12 / 15-Lipoxygenase Inhibitors

Abstract

The present application provides oxazole-containing compounds that are 12 / 15-LOX inhibitors, or pharma- ceutical acceptable salts thereof. Pharmaceutical compositions and methods of using these compounds to treat various conditions in which 12 / 15-LOX is implicated, such as stroke, are also provided.

Description

[Technical field]

[0001] Claiming priority This application claims priority to U.S. Patent Application No. 63 / 231,061, filed August 9, 2021, the entire contents of which are hereby incorporated by reference herein.

[0002] Federally Sponsored Research or Development This invention was made with United States Government support under Grant NS106854 awarded by the National Institutes of Health. The Government has certain rights in this invention.

[0003] The present invention relates to 2-(2,3,5-trisubstituted phenyl)oxazole compounds that are useful in treating or preventing diseases and conditions involving 12 / 15-lipoxygenase ("12 / 15-LOX") or the ALOX15 gene encoding it. [Background technology]

[0004] There are many deadly diseases that affect the current human population. For example, stroke is a leading cause of mortality and disability worldwide, and the economic costs of treatment and post-stroke care are significant. Each year, more than 14 million people are affected by stroke, and more than 6 million stroke patients die from the condition and associated complications. Summary of the Invention [Problem to be solved by the invention]

[0005] The present disclosure is based, at least in part, on the recognition that 2-(2,3,5-trisubstituted phenyl)oxazole compounds potently inhibit 12 / 15-LOX.Accordingly, the compounds of the present disclosure are advantageously useful for treating or preventing various disorders in which 12 / 15-LOX is involved in the pathology of the disorder (e.g., stroke). [Means for solving the problem]

[0006] In one general aspect, the disclosure provides a compound of formula (I): [ka] or a pharma- ceutical acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , and X 1 The present invention provides compounds of formula (I) or a pharma- ceutically acceptable salt thereof, wherein:

[0007] In another general aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0008] In yet another general aspect, the disclosure provides a method for treating or preventing a disease or disorder in which 12 / 15-lipoxygenase (12 / 15-LOX) is implicated in a pathological nature (e.g., any one of the disorders described herein), comprising administering a therapeutically effective amount of any one of the compounds described herein, or a pharma- ceutical salt thereof, or a pharmaceutical composition comprising same, to a subject in need thereof.

[0009] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Methods and materials are described herein for use in this application, and other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0010] Other features and advantages of the present application will be apparent from the following detailed description and drawings, and from the claims. [Brief description of the drawings]

[0011] [Figure 1] Included are chemical schemes showing the in vivo conversion of prodrug compounds 51, 52, 53 to their parent compounds 22, 1, and 1, respectively. [Diagram 2] 1 includes bar graphs showing that Compound 1 provided significant protection in both male and female mice, reducing infarct size at 24 hours by 33.4% and 37.2%, respectively, when administered intraperitoneally. [Diagram 3] 1 includes a bar graph showing that deuterated compound 44 has similar efficacy compared to compound 1. [Figure 4] 1 includes a bar graph showing that compound 32 leads to a 31.8% reduction in infarct size. [Diagram 5] 1 includes a bar graph showing the efficacy of Compound 52 after intravenous delivery. Compound 52 was dissolved in 50% Captisol and injected intravenously at a dosage of 40 mg / kg immediately after reperfusion. There was a 31.7% reduction in infarct size at 24 hours, p<0.01. [Figure 6] 1 includes a bar graph showing the efficacy of Compound 1 after intravenous delivery. Compound 1 was dissolved in 10% Solutol / 90% PEG400 and injected intravenously at a dosage of 40mg / kg 2 hours after reperfusion. There was a 34.1% reduction in infarct size at 24 hours. n=8 / group, p<0.01. [Figure 7] 1 includes a bar graph showing reduction in infarct size in mice following intravenous administration of Compound 1 at 20 mg / kg 2 hours after reperfusion. [Figure 8A] Included is a line plot showing the Garcia score for mice following administration of Compound 1 at 40 mg / kg 2 hours after reperfusion. Four weeks after stroke, there was a 68.5% improvement compared to vehicle treatment (p<0.01). [Figure 8B]1 includes a line plot showing the results of the corner test for mice after Compound 1 was administered at 40 mg / kg 2 hours after reperfusion. Four weeks after stroke, there was a 75.4% improvement compared to vehicle treatment (p<0.0001). [Figure 8C] 1 includes a line plot showing the results of the foot fault test for mice following administration of Compound 1 at 40 mg / kg 2 hours after reperfusion. Four weeks after stroke, there was a 77.0% improvement compared to vehicle treatment (p<0.0001). [Figure 8D] 1 includes a line plot showing the results of tape removal testing on mice following administration of Compound 1 at 40 mg / kg 2 hours after reperfusion. Four weeks after stroke, there was a 93.3% improvement compared to vehicle treatment (p<0.01). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Lipoxygenases form a large family of enzymes capable of oxidizing arachidonic acid (AA) and related polyunsaturated fatty acids. In humans, in addition to 12 / 15-LOX, other members include 5-LOX, platelet-type-12-LOX ("P-12-LOX"), 12(R)-LOX, epidermal LOX-3, and 15-LOX-2. The nomenclature of lipoxygenase enzymes is based in part on the carbon atom in the AA that it oxidizes with the aid of the enzyme. Similarly, 12 / 15-LOX can oxidize both the C12 and C15 carbons of AA to form 12- or 15-hydroperoxyeicosatetraenoic acid (12- or 15-HPETE), respectively. Lipoxygenases, including 12 / 15-LOX and its metabolites, are involved in many disease states.

[0013] The present disclosure provides compounds containing a 2-(2,3,5-trisubstituted phenyl)oxazole moiety. These compounds are useful in treating or preventing pathological conditions associated with 12 / 15-LOX. Specific embodiments of the compounds and the 12 / 15-LOX-related conditions are described in the present disclosure. Pharmaceutical compositions, dosage forms, and combination treatments are also described.

[0014] therapeutic compounds In some embodiments, the present disclosure provides a compound of formula (I), i.e. [ka] or a pharma- ceutical acceptable salt thereof, wherein: X 1 is selected from O and S; R 1 , R 2 , and R 3 each independently represents halo, CN, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy and C 1~3 haloalkoxy; R 4 But, H, C 1~3 Alkyl, and HO-C 1~3 alkylene; R 5 But, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C(O)OR a1 , C(O)N(R a1 )2, P(=O)(OR a1 )2, and C(O)R b1 C is selected from 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Each alkynyl is OR a1 and OP(=O)(OR a1 ) optionally substituted with a substituent selected from Each R a1 are independent, H, C 1~6 Alkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10 Aryl and C 1~6 Alkyl-C 6~10 Aryl-C 1~6 alkyl, 1~6 Alkyl, C 6~10Aryl, C 1~6 Alkyl-C 6~10 Aryl and C 1~6 Alkyl-C 6~10 Aryl-C 1~6 Each of the alkyl groups is amino, C 1~6 Alkylamino, (C 1~6 haloalkyl)amino, di(C 1~6 alkyl)amino, (C 1~6 Alkyl)(C 1~6 haloalkyl)amino, (C 6~10 aryl)amino, (C 6~10 Aryl)(C 1~6 alkyl)amino, (5-6 membered heteroaryl)amino, (5-6 membered heteroaryl)(C 1~6 Alkyl)amino, C 6~10 Aryl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, and OR a2 and wherein C is optionally substituted with a substituent selected from 6~10 Aryl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each selected from amino, C 1~6 Alkylamino, di(C 1~6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, amino, carboxy, and halo; Each R a2 are independent, H, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy-C 1~3 Alkyl, 4-7 membered heterocycloalkyl-C 1~3 Alkyl, 5-6 membered heteroaryloxy-C 1~3 Alkyl, C 6~10 aryl, and 5- to 6-membered heteroaryl; 6~10 Aryl and 5-6 membered heteroaryl are each selected from halo, C 1~3 Alkoxy, C 1~3 Haloalkoxy, C 1~3 Alkyl, and C 1~3 optionally substituted with 1, 2, or 3 substituents independently selected from haloalkyl; R b1 But, Amino, C1~6 Alkylamino, di(C 1~6 C optionally substituted with a substituent selected from: alkyl)amino, and a 4- to 7-membered heterocycloalkyl ring containing at least one N atom 1~6 The present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein R is 1, R is 2, R is 3, R is 4, R is 5, R is 6, R is 7, R is 8, R is 9, R is 10, R is 11,

[0015] In some embodiments, X 1 is O.

[0016] In some embodiments, X 1 is S.

[0017] In some embodiments, the compound has the formula: [ka] or a pharma- ceutical acceptable salt thereof.

[0018] In some embodiments, the compound has the formula: [ka] or a pharma- ceutical acceptable salt thereof.

[0019] In some embodiments, R 1 is halo. In some embodiments, R 1 is CN. In some embodiments, R 1 is C 1~3 In some embodiments, R 1 is C 1~3 It is haloalkyl.

[0020] In some embodiments, R 2 is halo. In some embodiments, R 2 is CN. In some embodiments, R 2 is C 1~3In some embodiments, R 2 is C 1~3 It is haloalkyl.

[0021] In some embodiments, R 3 is halo. In some embodiments, R 3 is CN. In some embodiments, R 3 is C 1~3 In some embodiments, R 3 is C 1~3 It is haloalkyl.

[0022] In some embodiments, R 1 , R 2 , and R 3 are each halos.

[0023] In some embodiments, R 2 and R 3 are each a halo, and R 1 is C 1~3 Alkyl, C 1~3 Alkoxy and C 1~3 haloalkoxy.

[0024] In some embodiments, R 1 and R 3 are each a halo, and R 2 is C 1~3 Alkyl, C 1~3 Alkoxy and C 1~3 haloalkyl.

[0025] In some embodiments, R 1 and R 2 are each a halo, and R 3 is C 1~3 Alkyl, C 1~3 haloalkyl, and CN.

[0026] In some embodiments, the compound has the formula: [ka] or a pharma- ceutical acceptable salt thereof.

[0027] In some embodiments, R 5 is C 1~3 It is an alkyl.

[0028] In some embodiments, R 5 OR a1 C optionally replaced with 2~6 It is alkenyl.

[0029] In some embodiments, R 5 OR a1 C optionally replaced with 2~6 It is alkynyl.

[0030] In some embodiments, R 5 OR a1 C replaced with 1~6 It is an alkyl.

[0031] In some embodiments, R 5 OP(=O)(OR a1 )2 replaced by C 1~6 It is an alkyl.

[0032] In some embodiments, R a1 is H.

[0033] In some embodiments, R a1 is C 6~10 Aryl or OR a2 C optionally replaced with 1~6 It is an alkyl.

[0034] In some embodiments, R 4 is H.

[0035] In some embodiments, R 5 is C(O)OR a1 It is.

[0036] In some embodiments, R a1 is amino, C 1~6 Alkylamino and di(C 1~6 C optionally substituted with a substituent selected from 1~6 It is an alkyl.

[0037] In some embodiments, R 5 is C(O)R b1 It is.

[0038] In some embodiments, R 4 , H, C 1~3 Alkyl, and HO-C 1~3 alkylene; and R 5 are OR a1 and OP(=O)(OR a1 C optionally substituted with a substituent selected from 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 alkynyl, and Each R a1 are independently H and C 1~6 alkyl, 1~6 Alkyl is C 6~10 Aryl and OR a2 is optionally substituted with a substituent selected from:

[0039] In some embodiments, R 4 is C(O)OR a1 and C(O)R b1 is selected from R 5 is C 1~3 is alkyl, and R a1is amino, C 1~6 Alkylamino and di(C 1~6 C optionally substituted with a substituent selected from 1~6 It is an alkyl.

[0040] In some embodiments, the compound of formula (I) is any one of the following compounds: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutical acceptable salt thereof.

[0041] In some embodiments, the compound of formula (I) is any one of the following compounds: [ka] or a pharma- ceutical acceptable salt thereof.

[0042] Pharmaceutically acceptable salts In some embodiments, a salt of a compound of formula (I) is formed between an acid and a basic group, such as an amino functional group, of the compound, or between a base and an acidic group, such as a carboxyl functional group, of the compound. According to another embodiment, the compound is a pharma- ceutically acceptable acid addition salt.

[0043] In some embodiments, acids commonly employed to form pharma- ceutically acceptable salts of compounds of formula (I) include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Accordingly, such pharma- ceutically acceptable salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In one embodiment, pharma- ceutically acceptable acid addition salts include those formed with mineral acids, such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids, such as maleic acid.

[0044] In some embodiments, bases commonly employed to form pharma- ceutically acceptable salts of compounds of formula (I) include hydroxides of alkali metals including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc; ammonia, and organic amines such as unsubstituted or hydroxy-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(C1-C6)-alkylamines such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like.

[0045] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is substantially isolated.

[0046] How to use The compounds of the present disclosure advantageously and potently inhibit 12 / 15-LOX. As such, in some embodiments, the present disclosure provides a method of inhibiting 12 / 15-lipoxygenase (12 / 15-LOX) in a cell, comprising contacting a cell of a subject with an effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof. In some embodiments, the cell is contacted in vitro, in vivo, or ex vivo. In some embodiments, the present disclosure provides a method of inhibiting 12 / 15-lipoxygenase (12 / 15-LOX) in a cell of a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof.

