DIFLUOROHALOALLYLAMINE SULFONE DERIVATIVE INHIBITORS OF LYSYL OXIDASES, METHODS OF PREPARATION, AND USES THEREOF

Technical Field

[0001] The present invention relates to methods for preparing a variety of difluorohaloallylamine derivatives. The present invention also relates to novel difluorohaloallylamine derivatives that are capable of inhibiting certain amine oxidase enzymes. These compounds are useful for the treatment of a variety of indications, e.g., fibrosis, cancer and/or scarring 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 uses thereof.

Background

[0002] A family of five closely related enzymes have been linked to fibrotic disease and to metastatic cancer. 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 including monoamine oxidase- A (MAO- A), mono amine oxidase-B (MAO-B), polyamine oxidase and lysine demethylase (LSD1), and the copper -dependent enzymes include 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: HI - 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 Vase. 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] Keloid, or keloidal scar, is the formation of a type of scar that results from abnormal deposition of granulation tissue (collagen type 3) at the site of a healed skin injury which is then slowly replaced by collagen type 1. This abnormal deposition of collagen, in turn, results from an imbalance in net collagen synthesis and deposition and collagenolysis. Keloids are firm, rubbery lesions or shiny, fibrous nodules, and can vary from pink to the color of the person's skin or red to dark brown in color.

[0015] Histologically, keloids are fibrotic tumours characterized by a collection of atypical fibroblasts with excessive deposition of extracellular matrix components, especially collagen, fibronectin, elastin, and proteoglycans. In most cases, they contain relatively acellular centers with thick, abundant collagen bundles that form nodules in the deep dermal region of the lesion. Keloids present a therapeutic challenge, as these lesions can cause significant pain, pruritus, and physical disfigurement. Furthermore, they may not improve in appearance over time and can limit mobility if located over a joint.

[0016] Physiologic manipulation of collagen deposition/crosslinking and collagenolysis (through collagenase activity) is, at least theoretically, an opportunity to reduce keloid severity and induce scarring with improved physical properties

[0017] A study on patients with massive, pedunculated keloids has shown that, following excision of the keloid and grafting the defect, treatment by administration of beta aminopropionitrile (BAPN) or penicillamine (non-selective, pan LOX inhibitors) and colchicine (a stimulator of collagenase activity) exerted a measurable beneficial effect on surface scarring ( Ann surg 1981 ; 193: 592 -597).

[0018] 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-b induced fibrotic phenotypes (Lab. Invest. 2019; 99: 514 - 527).

[0019] 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).

[0020] 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.

[0021] 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-b stimulation of lysyl oxidase enzyme activity and contribute to connective tissue fibrosis ( Lab Invest 1999; 79: 1655 - 1667).

[0022] 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.

[0023] 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 tumour 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.

[0024] 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 b-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).

[0025] Whilst there is no cure for RA, there are a number of treatments available that alleviate symptoms and modify disease progression. Flowever, 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.

[0026] 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.

[0027] 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.

[0028] 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).

[0029] 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.

[0030] 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. fiver, 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).

[0031] 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), el 12391).

[0032] 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 fines 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.

[0033] 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-tumourigenic, 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.

[0034] 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).

[0035] 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

[0036] 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 ( Nature . 2015; 522 (7554) 106 - 110). In vivo models demonstrated that the LOX inhibitors have potential in breast cancer patients with bone metastasis, by modulating bone homeostasis independent of receptor activator of nuclear factor kappa-B ligand (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).

[0037] 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 1 low 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).

[0038] In most tumour 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).

[0039] In colon, breast cancer and melanoma models, tumour 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).

[0040] 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).

[0041] 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.

[0042] 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) eOl 19781). Lysyl oxidase isoenzyme protein expression was increased in glioblastoma and astrocytoma tissues, and in invasive U343 and U251 cultured astrocytoma cells.

[0043] 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).

[0044] In renal clear cell carcinoma (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).

[0045] 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).

[0046] 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).

[0047] 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 tumours. 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 (/ Dent Res 2019; 98(5): 517 - 525).

[0048] The findings described herein, provide a strong rationale for combination therapies involving LOX isoenzyme inhibitors and anti-tumour therapy in patients.

[0049] More recently, CCT365623 a reversible pan LOX inhibitor has been utilised in breast cancer model (MMTV-PyMT) to reduce metastasis and increase survival (Nat Commun. 2017; 18 (8): 14909).

[0050] 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. Lluoroallylamine 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.

[0051] Additional fluoroallylamine inhibitors are described US Patent 4,699,928. Other examples structurally related to Mofegiline can be found in WO 2007/120528.

[0052] 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.

[0053] 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.

[0054] WO 2017/136871 and WO 2017/136870 disclose haloallylamine indole and azaindole derivative inhibitors of lysyl oxidases and uses thereof.

[0055] WO 2018/157190 discloses haloallylamine pyrazole derivative inhibitors of lysyl oxidases and uses thereof.

[0056] WO 2020/024017 discloses haloallylamine sulfone derivative inhibitors of lysyl oxidases and uses thereof.

[0057] 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.

[0058] WO 2003/097612, WO 2006/053555, and US 2008/0293936 disclose another class of lysyl oxidase inhibitors.

[0059] WO 2020/099886, WO 2018/048930, WO 2017/015221, WO 2017/003862, WO 2016/144702 and WO 2016/144703 disclose further LOXL2 inhibitors.

