HALOALLYLAMINE SULFONE DERIVATIVE INHIBITORS OF LYSYL OXIDASES

AND USES THEREOF

Technical Field

[0001] The present invention relates to novel compounds which are capable of inhibiting certain amine oxidase enzymes. These compounds are useful for treatment of a variety of indications, e.g., fibrosis, cancer and/or angiogenesis in human subjects as well as in pets and livestock. In addition, the present invention relates to pharmaceutical compositions containing these compounds, as well as various uses thereof.

Background

[0002] The enzymes are lysyl oxidase (LOX), the first family member to be described and LOX-like1 (LOXL1), LOXL2, LOXL3, and LOXL4 (J Cell Biochem 2003; 88: 660 - 672). Lysyl oxidase isoenzymes are copper-dependent amine oxidases which initiate the covalent cross-linking of collagen and elastin. A major function of lysyl oxidase isoenzymes is to facilitate the cross-linking of collagen and elastin by the oxidative deamination of lysine and hydroxylysine amino acid side chains to aldehydes which spontaneously react with neighbouring residues. The resulting cross-linked strands contribute to extracellular matrix (ECM) stability and render it less susceptible to proteolytic degradation by enzymes such as matrix metalloproteases (MMPs). The activity of lysyl oxidase enzymes is crucial for the maintenance of normal tensile and elastic features of connective tissue of many organ systems of the body.

[0003] Lysyl oxidase isoenzymes belong to a larger group of amine oxidases which include flavin-dependent and copper-dependent oxidases which are described by the nature of the catalytic co-factor. Flavin-dependent enzymes include monoamine oxidase-A (MAO-A), monoamine oxidase-B (MAO-B), polyamine oxidase and lysine demethylase (LSD1), and the copper-dependent enzymes including semicarbazide sensitive amine oxidase (vascular adhesion protein-1, SSAO/VAP-1), retinal amine oxidase, diamine oxidase and the lysyl oxidase isoenzymes. The copper-dependent amine oxidases have a second co-factor which varies slightly from enzyme to enzyme. In SSAO/VAP-1 it is an oxidized tyrosine residue (TPQ, oxidized to a quinone), whereas in the lysyl oxidase isoenzymes the TPQ has been further processed by addition of a neighbouring lysine residue (to form LTQ) (J Cell Biochem 2003; 88: 660 - 672).

[0004] Lysyl oxidase isoenzymes exhibit different in vivo expression patterns, which suggests that specific isoenzymes will have specific biological roles. Catalytically active forms of LOX have been identified in the cytosolic and nuclear compartments and research is in progress to define their roles in these compartments. LOX itself, for example, plays a major role in epithelial-to-mesenchymal transition (EMT), cell migration, adhesion, transformation and gene regulation. Different patterns of LOX expression/activity have been associated with distinct pathological processes including fibrotic diseases, Alzheimer’s disease and other neurodegenerative processes, as well as tumour progression and metastasis (Am J Surg 2005; 189: 297 - 301).

[0005] Directed replacement of dead or damaged cells with connective tissue after injury represents a survival mechanism that is conserved throughout evolution and appears to be most pronounced in humans, serving a valuable role following traumatic injury, infection or diseases. Progressive scarring can occur following more chronic and/or repeated injuries that causes impaired function to parts or the entire affected organ. A variety of causes, such as chronic infections, chronic exposure to alcohol and other toxins, autoimmune and allergic reactions or surgery, radio-and chemotherapy can all lead to fibrosis. This pathological process, therefore, can occur in almost any organ or tissue of the body and, typically, results from situations persisting for several weeks or months in which inflammation, tissue destruction and repair occur simultaneously. In this setting, fibrosis most frequently affects the lungs, liver, skin, kidneys and cardiovascular system.

[0006] Liver fibrosis for example can occur as a complication of haemochromatosis, Wilson's disease, alcoholism, schistosomiasis, viral hepatitis, bile duct obstruction, exposure to toxins and metabolic disorders. Liver fibrosis is characterized by the accumulation of extracellular matrix that can be distinguished qualitatively from that in normal liver. This fibrosis can progress to cirrhosis, liver failure, cancer and eventually death (Pathology – Research and Practice 1994; 190: 910 - 919).

[0007] Fibrotic tissues can accumulate in the heart and blood vessels as a result of hypertension, hypertensive heart disease, atherosclerosis and myocardial infarction where the accumulation of extracellular matrix or fibrotic deposition results in stiffening of the vasculature and stiffening of the cardiac tissue itself (Am J Physiol Heart Circ Physiol 2010; 299: H1 - H9).

[0008] Pulmonary arterial hypertension (PAH) is a rare and rapidly lethal condition characterised by elevated pulmonary arterial pressure and caused by increased pulmonary vascular resistance. Although a heterogeneous condition with a wide range of causes, there is increasing recognition

that PAH is associated with other diseases such as connective-tissue disease and scleroderma. Pathological hallmarks of PAH include vascular wall remodelling with excessive extracellular matrix (ECM) deposition and cross-linking. Lysyl oxidases are dysregulated in pulmonary vasculature of patients with idiopathic pulmonary arterial hypertension (IPAH) and contribute to the persistence of ECM components and improper collagen and elastin remodelling through cross-linking (Arterioscler. Thromb Vasc. Biol.2014; 34: 1446– 1458). Prognosis for patients with PAH is poor. Targeting the lysyl oxidases pharmacologically could provide therapeutic intervention where few or none currently exist.

[0009] A strong association between fibrosis and increased lysyl oxidase activity has been demonstrated. For example, in experimental hepatic fibrosis in rat (Proc. Natl. Acad. Sci. USA 1978; 75: 2945 - 2949), in models of lung fibrosis (J Pharmacol Exp Ther 1981; 219: 675 - 678), in arterial fibrosis (Arteriosclerosis 1981; 1: 287 - 291.), in dermal fibrosis (Br J Dermatol 1995; 133: 710 - 715) and in adriamycin-induced kidney fibrosis in rat (Nephron 1997; 76: 192-200). Of these experimental models of human disease, the most striking increases in enzyme activity were seen in the rat model of CCl4-induced liver fibrosis. In these studies, the low level of enzyme activity in the healthy liver increased 15- to 30-fold in fibrotic livers.

[0010] In humans, there is also a significant association between lysyl oxidase activity measured in the plasma and liver fibrosis progression. Lysyl oxidase activity level is normally low in the serum of healthy subjects, but significantly increased in chronic active hepatitis and even more in cirrhosis. Therefore, lysyl oxidase might serve as a marker of internal fibrosis.

[0011] Lysyl oxidase isoenzymes are highly regulated by Hypoxia-Inducible Factor 1a (HIF-1a) and TGF-b, the two most prominent growth factors that cause fibrosis (Cell Biol 2009; 29: 4467 -4483). Collagen cross-linking occurs in every type of fibrosis, hence a lysyl oxidase isoenzyme inhibitor could be used in idiopathic pulmonary fibrosis, scleroderma, kidney or liver fibrosis.

[0012] In normal wound healing, granulation tissue formation is a short-lived process, providing a scaffold for re-epithelialisation and repair. Subsequently, the tissue is remodelled and a normotrophic scar is formed. However, after an injury, humans cannot regenerate normal skin. Instead, the repair (or healing) process leads to scar formation (cicatrisation). Scars are both aesthetically and functionally inferior to skin. Scars are a chronic problem and excessive or hypertrophic scarring and its accompanying aesthetic, functional and psychological sequelae remain key challenges for the treatment of deep skin injury and burns. A key factor in the poor appearance and pliability of scars, in particular hypertrophic scars, are the changes to collagen in the dermal layer. In scar tissue the collagen (predominantly Collagen I) is more densely packed and closely aligned in parallel bundles. In normal skin, collagen is not densely packed and is more of a ‘basket-weave’ structure. These alterations, both in structure and quantity of collagen, largely underlie the poor appearance of scar and lead to loss of pliability, discomfort and functional problems.

[0013] Dermal fibrosis, or excessive scarring of the skin, is a consequence of exaggerated healing response and is characterized by disproportionate fibroblast proliferation and extracellular matrix (ECM) production in the dermis. Clinically, dermal fibrosis manifests as thickened, tightened and hardened areas of the skin. The spectrum of fibrotic skin disorders is wide, including, but not limited to: hypertrophic scarring, keloids, scleroderma (diffuse and limited subtypes), 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) and eosinophilic fasciitis. Although each of these disorders has its own etiology and clinical characteristics, all involve excessive collagen production, and altered collagen remodelling. One possible mechanism for altered ECM remodelling is through covalent cross-linking. This directly implicates the LOX family of enzymes in the pathogenesis of cutaneous fibrosis (Laboratory investigation 2019; 99: 514– 527). LOX and LOXL1-4 expression is elevated in scar fibroblasts compared to normal skin fibroblasts, with LOX and LOXL1 being the dominant isoforms found in skin tissue.

[0014] Studies involving two complimentary, in-vitro skin-like models– human skin equivalent (hSEs), and self-assembled stromal tissues identified LOXL4 as the key isoform mediating TGF-beta induced fibrotic phenotypes (Lab. Invest.2019; 99: 514– 527).

[0015] Scarring processes are a considerable problem and challenge in the eye and surrounding structures. Ocular scarring plays a major role in either primary disease (e.g. corneal and conjunctival scarring) or treatment failure (e.g. postoperative trabeculectomy) (Ocular Surgery News U. S. Edition, October 1, 2002).

[0016] Glaucoma is a disease in which the optic nerve is being damaged, leading to progressive and irreversible loss of vision. Elevated intraocular pressure (IOP) is one of the major risk factors for the development and progression of glaucoma. Most treatments for glaucoma are targeted at lowering the intraocular pressure, either by decreasing the formation of aqueous fluid in the eye, or, as in the case of glaucoma filtration surgery, by increasing the outflow of fluid from the eye. Trabeculectomy– the current gold standard for the management of IOP - is a filtering surgery where an ostium is created into the anterior chamber from underneath a partial thickness scleral flap to allow for aqueous flow out of the eye. Post-operative scarring is the main cause of treatment failure. The antimetabolites mitomycin-C (MMC) and 5-fluorouracil (5-FU) are used in current clinical practice to help limit post-operative ocular scar tissue formation. While these agents have been shown to improve the IOP outcome of filtration surgery, they do so in a non-selective manner and are associated with significant side effects (Arch. Ophthalmol.2002; 120: 297– 300). Safer, more targeted, anti-fibrotic agents are needed.

