3 to 12 ring atoms. In some instances a cycloalkyl group may contain 4 to 10 ring atoms (e.g., 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, etc.). Representative examples include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl, norbornenyl, bicyclo[2.2.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[3.3.2]decane. Suitably, cycloalkyl groups are selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
[0063] As used herein by themselves or in conjunction with another term or terms, “haloalkyl” and “haloalkyl group” refer to alkyl groups in which one or more hydrogen atoms are replaced by halogen atoms. Haloalkyl includes both saturated alkyl groups as well as unsaturated alkenyl and alkynyl groups. Representative examples include, but are not limited to, -CF3, - CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, - CF2CH2CH3, -CF=CF2, -CCI=CH2, -CBr=CH2, -CI=CH2, -C C-CF3, -CHFCH2CH3 and - CHFCH2CFS. Haloalkyl groups can be substituted or unsubstituted. Suitably, a haloalkyl group is selected from CHF2 and CF3, suitably CF3.
[0064] As used herein by themselves or in conjunction with another term or terms, “haloalkoxy” and “haloalkoxy group” refer to alkoxy groups (i.e. O-alkyl groups) in which one or more hydrogen atoms are replaced by halogen atoms. Haloalkoxy includes both saturated alkoxy groups as well as unsaturated alkenyl and alkynyl groups. Representative examples include, but are not limited to, -OCF3, -OCHF2, -OCH2F, -OCF2CF3, -OCHFCF3, -OCH2CFs, -OCF2CH3, -OCHFCHs, -OCF2CF2CF3, -OCF2CH2CH3, -OCF=CF2, -OCCI=CH2, - 0CBr=CH2, -OCHFCH2CH3 and -OCHFCH2CF3. Haloalkoxy groups can be substituted or unsubstituted. Suitably, a haloalkyoxy group is selected from -OCHF2 and -OCF3, suitably - OCF3.
[0065] As used herein by themselves or in conjunction with another term or terms, “halo” and “halogen” include fluorine, chlorine, bromine and iodine atoms and substituents.
[0066] As used herein by themselves or in conjunction with another term or terms, “heteroaryl” and “heteroaryl group” refer to (a) 5 and 6 membered monocyclic aromatic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and (b) 7 to15 membered bicyclic and tricyclic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and in which at least one of the rings is aromatic. In some instances, a heteroaryl group can contain two or more heteroatoms, which may be the same or different. Heteroaryl groups can be substituted or unsubstituted, and may be bridged, spiro, and/or fused. In some instances, a heteroaryl group may contain 5, 6, or 8 to 15 ring atoms. In other instances, a heteroaryl group may contain 5 to 10 ring atoms, such as 5, 6, 9, or 10 ring atoms. Representative examples include, but are not limited to, 2,3-dihydrobenzofuranyl, 1 ,2-dihydroquinolinyl, 3,4-dihydroisoquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, 1 ,2,3,4-tetrahydroquinolinyl, benzoxazinyl, benzthiazinyl, chromanyl, furanyl, 2-furanyl, 3-furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl, 2-, 4-, or 5-pyrimidinyl, pyrazolyl, pyrrolyl, 2- or 3-pyrrolyl, pyrazinyl, pyridazinyl, 3- or 4-pyridazinyl, 2-pyrazinyl, thienyl, 2-thienyl, 3- thienyl, tetrazolyl, thiazolyl, thiadiazolyl, triazinyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidin- 2-yl, pyridazin-4-yl, pyrazin-2-yl, naphthyridinyl, pteridinyl, phthalazinyl, purinyl, alloxazinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1 -benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, cinnolinyl, furopyridinyl, indolinyl, indolizinyl, indolyl, or 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 3H-indolyl, quinazolinyl, quinoxalinyl, isoindolyl, isoquinolinyl, 10-aza-tricyclo[6.3.1.027]dodeca-2(7), 3, 5-trienyl, 12- oxa-10-aza-tricyclo[6.3.1.02’7]dodeca-2(7), 3, 5-trienyl, 12-aza-tricyclo[7.2.1.02’7]dodeca- 2(7), 3, 5-trienyl, 10-aza-tricyclo[6.3.2.02’7]trideca-2(7),3,5-trienyl, 2,3,4,5-tetrahydro-1 H- benzo[d]azepinyl, 1 ,3,4,5-tetrahydro-benzo[d]azepin-2-onyl, 1 ,3,4,5-tetrahydro- benzo[b]azepin-2-onyl, 2,3,4,5-tetrahydro-benzo[c]azepin-1-onyl, 1 ,2,3,4-tetrahydro- benzo[e][1 ,4]diazepin-5-onyl, 2,3,4,5-tetrahydro-1 H-benzo[e][1 ,4]diazepinyl , 5, 6,8,9- tetrahydro-7-oxa-benzocycloheptenyl, 2,3,4,5-tetrahydro-1 H-benzo[b]azepinyl, 1 ,2,4,5- tetra hydro- be nzo[e][1 ,3]diazepin-3-onyl, 3,4-dihydro-2H-benzo[b][1 ,4]dioxepinyl , 3,4-dihydro- 2H-benzo[f][1 ,4]oxazepin-5-onyl, 6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptenyl, 5,5- dioxo-6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptenyl, and 2,3,4,5-tetrahydro- benzo[f][1 ,4]oxazepinyl. Suitably, a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.
[0067] As used herein by themselves or in conjunction with another term or terms, “heterocyclic group” and “heterocycle” refer to monocyclic and polycyclic ring systems that contain carbon atoms and at least one heteroatom selected from nitrogen, oxygen, sulfur or phosphorus in the ring(s), without regard or reference to aromaticity or degree of unsaturation. Thus, a heterocyclic group should be understood as referring to and including ring systems that are fully saturated (such as, for example, a piperidinyl group), ring systems that are aromatic (such as, for example, a pyridinyl group), as well as ring systems having fully saturated, aromatic and/or unsaturated portions (such as, for example, 1 , 2,3,6- tetrahydropyridinyl and 6,8-dihydro-5H-[1 ,2,4]triazolo[4,3-a]pyrizinyl). The terms heterocyclic and heterocycle further include bridged, fused, and spirocyclic ring systems.
[0068] As used herein by themselves or in conjunction with another term or terms, “heterocycloalkyl” and “heterocycloalkyl group” refer to 3 to15 membered monocyclic, bicyclic, and tricyclic non-aromatic ring systems, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen, sulfur or phosphorus. Heterocycloalkyl groups may be fully saturated or contain unsaturated portions and may be bridged, spiro, and/or fused ring systems. In some instances a heterocycloalkyl group may contain at least two or heteroatoms, which may be the same or different. Heterocycloalkyl groups can be substituted or unsubstituted. In some instances a heterocycloalkyl group may contain from 3 to 10 ring atoms or from 3 to 7 ring atoms or from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms. Representative examples include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl, homopiperazinyl, thiomorpholinyl-5-oxide, thiomorpholinyl-S,S-dioxide, pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-5-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-5-oxide, quinuclidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, 3,8-diaza- bicyclo[3.2.1]octanyl, 2,5-diaza-bicyclo[2.2.1]heptanyl, 3,8-diaza-bicyclo[3.2.1]octanyl, 3,9- diaza-bicyclo[4.2.1]nonanyl, 2,6-diaza-bicyclo[3.2.2]nonanyl, [1 ,4]oxaphosphinanyl- 4-oxide, [1 ,4]azaphosphinanyl- 4-oxide, [1 ,2]oxaphospholanyl- 2-oxide, phosphinanyl-1 -oxide, [1 ,3]azaphospholidinynl- 3-oxide, [1 ,3]oxaphospholanyl- 3-oxide, 7-oxabicyclo[2.2.1]heptanyl, 6.8-dihydro-5H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl, 6,8-dihydro-5H-imidazo[1 ,5-a]pyrazin-7-yl,
6.8-dihydro-5H-imidazo[1 ,2-a]pyrazin-7-yl, 5,6,8,9-tetrahydro-[1 ,2,4]triazolo[4,3- d][1 ,4]diazepin-7-yl and 6,8-dihydro-5H-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl. Suitably, a heterocyclylalkyl group as defined herein is a monocyclic, bicyclic or spiro heterocyclyl group comprising one, two or three heteroatoms selected from N, O or S.
[0069] As used herein, “oxo” refers to a double bond to oxygen, i.e. =0.
[0070] As used herein by itself or in conjunction with another term or terms, “pharmaceutically acceptable” refers to materials that are generally chemically and/or physically compatible with other ingredients (such as, for example, with reference to a formulation), and/or is generally physiologically compatible with the recipient (such as, for example, a subject) thereof.
[0071] As used herein by itself or in conjunction with another term or terms, “pharmaceutical composition” refers to a composition that can be used to treat a disease, condition, or disorder in a subject, including a human.
[0072] As used herein by themselves or in conjunction with another term or terms, “stable” and “chemically stable” refer to a compound that is sufficiently robust to be isolated from a reaction mixture with a useful degree of purity. The present application is directed solely to the preparation of stable compounds. When lists of alternative substituents include members which, owing to valency requirements, chemical stability, or other reasons, cannot be used to substitute a particular group, the list is intended to be read in context to include those members of the list that are suitable for substituting the particular group. For example, when considering the degree of optional substitution of a particular moiety, it should be understood that the number of substituents does not exceed the valency appropriate for that moiety.
[0073] As used herein by themselves or in conjunction with another term or terms, “subject(s)” and “patient(s)” refer to mammals, in particular humans.
[0074] As used herein by itself or in conjunction with another term or terms, “substituted” indicates that a hydrogen atom on a molecule has been replaced with a different atom or group of atoms and the atom or group of atoms replacing the hydrogen atom is a “substituent.” It should be understood that the terms “substituent”, “substituents”, “moiety”, “moieties”, “group”, or “groups” refer to substituent(s).
[0075] As used herein by themselves or in conjunction with another term or terms, “therapeutic” and “therapeutically effective amount” refer to an amount a compound, composition or medicament that (a) inhibits or causes an improvement in a particular disease, condition or disorder; (b) attenuates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder. It should be understood that the terms “therapeutic” and “therapeutically effective” encompass any one of the aforementioned effects (a)-(b), either alone or in combination with any of the others (a)-(b). It should be understood that in, for example, a human or other mammal, a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or a therapeutically effective amount may be the amount required by the guidelines of the United States Food and Drug Administration (FDA) or equivalent foreign regulatory body, for the particular disease and subject being treated. It should be appreciated that determination of proper dosage forms, dosage amounts, and routes of administration is within the level of ordinary skill in the pharmaceutical and medical arts.
[0076] As used herein whether by themselves or in conjunction with another term or terms, “treating”, “treated” and “treatment”, refer to and include ameliorative, palliative, and curative uses and results. In some embodiments, the terms “treating”, “treated”, and “treatment” refer to curative uses and results as well as uses and results that diminish or reduce the severity of a particular condition, characteristic, symptom, disorder, or disease described herein. For example, treatment can include diminishment of several symptoms of a condition or disorder or complete eradication of said condition or disorder.
[0077] As used herein, the terms “prevent”, “preventative” or “prevention”, refers to diminishing the likelihood, or delaying the onset, of one or more symptoms of a particular disease, condition or disorder described herein. It should be understood that the terms “prevent”, “preventative” or “prevention” are not necessarily used in an absolute sense, but also refers to uses and results where the administration of a compound or composition diminishes the likelihood or seriousness of a condition, symptom, or disease state, and/or delays the onset of a condition, symptom, or disease state for a period of time.
[0078] As used herein, a ’’therapeutic agent” or “therapeutically active agent”, whether used alone or in conjunction with another term or terms, refers to any compound, i.e. a drug, that has been found to be useful in the treatment of a disease, disorder or condition and is not described by Formula I. It should be understood that a therapeutic agent may or may not be approved by the FDA or an equivalent foreign regulatory body.
[0079] A “therapeutically effective amount” means the amount of a compound that, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject or patient to be treated. [0080] A bond terminating in a “ ” represents that the bond is connected to another atom that is not shown in the structure. A bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be variably connected to atoms in the ring structure where allowed by valency unless otherwise defined.
Compounds
[0081] In one aspect the present invention relates to a compound, or a salt or solvate thereof, according to formula I:
Figure imgf000019_0001
wherein,
X is selected from the group consisting of S, NR1 and O;
R1 is selected from hydrogen and C1.4 alkyl;
Y is selected from N and CR4;
R4 is selected from hydrogen, halogen and C1.4 alkyl; one of W and Z is carbon and is bonded to the sulfone moiety,
Figure imgf000019_0002
, and the other of W and Z is N or CH;
R2 is selected from a phenyl, 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl group, each of which may be optionally substituted by one or more R3 groups; and
R3 is selected from the group consisting of halogen, oxo, RA3, -ORB3, -NRB3RC3, -SRB3, -CN, -NO2, -NRB3C(O)RC3, -C(O)NRB3RC3, -NRB3C(O)ORC3, -OC(O)NRB3RC3, -NRB3SO2RC3, - SC>2NRB3RC3, -SC>2RB3, -C(O)RB3, -C(O)ORB3, 3-7 membered heterocycloalkyl optionally substituted with one or more RD3 and C3-6 cycloalkyl optionally substituted with one or more RD3; where RA3 is selected from the group consisting of Ci-e alkyl, Ci-e alkenyl, C2-6 alkynyl, Ci-e haloalkyl and Ci-e haloalkoxy, each of which may be optionally substituted with a substituent selected from the group consisting of C1.4 alkoxy, hydroxy, -NH2, NHMe and NMe2; where RB3 and RC3 are independently selected from the group consisting of hydrogen, C1.4 alkyl, C1.4 alkenyl, C2-4 alkynyl, C1.4 haloalkyl, each of which may be optionally substituted with a substituent selected from the group consisting of C1.4 alkoxy, phenyl and hydroxy; or in any occurrence of the moiety -NRB3RC3, RB3 and RC3, together with the nitrogen atom to which they are bonded can form a 4- to 7-membered ring system; which may optionally be substituted by one or more RE3; where RD3 and RE3 are independently selected from the group consisting of Ci- 4 alkyl, C1.4 haloalkyl, C1.4 alkoxy, C1.4 haloalkoxy, C3-6 cycloalkyl, phenyl, oxo, and hydroxy.
[0082] The compounds of Formula I and sub-formulae thereof are pro-drugs which are broken down in the human or animal body to release a parent compound. Without being bound by theory, the compounds of Formula I and sub-formulae thereof include an in vivo cleavable ethyl ester group which is metabolically cleaved after administration to a subject to give the corresponding free carboxy group (i.e. parent acid).
[0083] In one embodiment, R1 is selected from hydrogen, methyl or ethyl. Suitably, R1 is hydrogen.
[0084] In one embodiment, R4 is selected from hydrogen, chloro, methyl and ethyl. Suitably, R4 is hydrogen, methyl or ethyl. More suitably, R4 is hydrogen.
[0085] In one embodiment, X is selected from the group consisting of S, NH, NMe and O.
[0086] In another embodiment, X is S or O. In another embodiment, X is S.
[0087] In one embodiment, Y is N or CH. Suitably, Y is N.
[0088] In one embodiment, W is carbon and is bonded to the sulfone moiety. In another embodiment, Z is carbon and is bonded to the sulfone moiety. [0089] In one embodiment, W is carbon and is bonded to the sulfone moiety and Z is CH. In another embodiment, Z is carbon and is bonded to the sulfone moiety and W is CH.
[0090] In one embodiment, X is S and Y is N. In another embodiment, X is S and Y is CH.
[0091] In one embodiment, X is S, Y is N and W is carbon and is bonded to the sulfone moiety. In another embodiment, X is S, Y is CH and W is carbon and is bonded to the sulfone moiety.
[0092] In one embodiment, X is S, Y is N and Z is carbon and is bonded to the sulfone moiety. In another embodiment, X is S, Y is CH and Z is carbon and is bonded to the sulfone moiety.
[0093] In one embodiment, the compound of formula I is a compound according to one of sub-formula la to Ig:
Figure imgf000021_0001
Figure imgf000022_0001
[0094] In one embodiment, the compound of formula I is a compound according to one of subformula la, lb or Ic. In another embodiment, the compound of formula I is a compound according to sub-formula la. In another embodiment, the compound of formula I is a compound according to sub-formula lb. In another embodiment, the compound of formula I is a compound according to sub-formula Ic.
[0095] In one embodiment, R2 is selected from a phenyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl and piperazinyl group, each of which may be optionally substituted by one or more R3 groups.
[0096] In another embodiment, R2 is selected from a phenyl, imidazolyl, pyrazolyl, triazolyl, pyridyl and pyrimidinyl, each of which may be optionally substituted by one or more R3 groups. [0097] In another embodiment, R2 is selected from a phenyl, pyrrolidinyl, pyrazolyl and pyridyl group, each of which may be optionally substituted by one or more R3 groups.
[0098] In another embodiment, R2 is a phenyl or pyrazolyl group, each of which may be optionally substituted by one or more R3 groups.
[0099] In one embodiment, R2 is selected from:
Figure imgf000023_0001
each of which may be optionally substituted by one or more R3 groups.
[00100] In one embodiment, R2 is selected from:
Figure imgf000023_0002
[00102] In one embodiment, R3 is selected from the group consisting of halogen, RA3, - ORB3, -NRB3RC3, -CN, -NRB3C(O)RC3, -C(O)NRB3RC3, -NRB3C(O)ORC3, -NRB3SO2RC3, - SC>2NRB3RC3, -SC>2RB3, -C(O)RB3, -C(O)ORB3, 3-7 membered heterocycloalkyl optionally substituted with one or more RD3 and C3-6 cycloalkyl optionally substituted with one or more RD3. [00103] In one embodiment, R3 is selected from the group consisting of halogen, RA3, - ORB3, -C(O)NRB3RC3, -C(O)RB3, 3-7 membered heterocycloalkyl optionally substituted with one or more RD3 and C3-6 cycloalkyl optionally substituted with one or more RD3.
[00104] In one embodiment, R3 is selected from the group consisting of halogen, RA3, - ORB3, - 3-7 membered heterocycloalkyl optionally substituted with one or more RD3 and C3-6 cycloalkyl optionally substituted with one or more RD3.
[00105] In one embodiment, R3 is selected from the group consisting of halogen, RA3, - ORB3 and C3-6 cycloalkyl optionally substituted with one or more RD3.
[00106] In one embodiment, R3 is selected from the group consisting of halogen, RA3 and -ORB3.
[00107] In one embodiment, R3 is RA3 or -ORB3.
[00108] In one embodiment, RA3 is selected from the group consisting of Ci-e alkyl, C2- 6 alkynyl and Ci-e haloalkyl, each of which may be optionally substituted with a substituent selected from the group consisting of C1.4 alkoxy, hydroxy, -NH2, NHMe and NMe2.
[00109] In one embodiment, RA3 is Ci-e alkyl optionally substituted with a substituent selected from the group consisting of C1.4 alkoxy, hydroxy, -NH2, NHMe and NMe2.
[00110] In one embodiment, RB3 and RC3 are independently selected from hydrogen and C1.4 alkyl, each of which may be optionally substituted with a substituent selected from the group consisting of C1.4 alkoxy, phenyl and hydroxy.
[00111] In one embodiment, RD3 and RE3 are independently selected from the group consisting of C1.4 alkyl, C1.4 haloalkyl, C1.4 alkoxy and hydroxy. In another embodiment, RD3 and RE3 are independently selected from C1.4 alkyl or C1.4 alkoxy.
