Uses of a lysyl oxidase-like 2 inhibitor

Abstract

Described herein is the use of a LOXL2 inhibitor in the treatment or prevention of conditions, diseases, or disorders associated with LOXL2 activity.

What is claimed is: 
     
         1 . A method for treating a disease or condition in a mammal that would benefit from inhibition or reduction of LOXL2 activity, comprising administering a small molecule LOXL2 inhibitor to the mammal in need thereof, wherein the small molecule LOXL2 inhibitor is at least 10 times more selective for inhibiting or binding to LOXL2 than for LOX. 
     
     
         2 . The method of  claim 1 , wherein the small molecule LOXL2 inhibitor is at least at least 100 times more selective for LOXL2 than for LOX. 
     
     
         3 . The method of  claim 2 , wherein the disease or condition is lung disease, liver disease, kidney disease, fibrosis of the heart, fibrosis of the eye, ear fibrosis, myelofibrosis, scleroderma, cancer, an autoimmune disease or condition, an inflammatory disease or condition, or combination thereof. 
     
     
         4 . The method of  claim 3 , wherein the small molecule LOXL2 inhibitor is trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone, or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         5 . The method of  claim 4 , wherein the small molecule LOXL2 inhibitor is (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone or a pharmaceutically acceptable salt or solvate thereof, (S,S)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone or a pharmaceutically acceptable salt or solvate thereof, or a mixture thereof. 
     
     
         6 . The method of  claim 3 , wherein the small molecule LOXL2 inhibitor is (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         7 . The method of  claim 6 , wherein (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is substantially free of (S,S)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone, or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         8 . The method of  claim 6  or  claim 7 , wherein the pharmaceutically acceptable salt of (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is formed from (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone and an acid selected from the group consisting of hydrochloride acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, metaphosphoric acid, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (−L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (−L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid. 
     
     
         9 . The method of  claim 6  or  claim 7 , wherein (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is administered to the mammal as the mesylate salt, hydrochloride salt, sulfate salt, maleate salt, phosphate salt, L-tartrate salt, fumarate salt, succinate salt, citrate salt or acetate salt. 
     
     
         10 . The method of  claim 6  or  claim 7 , wherein (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is administered to the mammal as the mesylate salt. 
     
     
         11 . The method of  claim 5 , wherein the small molecule LOXL2 inhibitor is (S,S)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         12 . The method of  claim 11 , wherein (S,S)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is substantially free of (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hy droxypyrrolidin-1-yl)methanone, or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         13 . The method of  claim 11  or  claim 12 , wherein the pharmaceutically acceptable salt of (S,S)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is formed from (S,S)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone and an acid selected from the group consisting of hydrochloride acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, metaphosphoric acid, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (−L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (−L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid. 
     
     
         14 . The method of  claim 11  or  claim 12 , wherein (S,S)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is administered to the mammal as the mesylate salt, hydrochloride salt, sulfate salt, maleate salt, phosphate salt, L-tartrate salt, fumarate salt, succinate salt, citrate salt or acetate salt. 
     
     
         15 . The method of  claim 11  or  claim 12 , wherein (S,S)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is administered to the mammal as the mesylate salt. 
     
     
         16 . The method of any one of  claims 3 - 15 , wherein:
 the lung disease is lung fibrosis.   
     
     
         17 . The method of any one of  claims 3 - 15 , wherein:
 the lung disease is interstitial lung disease (ILD).   
     
     
         18 . The method of any one of  claims 3 - 15 , wherein:
 the lung disease is idiopathic interstitial pneumonia, connective tissue disease-associated interstitial lung disease (CTD-ILD), sarcoidosis, hypersensitivity pneumonitis, iatrogenic pneumonitis/fibrosis (drug-induced ILD, radiation injury), eosinophilic ILD (e.g. eosinophilic pneumonia), occupational lung disease, familial pulmonary fibrosis, Hermansky-Pudlak syndrome), or pulmonary Langerhans cell histiocytosis.   
     