[0017] Gingival fibromatosis is a rare and heterogeneous group of disorders that develop as slow progressive, local or diffuse, fibrous enlargements of keratinized gingiva (gingival overgrowth or enlargement). In severe cases, the excess tissue may cover the crowns of the teeth, thus causing masticatory, aesthetic, phonetic, functional and periodontal problems. Gingival overgrowth may be inherited, of idiopathic origin, associated with inflammatory diseases of the oral cavity, or associated with other systemic diseases. However, the majority of cases are due to side-effects of systemic medications such as the anti-seizure drug phenytoin, the immunosuppressant cyclosporin A, and certain anti-hypertensive dihydropyridine anti-calcium-channel-blockers, in particular nifedipine (crit rev oral biol 2004; 15: 165– 175). The pathological manifestation of gingival overgrowth comprises excessive accumulation of extracellular matrix proteins, of which Collagen I is the most predominant. One recognized concept of mechanism for drug induced gingival overgrowth is EMT, a process in which interaction of gingival cells and the extracellular matrix are weakened as epithelial cells transdifferentiate into fibrogenic fibroblast-like cells (AJP 2010; 177: 208– 218). The damaged epithelium, basement membrane and underlying stroma result in TGF-stimulation of lysyl oxidase enzyme activity and contribute to connective tissue fibrosis (Lab Invest 1999; 79: 1655– 1667).

[0018] The rationale for the consistent and strong inhibition of fibrosis by lysyl oxidase isoenzyme blockers is that the lack of cross-linking activity renders the collagen susceptible to degradation by proteolytic enzymes such as MMPs. Hence, any type of fibrosis should be reversed by treatment with lysyl oxidase isoenzyme inhibitors. Given the varied involvement of all lysyl oxidase isoenzymes in fibrosis, an inhibitor that demonstrates sustained, strong inhibition of all lysyl oxidase isoenzymes, i.e. a pan LOX inhibitor, should be most efficacious.

[0019] Rheumatoid Arthritis (RA) is a systemic autoimmune disorder characterized by chronic, painful inflammation of the lining of the joints. In some people, however, the condition can progress to involve painful swelling and inflammation of the surrounding tissue, and other body systems, including the skin, eyes, lungs, heart and blood vessels. Rheumatoid arthritis is thus a painful and debilitating disease that can result in substantial loss of function and mobility in the hands, wrists and feet. Active rheumatoid arthritis emanates from a few joints, but can subsequently progress to affect multiple joints. Synovial hyperplasia, involving infiltrated immune cells and resident synovial fibroblasts (SFs), is a typical feature of RA. Rheumatoid arthritis synovial fibroblasts (RASFs) are the most common cell type at sites of invasion and are the main culprit in joint destruction. Activated RASFs are able to transmigrate and, as such, have been implicated in the spread of arthritis between joints. Cytokines from the infiltrated immune cells induce activation and proliferation of synovial fibroblasts. These activated SFs in turn generate the pathogenic stroma to perpetuate chronic inflammation, ultimately leading to cartilage and bone destruction. By implanting RASFs together with human cartilage into severe combined immunodeficient mice, it has been demonstrated that activated RASFs migrate in vivo, spreading the disease to the sites of implanted human cartilage. Furthermore, whilst RASFs actively degrade cartilage, controls implanted with synovial fibroblasts from osteoarthritis (OA) patients and cutaneous fibroblasts from healthy donors did not (Nat. Med.2009; 15: 1414– 1420). RASFs differ from unactivated, healthy fibroblasts by their morphology and gene expression. RASFs are characterised by the expression of antiapoptotic, proto-oncogenes and lack of expression of tumor suppressor genes. The production of pro-inflammatory cytokines and chemokines by RASFs further enable attraction of immune cells to the synovium. Furthermore, the production of matrix metalloprotease (MMP) enzymes promotes invasion into and destruction of cartilage.

[0020] The type II collagen-induced arthritis (CIA) model is a commonly used animal model for RA as it recapitulates well the signature immunological, pathological and arthritic presentations observed in RA in humans. In CIA rats, high expressions levels of LOX in the synovial membranes, synovial fluid and serum have been demonstrated. Inhibition of LOX with beta-aminopropionitrile (BAPN; a pan LOX inhibitor) was found to attenuate inflammation, synovial hyperplasia, angiogenesis and expression of MMP-2 and MMP-9, indicating that LOX promotes synovial hyperplasia and angiogenesis in CIA rats. Furthermore, knockdown of LOXL2 and antibodies against LOXL2 attenuated collagen deposition, proliferation and invasion of RASF (Mol. Med. Rep. 2017: 6736– 6742).

[0021] Whilst there is no cure for RA, there are a number of treatments available that alleviate symptoms and modify disease progression. However, such treatments come with significant side effects associated, in part, with the suppression of the immune system. Selective drugs that target RASF would represent more useful therapy for RA.

[0022] Osteoarthritis (OA) is a disease characterised by degeneration of joint cartilage and underlying bone. Predominantly resulting from“wear and tear’, OA causes pain and stiffening of the joint. The most commonly affected joints are those of the fingers, knees, back and hips. Unlike other forms of arthritis (such as RA), osteoarthritis only affects the joints. Often, joints on one side of the body are affected more than those on the other. OA is a progressive and debilitating disease that can have a significant impact on work and normal daily activities.

[0023] Synovial fibrosis is a key contributor to OA, and is a manifestation of fibroblast proliferation and an imbalance in collagen synthesis and collagen degradation. This imbalance leads to excessive deposition of collagen into the extracellular matrix (ECM) and results in thickening and stiffening of the synovial membrane.

[0024] Genes encoding a number of the lysyl oxidase family of enzymes including LOX, LOXL2, LOXL3 and LOXL4 have been shown to be highly expressed in mice with experimental OA, and humans with end-stage OA (Arthritis and Rheumatology 2014; 66: 647– 656).

[0025] Given the varied contribution of many of the members of the lysyl oxidase family of enzymes to the development of both rheumatoid arthritis and osteoarthritis, a pan LOX inhibitor may provide for a potentially more efficacious therapy.

[0026] BAPN is a widely used, nonselective mechanism-based, irreversible lysyl oxidase inhibitor. Since the 1960s BAPN has been used in animal studies (mainly rat, mouse and hamster) and has been efficacious in reducing collagen content in various models (e.g. CCl4, bleomycin, quartz, cancer) and tissues (e.g. liver, lung and dermis) (J Cell Biochem 2003; 88: 660 - 672). However, studies in human patients with scleroderma, found BAPN to be poorly tolerated and highlights the need for safer alternatives (Clin. Pharmacol. Ther.1967: 593– 602).

[0027] Lysyl oxidase catalysed collagen cross-linking can proceed via two pathways: the allysine and hydroxyallysine pathways. In the hydroxyallysine pathway, immature divalent crosslinks are formed first, including dehydro-dihydroxylysinonorleucine (deH-DHLNL) and dehydro-hydroxylysinonorleucine (deH-HLNL), and then further progress (via lysyl oxidase independent

reactions) to mature trivalent crosslinks, between three collagen molecules to form deoxypyridinoline (DPD) and pyridinoline (PYD). These mature and immature crosslinks can be measured by LC-MS/MS (PLoS One 2014; 9 (11), e112391).

[0028] Lysyl oxidase isoenzymes are not only involved in the cross-linking of elastin and collagen during wound healing and fibrosis, but also regulate cell movement and signal transduction. Its intracellular and intranuclear function is associated with gene regulation and can lead to tumourigenesis and tumour progression (Inflammapharmacol 2011; 19: 117-129). Both down and upregulation of lysyl oxidase isoenzymes in tumour tissues and cancer cell lines have been described, suggesting a dual role for lysyl oxidase isoenzymes and LOX pro-peptide as a metastasis promoter gene as well as a tumour suppressor gene.

[0029] In addition to its role in tissue remodelling, the LOX isoenzymes also play a critical role in primary cancer and metastasis. Tumour growth is associated with a reactive stroma, which is predominantly composed of fibroblasts; termed cancer associated fibroblasts (CAFs). Mice subcutaneously inoculated with an equal mixture of tumour and CAFs cells are known to have a faster growth rate and higher incidence of metastases (Trends Mol Med. 2013;19(8): 447 - 453). CAF knockout models have shown to be pro-tumorigenic, however this is quite an abstract scenario when comparing to a patient’s tumour microenvironment. CAFs have been shown to have an increased expression of LOXs compared to normal fibroblasts (Dis Model Mech. 2018; 11 (4)). Utilising a LOX inhibitor in a cancer setting potentially will affect both the tumour and stromal compartment to assist in decreasing tumour growth and metastasis.

[0030] Emerging evidence suggests an association between idiopathic pulmonary fibrosis and lung cancer, however, more studies are needed. Chemical or irradiation induced fibrosis in both, lung and liver mouse models causes an increase in alpha smooth muscle actin (a marker of fibroblasts), LOX expression and metastatic tumour growth, which is reversed by a LOX antibody (Cancer Res.2013; 73 (6): 1721 - 1732).

[0031] To date, an increase in lysyl oxidase isoenzymes mRNA and/or protein has been observed in breast, CNS cancer cell lines, head and neck squamous cell, esophageal, kidney, lung, prostatic, clear cell renal cell and lung carcinomas, ovarian, uterine, melanoma and osteosarcoma patient samples from The Cancer Genome Atlas (TCGA). Shown in Table 1 is the TCGA patient gene expression data for the LOX family. A plus symbol indicates higher than the average gene expression within this dataset.

Table 1

TCGA patient gene expression data for the LOX family

[0032] Statistically significant clinical correlations between lysyl oxidase isoenzymes expression and tumour progression have been observed in breast, head and neck squamous cell, myelofibrosis, prostatic, pancreatic, ovarian, and clear cell renal cell carcinomas. The role of lysyl oxidase isoenzymes in tumour progression has been most extensively studied in breast cancer using in vitro models of migration/invasion and in in vivo tumourigenesis and metastasis mouse models (Nature. 2006; 440 (7088): 1222 - 1226). Increased lysyl oxidase isoenzymes expression was found in hypoxic patients, and was associated with negative estrogen receptor status (ER-), decreased overall survival in ER- patients and node-negative patients who did not receive adjuvant systemic treatment, as well as shorter bone metastasis-free survival in ER- patients and node negative patients; in vivo models demonstrated that the LOX inhibitors have potential in breast cancer patients with bone metastasis, by modulating bone homeostasis independent of RANKL (Nature. 2015; 522 (7554): 106 - 110). Lysyl oxidase isoenzymes mRNA was demonstrated to be up-regulated in invasive and metastatic cell lines (MDA-MB-231 and Hs578T), as well as in more aggressive breast cancer cell lines and distant metastatic tissues compared with primary cancer tissues (Cancer Res.2002; 62 (15): 4478 - 4483).

[0033] Pathogenic processes in primary myelofibrosis involve a primary megakaryocyte-weighted clonal myeloproliferation and paraneoplastic stromal reaction that includes bone marrow fibrosis, osteosclerosis, angiogenesis, and extramedullary hematopoiesis. The bone marrow reaction includes excess deposition of extracellular matrix proteins such as fibrillary collagen, hypocellularity, activation and recruitment of bone marrow fibroblasts, excessive cytokine and growth factor production, and other changes that result in a reduction in hematopoietic capacity. Secondary myelofibrosis can result from polycythaemia rubra vera or essential thrombocytosis. In myelofibrosis, disease progression correlates with increased numbers of megakaryocytes, which overexpress LOX. In a GATA 1low mouse model of myelofibrosis, disease progression (including increase in megakaryocytes number, fibrosis and spleen size), were significantly attenuated by a pan LOX inhibitor (J Biol Chem.2011; 286(31): 27630 - 27638).