[00112] The compounds of the invention will now be further described by way of the following numbered paragraphs:
1. A compound, or a salt or solvate thereof, according to formula I:
Figure imgf000025_0001
wherein,
X is selected from the group consisting of: S, NR1 and O;
R1 is selected from hydrogen and C1.4 alkyl;
Y is selected from N and CR4;
R4 is selected from hydrogen, halogen and C1.4 alkyl; one of W and Z is carbon and is bonded to the sulfone moiety,
Figure imgf000025_0002
, and the other of W and Z is N or CH;
R2 is selected from a phenyl, 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl group, each of which may be optionally substituted by one or more R3 groups; and
R3 is selected from the group consisting of halogen, oxo, RA3, -ORB3, -NRB3RC3, -SRB3, -CN, -NO2, -NRB3C(O)RC3, -C(O)NRB3RC3, -NRB3C(O)ORC3, -OC(O)NRB3RC3, -NRB3SO2RC3, - SC>2NRB3RC3, -SC>2RB3, -C(O)RB3, -C(O)ORB3, 3-7 membered heterocycloalkyl optionally substituted with one or more RD3 and C3-6 cycloalkyl optionally substituted with one or more RD3; where RA3 is selected from the group consisting of Ci-e alkyl, Ci-e alkenyl, C2-6 alkynyl, Ci-e haloalkyl and Ci-e haloalkoxy each of which may be optionally substituted with a substituent selected from the group consisting of C1.4 alkoxy, hydroxy, -NH2, NHMe and NMe2; where RB3 and RC3 are independently selected from the group consisting of hydrogen, C1.4 alkyl, C1.4 alkenyl, C2-4 alkynyl, C1.4 haloalkyl, each of which may be optionally substituted with a substituent selected from the group consisting of C1.4 alkoxy, phenyl and hydroxy; or in any occurrence of the moiety -NRB3RC3, RB3 and RC3, together with the nitrogen atom to which they are bonded can form a 4- to 7-membered ring system; which may optionally be substituted by one or more RE3; where RD3 and RE3 are independently selected from the group consisting of C1.4 alkyl, C1.4 haloalkyl, C1.4 alkoxy, C1.4 haloalkoxy, C3-6 cycloalkyl, phenyl, oxo, and hydroxy.
2. A compound, or a salt or solvate thereof, according to paragraph 1 , wherein X is S, NH, NMe or O.
3. A compound, or a salt or solvate thereof, according to paragraph 2, wherein X is S.
4. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein Y is N or CH.
5. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein Y is N.
6. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein W is carbon and is bonded to the sulfone moiety.
7. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein Z is CH.
8. A compound, or a salt or solvate thereof, according to any one of paragraphs 1 to 5, wherein Z is carbon and is bonded to the sulfone moiety.
9. A compound, or a salt or solvate thereof, according to paragraph 8, wherein W is CH.
10. A compound, or a salt or solvate thereof, according to paragraph 1 of sub-formula la:
Figure imgf000026_0001
11. A compound, or a salt or solvate thereof, according to paragraph 1 of sub-formula lb:
Figure imgf000026_0002
Figure imgf000028_0001
17. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R2 is selected from a phenyl or 5-6 membered heteroaryl, each of which may be optionally substituted by one or more R3 groups.
18. A compound, or a salt or solvate thereof, according to any one of paragraphs 1 to 16, wherein R2 is selected from a phenyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl group, each of which may be optionally substituted by one or more R3 groups.
19. A compound, or a salt or solvate thereof, according to any one of paragraphs 1 to 16, wherein R2 is selected from a phenyl, imidazolyl, pyrazolyl, triazolyl, pyridyl and pyrimidinyl, each of which may be optionally substituted by one or more R3 groups.
20. A compound, or a salt or solvate thereof, according to any one of paragraphs 1 to 16, wherein R2 is a phenyl, pyrrolidinyl, pyrazolyl and pyridyl group, each of which may be optionally substituted by one or more R3 groups.
21 . A compound, or a salt or solvate thereof, according to any one of paragraphs 1 to 16, wherein R2 is a phenyl or pyrazolyl group, each of which may be optionally substituted by one or more R3 groups.
22. A compound, or a salt or solvate thereof, according to any one of paragraphs 1 to 16, wherein R2 is selected from:
Figure imgf000028_0002
each of which may be optionally substituted by one or more R3 groups. 23. A compound, or a salt or solvate thereof, according to any one of paragraphs 1 to 16, wherein R2 is selected from:
Figure imgf000029_0001
, each of which may be optionally substituted by one or more
R3 groups.
24. A compound, or a salt or solvate thereof, according to any one of paragraphs 1 to 16, wherein R2 is
Figure imgf000029_0002
25. A compound, or a salt or solvate thereof, according to any one of paragraphs 1 to 16, wherein R2 is phenyl.
26. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R3 is selected from the group consisting of halogen, RA3, -ORB3, - NRB3RC3, -CN, -NRB3C(O)RC3, -C(O)NRB3RC3, -NRB3C(O)ORC3, -NRB3SO2RC3, -SO2NRB3RC3, - SO2RB3, -C(O)RB3, -C(O)ORB3, 3-7 membered heterocycloalkyl optionally substituted with one or more RD3 and C3-6 cycloalkyl optionally substituted with one or more RD3.
27. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R3 is selected from the group consisting of halogen, RA3, -ORB3, - C(O)NRB3RC3, -C(O)RB3, 3-7 membered heterocycloalkyl optionally substituted with one or more RD3 and C3-6 cycloalkyl optionally substituted with one or more RD3.
28. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R3 is selected from the group consisting of halogen, RA3, -ORB3, - 3-7 membered heterocycloalkyl optionally substituted with one or more RD3 and C3-6 cycloalkyl optionally substituted with one or more RD3. 29. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R3 is selected from the group consisting of halogen, RA3, -ORB3 and C3-6 cycloalkyl optionally substituted with one or more RD3.
30. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R3 is selected from the group consisting of RA3 and -ORB3 and C3-6 cycloalkyl optionally substituted with one or more RD3.
31. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein R3 is a group RA3.
32. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein RA3 is selected from the group consisting of Ci-e alkyl, C2-6 alkynyl and C1.6 haloalkyl, each of which may be optionally substituted with a substituent selected from the group consisting of C1.4 alkoxy, hydroxy, -NH2, NHMe and NMe2.
33. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein RA3 is Ci-e alkyl optionally substituted with a substituent selected from the group consisting of C1.4 alkoxy, hydroxy, -NH2, NHMe and NMe2.
34. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein RB3 and RC3 are independently selected from hydrogen and C1.4 alkyl, each of which may be optionally substituted with a substituent selected from the group consisting of C1.4 alkoxy, phenyl and hydroxy.
35. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein RD3 and RE3 are independently selected from the group consisting of Ci- 4 alkyl, C1.4 haloalkyl, C1.4 alkoxy and hydroxy.
36. A compound, or a salt or solvate thereof, according to any one of the preceding paragraphs, wherein RD3 and RE3 are independently C1.4 alkyl or C1.4 alkoxy.
37. A compound, or a salt or solvate thereof, selected from:
Figure imgf000030_0001
Figure imgf000031_0004
38. A compound, or a salt or solvate thereof, which is ethyl 5-((2-(aminomethyl)thiazol-5- y I) s u Ifony l)-[ 1 , 1 '-biphenyl]-3-carboxylate:
Figure imgf000031_0001
39. A compound, or a salt or solvate thereof, which is ethyl 3-((2-(aminomethyl)thiazol-5- yl)sulfonyl)-5-(1-methyl-1/7-pyrazol-4-yl)benzoate:
Figure imgf000031_0002
40. A compound, or a salt or solvate thereof, which is ethyl 3-((2-(aminomethyl)thiazol-5- yl)sulfonyl)-5-(pyrrolidin-1-yl)benzoate:
Figure imgf000031_0003
41. A compound according to any one of the preceding paragraphs as a pharmaceutically acceptable salt, or solvate thereof.
[00113] Though the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.
[00114] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein.
Salts and Solvates
[00115] The compounds (including final products and intermediates) described herein may be isolated and used per se or may be isolated in the form of a salt, suitably pharmaceutically acceptable salts. It should be understood that the terms “salt(s)” and “salt form(s)” used by themselves or in conjunction with another term or terms encompasses all inorganic and organic salts, including industrially acceptable salts, as defined herein, and pharmaceutically acceptable salts, as defined herein, unless otherwise specified. As used herein, industrially acceptable salts are salts that are generally suitable for manufacturing and/or processing (including purification) as well as for shipping and storage, but may not be salts that are typically administered for clinical or therapeutic use. Industrially acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more.
[00116] Pharmaceutically acceptable salts, as used herein, are salts that are generally chemically and/or physically compatible with the other ingredients comprising a formulation, and/or are generally physiologically compatible with the recipient thereof. Pharmaceutically acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more. It should be understood that pharmaceutically acceptable salts are not limited to salts that are typically administered or approved by the FDA or equivalent foreign regulatory body for clinical or therapeutic use in humans. A practitioner of ordinary skill will readily appreciate that some salts are both industrially acceptable as well as pharmaceutically acceptable salts. It should be understood that all such salts, including mixed salt forms, are within the scope of the application.
[00117] In one embodiment, the compounds of Formula I and sub-formulae thereof are isolated as pharmaceutically acceptable salts.
[00118] A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric or maleic acid. In addition a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
[00119] In general, salts of the present application can be prepared in situ during the isolation and/or purification of a compound (including intermediates), or by separately reacting the compound (or intermediate) with a suitable organic or inorganic acid or base (as appropriate) and isolating the salt thus formed. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised. In practice, the various salts may be precipitated (with or without the addition of one or more co-solvents and/or anti-solvents) and collected by filtration or the salts may be recovered by evaporation of solvent(s). Salts of the present application may also be formed via a “salt switch” or ion exchange/double displacement reaction, i.e. reaction in which one ion is replaced (wholly or in part) with another ion having the same charge. One skilled in the art will appreciate that the salts may be prepared and/or isolated using a single method or a combination of methods.
[00120] Representative salts include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate and the like. Other examples of representative salts include alkali or alkaline earth metal cations such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzathine, choline, tromethamine, diolamine, glycine, meglumine, olamine and the like.
[00121] Certain compounds of the Formula I and sub-formulae thereof may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess the biological activity described herein. Polymorphs
[00122] It is also to be understood that certain compounds of the Formula I and sub-formulae thereof may exhibit polymorphism, and that the invention encompasses all such forms that possess the biological activity described herein.
N-oxides
[00123] Compounds of the Formula I and sub-formulae thereof containing an amine function may also form N-oxides. A reference herein to a compound of the Formula I and sub-formulae thereof that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.
Tautomers
[00124] Compounds of the Formula I and sub-formulae thereof may exist in a number of different tautomeric forms and references to compounds of the Formula I and sub-formulae thereof include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula I and sub-formulae thereof. Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), pyrimidone/hydroxypyrimidine, imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
Figure imgf000034_0001
keto enol enolate
Isomers [00125] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
[00126] Certain compounds of Formula I and sub-formulae thereof may have one or more asymmetric centres and therefore can exist in a number of stereoisomeric configurations. Consequently, such compounds can be synthesized and/or isolated as mixtures of enantiomers and/or as individual (pure) enantiomers, and, in the case of two or more asymmetric centres, single diastereomers and/or mixtures of diastereomers. It should be understood that the present application includes all such enantiomers and diastereomers and mixtures thereof in all ratios.
Isotopes
[00127] The compounds of the present invention are described herein using structural formulas that do not specifically recite the mass numbers or the isotope ratios of the constituent atoms. As such it is intended that the present application includes compounds in which the constituent atoms are present in any ratio of isotope forms. For example, carbon atoms may be present in any ratio of 12C, 13C, and 14C; hydrogen atoms may be present in any ratio of 1H, 2H, and 3H; etc. Preferably, the constituent atoms in the compounds of the present invention are present in their naturally occurring ratios of isotope forms.
Pharmaceutical Compositions
[00128] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier. [00129] In one embodiment, the compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs). Suitably, the compositions of the invention are solid dosage forms for oral use (for example as tablets, lozenges, hard or soft capsules).
[00130] The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more disintegrant, lubricant, glidant, filler, colouring, sweetening, flavouring and/or preservative agent.
[00131] An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
[00132] 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 individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
[00133] The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
[00134] It is to be noted that dosages and dosing regimens may vary with the type and severity of the condition to be alleviated, and may include the administration of single or multiple doses, i.e. QD (once daily), BID (twice daily), etc., over a particular period of time (days or hours). It is to be further understood that for any particular subject or patient, specific dosage regimens may need to be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the pharmaceutical compositions. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the present application encompasses intrapatient dose-escalation as determined by the person skilled in the art. Procedures and processes for determining the appropriate dosage(s) and dosing regimen(s) are well-known in the relevant art and would readily be ascertained by the skilled artisan. As such, one of ordinary skill would readily appreciate and recognize that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the pharmaceutical compositions described herein.
[00135] In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses. Oral administration may also be suitable, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
Therapeutic Uses and Applications
[00136] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.
[00137] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a disease or medical condition mediated by lysyl oxidase (LOX).
[00138] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a disease or medical condition mediated by lysyl oxidase (LOX).
[00139] In another aspect, the present invention provides a method of treating or preventing a disease or medical condition mediated by lysyl oxidase (LOX), said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
[00140] In each of the above aspects, unless stated otherwise, reference to the treatment of a disease or medical condition mediated by LOX is intended to encompass diseases or medical conditions mediated by any one of LOX, LOXL1 , LOXL2, LOXL3 or LOXL4. [00141] In one embodiment, the disease or medical condition mediated by LOX may be any of the diseases or medical conditions listed in this application. LOX is known to mediate a variety of diseases or medical conditions, for instance, proliferative diseases, cancer, fibrotic diseases, cardiovascular disease, neurological disorders, pulmonary diseases, ocular conditions, inflammatory conditions, metabolic disease, bacterial infections and endometriosis.
Proliferative Diseases
[00142] A further aspect of the invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a proliferative disease.
[00143] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a proliferative disease.
[00144] In another aspect, the present invention provides a method of treating or preventing a proliferative disease, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
[00145] The proliferative disease may be malignant or non-malignant.
[00146] Accordingly, in another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of cancer.
[00147] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of cancer.
[00148] In another aspect, the present invention provides a method of treating or preventing cancer, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein. [00149] In one embodiment, the compound of the invention, or a pharmaceutically acceptable salt thereof is for use in the treatment of metastatic cancer in a subject.
[00150] In another embodiment of the invention there is provided a compound of the invention, or a pharmaceutically acceptable salt thereof may be for use as an inhibitor of the motility of tumour cells. In another embodiment the compound of the invention, or a pharmaceutically acceptable salt thereof may be for use as an inhibitor of the dissemination and invasiveness of mammalian cancer cells leading to inhibition of metastatic tumour growth. In particular a compound of the invention, or a pharmaceutically acceptable salt thereof may be for use as an anti-invasive agent for use in the containment and/or treatment of solid tumour disease.
[00151] The compound of the invention, or a pharmaceutically acceptable salt thereof may be for use in the treatment of a cancer, which may be a solid tumour or a haematological (“liquid”) cancer. In one embodiment, the cancer is selected from:
(1) Carcinoma, including for example tumours derived from stratified squamous epithelia (squamous cell carcinomas) and tumours arising within organs or glands (adenocarcinomas). Examples include breast, colon, lung, prostate, ovary, esophageal carcinoma (including, but not limited to, esophageal adenocarcinoma and squamous cell carcinoma), basal-like breast carcinoma, basal cell carcinoma (a form of skin cancer), squamous cell carcinoma (various tissues), head and neck carcinoma (including, but not limited to, squamous cell carcinomas), stomach carcinoma (including, but not limited to, stomach adenocarcinoma, gastrointestinal stromal tumor), signet ring cell carcinoma, bladder carcinoma (including transitional cell carcinoma (a malignant neoplasm of the bladder)), bronchogenic carcinoma, colorectal carcinoma (including, but not limited to, colon carcinoma and rectal carcinoma), anal carcinoma, gastric carcinoma, lung carcinoma (including but not limited to small cell carcinoma and non-small cell carcinoma of the lung, lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, bronchioloalveolar carcinoma, and mesothelioma), neuroendocrine tumors (including but not limited to carcinoids of the gastrointestinal tract, breast, and other organs), adrenocortical carcinoma, thyroid carcinoma, pancreatic carcinoma (including, but not limited to, pancreatic ductal adenocarcinoma, pancreatic adenocarcinoma, acinar cell carcinoma, intraductal papillary mucinous neoplasm with invasive carcinoma, mucinous cystic neoplasm with invasive carcinoma, islet cell carcinoma and neuroendocrine tumors), breast carcinoma (including, but not limited to, ductal carcinoma, lobular carcinoma, inflammatory breast cancer, clear cell carcinoma, mucinous carcinoma), ovarian carcinoma (including, but not limited to, ovarian epithelial carcinoma or surface epithelial-stromal tumor including serous tumor, endometrioid tumor and mucinous cystadenocarcinoma, sex-cord-stromal tumor), liver and bile duct carcinoma (including, but not limited to, hepatocellular carcinoma, cholangiocarcinoma and hemangioma), prostate carcinoma, adenocarcinoma, brain tumours (including, but not limited to glioma, glioblastoma and medulloblastoma), germ cell tumors, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, kidney carcinoma (including, but not limited to, renal cell carcinoma, clear cell carcinoma and Wilm's tumor), medullary carcinoma, ductal carcinoma in situ or bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, cervical carcinoma, uterine carcinoma (including, but not limited to, endometrial adenocarcinoma, uterine papillary serous carcinoma, uterine clear-cell carcinoma, uterine sarcomas and leiomyosarcomas, mixed mullerian tumors), testicular carcinoma, osteogenic carcinoma, epithelial carcinoma, sarcomatoid carcinoma, nasopharyngeal carcinoma, laryngeal carcinoma; oral and oropharyngeal squamous carcinoma;
(2) Sarcomas, including: osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesothelial sarcoma and mesothelioma (membranous lining of body cavities); fibrosarcoma (fibrous tissue); angiosarcoma and hemangioendothelioma (blood vessels); liposarcoma (adipose tissue); glioma and astrocytoma (neurogenic connective tissue found in the brain); myxosarcoma (primitive embryonic connective tissue); chordoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, Ewing's sarcoma, mesenchymous and mixed mesodermal tumor (mixed connective tissue types) and other soft tissue sarcomas;
(3) Myeloma and multiple myeloma;
(4) Hematopoietic tumours, including: myelogenous and granulocytic leukemia (malignancy of the myeloid and granulocytic white blood cell series); lymphatic, lymphocytic, and lymphoblastic leukemia (malignancy of the lymphoid and lymphocytic blood cell series); polycythemia vera and erythremia (malignancy of various blood cell products, but with red cells predominating); myelofibrosis.
(5) Lymphomas, including: Hodgkin and Non-Hodgkin lymphomas;
(6) Solid tumors of the nervous system including medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma and schwannoma;
(7) Melanoma, uveal melanoma and retinoblastoma; and (8) Mixed Types, including, e.g., adenosquamous carcinoma, mixed mesodermal tumor, carcinosarcoma or teratocarcinoma.
[00152] In one embodiment, the cancer is selected from anus cancer, bile duct cancer, bladder cancer, blood cancer, brain cancer, breast cancer, uterine cervix cancer, colon cancer, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, head and neck cancer, hypopharyngeal cancer, pancreatic cancer, pharyngeal cancer, lip and oral cancer, liver cancer, lung cancer, melanoma, mesothelioma, multiple myeloma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, stomach cancer, testicular cancer and thyroid gland cancer.
[00153] In another embodiment, the cancer is selected from bladder cancer, blood cancer, brain cancer, breast cancer, colon cancer, esophageal cancer, head and neck cancer, pancreatic cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, stomach cancer, testicular cancer and thyroid gland cancer.