     
         19 . The method of any one of  claims 3 - 15 , wherein:
 the lung disease is Idiopathic pulmonary fibrosis (IPF), Non-specific interstitial pneumonia (NSIP), Cryptogenic organizing pneumonia (COP), Respiratory bronchiolitis interstitial lung disease (RBILD), Desquamative interstitial pneumonia (DIP), acute interstitial pneumonia (AIP), or lymphoid interstitial pneumonia (LIP).   
     
     
         20 . The method of any one of  claims 3 - 15 , wherein:
 the lung disease is idiopathic pulmonary fibrosis (IPF).   
     
     
         21 . The method of any one of  claims 3 - 20 , wherein:
 the compound reduces serum LOXL2 (sLOXL2) levels in the mammal.   
     
     
         22 . The method of any one of  claims 3 - 21 , wherein:
 the compound slows the decline in lung function, reduces the frequency of exacerbations of the lung disease, improves survival of the mammal with lung disease, or combinations thereof.   
     
     
         23 . The method of any one of  claims 3 - 22 , further comprising:
 administering at least one additional therapeutic to the mammal.   
     
     
         24 . The method of  claim 23 , wherein:
 the at least one additional therapeutic agent is a vaccination against pneumonia, a cough suppression medication, a corticosteroid, an immunosuppressant, N-acetyl cysteine (NAC), an anti-fibrotic therapeutic agent, or combinations thereof.   
     
     
         25 . The method of  claim 23 , wherein:
 the at least one additional therapeutic agent is N-acetyl cysteine, a corticosteroid, an immunosuppressant, pirfenidone, nintedanib, imatinab, a tyrosine kinase inhibitor, PBI-4050, recombinant pentraxin-2/SAP (PRM-151), aerosol IFN-γ, an inhibitor of CTGF activity, a LPA receptor antagonist, an autotaxin inhibitor, a galectin-3 inhibitor, tipelukast, an integrin antagonist, a PI3K inhibitor, a JNK inhibitor, a ROCK inhibitor, an anti-IL-13 compound, a CCL2 antagonist, a CCR2 antagonist, an anti-CD20 compound, an anticoagulant, a collagen V treatment, an ASK1 inhibitor, or combination thereof.   
     
     
         26 . The method of any one of  claims 3 - 25 , wherein:
 the mammal is a human.   
     
     
         27 . The method of  claim 26 , wherein:
 the human is an adult human.   
     
     
         28 . The method of any one of  claims 3 - 15 , wherein:
 the lung disease is pulmonary alveolar proteinosis (PAP).   
     
     
         29 . The method of  claim 28 , further comprising:
 whole-lung lavage, administering at least one additional therapeutic agent, or combinations thereof.   
     
     
         30 . The method of  claim 29 , wherein:
 the at least one additional therapeutic agent is a corticosteroid, a mucolytic, or a proteinase inhibitor.   
     
     
         31 . The method of any one of  claims 3 - 30 , wherein:
 the compound, or a pharmaceutically acceptable salt or solvate thereof, is systemically administered to the mammal.   
     
     
         32 . The method of any one of  claims 3 - 30 , wherein:
 the compound, or a pharmaceutically acceptable salt or solvate thereof, is administered to the mammal orally, by injection or intraveneously.   
     
     
         33 . The method of  claim 32 , wherein:
 the compound, or a pharmaceutically acceptable salt or solvate thereof, is administered to the mammal in the form of an oral solution, oral suspension, powder, pill, tablet or capsule.   
     
     
         34 . The method of any one of  claims 3 - 30 , wherein:
 the compound, or a pharmaceutically acceptable salt or solvate thereof, is administered directly to the lungs of the mammal.   
     
     
         35 . The method of  claim 34 , wherein:
 the compound, or a pharmaceutically acceptable salt or solvate thereof, is administered directly to the lungs of the mammal with the use of a nebulizer, metered-dose inhaler, or dry powder inhaler.   
     
     
         36 . The method of any one of  claims 3 - 15 , wherein:
 the liver disease is a fibrotic liver disease.   
     
     
         37 . The method of any one of  claims 3 - 15 , wherein:
 the liver disease is a fibrotic liver disease resulting from hepatitis C virus (HCV), nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), cirrhosis, liver fibrosis, alpha 1 antitrypsin deficiency disease, hereditary hemochromatosis, Wilson's disease, hepatitis B virus (HBV), and HIV associated steatohepatitis and cirrhosis, and associated conditions such as chronic viral hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), nonalcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), or biliary cirrhosis.   
     
