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

Background

[0002] A family of five closely relating enzymes have been linked to fibrotic disease and to metastatic cancer. The enzymes are related to lysyl oxidase (LOX), the first family member to be described and four closely related enzymes, LOX-likel (LOXL l), LOXL2, LOXL3, and LOXL4 (Kagan H.M. and Li W., Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. 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. Lysyl oxidase activity is essential to maintain the tensile and elastic features of connective tissues of skeletal, pulmonary, and cardiovascular systems, among others. The biosynthesis of LOX is well understood; the protein is synthesized as a pre-proLOX that undergoes a series of post-translational modifications to yield a 50 kDa pro-enzyme which is secreted into the extracellular environment. For LOX and LOXLl proteolysis by bone morphogenetic protein- 1 (BMP-1 ) and other procollagen C -proteinases releases the mature and active form. LOXL2, LOXL3 and LOXL4 contain scavenger receptor cysteine-rich protein domains and are directly secreted as active forms.

[0003] Lysyl oxidase isoenzymes belong to a larger group of amine oxidases which include flavin-dependent and copper-dependent oxidases which are described by the nature of the catalytic co-factor. Flavin-dependent enzymes include monoamine oxidase-A (MAO-A), 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 neighboring lysine residue (to form LTQ); see Kagan, H.M. and Li, W., Lysyl oxidase: Properties, specificity, and biological roles inside and outside of the cell. J Cell Biochem 2003; 88: 660-672.

[0004] Since lysyl oxidase isoenzymes exhibit different in vivo expression patterns it is likely that specific isoenzymes will have specific biological roles. Catalytically active forms of LOX have been identified in the cytosolic and nuclear compartments which suggest the existence of undefined roles of LOX in cellular homeostasis. Significant research is currently underway to define these roles. 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. See, for example, Woznick, A.R., et al. Lysyl oxidase expression in bronchogenic carcinoma. Am J Surg 2005; 189: 297-301. Catalytically active forms of LOXL2 can be also found in the nucleus (J Biol Chem. 2013;288 : 30000-30008) and can deaminate lysine 4 in histone H3 (Mo Cell 2012 46: 369-376).

[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 all of the affected organ. A variety of causes, such as chronic infections, chronic exposure to alcohol and other toxins, autoimmune and allergic reactions or 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 and kidneys. [0006] Liver fibrosis occurs 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. This is reviewed in Kagan, H.M. Lysyl oxidase: Mechanism, regulation and relationship to liver fibrosis. 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. See Lopez, B., et al. Role of lysyl oxidase in myocardial fibrosis: from basic science to clinical aspects. Am J Physiol Heart Circ Physiol 2010; 299: H 1-H9.

[0008] A strong association between fibrosis and increased lysyl oxidase activity has been demonstrated. For example, in experimental hepatic fibrosis in rat (Siegel, R.C., Chen, .H. and Acquiar, J.M, Biochemical and immunochemical study of lysyl oxidase in experimental hepatic fibrosis in the rat. Proc. Natl. Acad. Sci. USA 1978; 75: 2945-2949), in models of lung fibrosis (Counts, D.F., et al., Collagen lysyl oxidase activity in the lung decreases during bleomycin-induced lung fibrosis. J Pharmacol Exp Ther 1981; 219: 675-678) in arterial fibrosis (Kagan, H.M., Raghavan, J. and Hollander, W., Changes in aortic lysyl oxidase activity in diet-induced atherosclerosis in the rabbit. Arteriosclerosis 1981 ; 1 : 287-291.), in dermal fibrosis (Chanoki, M., et al., Increased expression of lysyl oxidase in skin with scleroderma. Br J Dermatol 1995; 133: 710-715) and in adriamycin-induced kidney fibrosis in rat (Di Donato, A., et al, Lysyl oxidase expression and collagen cross-linking during chronic adriamycin nephropathy. Nephron 1997; 76: 192-200). Of these experimental models of human disease, the most striking increases in enzyme activity are 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. 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 matrix metalloproteinases and causes degradation. Hence, any type of fibrosis should be reversed by treatment with lysyl oxidase isoenzyme inhibitors. 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 negligible 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.

[0009] BAPN (β-aminopropionitrile) is a widely used, nonselective 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 (eg. CC14, bleomycin, quartz) and tissues (eg. liver, lung and dermis). See Kagan, H.M. and Li, W., Lysyl oxidase: Properties, specificity and biological roles inside and outside of the cell. J Cell Biochem 2003; 88: 660-672.

[0010] Lysyl oxidase isoenzymes are highly regulated by Hypoxia-Induced Factor la (HIF- la) and TGF-β, the two most prominent growth factor that cause fibrosis (Halberg et al., Hypoxia-inducible factor la induces fibrosis and insulin resistance in white adipose tissue. 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. 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 tumorgenesis and tumor progression (Siddikiuzzaman, Grace, V.M and Guruvayoorappan, C, Lysyl oxidase: a potential target for cancer therapy. Inflammapharmacol 201 1 ; 19: 1 17-129). Both down and upregulation of lysyl oxidase isoenzymes in tumour tissues and cancer cell lines have been described, suggesting a dual role for lysyl oxidase isoenzymes and LOX pro-peptide as a metastasis promoter gene as well as a tumour suppressor gene.

[0011] 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, prostatic, clear cell renal cell and lung carcinomas, and in melanoma and osteosarcoma cell lines. Statistically significant clinical correlations between lysyl oxidase isoenzymes expression and tumor progression have been observed in breast, head and neck squamous cell, prostatic and clear cell renal cell carcinomas. The role of lysyl oxidase isoenzymes in tumor progression has been most extensively studied in breast cancer using in vitro models of migration/invasion and in in vivo tumorgenesis and metastasis mouse models. 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 metastasis-free survival in ER- patients and node negative patients. Lysyl oxidase isoenzymes mRNA was demonstrated to be up-regulated in

invasive and metastatic cell lines (MDA-MB-23 1 and Hs578T), as well as in more aggressive breast cancer cell lines and distant metastatic tissues compared with primary cancer tissues.

[0012] 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. In oral squamous cell carcinoma, lysyl oxidase isoenzyme mRNA expression was upregulated compared to normal mucosa.

[0013] 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 tumors that are strongly correlated with poor patient survival. Lysyl oxidase isoenzyme protein expression was increased in glioblastoma and astrocytoma tissues, and in invasive U343 and U251 cultured astrocytoma cells.

[0014] 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 (Stewart, G.D., et al., Analysis of hypoxia-associated gene expression in prostate cancer: lysyl oxidase and glucose transporter- 1 expression correlate with Gleason score. Oncol Rep 2008; 20: 1561- 1567).

[0015] Up-regulation of lysyl oxidase isoenzyme mRNA expression was detected in renal cell carcinoma (RCC) cell lines and tissues. Clear cell RCC also demonstrated lysyl oxidase isoenzyme up-regulation. Indeed, LOX over expression appeared preferentially in clear cell RCC compared to mixed clear and granular, granular, oxyphil, tubulopapillary and chromophobe RCC/ontocytomas. In clear cell RCC, smoking was associated with allelic imbalances at chromosome 5q23. 1 , where the LOX gene is localized, and may involve duplication of the gene.

[0016] 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.

[0017] The scientific and patent literature describes small molecule inhibitors of lysyl oxidase isoenzymes and antibodies of LOX and LOXL2 with therapeutic effects in animal models of fibrosis and cancer metastasis. Some known MAO inhibitors also are reported to inhibit lysyl oxidase isoenzyme (e.g., the MAO-B inhibitor Mofegiline illustrated below). This inhibitor is a member of the haloallylamine family of MAO inhibitors; the halogen in Mofegiline is fluorine. Fluoroallylamine inhibitors are described in US Patent No. 4,454, 158. There are issued patents claiming fluoroallylamines and chloroallylamines, for example MDL72274 (illustrated below) as inhibitors of lysyl oxidase (US Patents 4,943,593; 4,965,288; 5,021 ,456; 5,059,714; 5, 182,297; 5,252,608). Many of the compounds claimed in these patents are also reported to be potent MAO-B and SSAO/VAP- 1 inhibitors.

Mofegiline MDL72274.

[0018] Additional fluoroallylamine inhibitors are described US Patent 4,699,928. Other examples structurally related to Mofegiline can be found in WO 2007/120528.

[0019] 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 (1) according to the present invention.

[0020] 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 201 1/0044907.

Summary

[0021] The present invention provides substituted fluoroallylamine compounds that inhibit lysyl oxidase (LOX), lysyl oxidase-like2 (LOXL2) and other lysyl oxidase isoenzymes. Surprisingly, modification of 3 -substituted-3 -fluoroallylamine structures described previously has led to the discovery of novel compounds that are potent inhibitors of the human LOX and LOXL isoenzymes. Furthermore, certain of these novel compounds also selectively inhibit certain LOX and LOXL isoenzymes with respect to the other enzymes in the amine oxidase family.

[0022] A first aspect of the invention provides for a compound of Fonnula I:

Formula I

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

a is N or CR3;

b is N or CR4;

c is N or CR5;

d is N or CR6;

and from 0 to 2 of a, b, c and d are N;

R1 is selected from the group consisting of hydrogen, halogen, d_6alkyl, C3_7cycloalkyl, -O-C^alkyl, -0-C3_7cycloalkyl, -C(0)OR8, -C(0)NR9R10 and -NR9C(0)Ru; wherein each C,_ 6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C _7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -C,-3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3;

R2 is aryl or heteroaryl; wherein each R2 is optionally substituted by one or more R12;

R3, R4, R5 and R6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, Cj.6alkyl, C3.7cycloalkyl, -0-Ci_6alkyl, -0-C3_7cycloalkyl, -CN, -N02, -NR9R10, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Rn, -S(02)NR9R10, -NR9S(02)Rn, -S(0)Ru, -S(02)Rn, tetrazole and oxadiazole; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_f)alkyl and C .7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R8 is selected from the group consisting of hydrogen, Ci_6alkyl, and C3.7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R9 and R10 arc independently selected from the group consisting of hydrogen, Cj.6alkyl and C3_7cycloalkyl; wherein each C].6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3_7cycloalkyl is optionally substituted by one or more substitucnts selected from the group consisting of halogen, -OH, -SH, -Ci-3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF ; or

R9 and R10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;

Rn is selected from the group consisting of Ci_6alkyl and C3.7cycloalkyl; wherein each C fialkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, - SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3; and

R12 is selected from the group consisting of halogen, Cj.6alkyl, -O-CVcalkyl, -S-C^alkyl, C3_7cycloalkyl, -0-C3_7cycloalkyl, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Ru, -S(02)NR9RH), -NR9S(02)R1 1 , -S(0)Ru and -S(02)Rn; wherein each C,.6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -Ci_3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3.

[0023 ] A second aspect of the invention provides for a pharmaceutical composition comprising a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and at least one pharmaceutically acceptable excipient, carrier or diluent.

[0024] A third aspect of the invention provides for a method of inhibiting the amine oxidase activity of LOX, LOXL l , 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, solvate or prodrug thereof, or a pharmaceutical composition according to the second aspect of the invention.