[00154] In another embodiment, the cancer is wherein the cancer is selected from pancreatic cancer, colon cancer, breast cancer and lung cancer.
Fibrotic Diseases
[00155] LOX and LOXL are implicated in fibrotic diseases. Accordingly, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a fibrotic disorder.
[00156] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a fibrotic disorder.
[00157] In another aspect, the present invention provides a method of treating or preventing a fibrotic disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
[00158] The fibrotic disorder may be a disorder characterised by excess fibrosis, e.g., an excess of fibrous connective tissue in a tissue or organ, e.g., triggered by a reparative or reactive process, e.g., in response to injury (e.g., scarring, healing, radiotherapy) or excess fibrotic tissue arising from a single cell line (e.g., fibroma).
[00159] In one embodiment the compound of the invention or a pharmaceutically acceptable salt thereof may be for use in the treatment of a fibrotic disorder selected from:
(i) a fibrotic condition affecting the lungs, for example pulmonary fibrosis secondary to cystic fibrosis; idiopathic pulmonary fibrosis; coal worker’s progressive massive fibrosis; cryptogenic fibrosing alveolitis, chronic fibrosing interstitial pneumonia, interstitial lung disease (ILD), diffuse parenchymal lung disease (DPLD), emphysema and chronic obstructive pulmonary disease (COPD), or chronic asthma; or
(ii) a fibrotic condition affecting the liver, for example cirrhosis, and associated conditions such as chronic viral hepatitis B or C, Wilson’s disease, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), biliary cirrhosis or autoimmune hepatitis; or
(iii) a fibrotic condition affecting the kidneys, for example diabetic nephropathy, vesicoureteral reflux, tubulointerstitial renal fibrosis; glomerulonephritis or glomerular nephritis, including focal segmental glomerulosclerosis and membranous glomerulonephritis or mesangiocapillary glomerular nephritis;
(iv) a fibrotic condition affecting the heart or vascular system, for example endomyocardial fibrosis; old myocardial infarction; atrial fibrosis; congestive heart failure, cardiomyopathy, hypertensive heart disease (HHD), hypertension (for example pulmonary hypertension) and fibrosis associated with hypertension, atherosclerosis, restenosis (e.g. coronary, carotid, and cerebral lesions), and heart disease associated with cardiac ischemic events; or
(v) a fibrotic condition affecting the mediastinum, for example mediastinal fibrosis; or
(vi) a fibrotic condition affecting bone, for example myelofibrosis, including primary myelofibrosis, post polycythemia vera or post essential thrombocythemia myelofibrosis; or
(vii) a fibrotic condition affecting the retroperitoneum, for example retroperitoneal fibrosis skin; or
(viii) a fibrotic condition affecting the skin, for example nephrogenic systemic fibrosis, keloid formation and scarring, systemic sclerosis, scleroderma, hypertrophic scarring, scleredema (Buschke disease), systemic amyloidosis, lipodermatosclerosis, progeroid disorders, stiff skin syndrome, Dupuytren's contracture, nephrogenic fibrosing dermopathy (NFD), mixed connective tissue disease, scleromyxedema, graft-versus-host disease (GVHD), Peyronie’s disease and eosinophilic fasciitis; or
(ix) a fibrotic condition affecting the Gl tract, for example a fibrotic intestinal disorder, inflammatory bowel disease, ulcerative colitis or Crohn’s disease; or
(x) a fibrotic condition affecting connective tissue, for example arthrofibrosis; or capsulitis; or
(xi) a fibrotic condition affecting the eye, for example ocular scarring, ocular fibrosis following surgery or pseudoexfoliation syndrome glaucoma.
(xii) a fibrotic condition induced by radiation, such as fibrosis following radiotherapy. The fibrotic condition induced by radiation may occur in any tissue treated by radiotherapy, for instance, the skin and subcutaneous tissue, lungs, breast, gastrointestinal and genitourinary tracts, muscles, and other organs.
Cardiovascular Disease
[00160] LOX and LOXL are implicated in cardiovascular disease. Accordingly, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a cardiovascular disease.
[00161] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a cardiovascular disease.
[00162] In another aspect, the present invention provides a method of treating or preventing a cardiovascular disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
[00163] In one embodiment, the cardiovascular disease is selected from hypertensive heart disease (HHD), heart failure, cardiac hypertrophy and atherosclerosis.
Neurological Disorders
[00164] LOX and LOXL are implicated in neurological disorders. Accordingly, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a neurological disorder.
[00165] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a neurological disorder.
[00166] In another aspect, the present invention provides a method of treating or preventing a neurological disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
[00167] In one embodiment, the neurological disorder is selected from bipolar disorder (BD), schizophrenia, Alzheimer’s disease and non-Alzheimer’s dementia.
Pulmonary Diseases
[00168] LOX and LOXL are implicated in pulmonary diseases. Accordingly, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a pulmonary disease.
[00169] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a pulmonary disease.
[00170] In another aspect, the present invention provides a method of treating or preventing a pulmonary disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
[00171] In one embodiment, the pulmonary disease is selected from pulmonary edema, acute respiratory distress syndrome (ARDS), endotoxin-induced lung injury and asthma.
Ocular Conditions
[00172] LOX and LOXL are implicated in ocular conditions. Accordingly, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of an ocular condition.
[00173] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of an ocular condition.
[00174] In another aspect, the present invention provides a method of treating or preventing an ocular condition, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
[00175] In one embodiment, the ocular condition is glaucoma.
Inflammatory Conditions
[00176] LOX and LOXL are implicated in inflammatory conditions. Accordingly, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of an inflammatory condition.
[00177] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of an inflammatory condition.
[00178] In another aspect, the present invention provides a method of treating or preventing an inflammatory condition, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
[00179] In one embodiment, the inflammatory condition is arthritis, such as osteoarthritis or rheumatoid arthritis.
Metabolic Diseases
[00180] LOX and LOXL are implicated in metabolic diseases. Accordingly, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a metabolic disease.
[00181] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a metabolic disease.
[00182] In another aspect, the present invention provides a method of treating or preventing a metabolic disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
Bacterial Infections
[00183] LOX and LOXL are implicated in bacterial infections. Accordingly, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a bacterial infection.
[00184] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a bacterial infection.
[00185] In another aspect, the present invention provides a method of treating or preventing a bacterial infection, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
Endometriosis
[00186] LOX and LOXL are implicated in endometriosis. Accordingly, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of endometriosis.
[00187] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prevention of endometriosis. [00188] In another aspect, the present invention provides a method of treating or preventing endometriosis, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
Routes of Administration
[00189] The compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e., at the site of desired action).
[00190] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.
[00191] Suitably, the compounds of the invention or pharmaceutical compositions comprising these compounds are for oral administration.
Combinations
[00192] LOX inhibition can be a useful method for improving the efficacy of other drugs or addressing resistance to drug treatment through a number of mechanisms. Interfering with collagen stabilization by inhibition of lysyl oxidases significantly enhanced response to chemotherapy in various tumor models (Rossow et al. 2018). Specific inhibition of LOX with siRNA can induce apoptosis of laryngeal cancer Hep-2 cells and enhance the sensitivity of Hep-2 cells to chemotherapeutic drugs such as cisplatin (Dong, Lu et al. 2014) and to radiation (Dong, Xin et al. 2014). LOX and LOXL2 inhibition can alter vascular permeability or normalise vasculature in a tumour environment, which can enhance the delivery or effectiveness of drugs (Ingber and Mammoto 2014) (Marshall, Spangler et al. 2012), for example improved efficacy of treatment in ovarian xenograft and lung allograft mice models with chemotherapeutic agents such as taxol (Zaffryar-Eilot, Marshall et al. 2013) or triple negative breast cancer models with doxorubicin (Saatchi et al. 2020) or epirubicin-loaded nanoparticles (De Vita et al. 2021). The extracellular matrix has an important role in the resistance to chemotherapeutics. Inhibition of LOX for cells grown in collagen (as a surrogate of ECM) reverses their collagen-dependent increased resistance to chemotherapeutics such as erlotinib, cisplatin or methotrexate (Smith and Holzer 2010). Drug diffusion and efficacy is reduced by the enzymatic action of LOX and LOXLs on the ECM in a 3D cell culture (not in 2D) and sensitivity to doxorubicin and paclitaxel can be restored by inhibition with BAPN (Schuetze, Roehrig et al. 2015). LOX inhibition synergized with gemcitabine to kill tumors and significantly prolonged tumor-free survival in a pancreatic mouse model. This was associated with stromal alterations and increased infiltration of macrophages and neutrophils into tumors. Therefore, targeting LOX could improve outcome in surgically resectable disease (Miller, Morton et al. 2015). Only a fraction of cancer patients benefits from immune checkpoint inhibitors (ICIs). This may be partly due to the dense ECM that forms a barrier for T cells. LOX inhibition reduces ECM content and tumor stiffness leading to improved T cell migration and increased efficacy of anti-PD-1 blockade in murine models (Nicolas-Boluda, Donnadieu et al. 2021). The combined use of LOX inhibitors and ICIs can therefore improve patient’s response rate to immunotherapy.
[00193] LOX-expression and secretion is increased in response to ionizing radiation (IR) and hypoxia, suggesting that LOX may contribute towards an IR-induced migratory phenotype in sub lethally-irradiated tumor cells and tumor progression; therefore LOX inhibitors can be used in combination with radiotherapy to reduce side effects in surrounding tissues receiving a reduced radiation dose (Shen, Sharma et al. 2014), including in breast cancer cells that becomes resistant to radiotherapy (Ko et al, 2020). In the in vivo A549 lung carcinoma xenograft model, highly specific tumor targeting of LOX-traceable nanoparticles consisting of LOX antibodies and paclitaxel (LOX-NPs(P) was shown in irradiated tumors, with delayed tumor growth and reduced tumor volumes compared with non-irradiated groups Cho et al., 2020). Increased LOX expression from radiotherapy (RT) also leads to tissue fibrosis (Chung, Citrin et al. 2014; Guo, Chen et al. 2020), which are common side effects with debilitating consequences to patients (Straub, Thomas et al., 2015). Pre-exisiting lung diseases such as I PF are a major risk factor for radiation-induced lung fibrosis (RIF) (Kong, Wang 2015; I PF - Kim et al. 2019). Therefore LOX inhibitors can be used in combination with RT to reduce side effects in surrounding tissues as well as to improve radiotherapy efficacy.
[00194] Host response to tumour surgery can promote further lung metastases in a mechanism mediated by LOX. LOX activity inhibition or depletion reduces lung metastasis after surgery and increases survival. Therefore LOX inhibitors have utility in combination with surgery to reduce the risk of subsequent metastasis (Rahman-Tzemah et al, 2017). [00195] The compounds of the invention may be used alone to provide a therapeutic effect. The compounds of the invention may also be used in combination with one or more additional therapeutic agents or methods.
[00196] In one embodiment, the present invention provides a compound of formula I as defined herein in combination with an anti-cancer agent and/or radiotherapy.
[00197] In one embodiment, the anti-cancer agent may be selected from one or more of the following:
(i) antiproliferative/antineoplastic drugs and combinations thereof, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustin, melphalan, chlorambucil, chlormethine, busulphan, temozolamide, nitrosoureas, ifosamide, melphalan, pipobroman, triethylene-melamine, triethylenethiophoporamine, carmustine, lomustine, stroptozocin, temozolomide and dacarbazine); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, leucovorin, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine and hydroxyurea, and trifluridine with trifluracil); antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors; eribulin); proteasome inhibitors, for example carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan, irinotecan, mitoxantrone and camptothecin); bleomcin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol™), nabpaclitaxel, docetaxel, mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-alpha), etoposide, teniposide, DNA-demethylating agents, (for example, azacitidine or decitabine); and histone de-acetylase (HDAC) inhibitors (for example vorinostat, MS-275, panobinostat, romidepsin, valproic acid, mocetinostat (MGCD0103) and pracinostat SB939; and belinostat, panobinostat); trabectedin; ivosidenib; belzutifan; lurbinectedin; tazemetostat; selinexor;
(ii) cytostatic agents such as antiestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride; and navelbene, CPT-II, anastrazole, letrazole, capecitabine, reloxafme and droloxafine; and abiraterone, Enzalutamide; analogues of somatostatin such as lanreotide; relugolix
(iii) anti-invasion agents, for example dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase;
(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies, for example anti-erbB2 antibodies trastuzumab, margetuximab, the anti-HER2 antibody pertuzumab; the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family: gefitinib, erlotinib, , afatinib, vandetanib, osimertinib and rociletinib); erbB2 tyrosine kinase inhibitors such as lapatinib, neratinib, mobocertinib, tucatinib and antibodies to costimulatory molecules such as CTLA-4, 4-IBB and PD-1 , or antibodies to cytokines (IL-IO, TGF-beta); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of protein regulators of cell apoptosis (for example Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family such as imatinib, nilotinib,; inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, sorafenib, tipifarnib and lonafarnib, vemurafenib, dabrafenib, encorafenib, sotorasib), inhibitors of cell signalling through MEK (such as trametinib, cobimetinib, selumetinib) and/or AKT kinases, c-kit inhibitors, for example ripretinib, abl kinase inhibitors such as ponatinib, PI3 kinase inhibitors for example idelalisib, perifosine, alpelisib, umbralisib, Plt3 kinase inhibitors, CSF-1 R kinase inhibitors, IGF receptor, kinase inhibitors; FGFR inhibitors, e.g. erdafitinib, infigratinib, pemigatinib; aurora kinase inhibitors and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors or CDK4/CDK6 inhibitors such as palbociclib, abemaciclib, ribociclib; CCR2, CCR4 or CCR6 antagonists; mTOR kinase inhibitors such as Everolimus; Janus kinase family inhibitors such as ruxolitinib; Brunton’s tyrosine kinase inhibitors such as Ibrutinib, zanubrutinib; anaplastic lymphoma kinase - ALK - such as ceritinib, crizotinib, alectinib, lorlatinib, brigatinib; c-Met kinase inhibitors such as cabozantinib, tepotinib, capmatinib; RET kinase inhibitors such as pralsetinib; hedgehog signalling pathway inhibitors such as vismodegib, sonidegib; and RAF kinase inhibitors such as those described in W02006043090, W02009077766, WO2011092469 or WO2015075483;
(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, for example bevacizumab (Avastin™), anti-VEGF2 antibody ramucirumab; recombinant fusion protein ziv-aflibercept]; thalidomide; pomalidomide; lenalidomide; and for example, a VEGF receptor tyrosine kinase inhibitor such as regorafenib, vandetanib, vatalanib, sunitinib, axitinib, pazopanib, lenvatinib, tivozanib;
(vi) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2; oncolytic viruses such as talimogene laherparepvec; CAR-T cells based therapies such as ciltacabtagene autoleucel, brexucabtagene autoleucel
(vii) immunotherapy approaches, including for example antibody therapy such as denosumab, obinutuzumab, blinatomumab, dinutuximab, idarucizumab, daratumumab, necitumumab, elotuzumab, olaratumab, alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®), isatuximab, avelumab, tafasitamab, naxitamab and ofatumumab; interferons such as interferon a, peginterferon alpha-2b; interleukins such as IL-2 (aldesleukin); interleukin inhibitors for example IRAK4 inhibitors; cancer vaccines including prophylactic and treatment vaccines such as HPV vaccines, for example Gardasil, Cervarix, Oncophage and Sipuleucel- T (Provenge); gp100;dendritic cell-based vaccines (such as Ad.p53 DC); toll-like receptor modulators for example TLR-7 or TLR-9 agonists; PD-1, PD-L1 , PD-L2 and CTL4-A antibodies (for example Nivolumab, pembrolizumab, atezolizumab, ipilimumab, dostarlimab, cemiplimab), antibodies and vaccines; other IDO inhibitors (such as indoximod); LAG-3- blocking antibody such as relatlimab; antibody-drug conjugates such as Brentuximab vedotin, trastuzumab emtansine, fam-trastuzumab deruxtecan. tisotumab vedotin, sacituzumab govitecan; luspatercept;
(viii) cytotoxic agents for example fludaribine (fludara), cladribine, pentostatin (Nipent™);
(ix) targeted therapies, for example; SMAC (second mitochondria-derived activator of caspases) mimetics, also known as Inhibitor of Apoptosis Proteins (IAP) antagonists (for example XIAP, clAP1 and clAP2), including Birinapant and LCL161 (Novartis), ; and agents which target ubiquitin proteasome system (UPS), for example, bortezomib, ixazomib, carfilzomib and marizomib; and DNA repair inhibitors such as Olaparib, rucaparib, niraparib; antiapoptotic BCL proteins family inhibitors such as venetoclax.
(xii) chimeric antigen receptors, anticancer vaccines and arginase inhibitors.
[00198] In one embodiment, the present invention provides a compound of formula I as defined herein in combination with an anti-fibrotic agent. [00199] In one embodiment, the anti-fibrotic agent may be selected from one or more of the following:
(i) Antifibrotic agents such as pirfenidone, nintedanib; CTFG antibody inhibitors such as pamrevlumab; recombinant human pentraxin-2 (PRM-151); anti-inflammatory agents such as corticosteroids, interferon-gamma; cardiovascular drugs such as pentoxifylline; ROS scavengers such as Vitamin E, superoxide dismutase.
[00200] Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within a therapeutically effective dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
[00201] Herein, where the term “combination” is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.
[00202] In some embodiments in which a combination treatment is used, the amount of the compound of the invention and the amount of the other pharmaceutically active agent(s) are, when combined, therapeutically effective to treat a targeted disorder in the patient. In this context, the combined amounts are “therapeutically effective amount” if they are, when combined, sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder; cure the disorder; reverse, completely stop, or slow the progress of the disorder; or reduce the risk of the disorder getting worse. Typically, such amounts may be determined by one skilled in the art by, for example, starting with the dosage range described in this specification for the compound of the invention and an approved or otherwise published dosage range(s) of the other pharmaceutically active compound(s).
[00203] According to a further aspect of the invention there is provided a compound of the invention as defined hereinbefore and an additional anti-cancer agent as defined hereinbefore, for use in the conjoint treatment of cancer. [00204] According to a further aspect of the invention there is provided a pharmaceutical product comprising a compound of the invention as defined hereinbefore and an additional anti-cancer agent as defined hereinbefore for the conjoint treatment of cancer.
[00205] According to a further aspect of the invention there is provided a method of treatment of a human or animal subject suffering from a cancer comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with an additional anticancer agent as defined hereinbefore.
[00206] According to a further aspect of the invention there is provided a compound of the invention, or a pharmaceutically acceptable salt thereof for use simultaneously, sequentially or separately with an additional anti-cancer agent as defined hereinbefore, in the treatment of a cancer.
[00207] The compound of the invention may also be used be used in combination with radiotherapy. Suitable radiotherapy treatments include, for example X-ray therapy, proton beam therapy or electron beam therapies. Radiotherapy may also encompass the use of radionuclide agents, for example 1311, 32P, 90Y, 89Sr, 153Sm or 223Ra. Such radionuclide therapies are well known and commercially available.
[00208] According to a further aspect of the invention there is provided a compound of the invention, or a pharmaceutically acceptable salt thereof as defined hereinbefore for use in the treatment of cancer conjointly with radiotherapy.
[00209] According to a further aspect of the invention there is provided a method of treatment of a human or animal subject suffering from a cancer comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with radiotherapy.
[00210] In another embodiment, there is provided a combination of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, an anti-fibrotic agent.
[00211] According to a further aspect of the invention there is provided a compound of the invention as defined hereinbefore and an additional anti-fibrotic agent as defined hereinbefore, for use in the conjoint treatment of a fibrotic disorder. [00212] According to a further aspect of the invention there is provided a pharmaceutical product comprising a compound of the invention as defined hereinbefore and an additional anti-fibrotic agent as defined hereinbefore for the conjoint treatment of a fibrotic disorder.
