Haloallylamine pyrazole derivative inhibitors of lysyl oxidase and uses thereof

文档序号：1549005 发布日期：2020-01-17 浏览：34次中文

阅读说明：本技术 赖氨酰氧化酶的卤代烯丙胺吡唑衍生物抑制剂及其用途 (Haloallylamine pyrazole derivative inhibitors of lysyl oxidase and uses thereof ) 是由艾莉森·桃乐丝·芬得利克雷格·伊旺·特纳曼达·迪奥达强纳森·史都华·甫特周文斌沃于 2018-03-02 设计创作，主要内容包括：本发明涉及能够抑制某些胺氧化酶的新型化合物。这些化合物适用于治疗人类受试者以及宠物和牲畜的多种适应症,例如纤维化、癌症和/或血管生成。另外,本发明还涉及包含这些化合物的药物组合物以及其各种用途。(The present invention relates to novel compounds capable of inhibiting certain amine oxidases. These compounds are useful for treating a variety of indications, such as fibrosis, cancer and/or angiogenesis, in human subjects as well as in companion animals and livestock. In addition, the invention also relates to pharmaceutical compositions comprising these compounds and various uses thereof.)

1. A compound having the formula I:

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

each one of which is

a is C or N;

b is C (R)³) Or N;

c is C (R)⁴) Or N;

d is C or N;

and 2 of a, b, c and d are N, wherein 2N atoms are adjacent to each other;

R²、R³and R⁴Independently selected from the group consisting of: hydrogen, halogen, C_1-4Alkyl, -C_3-5Cycloalkyl, -O-C_1-4Alkyl, -O-C_3-5Cycloalkyl, -C (O) OR⁵、-C(O)NR⁶R⁷and-NR⁶C(O)R⁸(ii) a Wherein each C_1-4Alkyl is straight or branched chain alkyl; and wherein each C_1-4Alkyl and C_3-5The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -SH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃；

X is O or- (CH)₂)_m-；

R¹Selected from the group consisting of aryl and heteroaryl; wherein each R¹Optionally substituted by one or more R⁹Substitution;

R⁵selected from hydrogen, -C_1-6Alkyl and-C_3-7Cycloalkyl groups; wherein each C_1-6Alkyl is straight or branched chain alkyl, and wherein each C_1-6Alkyl and C_3-7The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -SH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃；

R⁶And R⁷Independently selected from hydrogen, C_1-6Alkyl and C_3-7Cycloalkyl groups; wherein each C_1-6Alkyl is straight or branched chain alkyl; and wherein each C_1-6Alkyl and C_3-7The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -SH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃(ii) a Or

R⁶And R⁷Combined to form a compound having 0 to 2 additional atoms when attached to the same nitrogen atomA 3-to 7-membered ring with the heteroatom as a ring member;

R⁸selected from the group consisting of C_1-6Alkyl and C_3-7Cycloalkyl groups; wherein each C_1-6Alkyl is straight or branched chain alkyl; and wherein each C_1-6Alkyl and C_3-7The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -SH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃(ii) a And is

Each R⁹Independently selected from the group consisting of: halogen, C_1-6Alkyl, -O-C_1-6Alkyl, -S-C_1-6Alkyl radical, C_3-7Cycloalkyl, -O-C_3-7Cycloalkyl, -C (O) OR⁵、-C(O)NR⁶R⁷、-NR⁶C(O)R⁸、-S(O₂)NR⁶R⁷、-NR⁶S(O₂)R⁸、-S(O)R⁸and-S (O)₂)R⁸(ii) a Wherein each C_1-6Alkyl is straight or branched chain alkyl; and wherein each C_1-6Alkyl and C_3-7The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃(ii) a And is

m is 0 or 1.

2. The compound of claim 1 having formula Ia,

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R²and R⁴Independently selected from the group consisting of: hydrogen, halogen, C_1-4Alkyl, -C_3-5Cycloalkyl, -O-C_1-4Alkyl, -O-C_3-5Cycloalkyl, -C (O) OR⁵、-C(O)NR⁶R⁷and-NR⁶C(O)R⁸(ii) a Wherein each C_1-4Alkyl is straight or branched chain alkyl; and wherein each C_1-4Alkyl and C_3-5The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -SH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃；

X is O or- (CH)₂)_m-；

R¹Selected from the group consisting of aryl and heteroaryl; wherein each R¹Optionally substituted by one or more R⁹Substitution;

R⁶And R⁷Independently selected from the group consisting of hydrogen, C_1-6Alkyl and C_3-7A cycloalkyl group; wherein each C_1-6Alkyl is straight or branched chain alkyl; and wherein each C_1-6Alkyl and C_3-7The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -SH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃(ii) a Or

R⁶And R⁷Combine to form a 3-to 7-membered ring having 0 to 2 additional heteroatoms as ring members when attached to the same nitrogen atom;

m is 0 or 1.

3. The compound of claim 1 having formula Ib,

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R²and R³Independently selected from the group consisting of: hydrogen, halogen, C_1-4Alkyl, -C_3-5Cycloalkyl, -O-C_1-4Alkyl, -O-C_3-5Cycloalkyl, -C (O) OR⁵、-C(O)NR⁶R⁷and-NR⁶C(O)R⁸(ii) a Wherein each C_1-4Alkyl is straight or branched chain alkyl; and wherein each C_1-4Alkyl and C_3-5The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -SH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃；

X is O or- (CH)₂)_m-；

R¹Selected from the group consisting of aryl and heteroaryl; wherein each R¹Optionally substituted by one or more R⁹Substitution;

R⁶And R⁷Combine to form a 3-to 7-membered ring having 0 to 2 additional heteroatoms as ring members when attached to the same nitrogen atom;

R⁸selected from the group consisting of C_1-6Alkyl and C_3-7Cycloalkyl groups; wherein each C_1-6Alkyl is straight or branched chain alkyl; and wherein each C_1-6Alkyl and C_3-7The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen element、-OH、-SH、-C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃(ii) a And is

m is 0 or 1.

4. A compound according to any one of claims 1 to 3, wherein m is 0.

5. A compound according to any one of claims 1 to 3, wherein m is 1.

6. A compound according to any one of claims 1 to 5, wherein R¹Selected from phenyl, naphthyl or pyridyl.

7. A compound according to any one of claims 1 to 6, wherein R²、R³And R⁴Independently selected from the group consisting of: hydrogen, halogen, C_1-4Alkyl, -C (O) OR⁵and-C (O) NR⁶R⁷(ii) a Wherein each C_1-4Alkyl is straight or branched chain alkyl; and wherein each C_1-4The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -OHand-O-C_1-3An alkyl group.

8. A compound according to any one of claims 1 to 7, wherein R²、R³And R⁴Independently selected from the group consisting of: hydrogen, chlorine, methyl, ethyl, isopropyl, tert-butyl, -CF₃、-CH₂OH、CHOHCH₃、-C(CH₃)₂OH、-C(O)OEt、-C(O)OH、-C(O)N(CH₃)₂、-C(O)NHC(CH₃)₃、-CHCH₃OH and-CH₂OCH₃。

9. A compound according to any one of claims 1 to 8, wherein R⁵Selected from hydrogen and C_1-6Alkyl groups.

10. The compound according to any one of claims 1 to 9, wherein R⁶And R⁷Independently selected from hydrogen and C_1-6Alkyl groups; wherein each C_1-6Alkyl is straight or branched chain alkyl; or

R⁶And R⁷When attached to the same nitrogen atom combine to form a 3-to 7-membered ring having from 0 to 2 additional heteroatoms as ring members.

11. The compound according to any one of claims 1 to 10, wherein R⁸Is C_1-6An alkyl group.

12. The compound according to any one of claims 1 to 11, wherein each R⁹Independently selected from hydrogen, C_1-6Alkyl, -O-C_1-6Alkyl, -C (O) NR⁶R⁷、-S(O₂)NR⁶R⁷and-S (O)₂)R⁸A group of (a); wherein each C_1-6Alkyl is straight or branched chain alkyl; and wherein each C_1-6Alkyl is optionally substituted with one or more halogens.

13. The compound according to any one of claims 1 to 12, wherein each R⁹Independently selected from the group consisting of: fluorine, chlorine, -CF₃、-OCF₃、-C(O)N(CH₃)₂、-S(O₂)NR⁶R⁷、-S(O₂)CF₃、-S(O₂)CH(CH₃)₂and-S (O)₂)CH₃。

14. The compound of claim 1, selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and at least one pharmaceutically acceptable excipient, carrier or diluent.

16. A method of inhibiting the amine oxidase activity of LOX, LOXL1, LOXL2, LOXL3, and LOXL4 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition of claim 15.

17. A method of treating a condition associated with LOX, LOXL1, LOXL2, LOXL3, and LOXL4 proteins, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition of claim 15.

18. The method of claim 17, wherein the condition is a liver disorder.

19. The method of claim 18, wherein the liver condition is selected from the group consisting of: biliary atresia, cholestatic liver disease, chronic liver disease, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), fatty liver disease associated with conditions such as hepatitis or metabolic syndrome; hepatitis c infection, alcoholic liver disease, Primary Biliary Cirrhosis (PBC), Primary Sclerosing Cholangitis (PSC), liver damage due to progressive fibrosis, liver fibrosis, and cirrhosis.

20. The method of claim 17, wherein the condition is a renal disorder.

21. The method of claim 20, wherein the kidney disorder is selected from the group consisting of: kidney fibrosis, acute kidney injury, chronic kidney disease, diabetic nephropathy, glomerulosclerosis, vesicoureteral reflux, tubulointerstitial fibrosis and glomerulonephritis.

22. The method of claim 17, wherein the condition is a cardiovascular disease.

23. The method of claim 22, wherein the cardiovascular disease is selected from the group consisting of: atherosclerosis, arteriosclerosis, hypercholesterolemia, and hyperlipidemia.

24. The method of claim 17, wherein the condition is fibrosis.

25. The method of claim 24, wherein the fibrosis is selected from the group consisting of: liver fibrosis, lung fibrosis, kidney fibrosis, myocardial fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis, radiation-induced fibrosis, ocular fibrosis, peyronie's disease, and scleroderma, or associated with respiratory diseases, abnormal wound healing and repair, post-operative surgery, cardiac arrest, and all conditions in which excessive or abnormal deposition of fibrous matter is associated with diseases including crohn's disease and inflammatory bowel disease.

26. The method of claim 17, wherein the condition is cancer.

27. The method of claim 26, wherein the cancer is selected from the group consisting of: lung cancer; breast cancer; colorectal cancer; anal cancer; pancreatic cancer; prostate cancer; ovarian cancer; hepatobiliary cancer; esophageal cancer; non-hodgkin lymphoma; bladder cancer; uterine cancer; gliomas, glioblastoma, medulloblastoma and other brain tumors; myelofibrosis, kidney cancer; head and neck cancer; gastric cancer; multiple myeloma; testicular cancer; germ cell tumors; neuroendocrine tumors; cervical cancer; oral cancer; carcinoids of the gastrointestinal tract, breast and other organs; signet ring cell carcinoma; interstitial tumors, including sarcomas, fibrosarcomas, hemangiomas, angiomatosis, hemangiopericytomas, pseudohemangiomatoid matrix hyperplasia, myofibroblastic tumors, fibromatosis, inflammatory myofibroblastoma, lipomas, angiolipomas, granulocytomas, neurofibromas, schwannoma, angiosarcoma, liposarcoma, rhabdomyosarcoma, osteosarcoma, leiomyoma, or leiomyosarcoma.