[0025] A fourth aspect of the invention provides for a method of treating a condition associated with LOX, LOXL l , LOXL2, LOXL3 and LOXL4 protein, comprising administering to a subject in need thereof a therapeutically effective amount of compound according to the first aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second aspect of the invention.

[0026] A fifth aspect of the invention provides for use of a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the manufacture of a medicament for tieating a condition associated with LOX, LOXLl , LOXL2, LOXL3 and LOXL4 protein.

[0027] A sixth aspect of the invention provides for a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in treating a condition associated with LOX, LOXL l , LOXL2, LOXL3 and LOXL4 protein.

[0028] In one embodiment of the methods and uses of the present invention the condition is selected from a liver disorder, kidney disorder, cardiovascular disease, fibrosis, cancer and angiogenesis.

[0029] Contemplated herein is combination therapy in which the methods further comprise co-administering additional therapeutic agents that are used for the treatment of liver disorders, kidney disorders, cardiovascular diseases, cancer, fibrosis, angiogenesis and inflammation.

Definitions

[0030] 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 tenns alone, but are put forth for a better understanding of the following description.

[0031] 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.

[0032] 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".

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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. In the context of the present disclosure the cycloalkyl group may also have from 3 to 7 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.

[0037] 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, dihydrobenzopyranyl, 1 ,3-benzodioxolyl, 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.

[0038] 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.

[0039] 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 fiom 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 C5.8 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, quinolyl, indolyl, isoquinolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 2,2'-bipyridyl, phenanthrolinyl, quinolinyl, 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.

[0040] The term "heterocyclyl" and variants such as "heterocycloalkyl" as used herein, includes within its meaning monovalent ("heterocyclyl") and divalent ("heterocyclylene"), saturated, monocyclic, bicyclic, polycyclic or fused hydrocarbon radicals having from 3 to 10 ring atoms, wherein from 1 to 5, or from 1 to 3, ring atoms are heteroatoms independently selected from O, N, NH, or S, 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 aziridinyl, pyrrolidinyl, thiazolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, quinuclidinyl, azetidinyl, morpholinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, and the like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N-substituted uracils.

[0041] The term "halogen" or variants such as "halide" or "halo" as used herein refers to fluorine, chlorine, bromine and iodine.

[0042] The term "heteroatom" or variants such as "hetero-" or "heterogroup" as used herein refers to O, N, NH and S.

[0043] 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.

[0044] 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, haloalkynyl, hydroxyl, hydroxyalkyl, alkoxy, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, N02, NH(alkyl), N(alkyl)2, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroheterocyclyl, alkylamino, dialkylamino, alkenylamine, alkynylamino, acyl, alkenoyl, alkynoyl, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, heterocycloxy, heterocycloamino,

haloheterocycloalkyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl, heteroaryl, alkylaryl, aralkyl, alkylheteroaryl, cyano, cyanatc, isocyanate, C02H, C02alkyl, ("( O )M I -. -C(0)NH(alkyl), and -C(0)N(alkyl)2. Preferred substituents include halogen, Ci-C6alkyl, C2-C6alkenyl, Ci-C6haloalkyl, Ci-C6alkoxy, hydroxyCC f alkyl, C3-C6cycloalkyl, C(0)H, C(0)OH, NHC(0)H, NHC(0)C1-C4alkyl, C(0)C1-C4alkyl, NH2, NHd-C4alkyl, N(C C4alkyl)2, N02, OH and CN. Particularly preferred substituents include Ci-3alkyl, Ci_3alkoxy, halogen, OH, hydroxy(Ci_3)alkyl (e.g. CH2OH), C(0)Ci-C4alkyl (e.g. C(0)CH3), and C]_3haloalkyl (e.g. CF3, CH2CF3). Further preferred optional substituents include halogen, -OH, -SH, -Ci_3alkyl, -0-Cj.3alkyl, -CF3, -CH2CF3, and -0-CF3.

[0045] The term "bioisostere" refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioiosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physiochemically or topologically based.

[0046] The present invention includes within its scope all stereoisomeric and isomeric forms of the compounds disclosed herein, including all diastereomeric isomers, racemates, enantiomers and mixtures thereof. It is also understood that the compounds described by Formula 1 may be present as E and Z isomers, also known as cis and trans isomers. Thus, the present disclosure should be understood to include, for example, E, Z, cis, trans, (R), (S), (L), (D), (+), and/or (-) forms of the compounds, as appropriate in each case. Where a structure has no specific stereoisomerism indicated, it should be understood that any and all possible isomers are encompassed. Compounds of the present invention embrace all conformational isomers. Compounds of the present invention may also exist in one or more tautomeric forms, including both single tautomers and mixtures of tautomers. Also included in the scope of the present invention are all polymorphs and crystal forms of the compounds disclosed herein.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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

[0051] Figure 1 shows the ability of Compound 25 to reduce fibrosis in a rat model of liver fibrosis.

[0052] Figure 2 shows the ability of Compound 12 to reduce fibrosis in a mouse model of lung fibrosis.

[0053] Figure 3A-3C shows the ability of Compound 12 to reduce fibrosis and to improve kidney function in a mouse model of kidney fibrosis.

[0054] Figure 4 shows the ability of Compound 12 to improve kidney function in a mouse model of kidney fibrosis.

[0055] Figure 5 shows the ability of Compound 25 to reduce fibrosis after carotic ligation in a mouse model of myocardial infarction.

[0056] Figure 6 shows the ability of Compound 1 12 to reduce lilver fibrosis in a STAM™ mice model.

[0057] Figures 7a and 7b show the ability of Compound 1 12 to reduce collagen cross-link formation in an in vitro fibroblastic foci model of idiopathic pulmonary fibrosis (IPF).

Detailed Description

[0058] The present invention relates to substituted fluoroallylamine derivatives which may inhibit lysyl oxidase (LOX), lysyl oxidase-like2 (LOXL2) and other lysyl oxidase isoenzymes. In particular the present invention relates to substituted fluoroallylamine derivatives with an indole or azaindole group.

[0059] In particular the present invention relates to compounds of Formula I:

Formula I

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

a is N or CR3;

b is N or CR4;

c is N or CR5;

d is N or CR6;

and from 0 to 2 of a, b, c and d are N;

R1 is selected from the group consisting of hydrogen, halogen, Chalky 1, C3_7cycloalkyl, -O-C^alkyl, -0-C3_7cycloalkyl, -C(0)OR8, -C(0)NR9R1 () and -NR9C(0)Rn; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each d_6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -C1-3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3;

R2 is aryl or heteroaryl; wherein each R2 is optionally substituted by one or more R12;

R3, R4, R5 and R6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, Ci_6alkyl, C3_7cycloalkyl, -0-Ci_6alkyl, -0-C3_7cycloalkyl, -CN, -NO2, -NR9R10, -C(0)OR8, -C(0)NR9R10, -NR9C(0)R , -S(02)NR9R10, -NR9S(02)Rn, -S(0)Rn, -S(02)Rn, tetrazole and oxadiazole; wherein each Chalky 1 is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C _7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -C]_3alkyl, -0-Ci_3alkyI, -CF3, -CH2CF3, and -0-CF3;

R8 is selected from the group consisting of hydrogen, d-6alkyl, and C3_7cycloalkyl; wherein each Cj.6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -C].3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF , and -0-CF3;

R9 and R10 are independently selected from the group consisting of hydrogen, Ci_6alkyl and C3.7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each CV6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3; or

R9 and R10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;

R11 is selected from the group consisting of Ci_6alkyl and C3.7cycloalkyl; wherein each C^alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, - SH, -Ci_3alkyl, -0-C,_3alkyl, -CF3, -CH2CF3, and -0-CF3; and

R12 is selected from the group consisting of halogen, Ci_6alkyl, -0-C]_6alkyl, -S-C1-6alkyl, C3.7cycloalkyl, -0-C3.7cycloalkyl, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Ru, -S(02)NR9R10, -NR9S(02)Rn, -S(0)R1 1 and -S(02)Rn; wherein each C,_6alkyl is a straight or branched chain alkyl; and wherein each C].6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C^alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3

[0060] In one embodiment of compounds of the present invention none of a, b, c and d is N and a is CR3, b is CR4, c is CR5 and d is CR6 so that the compounds of Formula I are indole derivatives. In a further embodiment of compounds of the present invention one of a, b, c and d is N so that the compounds of Formula I are azaindole derivatives. In another embodiment of compounds of the present invention a is N, b is CR4, c is CR5 and d is CR6. In a further embodiment of compounds of the present invention a is CR3, b is N, c is CR3 and d is CR6. In another embodiment of compounds of the present invention a is CR3, b is CR4, c is N and d is CR6. In a still further embodiment of compounds of the present invention a is CR', b is CR4, c is CR5 and d is N. In another embodiment of compounds of the present invention two of a, b, c and d are N. In a further embodiment of compounds of the present invention a is CR', b is CR4, c is N and d is N. In another embodiment of compounds of the present invention a is CR3, b is N, c is CR5 and d is N. In another embodiment of compounds of the present invention a is N, b is CR4, c is N and d is CR6. In a further embodiment of compounds of the present invention a is CR3, b is N, c is N and d is CR6. In another embodiment of compounds of the present invention a is N, b is N, c is CR5 and d is CR6. In a further embodiment of compounds of the present invention a is N, b is CR4, c is CR5 and d is N.

[0061] In one embodiment of compounds of the present invention R1 is selected from the group consisting of hydrogen, halogen, Chalky!, C3_7cycloalkyl, -0-Ci_6alkyl, -0-C3_7cycIoaIkyl, -C(0)OR8, -C(0)NR9R'° and -NR9C(0)Rn; wherein each C^alkyl is a straight or branched chain alkyl; and wherein each Cj_6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3. In another embodiment of compounds of the present invention each R1 is independently selected from the group consisting of hydrogen, halogen, Ci_6alkyl, and -C(0)NR9R10; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3. In a further embodiment of compounds of the present invention each R1 is independently selected from the group consisting of hydrogen, halogen, Cj.3alkyl, and -C(0)N(CH3)2; wherein each Ci_3alkyl is a straight or branched chain alkyl; and wherein each C^alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and -OH. In one embodiment of compounds of the present invention R1 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, 1 -hydroxyethyl, 2-hydroxyisopropyl, chloro and -C(0)N(CH3)2. In another embodiment of compounds of the present invention R1 is selected from the group consisting of hydrogen, methyl and isopropyl. In a further embodiment of compounds of the present invention R1 is methyl. In another embodiment of compounds of the present invention R1 is isopropyl.