[00213] According to a further aspect of the invention there is provided a method of treatment of a human or animal subject suffering from a fibrotic disorder comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with an additional anti-fibrotic agent as defined hereinbefore.
[00214] According to a further aspect of the invention there is provided a compound of the invention, or a pharmaceutically acceptable salt thereof for use simultaneously, sequentially or separately with an additional anti-fibrotic agent as defined hereinbefore, in the treatment of a fibrotic disorder.
EXAMPLES
Chemistry
[00215] The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.
[00216] The compounds of the invention may be prepared using synthetic techniques that are known in the art (as illustrated by the examples herein).
[00217] Several methods for the chemical synthesis of the compounds of the present application are described herein. These and/or other well-known methods may be modified and/or adapted in various ways in order to facilitate the synthesis of additional compounds within the scope of the present application and claims. Such alternative methods and modifications should be understood as being within the spirit and scope of this application and claims. Accordingly, it should be understood that the methods set forth in the following descriptions, schemes and examples are intended for illustrative purposes and are not to be construed as limiting the scope of the disclosure.
[00218] All chemicals, reagents, and solvents were purchased from commercial sources and were used as received.
[00219] Flash chromatography was performed on a Biotage Isolera or Combiflash Rf + UV-vis flash purification system using prepacked silica gel cartridges with HPLC grade solvents. [00220] Thin layer chromatography (TLC) analysis was performed using silica gel 60 F- 254 thin layer plates and visualized using UV light (254 nm) and/or developed with vanillin stain.
[00221] LCMS and HRMS analyses of chemical compounds were performed on an Agilent 1200 series HPLC and diode array detector coupled to an Agilent 6210 time-of-flight mass spectrometer with a multimode ESI source; or a Waters Acquity LIPLC or l-class LIPLC with a diode array detector coupled to a Waters G2 QToF, SQD, or QDa mass spectrometer fitted with a multimode ESI/APCI source.
[00222] 1H, 19F, and 13C NMR spectra were recorded using a Bruker Avance 500, 400, or 300 MHz spectrometer using an internal deuterium lock. Chemical shifts are expressed in parts per million (ppm), and splitting patterns are indicated as follows: br, broad; s, singlet; d, doublet; t, triplet; q, quartet; p, pentet; h, hextet; m, multiplet. All coupling constants (J) are reported in hertz (Hz).
Synthesis and Characterisation
General procedures:
GP01 - ester formation
[00223] Thionyl chloride (3 equiv.) was added drop-wise to a solution of carboxylic acid (1 equiv.) in methanol or ethanol or isopropanol (0.05 M), with stirring at room temperature and the reaction mixture was heated at reflux for 3-18 hours. After cooling to room temperature the reaction mixture was concentrated to dryness and the residue was washed with diethyl ether and dried under vacuum to give the desired ester product.
GP02 - Boc deprotection
[00224] A mixture of terf-butyl carbamate (1 equiv.), 4 M HCI in dioxane (0.2 M) and dichloromethane (0.2 M) was stirred at room temperature for 3 hours. EtOAc was added to precipitate the solid if necessary. The solids were filtered, washed with EtOAc and dried under vacuum to afford the desired amine hydrochloride.
Example 1
[00225] Ethyl 5-((2-(aminomethyl)thiazol-5-yl)sulfonyl)-[1,1'-biphenyl]-3- carboxylate hydrochloride
Figure imgf000056_0001
[00226] Synthesised according to general procedures GP01 - from thionyl chloride (0.045 mL, 0.614 mmol), 5-((2-(aminomethyl)thiazol-5-yl)sulfonyl)-[1 ,1'-biphenyl]-3-carboxylic acid trifluoroacetate salt (WO 2017/141049; 100 mg, 0.205 mmol) and ethanol (4 mL); 88 mg (98%), light brown solid. 1H NMR (DMSO-d6, 500 MHz) 8 8.87 (s, 3H), 8.78 (s, 1 H), 8.50 (t, 1 H, J = 1.8 Hz), 8.46 (t, 1 H, J = 1.6 Hz), 8.42 (t, 1 H, J = 1.6 Hz), 7.79 (d, 2H, J = 7.1 Hz), 7.55 (t, 2H, J = 7.4 Hz), 7.50 (t, 1 H, J = 7.3 Hz), 4.48 (s, 2H), 4.41 (q, 2H, J = 7.1 Hz), 1.37 (t, 3H, J = 7.1 Hz) ppm; 13C NMR (DMSO-d6, 125 MHz) 8 170.9, 164.0, 148.4, 143.0, 142.3, 139.2, 137.0, 132.6, 132.4, 129.3, 129.11 , 129.06, 127.3, 125.8, 61.9, 39.7, 14.1 ppm; LCMS m/z 403.0787 found (M+H)+, 403.0781 calculated for C19H19N2O4S2.
Example 2
[00227] Ethyl 3-((2-(aminomethyl)thiazol-5-yl)sulfonyl)-5-(1-methyl-1H-pyrazol-4- yl)benzoate hydrochloride
Figure imgf000056_0002
[00228] Synthesised according to general procedures GP01 - from thionyl chloride (0.025 mL, 0.34 mmol), 3-((2-(aminomethyl)thiazol-5-yl)sulfonyl)-5-(1-methyl-1/7-pyrazol-4- yl)benzoic acid hydrochloride (WO 2017/141049; 56 mg, 0.11 mmol) and ethanol (3.0 mL); 42 mg (83%), brown solid. 1H NMR (DMSO-d6, 300 MHz) 8 8.76 (s, 1 H), 8.72 (br s, 3H), 8.53 (s, 1 H), 8.44 (t, 1 H, J = 1.8 Hz), 8.38 (t, 1 H, J = 1.6 Hz), 8.22 (t, 1 H, J = 1.6 Hz), 8.14 (d, 1 H, J = 0.7 Hz), 4.49 (q, 2H, J = 5.3 Hz), 4.39 (q, 2H, J = 7.1 Hz), 3.88 (s, 3H), 1.36 (t, 3H, J = 7.1 Hz) ppm; 13C NMR (DMSO-d6, 75 MHz) 8 170.8, 164.1 , 148.2, 142.3, 139.4, 136.9, 135.9, 132.4, 130.4, 129.6, 126.8, 124.0, 119.1 , 61.8, 38.9, 14.2 ppm; LCMS m/z 407.2 found (M+H)+, 407.0842 calculated for C17H19N4O4S2.
Example 3
[00229] Ethyl 3-((2-(aminomethyl)thiazol-5-yl)sulfonyl)-5-(pyrrolidin-1 - yl)benzoate hydrochloride
Figure imgf000057_0001
[00230] Synthesised according to general procedures GP01 - from thionyl chloride (0.054 mL, 0.743 mmol), 3-((2-(aminomethyl)thiazol-5-yl)sulfonyl)-5-(pyrrolidin-1-yl)benzoic acid hydrochloride (WO 2017/141049; 100 mg, 0.248 mmol) and ethanol (5 mL); 81 mg (76%), brown solid. 1H NMR (DMSO-d6, 300 MHz) 8 8.78 (br s, 3H), 8.66 (s, 1 H), 7.59 (t, 1 H, J = 1.4 Hz), 7.29-7.28 (m, 1 H), 7.20-7.18 (m, 1 H), 4.50-4.45 (m, 2H), 4.34 (q, 2H, J = 7.1 Hz), 3.34- 3.30 (m, 4H), 2.00-1.96 (m, 4H), 1.32 (t, 3H, J = 7.1 Hz) ppm; 13C NMR (DMSO-d6, 75 MHz) 8 170.3, 164.7, 148.2, 147.6, 142.1 , 139.9, 132.2, 116.6, 112.3, 112.1 , 61.5, 47.6, 39.7* (*under DMSO peak), 25.0, 14.2 ppm; LCMS m/z 396.2 found (M+H)+, 396.1046 calculated for C17H22N3O4S2.
Reference Example 1
[00231] Methyl 5-((2-(aminomethyl)thiazol-5-yl)sulfonyl)-[1,1'-biphenyl]-3- carboxylate hydrochloride
Figure imgf000057_0002
[00232] Synthesised according to general procedures GP01 - from thionyl chloride (0.045 mL, 0.614 mmol), 5-((2-(aminomethyl)thiazol-5-yl)sulfonyl)-[1 ,1'-biphenyl]-3-carboxylic acid trifluoroacetate salt (WO 2017/141049; 100 mg, 0.205 mmol) and methanol (4 mL); 80 mg (92%), light brown solid. 1H NMR (DMSO-d6, 500 MHz) 8 8.85 (br s, 3H), 8.78 (s, 1 H), 8.50 (t, 1 H, J = 1.8 Hz), 8.47 (t, 1 H, J = 1 .6 Hz), 8.43 (t, 1 H, J = 1.6 Hz), 7.80 (d, 2H, J = 7.2 Hz), 7.55 (t, 2H, J = 7.4 Hz), 7.50 (t, 1 H, J = 7.3 Hz), 4.48 (s, 2H), 3.94 (s, 3H) ppm; 13C NMR (DMSO-cfe, 125 MHz) 8 170.9, 164.5, 148.4, 143.0, 142.3, 139.2, 137.0, 132.6, 132.2, 129.3, 129.11 , 129.05, 127.3, 125.9, 53.0, 39.8 ppm; LCMS m/z 389.0625 found (M+H)+, 389.0624 calculated for C18H17N2O4S2.
Reference Example 2
[00233] Isopropyl 5-((2-(aminomethyl)thiazol-5-yl)sulfonyl)-[1,1'-biphenyl]-3- carboxylate hydrochloride
Figure imgf000058_0001
[00234] Synthesised according to general procedures GP01 - from thionyl chloride (0.045 mL, 0.614 mmol), 5-((2-(aminomethyl)thiazol-5-yl)sulfonyl)-[1 ,1'-biphenyl]-3-carboxylic acid trifluoroacetate salt (WO 2017/141049; 100 mg, 0.205 mmol) and isopropanol (4 mL); 70 mg (82%), light brown solid. 1H NMR (DMSO-d6, 500 MHz) 8 8.80 (s, 1 H), 8.70 (s, 3H), 8.50 (t, 1 H, J = 1.8 Hz), 8.45 (t, 1 H, J = 1 .6 Hz), 8.41 (t, 1 H, J = 1.6 Hz), 7.80 (d, 2H, J = 7.0 Hz), 7.56 (t, 2H, J = 7.4 Hz), 7.51 (t, 1 H, J = 7.3 Hz), 5.21 (p, 1 H, J = 6.3 Hz), 4.49 (s, 1 H), 1.37 (d, 6H, J = 6.3 Hz) ppm; 13C NMR (DMSO-d6, 125 MHz) 8 170.8, 163.5, 148.4, 143.0, 142.3, 139.2, 137.1 , 132.8, 132.6, 129.4, 129.1 , 129.0, 127.3, 125.7, 69.7, 39.7, 21.6 ppm; LCMS m/z 417.0933 found (M+H)+, 417.0937 calculated for C20H21N2O4S2.
Biology
In vitro conversion of prodrug to free acid parent by liver microsomes
[00235] The compound of Example 1 at 10 pM final concentration was incubated with rat (RLM), dog (DLM) or human (HLM) liver microsomes for 0, 15, and 30 min. Control samples containing no microsomes and no cofactors were also assessed at 0 and 30 min. Samples were extracted by protein precipitation and centrifugation for 20 min in a refrigerated centrifuge (4 °C) at 3700 rpm. The supernatant was analyzed by LCMS/MS for the free acid parent, 5- ((2-(aminomethyl)thiazol-5-yl)sulfonyl)-[1 , 1 '-biphenyl]-3-carboxylic acid.
[00236] As shown in Figure 1 , rapid conversion of the ethyl ester prodrug to free carboxylic acid is observed in rat (Figure 1a), dog (Figure 1b) and human (Figure 1c) microsomes, with full conversion achieved within 15 minutes.
Caco2 permeability assay
[00237] The permeability assay was performed by Cyprotex Ltd following their protocol, as described below.
[00238] Caco-2 cells (ATCC) were seeded onto Millicell 96 well plates (Millipore, MA, USA) at 1 x 105 cells/cm2. The cells were cultured in DMEM (37°C, 5% CO2, relative humidity 95%) and media was changed every two or three days for 20 days for confluent cell monolayer formation. On the day of the experiment, the monolayers were prepared by rinsing both apical and basolateral surfaces twice with HBSS. Cells were incubated with Hanks Balanced Salt Solution (HBSS, supplemented with 25mM HEPES and 4.45 mM glucose and the pH adjusted to 7.4) in both apical and basolateral compartments for 40 minutes to stabilise physiological parameters.
[00239] The dosing solutions were prepared by diluting test compound with HBSS to give a final test compound concentration of 10 pM (final DMSO concentration of 1 % v/v). The fluorescent integrity marker lucifer yellow (PromoCell) was also included in the dosing solution. For assessment of A-B permeability, HBSS was removed from the apical compartment and replaced with test compound dosing solution. The apical compartment insert was then placed into a companion plate containing fresh buffer (containing 1 % v/v DMSO). At 120 minutes the apical compartment inserts and the companion plates were separated and apical and basolateral samples diluted for analysis.
[00240] Test compounds were quantified by LC/MS/MS analysis using a 7 point calibration with appropriate dilution of the samples. The integrity of the monolayer throughout the experiment was checked by monitoring lucifer yellow permeation using fluorimetric analysis. The final receiver concentration (FRC) is the concentration of test compound at the basolateral compartment at 120 minutes.
[00241] The results are presented in Table 1. The column entitled ratio refers to ratio of drug delivered from the prodrug versus drug delivered from the parent drug.
Table 1
Figure imgf000059_0001
Figure imgf000060_0001
[00242] The prodrugs of Examples 1 to 3 deliver a much higher concentration of drug through a monolayer of human colon epithelial cells (Caco2). In particular, the prodrug of Example 1 delivers approximately 17-fold higher concentration of parent drug across Caco2 cells compared to treatment with the free carboxylic acid parent. The ethyl prodrug of Example 2 delivers approximately 24-fold higher concentration of parent drug compared with the free carboxylic acid parent. The prodrug of Example 3 delivers approximately 11-fold higher concentration of parent drug compared with the free carboxylic acid parent. This data indicates an advantage for the prodrugs compared to parent drugs for treatment of patients via oral administration.
Animal procedures
[00243] All procedures involving animals were approved by the Animal Welfare and Ethical Review Body of the Institute of Cancer Research and Cancer Research UK Manchester Institute in accordance with National Home Office regulations under the Animals (Scientific Procedures) Act 1986 and according to the guidelines of the Committee of the National Cancer Research Institute. Tumour size was determined by caliper measurements of tumour length, width and depth and volume was calculated as volume = 0.5236 x length x width x depth (mm). In accordance with our licence to perform animal experiments, animals were excluded from the experiments if they displayed signs of distress, excessive bodyweight loss (>20%) or illness.
In vivo pharmacokinetic studies
[00244] Mouse - female CD1 , NcR, FVB or C57/BI6 mice (Charles River Laboratories) at 6 weeks of age were used for the PK analyses. The mice were dosed orally by gavage (50 mg/kg in dimethyl sulfoxide (DMSO)/water 1 :19 v/v) or by intravenous injection (2 or 10 mg/kg in DMSO/tween/saline 10:1 :89 v/v/v). Two groups of three mice were used. Blood samples were taken from the tail vein of each group into K2EDTA or heparinised syringes at four time points, alternated at: group 1) 5, 30 minutes, 2 and 6 hours; and group 2) 15 min, 1 , 4 and 8 or 24 hours. Plasma samples were snap-frozen in liquid nitrogen and then stored at -80 °C prior to LC-MS/MS analysis.
[00245] Rat (performed by Evotec Ltd) - 2 female Sprague Dawley rats were dosed orally by gavage (20 mg/kg in DMSO/water 1 :19 v/v) or by intravenous injection (4 mg/kg in DMSO/tween/saline 10:1 :89 v/v/v). Blood samples were taken from the tail vein into K2EDTA or heparinised syringes at 8 time points: 15, 30, 45 minutes, 1 , 2, 4, 8 and 24 hours. Plasma samples were snap-frozen in liquid nitrogen and then stored at -80 °C prior to LC-MS/MS analysis.
[00246] Dog (performed by Covance Ltd) - 3 female Beagle dogs were dosed orally by gavage (5 mg/kg in DMSO/water 1 :19 v/v) or intravenous injection (2 mg/kg in DMSO/tween/saline 10:1 :89 v/v/v). Blood samples were taken from the jugular vein into heparinised syringes at 8 time points: 15, 30, 45 minutes, 1 , 2, 4, 8 and 24 hours. Plasma samples were snap-frozen in liquid nitrogen and then stored at -80 °C prior to LC-MS/MS analysis.
[00247] Test compound solutions (1 mg/mL in DMSO) were used to make stock Standard Curve (SC) and Quality Control (QC) solutions at appropriate concentrations. Blank plasma was spiked with stock solutions to produce a 9-point standard curve ranging from 1.5- 10,000 pg/mL; with 2 QC concentrations within this range and where the DMSO concentration was 10% of the plasma volume. Plasma PK samples, Standards and QC’s were added to individual Eppendorf tubes and DMSO (10% of plasma volume) was added to the plasma PK samples. SC, QC and plasma samples were extracted with methanol (100 pL) containing internal standard. Following protein precipitation, the samples were centrifuged for 10 minutes in a refrigerated centrifuge (4°C) at 14000 rpm. The supernatants were removed to a 96-well plate and centrifuged for a further 10 minutes in a refrigerated centrifuge (4°C) at 3700 rpm. Samples were analysed by Liquid Chromatography Mass Spectrometry (LC-MS/MS) for the compound plasma concentrations. Non-compartmental analysis was performed on plasma concentration data using the Excel macro PK Solver 2.0.
[00248] A summary of the results is presented in Tables 2 and 3.
Table 2
Figure imgf000062_0001
*Cmax and AUC values adjusted to the molar dose of the corresponding parent drug. AUC = area under curve; Cmax = maximal concentration; F = bioavailability.
[00249] It is clear from Table 2 that while all the prodrugs are capable of releasing parent drug when administered orally in multiple species, there are surprising differences between different ester prodrugs. In mouse, the species where clinical efficacy of LOX inhibitors is demonstrated in tumour models, the maximum concentration (Cmax) and exposure (AUC) of inhibitor the free carboxylic acid parent is similar whether generated from ethyl ester prodrugs (Example 1) or isopropyl ester (Reference Example 2), which are all superior to methyl ester prodrug (Reference Example 1).
[00250] Despite similar mouse data, surprisingly, in rat ethyl ester prodrug (Example 1) has superior PK properties compared to the isopropyl ester prodrug (Reference Example 2), with a Cmax for released drug >5-fold higher, and with superior AUC of > 3-fold higher.
[00251] In a non-rodent species (dog), the ethyl ester prodrug (Example 1) is superior to free carboxylic acid having approximately 4-fold increase in Cmax, approximately 2-fold increase in AUC and approximately 2-fold better oral bioavailability. Both rat and dog are species of preclinical development for drug candidates and used to predict human pharmacokinetics, therefore Example 1 is surprisingly better than the free carboxylic acid parent and closely related ester prodrugs (Reference Examples 1 and 2) in terms of preclinical pharmacokinetics and developability.
Table 3
Figure imgf000063_0001
*Cmax and AUC values adjusted to the molar dose of the corresponding parent drug. AUC = area under curve; Cmax = maximal concentration; F = bioavailability.
[00252] The PK profile of the ethyl ester prodrug of Example 2 is superior in mouse to the corresponding parent drug, with approximately 7-fold increase in Cmax and approximately 4-fold improvements in AUC and F%.