28. The method of claim 17, wherein the condition is angiogenesis.

29. The method of any one of claims 17 to 28, further comprising administering a second therapeutic agent.

30. The method of claim 29, wherein the second therapeutic agent is selected from the group consisting of: anti-cancer agents, anti-inflammatory agents, hypotensive agents, anti-fibrotic agents, anti-angiogenic agents, and immunosuppressive agents.

31. Use of a compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a condition associated with LOX, LOXL1, LOXL2, LOXL3, and LOXL4 proteins.

Technical Field

The present invention relates to novel compounds capable of inhibiting certain amine oxidases. These compounds are useful for treating a variety of indications, such as fibrosis, cancer and/or angiogenesis, in human subjects as well as in companion animals and livestock. In addition, the invention also relates to pharmaceutical compositions comprising these compounds and various uses thereof.

Background

Five families of closely related enzymes have been associated with fibrotic diseases and metastatic cancer. These enzymes are of Lysyl Oxidase (LOX), a member of the first family to be described and the four closely related enzymes LOX-like 1(LOXL1), LOXL2, LOXL3 and LOXL4(Kagan H.M. and Li W., Lysyl oxidases: properties, specificity, intracellular characteristics, specificity and biology ] J Cell Biochem [ J. Biochem. J. Biochem ] 2003; 88: 660-. Lysyl oxidase isoenzymes are copper-dependent amine oxidases that initiate covalent crosslinking of collagen and elastin. The primary function of lysyl oxidase isozymes is to promote crosslinking of collagen and elastin by oxidative deamination of lysine and hydroxylysine amino acid side chains into aldehydes that spontaneously react with adjacent residues. The resulting cross-linked chains contribute to extracellular matrix (ECM) stability. Lysyl oxidase activity is required to maintain the tensile and elastic properties of the connective tissue in the bone, lung and cardiovascular system, as well as other sites. The biosynthesis of LOX is well understood; the protein is synthesized as pre-proLOX, which undergoes a series of post-translational modifications to produce a 50kDa proenzyme that is secreted into the extracellular environment. For LOX and LOXL1, the mature and active forms are released by proteolysis by bone morphogenetic protein-1 (BMP-1) and other procollagen C-proteases. LOXL2, LOXL3, and LOXL4 contain scavenger receptor cysteine rich protein domains and are directly secreted into the active form.

Lysyl oxidase isozymes belong to a larger family of amine oxidases, which include flavin-dependent and copper-dependent oxidases, which are described by the nature of the catalytic cofactors. The 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 lysyl oxidase isozymes. Copper-dependent amine oxidases have a second cofactor, which varies slightly from enzyme to enzyme. In SSAO/VAP-1, the cofactor is an oxidized tyrosine residue (TPQ, oxidized to quinone), whereas in the lysyl oxidase isozyme, TPQ has been further processed by the addition of an adjacent lysine residue (to form LTQ); see Kagan, h.m.and Li, w., Lysyl oxidase, Properties, specificity, and biological roles side and out of the cell, [ Lysyl oxidase: characteristics, specificity and biological action inside and outside cells ] J Cell Biochem [ journal of cellular biochemistry ] 2003; 88:660-672.

Since lysyl oxidase isozymes exhibit different in vivo expression patterns, it is likely that specific isozymes will have particular biological effects. The catalytically active form of LOX has been identified in the cytoplasmic and nuclear compartments, suggesting an undefined role for LOX in cellular homeostasis. A great deal of research is currently being conducted to define these effects. LOX itself plays a major role, for example, in epithelial to mesenchymal transition (EMT), cell migration, adhesion, transformation, and gene regulation. Different patterns of LOX expression/activity have been associated with different pathological processes including fibrotic diseases, alzheimer's disease and other neurodegenerative processes as well as tumor progression and metastasis. See, e.g., Woznick, a.r. et al, Lysyl oxidase expression in branched carcinogenic carcinoma, [ Lysyl oxidase expression in bronchial cancer ] Am J Surg [ american journal of surgery ] 2005; 189:297-301. Catalytically active forms of LOXL2 are also found in the nucleus (J BiolChem. [ J. Biochem ] 2013; 288:30000-30008) and deaminate lysine 4 in histone H3 (MolCell [ molecular cell ] 201246: 369-376).

Direct 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 evident in humans, playing a valuable role after traumatic injury, infection or disease. After slower and/or repeated injury, progressive scarring occurs, which causes impaired function to some or all of the affected organs. Fibrosis can be caused by a variety of causes such as chronic infection, long-term exposure to alcohol and other toxins, autoimmunity and allergies or radiotherapy and chemotherapy. This pathological process can thus occur in almost any organ or tissue of the body and is typically caused by a condition lasting weeks or months, where inflammation, tissue destruction and repair occur simultaneously. In this case, fibrosis most frequently affects the lungs, liver, skin, and kidneys.

Liver fibrosis occurs as a complication of hemochromatosis, 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, which can be qualitatively distinguished from conditions in normal liver. This fibrosis can progress to cirrhosis, liver failure, cancer and ultimately death. This is described in Kagan, H.M. Lysyl oxidase: Mechanism, regulation and optimization to lever fibrosis [ lysyl oxidase: mechanistic-Research and Practice 1994; 190:910-919.

Fibrotic tissue can accumulate in the heart and blood vessels as a result of hypertension, hypertensive heart disease, atherosclerosis, and myocardial infarction, with accumulation of extracellular matrix or fibrotic deposition leading to hardening of the vasculature and hardening of the cardiac tissue itself. See Lopez, B. et al, Role of lysyl oxidase in myocatalytic fibrosis from basics science to clinical aspects [ the Role of lysyl oxidase in myocardial fibrosis: am J Physiol Heart Circ Physiol [ journal of physiology-cardiac and circulatory system ] 2010; 299H 1-H9.

A close correlation between fibrosis and increased lysyl oxidase activity has been demonstrated. For example, in experimental liver fibrosis in rats (Siegel, R.C., Chen, K.H.and Acquis, J.M, Biochemical and Biochemical study of lysyl oxidase in experimental liver fibrosis in rats Biochemical and immunochemical study of lysyl oxidase in experimental liver fibrosis in rats]proc.Natl.Acad.Sci.USA (Proc. Natl. Acad. Sci.) [ Proc. Natl. Acad. Sci. USA (Proc. Natl. Acad. Sci.) [ Proc. Acad. Sci. USA]1978; 75:2945-]J Pharmacol Exp Ther [ journal of Experimental therapeutics ]]1981; 219:675-678), in arterial fibrosis (Kagan, H.M., Raghavan, J. and Hollander, W., Change in an alpha lysyl oxidase activity in di-induced atheroclysis in the rabbit diet-induced atherosclerosis [ alterations in the activity of arterial lysyl oxidase in rabbit diet-induced atherosclerosis ]]Arteriosclerosis [ atherosclerosis ]]1981; 1:287-291.), Increased expression of lysyl oxidase in skin fibrosis (Chanoki, M. et al, incorporated expression of lysyl oxidase with scleroderma]Br JDermanol [ journal of British dermatology]1995; 133:710-715) and in doxorubicin-induced renal fibrosis in rats (Di Donato, A. et al, Lysyl oxidase expression)on and collagen cross-linking along with viral adenine neuropathiy [ lysyl oxidase expression and collagen cross-linking during chronic Doxorubicin nephropathy]Nephron [ urology and nephrology]1997; 76:192-200). In these experimental models of human disease, in CCl₄The most significant increase in enzyme activity was observed in a rat model of induced liver fibrosis. In these studies, low levels of enzyme activity in healthy liver increased 15 to 30-fold in fibrotic liver. The theory for the consistent and strong inhibition of fibrosis by lysyl oxidase isozyme blockers is that the lack of cross-linking activity makes collagen susceptible to matrix metalloproteinases and causes degradation. Thus, any type of fibrosis should be reversed by treatment with lysyl oxidase isozyme inhibitors. In humans, there is also a significant correlation between lysyl oxidase activity measured in plasma and liver fibrosis progression. Lysyl oxidase activity levels are usually negligible in the serum of healthy subjects, but increase significantly in chronic active hepatitis and even more in liver cirrhosis, and thus lysyl oxidase can be used as a marker for internal fibrosis.

The non-selective lysyl oxidase inhibitor BAPN (β -aminopropionitrile) is widely used. BAPN has been used in animal research (mainly rats, mice and hamsters) since the 60 s of the 20 th century and has been effective in reducing different models (e.g. CCl)₄Bleomycin, quartz) and tissues (e.g., liver, lung, and skin). See Kagan, H.M. and Li, W., Lysyl oxidases: Properties, specificity, and biological rollers inside and outside of the cell [ Lysyl oxidase: characteristics, specificity and biological action inside and outside the cell]J CellBiochem [ journal of cell biochemistry]2003；88:660-672。

Lysyl oxidase isozymes are highly regulated by two of the most prominent growth factors Hypoxia-inducible factor 1 alpha (HIF-1 alpha) and TGF-beta that cause fibrosis (Halberg et al, Hypoxia-inducible factor 1 alpha induced fibrosis and insulin resistance in white adipose tissue [ Hypoxia-inducible factor 1 alpha induces fibrosis and insulin resistance in white adipose tissue ]. Cell Biol [ cytobiology ] 2009; 29: 4467-4483). Collagen cross-linking occurs in each type of fibrosis, so lysyl oxidase isozyme inhibitors can be used for idiopathic pulmonary fibrosis, scleroderma, renal fibrosis, or hepatic fibrosis. Lysyl oxidase isozymes not only participate in the crosslinking of elastin and collagen during wound healing and fibrosis, but also regulate cellular motility and signal transduction. Their intracellular and nuclear functions are associated with gene regulation and can lead to tumorigenesis and tumor progression (Sidditiuzzaman, Grace, V.M and Guruvayoorappan, C., Lysyl oxidase: a potential target for cancer therapy [ Lysyl oxidase: potential target for cancer therapy ]. Inflammapharmarmacol [ inflammatory pharmacology ] 2011; 19: 117-. The down-and up-regulation of lysyl oxidase isozymes in tumor tissues and cancer cell lines has been described, suggesting a dual role of lysyl oxidase isozymes and LOX propeptides as metastasis promoter genes as well as tumor suppressor genes.

To date, increases in lysyl oxidase isozyme mRNA and/or protein have been observed in breast, CNS cancer cell lines, head and neck squamous cells, prostate, clear cell kidney and lung tumors, and melanoma and osteosarcoma cell lines. A statistically significant clinical correlation between lysyl oxidase isozyme expression and tumor progression was observed in breast, head and neck squamous cells, prostate, and clear cell renal cell tumors. The role of lysyl oxidase isozymes in tumor progression has been most extensively studied in breast cancer using migratory/invasive in vitro models as well as in vivo tumorigenesis and metastasis mouse models. Increased lysyl oxidase isozyme expression can be seen in hypoxic patients and is associated with a negative estrogen receptor state (ER-), reduced overall survival in ER-and node-negative patients who do not receive adjuvant systemic treatment, and shorter metastasis-free survival in ER-and node-negative patients. Lysyl oxidase isozyme mRNA has been shown to be up-regulated in invasive and metastatic cell lines (MDA-MB-231 and Hs578T) as well as in more invasive breast cancer cell lines and distant metastatic tissues compared to primary cancer tissues.