Summary

[0060] The present invention provides substituted difluorohaloallylamine 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. Certain of these novel compounds have been found to have favourable characteristics for topical application. 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.

[0061] A first aspect of the invention provides for a compound of Formula I:

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

W is F or Cl;

Y is -S(O)2- or -S(O)-;

Z is -(CH2)m-;

A is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C1-6alkyl, C1-6alkenyl, or C1-6alkynyl;

each R1 is independently selected from the group consisting of X-R2, deuterium, halogen, C1-6alkyl, -OH, -O- C1-6alkyl, -NR4R5, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -CN, -C(O)OR3, -C(O)NR4R5, -S(O)2NR4R5, -S(O)2R6, -NR8C(O)R9, and -NR8S(O)2R9; and 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;

n is 0, 1, 2, 3, 4 or 5; and

m is 0 or 1.

[0062] A second aspect of the invention provides for a process for preparing a compound of Formula la:

which comprises reaction steps (C), (D), (E) and (F), where:

(C) is the reaction of a compound of Formula IV :

with a compound of Formula V or VI:

to afford a compound of Formula VII:

(D) is the reaction of a compound of Formula VII with a compound of Formula VIII or

IX:

to obtain a compound of Formula X:

(E) is the oxidation of a compound of Formula X to obtain a compound of Formula XI:

; and

(F) is deprotection of a compound of Formula XI to afford a compound of Formula la:

(la), or a pharmaceutically acceptable salt thereof wherein U is Br, Cl or I;

W is F or Cl; and

P1 is a nitrogen protecting group;

P2 is hydrogen or a nitrogen protecting group; or

P1 and P2 together with the nitrogen to which they are attached form a cyclic nitrogen protecting group;

X+ is a metal counterion; and

R1, A, Z and n are as defined in the first aspect of the invention.

[0063] A third aspect of the invention provides for a process for preparing a single isomer of a compound of Formula IVc:

which comprises:

addition of a compound of Formula IIIc:

to a solution of Br2.

[0064] A fourth 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.

[0065] A fifth aspect of the invention provides for a method of inhibiting the amine oxidase activity of any one of LOX, LOXL1, LOXL2, LOXL3 and 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 fourth aspect of the invention.

[0066] A sixth aspect of the invention provides for a method of treating a condition by inhibiting the activity of any one of the LOX, LOXL1, LOXL2, LOXL3 and LOXL4 proteins, 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 fourth aspect of the invention.

[0067] A seventh 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 by inhibiting the activity of any one of the LOX, LOXL1, LOXL2, LOXL3 and LOXL4 proteins.

[0068] An eighth 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 by inhibiting the activity of any one of the LOX, LOXL1, LOXL2, LOXL3 and LOXL4 proteins.

[0069] In one embodiment of the methods and uses of the present invention the condition is selected from fibrosis, cancer, and arthritis.

[0070] In one embodiment of the methods and uses of the present invention the condition is scarring.

[0071] In one embodiment of the compositions of the present invention, the pharmaceutical composition is a topical composition. In one embodiment of the methods of the present invention the pharmaceutical composition is for topical administration.

[0072] 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, inflammation, immunosuppression, angiogenesis, fungal infections, bacterial infections, metabolic conditions, pain and puritis.

Definitions

[0073] 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.

[0074] 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.

[0075] 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”.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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, thiomorpholinyl- 1,1 -dioxide, 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.

[0084] The term“halogen” or variants such as“halide” or“halo” as used herein refers to fluorine, chlorine, bromine and iodine.

[0085] The term“heteroatom” or variants such as“hetero-” or“heterogroup” as used herein refers to O, N, NH and S.

[0086] 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.

[0087] 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)C1-4 alkyl, C(O)C1-4 alkyl, NH2, NHC1-C4alkyl, N(C1-4 alkyl)2, SO2(C1-4 alkyl), OH and CN. Particularly

preferred substituents include C1-4 alky, C1-4alkoxy, SO2(C1-4 alkyl), halogen, OH, hydroxy(C1-3)alkyl (e.g. C(CH3)2OH), and C1-3haloalkyl (e.g. CF3, CH2CF3).

[0088] The present invention includes within its scope all diastereomeric isomers, racemates, enantiomers and mixtures thereof. Thus, the present disclosure should be understood to include, for example, (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 optical 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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. [0094] 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

[0095] Figure 1 A schematic representation of the experimental setup for the preparation of (Z)-1,4-dibromo-1,1,2-trifluorobut-2-ene.

[0096] Figure 2 (a and b) shows reduction in immature (a) and mature (b) cross-links in mouse scar tissue after injury when treated with topical Compound 1 (cmp 1).

[0097] Figure 3 shows reduction in LOX activity in the skin of rats after topical application of cream containing Compound 1 versus control.

[0098] Figure 4 (a-c) Histological analysis of sclerosis mouse skin model with topical treatment with Compound 1 (cmp 1). (A) Composite skin score; (B) Average collagen score; (C) Average LOX score.

[0099] Figure 5: UV spectrum for Compound 1 from 200 nm to 680 nm (Shimadzu LCMS 2020 instrument).

[0100] Figure 6 shows a dose-dependent improvement in pig scar appearance following topical treatment with Compound 1 (0, 0.5, 1.5 and 3%).