LOX inhibitor treatment in in vivo tumour models
M MTV-PyMT transgenic mouse breast cancer model.
[00253] MTV-PyMT (Guy et al, 1992) (FVB) female mice were selected randomly for LOX inhibitor treatments from day 70 post-birth, when animals had no detectable tumour. Mice were treated daily with LOX inhibitor in vehicle, or daily vehicle (5% DMSO/2.5% Tween20 in water) by oral gavage. Mammary tumours and lungs were collected when the primary tumours reached ethical limits.
[00254] For therapeutic efficacy assessment, the ratio of average tumour volume between compound treated and vehicle control treated (T/C) is calculated. Reduction in tumour volume in the compound treated group compared to vehicle-treated control group results in T/C < 1. The efficacy of LOX inhibitors described in this invention, as measured by T/C in breast cancer models is shown in Table 4 and is significant (p<0.05) for all the data presented.
M MTV-PyMT orthotopic allografts.
[00255] Tumour growth inhibition assessment - CD-1 female mice at 6-7 weeks old from Charles River were injected into the third upper nipple mammary fat pad with cells dissociated from the PyMT tumours (6 x105 in 100ul PBS). When tumours reached a mean volume of 20 mm3 the animals were allocated in groups of 8. LOX inhibitor (100 mg/kg) or vehicle (5% DMSO in water) was then administrated by oral gavage dosing, at 0.2ml/20g bodyweight once daily for up to 21 consecutive days. Tumours and weights were measured twice weekly using calipers. At the end of the study the animals were culled, and samples taken, fixed in 10% formalin or snap frozen in liquid nitrogen. Frozen samples were kept at - 80 degree centigrade until being analysed and the fixed samples stained according to the desired marker.
[00256] Metastasis inhibition assessment - CD-1 female mice at 6-7 weeks old from Charles River were injected into the third upper nipple mammary fat pad with cells dissociated from the PyMT tumours (4 x106 in 100ul PB). When tumours reached a mean of 20 mm3 the animals were allocated in groups of 8. LOX inhibitor or vehicle was administrated by oral gavage dosing, at 0.2ml/20g bodyweight once daily for up to 21 consecutive days. Tumours and weights were measured twice weekly using calipers. When the mean tumour volume of any group reached around 500 mm3, tumour resection was performed for all animal groups and tumour regrowth was monitored. Inhibitor treatment continued until the tumour volume of any one animal reached the ethical size limit, at which all animals were be culled for metastasis assessment in lungs as described above.
Table 4
Figure imgf000064_0001
[00257] It is clear from the data presented in Table 4 that the ethyl ester prodrug (Example 1) is at least as effective as the parent drug in reducing breast cancer growth in a GEMM model, in agreement with mouse PK data; the ethyl ester prodrug also reduces significantly metastasis formation in an orthotopic breast cancer model. REFERENCES
Abourbih, D. A., et al. (2010). "Lysyl oxidase expression and inhibition in uveal melanoma." Melanoma research 20(2): 97-106.
Adam, O., et al. (2011). "Increased lysyl oxidase expression and collagen cross-linking during atrial fibrillation." J. Mol. Cell. Cardiol. 50(4): 678-685.
Akiri, G., et al. (2003). "Lysyl oxidase-related protein-1 promotes tumor fibrosis and tumor progression in vivo." Cancer research 63(7): 1657-1666.
Albinger-Hegyi, A., et al. (2010). "Lysyl oxidase expression is an independent marker of prognosis and a predictor of lymph node metastasis in oral and oropharyngeal squamous cell carcinoma (OSCC)." International journal of cancer Journal international du cancer 126(11): 2653-2662.
Anderson, C., et al. (2007). "Chemical genetics suggests a critical role for lysyl oxidase in zebrafish notochord morphogenesis." Mol Biosyst 3(1): 51-59.
Aslam, T., et al. (2015). "Optical molecular imaging of lysyl oxidase activity - detection of active fibrogenesis in human lung tissue." Chemical Science 6(8): 4946-4953.
Aiting, Y., et al. (2021) " Hepatic stellate cells-specific LOXL1 deficiency abrogates hepatic inflammation, fibrosis, and corrects lipid metabolic abnormalities in non-obese NASH mice" Hepatology International, 15(5), 1122-1135
Baker, A.-M., et al. (2011). "The role of lysyl oxidase in SRC-dependent proliferation and metastasis of colorectal cancer." Journal of the National Cancer Institute 103(5): 407-424.
Barker, H. E., et al. (2012). "The rationale for targeting the LOX family in cancer." Nature reviews Cancer 12(8): 540-552.
Barry-Hamilton, V., et al. (2010). "Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment." Nat Med 16(9): 1009-1017.
Becker, J. et al. (2021) "Transcriptome analysis of hypoxic lymphatic endothelial cells indicates their potential to contribute to extracellular matrix rearrangement" Cells, 10(5), 1008
Beerlage, C., et al. (2013). "Hypoxia-inducible factor 1-regulated lysyl oxidase is involved in Staphylococcus aureus abscess formation." Infect. Immun. 81 (7): 2562-2573.
Boufraqech, M., et al. (2015). "miR30a Inhibits LOX Expression and Anaplastic Thyroid Cancer Progression." Cancer research 75(2): 367-377.
Brasselet, C., et al. (2005). "Collagen and elastin cross-linking: A mechanism of constrictive remodeling after arterial injury." Am. J. Physiol. 289(5, Pt. 2): H2228-H2233.
Burchardt, E. R. (2006). "Preparation of 2-phenyl-3-pyridazinones as lysyl oxidase inhibitors". DE102004056226A1
Burke A. A., et al (2017) Comparing hydrazine-derived reactive groups as inhibitors of quinone-dependent amine oxidases, Journal of Enzyme Inhibition and Medicinal Chemistry, 32:1 , 496-503, Carrington, M. J., et al. (1984). "The inhibition of lysyl oxidase in vivo by isoniazid and its reversal by pyridoxal. Effect on collagen cross-linking in the chick embryo." Biochem J 221(3): 837-843.
Chang, J. et al (2017) Pre-clinical evaluation of small molecule LOXL2 inhibitors in breast cancer. Oncotarget, Advance Publication
Chanoki, M., et al. (1995). "Increased expression of lysyl oxidase in skin with scleroderma." Br J Dermatol 133(5): 710-715.
Chen, W.-C., et al. (2015). "Matrix-Stiffness-Regulated Inverse Expression of Kruppel-Like Factor 5 and Kruppel-Like Factor 4 in the Pathogenesis of Renal Fibrosis." The American Journal of Pathology 185(9): 2468-2481.
Chien, J. W., et al. (2014). "Serum lysyl oxidase-like 2 levels and idiopathic pulmonary fibrosis disease progression." European Respiratory Journal 43(5): 1430-1438.
Cho, W., et al. (2020) "Ionizing radiation attracts tumor targeting and apoptosis by radiotropic lysyl oxidase traceable nanoparticles" Nanomedicine, 24, 102141
Chung, E. J., et al (2014). "Transforming Growth Factor Alpha is a Critical Mediator of Radiation Lung Injury." Radiation Research 182, 350-362
Cox, T. R., et al. (2013). "LOX-Mediated Collagen Crosslinking Is Responsible for Fibrosis- Enhanced Metastasis." Cancer research 73(6): 1721-1732.
Cox, T. R., et al. (2015). "The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase." Nature 522(7554): 106-110. da Silva, R., et al. (2015). "LOX Expression and Functional Analysis in Astrocytomas and Impact of IDH1 Mutation." PLoS One 10(3): e0119781. de Bruyn, J. R., et al. (2018). "Fibrostenotic Phenotype of Myofibroblasts in Crohn's Disease is Dependent on Tissue Stiffness and Reversed by LOX Inhibition." J Crohns Colitis 12(7): 849-859.
Decitre, M., et al. (1998). "Lysyl oxidase-like protein localizes to sites of de novo fibrinogenesis in fibrosis and in the early stromal reaction of ductal breast carcinomas." Lab. Invest. 78(2): 143-151.
Dentillo, D. B., et al. (2010). "Deregulation of LOXL1 and HTRA1 Gene Expression in Endometriosis." Reproductive Sciences 17(11): 1016-1023.
De Vita, A., et al. (2021) " Lysyl oxidase engineered lipid nanovesicles for the treatment of triple negative breast cancer" Scientific Reports, 11(1), 5107
Di Donato, A., et al. (1997). "Lysyl oxidase expression and collagen cross-linking during chronic adriamycin nephropathy." Nephron 76(2): 192-200.
Dong, K.-f., et al. (2014). "Effects on apoptosis and chemosensitivity in human laryngeal cancer Hep-2 cells by silencing the lysyl oxidase gene expression." Zhongguo Xiandai Yixue Zazhi 24(29): 13-17.
Dong, K., et al. (2014). "Effects of lox gene expression on proliferation, invasion and radiosensitivity of laryngeal cancer hep-2 cells." Tianjin Yiyao 42(5): 417-420. Erler, J. T., et al. (2009). "Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche." Cancer Cell 15(1): 35-44.
Gao, Y., et al. (2010). "LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling." Proceedings of the National Academy of Sciences 107(44): 18892-18897.
Georges, P. C., et al. (2007). "Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis." Am. J. Physiol. 293(6, Pt. 1): G1147-G1154.
Giboda, M., et al. (1992). "Experimental schistosomiasis mansoni: modulation of granulomas by inhibition of collagen cross-link formation. Preliminary report." Ann Trop Med Parasitol 86(6): 631-636.
Gilad, G. M. and V. H. Gilad (2001). "P-Aminopropionitrile treatment can accelerate recovery of mice after spinal cord injury." Eur. J. Pharmacol. 430(1): 69-72.
Gilad, G. M., et al. (2001). "Lysyl oxidase, the extracellular matrix-forming enzyme, in rat brain injury sites." Neurosci. Lett. 310(1): 45-48.
Gilad, G. M., et al. (2005). "Evidence for increased lysyl oxidase, the extracellular matrixforming enzyme, in Alzheimer's disease brain." Neurosci Lett 376(3): 210-214.
Goeroegh, T., et al. (2007). "Selective upregulation and amplification of the lysyl oxidase like- 4 (LOXL4) gene in head and neck squamous cell carcinoma." J Pathol 212(1): 74-82.
Gonzalez, G. E., et al. (2014). "N-acetyl-seryl-aspartyl-lysyl-proline reduces cardiac collagen cross-linking and inflammation in angiotensin Il-induced hypertensive rats." Clin. Sci. 126(1): 85-94.
Gonzalez-Santamaria, J et al, (2016) "Matrix cross-linking lysyl oxidases are induced in response to myocardial infarction and promote cardiac dysfunction". Cardiovascular Research 109, (1), 67-78.
Guo, K., et al. (2020). "Triptolide alleviates radiation-induced pulmonary fibrosis via inhibiting IKKp stimulated LOX production." Biochemical and Biophysical Research Communications 527, 283-288.
Guy, C. T., Cardiff, R. D. & Muller, W. J. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol 12, 954-961 (1992)
Haase, V. H. (2009). "Pathophysiological Consequences of HIF Activation." Annals of the New York Academy of Sciences 1177(1): 57-65.
Halberg, N., et al. (2009). "Hypoxia-inducible factor 1a induces fibrosis and insulin resistance in white adipose tissue." Mol. Cell. Biol. 29(16): 4467-4483.
Hamprecht, D. W., et al (2021). "Difluorohaloallylamine sulfone derivative inhibitors of lysyl oxidases, methods of preparation, and uses thereof." W02021/012014A1
Hase, H., et al. (2014). "LOXL2 Status Correlates with Tumor Stage and Regulates Integrin Levels to Promote Tumor Progression in ccRCC." Molecular Cancer Research 12(12): 1807- 1817. Hernandez, D.R., et al. (2021) " Inhibition of Lysyl Oxidase with p-aminopropionitrile Improves Venous Adaptation after Arteriovenous Fistula" Kidney360, 2(2), 270-278.
Huang, C.-S., et al. (2013). "Long-term ethanol exposure-induced hepatocellular carcinoma cell migration and invasion through lysyl oxidase activation are attenuated by combined treatment with pterostilbene and curcumin analogues." Journal of Agricultural and Food Chemistry 61 (18): 4326-4335.
Ingber, D. E. and A. Mammoto (2014). "Methods of altering vascular permeability by changing the mechanical properties of extracellular matrixes using agents such as lysyl oxidase (LOX)- modulating agents and uses for treatment of diseases". WO2014152122A2
Jiang, W.-P., et al. (2014). "Identification of the involvement of LOXL4 in generation of keratocystic odontogenic tumors by RNA-Seq analysis." In J Oral Sci 6(1): 31-38.
Jourdan-Le Saux, C., et al. (1994). "Lysyl oxidase cDNA of myofibroblast from mouse fibrotic liver." Biochem Biophys Res Commun 199(2): 587-592.
Kagan, H. M. (1994). "Lysyl oxidase: mechanism, regulation and relationship to liver fibrosis." Pathol Res Pract 190(9-10): 910-919.
Kagan, H. M., et al. (1981). "Changes in aortic lysyl oxidase activity in diet-induced atherosclerosis in the rabbit." Arteriosclerosis 1 (4): 287-291.
Kasashima, H., et al. (2014). "Lysyl oxidase-like 2 (LOXL2) from stromal fibroblasts stimulates the progression of gastric cancer." Cancer Letters 354(2): 438-446.
Kasashima, H., et al. (2015). "Lysyl oxidase is associated with the epithelial-mesenchymal transition of gastric cancer cells in hypoxia." Gastric Cancer: 1-12.
Kim, H., et al (2019). "Preliminary result of definitive radiotherapy in patients with non-small cell lung cancer who have underlying idiopathic pulmonary fibrosis: comparison between X- ray and proton therapy." Radiation Oncology 14: 19
Kim, Y., et al. (1999). "Coexpression of the lysyl oxidase-like gene (LOXL) and the gene encoding type III procollagen in induced liver fibrosis." Journal of cellular biochemistry 72(2): 181-188.
Kirschmann, D. A., et al. (2002). "A molecular role for lysyl oxidase in breast cancer invasion." Cancer research 62(15): 4478-4483.
Knitlova, J., et al. (2021). "Increased Collagen Crosslinking in Stiff Clubfoot Tissue: Implications for the Improvement of Therapeutic Strategies" International Journal of Molecular Sciences, 22(21), 11903
Ko, Y.S., et al. (2020) "Radiotherapy-resistant breast cancer cells enhance tumor progression by enhancing premetastatic niche formation through the HIF-1a-LOX axis" International Journal of Molecular Sciences, 21(21), 8027
Kong, F-M., et al. (2015). "Non-dosimetric risk factors for radiation-induced lung toxicity." 25(2), 100-109. Kumarasamy, A., et al. (2009). "Lysyl oxidase activity is dysregulated during impaired alveolarization of mouse and human lungs." Am. J. Respir. Crit. Care Med. 180(12): 1239- 1252.
Lee, G.-H., et al. (2011). "Lysyl oxidase-like- 1 enhances lung metastasis when lactate accumulation and monocarboxylate transporter expression are involved." Oncology Letters 2(5): 831-838.
Leiva, O., et al. (2019). "Novel lysyl oxidase inhibitors attenuate hallmarks of primary myelofibrosis in mice." Int J Hematol 110(6): 699-708.
Levene, C. I., et al. (1992). "Inhibition of chick embryo lysyl oxidase by various lathyrogens and the antagonistic effect of pyridoxal." Int J Exp Pathol 73(5): 613-624.
Levental, K. R., et al. (2009). "Matrix crosslinking forces tumor progression by enhancing integrin signaling." Cell 139(5): 891-906.
Li, R.-k., et al. (2015). "Lysyl oxidase-like 4 (LOXL4) promotes proliferation and metastasis of gastric cancer via FAK/Src pathway." Journal of Cancer Research and Clinical Oncology 141 (2): 269-281.
Liu, G., et al. (1997). "Irreversible inhibition of lysyl oxidase by homocysteine thiolactone and its selenium and oxygen analogues. Implications for homocystinuria." J Biol Chem 272(51): 32370-32377.
Liu, J., et al. (2014). "Correlations of lysyl oxidase with MMP2/MMP9 expression and its prognostic value in non-small cell lung cancer." Int J Clin Exp Pathol 7(9): 6040-6047.
Liu, X. et al, (2022) “Obesity induces adipose fibrosis and collagen cross-linking through suppressing AMPK and enhancing lysyl oxidase expression” Biochimica et Biophysica Acta, Molecular Basis of Disease, 1868(9), 166454
Lopez, B., et al. (2010). "Role of lysyl oxidase in myocardial fibrosis: from basic science to clinical aspects." Am. J. Physiol. 299(1 , Pt. 2): H1-H9.
Lopez, B., et al. (2013). "Osteopontin-mediated myocardial fibrosis in heart failure: a role for lysyl oxidase?" Cardiovasc. Res. 99(1): 111-120.
Lopez, B., et al. (2012). "Collagen Cross-Linking But Not Collagen Amount Associates With Elevated Filling Pressures in Hypertensive Patients With Stage C Heart Failure: Potential Role of Lysyl Oxidase." Hypertension 60(3): 677-683.
Mambetsariev, I., et al. (2014). "Stiffness-activated GEF-H1 expression exacerbates LPS- induced lung inflammation." PLoS One 9(4): e92670/92671-e92670/92612, 92612 pp.
Mammoto, A., et al. (2013). "Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics." Nature communications 4: 1759.
Mammoto, T., et al. (2013). "Role of Collagen Matrix in Tumor Angiogenesis and Glioblastoma Multiforme Progression." The American Journal of Pathology 183(4): 1293-1305.
Marshall, D. and V. Smith (2011). "In vivo screening assays for identifying inhibitors of LOXL2 activity". WO 2011022670 Marshall, D., et al. (2012). "Anti-LOXL2 antibody, siRNA, shRNA, ribozyme and triplex oligonucleotide to increase efficacy of antitumor agent and treat cancer". WO2012139045A1
Miana, M., et al. (2015). "The lysyl oxidase inhibitor p-aminopropionitrile reduces body weight gain and improves the metabolic profile in diet-induced obesity in rats." Dis. Models Meeh. 8(6): 543-551.
Miller, B. W., et al. (2015). "Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy." EMBO Mol Med 7(8): 1063-1076.
Murawaki, Y., et al. (1991). "Serum lysyl oxidase activity in chronic liver disease in comparison with serum levels of prolyl hydroxylase and laminin." Hepatology 14(6): 1167-1173.
Nave, A. H., et al. (2014). "Lysyl Oxidases Play a Causal Role in Vascular Remodeling in Clinical and Experimental Pulmonary Arterial Hypertension." Arterioscler., Thromb., Vase. Biol. 34(7): 1446-1458.
Neufeld, G. and V. Brekhman (2009). "Use of shRNA targeting LOXL2 gene in modulating angiogenesis and treating tumors, metastasis, fibrosis, and pulmonary alveolar proteinosis". W02009010974A2
Nguyen, L.T., et al. (2021) " Lysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse" Scientific Reports, 11 (1), 12437
Nicolas-Boluda, A., et al. (2021). "Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment." eLife 10, e58688.
Nishikawa, R., et al. (2015). "Tumour-suppressive microRNA-29s directly regulate LOXL2 expression and inhibit cancer cell migration and invasion in renal cell carcinoma." FEBS letters 589(16): 2136-2145.
Nuthakki, V. K., et al. (2004). "Lysyl oxidase expression in a rat model of arterial balloon injury." J Vase Surg 40(1): 123-129.
Ohmura, H., et al. (2012). "Cardiomyocyte-specific transgenic expression of lysyl oxidase-like protein-1 induces cardiac hypertrophy in mice." Hypertens. Res. 35(11): 1063-1068.