In head and neck squamous cell carcinoma, increased expression of the lysyl oxidase isozyme was found to be associated with the hypoxia marker CA-IX, and with decreased cancer specific survival, decreased overall survival and decreased metastasis-free survival. In oral squamous cell carcinoma, lysyl oxidase isoenzyme mRNA expression is up-regulated compared to normal mucosa.

The gene expression profile of gliomas identified overexpressed lysyl oxidase isozymes as part of a molecular signature indicative of invasiveness and correlated with higher-grade tumors that were strongly associated with poor patient survival. Lysyl oxidase isozyme protein expression was increased in glioblastoma and astrocytoma tissues and in invasive U343 and U251 cultured astrocytoma cells.

Lysyl oxidase isoenzyme mRNA is upregulated in prostate cancer compared to benign prostate hypertrophy, is associated with the Gleason score (Gleason score), and is associated with both high-grade and short-term recurrence in tissue (Stewart, G.D. et al, Analysis of hypoxia-associated gene expression in a pro state cancer: Analysis of lysyl oxidase and glucose transporter-1expression with Gleason score [ Analysis of hypoxia-associated gene expression in prostate cancer: lysyl oxidase and glucose transporter-1expression are associated with the Gleason score ]. Oncol Rep [ Oncol report ] 2008; 20: 1561-.

Upregulation of lysyl oxidase isozyme mRNA expression was detected in Renal Cell Carcinoma (RCC) cell lines and tissues. Clear cell RCC also demonstrated lysyl oxidase isozyme up-regulation. Indeed, LOX appears to be preferentially expressed in clear cell RCC compared to mixed clear and granulosa cells, eosinophils, mixed tubular papillae and refractory cells RCC/large eosinophilic neoplasm. In clear cell RCC, smoking is associated with an allelic imbalance in chromosome 5q23.1 in which the LOX gene is located, and may involve replication of the gene.

SiHa cervical cancer cells demonstrate increased invasiveness in vitro under hypoxic/anoxic conditions; this is inhibited by inhibiting extracellular catalytically active lysyl oxidase activity via treatment with BAPN and LOX antisense oligomer, LOX antibody, LOX shRNA or extracellular copper chelator.

The scientific and patent literature describes small molecule inhibitors of lysyl oxidase isozymes and antibodies to LOX and LOXL2 that have therapeutic effects in animal models of fibrosis and cancer metastasis. Some known MAO inhibitors have also been reported to inhibit lysyl oxidase isozymes (e.g., the MAO-B inhibitor mofetiline (Mofegiline), described below). This inhibitor is a member of the haloalkallylamine family of MAO inhibitors; the halogen in mofiglan is fluorine. Fluoroallylamine inhibitors are described in U.S. patent No. 4,454,158. There have been issued patents that propose fluoroallylamine and chloroallylamine such as MDL72274 (described below) as lysyl oxidase inhibitors (U.S. Pat. Nos. 4,943,593; 4,965,288; 5,021,456; 5,059,714; 5,182,297; 5,252,608). Many of the compounds proposed in these patents are also reported to be potent MAO-B and SSAO/VAP-1 inhibitors.

Additional fluoroallylamine inhibitors are described in U.S. patent 4,699,928. Other examples structurally related to mofetil can be found in WO 2007/120528.

WO 2009/066152 discloses a group of 3-substituted 3-haloallylamines which are SSAO/VAP-1 inhibitors useful as treatments for a variety of indications, including inflammatory diseases. These documents do not specifically disclose fluoroallylamine compounds of formula (I) according to the invention.

Antibodies to LOX and LOXL2 have been disclosed in US 2009/0053224 with methods of diagnostic and therapeutic use. anti-LOX and anti-LOXL 2 antibodies can be used to identify and treat conditions such as fibrotic conditions, angiogenesis or to prevent the transition from an epithelial to a mesenchymal state: US 2011/0044907.

Disclosure of Invention

The present invention provides substituted fluoroallylamine compounds that inhibit Lysyl Oxidase (LOX), lysyl oxidase-like 2(LOXL2), and other lysyl oxidase isoenzymes. Surprisingly, the previously described modifications of the 3-substituted-3-fluoroallylamine structure have led to the discovery of novel compounds that are potent inhibitors of the human LOX and LOXL isozymes. In addition, certain of these novel compounds also selectively inhibit certain LOX and LOXL isozymes relative to other enzymes in the amine oxidase family.

A first aspect of the invention provides a compound having formula I:

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

each one of which isIndependently a single or double bond arranged to provide a pyrazole ring;

a is C or N;

b is C (R)³) Or N;

c is C (R)⁴) Or N;

d is C or N;

and 2 of a, b, c and d are N, wherein 2N atoms are adjacent to each other;

X is O or- (CH)₂)_m-；

R¹Selected from the group consisting of aryl and heteroaryl; wherein each R¹Optionally substituted by one or more R⁹Substitution;

R⁵independently selected from the group consisting of hydrogen, -C_1-6Alkyl and-C_3-7A cycloalkyl group; wherein each C_1-6Alkyl is straight or branched chain alkyl, and wherein each C_1-6Alkyl and C_3-7The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -SH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃；

R⁶And R⁷Combine to form a 3-to 7-membered ring having 0 to 2 additional heteroatoms as ring members when attached to the same nitrogen atom;

R⁸independently selected from the group consisting of C_1-6Alkyl and C_3-7A cycloalkyl group; wherein each C_1-6Alkyl is straight or branched chain alkyl, and wherein each C_1-6Alkyl and C_3-7The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -SH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃(ii) a And is

m is 0 or 1.

A second aspect of the invention provides 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.

A third aspect of the invention provides a method of inhibiting the amine oxidase activity of LOX, LOXL1, LOXL2, LOXL3 and LOXL4 in a subject in need thereof, the method 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.

A fourth aspect of the invention provides a method of treating a condition associated with LOX, LOXL1, LOXL2, LOXL3 and LOXL4 proteins, the method comprising administering to a subject in need thereof a therapeutically 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.

A fifth aspect of the invention provides the 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 the treatment of a condition associated with LOX, LOXL1, LOXL2, LOXL3 and LOXL4 proteins.

A sixth aspect of the invention provides a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in the treatment of a condition associated with LOX, LOXL1, LOXL2, LOXL3 and LOXL4 proteins.

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

Combination therapies are contemplated herein, wherein the methods further comprise co-administering an additional therapeutic agent for treating liver disorders, kidney disorders, cardiovascular disease, cancer, fibrosis, angiogenesis, and inflammation.

Definition of

The following are some definitions that may be helpful in understanding the description of the present invention. These definitions are intended to be general definitions and in no way limit the scope of the present invention to only those terms, but are set forth to provide a better understanding of the following description.

Integers, steps or elements of the invention recited herein as a single integer, step or element clearly encompass both singular and plural forms of the recited integer, step or element, unless the context requires otherwise or specifically contradicts the context.

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 primarily but not necessarily exclusively".

It will be appreciated by persons skilled in the art 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 the specification, individually or collectively, and any and all combinations or any two or more of said steps or features.

As used herein, the term "alkyl" includes within its meaning monovalent ("alkyl") and divalent ("alkylene") straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, for example 1,2, 3,4, 5, or 6 carbon atoms. Straight or branched chain alkyl groups are attached at any available point to produce stable compounds. For example, the term alkyl includes, but is not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, tert-butyl, pentyl, 1, 2-dimethylpropyl, 1-dimethylpropyl, pentyl, isopentyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 2, 2-dimethylbutyl, 3-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 1,2, 2-trimethylpropyl, 1, 2-trimethylpropyl, and the like.

As used herein, the term "alkoxy" or "alkyloxy" refers to a straight or branched alkyloxy (i.e., O-alkyl) group, wherein alkyl is as defined above. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy and isopropoxy.

As used herein, the term "cycloalkyl" includes within its meaning monovalent ("cycloalkyl") and divalent (cycloalkylene) saturated monocyclic, bicyclic, polycyclic or fused analogs. In the context of the present disclosure, a cycloalkyl group may have from 3 to 10 carbon atoms. In the context of the present disclosure, cycloalkyl groups may also have from 3 to 7 carbon atoms. Fused analogs of cycloalkyl means a single ring fused to an aryl or heteroaryl group, wherein the point of attachment is on the non-aromatic moiety. Examples of cycloalkyl and fused analogues thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, adamantyl and the like.

As used herein, the term "aryl" or variants such as "arylene" refers to mono ("aryl") and divalent ("arylene") mononuclear, polynuclear, conjugated and fused analogs of aromatic hydrocarbons having from 6 to 10 carbon atoms. By fused analog of aryl is meant an aryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group, wherein the point of attachment is on the aromatic moiety. Examples of aryl and fused analogues thereof include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2, 3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1,3-benzodioxolyl (1,3-benzodioxolyl), 1, 4-benzodioxanyl, and the like. A "substituted aryl" is an aryl substituted with one or more (preferably 1,2, or 3) substituents attached at any available atom to produce a stable compound.

As used herein, the term "alkylaryl" includes within its meaning monovalent ("aryl") and divalent ("arylene") mononuclear, polynuclear, conjugated and fused aromatic hydrocarbon radicals attached to a divalent saturated straight or branched chain alkylene radical. Examples of alkylaryl groups include benzyl.

As used herein, the term "heteroaryl" and variants such as "heteroaromatic group" or "heteroarylene group" includes within its meaning monovalent ("heteroaryl") and divalent ("heteroarylene") mononuclear, polynuclear, conjugated and fused heteroaromatic groups having from 5 to 10 atoms, wherein 1 to 4 ring atoms or 1 to 2 ring atoms are heteroatoms independently selected from O, N, NH and S. Heteroaryl is also intended to include oxidized S or N of the ring tertiary nitrogen, such as sulfinyl, sulfonyl, and N-oxide. The carbon or nitrogen atom is the attachment point of the heteroaryl ring structure, such that a stable compound is produced. The heteroaromatic group may be C_5-8A heteroaromatic. Fused analogs of heteroaryl means a heteroaryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group, wherein the point of attachment is on the aromatic moiety. Examples of heteroaryl groups and their fused analogs include pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, triazinyl, thienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothienyl, furo (2,3-b) pyridyl, quinolinyl, indolyl, isoquinolinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 2' -bipyridyl, phenanthrolinyl, quinolinyl, isoquinolinyl, imidazolinyl, thiazolinyl, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, and the like. "Nitrogen-containing heteroaryl" refers to heteroaryl wherein any heteroatom is N. A "substituted heteroaryl" is a heteroaryl substituted with one or more (preferably 1,2, or 3) substituents attached at any available atom to produce a stable compound.