Detailed Description

[0101] The present invention relates to substituted difluorohaloallylamine 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:

or a pharmaceutically acceptable salt, polymorphic form, solvate, hydrate or tautomeric form thereof; where

W is F or Cl;

Y is -S(O)2- or -S(O)-;

Z is -(CH2)m- A is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C1-6alkyl, C1-6alkenyl, or C1-6alkynyl;

each R1 is independently selected from the group consisting of X-R2, deuterium, halogen, C1-6alkyl, -OH, -O-C1-6alkyl, -NR4R5, 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-C1-4aIkyI, -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-C1-4aIkyI, -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-C1-4aIkyI, -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;

n is 0, 1, 2, 3, 4 or 5; and

m is 0 or 1.

[0103] In one embodiment of compounds of the present invention, W is F. In another embodiment of compounds of the present invention, W is Cl.

[0104] In one embodiment of compounds of the present invention, Y is -S(O)2-. In another embodiment of compounds of the present invention, Y is -S(O)-.

[0105] In one embodiment of the present invention, A is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C1-6alkyl, C1-6alkenyl, or C1-6alkynyl. In another 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, quinolinyl, thiophenyl. furanyl and cyclopentyl. In a further embodiment of compounds of the present invention, A is selected from the group consisting of:

and
. In another embodiment of compounds of the present invention A is phenyl.

[0106] In one embodiment of compounds of the present invention, each R1 is independently selected from the group consisting of X-R2, deuterium, halogen, C1-6alkyl, -OH, -O-C1-6alkyl, -NR4R5, 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, -C1-4 alky, -O-C1-4aIkyI, -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, halogen, C1-6alkyl, -OH, -O-C1-6alkyl, -NR4R5, 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 a further embodiment of compounds of the present invention, each R1 is independently selected from the group consisting of X-R2, deuterium, C1-6alkyl, -OH, O-C1-6alkyl, heterocycloalkyl, -NR4R5, and -S(O)2R6; wherein each C1-6alkyl 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 one embodiment of compounds of the present invention, each R1 is independently selected from the group consisting of X-R2, deuterium, methyl, OCH3, -OH, -NHCH3, heterocycloalkyl and SO2CH3. In a further embodiment of compounds of the present invention each R1 is independently selected from the group consisting of X-R2, deuterium, methyl, OCH3, -OH, -NHCH3 and SO2CH3. In another embodiment of compounds of the present invention each R1 is independently selected from the group consisting of X-R2, methyl, OCH3, -OH, -NHCH3 and SO2CH3. In a further embodiment of compounds of the present invention each R1 is independently selected from the group consisting of methyl, OCH3, -OH, -NHCH3 and SO2CH3.

[0107] 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, CH2O, CONH and NHCO. In another embodiment of compounds of the present invention, X is selected from the group consisting of O, OCH2, CH2O, 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 another embodiment of compounds of the present invention X is O or OCH2. 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.

[0108] 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, R2 is phenyl optionally substituted by -S(O)2R6. In a further embodiment R2 is phenyl substituted by -S(O)2CH3.

[0109] 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.

[0110] 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, -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 and C3-7cycloalky. 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.

[0111] 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, -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.

[0112] 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.

[0113] 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. In another embodiment R6 is CH3.

[0114] 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)2R6. In a further embodiment of compounds of the present invention R7 is -S(O)2CH3.

[0115] In one embodiment of compounds of the present invention, R8 is 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.

[0116] 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.

[0117] 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.

[0118] 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 0, 1, 2 or 5. In a further embodiment of compounds of the present invention n is 0, 1 or 5. In In another embodiment of the compounds of the present invention n is 1 or 5.

[0119] In one of embodiment of compounds of the present invention, m is 0 or 1. In another embodiment of compounds of the present invention, m is 0. In a further embodiment of compounds of the present invention, m is 1.

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

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

W is F or Cl;

Z is -(CH2)m-;

A is aryl or heteroaryl;

each R1 is independently selected from the group consisting of X-R2, deuterium, halogen, C1-6alkyl, -OH, -O-C1-6alkyl, -NR4R5, 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, -C14alkyl, -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;

n is 0, 1, 2 or 5; and

m is 0 or 1.

[0121] In another embodiment, the present invention also relates to compounds of Formula lb:

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

W is F or Cl;

A is aryl or heteroaryl;

each R1 is independently selected from the group consisting of X-R2, deuterium, halogen, C1-6alkyl, -OH, -O-C1-6alkyl, -NR4R5, 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 2 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, 0-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;

n is 0, 1, 2 or 5; and

m is 0 or 1.

[0122] In one embodiment of compounds of Formula I, Formula la, or Formula lb W is F.

[0123] In one embodiment, the present invention also relates to compounds of Formula Ic:

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

each R1 is independently selected from the group consisting of X-R2, deuterium, halogen, C1-6alkyl, -OH, -O-C1-6alkyl, -NR4R5, 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 4- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members; and

n is 0, 1, 2 or 5.

[0124] In one embodiment of compounds of Formula I, la, lb or Ic, n is 0.

[0125] In one embodiment of compounds of Formula I, la, lb or Ic of the invention, each R1 is independently selected from the group consisting of X-R2, deuterium, C1-6alkyl, -OH, O-C1-6alkyl, heterocycloalkyl, -NR4R5, and -S(O)2R6; wherein each C1-6alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -C1-4alkyl, -O-C1-4alkyl, -CF3, - CH2CF3 and -O-CF3; X is selected from the group consisting of O and OCH2; R2 is aryl optionally substituted by one or more R7; R4 and R5 are independently selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl; R6 is selected from the group consisting of C1-6alkyl and C3-7cycloalkyl; R7 is -S(O)2R6 and n is 0, 1, or 5.