[0047] In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder in which 12 / 15-lipoxygenase (LOX) is implicated in a pathological nature, comprising administering to a subject (e.g., in need of treating or preventing the disease) a therapeutically effective amount of any one of the compounds of the present disclosure or a pharma- ceutically acceptable salt thereof. Examples of such diseases or disorders include conditions that are exacerbated by the activity of 12 / 15-LOX, and also conditions whose progression is linked to the activity of 12 / 15-LOX. Without being bound by any theory, it is believed that such conditions can be therapeutically treated in a subject by inhibiting 12 / 15-LOX with a compound of the present disclosure. A subject is said to be "in need thereof" (i.e., in need of treatment) when the need to treat or prevent the above-mentioned disease or disorder in a subject is based on a physician diagnosing the subject with the disease or disorder. Diagnostic methods for diagnosing a subject will be readily apparent to a skilled physician. Such methods include, for example, visual observation, study of medical history, and physical examination, as well as various imaging techniques and laboratory tests. For example, stroke, brain injury, or ischemic events can be diagnosed with the aid of neuroimaging (e.g., magnetic resonance imaging, computed tomography, diffuse optical imaging, event-related optical signals, magnetoencephalography, positron emission tomography, or single-photon emission computed tomography).

[0048] Numerous scientific publications have demonstrated that 12 / 15-LOX has the potential to prevent and treat a variety of conditions, including diabetic retinopathy, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), stroke, diabetes, obesity, asthma, glomerulonephritis, osteoporosis, periventricular leukomalacia, resuscitation cardiac arrest, atherosclerosis, neurodegenerative or neuroinflammatory disorders (e.g., Parkinson's disease, Alzheimer's disease, or dementia), cancer, brain injury, diseases involving hypoxia or anoxia, myocardial infarction, cardiovascular disease, heart failure (e.g., chronic or congestive heart failure), ischemia (e.g., cerebral ischemia, retinal ischemia, myocardial ischemia, or postoperative cognitive dysfunction), inflammatory diseases (e.g., arterial inflammation, inflammatory bowel disease, Crohn's disease, renal disease, The patient has provided credible evidence that the compound is involved in the pathology of a disease or condition selected from the group consisting of asthma, allergic rhinitis, gout, cardiopulmonary inflammation, rheumatoid arthritis, osteoarthritis, muscle fatigue, acne, dermatitis, or psoriasis, chronic bronchitis, mucus hypersecretion, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (including fibrosis caused by chemotherapy), idiopathic pulmonary fibrosis, cystic fibrosis, adult respiratory distress syndrome, central nervous system disorders, psychiatric disorders (e.g., anxiety or depression), peripheral neuropathy (e.g., spinal cord injury, head injury, or surgical trauma), graft rejection of allogeneic tissue or organ transplants, autoimmune disorders (e.g., eczema), and disorders involving bone loss or bone formation.

[0049] In some embodiments, the present disclosure provides a method of treating stroke, comprising administering to a subject (e.g., in need of treating stroke) a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof. Stroke is an acute neurological disorder that occurs when blood flow to the brain is disrupted. There are two types of stroke. One is called acute ischemic stroke (AIS) and is caused by blockage of blood flow. AIS is an episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia with evidence of acute infarction. There are at least four different causes of blockage of blood flow: (1) a blood clot in a blood vessel, (2) a blood clot in the dural sinuses that drain blood from the brain, (3) an embolism that occludes a blood vessel, or (4) a sudden drop in blood pressure. If the patient survives the initial injury, stroke symptoms can and often do last for more than 24 hours. The other type of stroke is called hemorrhagic stroke, which is caused by fragile blood vessels that burst and bleed into the surrounding brain tissue. Transient ischemic attack (TIA) is a condition similar to AIS, where temporary interruption of blood flow to a part of the brain leads to impaired brain function but not necessarily brain tissue damage. Without being bound by any theory, it is believed that oxidative stress, including the generation of AA metabolites by LOX enzymes, contributes to the pathology of ischemic diseases such as stroke. Numerous scientific papers have demonstrated increased 12 / 15-LOX activity in neurons and cerebral vasculature during and after stroke. Without being bound by any theory, it is believed that LOX inhibitor compounds reduce infarct size, leakage or formation of blood-brain barrier and edema, as well as hemorrhagic transformation after infusion of tPA. In some embodiments, the present disclosure provides a method for improving symptoms of stroke (e.g., ischemic stroke). Pertinent examples of such symptoms include sudden numbness, tingling, weakness, or loss of movement in the face, arm, or leg, especially on only one side of the body; sudden vision changes; sudden difficulty speaking; sudden confusion or difficulty understanding simple statements; sudden problems with walking or balance, and a sudden severe headache that is different from previous headaches. Another example may be a reduction in infarct size in persistent focal ischemia.

[0050] Furthermore, with respect to stroke, the inhibitors of the present disclosure can be used (i) as a stand-alone treatment in emergency or after arrival at the hospital; (ii) in combination with tPA, as the only drug currently approved by the US Food and Drug Administration for the treatment of acute stroke; (iii) in combination with endovascular treatment with stent retriever to provide neuroprotection and protect the vasculature. The compounds can also be used to treat hemorrhagic forms of stroke, such as subarachnoid hemorrhage (SAH). The compounds can be administered orally or by parenteral delivery, for example, via intravenous injection / infusion. In a similar vein, the compounds can be administered to a subject to treat other ischemic and / or lipoxygenase-related diseases, such as diabetes, diabetic retinopathy, liver disease, and cancer.

[0051] In some embodiments, the 12 / 15-LOX inhibitors disclosed herein can be used to treat stroke with hemorrhagic transformation. Hemorrhagic transformation refers to bleeding that occurs within the area of ​​ischemia. For example, subjects who take oral anticoagulants and develop stroke can be treated with the 12 / 15-LOX inhibitors disclosed herein. In some embodiments, the 12 / 15-LOX inhibitors disclosed herein can be administered as an adjuvant to tPA. For the treatment of stroke, the 12 / 15-LOX inhibitors provided in the present disclosure can be administered during the early phase of stroke or after (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) days of stroke to assist in stroke recovery.

[0052] In some embodiments, the present disclosure provides a method for treating periventricular leukomalacia (PVL), comprising administering a therapeutically effective amount of a compound of the present disclosure or a pharmacologic acceptable salt thereof to a subject in need of treating PVL.Scientific evidence clearly shows that PVL patients are also characterized by elevated 12 / 15-LOX.Periventricular leukomalacia is the most frequent cause of cerebral palsy in premature infants.This early neonatal disorder results from the formation of single or multiple lesions of periventricular white matter rings that occur before birth or during neonatal life.Periventricular leukomalacia is responsible for the majority of motor sequelae of prematurity.

[0053] In some embodiments, the present disclosure provides a method of treating cancer, comprising administering to a subject (e.g., in need of treating cancer) a therapeutically effective amount of a compound of the present disclosure or a medicament acceptable salt thereof. Suitable examples of cancer include prostate cancer, gastric cancer, breast cancer, pancreatic cancer, colon cancer, esophageal cancer, and respiratory tract cancer.

[0054] In some embodiments, the disclosure provides a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for use in treating or preventing any of the diseases, disorders, or conditions disclosed herein.

[0055] In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of the disclosure, or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable carrier, for use in treating or preventing any of the diseases, disorders, or conditions disclosed herein.

[0056] In some embodiments, the disclosure provides for the use of a compound of the disclosure or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment of any of the diseases, disorders, or conditions described herein.

[0057] Pharmaceutical Compositions The present application also provides a pharmaceutical composition comprising an effective amount of any of the disclosed compounds or a pharma- ceutically acceptable salt thereof and a pharma- ceutical acceptable carrier. The pharmaceutical composition may also include any one of the additional therapeutic agents described herein. In certain embodiments, the present application also provides pharmaceutical compositions and dosage forms comprising any one of the additional therapeutic agents described herein. The carrier(s) is "acceptable" in the sense of being compatible with the other ingredients in the formulation and, in the case of pharma- ceutical acceptable carriers, not deleterious to the recipient thereof in the amounts used in pharmaceutical preparations.

[0058] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and wool fat.

[0059] A composition or dosage form may contain any one of the compounds and therapeutic agents described herein in the range of 0.005%-100%, with the remainder consisting of suitable pharma- ceutically acceptable excipients. Contemplated compositions may contain any one of the compounds and therapeutic agents provided herein in the range of 0.001%-100%, in one embodiment 0.1-95%, in another embodiment 75-85%, and in a further embodiment 20-80%, with the remainder consisting of any pharma- ceutically acceptable excipients described herein, or any combination of these excipients.

[0060] Route of administration and dosage form The pharmaceutical compositions of the present application include those suitable for any acceptable route of administration, including, but not limited to, buccal, dermal, intracervical, intrasinus, intratracheal, enteral, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intracapsular, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intranasal, intramedullary, intrasynovial, intratesticular, intrathecal, intraductal, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory, inhalation, subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal.

[0061] The compositions and formulations described herein can be conveniently presented in unit dosage form, for example, tablets, sustained release capsules, and liposomes, and can be prepared by any method well known in the art of pharmacy.See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed.2000). Such preparation methods include the step of bringing the molecule into association with the ingredients to be administered, such as carriers, which constitute one or more accessory ingredients.In general, the compositions are prepared by uniformly and essentially bringing into association the active ingredient with liquid carriers, liposomes, or finely divided solid carriers, or any of them, and then, if necessary, shaping the product.

[0062] In some embodiments, any one of the compounds and therapeutic agents disclosed herein is administered orally. The compositions of the present application suitable for oral administration can be presented as discrete units, such as capsules, sachets, granules, or tablets, each containing a predetermined amount (e.g., an effective amount) of active ingredient, as powders or granules, as a solution or suspension in an aqueous or non-aqueous liquid, as an oil-in-water emulsion, as a water-in-oil emulsion, packaged in liposomes, as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which can beneficially increase the rate of compound absorption. In the case of tablets for oral use, commonly used carriers include lactose, sucrose, glucose, mannitol, and silicic acid, as well as starch. Other acceptable excipients may include a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) humectants such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspension is administered orally, the active ingredient is combined with emulsifying and suspending agents.If desired, certain sweeteners and / or flavorings and / or colorings can be added.Compositions suitable for oral administration include lozenges that contain the ingredient in a flavored base, usually sucrose and acacia or tragacanth; and pastilles that contain the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia.

[0063] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending and thickening agents. The preparations may be in single- or multi-dose containers, for example sealed ampoules and vials, and may be stored in a lyophilized condition requiring only the addition of a sterile liquid carrier, for example water for injection, saline (for example 0.9% saline) or 5% dextrose solution immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Injection solutions may be, for example, sterile injectable aqueous or oleaginous suspensions. The suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland, fixed oil may be employed, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are pharma-ceutically acceptable natural oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oily solutions or suspensions may also contain long-chain alcohol diluents or dispersants.

[0064] The pharmaceutical composition of the present application can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of the present application with suitable non-irritating excipients, which are solid at room temperature but liquid at rectal temperature, and therefore melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.

[0065] The pharmaceutical compositions of the present application can be administered by nasal aerosol or inhalation. Such compositions can be prepared by techniques well known in the art of pharmaceutical formulations and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. See, for example, U.S. Patent No. 6,803,031. Additional formulations and methods for intranasal administration can be found in Ilium, L., J Pharm Pharmacol, 56:3-17, 2004 and Ilium, L., Eur J Pharm Sci11:1-18, 2000.

[0066] The topical compositions of the present disclosure can be prepared and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other forms commonly employed in the field of topical administration and / or cosmetic and skin care formulations. The topical composition can be in emulsion form. Topical administration of the pharmaceutical compositions of the present application is particularly useful when the desired treatment involves areas or organs readily accessible by topical application. In some embodiments, a topical composition comprises any one of the compounds and therapeutic agents disclosed herein in combination with one or more additional ingredients, carriers, excipients, or diluents, including, but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, colorants / pigments, emollients (moisturizers), emulsifiers, film forming / retentive agents, fragrances, leave-on exfoliants, formulas, preservatives, exfoliants, silicones, skin-identical / repair agents, slip agents, sunscreens, surfactants / cleansing agents, penetration enhancers, and thickeners.

[0067] The compounds and therapeutic agents of the present application may be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents, or catheters. Suitable coatings and the general preparation of coated implantable devices are known in the art and are embodied in U.S. Patents 6,099,562, 5,886,026, and 5,304,121. The coatings are typically biocompatible polymeric materials such as hydrogel polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further coated with a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids, or combinations thereof to impart controlled release characteristics to the composition. Coatings for invasive devices are meant to be included within the definition of pharma- ceutical acceptable carrier, adjuvant, or vehicle as used herein.

[0068] According to another embodiment, the present application provides an implantable drug release device impregnated with or containing a compound or therapeutic agent, or a composition including a compound or therapeutic agent of the present application, whereby the compound or therapeutic agent is released from the device and becomes therapeutically active.

[0069] Dosage and Administration Regimens In the pharmaceutical compositions of the present application, any of the compounds of the present disclosure are present in an effective amount (e.g., a therapeutically effective amount). The effective dose may vary depending on the disease being treated, the severity of the disease, the route of administration, the sex, age, and general health of the subject, the use of excipients, the possibility of co-administration with other therapeutic treatments such as the use of other drugs, and the judgment of the treating physician.