As used herein, the term "heterocyclyl" and variants such as "heterocycloalkyl" include within its meaning monovalent ("heterocyclyl") and divalent ("heterocyclylene") saturated monocyclic, bicyclic, polycyclic or fused hydrocarbon groups 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, wherein the point of attachment may be carbon or nitrogen. Fused analogs of heterocycloalkyl mean monocyclic heterocycles fused to an aryl or heteroaryl group, where the point of attachment is on the non-aromatic moiety. The heterocyclyl radical may be C_3-8A heterocyclic group. The heterocyclylalkyl group may be C_3-6A heterocyclic group. The heterocyclyl radical may be C_3-5A heterocyclic group. Examples of heterocyclyl groups and their fused analogues include aziridinyl, pyrrolidinyl, tetrahydrothiazolyl, piperidinyl, piperazinyl, imidazolidinyl, 2, 3-dihydrofuro (2,3-b) pyridyl, benzoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, quinuclidinyl, azetidinyl, morpholinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl and the like. The term also includes partially unsaturated non-aromatic monocyclic rings, such as 2-or 4-pyridones or N-substituted uracils attached through a nitrogen.

As used herein, the term "halogen" or variants such as "halide" or "halo" refers to fluorine, chlorine, bromine, and iodine.

As used herein, the term "heteroatom" or variants such as "hetero-" or "hetero group" refers to O, N, NH and S.

In general, "substituted" refers to an organic group (e.g., an alkyl group) as defined herein, wherein one or more bonds contained in the group that are bonded to a hydrogen atom are replaced with bonds that are bonded to a non-hydrogen or non-carbon atom. Substituted groups also include groups in which one or more bonds to a carbon or hydrogen atom are replaced with one or more bonds (including double or triple bonds) to a heteroatom. Thus, unless otherwise indicated, a substituted group will be substituted with one or more substituents. In some embodiments, a substituted group is substituted with 1,2, 3,4, 5, or 6 substituents.

As herein describedThe term "optionally substituted" as used herein means that the group referred to by this term may be substituted or may be substituted by one or more groups independently selected from: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, halo, haloalkyl, haloalkynyl, hydroxy, hydroxyalkyl, alkoxy, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, NO₂NH (alkyl), N (alkyl)₂Nitroalkyl, nitroalkenyl, nitroalkynyl, nitroheterocyclyl, alkylamino, dialkylamino, alkenylamino, alkynylamino, acyl, alkenyloxy, alkynyloxy, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, heterocyclyloxy, heterocyclylamino, haloheterocyclylalkyl, alkylthionylene, alkylcarbonyloxy, alkylthio, acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, cyano, cyanate, isocyanate, CO₂H、CO₂Alkyl, C (O) NH₂-C (O) NH (alkyl) and-C (O) N (alkyl)₂. Preferred substituents include halogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy, hydroxy (C)_1-6) Alkyl radical, C₃-C₆Cycloalkyl, C (O) H, C (O) OH, NHC (O) H, NHC (O) C₁-C₄Alkyl, C (O) C₁-C₄Alkyl, NH₂、NHC₁-C₄Alkyl, N (C)₁-C₄Alkyl radical)₂、NO₂OH and CN. Particularly preferred substituents include C_1-3Alkyl radical, C_1-3Alkoxy, halogen, OH, hydroxy (C)_1-3) Alkyl (e.g. CH)₂OH)、C(O)C₁-C₄Alkyl (e.g. C (O) CH)₃) And C_1-3Haloalkyl (e.g. CF)₃、CH₂CF₃). Further preferred optional substituents include halogen, -OH, -SH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃。

The term "bioisostere" refers to a compound that results from the exchange of an atom or group of atoms with another broadly similar atom or group of atoms. Bioisosteric replacement aims at the formation of new compounds with similar biological properties as the parent compound. Bioisosteric replacement can be physiochemically or topologically based.

The present invention includes within its scope all stereoisomers and isomeric forms of the compounds disclosed herein, including all diastereomers, racemates, enantiomers and mixtures thereof. It is understood that the compounds described by formula I may be present as E and Z isomers, also referred to as cis and trans isomers. The present invention is therefore to be understood as including in each case where appropriate, for example, the E, Z, cis, trans, (R), (S), (L), (D), (+) and/or (-) forms of the compounds. Where a structure does not have a specific stereoisomerism specified, it is to be understood that any and all possible isomers are contemplated. The compounds of the present invention include all conformational isomers. The compounds of the invention may also exist in one or more tautomeric forms, including tautomers and mixtures of tautomers. Also included within the scope of the invention are all polymorphs and crystalline forms of the compounds disclosed herein.

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

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

In the context of the present specification, the term "administering" and variations of the term (including "administering" and "administration") include contacting, applying, delivering, or providing a compound or composition of the present invention to an organism or surface by any suitable means. In the context of this specification, the term "treatment" refers to any and all uses that correct a disease state or condition, prevent the development of a disease, or otherwise prevent, hinder, delay, or reverse the progression of a disease or other undesirable condition in any way whatsoever.

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 the 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 present invention that provides the desired therapeutic effect. The exact amount required will vary from subject to subject depending on factors such as: the species 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 the like. Therefore, it is not possible to specify an exact "effective amount". However, for any given situation, an appropriate "effective amount" may be determined by one of ordinary skill in the art using only routine experimentation.

Drawings

Figure 1 shows the ability of compound 15 to reduce fibrosis in a mouse model of liver fibrosis.

Figure 2 shows the ability of compound 15 to reduce tongue cancer volume in a mouse model of oral metastatic cancer.

Detailed Description

The present invention relates to substituted fluoroallylamine derivatives that inhibit Lysyl Oxidase (LOX), lysyl oxidase-like 2(LOXL2), and other lysyl oxidase isoenzymes. In particular, the present invention relates to substituted fluoroallylamine derivatives having a pyrazole group.

In particular, the present invention relates to compounds having formula I:

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

each one of which is

Independently a single or double bond arranged to provide a pyrazole ring;

a is C or N;

b is C (R)³) Or N;

c is C (R)⁴) Or N;

d is C or N;

and 2 of a, b, c and d are N, wherein 2N atoms are adjacent to each other;

X is O or- (CH)₂)_m-；

R¹Selected from the group consisting of aryl and heteroaryl; wherein each R¹Optionally substituted by one or more R⁹Substitution;

R⁶And R⁷Independently selected from the group consisting of hydrogen, C_1-6Alkyl and C_3-7A cycloalkyl group; wherein each C_1-6Alkyl radicalIs a straight or branched chain alkyl group; and wherein each C_1-6Alkyl and C_3-7The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -SH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃(ii) a Or

R⁶And R⁷Combine to form a 3-to 7-membered ring having 0 to 2 additional heteroatoms as ring members when attached to the same nitrogen atom;

m is 0 or 1.

In one embodiment of the compounds of the invention, a and b are N, and C is C (R)⁴) And d is C. In another embodiment of the compounds of the present invention,a is C, b is C (R)³) And c and d are N.

In one embodiment of the compounds of the invention, the pyrazole ring in formula I consists of

And (4) showing. In another embodiment of the compounds of the invention, the pyrazole ring in formula I consists ofAnd (4) showing.

In one embodiment of the compounds of the invention, R²、R³And R⁴Independently selected from the group consisting of: hydrogen, halogen, C_1-4Alkyl, -C_3-5Cycloalkyl, -O-C_1-4Alkyl, -O-C_3-5Cycloalkyl, -C (O) OR⁵、-C(O)NR⁶R⁷and-NR⁶C(O)R⁸(ii) a Wherein each C_1-4Alkyl is straight or branched chain alkyl; and wherein each C_1-4Alkyl and C_3-5The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -SH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃. In another embodiment of the compounds of the invention, R²、R³And R⁴Independently selected from the group consisting of: hydrogen, halogen, C_1-4Alkyl, -C (O) OR⁵and-C (O) NR⁶R⁷(ii) a Wherein each C_1-4Alkyl is straight or branched chain alkyl; and wherein each C_1-4The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH and-O-C_1-3An alkyl group. In another embodiment of the compounds of the invention, R²、R³And R⁴Independently selected from the group consisting of: hydrogen, chlorine, methyl, ethyl, isopropyl, tert-butyl, -CF₃、-CH₂OH、CHOHCH₃、-C(CH₃)₂OH、-C(O)OEt、-C(O)OH、-C(O)N(CH₃)₂、-C(O)NHC(CH₃)₃、-CHCH₃OH and-CH₂OCH₃。

In one embodiment of the compounds of the invention, X is O or- (CH)₂)_m-; m is 0 or 1. In another embodiment of the compounds of the present invention, X is O. In another embodiment of the compounds of the invention, - (CH)₂)_mAnd m is 0 or 1. In one embodiment of the compounds of the invention, m is 1, thus X is-CH₂-. In another embodiment of the compounds of the invention, m is 0, thus X is d and R¹A bond between them.

In one embodiment of the compounds of the invention, R¹Is aryl or heteroaryl, wherein each R is¹Optionally substituted by one or more R⁹And (4) substitution. In another embodiment of the compounds of the invention, R¹Is optionally substituted by one or more R⁹A substituted aryl group. In another embodiment of the compounds of the invention, R¹Is optionally substituted by one R⁹A substituted phenyl group. In yet another embodiment of the compounds of the invention, R¹Is optionally substituted by one or more R⁹A substituted heteroaryl group. In yet another embodiment of the compounds of the invention, R¹Selected from the group consisting of phenyl, naphthyl, and pyridyl; by one or more R⁹And (4) substitution.

In one embodiment of the compounds of the invention, R¹Optionally substituted by one R⁹And (4) substitution. In another embodiment of the compounds of the invention, R¹Is divided into two R⁹And (4) substitution. In another embodiment of the compounds of the invention, R¹By one or two R⁹And (4) substitution. In yet another embodiment of the compounds of the invention, R¹Is divided into three R⁹And (4) substitution. In another embodiment of the compounds of the invention, R¹By four or five R⁹And (4) substitution.

In one embodiment of the compounds of the invention, R⁵Selected from the group consisting of: hydrogen, C_1-6Alkyl and C_3-7A cycloalkyl group; wherein each C_1-6Alkyl is straight or branched chain alkyl; and wherein each C_1-6Alkyl and C_3-7The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: : halogen, -OH, -SH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃. In another embodiment of the compounds of the invention, R⁵Is hydrogen. In yet another embodiment of the compounds of the invention, R⁵Is C_1-6Alkyl or C_3-7A cycloalkyl group. In yet another embodiment of the compounds of the invention, R⁵Is hydrogen or C_1-6An alkyl group. In another embodiment of the compounds of the invention, R⁵Is C_1-6An alkyl group. In another embodiment of the compounds of the invention, R⁵Is C_1-3An alkyl group. In yet another embodiment of the compounds of the invention, R⁵Is methyl or ethyl. In another embodiment of the compounds of the invention, R⁵Selected from the group consisting of hydrogen, methyl and ethyl. In yet another embodiment of the compounds of the invention, R⁵Is hydrogen or ethyl.