[0126] In another embodiment of compounds of Formula I, la, lb or Ic of the invention, R1 is independently selected from the group consisting of X-R2, deuterium, methyl, OCH3, -OH,

-NHCH3, heterocycloalkyl and SO2CH3; X is O or OCH2; R2 is phenyl substituted by SO2CH3 and n is 0, 1 or 5.

[0127] 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).

[0128] Exemplary compounds according to the present invention include the compounds set forth in Table 2:

Table 2

[0129] In one embodiment, the compound of the present invention is selected from the group

consisting of and , or a pharmaceutically

acceptable salt or solvate thereof. In another embodiment the compound of the present invention is

or a pharmaceutically acceptable salt or solvate thereof. In a further

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

Preparation of Compounds of Formula I

[0130] 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).

[0131] 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.

[0132] The preparation of compounds described by Formula la is described in Scheme 1 below.

Scheme 1

[0133] P1 is a functional group used to protect a nitrogen functionality. P2 is hydrogen or a functional group to protect a nitrogen functionality. Examples of P1 and P2 are carbamate forming groups such as the tert- butyloxycarbonyl (BOC), the 9-fluorenylmethyloxy-carbonyl (FMOC), and the benzyloxycarbonyl (CBZ) groups. Alternatively, P1 and P2, together with the nitrogen to which they are attached form a cyclic group to protect a nitrogen functionality. In one embodiment the protecting group is a phthalimide.

[0134] X+ is a metal counterion such as Li+, Na+ and K+

[0135] In one embodiment of compounds of Formula (II), W is F or Cl. In another embodiment of compounds of Formula (II), W is Cl. In a further embodiment of compounds of Formula (II), W is F.

[0136] In one embodiment of compounds of Formula (II), U' is Br, Cl, I, OMs, OTs. In another embodiment of compounds of Formula (II), U' is Br or I. In a further embodiment of compounds of Formula (II), U' is Br.

[0137] In general Scheme 1 the 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 heating a solution a compound of Formula II in the presence of a base, such as potassium hydroxide, in a solvent, such as xylene, to a temperature between 50 and 70 °C, for several hours. In one embodiment, the reaction described by Method A and B is conducted in accordance with the schematic representation of the experimental setup depicted in Figure 1.

[0138] In one embodiment of the process of the present invention, the compound of Formula III is not isolated and is added to a solution of U2, such as Br2 in a suitable solvent, such as dichloromethane that has been cooled to a temperature between -10 °C and 10 °C, such as a temperature of 0 °C. The product described by Formula IV can be recovered by standard work up procedures.

[0139] Whilst there are many ways to achieve the reaction described by Method C, one convenient protocol involves reaction of compounds described by Formulae IV and V in the presence of a base in a solvent such as N- - dimethylformamide that has been cooled to a temperature between -10 °C and 10 °C, such as a temperature of 0 °C for 1 hour to several hours. An alternative, convenient protocol involves reaction of compounds described by Formulae IV and VI in a solvent such as N- - dimethylformamide at a temperature between 0 °C and 40 °C for 1 hour to several hours. The product described by Formula VI can be recovered by standard work up procedures.

[0140] Whilst there are many ways to achieve the reaction described by Method D, one convenient protocol involves reaction of compounds described by Formulae VII and VIII in the presence of a base such as cesium carbonate or sodium hydride in a solvent such as N, - dimethylformamide at ambient temperature for several hours. An alternative, convenient protocol involves reaction of compounds described by Formulae VII and IX in a solvent such as N, - dimethylformamide at a temperature between 0 °C and 40 °C for 1 hour to several hours. Following standard extraction and purification methods the product described by Formula X can be obtained in good yield and purity.

[0141] Whilst there are many ways to achieve the reaction described by Method E, one convenient protocol involves reaction of compounds described by Formula X in a solvent such as acetic acid with an oxidising agent such as hydrogen peroxide at a temperature between 70 °C and 90 °C, such as 80 °C for several hours. Following standard extraction and purification methods the product described by Formula XI can be obtained in good yield and purity. A person skilled in the art would appreciate that through suitable modifcations of the oxidation conditions, sulfoxides can be obtained.

[0142] There are many well established chemical procedures for the deprotection of the compounds described by Formula XI to the compounds described by Formula la (Method F). For example if P1 is a BOC protecting group, compounds described by Formula XI can be treated with an acidic substance such as dry hydrogen chloride in a solvent such as ethyl acetate to furnish the compounds described by Formula la as the hydrochloride salts. If P1 and P2 together are phthalimide, compounds described by Formula XI can be heated in a solvent, such as methylamine for several hours before being treated with an acidic substance such as dry hydrogen chloride in a solvent such as ethyl acetate to furnish the compounds described by Formula la 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.

[0143] In one aspect, the present invention provides for a process for preparing a compound of Formula la:

which comprises reaction steps (C), (D), (E) and (F), where:

(C) is the reaction of a compound of Formula IV :

with a compound of Formula V or VI

to afford a compound of Formula VII:

(D) is the reaction of a compound of Formula VII with a compound of Formula VIII or

IX:

to obtain a compound of Formula X:

(E) is the oxidation of a compound of Formula X to obtain a compound of Formula XI:

; and

(F) is deprotection of a compound of Formula XI to afford a compound of Formula la:

(la), or a pharmaceutically acceptable salt thereof
wherein U is Br, Cl or I;

W is F or Cl;

Z is -(CH2)m-;

P1 is a nitrogen protecting group;

P2 is hydrogen or a nitrogen protecting group; or

P1 and P2 together with the nitrogen to which they are attached form a cyclic protected nitrogen group;

X+ is a metal counterion; and

R1, A and n are as defined above,

n is 0, 1, 2 or 3; and

m is 0 or 1.