[0034] In most tumor types, the first line of treatment is surgical resection. A wound healing response is initiated by surgery and may correlate with an increase in metastatic spread. Breast cancer models have shown that abdominal surgery increases lung metastasis. Furthermore, it was shown to be caused by systemic LOX. Injection of plasma, collected from abdominal surgery mice (which contained LOX), into tumour bearing mice resulted in an increase in lung metastasis. The surgery induced systemic LOX was blocked by BAPN, reducing metastasis and increasing survival (Cell Rep.2017; 19 (4): 774 - 784).

[0035] In colon, breast cancer and melanoma models, tumor associated endothelial cells have been shown to have an increased expression of LOX, which stimulates angiogenesis and tumour growth (Cancer Res.2015; 73(2): 583 - 594).

[0036] In pancreatic, breast, lung, ovarian and colon cancer patients, high collagen content has been correlated with high LOX gene expression, chemotherapy resistance and significantly decreased survival (Oncogene.2018; 37(36) 4921 - 4940, EMBO Mol Med.2015; 7(8) 1063 - 1076, Oncotarget. 2016; 7(22) 32100 - 32112). LOX inhibitors (both BAPN and a LOX antibody) and standard of care chemotherapies were combined in desmoplastic tumour mouse models to lower the tumour interstitial pressure causing expansion of vessels (Oncotarget. 2016; 7(22) 32100 -32112). The increased vascular flow increases the concentration of the chemotherapeutic agent at the site of the primary tumour, which leads to a lower metastatic load and increased survival (Oncotarget.2016 May 31; 7(22) 32100-32112).

[0037] In head and neck squamous cell carcinomas, increased lysyl oxidase isoenzyme expression was found in association with CA-IX, a marker of hypoxia, and was associated with decreased cancer specific survival, decreased overall survival and lower metastasis-free survival (Oncotarget. 2016; 7(31): 50781 - 50804). In oral squamous cell carcinoma, lysyl oxidase isoenzyme mRNA expression was upregulated compared to normal mucosa.

[0038] Gene expression profiling of gliomas identified over-expressed lysyl oxidase isoenzyme as part of a molecular signature indicative of invasion, and associated with higher-grade tumours that are strongly correlated with poor patient survival (PloS ONE.2015 Mar 19; 10(3) e0119781). Lysyl oxidase isoenzyme protein expression was increased in glioblastoma and astrocytoma tissues, and in invasive U343 and U251 cultured astrocytoma cells.

[0039] In tissues, lysyl oxidase isoenzyme mRNA was upregulated in prostate cancer compared to benign prostatic hypertrophy, correlated with Gleason score, and associated with both high grade and short time to recurrence (Oncol Rep 2008; 20: 1561-1567).

[0040] In clear cell RCC, smoking was associated with allelic imbalances at chromosome 5q23.1, where the LOX gene is localized, and may involve duplication of the gene (Cancer Genet Cytogenet.2005; 163(1)7: 7 - 11).

[0041] SiHa cervical cancer cells demonstrated increased invasion in vitro under hypoxic/anoxic conditions; this was repressed by inhibition of extracellular catalytically active lysyl oxidase activity by treatment with BAPN as well as LOX antisense oligos, LOX antibody, LOX shRNA or an extracellular copper chelator (Oncol Rep.2013; 29 (2), 541 - 548).

[0042] In ovarian cancer genetically engineered mouse models (ApoE knockout) a desmoplastic tumour with increased LOX gene expression is formed. Treatment with BAPN significantly increased survival and decreased lung metastasis (J Exp Clin Cancer Res.2018; 37: 32). Certain tumours from patients with ovarian cancer have a single nucleotide polymorphism of the LOX gene, G473A. Two independent studies have shown that people with the G473A polymorphism expressed have increased chances of developing ovarian cancer (J Int Med Res. 2012; 40(3): 917 - 923; Genet Test Mol Biomarkers.2012; 16 (8): 915 - 919).

[0043] In primary human oral squamous cell carcinoma (OSCC), levels of lysyl oxidase enzyme (in particular LOX and LOXL2) and lysyl hydroxylase expression are significantly increased, and markedly elevated in late-stage, regional lymph node metastasis (RLNM)-positive tumors. Both

reducible, or immature, cross-links (deH-DHLNL and deH-HLNL) and non-reducible, or mature cross-links (DPD and PYD) are significantly elevated in OSCCs compared to normal tissues (J Dent Res 2019; 98(5): 517– 525).

[0044] The findings described herein, provide a strong rationale for combination therapies involving LOX isoenzyme inhibitors and anti-tumor therapy in patients.

[0045] More recently, CCT365623 a reversible pan LOX inhibitor has been utilised in a breast cancer model (MMTV-PyMT) to reduce metastasis and increase survival (Nat Commun.2017; 18 (8): 14909).

[0046] The scientific and patent literature describes small molecule inhibitors of lysyl oxidase isoenzymes and antibodies of LOX and LOXL2 with therapeutic effects in animal models of fibrosis and cancer metastasis. Some known MAO inhibitors also are reported to inhibit lysyl oxidase isoenzyme (e.g., the MAO-B inhibitor Mofegiline illustrated below). This inhibitor is a member of the haloallylamine family of MAO inhibitors; the halogen in Mofegiline is fluorine. Fluoroallylamine inhibitors are described in US Patent No. 4,454,158. There are issued patents claiming fluoroallylamines and chloroallylamines, for example MDL72274 (illustrated below) as inhibitors of lysyl oxidase (US Patents 4,943,593; 4,965,288; 5,021,456; 5,059,714; 5,182,297; 5,252,608). Many of the compounds claimed in these patents are also reported to be potent MAO-B and SSAO/VAP-1 inhibitors.

[0047] Additional fluoroallylamine inhibitors are described US Patent 4,699,928. Other examples structurally related to Mofegiline can be found in WO 2007/120528.

[0048] WO 2009/066152 discloses a family of 3-substituted 3-haloallylamines that are inhibitors of SSAO/VAP-1 useful as treatment for a variety of indications, including inflammatory disease. None of these documents specifically disclose the fluoroallylamine compounds of formula (I) according to the present invention.

[0049] Antibodies to LOX and LOXL2 have been disclosed in US 2009/0053224 with methods to diagnostic and therapeutic applications. Anti-LOX and anti-LOXL2 antibodies can be used to identify and treat conditions such as a fibrotic condition, angiogenesis, or to prevent a transition from an epithelial cell state to a mesenchymal cell state: US 2011/0044907.

[0050] WO 2017/136871 and WO 2017/136870 disclose haloallylamine indole and azaindole derivative inhibitors of lysyl oxidases and uses thereof.

[0051] WO 2018/157190 disclose haloallylamine pyrazole derivative inhibitors of lysyl oxidases and uses thereof.

[0052] WO 2017/141049 and WO 2019/073251 disclose families of methylamine and bridged homopiperazine derivatives respectively as lysyl oxidase inhibitors and their use in the treatment of cancer and diseases associated with fibrosis.

[0053] WO 2003/097612, WO 2006/053555, and US 2008/0293936 disclose another class of lysyl oxidase inhibitors.

[0054] WO 2018/048930, WO 2017/015221, WO 2017/003862, WO 2016/144702 and WO 2016/144703 disclose further LOXL2 inhibitors.

Summary

[0055] The present invention provides substituted fluoroallylamine compounds that inhibit lysyl oxidase (LOX), lysyl oxidase-like2 (LOXL2) and other lysyl oxidase isoenzymes. Surprisingly, modification of 3-substituted-3-fluoroallylamine structures described previously has led to the discovery of novel compounds that are potent inhibitors of the human LOX and LOXL isoenzymes. Furthermore, certain of these novel compounds also selectively inhibit certain LOX and LOXL isoenzymes with respect to the other enzymes in the amine oxidase family.

[0056] A first aspect of the invention provides for a compound of Formula I:

Formula I

or a stereoisomer, pharmaceutically acceptable salt, polymorphic form, solvate, hydrate or tautomeric form thereof; wherein:

A is aryl or heteroaryl;

each R1 is independently selected from the group consisting of X-R2, halogen, deuterium, C1-6alkyl, O-C1-6alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -CN, -C(O)OR3, -C(O)NR4R5, -S(O)2NR4R5, -S(O)2R6, -NR8C(O)R9, and -NR8S(O)2R9; wherein each C1-6alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3 and–O-CF3;

X is selected from the group consisting of O, CH2, OCH2, CH2O, CH2S(O)2, CONH and NHCO;

R2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein each R2 is optionally substituted by one or more R7;

R3 is selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3 and–O-CF3;

R4 and R5 are independently selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, - CH2CF3 and–O-CF3; or

R4 and R5 when attached to the same nitrogen atom are combined to form a 4- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

R6 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3, and -O-CF3;

R7 is selected from the group consisting of halogen, OH, C1-6alkyl, O-C1-6alkyl, C3-7cycloalkyl, -C(O)OR3, -C(O)NR4R5, -NR4C(O)R6, -S(O)2NR4R5, -NR4S(O)2R6 and -S(O)2R6; wherein each C1-6alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and–OH;

R8 is hydrogen or C1-6alkyl;

R9 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3, and -O-CF3; or

R8 and R9 are combined to form a 5- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

and

n is 0, 1, 2, 3, 4, 5 or 6.

[0057] A second aspect of the invention provides for a pharmaceutical composition comprising a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, carrier or diluent.

[0058] A third aspect of the invention provides for a method of inhibiting the amine oxidase activity of any one of LOX, LOXL1, LOXL2, LOXL3 or LOXL4 in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the second aspect of the invention.

[0059] A fourth aspect of the invention provides for a method of treating a condition associated with any one of LOX, LOXL1, LOXL2, LOXL3 or LOXL4 protein, comprising administering to a subject in need thereof a therapeutically effective amount of compound according to the first aspect of the invention, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the second aspect of the invention.

[0060] A fifth aspect of the invention provides for use of a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for treating a condition associated with any one of LOX, LOXL1, LOXL2, LOXL3 or LOXL4 protein.

[0061] A sixth aspect of the invention provides for a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt or solvate thereof, for use in treating a condition associated with any one of LOX, LOXL1, LOXL2, LOXL3 or LOXL4 protein.

[0062] In one embodiment of the methods and uses of the present invention the condition is selected from fibrosis, cancer and angiogenesis.

[0063] Contemplated herein is combination therapy in which the methods further comprise co-administering additional therapeutic agents that are used for the treatment of cancer, fibrosis, angiogenesis, inflammation, hypertension, immunosuppression and metabolic conditions.

Definitions

[0064] The following are some definitions that may be helpful in understanding the description of the present invention. These are intended as general definitions and should in no way limit the scope of the present invention to those terms alone, but are put forth for a better understanding of the following description.

[0065] Unless the context requires otherwise or specifically states to the contrary, integers, steps, or elements of the invention recited herein as singular integers, steps or elements clearly encompass both singular and plural forms of the recited integers, steps or elements.

[0066] Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated step or element or integer or group of steps or elements or integers, but not the exclusion of any other step or element or integer or group of elements or integers. Thus, in the context of this specification, the term“comprising” means“including principally, but not necessarily solely”.