[0062] In one embodiment of compounds of the present invention R2 is aryl or heteroaryl where each R2 is optionally substituted by one or more R12. In another embodiment of compounds of the present invention R2 is aryl optionally substituted by one or more R12. In another embodiment of compounds of the present invention R2 is phenyl substituted by one R12. In a further embodiment of compounds of the present invention R2 is heteroaryl substituted by one or more R12. In another embodiment of compounds of the present invention R2 is heteroaryl substituted by one or more R12. In a further embodi of compounds of the present invention R2 is selected from the group

consisting

3-pyridinyl

optionally substituted more R12. In another embodiment of compounds of the present

invention R" is phenyl
substituted by one R " or 1 ,3-benzodioxolyl m a further embo

group consisti

5-pyrimidinyl
; wherein each R" is optionally substituted by one or more R ~. In another embodiment of compoun

group consisting of 2-pyridinyl

wherein each R2 is substituted by one or two R12. In a further embodiment of compounds of the

present invention R" is 3-pyridinyl
substituted by one or t In another

embodiment of compounds of the present invention R" is 3-pyridinyl
substituted by -S(0->)NR9R10 )Rn . In a further embodiment of compounds of the present invention

Rz is 3-pyridinyl
substituted by -S(02)N(CH3)2 or -S(02)CH3.

[0063] In one embodiment of compounds of the present invention R2 is substituted by one R12. In another embodiment of compounds of the present invention R2 is substituted by two R12. In another embodiment of compounds of the present invention R2 is substituted by one or two R12. In a further embodiment of compounds of the present invention R2 is substituted by three R12. In another embodiment of compounds of the present invention R2 is substituted by four or five R12.

[0064] In one embodiment of compounds of the present invention R3, R4, R^ and R6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C i_6alkyl, C3_7cycloalkyl, -0-C,_6alkyl, -0-C3.7cycloalkyl, -CN, -N02, -NR9R10, -C(0)OR8, -C(0)NR9R10, -NR9C(0)R" , -S(02)NR9R10, -NR9S(02)Rn, -S(0)Rn, -S(02)Ru, tetrazole and oxadiazole; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each C^alkyl and C3_7cycIoalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3. In another embodiment of compounds of the present invention R3, R4, R5 and R6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, CVealkyl, C3_7cycloalkyl, -0-Cj_6alkyl, -0-C3_7cycloalkyl, -CN, - N02, -NR9R10, -C(0)OR8, -C(0)NR9RI (l, -NR9C(0)Rn, -S(02)NR9R10, -NR9S(02)Ru, -S(0)Rn , -S(02)Rn ; wherein each C^alkyl is a straight or branched chain alkyl; and wherein each C^alkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH and -0-Ci_3alkyl. In a further embodiment of compounds of the present invention R3, R4, R" and R6 are each independently selected from the group consisting of hydrogen, fluoro, chloro, hydroxyl, methyl, cyclopropyl, -CN, -N02, -NH2, -C(0)OH, -C(0)OMe, -C(0)OEt, -C(0)NR9R10, -S(02)NR9R10, -NR9S(02)Ru, -S(0)Ru, -S(02)Ru, tetrazole, oxadiazole, -CH2F, -CHF2, -OCF3, -CH2OCH3, -CF3, -CHF2CH3, -C(CH3)2OH.

[0065] In one embodiment of compounds of the present invention R8 is selected from the group consisting of hydrogen, Cj.6alkyl and C3.7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each C^alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3. In another embodiment of compounds of the present invention R8 is hydrogen. In a further embodiment of compounds of the present invention R8 is Ci_6alkyl or C3.7cycloalkyl. In a still further embodiment of compounds of the present invention R8 is hydrogen or Cj.6alkyl. In another embodiment of compounds of the present invention R8 is Ci_6alkyl. In another embodiment of compounds of the present invention R8 is Ci_3alkyl. In a further embodiment of compounds of the present invention R8 is methyl or ethyl. In another embodiment of compounds of the present invention R is selected from the group consisting of hydrogen, methyl and ethyl.

[0066] In one embodiment of compounds of the present invention R9 and R10 are independently selected from the group consisting of hydrogen, Ci_6alkyl and C3_7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each d_6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -C].3alkyl, -0-C]_3aIkyl, -CF3, -CH2CF3, and -0-CF3. In another embodiment of compounds of the present invention R9 and R10 are independently selected from the group consisting of hydrogen, Ci_6alkyl and C3_7cycloalkyl. In another embodiment of compounds of the present invention R9 and RU) are independently selected from the group consisting of hydrogen and Ci_6alkyl. In another embodiment of compounds of the present invention R9 and R10 are hydrogen. In a further embodiment of compounds of the present invention R9 and R10 are Ci_6alkyl. In another embodiment of compounds of the present invention R9 and R10 are both methyl. In a further embodiment of compounds of the present invention R9 and R10 are independently selected from the group consisting of hydrogen and C3_7cycloalkyl. In another embodiment of compounds of the present invention R9 is hydrogen and RH) is Ci_6alkyl. In one embodiment of compounds of the present invention R9 is hydrogen and R10 is methyl or isopropyl. In a further embodiment of compounds of the present invention R9 is methyl and R10 is isopropyl.

[0067] In one embodiment of compounds of the present invention R9 and R10 when attached to the same nitrogen atom are combined to fonn a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members. In another embodiment R9 and R10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 1 additional heteroatoms as ring members. In a further embodiment R9 and R10 when attached to the same nitrogen atom are combined to fonn a 3- to 7-membered ring having 1 additional heteroatom as ring members. In another embodiment R9 and R10 when attached to the same nitrogen atom are combined to fonn a 3 - to 7-membered ring having 0 additional heteroatoms as ring members.

[0068] In one embodiment of compounds of the present invention R1 ' is selected from the group consisting of CV6alkyl and C3_7cycloalkyl; wherein each C]_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3. In another embodiment of compounds of the present invention R1 ' is selected from the group consisting of C halky] and C3.7cycloalkyl. In another embodiment of compounds of the present invention R1 1 is Chalky!. In a further embodiment of compounds of the present invention R11 is selected from the group consisting of methyl, ethyl and isopropyl. In another embodiment of compounds of the present invention R11 is selected from the group consisting of methyl and isopropyl. In a further embodiment of compounds of the present invention R1 1 is C3_7cycloalkyl. In another embodiment of compounds of the present invention R11 is cyclopropyl.

[0069] In one embodiment of compounds of the present invention R12 is selected from the group consisting of halogen, Ci_6alkyl, -0-C].6alkyl, -S-Ci_6alkyl, C3_7cycloalkyl,

-0-C3_7cycloalkyl, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Rn, -S(02)NR9Rl°, -NR9S(02)Ru,

-S(0)Rn and -S(02)Rn; wherein each Cj.6alkyl is a straight or branched chain alkyl; and wherein each C ealkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -Cj_3alkyl, -0-Ci_ alkyl, -CF3, -CH2CF3, and -0-CF3. In a further embodiment of compounds of the present invention R12 is selected from the group consisting of halogen, Ci_6alkyl, -0-Ci_6alkyl, -S-CVealkyl, C3.7cycloalkyl, -0-C3_7cycloalkyl,

-C(0)OR8, -C(0)NR9R10, -NR9C(0)Ru, -S(02)NR9R10, -NR9S(02)Rn, -S(0)RH and -S(02)Rn. In another embodiment of compounds of the present invention R12 is selected from the group consisting of halogen, C,.6alkyl, -0-C,_6alkyl, -S-C^alkyl, -C(0)OR8, -C(0)NR9R10, -S(02)NR9R10 -NR9S(02)R11 and -S(02)R11. In a further embodiment of compounds of the present invention R12 is selected from the group consisting of -S(02)NR9RH) and -S(02)Rn. In another embodiment of compounds of the present invention R12 is -S(02)NR9R10. In a further embodiment of compounds of the present invention R12 is -S(02)N(CH3)2. In another embodiment of compounds of the present invention R12 is -S(02)Rn . In a further embodiment of compounds of the present invention R12 is -S(02)CH3. In another embodiment of compounds of the present invention R12 is -S(02)'Pr.

[0070] In one embodiment the present invention also relates to compounds of Formula la:

the formula

or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein:

R1 is selected from the group consisting of hydrogen, halogen, Ci_6alkyl, C3_7cycloaIkyl, -0-C1-6alkyl, -0-C3-7cycloalkyl, -C(0)OR8, -C(0)NR9RU) and -NR9C(0)Rn; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each d_6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Cl-3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3;

R2 is aryl or heteroaryl; wherein each R2 is optionally substituted by one or more R12;

R3, R4, Rs and R6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, Ci_6alkyl, C3_7cycloalkyl, -0-Ci_6alkyl, -0-C3_7cycloalkyl, -CN, -NO2, -NR9R10, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Ru, -S(02)NR9R10, -NR9S(02)Rn, -S(0)Rn, -S(02)Ru, tetrazole and oxadiazole; wherein each Chalky! is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -C|.3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R8 is selected from the group consisting of hydrogen, Ci_6alkyl, and C3_7cycloalkyl; wherein each Cj.6alkyl is a straight or branched chain alkyl; and wherein each
and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Cj.3alkyl, -CF3, -CH2CF3, and -0-CF3;

R9 and R10 are independently selected from the group consisting of hydrogen, d_6alkyl and C _7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3; or

R9 and RU) when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;

Rn is selected from the group consisting of Ci_6alkyl and C3.7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, - SH, -C^alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3; and

R12 is selected from the group consisting of halogen, Ci_6alkyl, -0-CY5alkyI, -S-d^alkyl, C3.7cycloalkyl, -0-C3.7cycloalkyl, -C(0)OR8, -C(0)NR9R, (), -NR9C(0)Ru, -S(02)NR9R10, -NR9S(02)RH, -S(0)Rn and -S(02)Rn; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C^alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3.

[0071] In another embodiment of compounds of Formula la of the invention R1 is hydrogen, methyl or chlorine; R" is aryl or heteroaryl optionally substituted by one or more R12; R\ R4, R5 and R6 are each independently selected from the group consisting of hydrogen, halogen, hydroxy 1, Ci_6alkyl, C3_7cycloalkyl, -0-CV6alkyl, -0-C3_7cycloalkyl, -CN,

-N02, -NR9R10, -C(0)OR8, -C(0)NR9R10, -NR9C(0)RU, -S(02)NR9R10, -NR9S(02)RN , -S(0)RN , -S(02)RN, tetrazole and oxadiazole; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Cj.6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and -OH; and R12 is selected from the group consisting selected from the group consisting of halogen, Ci_6alkyl, -0-Ci_6alkyl, -S-C1-6alkyl, C3_7cycloalkyl, -0-C3.7cycloalkyl, -C(0)OR8, -C(0)NR9R10, -NR9C(0)RU, -S(02)NR9RH), -NR9S(02)RN , -S(0)RN and -S(02)R1 1 ; wherein each C,.6alkyl is a straight or branched chain alkyl; and wherein each Cj.6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and -OH.