In one embodiment of the compounds of the invention, R⁶And R⁷Independently selected from the group consisting of hydrogen, C_1-6Alkyl and C_3-7A cycloalkyl group; wherein each C_1-6Alkyl is straight or branched chain alkyl; and wherein each C_1-6Alkyl and C_3-7The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: : -OH, -SH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃. In another embodiment of the compounds of the invention, R⁶And R⁷Independently selected from the group consisting of hydrogen, C_1-6Alkyl and C_3-7A cycloalkyl group. In another embodiment of the compounds of the invention, R⁶And R⁷Independently selected from the group consisting of hydrogen and C_1-6And alkyl group. In the compounds of the inventionIn another embodiment of (b), R⁶And R⁷Is hydrogen. In yet another embodiment of the compounds of the invention, R⁶And R⁷Is C_1-6An alkyl group. In another embodiment of the compounds of the invention, R⁶And R⁷Both are methyl. In another embodiment of the compounds of the invention, R⁶And R⁷Independently selected from the group consisting of hydrogen and C_3-7A cycloalkyl group. In another embodiment of the compounds of the invention, R⁶Is hydrogen and R⁷Is C_1-6An alkyl group. In one embodiment of the compounds of the invention, R⁶Is hydrogen and R⁷Is methyl or isopropyl. In another embodiment of the compounds of the invention, R⁶Is methyl and R⁷Is isopropyl.

In one embodiment of the compounds of the invention, R⁶And R⁷When attached to the same nitrogen atom combine to form a 3-to 7-membered ring having from 0 to 2 additional heteroatoms as ring members. In another embodiment, R⁶And R⁷When attached to the same nitrogen atom combine to form a 3-to 7-membered ring having from 0 to 1 additional heteroatoms as ring members. In yet another embodiment, R⁶And R⁷When attached to the same nitrogen atom combine to form a 3-to 7-membered ring having 1 additional heteroatom as a ring member. In another embodiment, R⁶And R⁷Combine to form a 3-to 7-membered ring having 0 additional heteroatoms as ring members when attached to the same nitrogen atom; in yet another embodiment, R⁶And R⁷When attached to the same nitrogen atom combine to form a pyrrolidine ring. In another embodiment, R⁶And R⁷When attached to the same nitrogen atom combine to form a morpholine ring.

In one embodiment of the compounds of the invention, R⁸Independently selected from the group consisting of: c_1-6Alkyl and C_3-7A cycloalkyl group; wherein each C_1-6Alkyl is straight or branched chain alkyl; and wherein each C_1-6Alkyl and C_3-7The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: : halogen, -OH, -SH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃. In another embodiment of the compounds of the invention, R⁸Selected from the group consisting of_1-6Alkyl and C_3-7A cycloalkyl group. In another embodiment of the compounds of the invention, R⁸Is C_1-6An alkyl group. In another embodiment of the compounds of the invention, R⁸Selected from the group consisting of methyl, ethyl and isopropyl. In another embodiment of the compounds of the invention, R⁸Is methyl. In yet another embodiment of the compounds of the invention, R⁸Is C_3-7A cycloalkyl group.

In one embodiment of the compounds of the invention, each R is⁹Independently selected from the group consisting of: halogen, C_1-6Alkyl, -O-C_1-6Alkyl, -S-C_1-6Alkyl radical, C_3-7Cycloalkyl, -O-C_3-7Cycloalkyl, -C (O) OR⁵、-C(O)NR⁶R⁷、-NR⁶C(O)R⁸、-S(O₂)NR⁶R⁷、-NR⁶S(O₂)R⁸、-S(O)R⁸and-S (O)₂)R⁸(ii) a Wherein each C_1-6Alkyl is straight or branched chain alkyl; and wherein each C_1-6Alkyl and C_3-7The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃. In another embodiment of the compounds of the invention, each R is⁹Independently selected from the group consisting of halogen, C_1-6Alkyl, -O-C_1-6Alkyl, -C (O) NR⁶R⁷、-S(O₂)NR⁶R⁷and-S (O)₂)R⁸Composition is carried out; wherein each C_1-6Alkyl is straight or branched chain alkyl; and wherein each C_1-6Alkyl is optionally substituted byOne or more halogen substitutions. In another embodiment of the compounds of the invention, each R is⁹Independently selected from the group consisting of: fluorine, chlorine, CF₃、-OCF₃、-C(O)N(CH₃)₂、-S(O₂)NR⁶R⁷、-S(O₂)CF₃、-S(O₂)CH(CH₃)₂and-S (O)₂)CH₃. In another embodiment of the compounds of the invention, one R is⁹Selected from the group consisting of-S (O)₂)NR⁶R⁷and-S (O)₂)R⁸And (4) forming. In another embodiment of the compounds of the invention, one R is⁹is-S (O)₂)NR⁶R⁷. In yet another embodiment of the compounds of the invention, one R is⁹is-S (O)₂)N(CH₃)₂。

In one embodiment, the present invention also relates to compounds having formula Ia:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

X is O or- (CH)₂)_m-；

R¹Selected from the group consisting of aryl and heteroaryl;wherein each R¹Optionally substituted by one or more R⁹Substitution;

R⁶And R⁷Combine to form a 3-to 7-membered ring having 0 to 2 additional heteroatoms as ring members when attached to the same nitrogen atom;

m is 0 or 1.

In one embodiment of the compounds of formula Ia of the present invention, m is 0, thus X is a direct bond; r²And R⁴Independently selected from hydrogen, methyl and chlorine; and R is¹Is represented by-S (O)₂)N(CH₃)₂A substituted phenyl group.

In another embodiment of the compounds of the invention having formula Ia, X is CH₂；R²And R⁴Independently selected from the group consisting of hydrogen, halogen, C_1-4Alkyl, -C (O) OR⁵and-C (O) NR⁶R⁷Composition is carried out; wherein each C_1-4Alkyl is straight or branched chain alkyl; and wherein each C_1-4The alkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH and-O-C_1-3An alkyl group; r¹Is substituted by one or more R⁹Substituted phenyl, naphthyl or pyridyl; r⁵Is hydrogen or C_1-6An alkyl group; r⁶And R⁷Independently selected from the group consisting of hydrogen and C_1-6An alkyl group; wherein each C_1-6Alkyl is straight or branched chain alkyl; or R⁶And R⁷Combine to form a 3-to 7-membered ring having from 0 to 2 additional heteroatoms as ring members when attached to the same nitrogen atom; r⁸Is C_1-6An alkyl group; and each R⁹Independently selected from the group consisting of halogen, C_1-6Alkyl, -O-C_1-6Alkyl, -C (O) NR⁶R⁷、-S(O₂)NR⁶R⁷And-S(O₂)R⁸Composition is carried out; wherein each C_1-6Alkyl is straight or branched chain alkyl; and wherein each C_1-6Alkyl is optionally substituted with one or more halogens. In another embodiment of the compounds of the invention having formula Ia, X is CH₂；R²And R⁴Independently selected from the group consisting of chloro, methyl, ethyl, isopropyl, tert-butyl, -C (O) OEt, -C (O) OH, -C (O) N (CH)₃)₂、-CHCH₃OH and-CH₂OCH₃Composition is carried out; r¹Is substituted by one or more R⁹Substituted phenyl, naphthyl or pyridyl; r⁵Is hydrogen or ethyl; r⁶And R⁷Independently selected from the group consisting of hydrogen, methyl and isopropyl; or R⁶And R⁷Combine to form a pyrrolidine or morpholine ring when attached to the same nitrogen atom; and each R⁹Independently selected from the group consisting of fluorine, chlorine, -CF₃、-OCF₃、-C(O)N(CH₃)₂、-S(O₂)NR⁶R⁷and-S (O)₂)CH₃And (4) forming.

In another embodiment, the invention also relates to compounds having formula Ib:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

X is O or- (CH)₂)_m-；

R¹Selected from the group consisting of aryl and heteroaryl; wherein each R¹Optionally substituted by one or more R⁹Substitution;

R⁵selected from the group consisting of hydrogen, -C_1-6Alkyl and-C_3-7A cycloalkyl group; wherein each C_1-6Alkyl is straight or branched chain alkyl, and wherein each C_1-6Alkyl and C_3-7The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -SH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃；

R⁶And R⁷Combine to form a 3-to 7-membered ring having 0 to 2 additional heteroatoms as ring members when attached to the same nitrogen atom;

R⁸selected from the group consisting of_1-6Alkyl and C_3-7A cycloalkyl group; wherein each C_1-6Alkyl is straight or branched chain alkyl, and wherein each C_1-6Alkyl and C_3-7The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -SH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃(ii) a And is

Each R⁹Independently selected from the group consisting of: halogen element、C_1-6Alkyl, -O-C_1-6Alkyl, -S-C_1-6Alkyl radical, C_3-7Cycloalkyl, -O-C_3-7Cycloalkyl, -C (O) OR⁵、-C(O)NR⁶R⁷、-NR⁶C(O)R⁸、-S(O₂)NR⁶R⁷、-NR⁶S(O₂)R⁸、-S(O)R⁸and-S (O)₂)R⁸(ii) a Wherein each C_1-6Alkyl is straight or branched chain alkyl; and wherein each C_1-6Alkyl and C_3-7The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of: halogen, -OH, -C_1-3Alkyl, -O-C_1-3Alkyl, -CF₃、-CH₂CF₃and-O-CF₃(ii) a And is

m is 0 or 1.

In one embodiment of the compounds of the invention having formula Ib, X is CH₂；R²And R³Is methyl; r¹Is substituted by one or more R⁹Substituted phenyl; r⁶And R⁷Independently selected from the group consisting of hydrogen and methyl; and each R⁹Independently selected from the group consisting of fluorine, chlorine, -CF₃、-S(O₂)NR⁶R⁷and-S (O)₂)CH₃And (4) forming.

In the context of the present disclosure, any one or more aspects or embodiments may be combined with any other aspect or embodiment.

Exemplary compounds according to the present invention include the compounds listed in table 1:

TABLE 1

Preparation of compounds having formula I

Compounds having formula I can be readily prepared by those skilled in the art using methods and materials known in the art and referring 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.

Compounds having formula I can be synthesized as described below. The following schemes provide an overview of representative, non-limiting embodiments of the present invention. One skilled in the art will recognize that analogs having formula I (including different isomeric forms) can also be prepared from similar starting materials.

Scheme 1:

a compound described by formula Ia (wherein X is-CH)₂-) the preparation is described in scheme 1 below.

Scheme 1

P¹Is a functional group for protecting the nitrogen functionality. P¹Examples of (b) are carbonates such as tert-Butyloxycarbonyl (BOC), 9-Fluorenylmethoxycarbonyl (FMOC) and benzyloxycarbonyl (CBZ) groups.

In this general scheme, R depicted in formula II¹The starting material (where Y is a suitable leaving group such as Br, I, OT or OM) can be prepared by a number of methods well known in the art. Which is reacted with an anion derived from an appropriately substituted 1, 3-dicarbonyl compound, as described in formula III. For example, a solution of a compound described by formula III in a solvent such as ethanol or Tetrahydrofuran (THF) may be treated with a base such as sodium ethoxide or lithium bis (trimethylsilyl) amide, followed by addition of a solution of a compound described by formula II in a solvent such as ethanol or Tetrahydrofuran (THF) at a temperature between 0 ℃ and 80 ℃ for between 0.5 and 3 hours. The product described by formula IV can be recovered by standard work-up procedures.

One conventional scheme for converting the compound described by formula IV to the compound described by formula V is method B, which involves reaction with hydrazine in ethanol under reflux for several hours. The product described by formula V can be recovered by standard work-up procedures.

While there are many ways to achieve the reaction described by method C, one conventional approach involves reacting a compound described by formula V with a base such as sodium hydride in a solvent such as Tetrahydrofuran (THF) or Dimethylformamide (DMF), followed by addition of a compound described by formula VI at ambient temperature for about 1 hour. Following standard extraction and purification procedures, the product described by formula VII can be obtained in good yield and purity.