[0067] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features.

[0068] As used herein, the term "alkyl" includes within its meaning monovalent (“alkyl”) and divalent (“alkylene”) straight chain or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, e.g., 1, 2, 3, 4, 5 or 6 carbon atoms. The straight chain or branched alkyl group is attached at any available point to produce a stable compound. For example, the term alkyl includes, but is not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, tert-butyl, amyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, pentyl, isopentyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, and the like.

[0069] The term "alkoxy" or“alkyloxy” as used herein refers to straight chain or branched alkyloxy (i.e, O-alkyl) groups, wherein alkyl is as defined above. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy.

[0070] The term“cycloalkyl” as used herein includes within its meaning monovalent (“cycloalkyl”) and divalent (“cycloalkylene”) saturated, monocyclic, bicyclic, polycyclic or fused analogs. In the context of the present disclosure the cycloalkyl group may have from 3 to 10 carbon atoms. A fused analog of a cycloalkyl means a monocyclic ring fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl and fused analogs thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, adamantyl and the like.

[0071] The term“aryl” or variants such as“arylene” as used herein refers to monovalent (“aryl”) and divalent (“arylene”) single, polynuclear, conjugated and fused analogs of aromatic hydrocarbons having from 6 to 10 carbon atoms. A fused analog of aryl means an aryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion. Examples of aryl and fused analogs thereof include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, tetrahydrobenzopyranyl, 1,4-benzodioxanyl, and the like. A "substituted aryl” is an aryl that is independently substituted, with one or more, preferably 1, 2 or 3 substituents, attached at any available atom to produce a stable compound.

[0072] The term“alkylaryl” as used herein, includes within its meaning monovalent (“aryl”) and divalent (“arylene”), single, polynuclear, conjugated and fused aromatic hydrocarbon radicals attached to divalent, saturated, straight or branched chain alkylene radicals. Examples of alkylaryl groups include benzyl.

[0073] The term“heteroaryl” and variants such as“heteroaromatic group” or“heteroarylene” as used herein, includes within its meaning monovalent (“heteroaryl”) and divalent (“heteroarylene”), single, polynuclear, conjugated and fused heteroaromatic radicals having from 5 to 10 atoms, wherein 1 to 4 ring atoms, or 1 to 2 ring atoms are heteroatoms independently selected from O, N, NH and S. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable compound is produced. The heteroaromatic group may be C1-9 heteroaromatic. A fused analog of heteroaryl means a heteroaryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion. Examples of heteroaryl groups and fused analogs thereof include pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, triazinyl, thienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, indolyl, isoquinolyl,

imidazopyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyridonyl, phenanthrolinyl, quinolyl, isoquinolinyl, imidazolinyl, thiazolinyl, pyrrolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, and the like.“Nitrogen containing heteroaryl” refers to heteroaryl wherein any heteroatoms are N. A "substituted heteroaryl” is a heteroaryl that is independently substituted, with one or more, preferably 1, 2 or 3 substituents, attached at any available atom to produce a stable compound.

[0074] The term“heterocyclyl” and variants such as“heterocycloalkyl” as used herein, includes within its meaning monovalent (“heterocyclyl”) and divalent (“heterocyclylene”), saturated or partially saturated (non-aromatic), monocyclic, bicyclic, polycyclic or fused hydrocarbon radicals having from 3 to 10 ring atoms, wherein from 1 to 4, or from 1 to 2, ring atoms are heteroatoms independently selected from O, N, NH, or S, SO or SO2, in which the point of attachment may be carbon or nitrogen. A fused analog of heterocyclyl means a monocyclic heterocycle fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. The heterocyclyl group may be C3-8 heterocyclyl. The heterocycloalkyl group may be C3-6 heterocyclyl. The heterocyclyl group may be C3-5 heterocyclyl. Examples of heterocyclyl groups and fused analogs thereof include pyrrolidinyl, thiazolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, quinuclidinyl, azetidinyl, morpholinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, and the like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N-substituted uracils.

[0075] The term“halogen” or variants such as“halide” or“halo” as used herein refers to fluorine, chlorine, bromine and iodine.

[0076] The term“heteroatom” or variants such as“hetero-” or“heterogroup” as used herein refers to O, N, NH and S.

[0077] In general,“substituted” refers to an organic group as defined herein (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Thus, a substituted group will be substituted with one or more substituents, unless otherwise specified. In some embodiments, a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents.

[0078] The term“optionally substituted” as used herein means the group to which this term refers may be unsubstituted, or may be substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, halo, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, thioalkoxy, alkenyloxy, haloalkoxy, NO2, NH(alkyl), N(alkyl)2, alkylamino, dialkylamino, acyl, alkenoyl, alkynoyl, acylamino, diacylamino, acyloxy, alkylsulfonyl, alkylsulfonyloxy, sulfonamido, heterocycloxy, heterocycloamino, haloheterocycloalkyl, alkylsulfenyl, alkylcarbonyloxy, phosphorus-containing groups such as phosphono and phosphinyl, aryl, heteroaryl, alkylaryl, aralkyl, alkylheteroaryl, cyano, CO2H, CO2alkyl, C(O)NH2, -C(O)NH(alkyl), and -C(O)N(alkyl)2. Preferred substituents include halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, hydroxy(C1-6)alkyl, C3-C6cycloalkyl, C(O)OH, NHC(O)C1-C4alkyl, C(O)C1-C4alkyl, NH2, NHC1-C4alkyl, N(C1-C4alkyl)2, SO2(C1-C4alkyl), OH and CN. Particularly preferred substituents include C1-4alkyl, C1-4alkoxy, SO2(C1-C4alkyl), halogen, OH, hydroxy(C1-3)alkyl (e.g. C(CH3)2OH), and C1-3haloalkyl (e.g. CF3, CH2CF3).

[0079] The present invention includes within its scope all stereoisomeric and isomeric forms of the compounds disclosed herein, including all diastereomeric isomers, racemates, enantiomers and mixtures thereof. It is also understood that the compounds described by Formula I may be present as E and Z isomers, also known as cis and trans isomers. Thus, the present disclosure should be understood to include, for example, E, Z, cis, trans, (R), (S), (L), (D), (+), and/or (-) forms of the compounds, as appropriate in each case. Where a structure has no specific stereoisomerism indicated, it should be understood that any and all possible isomers are encompassed. Compounds of the present invention embrace all conformational isomers. Compounds of the present invention may also exist in one or more tautomeric forms, including both single tautomers and mixtures of tautomers. Also included in the scope of the present invention are all polymorphs and crystal forms of the compounds disclosed herein.

[0080] The present invention includes within its scope isotopes of different atoms. Any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Thus, the present disclosure should be understood to include deuterium and tritium isotopes of hydrogen.

[0081] All references cited in this application are specifically incorporated by cross-reference in their entirety. Reference to any such documents should not be construed as an admission that the document forms part of the common general knowledge or is prior art.

[0082] In the context of this specification the term“administering” and variations of that term including“administer” and“administration”, includes contacting, applying, delivering or providing a compound or composition of the invention to an organism, or a surface by any appropriate means. In the context of this specification, the term“treatment”, refers to any and all uses which remedy a disease state or symptoms, prevent the establishment of disease, or otherwise prevent, hinder, retard, or reverse the progression of disease or other undesirable symptoms in any way whatsoever.

[0083] In the context of this specification the term“topical administration” or variations on that term including“topical application” includes within its meaning applying, contacting, delivering or providing a compound or composition of the invention to the skin, or localized regions of the body.

[0084] In the context of this specification the term“local administration” or variations on that term including“local application” includes within its meaning applying, contacting, delivering or providing a compound or composition of the invention to the skin, or localized regions of the body.

[0085] In the context of this specification the term“effective amount” includes within its meaning a sufficient but non-toxic amount of a compound or composition of the invention to provide a desired effect. Thus, the term“therapeutically effective amount” includes within its meaning a sufficient but non-toxic amount of a compound or composition of the invention to provide the desired therapeutic effect. The exact amount required will vary from subject to subject depending on factors such as the species being treated, the sex, age and general condition of the subject, the severity of the condition being treated, the particular agent being administered, the mode of administration, and so forth. Thus, it is not possible to specify an exact“effective amount”. However, for any given case, an appropriate“effective amount” may be determined by one of ordinary skill in the art using only routine experimentation.

Brief Description of the Figures

[0086] Figure 1(a) and 1(b) depict survival curves comparing high and low gene expression in pancreatic adenocarcinoma patients based on the TCGA dataset. A. LOX gene expression. B. LOXL2 gene expression.

[0087] Figures 2(a-c) depicts dose-dependent block of lysyl oxidase enzymatic activity by Compound 1 and 33. Measurement of lysyl oxidase activity compared to untreated control in rat tissues (a) ear (24 hours after single oral dose at 10 and 30 mg/kg, Compound 1); (b) ear (4, 24, 48 and 120 hours after single oral dose of 30 mg/kg, Compound 33) and; (c) aorta (single oral dose at 5, 10 or 30 mg/kg, Compound 33)

[0088] Figure 3(a) Shows reduction in collagen in mouse scar tissue after injury when treated with topical Compound 1.

[0089] Figure 3(b) Histology shows thick parallel collagen bundles in control scar tissue.

[0090] Figure 3(c) Tissue treated with Compound 1 shows decreased density of bundles and more‘normal’ structure of collagen.

[0091] Figure 4(a-b) shows reduction in LOX activity and total collagen after daily topical treatment for 4 weeks with 3% Compound 1 solution versus control.

[0092] Figure 4(c-f) Gross morphology shows similar wounds at time of injury (c, control; d, treated) and at time of euthanasia treated wounds appear more healed (e, control, f treated).

[0093] Figure 4(g-h) Histology shows thick collagen bands in untreated scar tissue (highlighted by arrows, g). This appears to be reduced in treated tissue (h).

[0094] Figure 5(a-e) Tumour growth data from orthotopic human pancreatic cancer xenograft model: Efficacy data. A. Diagram of the growth and treatment strategy. B. In vivo monitoring of tumour growth by bioluminescent imaging. C. Ex vivo bioluminescent signal of the total tumour burden. D. Ex vivo bioluminescent signal of the primary tumour. E. Ex vivo bioluminescent signal of the metastatic burden.

[0095] Figure 6(a-c) Histological analysis of Sclerosis mouse skin model with topical treatment with Compound 1. A. Composite skin score. B. Average Collagen score. C. Average LOX score.

[0096] Figure 7(a-e) Analysis of the spleen from primary Myelofibrosis model (GATA-1low) treated with Compound 19. A. Gomori silver stain of spleen. B. Spleen weight. C. Quantification Spleen reticulin fibrosis. D. H&E stain image of spleen. E. Quantification of the Megakaryocytes in the spleen.

[0097] Figure 8(a-d) Analysis of the bone marrow from primary Myelofibrosis model (GATA-1low) treated with Compound 19. A. Gomori silver stain of bone marrow. B. Quantification bone marrow reticulin fibrosis. C. H&E stain image of bone marrow. D. Quantification of the Megakaryocytes in the bone marrow.