[0072] In another embodiment the present invention also relates to compounds of Formula

Formula lb

or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein:

R1 is selected from the group consisting of hydrogen, halogen, Ci_6alkyl, C3.7cycloalkyl, -O-C^alkyl, -0-C3_7cycloalkyl, -C(0)OR8, -C(0)NR9R10 and -NR9C(0)Ru; wherein each C^alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci.jalkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3;

R2 is aryl or heteroaryl; wherein each R2 is optionally substituted by one or more R12;

R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, Ci_6alkyl, C3_7cycloalkyl, -0-C].6alkyl, -S-C]_6alkyl, -0-C3.7cycloalkyl, -CN, -N02, -NR9Rl°, -C(0)OR8, -C(0)NR9Rl°, -NR9C(0)Rn, -S(02)NR9R10, -NR9S(02)Rn, -S(0)Ru, -S(02)Rn, tetrazole and oxadiazole; wherein each C].6alkyl is a straight or branched chain alkyl; and wherein each Cj.6alkyl and C3.7cycloalkyl is optionally substituted by one or more

substituents selected from the group consisting of halogen, -OH, -SH, -C]_3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3;

R8 is selected from the group consisting of hydrogen, Ci_6alkyl, and C3_7cycloalkyl; wherein each Cj.6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R9 and R10 are independently selected from the group consisting of hydrogen, Ci_6alkyl and C3_7cycloalkyl; wherein each Chalky 1 is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -C,_3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3; or

R9 and R10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;

R11 is selected from the group consisting of Ci_6alkyl and C3.7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each C^alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, - SH, -Ci_3alkyl, -0-C,_3alkyl, -CF3, -CH2CF3, and -0-CF3; and

R12 is selected from the group consisting of halogen, Ci_6alkyl, -0-Ci_6alkyl, -S-C^alkyl, C3_7cycloalkyl, -0-C3_7cycloalkyl, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Ru, -S(02)NR9RH), -NR9S(02)Rn , -S(0)Rn and -S(02)R1 1 ; wherein each C ,.6alkyl is a straight or branched chain alkyl; and wherein each Cj.6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -Ci_3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3.

[0073] In one embodiment of compounds of Formula lb of the invention R1 is hydrogen, methyl, chlorine, isopropyl, 1 -hydroxyethyl, 2-hydroxyisopropyl; R2 is phenyl or 3-pyridyI optionally substituted by one or more R12; R3, R4 and R5 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C].6alkyl, cyclopropyl, -0-Ci_6alkyl, -NR9R10, -C(0)OR8 and -C(0)NR9R1(l; wherein each Ci-ealkyl is a straight or branched chain alkyl; and wherein each Cj.6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen and -OH; and R12 is selected from the group consisting selected from the group consisting of halogen, -S-Ci_6alkyl, -S(02)NR9RH), -S(0)Rn and -S(02)Rn

[0074] In a further embodiment of compounds of Formula lb of the invention R1 is hydrogen, methyl, chlorine, isopropyl, 1 -hydroxyethyl, 2-hydroxyisopropyl; R2 is phenyl or 3-pyridyl optionally substituted by one or more R12; R3, R4 and R5 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, hydroxyl, methyl, cyclopropyl, -OCH , -CF3, -CH2F, -CHF2CH3, -CH2OCH3, -C(CH3)2OH, -N(CH3)2, -C(0)OH, -C(0)OEt, -C(0)NHCH3, -C(0)N(CH3)2, -C(0)NH'Pr; and R12 is selected from the group consisting selected from the group consisting of chlorine, -S-CH3, -S(02)N(CH3)2, -S(02)CH3, -S(02)Et, -S(02)'Pr and -S(02)cyclopropyl.

[0075] In another embodiment the present invention also relates to compounds of Formula Ic:

Formula Ic

or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein:

R1 is selected from the group consisting of hydrogen, halogen, Ci_6alkyl, C3.7cycIoalkyl, -O-CLealkyl, -0-C3.7cycloalkyl, -C(0)OR8, -C(0)NR9R10 and -NR9C(0)Rn; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -C.jalkyl, -0-C, _3alkyl, -CF3, -CH2CF3, and -0-CF3;

R2 is aryl or heteroaryl; wherein each R2 is optionally substituted by one or more R12;

R3, R4 and R6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C^alkyl, C3.7cycloalkyl, -0-C,.6alkyl, -0-C3.7cycloalkyl, -CN, -N02, -NR9R10, -C(0)OR8, -C(0)NR9RH), -NR9C(0)RH , -S(02)NR9R10, -NR9S(02)Ru, -S(0)Rn, -S(02)Ru, tetrazole and oxadiazole; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each C^alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF , -CH2CF3, and -0-CF3;

R8 is selected from the group consisting of hydrogen, d-6alkyl, and C .7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each C i_6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -CV3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3;

R9 and R10 are independently selected from the group consisting of hydrogen, Ci_6alkyl and C3.7cycloalkyl; wherein each C].6alkyl is a straight or branched chain alkyl; and wherein each Chalky! and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3; or

R9 and R10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;

Rn is selected from the group consisting of Ci_f)alkyl and C3.7cycloalkyl; wherein each CV6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, - SH, -C,_3alkyl, -0-d_3alkyl, -CF3, -CH2CF3, and -0-CF3; and

R12 is selected from the group consisting of halogen, Cj.6alkyl, -O-CVcalkyl, -S-C1-6alkyI, C3.7cycloalkyl, -0-C3.7cycloalkyl, -C(0)OR8, -C(0)NR9R1(), -NR9C(0)Rn, -S(02)NR9RH), -NR9S(02)R1 1 , -S(0)Ru and -S(02)Rn; wherein each C,_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -CV3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3.

[0076] In one embodiment of compounds of Formula Ic of the invention R1 is methyl, R2 is phenyl optionally substituted by S(02)N(CH3)2 or -S(02)CH3; and R\ R4 and R6 are independently selected from the group consisting of hydrogen and methyl.

[0077] In another embodiment the present invention also relates to compounds of Fonnula Id:

Formula Id

or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein:

R1 is selected from the group consisting of hydrogen, halogen, Ci_6alkyl, C3.7cycloalkyl,

-O-C ealkyl, -0-C3_7cycloalkyl, -C(0)OR8, -C(0)NR9RH) and -NR9C(0)Ru; wherein each

Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci.jalkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3;

R2 is aryl or heteroaryl; wherein each R2 is optionally substituted by one or more R12;

R-\ R" and R are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, Chalky., C3_7cycloalkyl, -0-C,.6alkyl, -0-C3_7cycloalkyl, -CN, -N02, -NR9R10, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Rn, -S(02)NR9R10, -NR9S(02)Rn, -S(0)Rn, -S(02)Ru, tetrazole and oxadiazole; wherein each C].6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-CV3alkyl, -CF3, -CH2CF3, and -0-CF3;

R8 is selected from the group consisting of hydrogen, Ci_6alkyl, and C3.7cycloalkyl; wherein each Cj.6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -C].3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R9 and R10 are independently selected from the group consisting of hydrogen, Ci_6alkyl and C3.7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -C,_3alkyl, -0-CV3alkyl, -CF3, -CH2CF3, and -0-CF3; or

R9 and R10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;

R11 is selected from the group consisting of Ci_6alkyl and C3.7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each C^alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, - SH, -Ci_3alkyl, -0-C,_3alkyl, -CF3, -CH2CF3, and -0-CF3; and

R12 is selected from the group consisting of halogen, Ci_6alkyl, -0-Ci_6alkyl, -S-C^alkyl, C3_7cycloalkyl, -0-C3_7cycloalkyl, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Ru, -S(02)NR9RH), -NR9S(02)Rn, -S(0)Rn and -S(02)R1 1; wherein each C,.6alkyl is a straight or branched chain alkyl; and wherein each Cj.6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -Ci_3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3.

[0078] In one embodiment of compounds of Formula Id of the invention R1 is methyl; R2 is phenyl substituted by S(02)N(CH3)2; and R3, R5 and R6 are hydrogen.

[0079] In another embodiment the present invention also relates to compounds of Formula Ie:

Formula Ie

or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein:

R1 is selected from the group consisting of hydrogen, halogen, Chalky 1, C3_7cycloalkyl, -O-C^alkyl, -0-C3_7cycloalkyl, -C(0)OR8, -C(0)NR9R1 () and -NR9C(0)Rn ; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each d_6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -C1-3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3;

R2 is aryl or heteroaryl; wherein each R2 is optionally substituted by one or more R12;

R4, R5 and R6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C^alkyl, C3.7cycloalkyl, -0-C,.6alkyl, -0-C3.7cycloalkyl, -CN, -N02, -NR9R10, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Rn, -S(02)NR9R10, -NR9S(02)Ru, -S(0)Rn, -S(02)Ru, tetrazole and oxadiazole; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R8 is selected from the group consisting of hydrogen, d_6alkyl, and C3.7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -C].3alkyl, -0-Ci_3alkyl, -CF , -CH2CF3, and -0-CF3;

R9 and R10 are independently selected from the group consisting of hydrogen, Ci_6alkyl and C3_7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Chalky! and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -CV3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3; or R9 and R10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;

R11 is selected from the group consisting of Ci_6alkyl and C3_7cycloaIkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, - SH, -C,_3alkyl, -0-C,_3alkyl, -CF3, -CH2CF3, and -0-CF3; and

R12 is selected from the group consisting of halogen, Ci_6alkyl, -O-CVf.alkyl, -S-C1-6alkyl, C3.7cycloalkyl, -0-C3_7cycloalkyl, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Rn, -S(02)NR9R10, -NR9S(02)Rn, -S(0)Ru and -S(02)Rn ; wherein each C,.6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C _7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C].3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3.

[0080] In one embodiment of compounds of Formula Ie of the invention R1 is methyl, R2 is phenyl or 3-pyridyl substituted by S(02)N(CH3)2; and R4, R5 and R6 are independently selected from the group consisting of hydrogen and chlorine.

[0081] In another embodiment the present invention also relates to compounds of Formula If:

Formula If

or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein:

R1 is selected from the group consisting of hydrogen, halogen, Chalky 1, C3.7cycloalkyl, -O-C^alkyl, -0-C3_7cycloalkyl, -C(0)OR8, -C(0)NR9R1 () and -NR9C(0)Rn ; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each C^alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -d_3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3;

R2 is aryl or hctcroaryl; wherein each R2 is optionally substituted by one or more R12;

R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C^alkyl, C3_7cycloalkyl, -0-C ,_6alkyl, -0-C3_7cycloalkyl, -CN, -N02, -NR9R10, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Rn , -S(02)NR9R10, -NR9S(02)Ru, -S(0)Rn, -S(02)Rn ,

tetrazole and oxadiazole; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each CV6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and

R8 is selected from the group consisting of hydrogen, Ci_6alkyl, and C3_7cycloalkyl; wherein each Cj.6alkyl is a straight or branched chain alkyl; and wherein each
and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Cj.3alkyl, -CF3, -CH2CF3, and -0-CF3;

R9 and R10 are independently selected from the group consisting of hydrogen, Ci_6alkyl and C _7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3; or

R9 and R10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;

Rn is selected from the group consisting of Ci_6alkyl and C3.7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, - SH, -C^alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3; and

R12 is selected from the group consisting of halogen, Ci_6alkyl, -0-CY5alkyI, -S-C^alkyl, C3.7cycloalkyl, -0-C3.7cycloalkyl, -C(0)OR8, -C(0)NR9R, (), -NR9C(0)Ru, -S(02)NR9RU), -NR9S(02)RH, -S(0)Rn and -S(02)Rn; wherein each C,_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C^alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3.