Palfreyman, M. G., et al. (1989). "Preparation of allylamines, inhibitors of lysyl oxidase". EP330218A2
Papadantonakis, N., et al. (2012). "Megakaryocyte pathology and bone marrow fibrosis: the lysyl oxidase connection." Blood 120(9): 1774-1781.
Park, H.-Y. L., et al. (2014). "Lysyl oxidase-like 2 level and glaucoma surgical outcomes." Invest. Ophthalmol. Visual Sci. 55(5): 3337-3343.
Peinado, H., et al. (2005). "A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression." EMBO J 24(19): 3446-3458.
Peng, L., et al. (2009). "Secreted LOXL2 is a novel therapeutic target that promotes gastric cancer metastasis via the Src/FAK pathway." Carcinogenesis 30(10): 1660-1669.
Perryman, L. et al. (2022) "Fibrosis in Mesothelioma: Potential Role of Lysyl Oxidases" Cancers, 14(4):981. Pinnell, S. R. and G. R. Martin (1968). "The cross-linking of collagen and elastin: enzymatic conversion of lysine in peptide linkage to alpha-aminoadipic-delta-semialdehyde (allysine) by an extract from bone." Proceedings of the National Academy of Sciences 61 (2): 708-716.
Priyanka, T. et al. (2016) "Lysyl oxidase (LOX) inhibitors as anti-scarring agents" Abstracts of Papers, 252nd ACS National Meeting & Exposition, Philadelphia, PA, United States, August 21-25, 2016, BIOL-98
Rachman-Tzemah, C., et al. (2017) "Blocking surgically induced lysyl oxidase activity reduces the risk of lung metastases." Cell Rep., 19, 774-784
Ramis, J. et al. (2022) "Lysyl oxidase-like 2 is increased in asthma and contributes to asthmatic airway remodelling" The European respiratory journal, 2004361.
Ricard-Blum, S., et al. (1996). "Mechanism of collagen network stabilization in human irreversible granulomatous liver fibrosis." Gastroenterology 111 (1): 172-182.
Rimar, D., et al. (2014). "Brief report: lysyl oxidase is a potential biomarker of fibrosis in systemic sclerosis." Arthritis Rheumatol 66(3): 726-730.
Rivera, A. D. and A. M. Butt (2019). "Astrocytes are direct cellular targets of lithium treatment: novel roles for lysyl oxidase and peroxisome-proliferator activated receptor-gamma as astroglial targets of lithium." Translational Psychiatry 9(1): 211.
Rosin, N. L., et al. (2015). "Disruption of Collagen Homeostasis Can Reverse Established Age-Related Myocardial Fibrosis." Am. J. Pathol. 185(3): 631-642.
Rossow, L., et al. (2018). "LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy". Oncogene 2018, 37, 4921-4940
Rowbottom, M. W. et al. (2016a). "Preparation of substituted pyridinylmethylamine compounds as lysyl oxidase-like 2 inhibitors". WO2016144702
Rowbottom, M. W. et al. (2016b). "Preparation of fluorinated pyridine derivatives as lysyl oxidase-like 2 inhibitors and uses thereof." WO2016144703
Rowbottom, M. W.; Hutchinson, J. H. (2017a). " Preparation of pyrimidine derivatives as Lysyl oxidase-like 2 inhibitors useful for the treatment of fibrosis." WO2017003862
Rowbottom, M. W.; Hutchinson, J. H. (2017b). "Lysyl oxidase-like 2 inhibitors and uses thereof." WO2017015221
Ruiz, L. A., et al. (2011). "Single-nucleotide polymorphisms in the lysyl oxidase-like protein 4 and complement component 3 genes are associated with increased risk for endometriosis and endometriosis-associated infertility." Fertil Steril 96(2): 512-515.
Saatchi, O., et al. (2020). " Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer" Nature Communications, 11(1), 2416
Sansom, O. (2012). Targeting the tumour microenvironment in pancreatic cancer. EACR- IACR Joint Conference: Tumour Microenvironment, Dublin, Ireland.
Sayre, L. M. (2007). "Amine compounds for amine oxidase inhibitors, and therapeutic use".
W02007005737A2 Schlotzer-Schrehardt, II., et al. (2008). "Genotype-correlated expression of lysyl oxidase-like 1 in ocular tissues of patients with pseudoexfoliation syndrome/glaucoma and normal patients." American Journal of Pathology 173(6): 1724-1735.
Schohe-Loop, R., et al. (2003). "Preparation of 2-phenyl-3(2H)-pyridazinones as lysyl oxidase inhibitors for preventing and treating fibrosis". DE10216144A1
Schuetze, F., et al. (2015). "Inhibition of Lysyl Oxidases Improves Drug Diffusion and Increases Efficacy of Cytotoxic Treatment in 3D Tumor Models." Sci. Rep. 5: 17576.
Scola, N. and T. Gorogh (2010). "LOXL4 as a selective molecular marker in primary and metastatic head/neck carcinoma." Anticancer Res 30(11): 4567-4571.
Sflomos, G., et al. (2021) "Intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1." EM BO Mol Med 13: e13180
Shen, C. J., et al. (2014). "Ionizing radiation induces tumor cell lysyl oxidase secretion." BMC Cancer 14: 532/531-532/510.
Siegel, R. C., et al. (1978). "Biochemical and immunochemical study of lysyl oxidase in experimental hepatic fibrosis in the rat." Proceedings of the National Academy of Sciences 75(6): 2945-2949.
Smith, V. and A. K. Holzer (2010). "Chemotherapeutic methods and compositions for treating cancer by inhibiting activity of lysyl oxidase-type enzyme". W02010080769A2
Smith, V. and P. Van Vlasselaer (2011). "Tumor therapy by inhibiting the activity or expression of lysyl oxidase-like 2 with antibodies or inhibitory nucleic acids". WO2011022710A1
Stalmans, I., et al. (2010). "Use of lysyl oxidase related protein inhibitors fortreatment of ocular neovascularization and fibrotic damage". W02010091279A1
Stalmans, I., et al. (2011). "Methods of treatmenting ocular fibrosis by modulating the activity of lysyl oxidase-type enzymes". US20110076285A1
Stewart, G. D., et al. (2008). "Analysis of hypoxia-associated gene expression in prostate cancer: lysyl oxidase and glucose transporter-1 expression correlate with Gleason score." Oncol Rep 20(6): 1561-1567.
Tadmor, T., et al. (2013). "The expression of lysyl-oxidase gene family members in myeloproliferative neoplasms." American Journal of Hematology 88(5): 355-358.
Tang, H et al. "Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface." Nat Commun. 8:14909
Tang, S. S., et al. (1984). "Beta-substituted ethylamine derivatives as suicide inhibitors of lysyl oxidase." J Biol Chem 259(2): 975-979.
Tjin, G., et al. (2017) “Lysyl oxidases regulate fibrillar collagen remodelling in idiopathic pulmonary fibrosis” Dis. Model Meeh. 10 (11): 1301-1312 llto, K., et al. (2021) "Inhibition of extracellular matrix integrity attenuates the early phase of aortic medial calcification in a rodent model" Atherosclerosis, 319, 10-20
Vadasz, Z., et al. (2005). "Abnormal deposition of collagen around hepatocytes in Wilson's disease is associated with hepatocyte specific expression of lysyl oxidase and lysyl oxidase like protein-2." J Hepatol 43(3): 499-507.
Van Bergen, T., et al. (2013). "The role of LOX and LOXL2 in scar formation after glaucoma surgery." Invest. Ophthalmol. Visual Sci. 54(8): 5788-5796. von Kleeck, R., et al. (2021) "Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of lysyl oxidase" Life Science Alliance, 4(5), e202000997
Wang, F., et al. (2017) " Lysyl oxidase is involved in synovial hyperplasia and angiogenesis in rats with collagen-induced arthritis" Mol Med Rep.;16(5):6736-6742
Wei, Q. et al. (2022) "Apoptosis Activation and Autophagy Inhibition of Chondrocytes by Leptin by the Upregulation of LOXL3 in Osteoarthritis Pathogenesis" Journal of healthcare engineering, 20224026128
Wiel, C., et al. (2013). "Lysyl oxidase activity regulates oncogenic stress response and tumorigenesis." Cell Death Dis 4: e855.
Wilgus, M.-L., et al. (2011). "Lysyl oxidase: A lung adenocarcinoma biomarker of invasion and survival." Cancer 117(10): 2186-2191.
Wilhelmus, M. M. M., et al. (2013). "Extracellular matrix modulator lysyl oxidase colocalizes with amyloid-beta pathology in Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type." Exp. Gerontol. 48(2): 109-114.
Williamson, P. R. and H. M. Kagan (1987). "Electronegativity of aromatic amines as a basis for the development of ground state inhibitors of lysyl oxidase." J Biol Chem 262(30): 14520- 14524.
Wong, C. C.-L., et al. (2011). "Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation." Proceedings of the National Academy of Sciences 108(39): 16369-16374.
Wong, C. C.-L., et al. (2014). "Lysyl oxidase-like 2 is critical to tumor microenvironment and metastatic niche formation in hepatocellular carcinoma." Hepatology (Hoboken, NJ, U. S.) 60(5): 1645-1658.
Xing, C., et al. (2022) “Lysyl oxidase inhibition enhances browning of white adipose tissue and adaptive thermogenesis” Genes and Diseases, 9(1), 140-150
Xu, J., et al. (2014). "67 laminin receptor promotes the malignant potential of tumour cells up- regulating lysyl oxidase-like 2 expression in cholangiocarcinoma." Digestive and Liver Disease 46(8): 750-757.
Yang, X., et al. (2013). "Inactivation of lysyl oxidase by p-aminopropionitrile inhibits hypoxia- induced invasion and migration of cervical cancer cells." Oncol Rep 29(2): 542-548. Yang, Z., et al. (2010). "Uric acid increases fibronectin synthesis through upregulation of lysyl oxidase expression in rat renal tubular epithelial cells." Am. J. Physiol. 299(2, Pt. 2): F336- F346.
Ying, M., et al. (2021) " Knockdown of lysyl oxidase like 1 inhibits the proliferation and pro- fibrotic effects of transforming growth factor-pi -induced hypertrophic scar fibroblasts" Canadian Journal of Physiology and Pharmacology, 99(12), 1272-1279
Zaffryar-Eilot, S., et al. (2013). "Lysyl oxidase-like-2 promotes tumour angiogenesis and is a potential therapeutic target in angiogenic tumours." Carcinogenesis 34(10): 2370-2379.
Zenkel, M., et al. (2011). "Regulation of lysyl oxidase-like 1 (LOXL1) and elastin-related genes by pathogenic factors associated with pseudoexfoliation syndrome." Invest Ophthalmol Vis Sci 52(11): 8488-8495.
Zhang, Q et al. (2020). " LOXL2 Upregulation in Gliomas Drives Tumorigenicity by Activating Autophagy to Promote TMZ Resistance and Trigger EMT". Frontiers in oncology, 10569584.
Zhi, C et al. (2017) "Elevated ischaemia-associated lysyl oxidase activity in delayed graft failure 6-12 months after renal transplantation" Experimental Physiology 102(2), 282-287
Zhu, J., et al. (2015). "Lysyl Oxidase Is Predictive of Unfavorable Outcomes and Essential for Regulation of Vascular Endothelial Growth Factor in Hepatocellular Carcinoma." Digestive Diseases and Sciences: 1-13.
Zibadi, S., et al. (2010). "T lymphocyte regulation of lysyl oxidase in diet-induced cardiac fibrosis." Cardiovasc Toxicol 10(3): 190-198.
[00258] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law).
[00259] All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.
[00260] The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise paragraphed. No language in the specification should be construed as indicating any non-paragraphed element as essential to the practice of the invention.
[00261] The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability, and/or enforceability of such patent documents.
[00262] This invention includes all modifications and equivalents of the subject matter recited in the paragraphs appended hereto as permitted by applicable law.

Claims

1. A compound, or a salt or solvate thereof, according to formula I:
Figure imgf000076_0001
wherein,
X is selected from the group consisting of S, NR1 and O;
R1 is selected from hydrogen and C1.4 alkyl;
Y is selected from N and CR4;
R4 is selected from hydrogen, halogen and C1.4 alkyl; one of W and Z is carbon and is bonded to the sulfone moiety,
Figure imgf000076_0002
, and the other of W and Z is N or CH;
R2 is selected from a phenyl, 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl group, each of which may be optionally substituted by one or more R3 groups; and
R3 is selected from the group consisting of halogen, oxo, RA3, -ORB3, -NRB3RC3, -SRB3, -CN, -NO2, -NRB3C(O)RC3, -C(O)NRB3RC3, -NRB3C(O)ORC3, -OC(O)NRB3RC3, -NRB3SO2RC3, - SC>2NRB3RC3, -SC>2RB3, -C(O)RB3, -C(O)ORB3, 3-7 membered heterocycloalkyl optionally substituted with one or more RD3 and C3-6 cycloalkyl optionally substituted with one or more RD3; where RA3 is selected from the group consisting of Ci-e alkyl, Ci-e alkenyl, C2-6 alkynyl, Ci-e haloalkyl and Ci-e haloalkoxy, each of which may be optionally substituted with a substituent selected from the group consisting of C1.4 alkoxy, hydroxy, -NH2, NHMe and NMe2; where RB3 and RC3 are independently selected from the group consisting of hydrogen, C1.4 alkyl, C1.4 alkenyl, C2-4 alkynyl, C1.4 haloalkyl, each of which may be optionally substituted with a substituent selected from the group consisting of C1.4 alkoxy, phenyl and hydroxy; or in any occurrence of the moiety -NRB3RC3, RB3 and RC3, together with the nitrogen atom to which they are bonded can form a 4- to 7-membered ring system; which may optionally be substituted by one or more RE3; where RD3 and RE3 are independently selected from the group consisting of C1.4 alkyl, C1.4 haloalkyl, C1.4 alkoxy, C1.4 haloalkoxy, C3-6 cycloalkyl, phenyl, oxo, and hydroxy.
2. A compound, or a salt or solvate thereof, according to claim 1 , wherein X is S.
3. A compound, or a salt or solvate thereof, according to claim 1 or 2, wherein Y is N or CH.
4. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein W is carbon and is bonded to the sulfone moiety.
5. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein W is carbon and is bonded to the sulfone moiety and Z is CH.
6. A compound, or a salt or solvate thereof, according to any one of the preceding claims of sub-formula la:
Figure imgf000077_0001
7. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein R2 is selected from phenyl, pyrrolidinyl, pyrazolyl and pyridinyl, each of which may be optionally substituted by one or more R3 groups.
8. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein R2 is selected from:
Figure imgf000078_0001
each of which may be optionally substituted by one or more R3 groups.
9. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein R2 is selected from:
Figure imgf000078_0002
, each of which may be optionally substituted by one or more
R3 groups.
10. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein R2 is selected from:
Figure imgf000078_0003
11. A compound, or a salt or solvate thereof, according to any one of the preceding claims, wherein R2 is phenyl.
12. A compound, or a salt or solvate thereof selected from:
Figure imgf000078_0004
Figure imgf000079_0002
13. A compound, or a salt or solvate thereof, according to claim 14 which is ethyl 5-((2- (aminomethyl)thiazol-5-yl)sulfonyl)-[1 , 1 '-biphenyl]-3-carboxylate:
Figure imgf000079_0001
14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.
15. A compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.
16. A compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a disease or medical condition mediated by lysyl oxidase (LOX).
17. A compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a proliferative disease.
18. A compound, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 17, wherein the proliferative disease is cancer.
19. A compound, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 18, wherein the cancer is selected from anus cancer, bile duct cancer, bladder cancer, blood cancer, brain cancer, breast cancer, uterine cervix cancer, colon cancer, endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladder cancer, head and neck cancer, hypopharyngeal cancer, pancreatic cancer, pharyngeal cancer, lip and oral cancer, liver cancer, lung cancer, melanoma, mesothelioma, multiple myeloma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, stomach cancer, testicular cancer and thyroid gland cancer.
20. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of cancer, wherein the compound, or a pharmaceutically acceptable salt or solvate thereof, is used simultaneously, sequentially or separately with radiotherapy.
21. A compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a fibrotic disorder.
22. A compound, or a pharmaceutically acceptable salt or solvate thereof, for use according to claim 21 , wherein fibrotic disorder is selected from:
(i) a fibrotic condition affecting the lungs, for example pulmonary fibrosis secondary to cystic fibrosis; idiopathic pulmonary fibrosis; coal worker’s progressive massive fibrosis; cryptogenic fibrosing alveolitis, chronic fibrosing interstitial pneumonia, interstitial lung disease (ILD), diffuse parenchymal lung disease (DPLD), emphysema and chronic obstructive pulmonary disease (COPD), or chronic asthma; or
(ii) a fibrotic condition affecting the liver, for example cirrhosis, and associated conditions such as chronic viral hepatitis B or C, Wilson’s disease, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), biliary cirrhosis or autoimmune hepatitis; or
(iii) a fibrotic condition affecting the kidneys, for example diabetic nephropathy, vesicoureteral reflux, tubulointerstitial renal fibrosis; glomerulonephritis or glomerular nephritis, including focal segmental glomerulosclerosis and membranous glomerulonephritis or mesangiocapillary glomerular nephritis; or
(iv) a fibrotic condition affecting the heart or vascular system, for example endomyocardial fibrosis; old myocardial infarction; atrial fibrosis; congestive heart failure, cardiomyopathy, hypertensive heart disease (HHD), hypertension (for example pulmonary hypertension) and fibrosis associated with hypertension, atherosclerosis, restenosis (e.g. coronary, carotid, and cerebral lesions), and heart disease associated with cardiac ischemic events; or (v) a fibrotic condition affecting the mediastinum, for example mediastinal fibrosis; or
(vi) a fibrotic condition affecting bone, for example myelofibrosis, including primary myelofibrosis, post polycythemia vera or post essential thrombocythemia myelofibrosis; or
(vii) a fibrotic condition affecting the retroperitoneum, for example retroperitoneal fibrosis skin; or
(viii) a fibrotic condition affecting the skin, for example nephrogenic systemic fibrosis, keloid formation and scarring, systemic sclerosis or scleroderma; or
(ix) a fibrotic condition affecting the Gl tract, for example a fibrotic intestinal disorder, inflammatory bowel disease, ulcerative colitis or Crohn’s disease; or
(x) a fibrotic condition affecting connective tissue, for example arthrofibrosis; or capsulitis;
(xi) a fibrotic condition affecting the eye, for example ocular fibrosis following surgery or pseudoexfoliation syndrome glaucoma; or
(xii) a fibrotic condition induced by radiation, such as fibrosis following radiotherapy.
23. A compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a cardiovascular disease, a neurological disorder, a pulmonary disease, an ocular condition, an inflammatory condition, a metabolic disease, a bacterial infections or endometriosis.
24. A combination comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, and one or more additional therapeutic agents.
25. A combination according to claim 24, wherein the one or more additional therapeutic agents is selected from an anti-cancer agent or an anti-fibrotic agent.