[0098] Figure 9 depicts changes in the area of fibrosis in a mouse UUO model.

[0099] Figure 10 depicts the ability of Compound 33 to reduce bleomycin-induced lung fibrosis (Ashcroft score) and weight gain.

[0100] Figure 11(a-d) depicts the ability of Compound 33 to reduce fibrosis associated metastasis in a CCl4 induced mouse liver fibrosis model with orthotopically injected breast cancer cell line (4t). (a) Schematic of the study design; (b) clinical measure of liver fibrosis; (c) concentration of cross-links in the liver; (d) measurement of liver metastasis.

Detailed Description

[0101] The present invention relates to substituted fluoroallylamine derivatives which may inhibit lysyl oxidase (LOX), lysyl oxidase-like2 (LOXL2) and other lysyl oxidase isoenzymes. In particular the present invention relates to substituted fluoroallylamine derivatives with a sulfone linker.

[0102] In particular the present invention relates to compounds of Formula I:

Formula I

or a stereoisomer, pharmaceutically acceptable salt, polymorphic form, solvate, hydrate or tautomeric form thereof; wherein:

A is aryl or heteroaryl;

each R1 is independently selected from the group consisting of X-R2, halogen, deuterium, C1-6alkyl, O-C1-6alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -CN, -C(O)OR3, -C(O)NR4R5, -S(O)2NR4R5, -S(O)2R6, -NR8C(O)R9, and -NR8S(O)2R9; wherein each C1-6alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3 and–O-CF3;

X is selected from the group consisting of O, CH2, OCH2, CH2O, CH2S(O)2, CONH and NHCO;

R2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein each R2 is optionally substituted by one or more R7;

R3 is selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3 and–O-CF3;

R4 and R5 are independently selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, - CH2CF3 and–O-CF3; or

R4 and R5 when attached to the same nitrogen atom are combined to form a 4- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

R6 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3, and -O-CF3;

R7 is selected from the group consisting of halogen, -OH, C1-6alkyl, O-C1-6alkyl, C3-7cycloalkyl, -C(O)OR3, -C(O)NR4R5, -NR4C(O)R6, -S(O)2NR4R5, -NR4S(O)2R6 and -S(O)2R6; wherein each C1-6alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and–OH;

R8 is hydrogen or C1-6alkyl;

R9 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3, and -O-CF3; or

R8 and R9 are combined to form a 5- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

and

n is 0, 1, 2, 3, 4, 5 or 6.

[0103] In one embodiment of compounds of the present invention, A is selected from aryl and heteroaryl. In another embodiment of compounds of the present invention, A is selected from the group consisting of phenyl, naphthyl, pyridinyl, quinolinyl, benzothiazolyl and indolyl. In a further embodiment of compounds of the present invention, A is selected from the group consisting of

. In a still further embodiment of compounds of the present invention, A is selected from the group consisting of

In a further embodiment, A is selected from the group

consisting of In a still further embodiment, A is

. In another embodiment, A is phenyl. In a further embodiment, A is heteroaryl.

[0104] In one embodiment of compounds of the present invention, R1 is independently selected from the group consisting of X-R2, halogen, deuterium, C1-6alkyl, O-C1-6alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -CN, -C(O)OR3, -C(O)NR4R5, -S(O)2NR4R5, -S(O)2R6, -NR8C(O)R9, and -NR8S(O)2R9; wherein each C1-6alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, - CH2CF3 and–O-CF3. In another embodiment of compounds of the present invention, each R1 is independently selected from the group consisting of -X-R2, C1-6alkyl, C1-6haloalkyl, -C(O)OR3, -C(O)NR4R5, -S(O)2NR4R5, -S(O)2R6. In a further embodiment of compounds of the present invention, each R1 is independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, and -S(O)2R6. In one embodiment of

compounds of the present invention, at least one of R1 is X-R2. In another embodiment of compounds of the present invention, one of R1 is X-R2.

[0105] In one embodiment of compounds of present invention, X is selected from the group consisting of O, CH2, OCH2, CH2O, CH2S(O)2, CONH and NHCO. In another embodiment of compounds of the present invention, X is selected from the group consisting of O, CH2, OCH2, CONH and NHCO. In another embodiment of compounds of the present invention, X is selected from the group consisting of O, OCH2 and CONH. In a further embodiment of compounds of the present invention, X is selected from the group consisting of O, CH2 and OCH2. In another embodiment of compounds of the present invention, X is selected from the group consisting of CONH and NHCO. In a further embodiment of compounds of the present invention, X is O. In another embodiment of compounds of the present invention, X is OCH2. In a further embodiment of compounds of the present invention, X is CONH.

[0106] In one embodiment of compounds of the present invention, R2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl where each R2 is optionally substituted by one or more R7. In another embodiment of compounds of the present invention, R2 is selected from the group consisting of aryl and cycloalkyl where each R2 is optionally substituted by one or more R7. In a further embodiment of compounds of the present invention, R2 is cycloalkyl where each R2 is optionally substituted by one or more R7. In another embodiment of compounds of the present invention, R2 is aryl optionally substituted by one or more R7. In another embodiment of compounds of the present invention, R2 is phenyl substituted by one R7. In another embodiment of compounds of the present invention, R2 is adamantyl or phenyl where each R2 is optionally substituted by one or more R7. In another embodiment, R2 is adamantyl or phenyl optionally substituted by–S(O)2NR4R5. In a further embodiment R2 is adamantyl. In another embodiment, R2 is phenyl optionally substituted by–S(O)2NR4R5.

[0107] In one embodiment of compounds of the present invention, R2 is substituted by one R7. In another embodiment of compounds of the present invention, R2 is substituted by two R7. In a further embodiment of compounds of the present invention, R2 is substituted by three R7. In another embodiment of compounds of the present invention, R2 is substituted by four or five R7.

[0108] In one embodiment of compounds of the present invention, R3 is selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, - CH2CF3 and–O-CF3. In another embodiment of compounds of the present invention, R3 is hydrogen. In a further embodiment of compounds of the present invention, R3 is C1-6alkyl or C3-7cycloalkyl. In a still further embodiment of compounds of the present invention, R3 is hydrogen or C1-6alkyl. In another embodiment of compounds of the present invention, R3 is C1-6alkyl. In a further embodiment of compounds of the present invention, R3 is methyl or ethyl. In another embodiment of compounds of the present invention, R3 is selected from the group consisting of hydrogen, methyl and ethyl.

[0109] In one embodiment of compounds of the present invention, R4 and R5 are independently selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, - CH2CF3 and–O-CF3. In another embodiment of compounds of the present invention, R4 and R5 are independently selected from the group consisting of hydrogen and C1-6alkyl. In another embodiment of compounds of the present invention, R4 and R5 are hydrogen. In a further embodiment of compounds of the present invention, R4 and R5 are C1-6alkyl. In another embodiment of compounds of the present invention, R4 and R5 are both methyl. In a further embodiment of compounds of the present invention, R4 and R5 are both isopropyl. In one embodiment of compounds of the present invention, R4 is hydrogen and R5 is isopropyl. In a further embodiment of compounds of the present invention, R4 and R5 are independently selected from the group consisting of hydrogen and C3-7cycloalkyl. In another embodiment of compounds of the present invention, R4 is hydrogen and R5 is C1-6alkyl. In one embodiment of compounds of the present invention, R4 is hydrogen and R5 is methyl. In a further embodiment of compounds of the present invention, R4 is hydrogen and R5 is C3-7cycloalkyl.

[0110] In one embodiment of compounds of the present invention, R4 and R5 when attached to the same nitrogen atom are combined to form a 4- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members. In a further embodiment, R4 and R5 when attached to the same nitrogen atom are combined to form a 4- to 7-membered ring having 1 additional heteroatom as ring members. In another embodiment, R4 and R5 when attached to the same nitrogen atom are combined to form a 4- to 7-membered ring having 0 additional heteroatoms as ring members.

[0111] In one embodiment of compounds of the present invention, R6 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3, and -O-CF3. In another embodiment, R6 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl. In another embodiment, R6 is C1-6alkyl. In a further embodiment, R6 is C3-7cycloalkyl.

[0112] In one embodiment of compounds of the present invention, R7 is selected from the group consisting of halogen, -OH, C1-6alkyl, O-C1-6alkyl, C3-7cycloalkyl, -C(O)OR3, -C(O)NR4R5, -NR4C(O)R6, -S(O)2NR4R5, -NR4S(O)2R6 and -S(O)2R6; wherein each C1-6alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and–OH. In another embodiment of compounds of the present invention, R7 is selected from the group consisting of halogen, C1-6alkyl, -C(O)NR4R5, -S(O)2NR4R5 and -S(O)2R6. In a further embodiment of compounds of the present invention, R7 is selected from the group consisting of -C(O)NR4R5, -S(O)2NR4R5 and -S(O)2R6. In another embodiment of compounds of the present invention, R7 is -S(O)2NR4R5. In a further embodiment of compounds of the present invention, R7 is -S(O)2N(CH3)2.

[0113] In one embodiment of compounds of the present invention, R8 hydrogen or C1-6alkyl. In another embodiment of compounds of the present invention, R8 is hydrogen. In a further embodiment of compounds of the present invention, R8 is selected from the group consisting of hydrogen, methyl and ethyl. In another embodiment of compounds of the present invention, R8 is hydrogen or methyl.

[0114] In one embodiment of compounds of the present invention, R9 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3, and -O-CF3. In another embodiment, R9 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl. In another embodiment, R9 is C1-6alkyl. In a further embodiment, R9 is C3-7cycloalkyl.

[0115] In one embodiment of compounds of the present invention, R8 and R9 are combined to form a 5- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members. In a further embodiment, R8 and R9 are combined to form a 5- to 7-membered ring having 1 additional heteroatom as ring members. In another embodiment, R8 and R9 are combined to form a 5- to 7-membered ring having 0 additional heteroatoms as ring members.

[0116] In one of embodiment of compounds of the present invention, n is 0, 1, 2, 3, 4 or 5. In another embodiment of compounds of the present invention, n is 0. In a further embodiment of compounds of the present invention, n is 0, 1 or 2. In another embodiment of compounds of the present invention, n is 1, 2 or 3. In another embodiment of compounds of the present invention n is 1 or 2. In a further embodiment of compounds of the present invention, n is 1. In another embodiment of compounds of the present invention, n is 2. In a further embodiment of compounds of the present invention, n is 3. In another embodiment of compounds of the present invention, n is 4. In a further embodiment of compounds of the present invention, n is 5. In another embodiment of compounds of the present invention, n is 6.