[0070] In some embodiments, an effective amount of any of the compounds of the present disclosure may be, for example, from about 0.001 mg / kg to about 500 mg / kg (e.g., from about 0.001 mg / kg to about 200 mg / kg, from about 0.01 mg / kg to about 200 mg / kg, from about 0.01 mg / kg to about 150 mg / kg, from about 0.01 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.01 mg / kg to about 5 mg / kg, from about 0.01 mg / kg to about 1 mg / kg, The effective dose of the compound may range from about 0.01 mg / kg to about 0.5 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 200 mg / kg, about 0.1 mg / kg to about 150 mg / kg, about 0.1 mg / kg to about 100 mg / kg, about 0.1 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 2 mg / kg, about 0.1 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 0.5 mg / kg. In some embodiments, the effective amount of the compound is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, or about 5 mg / kg.

[0071] The above-mentioned doses can be administered on a daily basis (e.g., as a single dose or as two or more divided doses, e.g., once a day, twice a day, three times a day) or on a non-daily basis (e.g., every other day, every third day, every third day, once a week, twice a week, once every two weeks, once a month).

[0072] kit The present invention also includes pharmaceutical kits, useful, for example, in the treatment of disorders, diseases and conditions mentioned herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. Such kits can further include one or more of various conventional pharmaceutical kit components, such as, for example, a container with one or more pharma- ceutically acceptable carriers, additional containers, etc., as desired. Instructions, either as a package insert or label, indicating the amounts of components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit. The kits can optionally include additional therapeutic agents as described herein.

[0073] combination The compounds of the present disclosure may be used in combination with at least one pharmaceutical agent or therapy useful, for example, in treating or alleviating the symptoms of 12 / 15-LOX-associated disorders. Suitable examples of such pharmaceutical agents include various pharmaceutical agents useful in treating stroke, such as antithrombotic agents, or pharma- ceutically acceptable salts thereof. Antithrombotic agents are further divided into three subtypes: anticoagulants, antiplatelet agents, and thrombolytic agents. Suitable examples of anticoagulants include coumarin, heparin, warfarin, acenocoumarol, phenprocoumon, atromentin, phenindione, fondaparinux, idraparinux, direct factor Xa inhibitors, direct thrombin inhibitors, antithrombin protein therapeutics, batroxobin, and hemectin. Suitable examples of antiplatelet agents include irreversible cyclooxygenase inhibitors (e.g., aspirin or triflusal), adenosine diphosphate receptor inhibitors (e.g., clopidogrel, prasugrel, ticagrelor, or ticlopidine), phosphodiesterase inhibitors (e.g., cilostazol), glycoprotein IIB / IIIA inhibitors (e.g., abciximab, eptifibatide, or tirofiban), adenosine reuptake inhibitors (e.g., dipyridamole), and thromboxane inhibitors (e.g., thromboxane synthase inhibitors or thromboxane receptor antagonists). Suitable examples of thrombolytic agents include tissue plasminogen activator t-PA (e.g., alteplase, reteplase, or tenecteplase), anistreplase, streptokinase, and urokinase. Ischemic stroke can also be treated by intravascular therapy, in which a catheter is delivered to the site of blood flow blockage to remove the clot. t-PA can optionally be administered during the intravascular treatment. The compounds of the present disclosure can be administered to a patient simultaneously (in the same pharmaceutical composition or dosage form, or in different compositions or dosage forms) or sequentially (the additional therapeutic agent can be administered in a separate pharmaceutical composition or dosage form before or after administration of the compounds of the present disclosure) with an additional therapeutic agent.

[0074] definition As used herein, the term "about" means "approximately" (eg, approximately plus or minus 10% of the indicated value).

[0075] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically contemplated that the invention includes any and all individual subcombinations of the members of such groups and ranges. For example, "C 1~6 The term "alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. In some embodiments, any alkyl group in any compound of the present disclosure can contain at least one deuterium ("D") atom.

[0076] Various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described in various places in this specification. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member allowed by valence. For example, the term "pyridine ring" or "pyridinyl" can refer to a pyridin-2-yl ring, a pyridin-3-yl ring, or a pyridin-4-yl ring.

[0077] It is further understood that certain features of the invention that are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0078] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. The substituents are independently selected, and the substitution can be at any chemically accessible position. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, for example, oxo, can replace two hydrogen atoms. It is understood that substitution at an atom is limited by the valence of the atom.

[0079] Throughout the definition, "C n~m The term "carbon atom" refers to a range inclusive of the endpoints, where n and m are integers and indicate the number of carbons. Examples include 1~4 , C 1~6 etc.

[0080] As used herein, "C" or "D" taken alone or in combination with other terms means n~m The term "alkyl" refers to a saturated hydrocarbon group having n to m carbons, which may be linear or branched. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, and higher homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, an alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. In some embodiments, any alkyl group in any compound of the present disclosure may contain at least one deuterium ("D") atom.

[0081] As used herein, "C" or "D" taken alone or in combination with other terms means n~mThe term "haloalkyl" refers to an alkyl group having from 1 halogen atom to 2s+1 halogen atoms, which may be the same or different, where "s" is the number of carbon atoms in the alkyl group, and the alkyl group has n to m carbons. In some embodiments, the haloalkyl group is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0082] As used herein, "C n~m "Alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds and having n to m carbons. Exemplary alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0083] As used herein, "C n~m "Alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds and having n to m carbons. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0084] As used herein, "C" or "D" taken alone or in combination with other terms means n~m The term "alkylene" refers to a divalent alkyl linking group having n to m carbons. Examples of alkylene groups include, but are not limited to, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1,-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propane-1,3-diyl, and the like. In some embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

[0085] As used herein, "C" or "D" taken alone or in combination with other terms means n~m The term "alkoxy" refers to a group of formula -O-alkyl, where the alkyl group has n to m carbons. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0086] As used herein, "C n~m "Haloalkoxy" refers to a group of the formula -O-haloalkyl having n to m carbon atoms. An exemplary haloalkoxy group is OCF3. In some embodiments, the haloalkoxy group is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0087] As used herein, the term "amino" refers to a group of formula -NH2.

[0088] As used herein, "C n~m The term "alkylamino" refers to a group of formula -NH(alkyl), where the alkyl group has n to m carbons. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, but are not limited to, N-methylamino, N-ethylamino, N-propylamino (e.g., N-(n-propyl)amino and N-isopropylamino), N-butylamino (e.g., N-(n-butyl)amino and N-(tert-butyl)amino).

[0089] As used herein, "di(C n~mThe term "-N(alkyl)amino" refers to a group of formula -N(alkyl)2, where the two alkyl groups each independently have n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0090] As used herein, "halo" refers to F, Cl, Br, or I. In some embodiments, halo is F, Cl, or Br.

[0091] As used herein, "hydrogen" or "H" refers to any stable isotope of a chemical element that has only one proton in its nucleus. These isotopes include hydrogen-1 (one proton and zero neutrons in its nucleus), hydrogen-2 (also known as deuterium, or D, which has one proton and one neutron in its nucleus), and hydrogen-3 (also known as tritium, or T, which has one proton and two neutrons in its nucleus). Unless otherwise stated, when a position is specifically designated as "D" or "deuterium," the position is understood to have deuterium in an abundance at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium). In some embodiments, compounds of the disclosure have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0092] As used herein, "heterocycloalkyl" refers to a non-aromatic monocyclic or polycyclic heterocycle having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Exemplary heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. The ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted with one or two independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). A heterocycloalkyl group can be bonded through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, a heterocycloalkyl group contains 0-3 double bonds. In some embodiments, a heterocycloalkyl group contains 0-2 double bonds. Also included within the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common) to a cycloalkyl ring, e.g., benzo or thienyl derivatives such as piperidine, morpholine, azepine, etc. Heterocycloalkyl groups that contain fused aromatic rings can be bonded through any ring-forming atom, including the ring-forming atoms of the fused aromatic ring. In some embodiments, a heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.

[0093] In certain places, the definitions or embodiments refer to certain rings (e.g., azetidine ring, pyridine ring, etc.). Unless otherwise stated, these rings can be attached to any ring member as long as the valence of the atom is not exceeded. For example, the azetidine ring can be attached at any position on the ring, while the pyridin-3-yl ring is attached at the 3-position.

[0094] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise indicated.

[0095] The compounds described herein may be asymmetric (e.g., have one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are contemplated unless otherwise specified. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods or procedures for preparing optically active forms from non-optically active starting materials, such as by resolution of racemic mixtures or by stereoselective synthesis, are known in the art. Many geometric isomers of olefins, C=N double bonds, N=N double bonds, and the like, can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compounds have the (R)-configuration. In some embodiments, the compounds have the (S)-configuration.

[0096] The compounds provided herein also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond with concomitant proton transfer. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Exemplary prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position of a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or can be sterically confined to one form by appropriate substitution.

[0097] As used herein, the term "cell" is intended to refer to a cell that is in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell may be part of a tissue sample removed from an organism, such as a mammal. In some embodiments, an in vitro cell may be a cell in cell culture. In some embodiments, an in vivo cell is a cell that is living in an organism, such as a mammal.

[0098] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or in an in vivo system. For example, "contacting" 12 / 15-LOX with a compound of the invention includes administering a compound of the invention to an individual or patient, such as a human, having 12 / 15-LOX, as well as introducing a compound of the invention into a sample containing, for example, a cell preparation or purified preparation containing 12 / 16-LOX.

[0099] As used herein, the terms "individual," "patient," or "subject," used interchangeably, refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, most preferably a human.

[0100] As used herein, the phrase "effective amount" or "therapeutically effective amount" refers to that amount of an active compound or pharmaceutical agent that elicits the biological or pharmaceutical response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, physician, or other qualified clinical practitioner.

[0101] As used herein, the term "treating" or "treatment" refers to 1) inhibiting a disease, e.g., inhibiting the disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder (i.e., arresting further development of the pathology and / or symptomology), or 2) ameliorating a disease, e.g., ameliorating a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder (i.e., reversing the pathology and / or symptomology). As used herein, the term "preventing" or "prevention" of a disease, condition, or disorder refers to reducing the risk of development of the disease, condition, or disorder in a subject or group of subjects (e.g., a subject or group of subjects predisposed to or susceptible to the disease, condition, or disorder). In some embodiments, preventing a disease, condition, or disorder refers to reducing the likelihood of acquiring the disease, condition, or disorder and / or its associated symptoms, hi some embodiments, preventing a disease, condition, or disorder refers to completely or nearly completely halting the disease, condition, or disorder from occurring. EXAMPLES

[0102] Examples 1-12 / 15 - Biological Activity of Exemplary Compounds as Inhibitors of LOX Assay: Compounds were dissolved in DMSO and IC was measured immediately after dilution to a concentration of 10 mM in DMSO. 50 To determine the inhibition of the enzyme, 10 μL of DMSO was placed in the first cuvette and 10 μL of the test compound stock solution was placed in the second cuvette. The enzyme was then added to the cuvette. IC 50 Experiments were performed for the following test compound concentrations: 20, 10, 3, 1, 0.3, 0.1, 0.03, and 0.01 μM. If the test compound was more potent than 0.3 μM, the IC 50 The concentrations used in the measurements were changed to lower values ​​such as 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, and 0.001 μM. The % inhibition for each test compound concentration was calculated as follows:

number

[0103] Example 1A - Preparation of exemplary compounds Preparation of 3-(dimethylamino)propyl(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)(methyl)carbamate hydrochloride (compound 52) [ka]

[0104] Step 1. 3-(Dimethylamino)propyl (4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)(methyl)carbamate. To a mixture of 5-(methylamino)-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (370 mg, 1.2 mmol) in anhydrous THF (10 mL, 27 volumes of oxazole) under nitrogen at 0° C., potassium bis(trimethylsilyl)amide (KHMDS, 1.8 mL, 1.0 M in THF, 1.8 mmol, 1.5 equiv) was added dropwise, and the mixture was then stirred for 15 minutes. In a separate flask, potassium bis(trimethylsilyl)amide (KHMDS, 3.1 mL, 1.0 M in THF, 3.1 mmol, 2.5 equiv) was added dropwise to a mixture of 3-dimethylamino-1-propanol (0.36 mL, 3.1 mmol, 2.5 equiv) in anhydrous THF (5 mL, 14 volumes of oxazole) under nitrogen at 0° C., and the mixture was then stirred for 15 minutes. To this mixture was added dropwise a solution of 4-nitrophenyl chloroformate (493 mg, 2.4 mmol, 2.0 equiv) in anhydrous THF (9 mL, 24 volumes of oxazole), after which the mixture was stirred at 0° C. for 30 minutes. To this mixture was then added dropwise the KHMDS / oxazole / THF solution, after which the resulting mixture was stirred at 0° C. for 30 minutes, then slowly warmed to room temperature and stirred for a total of 2 hours. The mixture was diluted with saturated aqueous sodium chloride solution (80 mL) and extracted with ethyl acetate (2×80 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with methanol / ethyl acetate (gradient 0:100 to 60:40) to give 3-(dimethylamino)propyl (4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)(methyl)carbamate (178 mg, 35%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 4.39 (t, J = 6.7 Hz, 2H), 3.46 (s, 3H), 2.34 (t, J = 7.0 Hz, 2H), 2.22 (s, 6H), 1.98-1.88 (m, 2H) ppm;ESI MS m / z 431 [M + H] + .