There are many well established chemical procedures (method D) for deprotecting the compound described by formula VII to the compound described by formula Ia. For example if P¹Is a BOC protecting group, the compound described by formula VII may be treated with an acidic substance such as anhydrous hydrogen chloride in a solvent such as diethyl ether to provide the compound described by formula Ia as a hydrochloride salt. 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-trifluoroacetic acid and methanesulfonate.

Scheme 2:

a compound described by formula Ia (where X is R)¹The bond to the pyrazole ring) is described in scheme 2 below.

Scheme 2

In general scheme 2, a Suzuki coupling (Suzuki coupling) reaction is used to bind together combinations of compounds described by formulas IIa (where Y is Br or I) and VIII. There are many variations of the suzuki reaction described in the literature. For example, solutions of the compounds described by the formulae IIa and VIII in K₂CO₃In the presence may be dissolved in a solvent such as aqueous dioxane under a nitrogen atmosphere and then treated with a catalytic amount of tetratriphenylphosphine palladium under reflux for several hours. Following standard extraction and purification procedures, the coupled product described by formula IX can be obtained in good yield and purity. Conversion of the protected compound described by formula IX to a compound described by formula V is readily achieved by the method most suitable for removal of the particular protecting group.

Scheme 3

A compound described by formula Ib (wherein X is-CH)₂-) the preparation is described in scheme 3 below.

Scheme 3

In general scheme 3, compounds having the general formula XII can be prepared by reacting a starting material as described by formula VI with an appropriately substituted 1, 3-dicarbonyl compound as described by formula XI. For example, a solution of a compound described by formula XI in a solvent such as ethanol or Tetrahydrofuran (THF) can be treated with a base such as sodium ethoxide or lithium bis (trimethylsilyl) amide, followed by addition of a solution of a compound described by formula VI in a solvent such as ethanol or Tetrahydrofuran (THF) at a temperature between 0 ℃ and 80 ℃ for between 0.5 and 3 hours. The product described by formula XII can be recovered by standard work-up procedures.

One conventional scheme for reacting a compound described by formula XII with a compound described by formula XIII is method H, which involves treating a solution of a compound described by formula XIII in a solvent such as ethanol with a base such as diisopropylamine, followed by addition of a compound described by formula XII at a temperature between ambient temperature and 80 ℃ for between 0.5 and 3 hours. The product described by formula XIV can be recovered by standard work-up procedures.

The cis/trans (E/Z) mixture may be separated into component isomers by conventional techniques well known to those skilled in the art. For example by using chromatography and/or fractional crystallisation.

The racemic mixture can be separated into the component R and S enantiomers by conventional techniques well known to those skilled in the art. For example, by using chiral chromatography.

Mixtures of diastereomers may be separated into component isomers by conventional techniques well known to those skilled in the art. For example by using chromatography and/or fractional crystallisation.

Therapeutic uses and formulations

Another aspect of the invention relates to a pharmaceutical composition comprising a compound having formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, in combination with a pharmaceutically acceptable diluent, excipient or adjuvant.

The invention also relates to the use of compounds having formula I in therapy, in particular to inhibit members of the lysyl oxidase family members LOX, LOXL1, LOXL2, LOXL3 and LOXL 4. In one embodiment, the invention provides selective inhibition of specific lysyl oxidase isozymes. In another embodiment, the invention provides simultaneous inhibition of 2,3 or 4 LOX isozymes. The relative inhibitory efficacy of these compounds can be determined in various ways by the amount required to inhibit the amine oxidase activity of LOX, LOXL1, LOXL2, LOXL3, and LOXL4, e.g., in vitro assays using recombinant or purified human proteins or using recombinant or purified non-human enzymes, in cell assays expressing normal rodent enzymes, in cell assays that have been transfected with human proteins, in vivo assays in rodents and other mammalian species, etc.

Accordingly, another aspect of the invention relates to a method of inhibiting the amine oxidase activity of LOX, LOXL1, LOXL2, LOXL3, and LOXL4 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

In one embodiment, the invention relates to a method of inhibiting the amine oxidase activity of LOXL 2. In another embodiment, the invention relates to inhibiting the amine oxidase activity of LOX and LOXL 2.

As previously discussed, LOX and LOXL1-4 enzymes are members of a large family of flavin-dependent and copper-dependent amine oxidases, including SSAO/VAP-1, monoamine oxidase-B (MAO-B), and diamine oxidase (DAO). In one embodiment, the compounds of the present invention inhibit members of the lysyl oxidase isozyme family selectively relative to SSAO/VAP-1, MAO-B, DAO, and other members of the amine oxidase family.

Also disclosed are methods of inhibiting one or more lysyl oxidase isozymes (LOX, LOXL1, LOXL2, LOXL3, and LOXL4) in a patient suffering from a fibrotic disease and methods of treating a fibrotic disease using compounds described by formula I. In addition, methods of inhibiting one or more lysyl oxidase isozymes (LOX, LOXL1, LOXL2, LOXL3, and LOXL4) in a patient suffering from cancer, including metastatic cancer, and methods of treating cancer and metastatic cancer using compounds described by formula I are disclosed.

In another aspect of the invention, there is provided a method of treating a condition associated with LOX, LOXL1, LOXL2, LOXL3, and LOXL4 proteins, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound having formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

In another aspect, there is provided a method of treating a condition modulated by LOX, LOXL1, LOXL2, LOXL3, and LOXL4, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound having formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

In one embodiment of the method of the invention, the condition is selected from the group consisting of fibrosis, cancer and angiogenesis.

In another aspect, the invention provides a method for reducing extracellular matrix formation by treating human subjects, pets and livestock with a fluoroallylamine inhibitor of the lysyl oxidase isozyme family having formula I as described herein.

Where the condition is a liver disorder, the methods described above are applicable. As used herein, the term "liver disorder" includes any disorder that affects the liver, and in particular any acute or chronic liver disease involving pathological destruction, inflammation, degeneration and/or proliferation of hepatocytes. In particular, the liver condition is liver fibrosis, cirrhosis or any other liver disease, wherein the level of some markers of hepatocyte damage, alteration or necrosis in the plasma is elevated when compared to normal plasma levels. The biochemical markers associated with liver activity and status may be selected from those disclosed in the literature and in particular alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), Alkaline Phosphatase (AP), Gamma Glutamyl Transpeptidase (GGT), cytokeratin-18 (CK-18) or resistin. In a specific embodiment, the liver condition is a fatty liver disease, wherein an increase in one or more of these markers is associated with more or less severe steatosis in the liver, which can be confirmed by liver biopsy. A non-exhaustive list of fatty liver diseases includes non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and fatty liver diseases associated with conditions such as hepatitis or metabolic syndrome (obesity, insulin resistance, hypertriglyceridemia, etc.). 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 Sclerosing Cholangitis (PSC), liver damage caused by progressive fibrosis, liver fibrosis, and cirrhosis.

Where the condition is a renal disorder, the methods described above are applicable. In one embodiment, the renal disorder is selected from the group consisting of: kidney fibrosis, acute kidney injury, chronic kidney disease, diabetic nephropathy, glomerulosclerosis, vesicoureteral reflux, tubulointerstitial fibrosis and glomerulonephritis.

Where the condition is cardiovascular disease, the methods described above are applicable. In one embodiment, the cardiovascular disease is selected from the group consisting of: atherosclerosis (atherosclerosis), arteriosclerosis (arterosclerosis), hypercholesterolemia, and hyperlipidemia.

Where the condition is fibrosis, the methods described above are applicable. As used herein, "fibrosis" includes diseases such as: cystic fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, kidney fibrosis, scleroderma, radiation-induced fibrosis, ocular fibrosis, Peyronie's disease, scarring, and other diseases in which excessive fibrosis can lead to diseases including Crohn's disease and inflammatory bowel disease.

In one embodiment, the fibrosis is selected from the group consisting of: liver fibrosis, lung fibrosis, kidney fibrosis, myocardial fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis, radiation-induced fibrosis and scleroderma, or associated with respiratory diseases, abnormal wound healing and repair, post-operative surgery, cardiac arrest and all conditions in which excessive or abnormal deposition of fibrous material is associated with a disease. In another embodiment, the fibrosis is selected from the group consisting of: liver fibrosis, lung fibrosis, kidney fibrosis, myocardial fibrosis and scleroderma.

In one embodiment, renal fibrosis includes, but is not limited to, diabetic nephropathy, vesicoureteral reflux, tubulointerstitial fibrosis; glomerulonephritis (glorulephritis) or glomerulonephritis (glorulephritis), including focal segmental glomerulosclerosis and membranous glomerulonephritis, and mesangial capillary glomerulonephritis. In one embodiment, liver fibrosis results in cirrhosis and includes associated conditions such as chronic viral hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (ASH), non-alcoholic fatty liver disease (NASH), Primary Biliary Cirrhosis (PBC), biliary cirrhosis, and autoimmune hepatitis.

Where the condition is cancer, the methods described above are also applicable. 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 cancer; hepatobiliary cancer; esophageal cancer; non-hodgkin lymphoma; bladder cancer; uterine cancer; gliomas, glioblastoma, medulloblastoma and other brain tumors; kidney cancer; myelofibrosis, head and neck cancer; gastric cancer; multiple myeloma; testicular cancer; germ cell tumors; neuroendocrine tumors; cervical cancer; oral cancer; carcinoids of the gastrointestinal tract, breast and other organs; signet ring cell carcinoma; interstitial tumors including sarcomas, fibrosarcomas, hemangiomas (haemingioma), angiomatosis (angiomatosis), vascular involucrima, pseudohemangiomatoid matrix hyperplasia, myofibroblasts, fibromatosis, inflammatory myofibroblastoma, lipoma, angiolipoma, granulocytoma, neurofibroma, schwannoma, angiosarcoma, liposarcoma, rhabdomyosarcoma, osteosarcoma, leiomyoma, or leiomyosarcoma.

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 tumor metastasis.

In one embodiment, lung cancer includes lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, bronchoalveolar carcinoma, non-small cell carcinoma, and mesothelioma. In one embodiment, the breast cancer comprises 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.

In one embodiment, the ovarian cancer comprises an ovarian epithelial cancer or a superficial epithelial-stromal tumor, including serous, endometrioid, and mucinous cystadenocarcinoma, and a genital cord-stromal tumor. In one embodiment, hepatobiliary cancer includes hepatocellular carcinoma, cholangiocarcinoma, and hemangioma. In one embodiment, esophageal cancer includes esophageal adenocarcinoma and squamous cell carcinoma. In one embodiment, uterine cancer includes endometrial adenocarcinoma, uterine papillary serous carcinoma, clear cell carcinoma of the uterus, uterine sarcoma and leiomyosarcoma, and mixed mullerian tumor (mixturerian tumor). In one embodiment, the kidney cancer includes renal cell carcinoma, clear cell carcinoma, and nephroblastoma. In one embodiment, the head and neck cancer comprises squamous cell carcinoma. In one embodiment, the gastric cancer comprises gastric adenocarcinoma and gastrointestinal stromal tumors.

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

Where the condition is angiogenesis, the methods described above are applicable.

In one embodiment of the method of the invention, the subject is selected from the group consisting of humans, pets and livestock. In another embodiment of the method of the invention, the subject is a human.