     
         38 . The method of any one of  claims 3 - 15 , wherein:
 the liver disease is a fibrotic liver disease resulting from hepatitis C infection, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), Wilson's disease, and primary biliary cirrhosis, or sclerosing cholangitis.   
     
     
         39 . The method of any one of  claims 3 - 15 , wherein:
 the liver disease is a fibrotic human liver disease resulting from non-alcoholic fatty liver disease (NAFLD).   
     
     
         40 . The method of any one of  claims 3 - 15 , wherein:
 the liver disease is a fibrotic human liver disease resulting from a viral hepatitic disease or condition.   
     
     
         41 . The method of any one of  claims 3 - 15 , wherein:
 the liver disease is liver fibrosis and the mammal is a human diagnosed with NASH.   
     
     
         42 . The method of any one of  claims 3 - 15 , wherein:
 the liver disease is liver fibrosis and the mammal is a human diagnosed with primary sclerosing cholangitis (PSC).   
     
     
         43 . The method of any one of  claims 3 - 15 , wherein:
 the liver disease is cirrhosis due to NASH.   
     
     
         44 . The method of any one of  claims 36 - 43 , further comprising:
 administering at least one additional therapeutic to the mammal.   
     
     
         45 . The method of  claim 44 , wherein:
 the at least one additional therapeutic agent is selected from the group consisting of PPAR agonists, Incretins, Glut2-I, FXR agonists, antioxidants, GLP-1 modulators, SGLT-2 inhibitors, Bile acids, Caspase protease inhibitors, Synthetic fatty acid/bile acid conjuagtes, dual CCR2/CC5 antagonists, Immunomodulators, Sirtuin stimulants, Fatty acid inhibitor, DGAT1 inhibitors, ACC inhibitors, CD3 antigens, PDE-4 modulators, AMPK stimulants, ROCK2 inhibitors, ASBT inhibitors, ASK1 inhibitors, TLR-4 antagonists, THR beta agonists, Cathepsin B inhibitors, Galectin-3 modulators, and combinations thereof.   
     
     
         46 . The method of any one of  claims 3 - 15 , wherein:
 the kidney disease is fibrosis of the kidney.   
     
     
         47 . The method of any one of  claims 3 - 15 , wherein:
 the kidney disease is chronic kidney disease.   
     
     
         48 . The method any one of  claims 3 - 15 , wherein:
 the kidney disease is tubulointerstitial renal fibrosis, IgA nephropathy, diabetic nephropathy, Alport syndrome, HIV associated nephropathy, glomerular nephritis, focal segmental glomerulosclerosis, membranous glomerulonephritis, interstitial fibrosis, tubular atrophy (IFTA), post acute kidney injury (AKI), acute obstructive nephropathy and drug induced fibrosis.   
     
     
         49 . The method any one of  claims 3 - 15 , wherein:
 the kidney disease is associated with metabolic syndrome, vesicoureteral reflux, or diabetes.   
     
     
         50 . The method of any one of  claims 46 - 49 , further comprising:
 administering at least one additional therapeutic to the mammal.   
     
     
         51 . The method of  claim 50 , wherein: the at least one additional therapeutic agent is selected from the group consisting of anti-hypertensive agents, including, but not limited to, ARBs, ACE inhibitors, calclium channel blockers, SGLT2 inhibitors,gliflozins, diuretic agents, PKC inhibitors, endothelin receptor antagonists, allopurinols, steroid mineralocorticoide receptor antagonists, anti-AGE therapies, JNK inhibitors, DPP-4 inhibitors, GLP1-receptor antagonists, and anti-inflammatory agents. 
     
     
         52 . The method of any one of  claims 3 - 15 , wherein:
 the myelofibrosis is primary myelofibrosis or secondary myelofibrosis.   
     
     
         53 . The method of any one of  claims 3 - 15 , wherein:
 the myelofibrosis is primary, post polycythemia vera or post essential thrombocythemia myelofibrosis.   
     