[0082] In another embodiment the present invention also relates to compounds of Formula Ig:

Formula Ig

or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein:

R1 is selected from the group consisting of hydrogen, halogen, d_6alkyl, C3_7cycloaIkyl, -0-C1-6alkyl, -0-C3-7cycloalkyl, -C(0)OR8, -C(0)NR9RU) and -NR9C(0)Rn; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Cl-3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3;

R2 is aryl or heteroaryl; wherein each R2 is optionally substituted by one or more R12;

R3 and R^ are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C1-6alkyl, C3-7cycloalkyl, -0-C,.6alkyl, -0-C3.7cycloalkyl, -CN, -NO,, -NR9R10, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Rn, -S(02)NR9R10, -NR9S(02)Ru, -S(0)Rn, -S(02)Rn, tetrazole and oxadiazole; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each CV6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and

R8 is selected from the group consisting of hydrogen, Ci_6alkyl, and C3_7cycloalkyl; wherein each Cj.6alkyl is a straight or branched chain alkyl; and wherein each
and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Cj.3alkyl, -CF3, -CH2CF3, and -0-CF3;

R9 and R10 are independently selected from the group consisting of hydrogen, Ci_6alkyl and C _7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3; or

R9 and R10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;

Rn is selected from the group consisting of Ci_6alkyl and C3.7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, - SH, -C^alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3; and

R12 is selected from the group consisting of halogen, Ci_6alkyl, -0-CY5alkyI, -S-d^alkyl, C3.7cycloalkyl, -0-C3.7cycloalkyl, -C(0)OR8, -C(0)NR9R, (), -NR9C(0)Ru, -S(02)NR9R10, -NR9S(02)RH, -S(0)Rn and -S(02)Rn; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -C^alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3.

[0083] 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).

[0084] Exemplary compounds according to the present invention include the compounds set forth in Table 1 :

Table 1

(Z)-3-(l -(4-amino-2-fluorobut-2-en-l -yl)- 5-(Λ' A7-dimethylsulfamoyl)-2 -methyl- 1 H- indol-3-yl)benzoic acid

(Z)- 1 -(4-amino-2-fluorobut-2-en- 1 -yI)-3 - ( 3 - (N, N-dimethyl sulfamoyl )pheny I ) -Ν - isopropyl-2 -methyl- 1 H-indole-5- carboxamide

(Z)- l -(4-amino-2-fluorobut-2-en- l-yl)-3- (3-(N,N-dimethyIsulfamoyl)phenyl)-N- isopropyl-N,2-dimethyl- lH-indole-5- carboxamide

(Z)-3-(l -(4-amino-2-fluorobut-2-en- 1 -yl)- 5 -hydr oxy-2 -methyl- 1 H-indol-3 -yl) -N N- dimethylbenzenesulfonamide

1 -yl)-

- 1 ) -

(Z)-3-(l -(4-amino-2-fluorobut-2-en-l -yl)- 5-(difluoromethyl)-2 -methyl- lH-indol-3- yl) -N, N-dimethyl benzene-sulfonamide

(Z)-3-(l -(4-amino-2-fluorobut-2-en- 1 -yl)- 5-hydroxy-2-methyl-lH-pyrrolo[ 3,2- b ]pyridin-3 -yl)-N, N-dimethylbenzene- sulfonamide

(Z)-3-(l -(4-amino-2-fluorobut-2-en- 1 -yl)- 5 -methoxy-2 -methyl- lH-pyrrolo[ 3,2- b ]pyridin-3-yl)-N,N-dimethylbenzene- sulfonamide

(Z)-3-(l -(4-amino-2-fluorobut-2-en- 1 -yl)- 5-chloro-2-methyl- 1 H-indol-3 -yl)-NN- dimethylbenzenesulfonamide

(Z)-5-(l -(4-amino-2-fluorobut-2-en-l -yl)- 63 2-methyl- lH-indol-3-yl)-NN- dimethylpyridine-3 -sulfonamide

(Z)-5-( 1 -(4-amino-2-fluorobut-2-en- 1 -yl)- 64 5-chloro-2-methyl- lH-indol-3-yl)-N,N- dimethylpyridine-3 -sulfonamide

(Z)-4-(5-chloro-2-methyl-3-(5- 65 (methylsulfonyl)pyridin-3 -yl)- 1 H-indol- 1 - yl)-3-fluorobut-2-en-l -amine

(Z)-5-(l -(4-amino-2-fluorobut-2-en-l -yl)- 66 5-chloro - 1 H-indol-3 -yl)-N N- dimethylpyridine-3 -sulfonamide

[ 3 ,2-

1 -yl)- -yl)-

(Z)-4-(5-chloro-2-methyl-3-(pyridin-3-yl)- 77

1H-indol-1-yl) -3-fluorobut-2-en-l -amine

(Z)-6-(l -(4-amino-2-fluorobut-2-en-l -yl)- 78 5-chloro-2-methyl- lH-indol-3-yl)-NN- dimethylpyridine-2 -sulfonamide

(Z)-5-(l -(4-amino-2-fluorobut-2-en- 1 -yl)- 79 5 -cycl opropy 1-2 -methyl - 1 H-indol -3 -yl ) - N, A'-dimethylpyridme-3 -sulfonami de

(Z)-4-(5-chloro-2-methyl-3-(pyrimidin-5- 80 yl)- 1 H-indol - 1 -yl)-3 -fluorobut-2-en- 1 - amine

(Z)- 1 -(4-amino-2-fluorobut-2-en- 1 -yl)- 81 N, N,2-trimethy l-3-(pyridin-4-yl)- 1 H- indole-5-sulfonamide

(Z)-5-(l -(4-amino-2-fluorobut-2-en-l -yl)- 2-chloro- lH-indol-3-yl)-N,N- dimethylpyridine-3 -sulfonamide

(Z)-3-( 1 -(4-amino-2-fluorobut-2-en- 1 -yl)- 2-methyl -5 -(methylsulfony 1)- 1 H-indol -3 - yl)-NN-dimethylbenzenesulfonamide

(Z)-3-fluoro-4-(3-(2-methoxypyridin-4- yl)-2 -methyl -5 -(methylsulfony 1)- 1 H- indol- 1 -yl)but-2-en- 1 -amine

(Z)-3-( 1 -(4-amino-2-fluorobut-2-en- 1 -yl)- 2-chloro- 1 H-pyrrolo[3,2-b ]pyridin-3-yl)- NN-dimethylbenzenesulfonamide

(Z)-3-(l -(4-amino-2-fluorobut-2-en- 1 -yl)- 2-chloro-5-(methylsulfonyl)-] H-indol-3- yl)-A',N-dimethylbenzenesulfonamide

-yl) - -yl) - o [3, 2-

Preparation of Compounds of Formula I

[0085] 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). [0086] Compounds of Formula I may be synthesised as described below. The following schemes provide an overview of representative non-limiting embodiments of the invention. Those skilled in the art will recognize that analogues of Formula I, including different isomeric forms, may also be prepared from the analogous starting materials.

Scheme 1:

[0087] The preparation of compounds described by Formula 1 is described in Scheme 1 below.

b.a N02

Formula II Formula I Formula IV Formula V

Method C

Formula IX Formula VIII Formula VII Formula VI

+

Formula I

Scheme 1

[0088] P' is a functional group used to protect a nitrogen functionality. Examples of P1 are carbonates such as the fer/-butyloxycarbonyl (BOC), the 9-fluorenylmethyloxycarbonyl (FMOC), and the benzyloxycarbonyl (CBZ) groups.

[0089] 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. Method A involves reaction of this starting material with the anion derived from an appropriately substituted 1,3-dicarbonyl compound, as is described by Formula III. For example, a solution of compounds described by Formulae II and III in a solvent such as N,N-dimethylformamide (DMF) can be

treated with a base, such as potassium carbonate, at ambient temperatures for up to 24 hours. The product described by Formula IV can be recovered by standard work-up procedures.

[0090] One convenient protocol for the conversion of compounds described by Formula IV to compounds described by Formula V is Method B which involves heating at 155 °C in DMSO/H20 (10: 1) for several hours. The product described by Formula V can be recovered by standard work-up procedures.

[0091] One convenient protocol for the conversion of compounds described by Formula V to compounds described by Formula VI is Method C which involves heating with palladium on carbon and ammonium formate at 70 °C in methanol for several hours. The product described by Formula VI can be recovered by standard work-up procedures.

[0092] One convenient protocol for the conversion of compounds described by Formula VI to compounds described by Formula VII is Method D which involves reaction with 1 -bromopyrrolidine-2,5-dione in dichloromethane at ambient temperatures for 1 hour followed by the in situ incorporation of a suitable protecting group. For example if P1 is a BOC protecting group, reaction with 4-(dimethylamino) pyridine and di-ter/-butyl dicarbonate will afford the desired protected product. The protected product described by Formula VII can be recovered by standard work-up procedures.

[0093] In general Scheme 1 Method E involves the use of a Suzuki coupling reaction to combine compounds described by Formulae VII and VIII. There are numerous variants of the Suzuki reaction described in the literature. For example, a solution of the compounds described by Formulae VII and VIII, in the presence of K2C03- can be dissolved in a solvent such as aqueous dioxane under an atmosphere of nitrogen, then treated with a catalytic amount of tetrakis(triphenyIphosphine)palladium(0) and heated at reflux for several hours. Following standard extraction and purification methods, the protected coupled product can be obtained. Conversion of the protected compound to compounds described by Formula IX is readily achieved by the method best suited to removal of the particular protecting group.

[0094] Whilst there are many ways to achieve the reaction described by Method F, one convenient protocol involves reaction of compounds described by Formulae IX and X with a base such as cesium carbonate in a solvent such as N,iV-dimethylformamide (DMF) at ambient temperature for approximately 16 hours. Following standard extraction and purification methods the product described by Formula XI can be obtained in good yield and purity.

[0095] There are many well established chemical procedures for the deprotection of the compounds described by Formula XI to the compounds described by Formula I (Method G). For example if P1 is a BOC protecting group, compounds described by Formula XI can be treated with an acidic reagent such as dry hydrogen chloride in a solvent such as diethyl ether or dichloromethane to furnish the compounds described by Formula I 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, methanesulfonate and toluenesulfonate salts.

[0096] Cisl 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

[0097] 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.

[0098] 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, LOXLl, LOXL2, LOXL3 and LOXL4. In one embodiment the invention provides for the selective inhibition of specific lysyl oxidase isoenzymes. In another embodiment the invention provides for the simultaneous inhibition of 2, 3 or 4 LOX isoenzymes. The relative inhibitory potencies of the compounds can be determined by the amount needed to inhibit the amine oxidase activity of LOX, LOXLl, 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.