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Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10216144A1 (en) 2002-04-12 2003-11-06 Bayer Ag New 2-phenyl-4-phenoxy-3(2H)-pyridazinone derivatives useful as lysyl oxidase inhibitors for preventing or treating fibrotic diseases
WO2006043090A1 (en) 2004-10-22 2006-04-27 Cancer Research Technology Limited Imidazo[4,5-b]pyridin-2-one and oxazolo[4,5-b]pyridin-2-one compounds and analogs thereof as therapeutic compounds
WO2007005737A2 (en) 2005-07-01 2007-01-11 Case Western Reserve University Amine oxidase inhibitors
WO2009077766A1 (en) 2007-12-19 2009-06-25 Cancer Research Technology Limited Pyrido[2,3-b]pyrazine-8-substituted compounds and their use
WO2010080769A2 (en) 2009-01-06 2010-07-15 Arresto Biosciences, Inc. Chemotherapeutic methods and compositions
WO2010091279A1 (en) 2009-02-06 2010-08-12 Arresto Biosciences, Inc. Methods and compositions for treatment of neovascularization
WO2011022710A1 (en) 2009-08-21 2011-02-24 Arresto Biosciences, Inc Therapeutic methods and compositions
WO2011022670A1 (en) 2009-08-21 2011-02-24 Arresto Biosciences, Inc In vivo screening assays
US20110076285A1 (en) 2009-09-29 2011-03-31 Ingeborg Stalmans Methods and Compositions For Treatment of Ocular Fibrosis
WO2011092469A1 (en) 2010-02-01 2011-08-04 Cancer Research Technology Limited 1-(5-tert-butyl-2-phenyl-2h-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-2-oxo-2,3-dihydro-1h-imidazo[4,5-b]pyridin-7-yloxy)-phenyl]-urea and related compounds and their use in therapy
WO2012139045A1 (en) 2011-04-08 2012-10-11 Gilead Biologics, Inc. Methods and compositions for normalization of tumor vasculature by inhibition of loxl2
WO2014152122A2 (en) 2013-03-15 2014-09-25 Children's Medical Center Corporation Methods of altering vascular permeability and uses thereof
WO2015075483A1 (en) 2013-11-25 2015-05-28 Cancer Research Technology Limited 1 -(5-tert-butyl-2-aryl-pyrazol-3-yl)-3-[2-fluoro-4-[(3-oxo-4h-pyrido[2, 3-b]pyrazin-8-yl)oxy]phenyl]urea derivatives as raf inhibitors for the treatment of cancer
WO2016144703A1 (en) 2015-03-06 2016-09-15 Pharmakea, Inc. Fluorinated lysyl oxidase-like 2 inhibitors and uses thereof
WO2016144702A1 (en) 2015-03-06 2016-09-15 Pharmakea, Inc. Lysyl oxidase-like 2 inhibitors and uses thereof
WO2017003862A1 (en) 2015-07-01 2017-01-05 Pharmakea, Inc. Lysyl oxidase-like 2 inhibitors and uses thereof
WO2017015221A1 (en) 2015-07-23 2017-01-26 Pharmakea, Inc. Lysyl oxidase-like 2 inhibitors and uses thereof
WO2017141049A1 (en) 2016-02-19 2017-08-24 The Institute Of Cancer Research: Royal Cancer Hospital Methylamine derivatives as lysysl oxidase inhibitors for the treatment of cancer
WO2021012014A1 (en) 2019-07-25 2021-01-28 Pharmaxis Ltd. Difluorohaloallylamine sulfone derivative inhibitors of lysyl oxidases, methods of preparation, and uses thereof

Patent Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10216144A1 (en) 2002-04-12 2003-11-06 Bayer Ag New 2-phenyl-4-phenoxy-3(2H)-pyridazinone derivatives useful as lysyl oxidase inhibitors for preventing or treating fibrotic diseases
WO2006043090A1 (en) 2004-10-22 2006-04-27 Cancer Research Technology Limited Imidazo[4,5-b]pyridin-2-one and oxazolo[4,5-b]pyridin-2-one compounds and analogs thereof as therapeutic compounds
WO2007005737A2 (en) 2005-07-01 2007-01-11 Case Western Reserve University Amine oxidase inhibitors
WO2009077766A1 (en) 2007-12-19 2009-06-25 Cancer Research Technology Limited Pyrido[2,3-b]pyrazine-8-substituted compounds and their use
WO2010080769A2 (en) 2009-01-06 2010-07-15 Arresto Biosciences, Inc. Chemotherapeutic methods and compositions
WO2010091279A1 (en) 2009-02-06 2010-08-12 Arresto Biosciences, Inc. Methods and compositions for treatment of neovascularization
WO2011022710A1 (en) 2009-08-21 2011-02-24 Arresto Biosciences, Inc Therapeutic methods and compositions
WO2011022670A1 (en) 2009-08-21 2011-02-24 Arresto Biosciences, Inc In vivo screening assays
US20110076285A1 (en) 2009-09-29 2011-03-31 Ingeborg Stalmans Methods and Compositions For Treatment of Ocular Fibrosis
WO2011092469A1 (en) 2010-02-01 2011-08-04 Cancer Research Technology Limited 1-(5-tert-butyl-2-phenyl-2h-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-2-oxo-2,3-dihydro-1h-imidazo[4,5-b]pyridin-7-yloxy)-phenyl]-urea and related compounds and their use in therapy
WO2012139045A1 (en) 2011-04-08 2012-10-11 Gilead Biologics, Inc. Methods and compositions for normalization of tumor vasculature by inhibition of loxl2
WO2014152122A2 (en) 2013-03-15 2014-09-25 Children's Medical Center Corporation Methods of altering vascular permeability and uses thereof
WO2015075483A1 (en) 2013-11-25 2015-05-28 Cancer Research Technology Limited 1 -(5-tert-butyl-2-aryl-pyrazol-3-yl)-3-[2-fluoro-4-[(3-oxo-4h-pyrido[2, 3-b]pyrazin-8-yl)oxy]phenyl]urea derivatives as raf inhibitors for the treatment of cancer
WO2016144703A1 (en) 2015-03-06 2016-09-15 Pharmakea, Inc. Fluorinated lysyl oxidase-like 2 inhibitors and uses thereof
WO2016144702A1 (en) 2015-03-06 2016-09-15 Pharmakea, Inc. Lysyl oxidase-like 2 inhibitors and uses thereof
WO2017003862A1 (en) 2015-07-01 2017-01-05 Pharmakea, Inc. Lysyl oxidase-like 2 inhibitors and uses thereof
WO2017015221A1 (en) 2015-07-23 2017-01-26 Pharmakea, Inc. Lysyl oxidase-like 2 inhibitors and uses thereof
WO2017141049A1 (en) 2016-02-19 2017-08-24 The Institute Of Cancer Research: Royal Cancer Hospital Methylamine derivatives as lysysl oxidase inhibitors for the treatment of cancer
WO2021012014A1 (en) 2019-07-25 2021-01-28 Pharmaxis Ltd. Difluorohaloallylamine sulfone derivative inhibitors of lysyl oxidases, methods of preparation, and uses thereof

Non-Patent Citations (140)

* Cited by examiner, † Cited by third party
Title
ABOURBIH, D. A. ET AL.: "Lysyl oxidase expression and inhibition in uveal melanoma", MELANOMA RESEARCH, vol. 20, no. 2, 2010, pages 97 - 106
ADAM, O. ET AL.: "Increased lysyl oxidase expression and collagen cross-linking during atrial fibrillation", J. MOL. CELL. CARDIOL., vol. 50, no. 4, 2011, pages 678 - 685, XP028186079, DOI: 10.1016/j.yjmcc.2010.12.019
AITING, Y. ET AL.: "Hepatic stellate cells-specific LOXL1 deficiency abrogates hepatic inflammation, fibrosis, and corrects lipid metabolic abnormalities in non-obese NASH mice", HEPATOLOGY INTERNATIONAL, vol. 15, no. 5, 2021, pages 1122 - 1135, XP037588069, DOI: 10.1007/s12072-021-10210-w
AKIRI, G. ET AL.: "Lysyl oxidase-related protein-1 promotes tumor fibrosis and tumor progression in vivo", CANCER RESEARCH, vol. 63, no. 7, 2003, pages 1657 - 1666
ALBINGER-HEGYI, A. ET AL.: "Lysyl oxidase expression is an independent marker of prognosis and a predictor of lymph node metastasis in oral and oropharyngeal squamous cell carcinoma (OSCC", INTERNATIONAL JOURNAL OF CANCER JOURNAL INTERNATIONAL DU CANCER, vol. 126, no. 11, 2010, pages 2653 - 2662
ANDERSON, C. ET AL.: "Chemical genetics suggests a critical role for lysyl oxidase in zebrafish notochord morphogenesis", MOL BIOSYST, vol. 3, no. 1, 2007, pages 51 - 59
ASLAM, T. ET AL.: "Optical molecular imaging of lysyl oxidase activity - detection of active fibrogenesis in human lung tissue", CHEMICAL SCIENCE, vol. 6, no. 8, 2015, pages 4946 - 4953
BAKER, A.-M. ET AL.: "The role of lysyl oxidase in SRC-dependent proliferation and metastasis of colorectal cancer", JOURNAL OF THE NATIONAL CANCER INSTITUTE, vol. 103, no. 5, 2011, pages 407 - 424, XP055547340, DOI: 10.1093/jnci/djq569
BARKER, H. E. ET AL.: "The rationale for targeting the LOX family in cancer", NATURE REVIEWS CANCER, vol. 12, no. 8, 2012, pages 540 - 552, XP055265384, DOI: 10.1038/nrc3319
BARRY-HAMILTON, V. ET AL.: "Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment", NAT MED, vol. 16, no. 9, 2010, pages 1009 - 1017, XP055019972, DOI: 10.1038/nm.2208
BECKER, J. ET AL.: "Transcriptome analysis of hypoxic lymphatic endothelial cells indicates their potential to contribute to extracellular matrix rearrangement", CELLS, vol. 10, no. 5, 2021, pages 1008
BEERLAGE, C. ET AL.: "Hypoxia-inducible factor 1-regulated lysyl oxidase is involved in Staphylococcus aureus abscess formation", INFECT. IMMUN., vol. 81, no. 7, 2013, pages 2562 - 2573
BOUFRAQECH, M. ET AL.: "miR30a Inhibits LOX Expression and Anaplastic Thyroid Cancer Progression", CANCER RESEARCH, vol. 75, no. 2, 2015, pages 367 - 377
BRASSELET, C. ET AL.: "Collagen and elastin cross-linking: A mechanism of constrictive remodeling after arterial injury", AM. J. PHYSIOL., vol. 289, 2005, pages H2228 - H2233
BURCHARDT, E. R., PREPARATION OF 2-PHENYL-3-PYRIDAZINONES AS LYSYL OXIDASE INHIBITORS, 2006
BURKE A. A. ET AL.: "Comparing hydrazine-derived reactive groups as inhibitors of quinone-dependent amine oxidases", JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, vol. 32, no. 1, 2017, pages 496 - 503
CARRINGTON, M. J. ET AL.: "The inhibition of lysyl oxidase in vivo by isoniazid and its reversal by pyridoxal. Effect on collagen cross-linking in the chick embryo", BIOCHEM J, vol. 221, no. 3, 1984, pages 837 - 843
CHANG, J. ET AL.: "Pre-clinical evaluation of small molecule LOXL2 inhibitors in breast cancer", ONCOTARGET, ADVANCE PUBLICATION, 2017
CHANOKI, M. ET AL.: "Increased expression of lysyl oxidase in skin with scleroderma", BR J DERMATOL, vol. 133, no. 5, 1995, pages 710 - 715
CHEN, W.-C. ET AL.: "Matrix-Stiffness-Regulated Inverse Expression of Kruppel-Like Factor 5 and Kruppel-Like Factor 4 in the Pathogenesis of Renal Fibrosis", THE AMERICAN JOURNAL OF PATHOLOGY, vol. 185, no. 9, 2015, pages 2468 - 2481
CHIEN, J. W. ET AL.: "Serum lysyl oxidase-like 2 levels and idiopathic pulmonary fibrosis disease progression", EUROPEAN RESPIRATORY JOURNAL, vol. 43, no. 5, 2014, pages 1430 - 1438
CHO, W. ET AL.: "Ionizing radiation attracts tumor targeting and apoptosis by radiotropic lysyl oxidase traceable nanoparticles", NANOMEDICINE, vol. 24, 2020, pages 102141
CHUNG, E. J. ET AL.: "Transforming Growth Factor Alpha is a Critical Mediator of Radiation Lung Injury", RADIATION RESEARCH, vol. 182, 2014, pages 350 - 362
COX, T. R. ET AL.: "LOX-Mediated Collagen Crosslinking Is Responsible for Fibrosis-Enhanced Metastasis", CANCER RESEARCH, vol. 73, no. 6, 2013, pages 1721 - 1732, XP055357201, DOI: 10.1158/0008-5472.CAN-12-2233
COX, T. R. ET AL.: "The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase", NATURE, vol. 522, no. 7554, 2015, pages 106 - 110
DA SILVA, R. ET AL.: "LOX Expression and Functional Analysis in Astrocytomas and Impact of IDH1 Mutation", PLOS ONE, vol. 10, no. 3, 2015, pages e0119781
DE BRUYN, J. R. ET AL.: "Fibrostenotic Phenotype of Myofibroblasts in Crohn's Disease is Dependent on Tissue Stiffness and Reversed by LOX Inhibition", J CROHNS COLITIS, vol. 12, no. 7, 2018, pages 849 - 859
DE VITA, A. ET AL.: "Lysyl oxidase engineered lipid nanovesicles for the treatment of triple negative breast cancer", SCIENTIFIC REPORTS, vol. 11, no. 1, 2021, pages 5107
DECITRE, M. ET AL.: "Lysyl oxidase-like protein localizes to sites of de novo fibrinogenesis in fibrosis and in the early stromal reaction of ductal breast carcinomas", LAB. INVEST., vol. 78, no. 2, 1998, pages 143 - 151, XP009173555
DENTILLO, D. B. ET AL.: "Deregulation of LOXL1 and HTRA1 Gene Expression in Endometriosis", REPRODUCTIVE SCIENCES, vol. 17, no. 11, 2010, pages 1016 - 1023
DI DONATO, A. ET AL.: "Lysyl oxidase expression and collagen cross-linking during chronic adriamycin nephropathy", NEPHRON, vol. 76, no. 2, 1997, pages 192 - 200
DONG, K. ET AL.: "Effects of lox gene expression on proliferation, invasion and radiosensitivity of laryngeal cancer hep-2 cells", TIANIIN YIYAO, vol. 42, no. 5, 2014, pages 417 - 420
DONG, K.-F. ET AL.: "Effects on apoptosis and chemosensitivity in human laryngeal cancer Hep-2 cells by silencing the lysyl oxidase gene expression", ZHONAAUO XIANDAI YIXUE ZAZHI, vol. 24, no. 29, 2014, pages 13 - 17
ERLER, J. T. ET AL.: "Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche", CANCER CELL, vol. 15, no. 1, 2009, pages 35 - 44, XP002625567, DOI: 10.1016/J.CCR.2008.11.012
GAO, Y. ET AL.: "LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 107, no. 44, 2010, pages 18892 - 18897, XP055039631, DOI: 10.1073/pnas.1004952107
GEORGES, P. C. ET AL.: "Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis", AM. J. PHYSIOL., vol. 293, 2007, pages G1147 - G1154, XP055722147, DOI: 10.1152/ajpgi.00032.2007
GIBODA, M. ET AL.: "Experimental schistosomiasis mansoni: modulation of granulomas by inhibition of collagen cross-link formation. Preliminary report", ANN TROP MED PARASITOL, vol. 86, no. 6, 1992, pages 631 - 636
GILAD, G. M. ET AL.: "Evidence for increased lysyl oxidase, the extracellular matrix-forming enzyme, in Alzheimer's disease brain", NEUROSCI LETT, vol. 376, no. 3, 2005, pages 210 - 214, XP004751553, DOI: 10.1016/j.neulet.2004.11.054
GILAD, G. M. ET AL.: "Lysyl oxidase, the extracellular matrix-forming enzyme, in rat brain injury sites", NEUROSCI. LETT., vol. 310, no. 1, 2001, pages 45 - 48
GILAD, G. M.V. H. GILAD: "β-Aminopropionitrile treatment can accelerate recovery of mice after spinal cord injury", EUR. J. PHARMACOL., vol. 430, no. 1, 2001, pages 69 - 72
GOEROEGH, T. ET AL.: "Selective upregulation and amplification of the lysyl oxidase like-4 (LOXL4) gene in head and neck squamous cell carcinoma", J PATHOL, vol. 212, no. 1, 2007, pages 74 - 82, XP055690429, DOI: 10.1002/path.2137
GONZALEZ, G. E. ET AL.: "N-acetyl-seryl-aspartyl-lysyl-proline reduces cardiac collagen cross-linking and inflammation in angiotensin II-induced hypertensive rats", CLIN. SCI., vol. 126, no. 1, 2014, pages 85 - 94
GONZALEZ-SANTAMARIA, J ET AL.: "Matrix cross-linking lysyl oxidases are induced in response to myocardial infarction and promote cardiac dysfunction", CARDIOVASCULAR RESEARCH, vol. 109, no. 1, 2016, pages 67 - 78
GUO, K. ET AL.: "Triptolide alleviates radiation-induced pulmonary fibrosis via inhibiting IKKβ stimulated LOX production", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 527, 2020, pages 283 - 288
GUY, C. T.CARDIFF, R. D.MULLER, W. J.: "Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease", MOL CELL BIOL, vol. 12, 1992, pages 954 - 961
HAASE, V. H.: "Pathophysiological Consequences of HIF Activation", ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, vol. 1177, no. 1, 2009, pages 57 - 65, XP071407299, DOI: 10.1111/j.1749-6632.2009.05030.x
HALBERG, N. ET AL.: "Hypoxia-inducible factor 1a induces fibrosis and insulin resistance in white adipose tissue", MOL. CELL. BIOL., vol. 29, no. 16, 2009, pages 4467 - 4483
HASE, H. ET AL.: "LOXL2 Status Correlates with Tumor Stage and Regulates Integrin Levels to Promote Tumor Progression in ccRCC", MOLECULAR CANCER RESEARCH, vol. 12, no. 12, 2014, pages 1807 - 1817
HERNANDEZ, D.R. ET AL.: "Inhibition of Lysyl Oxidase with β-aminopropionitrile Improves Venous Adaptation after Arteriovenous Fistula", KIDNEY360, vol. 2, no. 2, 2021, pages 270 - 278
HUANG, C.-S. ET AL.: "Long-term ethanol exposure-induced hepatocellular carcinoma cell migration and invasion through lysyl oxidase activation are attenuated by combined treatment with pterostilbene and curcumin analogues", JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, vol. 61, no. 18, 2013, pages 4326 - 4335
JIANG, W.-P. ET AL.: "Identification of the involvement of LOXL4 in generation of keratocystic odontogenic tumors by RNA-Seq analysis", IN J ORAL SCI, vol. 6, no. 1, 2014, pages 31 - 38
JOURDAN-LE SAUX, C. ET AL.: "Lysyl oxidase cDNA of myofibroblast from mouse fibrotic liver", BIOCHEM BIOPHYS RES COMMUN, vol. 199, no. 2, 1994, pages 587 - 592, XP024765488, DOI: 10.1006/bbrc.1994.1269
KAGAN, H. M. ET AL.: "Changes in aortic lysyl oxidase activity in diet-induced atherosclerosis in the rabbit", ARTERIOSCLEROSIS, vol. 1, no. 4, 1981, pages 287 - 291
KAGAN, H. M.: "Lysyl oxidase: mechanism, regulation and relationship to liver fibrosis", PATHOL RES PRACT, vol. 190, no. 9-10, 1994, pages 910 - 919, XP000609197
KASASHIMA, H. ET AL.: "Lysyl oxidase is associated with the epithelial-mesenchymal transition of gastric cancer cells in hypoxia", GASTRIC CANCER, 2015, pages 1 - 12