[0105] Step 2. 3-(Dimethylamino)propyl(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)(methyl)carbamate hydrochloride Hydrochloric acid (1.6 mL, 4.0 N solution in dioxane, 6.4 mmol, 10 equiv.) was added dropwise to a solution of 3-(dimethylamino)propyl(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)(methyl)carbamate (276 mg, 0.64 mmol) in anhydrous ethyl acetate (5.5 mL, 20 volumes of oxazole) at room temperature under nitrogen, and the mixture was then stirred for 10 minutes. Heptane (15 mL) was added and the resulting mixture was stirred for 5 minutes, and then the solvent was removed under reduced pressure to yield 3-(dimethylamino)propyl(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)(methyl)carbamate hydrochloride (294 mg, 98%) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 9.78 (br s, 1H), 8.16 (d, J = 2.5 Hz, 1H), 8.06 (d, J = 2.5 Hz, 1H), 4.33 (t, J = 6.2 Hz, 2H), 3.43 (s, 3H), 3.16 (t, J = 5.0 Hz, 2H), 2.76 (s, 6H), 2.14-2.04 (m, 2H) ppm;ESI MS m / z 431 [free base M + H] + .

[0106] The following compounds were prepared following similar methods and procedures as described above for compound 52. [Table 2]

[0107] Preparation of 3-(dimethylamino)propyl (4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)carbamate hydrochloride (compound 57) [ka]

[0108] Step 1. 3-(Dimethylamino)propyl (4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)carbamate A solution of triphosgene (102 mg, 0.35 mmol) in anhydrous dichloromethane (0.8 mL) was added dropwise to a solution of 5-amino-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (100 mg, 0.35 mmol) in anhydrous dichloromethane (0.8 mL) at room temperature under nitrogen, and the resulting suspension was then stirred at room temperature for 5 minutes. A solution of triethylamine (0.10 mL, 0.76 mmol) in anhydrous dichloromethane (0.4 mL) was added dropwise, and the resulting solution was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the residue was dissolved in anhydrous dichloromethane (4.0 mL) at room temperature under nitrogen. 3-Dimethylaminopropan-1-ol (60 μL, 0.52 mmol) was added, followed by triethylamine (96 μL, 0.69 mmol), and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (2×20 mL) and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with methanol / dichloromethane (gradient 0:100→10:90) and then a second purification by column chromatography on silica gel eluting with methanol / dichloromethane (gradient 2:98→15:85) to give 3-(dimethylamino)propyl(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)carbamate (17 mg, 11%) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 7.95 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 4.04 (t, J = 6.3 Hz, 2H), 3.11-3.03 (m, 2H), 2.74 (s, 6H), 2.11-1.90 (m, 2H) ppm;ESI MS m / z 417 [M + H] + .

[0109] Step 2. 3-(Dimethylamino)propyl (4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)carbamate hydrochloride 2N Hydrochloric acid (0.10 mL, 0.40 mmol) was added to a solution of 3-(dimethylamino)propyl(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)carbamate (17 mg, 0.041 mmol) in methanol (1 mL) at room temperature under nitrogen, then the solvent was removed under reduced pressure. The residue was redissolved in anhydrous acetonitrile (2 mL), the solvent was removed under reduced pressure, and lyophilized to give 3-(dimethylamino)propyl(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)carbamate hydrochloride (11 mg, 61%) as a light yellow solid. 1 H NMR(500MHz,DMSO-d6)δ 12.07(s,1H),9.57(s,1H),8.13(d,J=2.5Hz,1H), 7.90(d,J=2.5Hz,1H),4.28(t,J=6.3Hz,2H),3.19-3.11(m, 2H),2.79(s,6H),2.11-2.01(m,2H)ppm;ESI MS m / z 417[M+H] + .

[0110] The following compounds were prepared by methods and procedures similar to those described above for compound 57. [Table 3]

[0111] Preparation of N-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-6-(dimethylamino)-N-methylhexanamide hydrochloride (compound 61) [ka]

[0112] Step 1. N-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-6-(dimethylamino)hexanamide PyBOP (134 mg, 0.25 mmol) was added to a solution of 6-(dimethylamino)hexanoic acid (39 mg, 0.25 mmol) in anhydrous DMF (1.6 mL) at room temperature under nitrogen, followed by 5-(methylamino)-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (50 mg, 0.16 mmol) and diisopropylethylamine (71 μL, 0.41 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (2×30 mL) and saturated aqueous sodium chloride (3×20 mL) and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with (2:18:80 concentrated ammonium hydroxide / methanol / dichloromethane) / dichloromethane (gradient of 0:100 to 100:0) and then a second purification eluting with (2:18:80 concentrated ammonium hydroxide / methanol / dichloromethane) / dichloromethane (gradient of 5:95 to 40:60) to provide N-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-6-(dimethylamino)-N-methylhexanamide (39 mg, 53%) as a yellow solid. 1 H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 3.41 (s, 3H), 2.43 (t, J = 7.4 Hz, 2H), 2.24 (t, J = 7.4 Hz, 2H), 2.20 (s, 6H), 1.76-1.68 (m, 2H), 1.52-1.43 (m, 2H), 1.38-1.30 (m, 2H) ppm.

[0113] Step 2. N-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-6-(dimethylamino)-N-methylhexanamide hydrochloride Hydrochloric acid (24 μL, 0.096 mmol, 4N dioxane solution) was added to a solution of N-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-6-(dimethylamino)-N-methylhexanamide (39 mg, 0.088 mmol) in anhydrous dichloromethane (2 mL) at room temperature under nitrogen, and the mixture was then stirred at room temperature for 2 h. The resulting suspension was triturated with diethyl ether (20 mL). The solid was collected by filtration under reduced pressure to give N-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-6-(dimethylamino)-N-methylhexanamide hydrochloride (36 mg, 86%) as an off-white solid. 1 H NMR (500 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.15 (d, J = 2.5Hz, 1H), 8.06 (d, J = 2.5 Hz, 1H), 3.45 (s, 3H), 3.04-2.97 (m, 2H), 2.73 (s, 6H), 2.64 (t, J = 7.2 Hz, 2H), 1.71 (m, 4H), 1.38-1.28 (m, 2H) ppm;ESI MS m / z 443 [M + H] + .

[0114] The following compounds were prepared by methods and procedures similar to those described above for compound 61. [Table 4]

[0115] Preparation of N-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-6-(dimethylamino)hexanamide hydrochloride (compound 63) [ka]

[0116] Step 1. N-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-6-(dimethylamino)hexanamide PyBOP (135 mg, 0.26 mmol) was added to a solution of 6-(dimethylamino)hexanoic acid (41 mg, 0.26 mmol) in anhydrous DMF (1.8 mL) at room temperature under nitrogen, followed by 5-(methylamino)-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (50 mg, 0.17 mmol) and diisopropylethylamine (75 μL, 0.43 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (2×30 mL) and saturated aqueous sodium chloride (3×20 mL) and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with (2:18:80 concentrated ammonium hydroxide / methanol / dichloromethane) / dichloromethane (gradient of 0:100 to 100:0) to provide N-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-6-(dimethylamino)hexanamide (59 mg, 79%) as a yellow solid. 1 H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 2.5 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 2.83 (t, J = 6.5 Hz, 2H), 2.64 (s, 6H), 2.58-2.54 (m, 2H), 1.82-1.71 (m, 4H), 1.62-1.55 (m, 2H) ppm.

[0117] Step 2. N-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-6-(dimethylamino)hexanamide hydrochloride Hydrochloric acid (34 μL, 0.14 mmol, 4N dioxane solution) was added to a solution of N-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-6-(dimethylamino)hexanamide (59 mg, 0.14 mmol) in anhydrous dichloromethane (2 mL) at room temperature under nitrogen, and the resulting suspension was then triturated with diethyl ether (10 mL). The solid was collected by filtration under reduced pressure to give N-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-6-(dimethylamino)hexanamide hydrochloride (49 mg, 83%) as an off-white solid. 1 H NMR (500 MHz, MeOD-d4) δ 7.92 (d, J = 2.5 Hz, 1H), 7.86 (d, J = 2.5 Hz, 1H), 3.19-3.11 (m, 2H), 2.89 (s, 6H), 2.56 (t, J = 7.1 Hz, 2H), 1.83-1.72 (m, 4H), 1.53-1.43 (m, 2H) ppm;ESI MS m / z 429 [M + H] + .

[0118] The following compounds were prepared by methods and procedures similar to those described above for compound 63. [Table 5]

[0119] Preparation of 1-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-3-(3-(dimethylamino)propyl)-1-methylurea hydrochloride (compound 66) [ka]

[0120] Step 1. 1-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-3-(3-(dimethylamino)propyl)-1-methylurea A solution of triphosgene (983 mg, 0.33 mmol) in anhydrous dichloromethane (0.6 mL) was added dropwise to a solution of 5-(methylamino)-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (100 mg, 0.33 mmol) in anhydrous dichloromethane (0.6 mL) at room temperature under nitrogen, and the resulting suspension was then stirred at room temperature for 5 minutes. A solution of triethylamine (0.10 mL, 0.73 mmol) in anhydrous dichloromethane (0.3 mL) was added dropwise, and the resulting solution was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure, and the residue was dissolved in anhydrous dichloromethane (4.0 mL) at room temperature under nitrogen. 3-Dimethylaminopropylamine (83 μL, 0.66 mmol) was added, followed by triethylamine (91 μL, 0.66 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (2×20 mL) and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with (2:18:80 concentrated ammonium hydroxide / methanol / dichloromethane) / dichloromethane (25:75→75:25 gradient), followed by a second purification by column chromatography on silica gel eluting with (2:18:80 concentrated ammonium hydroxide / methanol / dichloromethane) / dichloromethane (0:100→20:80 gradient) to provide 1-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-3-(3-(dimethylamino)propyl)-1-methylurea (26 mg, 18%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.11-8.08 (m, 2H), 7.76 (s, 1H), 4.09-3.98 (m, 2H), 3.43 (s, 3H), 2.27 (t, J = 3.6 Hz, 2H), 2.12 (s, 6H), 1.77-1.66 (m, 2H) ppm.

[0121] Step 2. 1-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-3-(3-(dimethylamino)propyl)-1-methylurea hydrochloride Hydrochloric acid (16 μL, 0.066 mmol, 4N dioxane solution) was added to a solution of 1-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-3-(3-(dimethylamino)propyl)-1-methylurea (26 mg, 0.060 mmol) in anhydrous dichloromethane (2 mL) at room temperature under nitrogen, and the resulting suspension was then triturated with diethyl ether (20 mL). The solid was collected by filtration under reduced pressure to give 1-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-3-(3-(dimethylamino)propyl)-1-methylurea hydrochloride (25 mg, 83%) as an off-white solid. 1 H NMR (500 MHz, DMSO-d6) δ 10.63 (br s, 1H), 10.21 (br s, 2H), 8.27-8.16 (m, 2H), 4.15 (t, J = 7.1 Hz, 2H), 3.63 (s, 3H), 3.21-3.09 (m, 2H), 2.76 (s, 6H), 2.06-1.95 (m, 2H) ppm;ESI MS m / z 430 [M + H] + .

[0122] Preparation of 1-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-3-(3-(dimethylamino)propyl)urea hydrochloride (compound 67) [ka]

[0123] Step 1. 1-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-3-(3-(dimethylamino)propyl)urea A solution of triphosgene (103 mg, 0.35 mmol) in anhydrous dichloromethane (0.9 mL) was added dropwise to a solution of 5-amino-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (100 mg, 0.35 mmol) in anhydrous dichloromethane (0.9 mL) at room temperature under nitrogen, and the resulting suspension was then stirred at room temperature for 5 minutes. A solution of triethylamine (0.11 mL, 0.76 mmol) in anhydrous dichloromethane (0.5 mL) was added dropwise, and the resulting solution was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the residue was dissolved in anhydrous dichloromethane (4.0 mL) at room temperature under nitrogen. 3-Dimethylaminopropylamine (65 μL, 0.52 mmol) was added followed by triethylamine (95 μL, 0.69 mmol) and the mixture was stirred at room temperature for 18 h. The mixture was diluted with water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (2×20 mL) and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with (2:18:80 concentrated ammonium hydroxide / methanol / dichloromethane) dichloromethane (gradient of 0:100 to 50:50), followed by a second purification by column chromatography on silica gel eluting with (2:18:80 concentrated ammonium hydroxide / methanol / dichloromethane) / dichloromethane (gradient of 0:100 to 50:50) to provide 1-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-3-(3-(dimethylamino)propyl)urea (33 mg, 23%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.94 (br s, 2H), 8.09 (d, J = 2.5 Hz, 1H), 8.00 (d, J = 2.5 Hz, 1H), 3.97-3.85 (m, 2H), 2.31-2.22 (m, 2H), 2.18 (s, 6H), 1.82-1.71 (m, 2H) ppm.

[0124] Step 2. 1-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-3-(3-(dimethylamino)propyl)urea hydrochloride 2N hydrochloric acid (45 μL, 0.090 mmol) was added to a solution of 1-(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)-3-(3-(dimethylamino)propyl)urea (33 mg, 0.080 mmol) in methanol (2 mL) at room temperature under nitrogen, then the solvent was removed under reduced pressure. The residue was redissolved in anhydrous acetonitrile (2 mL), the solvent was removed under reduced pressure, and lyophilized to give 3-(dimethylamino)propyl(4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)carbamate hydrochloride (30 mg, 82%) as a light yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ 9.83 (br s, 1H), 8.75 (br s, 2H), 8.09 (d, J = 2.5 Hz, 1H), 7.99 (d, J = 2.5 Hz, 1H), 4.03 (t, J = 7.1 Hz, 2H), 3.15-3.07 (m, 2H), 2.78-2.74 (m, 6H), 2.00-1.90 (m, 2H) ppm;ESI MS m / z 416 [M + H] + .