[0099] Accordingly, a further aspect of the invention is directed to a method of inhibiting the amine oxidase activity of LOX, LOXLl, LOXL2, LOXL3 and 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.

[0100] 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.

[0101] 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 and other members of the amine oxidase family.

[0102] The present invention also discloses methods to use the compounds described by Fonnula 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, LOXL l , LOXL2, LOXL3 and LOXL4) in patients suffering from cancer, including metastatic cancer, and methods to treat cancer and metastatic cancer.

[0103] In a further aspect of the invention there is provided a method of treating a condition associated with LOX, LOXLl , LOXL2, LOXL3 and LOXL4 protein, comprising administering to a subject in need thereof a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0104] In another aspect there is a provided a method of treating a condition modulated by LOX, LOXLl , 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.

[0105] In one embodiment of the methods of the present invention the condition is selected from the group consisting of fibrosis, cancer and angiogenesis.

[0106] In another aspect, the present invention provides a method for decreasing extracellular matrix formation by treating human subjects, pets and livestock with fluoroallylamine inhibitors of lysyl oxidase isoenzyme family of Formula I as described herein.

[0107] The above-described methods are applicable wherein the condition is a liver disorder. As described herein the term "liver disorder" includes any disorder affecting the liver, and in particular any acute or chronic liver disease that involves the pathological disruption, inflammation, degeneration, and/or proliferation of liver cells. In particular, the liver disorder is liver fibrosis, liver cirrhosis, or any other liver disease in which the level in the plasma of some markers of hepatocellular injury, alteration or necrosis, is elevated when compared to normal plasma levels. These biochemical markers associated to liver activity and status can be selected among those disclosed in the literature and in particular Alanine aminotransferase (ALAT), Aspartate aminotransfersase (ASAT), Alkaline Phosphatase (AP), Gamma Glutamyl transpeptidase (GGT), Cytokeratin-18 (CK- 18) or Resistin. In a particular embodiment, the liver disorder is a fatty liver disease in which the elevation of one or more of these markers is associated to a more or less significant steatosis in the liver, as it can be confirmed by a liver biopsy. A non-exhaustive list of fatty liver diseases includes non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and fatty liver disease associated to disorders such as hepatitis or metabolic syndrome (obesity, insulin resistance, hypertriglyceridemia, and the like). In one embodiment the liver disorder is selected from the group consisting of biliary atresia, cholestatic liver disease, chronic liver disease, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), hepatitis C infection, alcoholic liver disease, primary biliary cirrhosis (PBC), primary schlerosing cholangitis (PSC), liver damage due to progressive fibrosis, liver fibrosis and liver cirrhosis.

[0108] The above-described methods are applicable wherein the condition is a kidney disorder. In one embodiment the kidney disorder is selected from the group consisiting of kidney fibrosis, renal fibrosis, acute kidney injury, chronic kidney disease, diabetic nephropathy, glomerulosclerosis, vesicoureteral reflux, tubulointerstitial renal fibrosis and glomerulonephritis.

[0109] The above-described methods are applicable wherein the condition is a cardiovascular disease. In one embodiment the cardiovascular disease is selected from the group consisting of atherosclerosis, arteriosclerosis, hypercholesteremia, and hyperlipidemia.

[0110] 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, ocular fibrosis, Peyronie's disease, scarring and other diseases where excessive fibrosis contributes to disease pathology including Crohn's disease and inflammatory bowel disease.

[0111] In one embodiment the fibrosis is selected from the group consisting of liver fibrosis, lung fibrosis, kidney fibrosis, cardiac fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis, radiation-induced fibrosis and scleroderma or is associated with respiratory disease, abnormal wound healing and repair, post-surgical operations, cardiac arrest and all conditions where excess or aberrant deposition of fibrous material is associated with disease. In another embodiment the fibrosis is selected from the group consisting of liver fibrosis, lung fibrosis, kidney fibrosis, cardiac fibrosis, and scleroderma.

[0112] 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, and mesangiocapiUary 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 steatohepantis (ASH), non-alcoholic steatohepatiris (NASH), primary biliary cirrhosis (PBC), biliary cirrhosis, and autoimmune hepatitis.

[0113] The above-described methods are also applicable wherein the condition is 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, medullablastoma, and other tumors of the brain; kidney cancer; myelofibrosis, cancer of the head and neck; cancer of the stomach; multiple myeloma; testicular cancer; germ cell tumor; neuroendocrine tumor; cervical cancer; oral cancer; carcinoids of the gastrointestinal tract, breast, and other organs; signet ring cell carcinoma; mesenchymal tumors 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.

[0114] 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.

[0115] 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 tumors.

[0116] In one embodiment ovarian carcinoma includes ovarian epithelial carcinoma or surface epithelial-stromal tumour including serous tumour, endometrioid tumor and mucinous cystadenocarcinoma, and sex-cord-stromal tumor. In one embodiment liver and bile duct carcinoma includes hepatocelluar carcinoma, cholangiocarcinoma and hemangioma. In one embodiment esophageal carcinoma includes esophageal adenocarcinoma and squamous cell carcinoma. In one embodiment carcinoma of the uterus includes endometrial adenocarcinoma, uterine papillary serous carcinoma, uterine clear-cell carcinoma, uterine sarcomas and leiomyosarcomas and mixed mullerian tumors. In one embodiment kidney cancer includes renal cell carcinoma, clear cell carcinoma and Wilm's tumor. 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 tumor.

[0117] In one embodiment, the cancer is selected from the group consisting of colon cancer, ovarian cancer, lung cancer, esophageal carcinoma, breast cancer and prostate cancer.

[0118] The above-described methods are applicable wherein the condition is angiogenesis.

[0119] 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.

[0120] 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 associated with LOX, LOXL1 , LOXL2, LOXL3 and LOXL4 protein.

[0121] 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 LOX, LOXL1 , LOXL2, LOXL3 and LOXL4.

Pharmaceutical and/or Therapeutic Formulations

[0122] 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.

[0123] 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.

[0124] 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, and the like).

[0125] 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.

[0126] S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 6(5: 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, ethanes ulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Suitable base salts are formed from bases that form non-toxic salts. Examples include the aluminium, 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, tetramethyl ammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, triethanolamine and the like.

[0127] 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.

[0128] 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.

[0129] 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, oxalic 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 incl ude acid addition salts.

[0130] 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.

[0131] 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 sulfhydryl 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 sulfhydryl 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(0)alkyl, -C(0)cycloalkyl, -C(0)aryl, -C(0)-arylalkyl,

C(0)heteroaryl, -C(0)-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).

[0132] 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 fonnulations 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).

[0133] In the compositions, effective concentrations of one or more compounds or pharmaceutically acceptable derivatives thereof is (are) mixed with a suitable pharmaceutical earner. 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.

[0134] 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.

[0135] 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 in PCT publication WO 04/018997, and then extrapolated from there for dosages for humans.

[0136] The concentration of active compound in the pharmaceutical composition will depend on absorption, distribution, inactivation and excretion 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.

[0137] In one embodiment, a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.1 ng/mL to about 50 - 100 μg/mL. The pharmaceutical compositions, in another embodiment, should provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day. Pharmaceutical dosage unit forms are prepared to provide from about 0.01 mg, 0.1 mg or 1 mg to about 500 mg, 1000 mg or 2000 mg, and in one embodiment from about 10 mg to about 500 mg of the active ingredient or a combination of essential ingredients per dosage unit form.

[0138] 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 1 g per kg of body weight per dosage. The dosage is preferably in the range of 1 μ to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to 1 g per kg of body weight per dosage. Suitably, the dosage is in the range of 1 μg to 500 mg per kg of body weight per dosage, such as 1 μg to 200 mg per kg of body weight per dosage, or 1 μg to 100 mg per kg of body weight per dosage. Other suitable dosages may be in the range of 1 mg to 250 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 μg to 100 mg per kg of body weight per dosage.

[0139] 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.

[0140] 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 TWEEN5, 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.

[0141] 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 earner or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.

[0142] The pharmaceutical compositions are provided for administration to humans and animals in unit dosage fonns, 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. 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 fonns 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 ampoles and syringes and individually packaged tablets or capsules. Unit-dose forms may be administered in fractions or multiples thereof. A multiple-dose fonn is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose fonn. Examples of multiple-dose fonns include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit-doses which are not segregated in packaging.

[0143] Actual methods of preparing such dosage fonns 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.

[0144] Dosage fonns 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%).

Modes of Administration

[0145] Convenient modes of administration include injection (subcutaneous, intravenous, etc.), oral administration, inhalation, transdermal application, topical creams or gels or powders, 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

[0146] Oral pharmaceutical dosage fonns 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 fonn with the combination of other ingredients known to those skilled in the art.

Solid compositions for oral administration

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

WE CLAIM

1. A compound of Formula I:

Formula I

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

a is N or CR3;

b is N or CR4;

c is N or CR5;

d is N or CR6;

and from 0 to 2 of a, b, c and d are N;

R1 is selected from the group consisting of hydrogen, halogen, d-6alkyl, C3.7cycloa.kyl, -0-Ci.6alkyl, -0-C3_7cycloalkyl, -C(0)OR8, -C(0)NR9R10 and -NR9C(0)RH ; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_ 6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R2 is aryl or heteroaryl; wherein each R2 is optionally substituted by one or more R12;

R3, R4, Rs and R6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, Ci_6alkyl, C3.7cycloalkyl, -0-Ci_6alkyl, -0-C3_7cycloalkyl, -CN, -N02, -NR9R'°, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Ru, -S(02)NR9R10, -NR9S(02)Ru, -S(0)Rn, -S(02)Rn , tetrazole and oxadiazole; wherein each d_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3_7cycIoaIkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -O-Cjalkyl, -CFj, -CH2CF3, and -0-CF3;

R is selected from the group consisting of hydrogen, C i_6alkyl, and C3-7cycIoalkyl; wherein each Cj.6alkyl is a straight or branched chain alkyl; and wherein each C j. 6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci-3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R and RU) are independently selected from the group consisting of hydrogen,

Cl-6alkyl and C3.7cycloalkyl; wherein each C] -6alkyl is a straight or branched chain alkyl; and wherein each C]-6aIkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3; or

R9 and R10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;

Rn is selected from the group consisting of Chalky! and C3.7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each C i_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, - SH, -C halky], -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3; and

R12 is selected from the group consisting of halogen, Cj.6alkyl, -0-Ci_5alkyl, -S-C, _6alkyl, C .7cycloalkyl, -0-C3_7cycloalkyl, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Ru, -S(02)NR9RH), -NR9S(02)Rn , -S(0)Ru and -S(02)Rn; wherein each C,.6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -Ci_3alkyl, -0-Ci_ 3alkyl, -CF3, -CH2CF3, and -0-CF3.