[0144] In one embodiment of the process, reaction step (C) is preceded by reaction steps (A) and (B), wherein:

(A) denotes the reaction of a compound of Formula II:

with a base to afford a compound of Formula III:

and (B) denotes the reaction of a compound of Formula III with U2 to afford a compound of Formula IV.

[0145] In one embodiment of the process of the present invention, the process is represented by Scheme 2.

Scheme 2

[0146] In one embodiment of the present invention, there is provided a process for preparing a compound of Formula Ic:

which comprises reaction steps (C), (D), (E) and (F), where:

(C) is the reaction of a compound of Formula IVc:

with a compound of Formula Vc or VIc:

to afford a compound of Formula VIlc:

(D) is the reaction of a compound of Formula VIIc with a compound of Formula VIIIc or

IXb:

to obtain a compound of Formula Xc:

(E) is the oxidation of a compound of Formula Xc to obtain a compound of Formula XIc:

(F) is deprotection of a compound of Formula XIc to afford a compound of Formula Ic:

, or a pharmaceutically acceptable salt thereof wherein

P1 is a nitrogen protecting group;

P2 is hydrogen or a nitrogen protecting group; or

P1 and P2 together with the nitrogen to which they are attached form a cyclic nitrogen protecting group

X+ is a metal counterion, and

R1 and n are as defined above.

[0147] A further aspect of the invention provides for a process for preparing a single isomer of a compound of Formula IVc:

which comprises:

addition of a compound of Formula IIIc:

to a solution of Br2.

[0148] The present invention also provides for compounds of Formula I prepared according to the processes of the invention.

[0149] Further aspects of the invention provide for intermediates of the processes of the invention.

[0150] One aspect of the invention provides for an intermediate of Formula VII,

wherein U, W, P1 and P2 are as defined above. In one embodiment the present invention

provides for an intermediate of Formula VIIc:
wherein P1 and P2 are as defined above. A further embodiment of the present invention provides for an intermediate of Formula

[0151] Another aspect of the invention provides for an intermediate of Formula X,

wherein W, Z, P1 and P2 , R1, A and n are as defined above. In one embodiment the present invention

provides for an intermediate of Formula Xc:
wherein P1 and P2, R1, and n are as defined above.

[0152] A further aspect of the invention provides for an intermediate of Formula XI,

wherein W, Z, P1 and P2 , R1, A and n are as defined above. In one embodiment the present invention

provides for an intermediate of Formula XIc: wherein P1
and P2, R1, and n are as defined above.

[0153] 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

[0154] 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.

[0155] 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, 4 or 5 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] In a further aspect of the invention, there is provided a method of treating a condition by inhibiting the activity of any one of the LOX, LOXL1, LOXL2, LOXL3 and LOXL4 proteins, 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.

[0162] In another aspect, there is a provided a method of treating a condition modulated by any one of LOX, LOXL1, LOXL2, LOXL3 and 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.

[0163] In one embodiment of the methods of the present invention, the condition is selected from the group consisting of fibrosis, cancer and arthritis.

[0164] In another aspect, the present invention provides a method for decreasing extracellular matrix formation by treating human subjects, pets and livestock with difluorohaloallylamine inhibitors of lysyl oxidase isoenzyme family of Formula I as described herein.

[0165] 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.

[0166] 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, scleroderma/systemic sclerosis, arthrofibrosis, Dupuytren's contracture, adhesive capsulitis, fibrosis of the pancreases, 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.

[0167] 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.

[0168] 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, piercing, scratches, surgical cuts or vaccination sites.

[0169] 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; non-Hodgkin's lymphoma; bladder carcinoma; carcinoma of the uterus; glioma, glioblastoma, meduhablastoma, 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.

[0170] 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.

[0171] 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.

[0172] 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 muherian 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.

[0173] In one embodiment, the cancer is selected from the group consisting of pancreatic cancer, liver cancer, breast cancer, myelofibrosis and mesothelioma.

[0174] In one embodiment, the compounds of the invention may be for use in the treatment of a non-metastatic cancer. In another embodiment, the compounds of the invention may be for use in the treatment of metastatic cancer. In a further embodiment, the compounds of the present invention may be for use in the prevention or treatment of tumour metastasis.

[0175] The above -described methods are applicable wherein the condition is arthritis. As used herein arthritis includes rheumatoid arthritis and osteoarthritis.

[0176] In one embodiment of the methods of the present invention, the subject is selected from the group consisting of humans, pets and livestock. In another embodiment of the methods of the present invention, the subject is a human.

[0177] A further aspect of the invention provides for use of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for

treating a condition by inhibiting the activity of any one of the LOX, LOXL1, LOXL2, LOXL3 and LOXL4 proteins.

[0178] Another aspect of the invention provides for use of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for treating a condition modulated by any one of LOX, LOXL1, LOXL2, LOXL3 and LOXL4.

Pharmaceutical and/or Therapeutic Formulations

[0179] In another embodiment of the present invention, there are provided compositions comprising a compound having Formula I and at least one pharmaceutically acceptable excipient, carrier or diluent thereof. The compound(s) of Formula I may also be present as suitable salts, including pharmaceutically acceptable salts.