[0125] Preparation of (4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)(methyl)phosphoramidic acid (compound 68) [ka]

[0126] Step 1. Diethyl (4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)(methyl)phosphoramidate Potassium bis(trimethylsilyl)amide (KHMDS, 0.94 mL, 0.94 mmol, 1.0 M THF solution, 1.5 equiv) was added dropwise to a solution of 5-(methylamino)-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (190 mg, 0.63 mmol) in anhydrous THF (5.7 mL, 30 volumes of oxazole) under nitrogen at 0° C., and the mixture was then stirred for 10 minutes. Diethyl chloridophosphate (0.27 mL, 1.9 mmol, 3.0 equiv) was added dropwise, and the mixture was then allowed to warm slowly to room temperature and stirred for a total of 2 hours. The mixture was poured into saturated aqueous sodium chloride solution (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate / heptane (0:100 to 50:50 gradient) to give diethyl (4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)(methyl)phosphoramidate (190 mg, 69%) as a light tan solid. 1 H NMR (300 MHz, CDCl3) δ 7.85 (d, J = 2.5 Hz, 1H), 7.61 (d, J = 2.6 Hz, 1H), 4.35-4.14 (m, 4H), 3.41 (d, J = 7.9 Hz, 3H), 1.63 (br s, 1H), 3.40 (t, J = 7.02 Hz, 6H) ppm.

[0127] Step 2. (4-Cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)(methyl)phosphoramidic acid Bromotrimethylsilane (0.55 mL, 4.3 mmol, 10.0 equiv) was added dropwise to a solution of diethyl (4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)(methyl)phosphoramidate (190 mg, 0.43 mmol) in anhydrous dichloromethane (1.9 mL, 10 volumes of phosphoramidate) under nitrogen at 0° C., after which the mixture was allowed to warm slowly to room temperature and stirred for a total of 17 hours. The solvent was removed under reduced pressure, the residue was dissolved in THF (5 mL), treated with water (1 mL), and the biphasic mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue was purified by reverse-phase column chromatography eluting with acetonitrile / water (gradient of 0:100 to 100:0) to yield (4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)(methyl)phosphoramidic acid (71 mg, 43%) as an off-white solid. 1 H NMR (500 MHz, DMSO-d6) δ 7.95 (d, J = 2.5 Hz, 1H), 7.91 (d, J = 2.2 Hz, 1H), 7.28 (br s, 1H), 6.98 (br s, 2H), 2.98 (d, J = 4.9 Hz, 3H) ppm.

[0128] Preparation of 5-((4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)amino)pentyl dihydrogen phosphate (compound 51) [ka]

[0129] Anhydrous DMF (4.1 mL, 21 volumes of oxazole) was charged to a flask containing 5-((5-hydroxypentyl)-amino)-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (200 mg, 0.54 mmol), tetrabutylammonium bisulfate (109 mg, 0.32 mmol, 0.60 equiv) and phosphoenolpyruvate monopotassium salt (PEP-K, 646 mg, 3.2 mmol, 6.0 equiv) at room temperature under nitrogen, then the mixture was heated to 100° C. and stirred for 6 h. The mixture was cooled to room temperature and directly purified by reverse-phase column chromatography eluting with acetonitrile / water (gradient of 5:95 to 100:0) to yield 5-((4-cyano-2-(2,3,5-trichlorophenyl)oxazol-5-yl)amino)pentyl dihydrogen phosphate (154 mg, 63%) as an off-white solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.74 (t, J = 5.8 Hz, 1H), 7.97 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 2.8 Hz, 1H), 3.80 (q, J = 6.8 Hz, 2H), 3.35 (q, J = 6.2 Hz, 2H), 1.65-1.57 (m, 4H), 1.44-1.38 (m, 2H) ppm;ESI MS m / z 454 [M + H] + .

[0130] Preparation of 5-((methyl-d3)amino)-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (compound 44) [ka]

[0131] Step 1. 2-Amino-3,3-dichloroacrylonitrile Dichloroacetonitrile (14.6 g, 181.9 mmol) was added to a mixture of anhydrous methyl tert-butyl ether (180 mL) and anhydrous acetonitrile (720 mL) in a 2 L flask wrapped in foil to protect from light under nitrogen at 0° C. Acetone cyanohydrin (18.3 mL, 200.1 mmol) was added followed by potassium cyanide (236 mg, 3.64 mmol) and the resulting mixture was allowed to warm slowly to room temperature and stirred for a total of 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between methyl tert-butyl ether (150 mL) and saturated aqueous sodium bicarbonate (150 mL) in a covered flask to protect from light, and the biphasic mixture was stirred at room temperature, protected from light, for 2 hours. The organic phase was collected and washed with saturated aqueous sodium bicarbonate (3×100 mL). The aqueous washes were then back-extracted with methyl tert-butyl ether (2×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (100 mL) and treated with anhydrous sodium sulfate and activated charcoal (6 g), and the resulting mixture was stirred at room temperature, protected from light, for 30 min. The mixture was filtered through Celite under reduced pressure, and the filtrate's solvent was removed under reduced pressure. The dried residue was again partitioned between methyl tert-butyl ether (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL) in a flask covered to protect from light, and the biphasic mixture was stirred at room temperature, protected from light, for 2.5 h. The organic phase was collected and washed with saturated aqueous sodium bicarbonate solution (4×75 mL). The aqueous washes were then back-extracted with methyl tert-butyl ether (3×75 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (100 mL), treated with anhydrous sodium sulfate and activated charcoal (6 g), and the resulting mixture was stirred at room temperature, protected from light, for 20 min. The mixture was filtered through Celite under reduced pressure and the filtrate's solvent was removed under reduced pressure, protected from light, to give 2-amino-3,3-dichloroacrylonitrile (15.3 g, 69%) as a light yellow solid. 1 H NMR (500 MHz, CDCl3) δ 3.66 (br s, 2H) ppm.

[0132] Step 2. 2,3,5-Trichlorobenzoyl chloride Thionyl chloride (5.27 g, 44.3 mmol) was added in portions to a solution of 2,3,5-trichlorobenzoic acid (2.00 g, 8.87 mmol) in anhydrous toluene (48 mL) at room temperature under nitrogen, and the mixture was then heated to reflux and stirred for 4.5 h. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was subjected to three repeated treatments with toluene (5 mL) followed by solvent removal under reduced pressure to yield 2,3,5-trichlorobenzoyl chloride (2.16 g, quantitative) as an orange waxy solid. 1 H NMR (300 MHz, CDCl3) δ 7.86 (d, J = 2.4 H, 1H), 7.69 (d, J = 2.4 Hz, 1H) ppm.

[0133] Step 3. 2,3,5-Trichloro-N-(2,2-dichloro-1-cyanovinyl)benzamide Trifluoromethanesulfonic acid (0.88 M solution in N-methylpyrrolidinone, 52.9 mL, 46.6 mmol) was added slowly via addition funnel to a solution of 2,3,5-trichlorobenzoyl chloride (10.78 g, 44.4 mmol) in anhydrous N-methylpyrrolidinone (24 mL) under nitrogen at 0° C. in a flask wrapped in foil to protect from light. 2-Amino-3,3-dichloroacrylonitrile (6.68 g, 48.8 mmol) was added in small portions and the resulting mixture was allowed to warm slowly to room temperature and stirred for a total of 18 hours. The mixture was diluted with water (300 mL) and the resulting solid was collected by filtration under reduced pressure and washed with water (100 mL). The solid was dissolved in ethyl acetate (1.5 L) in a flask wrapped in foil to protect from light, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure to give 2,3,5-trichloro-N-(2,2-dichloro-1-cyanovinyl)benzamide (14.2 g, 93%) as a yellow solid (14.2 g, 93%). 1 H NMR (300 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H) ppm.

[0134] Step 4. 5-((methyl-d3)amino)-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile In a flask wrapped in foil to protect from light, methane-d3-amine hydrochloride (0.107 g, 1.52 mmol) was added in portions to a solution of 2,3,5-trichloro-N-(2,2-dichloro-1-cyanovinyl)benzamide (350 mg, 1.02 mmol) in anhydrous N-methylpyrrolidinone (1.10 mL) at room temperature under nitrogen, and the resulting mixture was stirred at room temperature for 18 hours. Additional methane-d3-amine hydrochloride (20.0 mg, 0.284 mmol) was added, and the mixture was stirred at room temperature for an additional 4 hours. The mixture was diluted with water (100 mL), and the resulting solid was collected by filtration under reduced pressure and washed with water (50 mL). The solid was further purified by column chromatography on silica gel eluting with ethyl acetate / heptane (gradient 0:100 to 30:70) to afford 5-((methyl-d3)amino)-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (110 mg, 34%) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.86 (d, J = 2.5 Hz, 1H) ppm;ESI MS m / z 304 [M + H] + .

[0135] Preparation of 5-((2-(2-methoxyethoxy)ethyl)amino)-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (compound 32) [ka]

[0136] In a flask wrapped in foil to protect from light, trifluoromethanesulfonic acid (78 μL, 0.887 mmol) was added to a solution of 2,3,5-trichlorobenzoyl chloride (216 mg, 0.887 mmol) in anhydrous N-methylpyrrolidinone (1.0 mL) at room temperature under nitrogen. 2-Amino-3,3-dichloroacrylonitrile (133 mg, 0.976 mmol) was added in small portions and the resulting mixture was allowed to warm slowly to room temperature and stirred for a total of 18 hours. Triethylamine (0.61 mL, 4.43 mmol) was added followed by 2-(2-methoxyethoxy)ethan-1-amine (0.17 mL, 1.33 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (3×20 mL) and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with methanol / dichloromethane (0:100→10:90 gradient) to give 5-((2-(2-methoxyethoxy)ethyl)amino)-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (compound 32, 99 mg, 28%) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.76 (t, J = 5.8 Hz, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.87 (d, J ESI MS m / z 390 [M + H] + .

[0137] Preparation of 5-(methylamino)-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (compound 1) - synthetic route 1 [ka]

[0138] In a flask wrapped in foil to protect from light, methanesulfonic acid (1.44 mL, 22.2 mmol mmol) was added dropwise to a solution of 2,3,5-trichlorobenzoyl chloride (5.43 g, 22.2 mmol) in anhydrous N-methylpyrrolidinone (24 mL) at room temperature under nitrogen. 2-Amino-3,3-dichloroacrylonitrile (3.34 g, 24.4 mmol) was added in small portions and the resulting mixture was allowed to warm slowly to room temperature and stirred for a total of 18 hours. The mixture was cooled to 0° C., after which diisopropylethylamine (19.3 mL, 111 mmol) was added, followed by methylamine (22.2 mL, 44.4 mmol, 2.0 M in THF) and the resulting mixture was allowed to warm slowly to room temperature and stirred for a total of 188 hours. The mixture was diluted with water (500 mL) and the solid was collected by filtration under reduced pressure. This solid was triturated with methanol (50 mL) for 30 minutes, then the solid was collected by filtration under reduced pressure to give 5-(methylamino)-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (5.27 g, 78%) as an off-white solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.57 (q, J = 4.8 Hz, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.87 (d,J=2.4Hz,1H), 3.00 (d, J = 4.8 Hz, 3H) ppm;ESI MS m / z 302 [M+H] + .

[0139] Preparation of 5-(methylamino)-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (compound 1) - synthetic route 2 [ka]

[0140] The synthetic route described below is described in Rai, G., et al. J. Med. Chem., 2014, 57, 4035-4048.

[0141] Step 1. 5-Amino-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile 1-Propanephosphonic anhydride solution (T3P, 54 mL, 50% in ethyl acetate, 93.1 mmol, 2.1 equiv.) was added dropwise to a mixture of 2,3,5-trichlorobenzoic acid (10.0 g, 44.3 mmol) and aminomalononitrile p-toluenesulfonate (11.8 g, 46.6 mmol, 1.05 equiv.) in anhydrous pyridine (200 mL, 20 volumes of acid) under nitrogen at room temperature, and the resulting mixture was then stirred at room temperature for 22 hours. The mixture was poured into water (1.2 L), stirred for 20 minutes, and the solid was collected by filtration under reduced pressure, washed with water (2×30 mL), and dried overnight under high vacuum at 50° C. to give 5-amino-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (11.04 g, 86%) as a light pink solid. 1 H NMR (300 MHz, CDCl3) δ 7.78 (d, J = 2.5 Hz, 1H), 7.56 (d, J = 2.3 Hz, 1H), 5.22 (br s, 2H) ppm;ESI MS m / z 288 [M + H] + .