[0117] In one embodiment, the present invention also relates to compounds of Formula Ia:

Formula Ia

or a stereoisomer, pharmaceutically acceptable salt, polymorphic form, solvate, hydrate or tautomeric form thereof; wherein:

each R1 is independently selected from the group consisting of X-R2, halogen, C1-6alkyl, O-C1-6alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -CN, -C(O)OR3, -C(O)NR4R5, -S(O)2NR4R5, -S(O)2R6, -NR8C(O)R9, and -NR8S(O)2R9; wherein each C1-6alkyl, aryl, heteroaryl and cycloalkyl, heterocycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3 and–O-CF3;

X is selected from the group consisting of O, CH2, OCH2, CH2O, CH2S(O)2, CONH and NHCO;

R2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein each R2 is optionally substituted by one or more R7;

R3 is selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl;

R4 and R5 are independently selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; or

R4 and R5 when attached to the same nitrogen atom are combined to form a 4- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

R6 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl;

R7 is selected from the group consisting of halogen, -OH, C1-6alkyl, O-C1-6alkyl, C3-7cycloalkyl, -C(O)OR3, -C(O)NR4R5, -NR4C(O)R6, -S(O)2NR4R5, -NR4S(O)2R6 and -S(O)2R6; wherein each C1-6alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and–OH;

R8 is hydrogen or C1-6alkyl;

R9 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3, and -O-CF3; or

R8 and R9 are combined to form a 5- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

and

n is 0, 1, 2 or 3.

[0118] In one embodiment, the present invention also relates to compounds of Formula Ib:

Formula Ib

or a pharmaceutically acceptable salt or solvate thereof; wherein:

each R1 is independently selected from the group consisting of halogen, C1-6alkyl, O-C1-6alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -CN, -C(O)OR3, -C(O)NR4R5, -S(O)2NR4R5, -S(O)2R6, -NR8C(O)R9, and -NR8S(O)2R9; wherein each C1-6alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3 and–O-CF3;

X is selected from the group consisting of O, CH2, OCH2, CH2O, CH2S(O)2, CONH and NHCO;

R2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein each R2 is optionally substituted by one or more R7;

R3 is selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl;

R4 and R5 are independently selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; or

R4 and R5 when attached to the same nitrogen atom are combined to form a 4- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

R6 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl

R7 is selected from the group consisting of halogen, -OH, C1-6alkyl, O-C1-6alkyl, C3-7cycloalkyl, -C(O)OR3, -C(O)NR4R5, -NR4C(O)R6, -S(O)2NR4R5, -NR4S(O)2R6 and -S(O)2R6; wherein each C1-6alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and–OH;

R8 is hydrogen or C1-6alkyl;

R9 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3, and -O-CF3; or

R8 and R9 are combined to form a 5- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

and

n is 0, 1 or 2.

[0119] In one embodiment of compounds of Formula Ib of the invention, X is selected from the group consisting of O, OCH2 and CONH; R2 is selected from the group consisting of adamantyl and phenyl; wherein each R2 is optionally substituted by one or more R7; R4 and R5 are independently selected from the group consisting of hydrogen and C1-6alkyl; R7 is -S(O)2NR4R5; and n is 0.

[0120] In another embodiment, the present invention also relates to compounds of Formula Ic:

Formula Ic

or a pharmaceutically acceptable salt or solvate thereof; wherein:

each R1 is independently selected from the group consisting of halogen, C1-6alkyl, -O-C1-6alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -CN, -C(O)OR3, -C(O)NR4R5, -S(O)2NR4R5, -S(O)2R6, -NR8C(O)R9, and -NR8S(O)2R9; wherein each C1-6alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3 and–O-CF3;

X is selected from the group consisting of O, CH2, OCH2, CH2O, CH2S(O)2, CONH and NHCO;

R2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein each R2 is optionally substituted by one or more R7;

R3 is selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl;

R4 and R5 are independently selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; or

R4 and R5 when attached to the same nitrogen atom are combined to form a 4- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

R6 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl;

R7 is selected from the group consisting of halogen, -OH, C1-6alkyl, O-C1-6alkyl, C3-7cycloalkyl, -C(O)OR3, -C(O)NR4R5, -NR4C(O)R6, -S(O)2NR4R5, -NR4S(O)2R6 and -S(O)2R6; wherein each C1-6alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and–OH;

R8 is hydrogen or C1-6alkyl;

R9 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3, and -O-CF3; or

R8 and R9 are combined to form a 5- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

and

n is 0, 1 or 2.

[0121] In one embodiment of compounds of Formula Ic of the invention, X is selected from the group consisting of OCH2 and CONH; R2 is selected from the group consisting of adamantyl and phenyl; wherein each R2 is optionally substituted by one or more R7; R4 and R5 are independently selected from the group consisting of hydrogen and C1-6alkyl; R7 is -S(O)2NR4R5; and n is 0.

[0122] In another embodiment, the present invention also relates to compounds of Formula Id:

Formula Id

or a pharmaceutically acceptable salt or solvate thereof; wherein:

each R1 is independently selected from the group consisting of halogen, C1-6alkyl, O-C1-6alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -CN, -C(O)OR3, -C(O)NR4R5, -S(O)2NR4R5, -S(O)2R6, -NR8C(O)R9, and -NR8S(O)2R9; wherein each C1-6alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3 and–O-CF3;

X is selected from the group consisting of O, CH2, OCH2, CONH and NHCO;

R2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein each R2 is optionally substituted by one or more R7;

R3 is selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl;

R4 and R5 are independently selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; or

R4 and R5 when attached to the same nitrogen atom are combined to form a 4- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

R6 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl;

R7 is selected from the group consisting of halogen, -OH, C1-6alkyl, O-C1-6alkyl, C 5

3-7cycloalkyl, -C(O)OR3, -C(O)NR4R , -NR4C(O)R6, -S(O)2NR4R5, -NR4S(O)2R6 and -S(O)2R6;

wherein each C1-6alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and–OH;

R8 is hydrogen or C1-6alkyl;

R9 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3, and -O-CF3; or

R8 and R9 are combined to form a 5- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

and

n is 0, 1 or 2.

[0123] In one embodiment of compounds of Formula Id of the invention, X is selected from the group consisting of OCH2 and CONH; R2 is selected from the group consisting of adamantyl and phenyl; wherein each R2 is optionally substituted by one or more R7; R4 and R5 are independently selected from the group consisting of hydrogen and C1-6alkyl; R7 is -S(O)2NR4R5; and n is 0.

[0124] In another embodiment, the present invention also relates to compounds of Formula Ie:

Formula Ie

or a pharmaceutically acceptable salt or solvate thereof; wherein:

each R1 is independently selected from the group consisting of halogen, C1-6alkyl, O-C1-6alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -CN, -C(O)OR3, -C(O)NR4R5, -S(O)2NR4R5, -S(O)2R6, -NR8C(O)R9, and -NR8S(O)2R9; wherein each C1-6alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3 and–O-CF3;

R3 is selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl;

R4 and R5 are independently selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; or

R4 and R5 when attached to the same nitrogen atom are combined to form a 4- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

R6 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl;

R8 is hydrogen or C1-6alkyl;

R9 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3, and -O-CF3; or

R8 and R9 are combined to form a 5- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

and

n is 0, 1 or 2.

[0125] In another embodiment, the present invention also relates to compounds of Formula If:

Formula If

or a pharmaceutically acceptable salt or solvate thereof; wherein:

each R1 is independently selected from the group consisting of halogen, C1-6alkyl, O-C1-6alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -CN, -C(O)OR3, -C(O)NR4R5, -S(O)2NR4R5, -S(O)2R6, -NR8C(O)R9, and -NR8S(O)2R9; wherein each C1-6alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3 and–O-CF3;

R3 is selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl;

R4 and R5 are independently selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; or

R4 and R5 when attached to the same nitrogen atom are combined to form a 4- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

R6 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl;

R8 is hydrogen or C1-6alkyl;

R9 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3, and -O-CF3; or

R8 and R9 are combined to form a 5- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

and

n is 0, 1 or 2.

[0126] In another embodiment, the present invention also relates to compounds of Formula Ig:

Formula Ig

or a pharmaceutically acceptable salt or solvate thereof; wherein:

each R1 is independently selected from the group consisting of halogen, C1-6alkyl, O-C1-6alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -CN, -C(O)OR3, -C(O)NR4R5, -S(O)2NR4R5, -S(O)2R6, -NR8C(O)R9, and -NR8S(O)2R9; wherein each C1-6alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3 and–O-CF3;

R3 is selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl;

R4 and R5 are independently selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; or

R4 and R5 when attached to the same nitrogen atom are combined to form a 4- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

R6 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl;

R8 is hydrogen or C1-6alkyl;

R9 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3, and -O-CF3; or

R8 and R9 are combined to form a 5- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

and

n is 0, 1 or 2:

[0127] In another embodiment of compounds of Formula Ie, If and Ig of the invention, each R1 is a C1-6alkyl and n is 0 or 1.

[0128] In another embodiment of compounds of Formula I of the invention, each R1 is independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkyloxy, C1-6haloalkoxy, -CN, -C(O)OR3, -C(O)NR4R5, -NR4C(O)R6, -S(O)2NR4R5, -NR4S(O)2R6 and -S(O)2R6; R3 is selected from the group consisting of hydrogen, optionally substituted C1-6alkyl and optionally substituted C3-7cycloalkyl; R4 and R5 are independently selected from the group consisting of hydrogen, optionally substituted C1-6alkyl and optionally substituted C3-7cycloalkyl; or R4 and R5 when attached to the same nitrogen atom are combined to form a 4- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members; R6 is selected from the group consisting of optionally substituted C1-6alkyl, optionally substituted C3-7cycloalkyl and optionally substituted C1-6haloalkyl; and n is 0, 1, 2 or 3.

[0129] In another embodiment of compounds of Formula I of the invention, each R1 is independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, and -S(O)2R6; R6 is C1-6alkyl; and n is 0, 1 or 2.

[0130] In another embodiment of compounds of Formula I of the invention, each R1 is independently selected from the group consisting of chlorine, fluorine, methyl, isopropyl, OCH3, phenyl and SO2CH3; and n is 1 or 2.

[0131] In a further embodiment of compounds of Formula I of the invention,
n is 0.

[0132] In the context of the present disclosure, any one or more aspect(s) or embodiment(s) may be combined with any other aspect(s) or embodiment(s).

[0133] Exemplary compounds according to the present invention include the compounds set forth in Table 2:

Table 2

[0134] In one embodiment, the compound of the present invention is selected from the group

consisting
pharmaceutically acceptable salt or solvate thereof. In another embodiment, the compound of the present invention

a pharmaceutically acceptable salt or solvate thereof. In a further

embodiment, the compound of the present invention is
pharmaceutically acceptable salt or solvate thereof.

[0135] In one embodiment, the compound of the present invention is selected from the group

consisting
, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, the compound of the present invention

pharmaceutically acceptable salt or solvate thereof. In a further

embodiment, the compound of the present invention
or a pharmaceutically acceptable salt or solvate thereof.

Preparation of Compounds of Formula I

[0136] Compounds of Formula I can be readily prepared by those skilled in the art using methods and materials known in the art and with reference to standard textbooks, such as“Advanced Organic Chemistry” by Jerry March (third edition, 1985, John Wiley and Sons) or“Comprehensive Organic Transformations” by Richard C. Larock (1989, VCH Publishers).

[0137] Compounds of Formula I may be synthesised as described below. The following schemes provide an overview of representative non-limiting embodiments of the invention. Those skilled in the art will recognize that analogues of Formula I, including different isomeric forms, may also be prepared from the analogous starting materials.