Another aspect of the invention provides the use of a compound having formula I, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a condition associated with LOX, LOXL1, LOXL2, LOXL3, and LOXL4 proteins.

Pharmaceutical and/or therapeutic formulations

In another embodiment of the present invention, there is provided a composition comprising a compound having formula I and at least one pharmaceutically acceptable excipient, carrier or diluent thereof. The compounds of formula I may also be presented as suitable salts, including pharmaceutically acceptable salts.

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

The phrase "pharmaceutically acceptable salt" refers to any salt preparation suitable for use in pharmaceutical applications. Pharmaceutically acceptable salts are intended to mean those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art and include acid addition and base salts. Half salts of acids and bases may also be formed. Pharmaceutically acceptable salts include amine salts of mineral acids (e.g., hydrochloride, hydrobromide, sulfate, etc.); and amine salts of organic acids (e.g., formate, acetate, lactate, malate, tartrate, citrate, ascorbate, succinate, maleate, butyrate, valerate, fumarate, etc.).

For compounds having formula (I) with 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 a compound of the invention.

Pharmaceutically acceptable salts are described in detail in J.pharmaceutical Sciences [ J.Med. Sci ],1977,66:1-19, S.M.Berge et al. These salts are prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base functionality with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, sulfate, salicylate, and the like, Picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate, valerate, and the like. Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine (benzathine), calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine (olamine), potassium, sodium, tromethamine and zinc salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, triethanolamine, and the like.

Pharmaceutically acceptable salts of compounds having formula I can be prepared by methods known to those skilled in the art, including, for example:

(i) reacting a compound having formula I with a desired acid or base;

(ii) by removing acid-or base-labile protecting groups from suitable precursors of compounds having formula I or by ring-opening suitable cyclic precursors (e.g., lactones or lactams) using the desired acid or base; or

(iii) One salt of a compound having formula I is converted to another salt by reaction with an appropriate acid or base or by passage through a suitable ion exchange column.

Reactions (i) - (iii) above 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 ionization of the resulting salt can range from complete ionization to little ionization.

Thus, for example, suitable pharmaceutically acceptable salts of the compounds according to the invention may be prepared by mixing a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, phosphoric acid, acetic acid, oxalic acid, carbonic acid, tartaric acid or citric acid with a compound of the invention. Suitable pharmaceutically acceptable salts of the compounds of the invention include acid addition salts.

The compounds of the present invention may exist in unsolvated forms as well as solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g. ethanol). When the solvent is water, the term 'hydrate' is used.

In one embodiment, the compound having formula I may be administered in a "prodrug" form. The phrase "prodrug" refers to a compound that is metabolized or otherwise converted to a biologically, pharmaceutically, or therapeutically active form of the compound by one or more steps or methods when administered in vivo. Prodrugs can be prepared by modifying functional groups present in the compound in a manner such that the modifications are cleaved, either upon routine manipulation or in vivo, to the compounds 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 cleave to form a free hydroxy, 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 the alcohol and amine functional groups of the compounds of the present invention. Prodrug forms may be selected from functional groups such as-C (O) alkyl, -C (O) cycloalkyl, -C (O) aryl, -C (O) -arylalkyl, C (O) heteroaryl, -C (O) -heteroarylalkyl, and the like. With knowledge of the pharmacokinetic processes and drug metabolism in vivo, one skilled in the art, once aware of the pharmaceutically active compound, can design prodrugs of this compound (see, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach [ methods of Medicinal Chemistry biochemistry ], Oxford university Press [ Oxford university Press ], New York, p. 388-.

The compositions herein comprise one or more compounds provided herein. In one embodiment, these compounds are formulated into suitable pharmaceutical formulations such as solutions, suspensions, tablets, ointments, gels, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs for oral administration, or as sterile solutions or suspensions for parenteral administration, as well as transdermal patch formulations 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).

In the compositions, an effective concentration of one or more compounds or pharmaceutically acceptable derivatives thereof is admixed with a suitable pharmaceutical carrier. These compounds may be derivatized into 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 concentration of the compound in the composition is effective to deliver, upon administration, an amount that treats, prevents, or reduces one or more symptoms of the disease or disorder to be treated.

In one embodiment, the composition is formulated for single dose administration. To formulate a composition, parts by weight of a compound are dissolved, suspended, dispersed, or otherwise mixed in a selected carrier at an effective concentration such that the condition being treated is alleviated, prevented, or one or more symptoms are reduced.

The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically beneficial effect in the treated patient in the absence of undesirable side effects. Therapeutically effective concentrations can be determined empirically by testing compounds in vitro and in vivo systems as described herein and in PCT publication WO 04/018997, and then extrapolating dosages for use in humans therefrom.

The concentration of the active compound in the pharmaceutical composition will depend on the absorption, distribution, inactivation, and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosing schedule and amount administered, and other factors well known to those skilled in the art.

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

Administration may occur at intervals of minutes, hours, days, weeks, months or years or continuously over any of these periods. Suitable doses are in the range of about 0.1ng/kg body weight to 1g/kg body weight per dose. The dose is preferably in the range of 1 μ g to 1g/kg body weight/dose, such as in the range of 1mg to 1g/kg body weight/dose. Suitably, the dose is preferably in the range of 1 μ g to 500mg/kg body weight/dose, such as 1 μ g to 200mg/kg body weight/dose or 1 μ g to 100mg/kg body weight/dose. Other suitable doses may be in the range of 1mg to 250mg/kg body weight, including 1mg to 10, 20, 50 or 100mg/kg body weight/dose or 10 μ g to 100mg/kg body weight/dose.

The amount of suitable dosage and the dosing regimen may be determined by the attending physician and may depend on the particular condition being treated, the severity of the condition and the general health, age and weight of the subject.

In cases where the compound exhibits insufficient solubility, the method used to solubilize the compound may be used. Such methods are known to those skilled in the art and include, but are not limited to, the use of co-solvents such as dimethyl sulfoxide (DMSO), the use of surfactants such as

Dissolving in sodium bicarbonate water solution, preparing the target compound into nano particles and the like. Derivatives of the compounds (such as prodrugs of the compounds) may also be used to formulate effective pharmaceutical compositions.

Upon mixing or addition of the compounds, the resulting mixture may be a solution, suspension, emulsion, or the like. The form of the resulting mixture depends on a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient to alleviate symptoms of the disease, disorder, or condition being treated and can be determined empirically.

Pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil and water emulsions containing suitable amounts of the compounds or pharmaceutically acceptable derivatives thereof. In one embodiment, the pharmaceutically therapeutically active compound and its derivatives are formulated and administered in a unit dosage form or multiple dosage forms. The active ingredient may be administered immediately, or may be divided into a number of smaller doses to be administered at intervals. As used herein, unit dosage forms refer to physically discrete units suitable for use in human and animal subjects and packaged individually as is known in the art. Each unit dose contains a predetermined amount 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 dosage forms include ampoules and syringes and individually packaged tablets or capsules. The unit dosage forms may be administered in fractions or multiples thereof. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single container for administration in separate unit dosage forms. Examples of multiple dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons. Thus, a multiple dosage form is a plurality of unit doses that are not separated when packaged.

The actual methods of making such dosage forms are known, or will be apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences [ Remington's Pharmaceutical Sciences ], Mack Publishing Company [ Mark Press ], Easton, Pa., 15 th edition, 1975.

Dosage forms or compositions can be prepared containing the active ingredient in the range of 0.005% to 100% (by weight) with the balance being made up of non-toxic carriers. Methods for preparing these compositions are known to those skilled in the art. Contemplated compositions may contain from 0.001% to 100% (wt%) active ingredient, in one embodiment from 0.1% to 95% (wt%), and in another embodiment from 75% to 85% (wt%).

Mode of administration

Conventional modes of administration include injection (subcutaneous, intravenous, etc.), oral administration, inhalation, transdermal administration, topical ointment or gel or powder, vaginal or rectal administration. Depending on the route of administration, the formulation and/or the compound may be coated with a material to protect the compound from the action of enzymes, acids, and other natural conditions that may inactivate the therapeutic activity of the compound. The compounds may also be administered parenterally or intraperitoneally.

Compositions for oral administration

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

Solid compositions for oral administration

In certain embodiments, the formulation is a solid dosage form, in one embodiment, a capsule or tablet. Tablets, pills, capsules, dragees and the like may contain one or more of the following ingredients or compounds having similar properties: a binding agent; a lubricant; a diluent; a slip aid; a disintegrant; a colorant; a sweetener; a flavoring agent; a wetting agent; enteric coating; and a film coating. Examples of binders include microcrystalline cellulose, tragacanth, dextrose solution, acacia syrup, gelatin solution, molasses, polyvinylpyrrolidone, povidone, crospovidone, 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. Slip aids include, but are not limited to, colloidal silica. Disintegrating agents include croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Colorants include, for example, any of the following: approved certified water-soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on hydrated alumina. Sweeteners include sucrose, lactose, mannitol, and artificial sweeteners (such as saccharin), as well as any number of spray dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds that produce a pleasant sensation, such as, but not limited to, mint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Enteric coatings include fatty acids, fats, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. The film coating comprises hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000 and cellulose acetate phthalate.

The compound or pharmaceutically acceptable derivative thereof may be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition may be formulated in an enteric coating which leaves the composition intact 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.

When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. In addition, the dosage unit form may contain various other materials which modify the physical form of the dosage unit, such as sugars and other enteric agents. The compounds may also be administered as components of elixirs, suspensions, syrups, wafers, sprinkles, chewing gums and the like. Syrups may contain, in addition to the active ingredient, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

The active material may also be mixed with other active materials that do not impart the desired effect or with materials that supplement the desired effect (such as antacids, H2 blockers, and diuretics). The active ingredient is a compound as described herein or a pharmaceutically acceptable derivative thereof. Higher concentrations (up to about 98% by weight) of active ingredient may be included.

In all embodiments, the tablet and capsule formulations may be coated as known to those skilled in the art in order to modify or maintain dissolution of the active ingredient. Thus, for example, they may be coated with conventional enteric digestible coatings such as phenyl salicylate, waxes and cellulose acetate phthalate.

Liquid composition for oral administration

Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent formulations reconstituted from effervescent granules. Aqueous solutions, including for example elixirs and syrup emulsions, are oil-in-water or water-in-oil emulsions.

Liquid pharmaceutically administrable compositions can be prepared, for example, by dissolving, dispersing, or otherwise mixing the active ingredient and optional pharmaceutical adjuvants as defined above in a carrier, such as water, saline, aqueous dextrose, glycerol, ethylene glycol, ethanol, and the like, to form a solution or suspension. If desired, the pharmaceutical compositions to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifiers, solubilizers, pH adjusting agents and the like, for example, acetate, sodium citrate, cyclodextrin derivatives, sorbitol monolaurate, triethanolamine sodium acetate, triethanolamine oleate and other such agents.