[0142] Step 2. 5-Chloro-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile from 5-amino-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile tert-Butyl nitrite (1.7 mL, 13.9 mmol, 2.0 equiv.) was slowly added dropwise to a suspension of copper(II) chloride (1.86 g, 13.9 mmol, 2.0 equiv.) and 5-amino-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (2.0 g, 6.9 mmol) in anhydrous acetonitrile (40 mL, 20 volumes of oxazole) under nitrogen at room temperature, and the resulting mixture was then stirred at room temperature for 30 minutes. The mixture was diluted with 1N hydrogen chloride solution (100 mL) and extracted with ethyl acetate (80 mL). The organic extract was washed with saturated aqueous sodium chloride solution (60 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate / heptane (gradient 0:100 to 10:90) to give 5-chloro-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (548 mg, 26%) as an off-white solid. 1 H NMR (300 MHz, CDCl3) δ 7.86 (d, J = 2.4 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H) ppm;ESI MS m / z 307 [M + H] + Continued elution led to the isolation of the by-product 2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (215 mg, 11%) as a light yellow solid. 1 H NMR (300 MHz,CDCl3) δ 8.33 (s, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H) ppm;ESI MS m / z 274 [M + H] + .

[0143] Step 2a. 5-Chloro-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile from 2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile n-Butyllithium (1.24 mL, 2.5 M in hexane, 3.11 mmol, 1.05 equiv) was added dropwise to a solution of 2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (810 mg, 2.96 mmol) in anhydrous THF (20 mL, 25 volumes of oxazole) under nitrogen at -78°C, and the mixture was then stirred at -78°C for 15 minutes. Solid hexachloroethane (757 mg, 3.20 mmol, 1.1 equiv) was added in one portion, and the mixture was then allowed to warm slowly to room temperature and stirred for a total of 1 hour. The mixture was diluted with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate / heptane (gradient 0:100 to 15:85) to afford 5-chloro-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (230 mg, 25%) as a light yellow solid.

[0144] Step 3. 5-(Methylamino)-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile Methylamine (8.9 mL, 2.0 M in THF, 17.8 mmol, 10.0 equiv.) was added to a solution of 5-chloro-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (548 mg, 1.80 mmol) in anhydrous DMSO (16 mL, 30 volumes of oxazole) at room temperature under nitrogen, and the resulting mixture was then stirred at room temperature for 4 hours. The mixture was poured into saturated aqueous sodium chloride solution (100 mL) and extracted with ethyl acetate (2×70 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate / heptane (0:100→40:60 gradient) to give 5-(methylamino)-2-(2,3,5-trichlorophenyl)oxazole-4-carbonitrile (compound 1, 340 mg, 63%) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.57 (q, J = 4.8 Hz, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 3.00 (d, J = 4.8 Hz, 3H) ppm;ESI MS m / z 302 [M+H] + .

[0145] Preparation of intermediate amines Preparation of 2-(2-isopropoxyethoxy)ethan-1-amine [ka]

[0146] Step 1. 2-(2-isopropoxyethoxy)ethan-1-ol Diethylene glycol (8.63 g, 81.30 mmol) was placed in anhydrous DMSO (110 mL) at room temperature under nitrogen and the solution was stirred for 20 minutes. Potassium hydroxide (5.02 g, 89.43 mmol) and 2-bromopropane (3.81 mL, 40.62 mmol) were added sequentially and the mixture was then stirred at room temperature for 18 hours. The mixture was diluted with water (500 mL), treated with 2N HCl (5 mL) and extracted with ethyl acetate (3×80 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure to give 2-(2-isopropoxyethoxy)ethanol (339 mg, 6%) as a pale yellow oil. 1 H NMR (300 MHz, CDCl3) δ 3.74-3.57 (m, 9H), 1.18 (d, J = 6.1 Hz, 6H) ppm.

[0147] Step 2. 2-(2-(2-isopropoxyethoxy)ethyl)isoindoline-1,3-dione 1,1'-(Azodicarbonyl)dipiperidine (638 mg, 2.52 mmol) and phthalimide (370 mg, 2.74 mmol) were added sequentially to a solution of 2-(2-isopropoxyethoxy)ethanol (339 mg, 2.29 mmol) in anhydrous THF (20.8 mL) at 0°C (ice / water bath) under nitrogen, followed by the dropwise addition of tri-n-butylphosphine (0.68 mL, 2.74 mmol). The resulting solution was allowed to warm slowly to room temperature and stirred for a total of 18 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate / dichloromethane (0:100 to 50:50 gradient) to give 2-(2-(2-isopropoxyethoxy)ethyl)isoindoline-1,3-dione (471 mg, 74%) as an off-white solid. 1 H NMR (300 MHz, CDCl3) δ 7.86-7.83 (m, 2H), 7.72-7.70 (m, 2H), 3.92-3.89 (m, 2H), 3.77-3.73 (m, 2H), 3.64-3.59 (m, 3H), 3.55-3.51 (m, 2H), 1.09 (d, J = 6.1 Hz, 6H) ppm.

[0148] Step 3. 2-(2-isopropoxyethoxy)ethan-1-amine Hydrazine monohydrate (0.11 mL, 3.40 mmol) was added to a solution of 2-(2-(2-isopropoxyethoxy)ethyl)isoindoline-1,3-dione (471 mg, 1.70 mmol) in ethanol (15.5 mL) at room temperature under nitrogen, then the mixture was heated to reflux and stirred for 2 h. The mixture was cooled to room temperature and filtered under reduced pressure to remove a solid by-product. The filtrate's solvent was removed under reduced pressure to give 2-(2-isopropoxyethoxy)ethanamine (256 mg, >99%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 3.61-3.56 (m, 5H), 3.51 (t, J = 5.1 Hz, 2H), 2.86 (t, J = 5.2 Hz, 2H), 1.17 (d, J = 6.1 Hz, 6H) ppm.

[0149] Preparation of 2-(2-(pyridin-4-yloxy)ethoxy)ethan-1-amine [ka]

[0150] Step 1. 2-(2-(3-(pyridin-4-yl)propoxy)ethyl)isoindoline-1,3-dione 4-Hydroxypyridine (1.94 g, 20.41 mmol) and 1,1'-(azodicarbonyl)dipiperidine (6.44 g, 25.51 mmol) were added sequentially to a solution of 2-(2-(2-hydroxyethoxy)ethyl)isoindoline-1,3-dione (4.00 g, 17.00 mmol) in anhydrous THF (94.4 mL) at 0° C. (ice / water bath) under nitrogen, followed by the dropwise addition of tri-n-butylphosphine (6.37 mL, 25.51 mmol). The mixture was allowed to warm slowly to room temperature and stirred for a total of 18 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and cooled to 0° C. for 20 minutes, then the solid was removed by filtration under reduced pressure. The filtrate's solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with methanol / ethyl acetate (gradient 0:100→40:60) to give 2-(2-(3-(pyridin-4-yl)propoxy)ethyl)isoindoline-1,3-dione (1.48 g, 28%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.36-8.34 (m, 2H), 7.83-7.80 (m, 2H), 7.72-7.69 (m, 2H), 6.73-6.71 (m, 2H), 4.12-4.09 (m, 2H), 3.94-3.90 (m, 2H), 3.87-3.80 (m, 4H) ppm.

[0151] Step 2. 2-(2-(pyridin-4-yloxy)ethoxy)ethan-1-amine Hydrazine monohydrate (0.30 mL, 9.50 mmol) was added to a solution of 2-(2-(3-(pyridin-4-yl)propoxy)ethyl)isoindoline-1,3-dione (1.48 g, 4.75 mmol) in ethanol (43 mL) at room temperature under nitrogen, then the mixture was heated to reflux and stirred for 1 h. The mixture was cooled to room temperature and filtered under reduced pressure to remove a solid by-product. The filtrate's solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with methanol / dichloromethane (0:100→4:96 gradient) to give 2-(2-(pyridin-4-yloxy)ethoxy)ethan-1-amine (189 mg, 22%) as a colorless oil. 1 H NMR (300 MHz, CDCl3) δ 8.44-8.42 (m, 2H), 6.84-6.82 (m, 2H), 4.20-4.16 (m, 2H), 3.86-3.83 (m, 2H), 3.58 (t, J = 5.1 Hz, 2H), 2.90 (t, J = 5.1 Hz, 2H) ppm.

[0152] Preparation of 2-(2-(2-(pyridin-4-yloxy)ethoxy)ethoxy)ethan-1-amine [ka]

[0153] Step 1. 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)isoindoline-1,3-dione Potassium phthalamide (2.42 g, 13.05 mmol) was added to a solution of 2-(2-(2-chloroethoxy)ethoxy)ethan-1-ol (1.72 mL, 11.86 mmol) in anhydrous DMF (14.5 mL) at room temperature under nitrogen, then the mixture was heated to 100° C. and stirred for 18 h. The mixture was cooled to room temperature and the solid was removed by filtration under reduced pressure. The filtrate's solvent was removed under reduced pressure and the residue was diluted with water (60 mL) and extracted with dichloromethane (2×40 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to give 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)isoindoline-1,3-dione (2.66 g, 80%) as a pale yellow oil. 1 H NMR (300 MHz, CDCl3) δ 7.88-7.80 (m, 2H), 7.79-7.68 (m, 2H), 3.93-3.90 (m, 2H), 3.78-3.74 (m, 2H), 3.69-3.59 (m, 6H), 3.55-3.50 (m, 2H) ppm.

[0154] Step 2. 2-(2-(2-(2-(pyridine-4-oxy)ethoxy)ethoxy)ethyl)isoindoline-1,3-dione Triphenylphosphine (2.33 g, 8.92 mmol) was added to a solution of 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)isoindoline-1,3-dione (1.66 g, 5.94 mmol), 4-hydroxypyridine (0.85 g, 8.92 mmol) and diisopropyl azodicarboxylate (1.75 mL, 8.92 mmol) in anhydrous THF (30 mL) at 0° C. (ice / water bath) under nitrogen, then the mixture was allowed to warm slowly to room temperature and stirred for a total of 18 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with methanol / ethyl acetate (gradient 0:100 to 40:60) to give 2-(2-(2-(2-(pyridine-4-oxy)ethoxy)ethoxy)ethyl)isoindoline-1,3-dione (664 mg, 31%) as an off-white solid. 1 H NMR (300 MHz, CDCl3) δ 8.43-8.39 (m, 2H), 7.84-7.78 (m, 2H), 7.71-7.66 (m, 2H), 6.81-6.78 (m, 2H), 4.14-4.07 (m, 2H), 3.92-3.86 (m, 2H), 3.85-3.79 (m, 2H), 3.77-3.70 (m, 2H), 3.67 (s, 4H) ppm.

[0155] Step 3. 2-(2-(2-(pyridin-4-yloxy)ethoxy)ethoxy)ethan-1-amine Hydrazine monohydrate (0.12 mL, 3.72 mmol) was added to a solution of 2-(2-(2-(2-(pyridin-4-yloxy)ethoxy)ethoxy)ethyl)isoindoline-1,3-dione (664 mg, 1.86 mmol) in ethanol (20 mL) at room temperature under nitrogen, then the mixture was heated to reflux and stirred for 1.5 h. The mixture was cooled to room temperature and filtered under reduced pressure to remove a solid by-product. The filtrate's solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with methanol / dichloromethane (0:100→100:0 gradient) to give 2-(2-(2-(pyridin-4-oxy)ethoxy)ethoxy)ethan-1-amine (174 mg, 41%) as a colorless oil. 1 H NMR (300 MHz, CDCl3) δ 8.34-8.32 (m, 2H), 7.01-6.99 (m, 2H), 4.25-4.22 (m, 2H), 3.88-3.85 (m, 2H), 3.72-3.69 (m, 2H), 3.65-3.61 (m, 2H), 3.51 (t, J = 5.1 Hz, 2H), 2.78 (t, J = 5.4 Hz, 2H) ppm.

[0156] Preparation of 2-(2-(2-fluoroethoxy)ethoxy)ethan-1-amine [ka]

[0157] Step 1. 2-(2-(2-chloroethoxy)ethoxy)ethyl methanesulfonate Methanesulfonyl chloride (1.84 mL, 23.72 mmol) was added slowly dropwise to a solution of 2-(2-(2-chloroethoxy)ethoxy)ethan-1-ol (1.72 mL, 11.86 mmol) and triethylamine (4.93 mL, 35.58 mmol) in anhydrous dichloromethane under nitrogen at 0° C. (ice / water bath), then the mixture was allowed to warm slowly to room temperature and stirred for a total of 3.5 hours. The mixture was diluted with water (100 mL) and the organic layer was collected, washed with saturated aqueous sodium chloride solution (2×100 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to give 2-(2-(2-chloroethoxy)ethoxy)ethyl methanesulfonate (2.92 g, >99%) as a colorless oil. 1 H NMR (300 MHz, CDCl3) δ 4.40-4.37 (m, 2H), 3.80-3.73 (m, 4H), 3.68 (s, 4H), 3.65-3.61 (m, 2H), 3.08 (s, 3H) ppm.

[0158] Step 2. 1-Chloro-2-(2-(2-fluoroethoxy)ethoxy)ethane Tetrabutylammonium fluoride (23.72 mL, 23.72 mmol, 1.0 M in THF) was added to a solution of 2 (2.92 g, 11.86 mmol) in anhydrous THF (1.0 mL) at room temperature under nitrogen, then the mixture was heated to 60° C. and stirred for 18 h. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (25 mL), washed with water (2×100 mL) and saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give 1-chloro-2-(2-(2-fluoroethoxy)ethoxy)ethane (1.44 g, 72%) as an amber oil. 1 H NMR (300 MHz, CDCl3) δ 4.66-4.47 (m, 2H), 3.88-3.79 (m, 2H), 3.77-3.74 (m, 2H), 3.72-3.70 (m, 4H), 3.67-3.62 (m, 2H) ppm.