[0180] The phrase“pharmaceutically acceptable carrier” refers to any carrier known to those skilled in the art to be suitable for the particular mode of administration. In addition, the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients.

[0181] The phrase “pharmaceutically acceptable salt” refers to any salt preparation that is appropriate for use in a pharmaceutical application. By pharmaceutically acceptable salt it is meant those salts which, within the scope of sound medical judgement, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art and include acid addition and base salts. Hemisalts of acids and bases may also be formed. Pharmaceutically acceptable salts include amine salts of mineral acids (e.g., hydrochlorides, hydrobromides, sulfates, and the like); and amine salts of organic acids (e.g., formates, acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, maleates, butyrates, valerates, fumarates, sulfonates and the like).

[0182] For compounds of formula (I) having a basic site, suitable pharmaceutically acceptable salts may be acid addition salts. For example, suitable pharmaceutically acceptable salts of such compounds may be prepared by mixing a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, phosphoric acid, acetic acid, oxalic acid, carbonic acid, tartaric acid, or citric acid with the compounds of the invention.

[0183] S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, asparate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, pectinate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, toluenesulfonate, undecanoate, valerate salts, and the like. Suitable base salts are formed from bases that form non-toxic salts. Examples include the arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, dimethylamine, trimethylamine, triethylamine, triethanolamine and the like.

[0184] Pharmaceutically acceptable salts of compounds of formula I may be prepared by methods known to those skilled in the art, including for example:

(i) by reacting the compound of formula I with the desired acid or base;

(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula I or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or

(iii) by converting one salt of the compound of formula I to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

[0185] The above reactions (i)-(iii) are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.

[0186] Thus, for instance, suitable pharmaceutically acceptable salts of compounds according to the present invention may be prepared by mixing a pharmaceutically acceptable acid such as

hydrochloric acid, sulfuric acid, methanesulfonic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, phosphoric acid, acetic acid, carbonic acid, tartaric acid, or citric acid with the compounds of the invention. Suitable pharmaceutically acceptable salts of the compounds of the present invention therefore include acid addition salts.

[0187] The compounds of the invention may exist in both unsolvated and solvated forms. The term‘solvate’ is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term‘hydrate’ is employed when the solvent is water.

[0188] In one embodiment, the compounds of Formula I may be administered in the form of a “prodrug”. The phrase“prodrug” refers to a compound that, upon in vivo administration, is metabolized by one or more steps or processes or otherwise converted to the biologically, pharmaceutically or therapeutically active form of the compound. Prodrugs can be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to a compound described herein. For example, prodrugs include compounds of the present invention wherein a hydroxy, amino, or carboxylate group is bonded to any group that, when administered to a mammalian subject, can be cleaved to form a free hydroxyl, free amino, or free carboxylic acid group, respectively. Representative prodrugs include, for example, amides, esters, enol ethers, enol esters, acetates, formates, benzoate derivatives, and the like of alcohol and amine functional groups in the compounds of the present invention. The prodrug form can be selected from such functional groups as -C(O)alkyl, -C(O)cycloalkyl, -C(O)aryl, -C(O)-arylalkyl,

C(O)heteroaryl, -C(O)-heteroarylalkyl, or the like. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those of skill in this art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).

[0189] Compositions herein comprise one or more compounds provided herein. The compounds are, in one embodiment, formulated into suitable pharmaceutical preparations such as solutions, suspensions, tablets, creams, gels, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation and dry powder inhalers. In one embodiment, the compounds described above are formulated into pharmaceutical compositions

using techniques and procedures well known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Fourth Edition 1985, 126).

[0190] In the compositions, effective concentrations of one or more compounds or pharmaceutically acceptable derivatives thereof is (are) mixed with a suitable pharmaceutical carrier. The compounds may be derivatized as the corresponding salts, esters, enol ethers or esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs prior to formulation, as described above. The concentrations of the compounds in the compositions are effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates one or more of the symptoms of diseases or disorders to be treated.

[0191] In one embodiment, the compositions are formulated for single dosage administration. To formulate a composition, the weight fraction of compound is dissolved, suspended, dispersed or otherwise mixed in a selected carrier at an effective concentration such that the treated condition is relieved, prevented, or one or more symptoms are ameliorated.

[0192] The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated. The therapeutically effective concentration may be determined empirically by testing the compounds in in vitro and in vivo systems described herein, and then extrapolated from there for dosages for humans.

[0193] The concentration of active compound in the pharmaceutical composition will depend on absorption, distribution, inactivation and elimination rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art.

[0194] Dosing may occur at intervals of minutes, hours, days, weeks, months or years or continuously over any one of these periods. Suitable dosages lie within the range of about 0.1 ng per kg of body weight to 0.1 g per kg of body weight per dosage. The dosage is preferably in the range of 1 mg to 0.1 g per kg of body weight per dosage, such as is in the range of 1 mg to 0.1 g per kg of body weight per dosage. Suitably, the dosage is in the range of 1 mg to 50 mg per kg of body weight per dosage, such as 1 mg to 20 mg per kg of body weight per dosage, or 1 mg to 10 mg per kg of body weight per dosage. Other suitable dosages may be in the range of 1 mg to 25 mg per kg of body weight, including 1 mg to 10, 20, 50 or 100 mg per kg of body weight per dosage or 10 mg to 100 mg per kg of body weight per dosage. In one embodiment, the dosage is in the range of 1 mg to 10 mg per kg of body weight per dosage.