     
         54 . The method of any one of  claims 52 - 53 , further comprising:
 administering at least one additional therapeutic to the mammal.   
     
     
         55 . The method of  claim 54 , wherein:
 the at least one additional therapeutic agent is ruxolitinib.   
     
     
         56 . The method of any one of  claims 3 - 15 , wherein:
 the scleroderma is limited systemic sclerosis or diffuse systemic sclerosis.   
     
     
         57 . The method of any one of  claims 3 - 15 , wherein:
 the fibrosis of the eye comprises fibrosis of the vitreous, iris, ciliary body, lens, choroid, retinal pigment epithelium, cornea, retina, or combinations thereof.   
     
     
         58 . The method of any one of  claims 3 - 15 , wherein:
 the fibrosis of the eye is a result of eye surgery.   
     
     
         59 . The method of any one of  claims 3 - 15 , wherein:
 the mammal is diagnosed with glaucoma, age related macular degeneration (AMD), choroidal neovascularization (CNV), corneal degeneration, dry eye syndrome, keratitis, corneal ulcers, retinopathy of prematurity (ROP), pterygia, cataracts, diabetic retinopathy with retinal edema and neovascularization, proliferative vitreoretinopathy (PVR), retinal detachment, macular edema.   
     
     
         60 . The method of any one of  claims 3 - 15 , wherein:
 the cancer is breast cancer, colon cancer, gastric cancer, head and neck cancer, lung cancer, melanoma, or combinations thereof.   
     
     
         61 . The method of any one of  claims 3 - 15 , wherein:
 the cancer is colon cancer, esophageal tumors, oral squamous cell carcinomas, laryngeal squamous cell carcinomas, and head and neck squamous cell carcinomas.   
     
     
         62 . The method of any one of  claims 60 - 61 , further comprising:
 administering at least one additional therapeutic to the mammal.   
     
     
         63 . The method of  claim 62 , wherein:
 the at least one additional therapeutic agent is an anti-cancer agent.   
     
     
         64 . The method of any one of  claims 3 - 15 , wherein the autoimmune disease or condition is rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, osteoarthritis, Still's disease, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease Sjögren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, or vulvodynia. 
     
     
         65 . The method of any one of  claims 3 - 15 , wherein the autoimmune disease or condition is rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, osteoarthritis, or ankylosing spondylitis. 
     
     
         66 . The method of any one of  claims 3 - 15 , wherein the inflammatory disease or condition is asthma, inflammatory bowel disease, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis. 
     
     
         67 . The method of any one of  claims 64 - 66 , further comprising:
 administering at least one additional therapeutic to the mammal.   
     
     
         68 . The method of any one of  claims 28 - 67 , wherein:
 the mammal is a human.   
     
     
         69 . The method of any one of  claims 36 - 68 , wherein:
 the compound, or a pharmaceutically acceptable salt or solvate thereof, is systemically administered to the mammal.   
     
     
         70 . The method of any one of  claims 36 - 68 , wherein:
 the compound, or a pharmaceutically acceptable salt or solvate thereof, is administered to the mammal orally, by injection or intraveneously.   
     
     
         71 . The method of  claim 70 , wherein:
 the compound, or a pharmaceutically acceptable salt or solvate thereof, is administered to the mammal in the form of an oral solution, oral suspension, powder, pill, tablet or capsule.   
     
     
         72 . Use of a small molecule LOXL2 inhibitor in the treatment of a disease or condition in a mammal that would benefit from inhibition or reduction of LOXL2 activity, wherein the small molecule LOXL2 inhibitor is at least 10 times more selective for inhibiting or binding to LOXL2 than for LOX. 
     
     
         73 . The use of  claim 72 , wherein small molecule LOXL2 inhibitor is at least at least 100 times more selective for LOXL2 than for LOX. 
     
     
         74 . The use of  claim 72  or  73 , wherein the disease or condition is lung disease, liver disease, kidney disease, fibrosis of the heart, fibrosis of the eye, ear fibrosis, myelofibrosis, scleroderma, cancer, an autoimmune disease or condition, an inflammatory disease or condition, or combination thereof. 
     