Elixirs are clear, sweetened hydroalcoholic formulations. Pharmaceutically acceptable carriers for use in elixirs include solvents. Syrups are concentrated aqueous solutions of sugars (e.g., sucrose) and may contain preservatives. Emulsions are two-phase systems in which one liquid is dispersed throughout the other in the form of small droplets. Pharmaceutically acceptable carriers for use in the emulsion are non-aqueous liquids, emulsifiers and preservatives. Suspensions employ pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable materials for use in non-effervescent granules to be reconstituted into liquid oral dosage forms include diluents, sweeteners and wetting agents. Pharmaceutically acceptable materials for use in effervescent granules to be reconstituted into liquid oral dosage forms include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.

Solvents include glycerin, sorbitol, ethanol, and syrup. Examples of preservatives include glycerol, methyl and propyl parabens, benzoic acid, sodium benzoate and ethanol. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifiers include gelatin, gum arabic, tragacanth, bentonite, surfactants such as polyoxyethylene sorbitan monooleate. The suspending agent comprises sodium carboxymethylcellulose, pectin, tragacanth, gum coumaric and acacia. Sweeteners include sucrose, syrup, glycerin, and artificial sweeteners such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic acids include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Colorants include any of the approved certified water-soluble FD and C dyes and mixtures thereof. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds that produce a pleasant taste sensation.

For solid dosage forms, in one embodiment, a solution or suspension in, for example, propylene carbonate, vegetable oil, or triglycerides, is encapsulated in a gelatin capsule. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable, readily measurable liquid carrier (e.g., water) for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers and encapsulating these solutions or suspensions in hard or soft capsule shells. Other useful formulations include those listed in U.S. Pat. nos. RE28,819 and 4,358,603. Briefly, such formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono-or polyalkylene glycol including, but not limited to, 1, 2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol, and one or more antioxidants such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, and one or more antioxidants, Sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

Other formulations include, but are not limited to, hydroalcoholic solutions, including pharmaceutically acceptable acetals. The alcohol used in these formulations is any pharmaceutically acceptable water-miscible solvent having one or more hydroxyl groups, including but not limited to propylene glycol and ethanol. Acetals include, but are not limited to, di (lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal.

Injectables, solutions and emulsions

In one embodiment, parenteral administration characterized by subcutaneous, intramuscular, or intravenous injection is also contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension formation prior to injection, or as emulsions. Injectables, solutions and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, glucose, glycerol or ethanol. In addition, the pharmaceutical compositions to be administered may also contain, if desired, minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrins.

Also contemplated herein is the implantation of a slow or sustained release system such that a constant level of dosage is maintained. Briefly, the compounds provided herein are dispersed in a solid inner matrix surrounded by an outer polymeric film that is insoluble in body fluids, such as polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicon carbonate copolymers, hydrophilic polymers (such as hydrogels of esters of acrylic and methacrylic acid, collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate), such as polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, polyethylene/propylene copolymers, polyethylene/vinyl acetate copolymers, polyethylene, Silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomers polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene/vinyl alcohol copolymers, ethylene/vinyl acetate/vinyl alcohol terpolymers, and ethylene/ethyleneoxyethanol copolymers. The compound diffuses through the outer polymer membrane during the release rate controlling step. The percentage of active compound contained in such parenteral compositions is highly dependent on its specific properties as well as the activity of the compound and the needs of the subject.

Parenteral administration of the compositions includes intravenous, subcutaneous and intramuscular administration. Formulations for parenteral administration include sterile solutions ready for injection, sterile anhydrous soluble products such as lyophilized powders, including subcutaneous tablets, ready for injection in combination with a solvent immediately prior to use, sterile suspensions ready for injection, sterile anhydrous insoluble products ready for combination with a vehicle immediately prior to use, and sterile emulsions. The solution may be aqueous or non-aqueous.

If administered intravenously, suitable carriers include physiological saline or Phosphate Buffered Saline (PBS) and solutions containing thickening and solubilizing agents such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.

Pharmaceutically acceptable carriers for use in parenteral formulations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents, and other pharmaceutically acceptable materials.

Examples of aqueous vehicles include sodium chloride Injection, ringer's Injection, isotonic dextrose Injection, sterile water Injection, dextrose lactate ringer's Injection. Non-aqueous parenteral vehicles include fixed oils of vegetable origin, olive oil, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents, including phenol or cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride and benzalkonium chloride, must be added to the parenteral formulation packaged in a multi-dose container. Isotonic agents include sodium chloride and glucose. Buffers include phosphates and citrates. The antioxidant comprises sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. The emulsifier comprises polysorbate 80: (

80). The sequestering or chelating agent for metal ions includes EDTA. The pharmaceutical carrier also includes ethanol, polyethylene glycol, and propylene glycol for water-miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.

The concentration of the pharmaceutically active compound is adjusted so that the injection provides an effective amount to produce the desired pharmacological effect. The precise amount depends on the age, weight, and condition of the patient or animal, as is known in the art.

Multiple doses of parenteral formulations are packaged in ampoules, vials or syringes with needles. All formulations for parenteral administration must be sterile, as is known and practiced in the art.

By way of example, intravenous or intraarterial infusion of sterile aqueous solutions containing the active compounds is an effective mode of administration. Another embodiment is a sterile aqueous or oleaginous solution or suspension containing the active substance for injection as needed to produce the desired pharmacological effect.

Injectable agents are designed for local and systemic administration. In one embodiment, a therapeutically effective dose is formulated to contain the active compound at a concentration of at least about 0.1% w/w up to about 90% w/w or more, and in some embodiments, more than 1% w/w, relative to the tissue being treated.

The compounds may be suspended in micronized form or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends on a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient to alleviate symptoms of the condition and can be determined empirically.

Freeze-dried powder

Also of interest herein are lyophilized powders that can be reconstituted for administration as solutions, suspensions, and other mixtures. They may also be reconstituted and formulated as solids or gels.

Sterile lyophilized powders are prepared by dissolving a compound provided herein or a pharmaceutically acceptable derivative thereof in a suitable solvent. The solvent may contain excipients or powders to improve stability or other pharmacological components of the reconstituted solution prepared from the powder. Excipients that may be used include, but are not limited to, dextrose, sorbitol, fructose, corn syrup, xylitol, glycerol, glucose, sucrose, or other suitable agents. The solvent may also contain a buffer, such as citric acid, sodium or potassium phosphate or other such buffers known to those skilled in the art, in one embodiment, at about neutral pH. The solution is then sterile filtered and then lyophilized under standard conditions known to those skilled in the art to provide the desired formulation. In one embodiment, the resulting solution will be dispensed into vials for lyophilization. Each vial will contain a single dose or multiple doses of the compound. The lyophilized powder can be stored under suitable conditions, such as at about 4 ℃ to room temperature.

Reconstitution of this lyophilized powder with water for injection provides a formulation for parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier. The exact amount depends on the compound selected. Such amounts may be determined empirically.

Topical application

Topical mixtures were prepared as described for local and systemic administration. The resulting mixture may be a solution, suspension, emulsion, etc. and formulated as an ointment, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, paste, foam, aerosol, rinse, spray, suppository, bandage, skin patch, or any other formulation suitable for topical administration.

The compound or pharmaceutically acceptable derivative thereof may be formulated as an aerosol for topical administration, such as by inhalation. These formulations for administration to the respiratory tract may be in the form of an aerosol or solution for a nebulizer, or as a fine powder for insufflation, either alone or in combination with an inert carrier such as lactose. In this case, the particles of the formulation have a diameter of less than 50 microns in one embodiment, and less than 10 microns in one embodiment.

The compounds may be formulated for topical (local/local) administration, such as in the form of gels, ointments, and lotions, topically to the skin and mucosa, such as the eye, and into the eye or intracisternally or intraspinally. Topical administration is contemplated for transdermal delivery and also for administration to the eye or mucosa or for inhalation therapy. Nasal solutions of the active compounds may also be administered, alone or in combination with other pharmaceutically acceptable excipients.

These solutions, particularly those intended for ophthalmic use, can be formulated as 0.01% -10% (volume%) isotonic solutions with appropriate salts, at a pH of about 5-7.

Compositions for other routes of administration

Other routes of administration are also contemplated herein, such as transdermal patches, including iontophoretic and electrophoretic devices, vaginal and rectal administration.

Transdermal patches (including iontophoresis and electrophoresis devices) are well known to those skilled in the art. For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories are used herein mean solids which are intended to be inserted into the intestine and which melt or soften at body temperature, thereby releasing one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances for rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (cocoa butter), glycerogelatin, polyethylene glycols (polyoxyethylene glycols) and suitable mixtures of fatty acid monoglycerides, diglycerides, triglycerides. Combinations of different matrices may be used. Agents used to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared by compression methods or by modeling. In one embodiment, the rectal suppository weighs between about 2 and 3 gm.

Tablets and capsules for rectal administration are made using the same pharmaceutically acceptable materials and by the same methods as formulations for oral administration.

Targeted formulations

The compounds provided herein, or pharmaceutically acceptable derivatives thereof, may also be formulated to be targeted to specific tissues, receptors, or other areas of the body of the subject to be treated. Many such targeting methods are well known to those skilled in the art. All such targeting methods for use in the compositions of the present invention are contemplated herein.

In one embodiment, liposomal suspensions (including tissue-targeting liposomes, such as tumor-targeting liposomes) may also be suitable as pharmaceutically acceptable carriers. These suspensions may be prepared according to methods known to those skilled in the art. For example, liposome formulations can be prepared as described in U.S. Pat. No. 4,522,811. Briefly, liposomes, such as multilamellar lipid vesicles (MLV's), can be formed by drying egg phosphatidylcholine and brain phosphatidylserine (7:3 molar ratio) on the inside of the flask. A solution of the compounds provided herein in Phosphate Buffered Saline (PBS) lacking divalent cations was added and the flask shaken until the lipid membrane was dispersed. The resulting lipid vesicles were washed to remove unencapsulated compounds, pelleted by centrifugation, and then resuspended in PBS.

Co-administration with other drugs

According to another aspect of the invention, it is contemplated that a compound having formula I as described herein may be administered to a subject in need thereof in combination with an agent recognized by those skilled in the art as the current standard of care for the condition of interest. Such combinations provide one or more advantages to the subject, such as requiring reduced doses to achieve similar benefits, achieving the desired palliative effect in less time, and the like.

The compounds according to the invention may be administered with other drugs as part of a treatment regimen. It may be desirable to administer a combination of effective compounds, for example for the purpose of treating a particular disease or condition. It is therefore within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound according to the invention having formula I, may be combined in the form of a kit suitable for co-administration of the compositions.

In one embodiment of the methods of the present invention, the compound having formula I may be administered with a second therapeutic agent. In one embodiment, the second therapeutic agent is selected from the group consisting of: anti-cancer agents, anti-inflammatory agents, hypotensive agents, anti-fibrotic agents, anti-angiogenic agents, and immunosuppressive agents.

When two or more active ingredients are co-administered, the active ingredients may be administered simultaneously, sequentially or separately. In one embodiment, the compound having formula I is administered concurrently with the second therapeutic agent. In another embodiment, the compound having formula I and the second therapeutic agent are administered sequentially. In another embodiment, the compound having formula I and the second therapeutic agent are administered separately.

The invention will now be described in more detail, by way of illustration only, with reference to the following non-limiting examples. The examples are intended to be illustrative of the invention and should not be construed as limiting the generality of the disclosure described throughout this specification.

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Haloallylamine pyrazole derivative inhibitors of lysyl oxidase and uses thereof

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