[0195] Alternatively, an effective dosage may be up to about 10 mg/cm2, or it may be up to about 1 mg/cm2, about 0.5 mg/cm2, about 0.2 mg/cm2, about 0.1 mg/cm2, about 0.05 mg/cm2, about 0.02 mg/cm2, or about 0.01 mg/cm2. It may be, for example, in the range from about 0.1 mg/cm2 to about 1 mg/cm2, or from about 1 mg/cm2 to about 1 mg/cm2, about 10 mg/cm2 to about 1 mg/cm2, about 10 mg/cm2 to about 0.1 mg/cm2, about 10 mg/cm2 to about 0.01 mg/cm2, about 10 mg/cm2 to about 500 mg/cm2, about 10 mg/cm2 to about 200 mg/cm2, about 10 mg/cm2 to about 100 mg/cm2, about 10 mg/cm2 to about 50 mg/cm2, about 20 mg/cm2 to about 1 mg/cm2, about 50 mg/cm2 to about 1 mg/cm2, about 100 mg/cm2 to about 1 mg/cm2, about 200 mg/cm2 to about 1 mg/cm2, about 500 mg/cm2 to about 1 mg/cm2, about 50 mg/cm2 to about 500 mg/cm2, about 50 mg/cm2 to about 200 mg/cm2, about 100 mg/cm2 to about 500 mg/cm2, or about 200 mg/cm2 to about 500 mg/cm2.

[0196] Suitable dosage amounts and dosing regimens can be determined by the attending physician and may depend on the particular condition being treated, the severity of the condition, as well as the general health, age and weight of the subject.

[0197] In instances in which the compounds exhibit insufficient solubility, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN®, dissolution in aqueous sodium bicarbonate, formulating the compounds of interest as nanoparticles, and the like. Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions.

[0198] Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.

[0199] The pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof.

[0200] The pharmaceutically therapeutically active compounds and derivatives thereof are, in one embodiment, formulated and administered in unit-dosage forms or multiple-dosage forms. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. Unit-dose forms as used herein refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit-dose forms include ampules and syringes and individually packaged tablets or capsules. Unit-dose forms may be administered in fractions or multiples thereof. A multiple -dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit -dose form. Examples of multiple -dose forms include vials, bottles of tablets or capsules. Hence, multiple dose form is a multiple of unit-doses which are not segregated in packaging.

[0201] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975.

[0202] Dosage forms or compositions containing active ingredient in the range of 0.005% to 100% (wt %) with the balance made up from non-toxic carrier may be prepared. Methods for preparation of these compositions are known to those skilled in the art. The contemplated compositions may contain 0.001%-100% (wt %) active ingredient, in one embodiment 0.1-95% (wt %), in another embodiment 75-85% (wt %) and in another embodiment 0.1-25 %. (wt %) active ingredient. The amount of active in such therapeutically useful compositions is such that an effective dosage level can be attained.

Modes of Administration

[0203] Convenient modes of administration include injection (subcutaneous, intravenous, etc.), oral administration, inhalation, transdermal application, topical to skin, eyes, ears, oral surfaces, vaginal or rectal administration. Depending on the route of administration, the formulation and/or compound may be coated with a material to protect the compound from the action of enzymes, acids and other natural conditions which may inactivate the therapeutic activity of the compound. The compound may also be administered parenterally or intraperitoneally.

Compositions for oral administration

[0204] Oral pharmaceutical dosage forms are either solid, gel or liquid. The solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets which may be enteric -coated, sugar-coated or film-coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art.

Solid compositions for oral administration

[0205] In certain embodiments, the formulations are solid dosage forms, in one embodiment, capsules or tablets. The tablets, pills, capsules, troches and the like can contain one or more of the following ingredients, or compounds of a similar nature: a binder; a lubricant; a diluent; a glidant; a disintegrating agent; a coloring agent; a sweetening agent; a flavoring agent; a wetting agent; an emetic coating; and a film coating. Examples of binders include microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, molasses, polvinylpyrrolidine, povidone, crospovidones, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrating agents include crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as saccharin, and any number of spray dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether. Emetic -coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.

[0206] The compound, or pharmaceutically acceptable derivative thereof, could be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient.

[0207] When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

[0208] The active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound or pharmaceutically acceptable derivative thereof as described herein. Higher concentrations, up to about 98% by weight of the active ingredient may be included.

[0209] In all embodiments, tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate.

Liquid compositions for oral administration

[0210] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

AMENDED CLAIMS

received by the International Bureau on 25 November 2020 (25.1 1.2020)

CLAIMS:

1. A compound of Formula I:

Formula I

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

W is F or Cl;

Y is -S(O)2- or -S(O)-;

Z is -(CH2)m- A is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Ci 6alkyl, C1-6alkenyl, or C1-6alkynyl;

each R1 is independently selected from the group consisting of X-R2, deuterium, halogen, Ci 6alkyl, -OH, -O-C1-6alkyl, -NR4R5, 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;

n is 0, 1, 2, 3, 4 or 5; and

m is 0 or 1.