     
         75 . The use of  claim 74 , wherein the small molecule LOXL2 inhibitor is trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone, or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         76 . The use of  claim 74 , wherein the small molecule LOXL2 inhibitor is (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone or a pharmaceutically acceptable salt or solvate thereof, (S,S)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone or a pharmaceutically acceptable salt or solvate thereof, or a mixture thereof. 
     
     
         77 . The use of  claim 74 , wherein the small molecule LOXL2 inhibitor is (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         78 . The use of  claim 77 , wherein (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is substantially free of (S,S)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone, or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         79 . The use of  claim 77  or  claim 78 , wherein the pharmaceutically acceptable salt of (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is formed from (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone and an acid selected from the group consisting of hydrochloride acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, metaphosphoric acid, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (−L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (−L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid. 
     
     
         80 . The use of  claim 77  or  claim 78 , wherein (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is administered to the mammal as the mesylate salt, hydrochloride salt, sulfate salt, maleate salt, phosphate salt, L-tartrate salt, fumarate salt, succinate salt, citrate salt or acetate salt. 
     
     
         81 . The use of  claim 77  or  claim 78 , wherein (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is administered to the mammal as the mesylate salt. 
     
     
         82 . The use of  claim 74 , wherein the small molecule LOXL2 inhibitor is (S,S)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         83 . The use of  claim 82 , wherein (S,S)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is substantially free of (R,R)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hy droxypyrrolidin-1-yl)methanone, or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         84 . The use of  claim 82  or  claim 83 , wherein the pharmaceutically acceptable salt of (S,S)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is formed from (S,S)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone and an acid selected from the group consisting of hydrochloride acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, metaphosphoric acid, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (−L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (−L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid. 
     
     
         85 . The use of  claim 82  or  claim 83 , wherein (S,S)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is administered to the mammal as the mesylate salt, hydrochloride salt, sulfate salt, maleate salt, phosphate salt, L-tartrate salt, fumarate salt, succinate salt, citrate salt or acetate salt. 
     
     
         86 . The use of  claim 82  or  claim 83 , wherein (S,S)-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone is administered to the mammal as the mesylate salt. 
     
     
         87 . The use of any one of  claims 72 - 86 , wherein the lung disease is lung fibrosis. 
     
     
         88 . The use of any one of  claims 72 - 86 , wherein the lung disease is interstitial lung disease. 
     
     
         89 . The use of any one of  claims 72 - 86 , wherein:
 the lung disease is idiopathic interstitial pneumonia, connective tissue disease-associated interstitial lung disease, sarcoidosis, hypersensitivity pneumonitis, iatrogenic pneumonitis/fibrosis (drug-induced ILD, radiation injury), eosinophilic ILD, occupational lung disease, familial pulmonary fibrosis, Hermansky-Pudlak syndrome, or pulmonary Langerhans cell histiocytosis.   
     
     
         90 . The use of any one of  claims 72 - 86 , wherein the lung disease is Idiopathic pulmonary fibrosis (IPF), Non-specific interstitial pneumonia (NSIP), Cryptogenic organizing pneumonia (COP), Respiratory bronchiolitis interstitial lung disease (RBILD), Desquamative interstitial pneumonia (DIP), acute interstitial pneumonia (AIP), or lymphoid interstitial pneumonia (LIP). 
     
     
         91 . The use of any one of  claims 72 - 86 , wherein the lung disease is idiopathic pulmonary fibrosis (IPF). 
     
     
         92 . The use of any one of  claims 72 - 91 , wherein the compound reduces serum LOXL2 (sLOXL2) levels in the mammal. 
     
     
         93 . The use of any one of  claims 72 - 92 , wherein the compound slows the decline in lung function, reduces the frequency of exacerbations of the lung disease, improves survival of the mammal with lung disease, or combinations thereof. 
     
     
         94 . The use of any one of  claims 72 - 93 , in combination with at least one additional therapeutic to the mammal. 
     
     
         95 . The use of  claim 94 , wherein the at least one additional therapeutic agent is a vaccination against pneumonia, a cough suppression medication, a corticosteroid, an immunosuppressant, N-acetyl cysteine (NAC), an anti-fibrotic therapeutic agent, or combinations thereof. 
     