[0159] Step 3. 2-(2-(2-(2-fluoroethoxy)ethoxy)ethyl)isoindoline-1,3-dione Potassium phthalimide (1.71 g, 9.26 mmol) was added to a solution of 1-chloro-2-(2-(2-fluoroethoxy)ethoxy)ethane (1.44 g, 8.41 mmol) in anhydrous DMF (10.4 mL) at room temperature under nitrogen, then the mixture was heated to 100° C. and stirred for 18 h. The mixture was cooled to room temperature and the solid was removed by filtration under reduced pressure. The filtrate's solvent was removed under reduced pressure and the residue was diluted with water (100 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to give 2-(2-(2-(2-fluoroethoxy)ethoxy)ethyl)isoindoline-1,3-dione (441 mg, 19%) as an amber oil. 1 H NMR (300MHz,CDCl3) δ 7.87-7.82 (m, 2H), 7.75-7.67 (m, 2H), 4.58-4.39 (m, 2H), 3.93-3.86 (m, 2H), 3.77-3.72 (m, 2H), 3.70-3.62 (m, 6H) ppm.

[0160] Step 4. 2-(2-(2-fluoroethoxy)ethoxy)ethan-1-amine Hydrazine monohydrate (0.10 mL, 3.14 mmol) was added to a solution of 2-(2-(2-(2-fluoroethoxy)ethoxy)ethyl)isoindoline-1,3-dione (441 mg, 1.57 mmol) in ethanol (14 mL) at room temperature under nitrogen, then the mixture was heated to reflux and stirred for 1 h. The mixture was cooled to room temperature and filtered under reduced pressure to remove a solid by-product. The filtrate's solvent was removed under reduced pressure to give 2-(2-(2-fluoroethoxy)ethoxy)ethan-1-amine (146 mg, 62%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ (300 MHz, CDCl3) δ 4.67-4.48 (m, 2H), 3.72-3.63 (m, 6H), 3.52 (t, J = 5.1 Hz, 2H), 2.88 (t, J = 5.2 Hz, 2H) ppm.

[0161] Preparation of 2-(2-(3,3-difluoroazetidin-1-yl)ethoxy)ethan-1-amine [ka]

[0162] Step 1. 2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethyl methanesulfonate Triethylamine (0.44 mL, 3.18 mmol) and methanesulfonyl chloride (0.17 mL, 2.22 mmol) were added to a solution of 2-(2-(2-hydroxyethoxy)ethyl)isoindoline-1,3-dione (0.50 g, 2.12 mmol) in anhydrous THF (20 mL) at 0° C. (ice / water bath) under nitrogen, and the mixture was then stirred at 0° C. for 2 h. The mixture was diluted with water (75 mL), warmed to room temperature, and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (2×50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure to give 2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethyl methanesulfonate (0.61 g, 91%) as an off-white solid. 1 H NMR (300 MHz, CDCl3) δ 7.88-7.82 (m, 2H), 7.77-7.69 (m, 2H), 4.34-4.28 (m, 2H), 3.91 (t, J = 5.5 Hz, 2H), 3.79-3.70 (m, 4H), 3.00 (s, 3H)ppm.

[0163] Step 2. 2-(2-(2-(3,3-difluoroazetidin-1-yl)ethoxy)ethyl)isoindoline-1,3-dione 3,3-Difluoroazetidine hydrochloride (0.13 g, 1.02 mmol) and potassium carbonate (0.42 g, 3.06 mmol) were added to a solution of 2-(2-(1,3-dioxoindolin-2-yl)ethoxy)ethyl methanesulfonate (0.30 g, 0.50 mmol) in anhydrous acetonitrile (3.5 mL) in a sealed reaction vessel at room temperature under nitrogen, the vessel was then sealed and the mixture was heated to 80° C. and stirred for 18 hours. The mixture was cooled to room temperature and the solids were removed by filtration under reduced pressure. The filtrate's solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with ethyl acetate / heptane (0:100→50:50 gradient) to give 2-(2-(2-(3,3-difluoroazetidin-1-yl)ethoxy)ethyl)isoindoline-1,3-dione (194 mg, 73%) as a white solid. ESI MS m / z 311 [M+H] + .

[0164] Step 3. 2-(2-(pyridin-4-yloxy)ethoxy)ethan-1-amine Hydrazine monohydrate (61 μL, 1.05 mmol) was added to a solution of 2-(2-(2-(3,3-difluoroazetidin-1-yl)ethoxy)ethyl)isoindoline-1,3-dione (194 mg, 0.63 mmol) in ethanol (6 mL) at room temperature under nitrogen, then the mixture was heated to reflux and stirred for 5 h. The mixture was cooled to room temperature and filtered under reduced pressure to remove a solid by-product. The filtrate's solvent was removed under reduced pressure to give 2-(2-(pyridin-4-yloxy)ethoxy)ethan-1-amine (111 mg, 98%) as an off-white semi-solid. 1 H NMR (300 MHz, CDCl3) δ 3.68 (t, J = 12.1 Hz, 4H), 3.55-3.48 (m, 4H), 3.26 (br s, 2H), 2.97-2.90 (m, 2H), 2.82-2.76 (m, 2H) ppm;ESI MS m / z 181 [M+H] + .

[0165] Preparation of N-(2-(2-aminoethoxy)ethyl)-2,2,2-trifluoro-N-methylethan-1-amine [ka]

[0166] Step 1. 2-(2-(2-(methyl(2,2,2-trifluoroethyl)amino)ethoxy)ethyl)isoindoline-1,3-dione N-Methyl N-trifluoroethylamine (0.50 g, 4.42 mmol) was added to a solution of 2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethyl methanesulfonate (0.28 g, 0.88 mmol) in anhydrous DMF (5.0 mL) in a sealed reaction vessel at room temperature under nitrogen, after which the vessel was sealed and the mixture was heated to 80° C. and stirred for 96 h. The mixture was cooled to room temperature, diluted with water (25 mL) and extracted with ethyl acetate (3×40 mL). The combined organic extracts were washed successively with 10% aqueous lithium chloride solution (2×30 mL) and saturated aqueous sodium chloride solution (2×30 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate / heptane (0:100 to 50:50 gradient) to give 2-(2-(2-(methyl(2,2,2-trifluoroethyl)amino)ethoxy)ethyl)isoindoline-1,3-dione (174 mg, 59%) as a colorless oil. 1 H NMR (300 MHz, CDCl3) δ 7.88-7.81 (m, 2H), 7.75-7.68 (m, 2H), 3.92 (t, J = 5.6 Hz, 2H), 3.68 (t, J = 5.6 Hz, Hz, 2H), 3.58 (t, J = 5.4 Hz, 2H), 3.04 (q, J = 9.6 Hz, 2H), 2.75 (t, J = 5.4 Hz, 2H), 2.42 (s, 3H) ppm.

[0167] Step 2. N-(2-(2-aminoethoxy)ethyl)-2,2,2-trifluoro-N-methylethan-1-amine Hydrazine monohydrate (50 μL, 1.05 mmol) was added to a solution of 2-(2-(2-(methyl(2,2,2-trifluoroethyl)amino)ethoxy)ethyl)isoindoline-1,3-dione (174 mg, 0.53 mmol) in ethanol (5 mL) at room temperature under nitrogen, then the mixture was heated to reflux and stirred for 4 h. The mixture was cooled to room temperature and filtered under reduced pressure to remove a solid by-product. The filtrate's solvent was removed under reduced pressure to give N-(2-(2-aminoethoxy)ethyl)-2,2,2-trifluoro-N-methylethan-1-amine (97 mg, 92%) as an off-white semi-solid. 1 H NMR (300 MHz, CDCl3) δ 3.62-3.55 (m, 2H), 3.47 (t, J = 5.2 Hz, 2H),3.12 (q, J = 9.6 Hz, 2H), 2.86 (t, J = 5.3 Hz, 2H), 2.83-2.65 (m, 2H), 2.50 (s, 3H) ppm.

[0168] Preparation of 4-(pyridin-4-ylmethoxy)but-2-yn-1-amine ditosylate [ka]

[0169] Step 1. 4-((prop-2-yn-1-yloxy)methyl)pyridine Sodium hydride (1.47 g, 36.6 mmol, 60% suspension in mineral oil) was added in portions to a solution of 4-pyridinemethanol (2.00 g, 18.3 mmol) in anhydrous THF (200 mL) at 0 °C (ice / water bath) under nitrogen, then the mixture was stirred at 0 °C for 30 min. Propargyl bromide (4.0 mL, 36.6 mmol) was added dropwise, then the mixture was allowed to slowly warm to room temperature and stirred for a total of 23 h. The mixture was diluted with saturated aqueous ammonium chloride solution (5 mL), then water (300 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with methanol / dichloromethane (gradient of 0:100 to 10:90) to give 4-((prop-2-yn-1-yloxy)methyl)pyridine (1.89 g, 72%) as an orange oil. 1 H NMR (300 MHz, CDCl3) δ 8.58-8.56 (m, 2H), 7.29-7.27 (m, 2H), 4.63 (s, 2H), 4.24 (d, J = 2.4 Hz, 2H), 2.51 (t, J = 2.3 Hz, 1H) ppm.

[0170] Step 2. 4-(pyridin-4-ylmethoxy)but-2-yn-1-ol n-Butyllithium (6.16 mL, 15.4 mmol, 2.5 M solution in hexanes) was added dropwise to a solution of 4-((prop-2-yn-1-yloxy)methyl)pyridine (1.89 g, 12.8 mmol) in anhydrous THF (27.8 mL) under nitrogen at -78°C, then the mixture was stirred at -78°C for 1 h and then warmed to 0°C (ice / water bath). Paraformaldehyde (0.91 g) was added in one portion, then the mixture was allowed to warm slowly to room temperature and stirred for a total of 12 h. The reaction was quenched with saturated aqueous ammonium chloride solution (5 mL), followed by water (200 mL) and extracted with ethyl acetate (3 x 70 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with methanol / dichloromethane (gradient of 0:100 to 10:90) to give 4-(pyridin-4-ylmethoxy)but-2-yn-1-ol (0.99 g, 44%) as an opaque oil. 1 H NMR (300MHz, CDCl3) 8.48-8.46 (m, 2H), 7.27-7.24 (m, 2H), 4.54 (s, 2H), 4.18-4.16 (m, 4H) ppm.

[0171] Step 3. 2-(4-(pyridin-4-ylmethoxy)but-2-yn-1-yl)isoindoline-1,3-dione Tri-n-butylphosphine (1.67 mL, 6.70 mmol) was added dropwise to a solution of 1,1'-(azodicarbonyl)dipiperidine (1.55 g, 6.14 mmol), phthalimide (0.90 g, 6.14 mmol) and 4-(pyridin-4-ylmethoxy)but-2-yn-1-ol (0.99 g, 5.58 mmol) in anhydrous THF (27.9 mL) at 0° C. (ice / water bath) under nitrogen, after which the mixture was allowed to warm slowly to room temperature and stirred for a total of 18 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×70 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate / dichloromethane (gradient 0:100 to 60:40) to give 2-(4-(pyridin-4-ylmethoxy)but-2-yn-1-yl)isoindoline-1,3-dione (920 mg, 54%) as an off-white solid. 1 H NMR (300 MHz, CDCl3) δ 8.54 (d, J = 5.7 Hz, 2H), 7.89-7.87 (m, 2H), 7.76-7.73 (m, 2H), 7.25 (d, J = 5.9 Hz, 2H), 4.58 (s, 2H), 4.51 (t, J = 1.8 Hz, 2H), 4.22 (t, J = 1.8 Hz, 2H) ppm.

[0172] Step 4. 4-(Pyridin-4-ylmethoxy)but-2-yn-1-amine ditosylate Hydrazine monohydrate (0.09 mL, 2.93 mmol) was added to a solution of 2-(4-(pyridin-4-ylmethoxy)but-2-yn-1-yl)isoindoline-1,3-dione (448 mg, 1.46 mmol) in ethanol (13 mL) at room temperature under nitrogen, then the mixture was heated to reflux and stirred for 1 h. The mixture was cooled to room temperature and filtered under reduced pressure to remove a solid by-product. The filtrate was treated with p-toluenesulfonic acid (505 mg, 2.93 mmol) and the solvent was removed under reduced pressure to give 4-(pyridin-4-ylmethoxy)but-2-yn-1-amine ditosylate (809 mg, >99%) as an off-white solid. 1 H NMR (300 MHz, CDCl3) δ 8.56-8.54 (m, 2H), 7.49-7.46 (m, 4H), 7.33-7.31 (m, 2H), 7.13-7.10 (m, 4H), 4.60 (s, 2H), 4.33 (t, J = 1.8 Hz, 2H), 3.84 (t, J = 1.8 Hz, 2H), 2.51-2.46 (m, 2H), 2.28 (s, 6H) ppm.