Scheme 1:

[0138] The preparation of compounds described by Formula Ib wherein X is–OCH2- is described in Scheme 1 below. A person skilled in the art will recognise that compounds described by Formulae Ic, Id, Ie, If and Ig can be prepared by employing analogous synthetic methodologies with suitable starting materials.

Scheme 1

[0139] P1 is a functional group used to protect a nitrogen functionality. Examples of P1 are carbamate forming groups such as the tert-butyloxycarbonyl (BOC), the 9-fluorenylmethyloxy-carbonyl (FMOC), and the benzyloxycarbonyl (CBZ) groups.

[0140] In general Scheme 1 the R1-substituted hydroxythiophenol starting material described by Formula II can be obtained from commercial sources or can be prepared by many methods well known in the art. Whilst there are many ways to achieve the reaction described by Method A, one convenient protocol involves reaction of compounds described by Formulae II and III with a base such as potassium carbonate in a solvent such as N,N-dimethylformamide at ambient temperature for several hours. Following standard extraction and purification methods the product described by Formula IV can be obtained in good yield and purity.

[0141] Whilst there are many ways to achieve the reaction described by Method B, one convenient protocol involves reaction of compounds described by Formulae IV and V (in which Y is an appropriate leaving group, such as Br, I, OTs and OMs) with a base such as potassium carbonate in a solvent such as N,N-dimethylformamide at ambient temperature for several hours. The product described by Formula VI can be recovered by standard work up procedures.

[0142] One convenient protocol for the conversion of compounds described by Formula VI to those described by Formula VII is Method C which involves treatment of a solution of a compound described by Formula VI and a base such as sodium hydrogen carbonate in a solvent such as dichloromethane with an oxidising agent such as mCPBA (3-chloroperoxybenzoic acid) at temperatures between 0 °C and ambient for several hours. The product described by Formula VII can be recovered by standard work-up procedures.

[0143] There are many, well established, chemical procedures for the deprotection of the compounds described by Formula VII to the compounds described by Formula Ib (Method D). For example if P1 is a BOC protecting group, compounds described by Formula VII can be treated with an acidic substance such as dry hydrogen chloride in a solvent such as diethyl ether to furnish the compounds described by Formula Ib as the hydrochloride salts. In general, the free amino compounds are converted to acid addition salts for ease of handling and for improved chemical stability. Examples of acid addition salts include but are not limited to hydrochloride, hydrobromide, 2,2,2-trifluoroacetate and methanesulfonate salts.

Scheme 2:

[0144] The preparation of compounds described by Formula Ib wherein X is -CONH- is described in Scheme 2 below. A person skilled in the art will recognise that compounds described by Formulae Ic, Id, Ie, If and Ig can be prepared by employing analogous synthetic methodologies with suitable starting materials.

Scheme 2

[0145] In general Scheme 2 the R1-substituted mercaptobenzoic acid starting material can be obtained from commercial sources or can be prepared by many methods well known in the art.

[0146] Compounds described by Formula XI can be prepared by the reaction of an appropriately substituted benzoic acid fragment (described by Formula IX) with an amine fragment (Formula X) in the presence of a suitable coupling reagent (such as HATU) and a base (such as triethylamine) in as solvent such as N,N-dimethylformamide at ambient temperature for several hours (Method E). The product described by Formula XI can be recovered by standard work-up procedures.

Scheme 3:

[0147] The preparation of compounds described by Formula Ib wherein X is–O- is described in Scheme 3 below. A person skilled in the art will recognise that compounds described by Formulae Ic, Id, Ie, If and Ig can be prepared by employing analogous synthetic methodologies with suitable starting materials.

Scheme 3

[0148] In general Scheme 3 the R1-substituted hydroxythiophenol starting material can be obtained from commercial sources or can be prepared by many methods well known in the art.

[0149] A modification of the copper-catalysed Ullmann reaction can be employed to couple the compounds described by Formulae IV and XIII (Method F). There are numerous variants of this type of reaction described in the literature, with one example being the Chan-Evans-Lam modification. Compounds described by Formulae IV and XIII, in the presence of pyridine, can be dissolved in a solvent such as dichloromethane and then treated with copper (II) acetate at ambient temperature for several hours. Following standard extraction and purification methods, the coupled product described by Formula XIV can be obtained in good yield and purity.

Scheme 4:

[0150] The preparation of compounds described by Formula Ia is described in Scheme 4 below.

Scheme 4

[0151] In general Scheme 4 the R1-substituted thiol starting material can be obtained from commercial sources or can be prepared by many methods well known to persons skilled in the art.

Scheme 5:

[0152] The preparation of compounds described by Formula Ia is described in Scheme 5 below.

Scheme 5

[0153] In general Scheme 5 the R1-substituted aryl sulfinate starting material described by formula XVIII can be obtained from commercial sources or can be prepared by many methods well known to persons skilled in the art. One convenient protocol for achieving the conversion described by Method E involves reaction of compounds described by Formulae XVIII and III with a base such as potassium carbonate in a solvent such as N,N-dimethylformamide at ambient temperature for several hours. Following standard extraction and purification methods the product described by Formula XVII can be obtained in good yield and purity

[0154] A person skilled in the art will appreciate that compounds of Formula I where A is a heteroaryl can be prepared by procedures analogous to those described above.

[0155] Cis/trans (E/Z) isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

Therapeutic uses and formulations

[0156] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, together with a pharmaceutically acceptable diluent, excipient or adjuvant.

[0157] The present invention also relates to use of the compounds of Formula I in therapy, in particular to inhibit members of the lysyl oxidase family members, LOX, LOXL1, LOXL2, LOXL3 and LOXL4. In one embodiment, the invention provides for the selective inhibition of specific lysyl oxidase isoenzymes. In another embodiment, the invention provides for the simultaneous inhibition of 2, 3 or 4 LOX isoenzymes. The relative inhibitory potencies of the compounds can be determined by the amount needed to inhibit the amine oxidase activity of LOX, LOXL1, LOXL2, LOXL3 and LOXL4 in a variety of ways, e.g., in an in vitro assay with recombinant or purified human protein or with recombinant or purified non-human enzyme, in cellular assays expressing normal rodent enzyme, in cellular assays which have been transfected with human protein, in in vivo tests in rodent and other mammalian species, and the like.

[0158] In one embodiment, the compounds of the present invention are long lasting inhibitors of the lysyl oxidase family members LOX, LOXL1, LOXL2, LOXL3 and LOXL4. In one embodiment, the compounds of the present invention are long lasting inhibitors of the LOX or LOXL1-4 enzymes if the inhibition continues to be greater than 50% of the LOX or LOXL1-4 enzymes’ activity after the compound concentration has been reduced below the IC50. In one embodiment, the compounds of the present invention show sustained inhibition of the LOX or LOXL1-4 enzymes over a period of 24 hours. In one embodiment, the compounds of the present invention are irreversible inhibitors of the lysyl oxidase family members LOX, LOXL1, LOXL2, LOXL3 and LOXL4.

[0159] Accordingly, a further aspect of the invention is directed to a method of inhibiting the amine oxidase activity of any one of LOX, LOXL1, LOXL2, LOXL3 or LOXL4 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0160] In one embodiment, the present invention is directed to a method of inhibiting the amine oxidase activity of LOXL2. In another embodiment, the present invention is directed towards inhibiting the amine oxidase activity of LOX and LOXL2. In a further embodiment, the present invention is directed to a method of inhibiting the amine oxidase activity of LOX.

[0161] As discussed previously, LOX and LOXL1-4 enzymes are members of a large family of flavin-dependent and copper-dependent amine oxidases, which includes SSAO/VAP-1, monoamine oxidase-B (MAO-B) and diamine oxidase (DAO). In one embodiment, compounds of

the present invention selectively inhibit members of the lysyl oxidase isoenzyme family with respect to SSAO/VAP-1, MAO-B, DAO and other members of the amine oxidase family.

[0162] The present invention also discloses methods to use the compounds described by Formula I to inhibit one or more lysyl oxidase isoenzymes (LOX, LOXL1, LOXL2, LOXL3 and LOXL4) in patients suffering from a fibrotic disease, and methods to treat fibrotic diseases. Furthermore, the present invention discloses methods to use the compounds described by Formula I to inhibit one or more lysyl oxidase isoenzymes (LOX, LOXL1, LOXL2, LOXL3 and LOXL4) in patients suffering from cancer, including metastatic cancer, and methods to treat cancer and metastatic cancer.

[0163] In a further aspect of the invention there is provided a method of treating a condition associated with any one of LOX, LOXL1, LOXL2, LOXL3 or LOXL4 protein, comprising administering to a subject in need thereof a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0164] In another aspect there is a provided a method of treating a condition modulated by any one of LOX, LOXL1, LOXL2, LOXL3 or LOXL4, comprising administering to a subject in need thereof a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0165] In one embodiment, of the methods of the present invention, the condition is selected from the group consisting of fibrosis, cancer and angiogenesis.

[0166] In another aspect, the present invention provides a method for decreasing extracellular matrix formation by treating human subjects, pets and livestock with fluoroallylamine inhibitors of lysyl oxidase isoenzyme family of Formula I as described herein.

[0167] The above-described methods are applicable wherein the condition is fibrosis. As employed here“fibrosis” includes such diseases as cystic fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, kidney fibrosis, scleroderma, radiation-induced fibrosis, Peyronie’s disease, scarring and other diseases where excessive fibrosis contributes to disease pathology.

[0168] In one embodiment, the fibrosis is selected from the group consisting of mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's Disease, keloid, systemic sclerosis, arthrofibrosis, Dupuytren's contracture,

adhesive capsulitis, fibrosis of the pancreas, fibrosis of the intestine, liver fibrosis, lung fibrosis, kidney fibrosis, cardiac fibrosis, fibrostenosis, cystic fibrosis, idiopathic pulmonary fibrosis, radiation-induced fibrosis, Peyronie’s disease and scleroderma or is associated with respiratory disease, abnormal wound healing and repair, scarring, hypertrophic scarring/keloids, scarring post surgery, cardiac arrest and all conditions where excess or aberrant deposition of fibrous material is associated with disease, injury, implants or surgery. In another embodiment, the fibrosis is selected from the group consisting of liver fibrosis, lung fibrosis, kidney fibrosis, cardiac fibrosis, scarring and scleroderma. In a further embodiment the fibrosis is selected from the group consisitng of myelofibrosis, systemic sclerosis, liver fibrosis, lung fibrosis, kidney fibrosis, cardiac fibrosis and radiation induced fibrosis.

[0169] In one embodiment, kidney fibrosis includes, but is not limited to, diabetic nephropathy, vesicoureteral reflux, tubulointerstitial renal fibrosis, glomerulonephritis or glomerular nephritis, including focal segmental glomerulosclerosis and membranous glomerulonephritis, IgA nephropathy and mesangiocapillary glomerular nephritis. In one embodiment, liver fibrosis results in cirrhosis, and includes associated conditions such as chronic viral hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), biliary cirrhosis, and autoimmune hepatitis.