KASASHIMA, H. ET AL.: "Lysyl oxidase-like 2 (LOXL2) from stromal fibroblasts stimulates the progression of gastric cancer", CANCER LETTERS, vol. 354, no. 2, 2014, pages 438 - 446, XP029069735, DOI: 10.1016/j.canlet.2014.08.014
KIM, H. ET AL.: "Preliminary result of definitive radiotherapy in patients with non-small cell lung cancer who have underlying idiopathic pulmonary fibrosis: comparison between X-ray and proton therapy", RADIATION ONCOLOGY, vol. 14, 2019, pages 19
KIM, Y. ET AL.: "Coexpression of the lysyl oxidase-like gene (LOXL) and the gene encoding type III procollagen in induced liver fibrosis", JOURNAL OF CELLULAR BIOCHEMISTRY, vol. 72, no. 2, 1999, pages 181 - 188
KIRSCHMANN, D. A. ET AL.: "A molecular role for lysyl oxidase in breast cancer invasion", CANCER RESEARCH, vol. 62, no. 15, 2002, pages 4478 - 4483, XP002414351
KNITLOVA, J. ET AL.: "Increased Collagen Crosslinking in Stiff Clubfoot Tissue: Implications for the Improvement of Therapeutic Strategies", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 22, no. 21, 2021, pages 11903
KO, Y.S. ET AL.: "Radiotherapy-resistant breast cancer cells enhance tumor progression by enhancing premetastatic niche formation through the HIF-1a-LOX axis", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 21, no. 21, 2020, pages 8027
KONG, F-M. ET AL., NON-DOSIMETRIC RISK FACTORS FOR RADIATION-INDUCED LUNG TOXICITY, vol. 25, no. 2, 2015, pages 100 - 109
KUMARASAMY, A. ET AL.: "Lysyl oxidase activity is dysregulated during impaired alveolarization of mouse and human lungs", AM. J. RESPIR. CRIT. CARE MED., vol. 180, no. 12, 2009, pages 1239 - 1252
L. W. DEADY, SYN. COMM., vol. 7, 1977, pages 509 - 514
LEE, G.-H. ET AL.: "Lysyl oxidase-like-1 enhances lung metastasis when lactate accumulation and monocarboxylate transporter expression are involved", ONCOLOGY LETTERS, vol. 2, no. 5, 2011, pages 831 - 838
LEIVA, O. ET AL.: "Novel lysyl oxidase inhibitors attenuate hallmarks of primary myelofibrosis in mice", INT J HEMATOL, vol. 110, no. 6, 2019, pages 699 - 708, XP036945183, DOI: 10.1007/s12185-019-02751-6
LEVENE, C. I. ET AL.: "Inhibition of chick embryo lysyl oxidase by various lathyrogens and the antagonistic effect of pyridoxal", INT J EXP PATHOL, vol. 73, no. 5, 1992, pages 613 - 624, XP008004200
LEVENTAL, K. R. ET AL.: "Matrix crosslinking forces tumor progression by enhancing integrin signaling", CELL, vol. 139, no. 5, 2009, pages 891 - 906, XP029533710, DOI: 10.1016/j.cell.2009.10.027
LI, R.-K. ET AL.: "Lysyl oxidase-like 4 (LOXL4) promotes proliferation and metastasis of gastric cancer via FAK/Src pathway", JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY, vol. 141, no. 2, 2015, pages 269 - 281, XP035426335, DOI: 10.1007/s00432-014-1823-z
LIU, G. ET AL.: "Irreversible inhibition of lysyl oxidase by homocysteine thiolactone and its selenium and oxygen analogues. Implications for homocystinuria", J BIOL CHEM, vol. 272, no. 51, 1997, pages 32370 - 32377
LIU, J. ET AL.: "Correlations of lysyl oxidase with MMP2/MMP9 expression and its prognostic value in non-small cell lung cancer", INT J CLIN EXP PATHOL, vol. 7, no. 9, 2014, pages 6040 - 6047
LIU, X. ET AL.: "Obesity induces adipose fibrosis and collagen cross-linking through suppressing AMPK and enhancing lysyl oxidase expression", BIOCHIMICA ET BIOPHYSICA ACTA, MOLECULAR BASIS OF DISEASE, vol. 1868, no. 9, 2022, pages 166454
LOPEZ, B. ET AL.: "Collagen Cross-Linking But Not Collagen Amount Associates With Elevated Filling Pressures in Hypertensive Patients With Stage C Heart Failure: Potential Role of Lysyl Oxidase", HYPERTENSION, vol. 60, no. 3, 2012, pages 677 - 683
LOPEZ, B. ET AL.: "Osteopontin-mediated myocardial fibrosis in heart failure: a role for lysyl oxidase?", CARDIOVASC. RES., vol. 99, no. 1, 2013, pages 111 - 120
LOPEZ, B. ET AL.: "Role of lysyl oxidase in myocardial fibrosis: from basic science to clinical aspects", AM. J. PHVSIOL., vol. 299, no. 1, 2010, pages H1 - H9
MAMBETSARIEV, I. ET AL.: "Stiffness-activated GEF-H1 expression exacerbates LPS-induced lung inflammation", PLOS ONE, vol. 9, no. 4, 2014, pages 92612
MAMMOTO, A. ET AL.: "Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics", NATURE COMMUNICATIONS, vol. 4, 2013, pages 1759
MAMMOTO, T. ET AL.: "Role of Collagen Matrix in Tumor Angiogenesis and Glioblastoma Multiforme Progression", THE AMERICAN JOURNAL OF PATHOLOGY, vol. 183, no. 4, 2013, pages 1293 - 1305
MIANA, M. ET AL.: "The lysyl oxidase inhibitor β-aminopropionitrile reduces body weight gain and improves the metabolic profile in diet-induced obesity in rats", DIS. MODELS MECH., vol. 8, no. 6, 2015, pages 543 - 551
MILLER, B. W. ET AL.: "Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy", EMBO MOL MED, vol. 7, no. 8, 2015, pages 1063 - 1076
MURAWAKI, Y. ET AL.: "Serum lysyl oxidase activity in chronic liver disease in comparison with serum levels of prolyl hydroxylase and laminin", HEPATOLOGY, vol. 14, no. 6, 1991, pages 1167 - 1173, XP055120398, DOI: 10.1016/0270-9139(91)90145-L
NAVE, A. H. ET AL.: "Lysyl Oxidases Play a Causal Role in Vascular Remodeling in Clinical and Experimental Pulmonary Arterial Hypertension", ARTERIOSCLER., THROMB., VASC. BIOL., vol. 34, no. 7, 2014, pages 1446 - 1458
NEUFELD, G.V. BREKHMAN, USE OF SHRNA TARGETING LOXL2 GENE IN MODULATING ANGIOGENESIS AND TREATING TUMORS, METASTASIS, FIBROSIS, AND PULMONARY ALVEOLAR PROTEINOSIS, 2009
NGUYEN, L.T. ET AL.: "Lysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse", SCIENTIFIC REPORTS, vol. 11, no. 1, 2021, pages 12437
NICOLAS-BOLUDA, A. ET AL.: "Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment", ELIFE, vol. 10, 2021, pages e58688
NISHIKAWA, R. ET AL.: "Tumour-suppressive microRNA-29s directly regulate LOXL2 expression and inhibit cancer cell migration and invasion in renal cell carcinoma", FEBS LETTERS, vol. 589, no. 16, 2015, pages 2136 - 2145, XP055356306, DOI: 10.1016/j.febslet.2015.06.005
NUTHAKKI, V. K. ET AL.: "Lysyl oxidase expression in a rat model of arterial balloon injury", J VASE SURG, vol. 40, no. 1, 2004, pages 123 - 129
OHMURA, H. ET AL.: "Cardiomyocyte-specific transgenic expression of lysyl oxidase-like protein-1 induces cardiac hypertrophy in mice", HYPERTENS. RES., vol. 35, no. 11, 2012, pages 1063 - 1068
PALFREYMAN, M. G. ET AL., PREPARATION OF ALLYLAMINES, INHIBITORS OF LYSYL OXIDASE, 1989
PAPADANTONAKIS, N. ET AL.: "Megakaryocyte pathology and bone marrow fibrosis: the lysyl oxidase connection", BLOOD, vol. 120, no. 9, 2012, pages 1774 - 1781, XP086694274, DOI: 10.1182/blood-2012-02-402594
PARK, H.-Y. L. ET AL.: "Lysyl oxidase-like 2 level and glaucoma surgical outcomes", INVEST. OPHTHALMOL. VISUAL SCI., vol. 55, no. 5, 2014, pages 3337 - 3343
PEINADO, H. ET AL.: "A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression", EMBO J, vol. 24, no. 19, 2005, pages 3446 - 3458
PENG, L. ET AL.: "Secreted LOXL2 is a novel therapeutic target that promotes gastric cancer metastasis via the Src/FAK pathway", CARCINOGENESIS, vol. 30, no. 10, 2009, pages 1660 - 1669, XP002711315, DOI: 10.1093/CARCIN/BGP178
PERRYMAN, L. ET AL.: "Fibrosis in Mesothelioma: Potential Role of Lysyl Oxidases", CANCERS, vol. 14, no. 4, 2022, pages 981
PINNELL, S. R.G. R. MARTIN: "The cross-linking of collagen and elastin: enzymatic conversion of lysine in peptide linkage to alpha-aminoadipic-delta-semialdehyde (allysine) by an extract from bone", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 61, no. 2, 1968, pages 708 - 716
PRIYANKA, T. ET AL.: "Lysyl oxidase (LOX) inhibitors as anti-scarring agents", 252ND ACS NATIONAL MEETING & EXPOSITION, PHILADELPHIA, PA, UNITED STATES, AUGUST 21-25, 2016, 2016
RACHMAN-TZEMAH, C. ET AL.: "Blocking surgically induced lysyl oxidase activity reduces the risk of lung metastases", CELL REP., vol. 19, 2017, pages 774 - 784
RAMIS, J. ET AL.: "Lysyl oxidase-like 2 is increased in asthma and contributes to asthmatic airway remodelling", THE EUROPEAN RESPIRATORY JOURNAL, 2022, pages 2004361
RICARD-BLUM, S. ET AL.: "Mechanism of collagen network stabilization in human irreversible granulomatous liver fibrosis", GASTROENTEROLOGY, vol. 111, no. 1, 1996, pages 172 - 182
RIMAR, D. ET AL.: "Brief report: lysyl oxidase is a potential biomarker of fibrosis in systemic sclerosis", ARTHRITIS RHEUMATOL, vol. 66, no. 3, 2014, pages 726 - 730, XP072274309, DOI: 10.1002/art.38277
RIVERA, A. D.A. M. BUTT: "Astrocytes are direct cellular targets of lithium treatment: novel roles for lysyl oxidase and peroxisome-proliferator activated receptor-gamma as astroglial targets of lithium", TRANSLATIONAL PSYCHIATRY, vol. 9, no. 1, 2019, pages 211
ROSIN, N. L. ET AL.: "Disruption of Collagen Homeostasis Can Reverse Established Age-Related Myocardial Fibrosis", AM. J. PATHOL., vol. 185, no. 3, 2015, pages 631 - 642
ROSSOW, L. ET AL.: "LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy", ONCOGENE, vol. 37, 2018, pages 4921 - 4940, XP036582981, DOI: 10.1038/s41388-018-0320-2
RUIZ, L. A. ET AL.: "Single-nucleotide polymorphisms in the lysyl oxidase-like protein 4 and complement component 3 genes are associated with increased risk for endometriosis and endometriosis-associated infertility", FERTIL STERIL, vol. 96, no. 2, 2011, pages 512 - 515, XP028242633, DOI: 10.1016/j.fertnstert.2011.06.001
SAATCHI, O. ET AL.: "Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer", NATURE COMMUNICATIONS, vol. 11, no. 1, 2020, pages 2416
SANSOM, O.: "Targeting the tumour microenvironment in pancreatic cancer", EACR-IACR JOINT CONFERENCE: TUMOUR MICROENVIRONMENT, DUBLIN, IRELAND, 2012
SCHLOTZER-SCHREHARDT, U. ET AL.: "Genotype-correlated expression of lysyl oxidase-like 1 in ocular tissues of patients with pseudoexfoliation syndrome/glaucoma and normal patients", AMERICAN JOURNAL OF PATHOLOGY, vol. 173, no. 6, 2008, pages 1724 - 1735
SCHUETZE, F. ET AL.: "Inhibition of Lysyl Oxidases Improves Drug Diffusion and Increases Efficacy of Cytotoxic Treatment in 3D Tumor Models", SCI. REP., vol. 5, 2015, pages 17576
SCOLA, N.T. GOROGH: "LOXL4 as a selective molecular marker in primary and metastatic head/neck carcinoma", ANTICANCER RES, vol. 30, no. 11, 2010, pages 4567 - 4571
SFLOMOS, G. ET AL.: "Intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1", EMBO MOL MED, vol. 13, 2021, pages e13180
SHEN, C. J. ET AL.: "Ionizing radiation induces tumor cell lysyl oxidase secretion", BMC CANCER, vol. 14, 2014, XP021191708, DOI: 10.1186/1471-2407-14-532
SIEGEL, R. C. ET AL.: "Biochemical and immunochemical study of lysyl oxidase in experimental hepatic fibrosis in the rat", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 75, no. 6, 1978, pages 2945 - 2949
STEWART, G. D. ET AL.: "Analysis of hypoxia-associated gene expression in prostate cancer: lysyl oxidase and glucose transporter-1 expression correlate with Gleason score", ONCOL REP, vol. 20, no. 6, 2008, pages 1561 - 1567
TADMOR, T. ET AL.: "The expression of lysyl-oxidase gene family members in myeloproliferative neoplasms", AMERICAN JOURNAL OF HEMATOLOGY, vol. 88, no. 5, 2013, pages 355 - 358
TANG, H ET AL.: "Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface", NAT COMMUN, vol. 8, pages 14909, XP055539501, DOI: 10.1038/ncomms14909
TANG, S. S. ET AL.: "Beta-substituted ethylamine derivatives as suicide inhibitors of lysyl oxidase", J BIOL CHEM, vol. 259, no. 2, 1984, pages 975 - 979, XP002768513
TJIN, G. ET AL.: "Lysyl oxidases regulate fibrillar collagen remodelling in idiopathic pulmonary fibrosis", DIS. MODEL MECH., vol. 10, no. 11, 2017, pages 1301 - 1312
UTO, K. ET AL.: "Inhibition of extracellular matrix integrity attenuates the early phase of aortic medial calcification in a rodent model", ATHEROSCLEROSIS, vol. 319, 2021, pages 10 - 20, XP086494550, DOI: 10.1016/j.atherosclerosis.2020.12.015
VADASZ, Z. ET AL.: "Abnormal deposition of collagen around hepatocytes in Wilson's disease is associated with hepatocyte specific expression of lysyl oxidase and lysyl oxidase like protein-2.", J HEPATOL, vol. 43, no. 3, 2005, pages 499 - 507, XP025292968, DOI: 10.1016/j.jhep.2005.02.052
VAN BERGEN, T. ET AL.: "The role of LOX and LOXL2 in scar formation after glaucoma surgery", INVEST. OPHTHALMOL. VISUAL SCI., vol. 54, no. 8, 2013, pages 5788 - 5796
VON KLEECK, R. ET AL.: "Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of lysyl oxidase", LIFE SCIENCE ALLIANCE, vol. 4, no. 5, 2021, pages e202000997
WANG, F. ET AL.: "Lysyl oxidase is involved in synovial hyperplasia and angiogenesis in rats with collagen-induced arthritis", MOL MED REP., vol. 16, no. 5, 2017, pages 6736 - 6742
WEI, Q. ET AL.: "Apoptosis Activation and Autophagy Inhibition of Chondrocytes by Leptin by the Upregulation of LOXL3 in Osteoarthritis Pathogenesis", JOURNAL OF HEALTHCARE ENGINEERING, 2022, pages 20224026128
WIEL, C. ET AL.: "Lysyl oxidase activity regulates oncogenic stress response and tumorigenesis", CELL DEATH DIS, vol. 4, 2013, pages e855
WILGUS, M.-L. ET AL.: "Lysyl oxidase: A lung adenocarcinoma biomarker of invasion and survival", CANCER, vol. 117, no. 10, 2011, pages 2186 - 2191, XP071127150, DOI: 10.1002/cncr.25768
WILHELMUS, M. M. M. ET AL.: "Extracellular matrix modulator lysyl oxidase colocalizes with amyloid-beta pathology in Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type", EXP.GERONTOL., vol. 48, no. 2, 2013, pages 109 - 114
WILLIAMSON, P. R.H. M. KAGAN: "Electronegativity of aromatic amines as a basis for the development of ground state inhibitors of lysyl oxidase", J BIOL CHEM, vol. 262, no. 30, 1987, pages 14520 - 14524
WONG, C. C.-L. ET AL.: "Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 108, no. 39, 2011, pages 16369 - 16374, XP055067151, DOI: 10.1073/pnas.1113483108
WONG, C. C.-L. ET AL.: "Lysyl oxidase-like 2 is critical to tumor microenvironment and metastatic niche formation in hepatocellular carcinoma", HEPATOLOGY (HOBOKEN, NJ, U. S.), vol. 60, no. 5, 2014, pages 1645 - 1658
XING, C. ET AL.: "Lysyl oxidase inhibition enhances browning of white adipose tissue and adaptive thermogenesis", GENES AND DISEASES, vol. 9, no. 1, 2022, pages 140 - 150
XU, J. ET AL.: "67 laminin receptor promotes the malignant potential of tumour cells up-regulating lysyl oxidase-like 2 expression in cholangiocarcinoma", DIGESTIVE AND LIVER DISEASE, vol. 46, no. 8, 2014, pages 750 - 757, XP029008303, DOI: 10.1016/j.dld.2014.03.017
YANG, X. ET AL.: "Inactivation of lysyl oxidase by β-aminopropionitrile inhibits hypoxia-induced invasion and migration of cervical cancer cells", ONCOL REP, vol. 29, no. 2, 2013, pages 542 - 548
YANG, Z. ET AL.: "Uric acid increases fibronectin synthesis through upregulation of lysyl oxidase expression in rat renal tubular epithelial cells", AM. J. PHYSIOL., vol. 299, no. 2, 2010, pages F336 - F346
YING, M. ET AL.: "Knockdown of lysyl oxidase like 1 inhibits the proliferation and pro-fibrotic effects of transforming growth factor-β1-induced hypertrophic scar fibroblasts", CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY, vol. 99, no. 12, 2021, pages 1272 - 1279
ZAFFRYAR-EILOT, S. ET AL.: "Lysyl oxidase-like-2 promotes tumour angiogenesis and is a potential therapeutic target in angiogenic tumours", CARCINOGENESIS, vol. 34, no. 10, 2013, pages 2370 - 2379
ZENKEL, M. ET AL.: "Regulation of lysyl oxidase-like 1 (LOXL1) and elastin-related genes by pathogenic factors associated with pseudoexfoliation syndrome", INVEST OPHTHALMOL VIS SCI, vol. 52, no. 11, 2011, pages 8488 - 8495
ZHANG, Q ET AL.: "LOXL2 Upregulation in Gliomas Drives Tumorigenicity by Activating Autophagy to Promote TMZ Resistance and Trigger EMT", FRONTIERS IN ONCOLOGY, 2020, pages 10569584
ZHI, C ET AL.: "Elevated ischaemia-associated lysyl oxidase activity in delayed graft failure 6-12 months after renal transplantation", EXPERIMENTAL PHYSIOLOGY, vol. 102, no. 2, 2017, pages 282 - 287
ZHU, J. ET AL.: "Lysyl Oxidase Is Predictive of Unfavorable Outcomes and Essential for Regulation of Vascular Endothelial Growth Factor in Hepatocellular Carcinoma", DIGESTIVE DISEASES AND SCIENCES, 2015, pages 1 - 13
ZIBADI, S. ET AL.: "T lymphocyte regulation of lysyl oxidase in diet-induced cardiac fibrosis", CARDIOVASC TOXICOL, vol. 10, no. 3, 2010, pages 190 - 198

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