2. A compound acc la la:

Formula la

or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein:

R1 is selected from the group consistmg of hydrogen, halogen, C].6alkyl, C3-7cycIoalkyl, -0-CJ -6alkyl, -0-C3-7cycIoalkyl, -C(0)OR8, -C(0)NR9R10 and -NR9C(0)Rn; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each d_ 6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-C ] -3alkyl, -CF3, -CH2CF3, and -0-CF3;

R2 is aryl or heteroaryl; wherein each R2 is optionally substituted by one or more R12;

R3, R4, R5 and R6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C ^alkyl, C3.7cycloalkyl, -0-Ci_6alkyl, -0-C3.7cycloalkyl, -CN, -N02, -NR9Rl(), -C(0)OR8, -C(0)NR9R1(), -NR9C(0)Rn , -S(02)NR9RU), -NR9S(02)Rn, -S(0)Ru, -S(02)Ru, tetrazole and oxadiazole; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Cj.3alkyl, -O-Ci-3alkyl, -CF3, -CH2CF3, and -0-CF3;

R8 is selected from the group consisting of hydrogen, C i_6alkyl, and C3_7cycloalkyl; wherein each d-6alkyl is a straight or branched chain alkyl; and wherein each CY 6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R9 and R10 are independently selected from the group consisting of hydrogen, Ci_6alkyl and C3.7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci.3alkyl, -CF3, -CI 1 ( 1· ;. and -0-CF3; or

R9 and R10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;

R11 is selected from the group consisting of Ci_6alkyl and C3.7cycloalkyl; wherein each C^alkyl is a straight or branched chain alkyl; and wherein each C^alkyl and C3.7cycIoalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, - SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CI I ( \. and -0-CF3; and

R12 is selected from the group consisting of halogen, Ci_6alkyl, -O-C^alkyl, -S-C^alkyl, C3_7cycloalkyl, -0-C3.7cycloalkyl, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Ru,

-S(02)NR9R10, -NR9S(02)RH, -S(0)Rn and -S(02)Rn; wherein each C,.6alkyl is a straight or branched chain alkyl; and wherein each d_6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -Ci_3alkyl, -0-Ci_ 3alkyl, -CF3, -CH2CF3, and -0-CF3.

3. A compound according to claim 1 , of Formula lb:

Formula lb

or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein:

R1 is selected from the group consisting of hydrogen, halogen, Ci_6alkyl, C3_7cycloalkyl, -O-C^alkyl, -0-C3_7cycloalkyl, -C(0)OR8, -C(0)NR9RK) and -NR9C(0)Rn ; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Cj. 6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R2 is aryl or heteroaryl; wherein each R2 is optionally substituted by one or more R12;

R \ R4 and R5 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, Ci_6alkyl, C3.7cycloalkyl, -0-C!_6alkyl, -0-C3_7cycloalkyl, -CN, -N02, -NR9R10, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Rn, -S(02)NR9R10, -NR9S(02)Ru, -S(0)Ru, -S(02)Ru, tetrazole and oxadiazole; wherein each Ci_f)alkyl is a straight or branched chain alkyl; and wherein each Ci_5alkyl and C .7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -C alkyl, -O-Cualkyl, -CF3, -CH2CF3, and -0-CF3;

R8 is selected from the group consisting of hydrogen, CV6alkyl, and C3.7cycloalkyl; wherein each Cj.6alkyl is a straight or branched chain alkyl; and wherein each Cj. 6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R9 and R10 arc independently selected from the group consisting of hydrogen,

Ci_6alkyl and C3_7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each C].6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3; or

R9 and R10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;

R11 is selected from the group consisting of Ci_6alkyl and C3.7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each d.6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, - SH, -C].3alkyl, -0-CV3alkyl, -CF3, -CH2CF3, and -0-CF3; and

R12 is selected from the group consisting of halogen, Ci_6alkyl, -0-C]_6alkyl, -S-C1-6alkyl, C3.7cycloalkyl, -0-C3.7cycloalkyl, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Ru, -S(02)NR9R10, -NR9S(02)R11, -S(0)Ru and -S(02)Rn ; wherein each C ,_6alkyl is a straight or branched chain alkyl; and wherein each C].6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -Ci_3alkyl, -0-CV 3alkyl, -CF3, -CH2CF3, and -0-CF3.

4. A compound acc la Ic:

Formula Ic

or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein:

R1 is selected from the group consisting of hydrogen, halogen, C]-6alkyl, C3_7cycloalkyl, -O-C^alkyl, -0-C _7cycloalkyl, -C(0)OR8, -C(0)NR9R10 and -NR9C(0)R" ; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_ 6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R2 is aryl or heteroaryl; wherein each R2 is optionally substituted by one or more R12;

R3, R4 and R6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, Ci_6alkyl, C3_7cycloaIkyl, -0-Ci_6alkyl, -0-C3_7cycloalkyl, -CN, -N02, -NR9R10, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Rn, -S(02)NR9RK), -NR9S(02)Ru, -S(0)Ru, -S(02)Ru, tetrazole and oxadiazole; wherein each C i_6alkyl is a straight or branched chain alkyl; and wherein each Ci_5alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -C]_3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3;

R8 is selected from the group consisting of hydrogen, C i_6alkyl, and C3_7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_ 6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R9 and R10 are independently selected from the group consisting of hydrogen, Ci_6alkyl and C3_7cycloalkyl; wherein each d_6alkyl is a straight or branched chain alkyl; and wherein each C]_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3; or

R9 and R10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;

R11 is selected from the group consisting of Ci_6alkyl and C3.7cycloaIkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each C i_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, - SH, -C i_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3; and

R12 is selected from the group consisting of halogen, Ci_6alkyl, -0-CY5alkyI, -S-C^alkyl, C3_7cycloalkyl, -0-C3_7cycloalkyl, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Rn , -S(02)NR9RU), -NR9S(02)RH, -S(0)Rn and -S(02)Rn ; wherein each C,.6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -CYjalkyl, -0-CV 3alkyl, -CF3, -CH2CF3, and -0-CF3.

5. A compound according to claim 1 , of Formula Id:

Formula Id

or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein:

R1 is selected from the group consisting of hydrogen, halogen, C]-6alkyl, C3_7cycloalkyl, -O-C^alkyl, -0-C _7cycloalkyl, -C(0)OR8, -C(0)NR9R10 and -NR9C(0)R" ; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_ 6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R2 is aryl or heteroaryl; wherein each R2 is optionally substituted by one or more R12;

R ' , R-" and R" are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, Ci_6alkyl, C3_7cycloalkyl, -0-Ci_6alkyl, -0-C3.7cycIoalkyl, -CN, -N02, -NR9R10, -C(0)OR8, -C(0)NR9R10, -NR9C(0)RU, -S(02)NR9RI (), -NR9S(02)RU , -S(0)RU, -S(02)RU, tetrazole and oxadiazole; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -O-C^alkyl, -CF,, -CH2CF3, and -0-CF3;

R8 is selected from the group consisting of hydrogen, C i_6alkyl, and C3.7cycIoalkyl; wherein each Cj.6alkyl is a straight or branched chain alkyl; and wherein each Cj. 6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R and R U) are independently selected from the group consisting of hydrogen, CV6alkyl and C3.7cycloalkyl; wherein each C].6alkyl is a straight or branched chain alkyl; and wherein each C]_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3; or

R9 and R10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;

R11 is selected from the group consisting of Ci_6alkyl and C3_7cycloaIkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each C i_6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, - SH, -C i_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3; and

R12 is selected from the group consisting of halogen, Ci_6alkyl, -0-CY5alkyI, -S-C^alkyl, C3_7cycloalkyl, -0-C3_7cycloalkyl, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Rn , -S(02)NR9RU), -NR9S(02)RH, -S(0)Rn and -S(02)Rn ; wherein each C,.6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -Ci_3alkyl, -0-Ci_ 3alkyl, -CF3, -CH2CF3, and -0-CF3.

6. A compound acc la le:

Formula Ie

or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein:

R1 is selected from the group consisting of hydrogen, halogen, C].6alkyl, C3_7cycloalkyl, -O-C^alkyl, -0-C _7cycloalkyl, -C(0)OR8, -C(0)NR9R10 and -NR9C(0)R" ; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_ f,alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R2 is aryl or heteroaryl; wherein each R2 is optionally substituted by one or more R12;

R4, R5 and R6 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, Ci_6alkyl, C3.7cycloalkyl, -0-Ci_6alkyl, -0-C3.7cycIoalkyl, -CN, -N02, -NR9R1 (), -C(0)OR8, -C(0)NR9R10, -NR9C(0)R1 1 , -S(02)NR9R1 0, -NR9S(02)RU , -S(0)R1 1 , -S(02)RU, tetrazole and oxadiazole; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each C,_6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -O-Cioalkyl, -CF3, -CH2CF3, and -0-CF3;

R8 is selected from the group consisting of hydrogen, Ci_6alkyl, and C3_7cycloalkyl; wherein each C].6alkyl is a straight or branched chain alkyl; and wherein each C]_ 6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-C i_3alkyl, -CF , -CH2CF3, and -0-CF3;

R9 and R10 are independently selected from the group consisting of hydrogen, C^alkyl and C3.7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3; or

R9 and R10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;

selected from the group consisting of Ci_6alkyl and C3.7cycloalkyl; wherein each

CV6alkyl is a straight or branched chain alkyl; and wherein each C ^alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, - SH, -CV3aIkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3; and

R12 is selected from the group consisting of halogen, d_6alkyl, -0-Ci_6alkyl, -S-C^alkyl, C3.7cycloalkyl, -0-C3.7cycloalkyl, -C(0)OR8, -C(0)NR9R10, -NR9C(0)R1 1 , -S(02)NR9Rll), -NR9S(02)Ru , -S(0)Rn and -S(02)R11 ; wherein each C1-6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -Ci_3alkyl, -O-CV 3alkyl, -CF3, -CH2CF3, and -0-CF .

7. A compound acc la If:

Formula If

or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein:

R1 is selected from the group consisting of hydrogen, halogen, d-6alkyl, C3.7cycloa.kyl, -0-Ci.6alkyl, -0-C3_7cycloalkyl, -C(0)OR8, -C(0)NR9R10 and -NR9C(0)RH ; wherein each Ci-6alkyl is a straight or branched chain alkyl; and wherein each Cj. 6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R2 is aryl or heteroaryl; wherein each R2 is optionally substituted by one or more R12;

R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, Ci_6alkyl, C3_7cycloalkyl, -O-C^alkyl, -0-C _7cycloalkyl, -CN, -N02, -NR9R'°, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Ru, -S(02)NR9R10, -NR9S(02)Ru, -S(0)Rn, -S(02)Rn , tetrazole and oxadiazole; wherein each d_6alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and C3.7cycIoalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -O-Cjalkyl, -CFj, -CH2CF3, and -0-CF3;

R8 is selected from the group consisting of hydrogen, d_6alkyl, and C3.7cycloalkyl; wherein each Cj.6alkyl is a straight or branched chain alkyl; and wherein each Cj. 6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-C i_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R9 and R10 are independently selected from the group consisting of hydrogen, Ci_6alkyl and C3.7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each Chalky 1 and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3; or

R9 and R10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;

R11 is selected from the group consisting of Ci_6alkyl and C3.7cycloalkyl; wherein each Chalky! is a straight or branched chain alkyl; and wherein each C].6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, - SH, -C].3alkyl, -0-d_3alkyl, -CF3, -CH2CF3, and -0-CF3; and

R12 is selected from the group consisting of halogen, d_6alkyl, -0-Ci-6alkyl, -S-C^alkyl, C3-7cycIoalkyl, -0-C3-7cycloalkyl, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Rn , -S(02)NR9R10, -NR9S(02)R1 1, -S(0)Ru and -S(02)Rn; wherein each d^alkyl is a straight or branched chain alkyl; and wherein each Ci_6alkyl and d-7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -d_3alkyl, -O-d 3alkyl, -CF3, -CH2CF3, and -0-CF .