2. A compound according to claim 1 of Formula la:

Formula la

or a pharmaceutically acceptable salt, solvate, hydrate or tautomeric form thereof; wherein: W is F or Cl;

Z is -(CH2)m-;

A is aryl or heteroaryl;

each R1 is independently selected from the group consisting of X-R2, deuterium, halogen, Ci 6alkyl, -OH, -O-C1-6alkyl, -NR4R5, 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 2 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, 0-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;

n is 0, 1, 2 or 5; and

m is 0 or 1.

3. The compound according to claim 1 or 2 of Formula lb:

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

W is F or Cl;

A is aryl or heteroaryl;

each R1 is independently selected from the group consisting of X-R2, deuterium, halogen, Ci 6alkyl, -OH, -O-C1-6alkyl, -NR4R5, 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 2 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;

n is 0, 1, 2 or 5; and

m is 0 or 1.

4. The compound according to any one of claims 1 to 3, wherein W is F.

5. A compound according to any one of claims 1 to 4, wherein A is selected from the group consisting of phenyl, quinolinyl, thiophenyl, furanyl and cyclopentyl.

6. A compound according to any one of claims 1 to 5, wherein A is selected from the group consisting of:

and

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

or a pharmaceutically acceptable salt, solvate, hydrate or tautomeric form thereof; wherein: each R1 is independently selected from the group consisting of X-R2, deuterium, halogen, Ci 6alkyl, -OH, -O-C1-6alkyl, -NR4R5, 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 or 5.

8. A compound according to any one of claims 1 to 7, wherein n is 0.

9. A compound according to any one of claims 1 to 8, wherein

each R1 is independently selected from the group consisting of X-R2, deuterium, C1-6alkyl, -OH, O-C1-6alkyl, heterocycloalkyl, -NR4R5, and -S(O)2R6; wherein each C1-6alkyl 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 and OCH2;

R2 is aryl optionally substituted by one or more R7;

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

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

R7 is -S(O)2R6;

and

n is 0, 1, or 5.

10. A compound according to any one of claims 1 to 9, wherein

each R1 is independently selected from the group consisting of X-R2, deuterium, methyl, OCH3, -OH, -NHCH3, heterocycloalkyl and SO2CH3;

X is O or OCH2;

R2 is phenyl substituted by SO2CH3

and

n is 0, 1 or 5.

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

or a pharmaceutically acceptable salt or solvate thereof.

12. A process for preparing a compound of Formula la:

which comprises reaction steps (C), (D), (E) and (F), where:

(C) is the reaction of a compound of Formula IV :

with a compound of Formula V or VI:

to afford a compound of Formula VII:

(D) is the reaction of a compound of Formula VII with a compound of Formula VIII or IX:

to obtain a compound of Formula X:

(E) is the oxidation of a compound of Formula X to obtain a compound of Formula XI:

; and

(F) is deprotection of a compound of Formula XI to afford a compound of Formula la:
, or a pharmaceutically acceptable salt thereof

wherein U is Br, Cl or I;

W is F or Cl;

Z is -(CH2)m-;

P1 is a nitrogen protecting group;

P2 is hydrogen or a nitrogen protecting group; or

P1 and P2 together with the nitrogen to which they are attached form a cyclic nitrogen protecting group

X+ is a metal counterion, and

R1, A, m and n are as defined in claim 1.

13. The process according to claim 12, wherein reaction step (C) is preceded by reaction steps (A) and (B), wherein:

(A) denotes the reaction of a compound of Formula II:

wherein U' is Br, Cl, I, OMs, OTs;

with a base to afford a compound of Formula III:

and

(B) denotes the reaction of a compound of Formula III with U2 to afford a compound of

Formula IV.

14. An intermediate compound of Formula VII,

wherein U, W, P1 and P2 are as defined in claim 12.

15. An intermediate compound of Formula X,

wherein W, P1 and P2 are as defined in claim 12 and R1, A, Z and n are as defined in claim 1.

16. An intermediate compound of Formula XI,

wherein W, P1 and P2 are as defined in claim 12 and R1, A, Z and n are as defined in claim 1.

17. A compound of Formula la:

prepared according to the process of claim 12, wherein W, R1, Z, A and n are as defined in claim 1.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 , or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, carrier or diluent.

19. 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 11, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 18.

20. A method of treating a condition by inhibiting the activity of any one of the LOX, LOXL1, LOXL2, LOXL3 and LOXL4 proteins, comprising administering to a subject in need thereof a therapeutically effective amount of compound according to any one of claims 1 to 11, or a

pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 18.

21. The method of claim 20, wherein the condition is selected from the group consisting of fibrosis, cancer and arthritis.

22. The method of claim 21, 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, scleroderma/systemic sclerosis, arthrofibrosis, Dupuytren's contracture, adhesive capsulitis, fibrosis of the pancreases, 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 keloid, scarring, hypertrophic scarring, scleroderma, Dupuytren's contracture and Peyronie’s disease;

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; and

wherein in a case the condition is arthritis, the arthritis is rheumatoid arthritis or osteoarthritis.

23. The method according to any one of claims 19 to 22 further comprising administering a second therapeutic agent.

24. The method according to claim 23, wherein the second therapeutic agent is selected from the group consisting of anti-cancer agent, an anti-inflammatory agent, an anti-hypertensive agent, an anti-fibrotic agent, an anti-angiogenic agent, an immunosuppressive agent, a metabolic agent, an anti-pruritic agent, an anti-fungal agent and an anti-bacterial agent.

25. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for treating a condition by inhibiting the activity of any one of the LOX, LOXL1, LOXL2, LOXL3 and LOXL4 proteins.