[0170] In one embodiment, the fibrosis is selected from keloid, scarring, ocular scarring, hypertrophic scarring, scleroderma, Dupuytren's contracture and Peyronie’s disease. In one embodiment, the hypertrophic scarring results from a burn. In one embodiment, the hypertrophic scarring is caused by external injuries. In another embodiment, the hypertrophic scarring is caused by surgical procedures. In one embodiment, the keloid is caused by external injuries. In another embodiment, the keloid is caused by surgical procedures. In a further embodiment, the keloid is a result of a skin injury caused by acne, burns, chicken pox, ear piercing, scratches, surgical cuts or vaccination sites.

[0171] The above-described methods are also applicable wherein the condition is a proliferative disease for example cancer. In one embodiment, the cancer is selected from the group consisting of lung cancer; breast cancer; colorectal cancer; anal cancer; pancreatic cancer; prostate cancer; ovarian carcinoma; liver and bile duct carcinoma; esophageal carcinoma; mesothelioma, non-Hodgkin's lymphoma; bladder carcinoma; carcinoma of the uterus; glioma, glioblastoma, medullablastoma, and other tumours of the brain; myelofibrosis, kidney cancer; cancer of the head and neck; cancer of the stomach; multiple myeloma; testicular cancer; germ cell tumour;

neuroendocrine tumour; cervical cancer; oral cancer, carcinoids of the gastrointestinal tract, breast, and other organs; signet ring cell carcinoma; mesenchymal tumours including sarcomas, fibrosarcomas, haemangioma, angiomatosis, haemangiopericytoma, pseudoangiomatous stromal hyperplasia, myofibroblastoma, fibromatosis, inflammatory myofibroblastic tumour, lipoma, angiolipoma, granular cell tumour, neurofibroma, schwannoma, angiosarcoma, liposarcoma, rhabdomyosarcoma, osteosarcoma, leiomyoma or a leiomyosarcoma.

[0172] In one embodiment, the cancer is selected from the group consisting of breast cancer, head and neck squamous cell carcinoma, brain cancer, prostate cancer, renal cell carcinoma, liver cancer, lung cancer, oral cancer, cervical cancer and tumour metastasis.

[0173] In one embodiment, lung cancer includes lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, bronchoalveolar carcinoma, non-small-cell carcinoma, small cell carcinoma and mesothelioma. In one embodiment, breast cancer includes ductal carcinoma, lobular carcinoma, inflammatory breast cancer, clear cell carcinoma, and mucinous carcinoma. In one embodiment, colorectal cancer includes colon cancer and rectal cancer. In one embodiment, pancreatic cancer includes pancreatic adenocarcinoma, islet cell carcinoma and neuroendocrine tumours.

[0174] In one embodiment, ovarian carcinoma includes ovarian epithelial carcinoma or surface epithelial-stromal tumour including serous tumour, endometrioid tumour and mucinous cystadenocarcinoma, and sex-cord-stromal tumour. In one embodiment liver and bile duct carcinoma includes hepatocelluar carcinoma, cholangiocarcinoma and hemangioma. In one embodiment, esophageal carcinoma includes esophageal adenocarcinoma and squamous cell carcinoma. In one embodiment, carcinoma of the uterus includes endometrial adenocarcinoma, uterine papillary serous carcinoma, uterine clear-cell carcinoma, uterine sarcomas and leiomyosarcomas and mixed mullerian tumours. In one embodiment, kidney cancer includes renal cell carcinoma, clear cell carcinoma and Wilm's tumour. In one embodiment, cancer of the head and neck includes squamous cell carcinomas. In one embodiment, cancer of the stomach includes stomach adenocarcinoma and gastrointestinal stromal tumour.

[0175] In one embodiment, the cancer is selected from the group consisting of colon cancer, ovarian cancer, lung cancer, esophageal carcinoma, breast cancer and prostate cancer. In one embodiment, the cancer is selected from the group consisting of pancreatic cancer, liver cancer, breast cancer, myelofibrosis and mesothelioma.

CLAIMS:

1. A compound of Formula I:

Formula I

or a stereoisomer, pharmaceutically acceptable salt, polymorphic form, solvate, hydrate or tautomeric form thereof; wherein:

A is aryl or heteroaryl;

each R1 is independently selected from the group consisting of X-R2, halogen, deuterium, C1-6alkyl, O-C1-6alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -CN, -C(O)OR3, -C(O)NR4R5, -S(O)2NR4R5, -S(O)2R6, -NR8C(O)R9, and -NR8S(O)2R9; wherein each C1-6alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3 and–O-CF3;

X is selected from the group consisting of O, CH2, OCH2, CH2O, CH2S(O)2, CONH and NHCO;

R2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein each R2 is optionally substituted by one or more R7;

R3 is selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3 and–O-CF3;

R4 and R5 are independently selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, - CH2CF3 and–O-CF3; or

R4 and R5 when attached to the same nitrogen atom are combined to form a 4- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

R6 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3, and -O-CF3;

R7 is selected from the group consisting of halogen, -OH, C1-6alkyl, O-C1-6alkyl C3-7cycloalkyl, -C(O)OR3, -C(O)NR4R5, -NR4C(O)R6, -S(O)2NR4R5, -NR4S(O)2R6 and -S(O)2R6; wherein each C1-6alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and–OH;

R8 is hydrogen or C1-6alkyl;

R9 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3, and -O-CF3; or

R8 and R9 are combined to form a 5- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

and

n is 0, 1, 2, 3, 4, 5 or 6.

2. A compound according to claim 1, wherein A is selected from the group consisting of phenyl, naphthyl, pyridinyl, quinolinyl, benzothiazolyl and indolyl.

3. A compound according to claim 1 or 2, wherein A is selected from the group consisting of:

.

4. A compound according to claim 1, wherein A is heteroaryl.

5. A compound according to claim 1, wherein

A is selected from the group consisting of
; R1 is methyl or isopropyl; and

n is 0 or 1.

6. A compound according to claim 1, wherein A is and n is 0.

7. A compound according to claim 1, of Formula Ia:

Formula Ia

or a stereoisomer, pharmaceutically acceptable salt, polymorphic form, solvate, hydrate or tautomeric form thereof; wherein:

each R1 is independently selected from the group consisting of X-R2, halogen, C1-6alkyl, O-C1-6alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -CN, -C(O)OR3, -C(O)NR4R5, -S(O)2NR4R5, -S(O)2R6, -NR8C(O)R9, and -NR8S(O)2R9; wherein each C1-6alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SO2CH3, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3 and–O-CF3;

X is selected from the group consisting of O, CH2, OCH2, CH2O, CH2S(O)2, CONH and NHCO;

R2 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl; wherein each R2 is optionally substituted by one or more R7;

R3 is selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl;

R4 and R5 are independently selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; or

R4 and R5 when attached to the same nitrogen atom are combined to form a 4- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

R6 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl;

R7 is selected from the group consisting of halogen, -OH, C1-6alkyl, O-C1-6alkyl, C3-7cycloalkyl, -C(O)OR3, -C(O)NR4R5, -NR4C(O)R6, -S(O)2NR4R5, -NR4S(O)2R6 and -S(O)2R6; wherein each C1-6alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and–OH;

R8 is hydrogen or C1-6alkyl;

R9 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl; wherein each C1-6alkyl and C3-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C1-4alkyl, -O-C1-4alkyl, -CF3, -CH2CF3, and -O-CF3; or

R8 and R9 are combined to form a 5- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members;

and

n is 0, 1, 2 or 3.

8. A compound according to claim 7, wherein n is 0.

9. A compound according to claim 7, wherein

each R1 is independently selected from the group consisting of halogen, C1-6alkyl, O-C1-6alkyl, aryl, and -S(O)2R6; wherein each C1-6alkyl is optionally substituted by one or more halogen;

R6 is C1-6alkyl;

and

n is 1 or 2.

of

or a pharmaceutically acceptable salt or solvate thereof.

11. A compound according to claim 1 selected from the group consisting of

pharmaceutically acceptable salt or solvate thereof.

12. A compound according to claim 1 selected from the group consisting of

pharmaceutically acceptable salt or solvate thereof.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, carrier or diluent.

14. A method of inhibiting the amine oxidase activity of any one of LOX, LOXL1, LOXL2, LOXL3 or LOXL4 in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 13.

15. A method of treating a condition associated with any one of LOX, LOXL1, LOXL2, LOXL3 or LOXL4 protein, comprising administering to a subject in need thereof a therapeutically effective amount of compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 13.

16. The method of claim 15, wherein the condition is selected from the group consisting of fibrosis, cancer and angiogenesis.

17. The method of claim 16, wherein in a case that the condition is fibrosis, the fibrosis is selected from the group consisting of mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's Disease, keloid, systemic sclerosis, arthrofibrosis, Dupuytren's contracture, adhesive capsulitis, fibrosis of the pancreas, fibrosis of the intestine, liver fibrosis, lung fibrosis, kidney fibrosis, cardiac fibrosis, fibrostenosis, cystic fibrosis, idiopathic pulmonary fibrosis, radiation-induced fibrosis, Peyronie’s disease and scleroderma or is associated with respiratory disease, abnormal wound healing and repair, scarring, hypertrophic scarring/keloids, scarring post surgery, cardiac arrest and all conditions where excess or aberrant deposition of fibrous material is associated with disease, injury, implants or surgery; preferably the fibrosis is selected from the group consisting of myelofibrosis, systemic sclerosis, liver fibrosis, lung fibrosis, kidney fibrosis, cardiac fibrosis and radiation induced fibrosis; and

wherein in a case that the condition is cancer, the cancer is selected from the group consisting of lung cancer; breast cancer; colorectal cancer; anal cancer; pancreatic cancer; prostate cancer; ovarian carcinoma; liver and bile duct carcinoma; esophageal carcinoma; mesothelioma; non-Hodgkin's lymphoma; bladder carcinoma; carcinoma of the uterus; glioma, glioblastoma, medullablastoma, and other tumours of the brain; myelofibrosis, kidney cancer; cancer of the head and neck; cancer of the stomach; multiple myeloma; testicular cancer; germ cell tumour; neuroendocrine tumour; cervical cancer; oral cancer, carcinoids of the gastrointestinal tract, breast, and other organs; signet ring cell carcinoma; mesenchymal tumours including sarcomas, fibrosarcomas, haemangioma, angiomatosis, haemangiopericytoma, pseudoangiomatous stromal hyperplasia, myofibroblastoma, fibromatosis, inflammatory myofibroblastic tumour, lipoma, angiolipoma, granular cell tumour, neurofibroma, schwannoma, angiosarcoma, liposarcoma, rhabdomyosarcoma, osteosarcoma, leiomyoma or a leiomysarcoma.

18. The method according to any one of claims 15 to 17, further comprising administering a second therapeutic agent.

19. The method according to claim 18, wherein the second therapeutic agent is selected from the group consisting of an anti-cancer agent, an anti-inflammatory agent, an anti-hypertensive agent, an anti-fibrotic agent, an anti-angiogenic agent, an immunosuppressive agent and a metabolic agent.

20. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for treating a condition associated with any one of LOX, LOXL1, LOXL2, LOXL3 or LOXL4 protein.