8. A compound according to claim 1 , of Formula Ig:

Formula Ig

or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein:

R1 is selected from the group consisting of hydrogen, halogen, C i_6alkyl, d_7cycloalkyl, -0-Ci-6alkyl, -0-C3_7cycloalkyl, -C(0)OR8, -C(0)NR9R10 and -NR9C(0)R11 ; wherein each Ci-6alkyl is a straight or branched chain alkyl; and wherein each d_ 6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -0-Ci_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R2 is aryl or heteroaryl; wherein each R2 is optionally substituted by one or more R12;

R3 and R5 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, Ci.ealkyl, C3.7cycloalkyl, -0-Ci_6alkyl, -0-C3.7cycloalkyl, -CN, -N02, -NR9R10, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Ru, -S(02)NR9R10, -NR9S(02)Ru, -S(0)Ru, -S(02)Ru, tetrazole and oxadiazole; wherein each d_6alkyl is a straight or branched chain alkyl; and wherein each d_6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -O-d_3alkyl, -CF3, -CH2CF3, and -0-CF3;

R8 is selected from the group consisting of hydrogen, d_6alkyl, and C3.7cycloalkyl; wherein each C].6alkyl is a straight or branched chain alkyl; and wherein each d_ 6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -d_3alkyl, -0-Cj.3alkyl, -CF3, -CH2CF3, and -0-CF3;

R9 and R10 arc independently selected from the group consisting of hydrogen, Ci_6alkyl and C3_7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each C].6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -SH, -Ci_3alkyl, -O-C^alkyl, -CF3, -CH2CF3, and -0-CF3; or

R9 and R10 when attached to the same nitrogen atom are combined to form a 3- to 7-membered ring having from 0 to 2 additional heteroatoms as ring members;

R11 is selected from the group consisting of Ci_6alkyl and C3.7cycloalkyl; wherein each Ci_6alkyl is a straight or branched chain alkyl; and wherein each d.6alkyl and C3_7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, - SH, -C].3alkyl, -0-CV3alkyl, -CF3, -CH2CF3, and -0-CF3; and

R12 is selected from the group consisting of halogen, Ci_6alkyl, -0-C]_6alkyl, -S-C1-6alkyl, C3.7cycloalkyl, -0-C3.7cycloalkyl, -C(0)OR8, -C(0)NR9R10, -NR9C(0)Rn, -S(02)NR9R10, -NR9S(02)Ru, -S(0)Rn and -S(02)Ru; wherein each C,_6alkyl is a straight or branched chain alkyl; and wherein each C].6alkyl and C3.7cycloalkyl is optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -Ci_3alkyl, -0-CV 3alkyl, -CF3, -CH2CF3, and -0-CF3.

9. A compound accor one of claims 1 to 8, wherein R2 is selected

from the group consisting of phenyl
2-pyridinyl

3-pyridinyl , 4-pyridinyl and 5-pyrimidinyl ; wherein each R2 is optionally substituted by one or more R12.

10. A compound according to any one of claims 1 to 9, wherein R1 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, 1 -hydroxyethyl, 2-hydroxyisopropyl, chloro and -C(0)N(CH3)2.

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

(Z)- 1 -(4-amino-2-fluorobut-2-en- 1 -yl)- 3-(3-(Λ' A7-dimethylsulfamoyl)phenyl)- 2-methyl-lH-indoIe-7-carboxylic acid

(Z)-3-( 1 -(4-amino-2-fluorobut-2-en- 1 - yl)-5-methoxy-2 -methyl- lH-indol-3- yl)-NA'-dimethylbenzenesulfonamide

(Z)-l-(4-amino-2-fluorobut-2-en- l -yl)- N,A,,2-trimethyl-3-(3- (methylsulfonyl)phenyl)- 1 H-indole-5- carboxamide

(Z)-3-( 1 -(4-amino-2-fluorobut-2-en-l - yl) -5 -cyano -2 -methyl- 1 H-indol -3 -yl ) - N, Λ'-dimethylbenzenesulfonamide

(Z)- 1 -(4-amino-2-fluorobut-2-en- 1 -yl)- NN,2-trimethyl-3-(3- ((tr ifluoromethyl )sul fony l)pheny 1) - 1 H- indole-5-carboxamide

(Z)- 1 -(4-amino-2-fluorobut-2-en- 1 -yl)- 3 -( 3 -(N N-dimethylsulfamoyl)phenyl)- N, N,2-trimethyl- lH-indole-5- sulfonamide

(Z)-3-( 1 -(4-amino-2-fluorobut-2-en-] - yl)-5-(difluoromethyl)-2-met yl- 1 H- indol-3 -y 1 ) -N N-dimethyl benzene- sulfcm amide

(Z)-3-( 1 -(4-amino-2-fluorobut-2-en- 1 - yl)-5 -hydroxy-2-methyl- 1 H- pyrrolo[3,2-b]pyridin-3-yl)-N,N- dimethylbenzene-sulfonamide

-

-

-

(Z)-5-( l -(4-amino-2-fluorobut-2-en-l- 74 yl)-7-chloro-2-methyl-lH-indol-3-yl)- NN-dimethylpyri dine-3 -sulfonamide

(Z)-5-( 1 -(4-amino-2-fluorobut-2-en-l - 75 yl)-4-chloro-2-methyl-lH-indol-3-yl)- N, N-dimethylpyridine-3 -sulfonamide

(Z)-4-(5-chloro-2-methyl-3-(pyridin-4- 76 yl)-lH-indol-l -yl)-3-fluorobut-2-en-l - amine

(Z)-4-(5-chloro-2-methyl-3-(pyridin-3- 77 yl)-lH-indol-l -yl)-3-fluorobut-2-en-l - amine

(Z)-6-( 1 -(4-amino-2-fluorobut-2-en- 1 - 78 yl )-5 -chloro-2 -methyl- 1 H-indol-3 -yl )- NN-dimethylpyridine-2 -sulfonamide

(Z)-5-( 1 -(4-amino-2-fluorobut-2-en-l - yl)-5-cyclopropyl-2-methyl-lH-indol- 3 -yl)-N, N-dimethy lpyridine-3 - sulfonamide

(Z)-4-(5-chloro-2-methyl-3- (pyrimidin-5-yl)- lH-indol- 1 -yl)-3 - fluorobut-2-en- 1 -amine

(Z)- 1 -(4-amino-2-fluorobut-2-en- 1 -yl)- N,N,2-trimethyl-3-(pyridin-4-yl)-lH- indole-5-sulfonamide

(Z)-3-( 1 -(4-amino-2-fluorobut-2-en- 1 - yl)-5-chloro-7-fluoro-2-methyl-lH- indol-3-yl)-/V,N,4- trimethylbenzenesulfonamide

(Z)-5-( 1 -(4-amino-2-fluorobut-2-en-l - yl)-5-chloro-2 -methyl- lH-indol-3- yl)pyridine-3-sulfonamide

(Z)-4-(3-(2,6-dimethylpyridin-4-yl)-2- methyl-5-(methylsulfonyl)- 1 H-indol- 1 -yl)-3-fluorobut-2-en- 1 -amine

(Z)- 1 -(4-amino-2-fluorobut-2-en- 1 -yl)- 3-(2,6-dimethylpyridin-4-yl)-/V,N,2- trimethyl-lH-indole-5-carboxamide

(Z)- 1 -(4-amino-2-fluorobut-2-en- 1 -yl)- N-(tert-butyl)-2-mcthyl-3-(pyridin-4- yl)-lH-indole-5-carboxamide

(Z)-4-(3-(benzo[d]| l ,3]dioxol-5-yl)-2- methyl-5-(methylsulfonyl)-lH-indol- 1 -yl)-3-fluorobut-2-en- 1 -amine

1 -

-

1 -

1 - - 1 H-

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

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

13. A method of inhibiting the amine oxidase activity 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 any one of the claims 1 to 1 1 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to claim 12.

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

15. The method of claim 14, wherein the condition is a liver disorder.

16. The method of claim 15, wherein the liver disorder is selected from the group consisting of biliary atresia, cholestatic liver disease, chronic liver disease, nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), fatty liver disease associated with disorders such as hepatitis or metabolic syndrome; hepatitis C infection, alcoholic liver disease, primary biliary cirrhosis (PBC), primary schlerosing cholangitis (PSC), liver damage due to progressive fibrosis, liver fibrosis and liver cirrhosis.

17. The method of claim 14, wherein the condition is a kidney disorder.

18. The method of claim 17, wherein the kidney disorder is selected from the group consisting of kidney fibrosis, renal fibrosis, acute kidney injury, chronic kidney disease, diabetic nephropathy, glomerulosclerosis, vesicoureteral reflux, tubulointerstitial renal fibrosis and glomerulonephritis.

19. The method of claim 14, wherein the condition is a cardiovascular disease.

20. The method of claim 19, wherein the cardiovascular disease is selected from the group consisting of atherosclerosis, arteriosclerosis, hypercholesteremia, and hyperlipidemia.

21. The method of claim 14, wherein the condition is fibrosis.

22. The method of claim 21, wherein the fibrosis is selected from the group consisting of liver fibrosis, lung fibrosis, kidney fibrosis, cardiac fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis, radiation-induced fibrosis, ocular fibrosis, Peyronie's disease and scleroderma or is associated with respiratory disease, abnormal wound healing and repair, postsurgical operations, cardiac arrest and all conditions where excess or aberrant deposition of fibrous material is associated with disease, including Crohn's disease and inflammatory bowel disease.

23. The method of claim 14, wherein the condition is cancer.

24. The method of claim 23, wherein 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, medullablastoma, and other tumors of the brain; myelofibrosis, kidney cancer; cancer of the head and neck; cancer of the stomach; multiple myeloma; testicular cancer; germ cell tumor; neuroendocrine tumor; cervical cancer; oral cancer, carcinoids of the gastrointestinal tract, breast, and other organs; signet ring cell carcinoma; mesenchymal tumors 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.

25. The method of claim 14, wherein the condition is angiogenesis.

26. The method according to any one of claims 14 to 25 further comprising administering a second therapeutic agent.

27. The method according to claim 26, wherein the second therapeutic agent is selected from the group consisting of an anti-cancer agent, anti-inflammatory agent, anti-hypertensive agent, an anti-fibrotic agent, an anti-angiogenic agent and an immunosuppressive agent.

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