     
         96 . The use of  claim 94 , wherein the at least one additional therapeutic agent is N-acetyl cysteine, a corticosteroid, an immunosuppressant, pirfenidone, nintedanib, imatinab, a tyrosine kinase inhibitor, PBI-4050, recombinant pentraxin-2/SAP (PRM-151), aerosol IFN-γ, an inhibitor of CTGF activity, a LPA receptor antagonist, an autotaxin inhibitor, a galectin-3 inhibitor, tipelukast, an integrin antagonist, a PI3K inhibitor, a JNK inhibitor, a ROCK inhibitor, an anti-IL-13 compound, a CCL2 antagonist, a CCR2 antagonist, an anti-CD20 compound, an anticoagulant, a collagen V treatment, an ASK1 inhibitor, or combination thereof. 
     
     
         97 . The use of any one of  claims 72 - 86 , wherein the lung disease is pulmonary alveolar proteinosis (PAP). 
     
     
         98 . The use of  claim 97 , in combination with whole-lung lavage, administering at least one additional therapeutic agent, or combinations thereof. 
     
     
         99 . The use of  claim 98 , wherein the at least one additional therapeutic agent is a corticosteroid, a mucolytic, or a proteinase inhibitor. 
     
     
         100 . The use of any one of  claims 72 - 86 , wherein the liver disease is a fibrotic liver disease. 
     
     
         101 . The use of any one of  claims 72 - 86 , wherein the liver disease is a fibrotic liver disease resulting from hepatitis C virus (HCV), nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), cirrhosis, liver fibrosis, alpha 1 antitrypsin deficiency disease, hereditary hemochromatosis, Wilson's disease, hepatitis B virus (HBV), and HIV associated steatohepatitis and cirrhosis, and associated conditions such as chronic viral hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), nonalcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), or biliary cirrhosis. 
     
     
         102 . The use of any one of  claims 72 - 86 , wherein the liver disease is a fibrotic liver disease resulting from hepatitis C infection, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), Wilson's disease, and primary biliary cirrhosis, or sclerosing cholangitis. 
     
     
         103 . The use of any one of  claims 72 - 86 , wherein the liver disease is a fibrotic human liver disease resulting from non-alcoholic fatty liver disease (NAFLD). 
     
     
         104 . The use of any one of  claims 72 - 86 , wherein the liver disease is a fibrotic human liver disease resulting from a viral hepatitic disease or condition. 
     
     
         105 . The use of any one of  claims 72 - 86 , wherein the liver disease is liver fibrosis and the mammal is a human diagnosed with NASH. 
     
     
         106 . The use of any one of  claims 72 - 86 , wherein the liver disease is liver fibrosis and the mammal is a human diagnosed with primary sclerosing cholangitis (PSC). 
     
     
         107 . The use of any one of  claims 72 - 86 , wherein the liver disease is cirrhosis due to NASH. 
     
     
         108 . The use of any one of  claims 100 - 107 , in combination with at least one additional therapeutic to the mammal. 
     
     
         109 . The use of  claim 108 , wherein the at least one additional therapeutic agent is selected from the group consisting of PPAR agonists, Incretins, Glut2-I, FXR agonists, antioxidants, GLP-1 modulators, SGLT-2 inhibitors, Bile acids, Caspase protease inhibitors, Synthetic fatty acid/bile acid conjuagtes, dual CCR2/CC5 antagonists, Immunomodulators, Sirtuin stimulants, Fatty acid inhibitor, DGAT1 inhibitors, ACC inhibitors, CD3 antigens, PDE-4 modulators, AMPK stimulants, ROCK2 inhibitors, ASBT inhibitors, ASK1 inhibitors, TLR-4 antagonists, THR beta agonists, Cathepsin B inhibitors, Galectin-3 modulators, and combinations thereof. 
     
     
         110 . The use of any one of  claims 72 - 86 , wherein the kidney disease is fibrosis of the kidney. 
     
     
         111 . The use of any one of  claims 72 - 86 , wherein the kidney disease is chronic kidney disease. 
     
     
         112 . The use any one of  claims 72 - 86 , wherein the kidney disease is tubulointerstitial renal fibrosis, IgA nephropathy, diabetic nephropathy, Alport syndrome, HIV associated nephropathy, glomerular nephritis, focal segmental glomerulosclerosis, membranous glomerulonephritis, interstitial fibrosis, tubular atrophy (IFTA), post acute kidney injury (AKI), acute obstructive nephropathy and drug induced fibrosis. 
     
     
         113 . The use any one of  claims 72 - 86 , wherein the kidney disease is associated with metabolic syndrome, vesicoureteral reflux, or diabetes. 
     
     
         114 . The use of any one of  claims 110 - 113 , in combination with at least one additional therapeutic to the mammal. 
     
     
         115 . The use of  claim 114 , wherein the at least one additional therapeutic agent is selected from the group consisting of anti-hypertensive agents, including, but not limited to, ARBs, ACE inhibitors, calclium channel blockers, SGLT2 inhibitors, gliflozins, diuretic agents, PKC inhibitors, endothelin receptor antagonists, allopurinols, steroid mineralocorticoide receptor antagonists, anti-AGE therapies, JNK inhibitors, DPP-4 inhibitors, GLP1-receptor antagonists, and anti-inflammatory agents. 
     
     
         116 . The use of any one of  claims 72 - 86 , wherein the myelofibrosis is primary myelofibrosis or secondary myelofibrosis. 
     
     
         117 . The use of any one of  claims 72 - 86 , wherein the myelofibrosis is primary, post polycythemia vera or post essential thrombocythemia myelofibrosis. 
     
     
         118 . The use of any one of  claims 116 - 52 , in combination with at least one additional therapeutic to the mammal. 
     
     
         119 . The use of  claim 118 , wherein the at least one additional therapeutic agent is ruxolitinib. 
     
     
         120 . The use of any one of  claims 72 - 86 , wherein the scleroderma is limited systemic sclerosis or diffuse systemic sclerosis. 
     
     
         121 . The use of any one of  claims 72 - 86 , wherein the fibrosis of the eye comprises fibrosis of the vitreous, iris, ciliary body, lens, choroid, retinal pigment epithelium, cornea, retina, or combinations thereof. 
     
     
         122 . The use of any one of  claims 72 - 86 , wherein the fibrosis of the eye is a result of eye surgery. 
     
     
         123 . The use of any one of  claims 72 - 86 , wherein the mammal is diagnosed with glaucoma, age related macular degeneration (AMD), choroidal neovascularization (CNV), corneal degeneration, dry eye syndrome, keratitis, corneal ulcers, retinopathy of prematurity (ROP), pterygia, cataracts, diabetic retinopathy with retinal edema and neovascularization, proliferative vitreoretinopathy (PVR), retinal detachment, macular edema. 
     
     
         124 . The use of any one of  claims 72 - 86 , wherein the cancer is breast cancer, colon cancer, gastric cancer, head and neck cancer, lung cancer, melanoma, or combinations thereof. 
     
     
         125 . The use of any one of  claims 72 - 86 , wherein the cancer is colon cancer, esophageal tumors, oral squamous cell carcinomas, laryngeal squamous cell carcinomas, and head and neck squamous cell carcinomas. 
     
     
         126 . The use of any one of  claims 124 - 125 , in combination with at least one additional therapeutic to the mammal. 
     
     
         127 . The use of  claim 126 , wherein the at least one additional therapeutic agent is an anti-cancer agent. 
     
     
         128 . The use of any one of  claims 72 - 86 , wherein the autoimmune disease or condition is rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, osteoarthritis, Still's disease, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease Sjögren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, or vulvodynia. 
     
     
         129 . The use of any one of  claims 72 - 86 , wherein the autoimmune disease or condition is rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, osteoarthritis, or ankylosing spondylitis. 
     
     
         130 . The use of any one of  claims 72 - 86 , wherein the inflammatory disease or condition is asthma, inflammatory bowel disease, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis. 
     
     
         131 . The use of any one of  claims 128 - 130 , in combination with at least one additional therapeutic to the mammal.