[0173] Preparation of 4-((4-(2-morpholinoethyl)benzyl)oxy)but-2-yn-1-amine [ka]

[0174] Step 1. Methyl 4-(2-morpholino-2-oxoethyl)benzoate Propanephosphonic anhydride (26.1 mL, 43.8 mmol, 50 wt % in ethyl acetate) was added dropwise via addition funnel to a solution of morpholine (3.38 mL, 38.6 mmol), triethylamine (10.7 mL, 77.1 mmol) and 2-(4-(methoxycarbonyl)phenyl)acetic acid (5.00 g, 25.7 mmol) in anhydrous dichloromethane (122.3 mL) at 0° C. (ice / water bath) under nitrogen, then the mixture was allowed to warm slowly to room temperature and stirred for a total of 18 hours. The reaction was diluted with water (200 mL) and extracted with dichloromethane (3×100 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (200 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give methyl 4-(2-morpholino-2-oxoethyl)benzoate (6.75 g, >99%) as an off-white solid. 1 H NMR (300 MHz, CDCl3) δ 8.02-7.98 (m, 2H), 7.33-7.31 (m, 2H), 3.91 (s, 3H), 3.78 (s, 2H), 3.65 (s, 4H), 3.52-3.49 (m, 2H), 3.44-3.41 (m, 2H) ppm.

[0175] Step 2. (4-(2-morpholinoethyl)phenyl)methanol A solution of methyl 4-(2-morpholino-2-oxoethyl)benzoate (3.00 g, 11.40 mmol) in anhydrous THF (45.6 mL) was added dropwise via addition funnel to a solution of lithium aluminum hydride (17 mL, 34.10 mmol, 2.0 M in THF) in anhydrous THF (25 mL) at 0° C. (ice / water bath) under nitrogen, after which the mixture was allowed to warm slowly to room temperature and stirred for a total of 18 hours. The reaction was quenched with 2N sodium hydroxide solution (0.5 mL) and the resulting solid was removed by filtration under reduced pressure. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give (4-(2-morpholinoethyl)phenyl)methanol (2.81 g, >99%) as an off-white solid. 1 H NMR (300 MHz, CDCl3) δ 7.28 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 4.63 (s, 2H), 3.71 (t, J = 4.6 Hz, 4H), 2.80-2.74 (m, 2H), 2.58-2.47 (m, 6H) ppm.

[0176] Step 3. 4-(4-(chloromethyl)phenethyl)morpholine Thionyl chloride (0.72 mL, 9.80 mmol) was added to a solution of (4-(2-morpholinoethyl)phenyl)methanol (1.81 g, 8.17 mmol) in anhydrous dichloromethane (22.7 mL) at room temperature under nitrogen and the mixture was stirred for 40 min. The solvent was removed under reduced pressure to give 4-(4-(chloromethyl)phenethyl)morpholine (2.25 g, >99%) as a pale amber oil. 1 H NMR (300 MHz, CDCl3) δ 7.39-7.25 (m, 4H), 4.56 (s, 2H), 4.35-4.27 (m, 2H), 4.02-3.97 (m, 2H), 3.51 (d, J = 11.8 Hz, 2H), 3.33-3.15 (m, 4H), 2.98-2.85 (m, 2H) ppm.

[0177] Step 4. 4-((4-(2-morpholinoethyl)benzyl)oxy)but-2-yn-1-ol Potassium hydroxide (1.16 g, 20.66 mmol) was added to a solution of 1,4-butyndiol (3.20 g, 18.78 mmol) in anhydrous DMSO (10 mL) at room temperature under nitrogen and the mixture was stirred for 15 minutes. A solution of 4-(4-(chloromethyl)phenethyl)morpholine (2.25 g, 9.39 mmol) in anhydrous DMSO (15.3 mL) was added and the resulting mixture was stirred at room temperature for 5.5 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with methanol / dichloromethane (gradient of 0:100 to 10:90) to give 4-((4-(2-morpholinoethyl)benzyl)oxy)but-2-yn-1-ol (1.74 g, 63%) as a colorless oil. 1 H NMR (300 MHz, CDCl3) δ 7.28-7.26 (m, 2H), 7.20-7.17 (m, 2H), 4.55 (m, 2H), 4.32--4.31 (m, 2H), 4.20-4.19 (m, 2H), 3.74 (t, J = 4.6 Hz, 4H), 2.83-2.78 (m, 2H), 2.61-2.51 (m, 6H) ppm.

[0178] Step 5. 2-(4-((4-(2-morpholinoethyl)benzyl)oxy)but-2-yn-1-yl)isoindoline-1,3-dione Tri-n-butylphosphine (1.62 mL, 6.48 mmol) was added dropwise to a solution of 1,1'-(azodicarbonyl)dipiperidine (1.50 g, 5.94 mmol), phthalimide (0.87 g, 5.94 mmol) and 4-((4-(2-morpholinoethyl)benzyl)oxy)but-2-yn-1-ol (1.56 g, 5.40 mmol) in anhydrous THF (49.1 mL) at 0°C (ice / water bath) under nitrogen, after which the mixture was allowed to warm slowly to room temperature and stirred for a total of 18 hours. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with methanol / dichloromethane (gradient of 0:100 to 10:90) to give 2-(4-((4-(2-morpholinoethyl)benzyl)oxy)but-2-yn-1-yl)isoindoline-1,3-dione (2.79 g, >99%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.90-7.87(m,2H), 7.76-7.73 (m, 2H), 7.28-7.24 (m, 2H), 7.17-7.15 (m, 2H), 4.52-4.51 (m, 4H), 4.14-4.12 (m, 2H), 3.75-3.72 (m, 4H), 2.81-2.75 (m, 2H), 2.59-2.50 (m, 6H) ppm.

[0179] Step 6. 4-((4-(2-morpholinoethyl)benzyl)oxy)but-2-yn-1-amine Hydrazine monohydrate (0.43 mL, 13.34 mmol) was added to a solution of 2-(4-((4-(2-morpholinoethyl)benzyl)oxy)but-2-yn-1-yl)isoindoline-1,3-dione (2.79 g, 6.68 mmol) in ethanol (13 mL) at room temperature under nitrogen, then the mixture was heated to reflux and stirred for 1 h. The mixture was cooled to room temperature and filtered under reduced pressure to remove a solid by-product. The filtrate's solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with methanol / dichloromethane (10:90→30:70 gradient) to give 4-((4-(2-morpholinoethyl)benzyl)oxy)but-2-yn-1-amine (1.01 g, 53%) as a colorless oil. 1 H NMR (300 MHz, CDCl3) δ 7.29-7.26 (m, 2H), 7.20-7.17 (m, 2H), 4.55 (s, 2H), 4.16 (t, J = 1.8 Hz, 2H), 3.74 (t, J = 4.5 Hz, 4H), 3.48 (t, J = 1.8 Hz, 2H), 2.82-2.77 (m, 2H), 2.60-2.50 (m, 6H) ppm.

[0180] The following compounds were prepared following similar methods and procedures as described above for compound 1 (synthetic route 1 or synthetic route 2) using intermediate amines as starting materials. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5]

Table 6-6

Table 6-7

Table 6-8

Table 6-9

Table 6-10

Table 6-11

Table 6-12

Table 6-13

Table 6-14

Table 6-15

Table 6-16

Table 6-17

Table 6-18

Table 6-19

[0181] Example 2-12 / 15 - Biological Activity of Exemplary Compounds as Inhibitors of LOX [Table 7]

[0182] Example 2A - Analytical Data for the Compound of Example 2 [Table 8]

[0183] Example 3 - Solubility of exemplified compounds in water [Table 9]

[0184] The combination of Solutol HS-15 (also known as Kolliphor HS-15) and PEG400 provided a good medium for solubilizing the test compounds. Specifically, 10% Solutol / 90% PEG400 was used to prepare 20 mg / ml solutions of Compound 1, Compound 44, and Compound 32. 10% Solutol / 15% H2O / 90% PEG400 resulted in a 10 mg / ml solution of the test compounds.

[0185] Example 4 - Metabolic stability of exemplified compounds [Table 10]

[0186] Example 5 - Biological activity of exemplary compounds as prodrugs Compound 51 exhibited high aqueous solubility and was susceptible to hydrolysis in plasma relative to parent compound 22. Compound 52 surprisingly demonstrated activity against human 12 / 15-LOX in vitro, with an IC 50 = 1.4 μM. Compound 52 exhibits high solubility in Captisol, achieving 27 mg / ml in a 50% Captisol solution. 20 mg / ml was obtained in 20% Captisol, allowing intravenous delivery in a mouse stroke model. In vivo, compound 52 is processed to the parent molecule, compound 1 (see FIG. 1).

[0187] Example 6 - Evaluation of exemplary compounds in animal models of stroke Tests were performed using the filament model of middle cerebral artery infarction (MCAO) in an experimental model of stroke in mice. For intraperitoneal delivery, compounds were dissolved in DMSO. Many exemplified compounds were able to reduce infarct size when given at a dose of 40 mg / kg. The results are shown in Figures 2-6.

[0188] Example 7 - Summary of in vitro results for Compound 1 Human 12 / 15-LOX = 0.12 μM (94% max). Human 12 / 15-LOX E. coli IC 50 =0.11μΜ(88% max) Mouse 12 / 15-LOX E. coli IC 50 =0.18μΜ(82% max) Human 12 / 15-LOX HEK EC 50 =0.92μM Mouse HT22 EC 50 = 5.0 μM Rat primary neuron EC 50 = 9.5 μM 12-LOX, 15-LOX2, 5-LOX, COX-1 and COX-2 >400 fold

[0189] Example 8 - Mouse Stroke Model Compound 1 was administered intraperitoneally at 40 mg / kg at the time of reperfusion. Infarct size was measured 24 hours after 60 min of MCAO. A 33.4% reduction in infarct size was observed in male mice (n=9 / 9), whereas a 37.2% reduction in infarct size was observed in female mice (n=10 / 10).

[0190] When compound 1 was administered intravenously 2 hours after reperfusion, a 34.1% reduction in infarct size was observed when the compound was administered at 40 mg / kg (n=10 / 11, p<0.01, see FIG. 5B), and a 25.8% reduction in infarct size was observed when the compound was administered at 20 mg / kg (n=17 / 18, p<0.01, see FIG. 7).

[0191] Long-term outcome studies: Compound 1 was delivered at 40 mg / kg 2 hours after reperfusion, as in short-term, compared to vehicle (10% solution / 90% PEG400). 45 mice were operated on, 27 survived, and the mice were sacrificed after 30 days. Behavioral tests included Garcia score (23.8% after 3 days, 68.5% after 4 weeks, see FIG. 8A), corner test (68.7% after 1 week, 75.4% after 4 weeks, see FIG. 8B), foot-fault test (61.7% after 1 week, 77.0% after 4 weeks, see FIG. 8C), grid-walk test, adhesive removal test (65.6% after 1 week, 93.3% after 4 weeks, see FIG. 8D), and Y-maze (% alternations, not significant, see FIG. 8E; number of entries, not different between treatment groups, see FIG. 8F).

[0192] MCAO (experimental middle cerebral artery ischemia and functional recovery) experiments: 40 mg / kg of compound was delivered intraperitoneally 2 hours after reperfusion, MCAO was performed for 60 minutes, and the animals were sacrificed at 24 hours, and infarct size was measured by TTC staining. [Table 11]

[0193] Additional Experiments The effect of exemplary compounds (e.g., inhibitors of 12 / 15-LOX as described herein) on the treatment of brain injury following subarachnoid hemorrhage can be evaluated, for example, in a mouse model as described in Gaberel et al, Stroke, 2019, 50, 520-523, which is incorporated herein by reference in its entirety. Subarachnoid hemorrhage (SAH) is a devastating stroke. This can lead to substantial brain damage. Mouse models for studying the effects of 12 / 15-LOX inhibitors on subarachnoid hemorrhage include C57Bl6 wild-type mice and Alox15 knockout mice. These mice are subjected to SAH using a direct blood injection technique. In the SAH wild-type mice, half received a 12 / 15-LOX inhibitor within the scope of the present claims and half received a vehicle. Immunohistochemistry, brain edema, blood-brain barrier leakage, and functional outcomes were evaluated 1 and 3 days after SAH induction. Generally, SAH leads to the elevation of 12 / 15-LOX in macrophages of brain parenchyma adjacent to subarachnoid blood.The death of neuronal cells after SAH is reduced in Alox15 knockout mice and wild-type models treated with exemplary compounds (e.g., compound 1 herein), and has improved efficacy compared to ML351, a 12 / 15-LOX inhibitor compound. [ka]

[0194] Moreover, inhibitor treatment at SAH in Alox15 gene knockout and wild-type mice led to improved behavioral outcomes.

[0195] Animals and study design All animal studies were performed according to protocols approved by the Massachusetts General Hospital Institutional Animal Care and Use Committee in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Both surgeons performing the surgery and investigators evaluating the data were blinded to the treatment groups, except for the functional evaluation of ALOX15 knockout mice. Reporting on this study complies with the ARRIVE guidelines. Experiments were performed in 10-week-old male ALOX15 knockout mice (n = 11, 20-28 g, landrace; C57B16 genetic background) and age-matched C57B16 wild-type mice (n = 80; 20-28 g; Jackson laboratory, Bar Harbor, Maine). Sample size was assessed as follows: based on previous experience, a coefficient of variation between mice of approximately 35% is expected. Power analysis with α = 0.05, β = 0.8 suggests that for an effect size of about 40-50% (which can typically predict the success of a neuroprotective agent), the minimum n-number required for comparison of functional tests is 16, and for brain water content and blood-brain barrier permeability tests it is approximately 8. Here, except for ALOX15 knockout mice, the number of animals per group was increased slightly due to their low availability to 20 animals. For all surgical procedures, mice were anesthetized with isoflurane (2%) in 70% / 30% NO2 / O2. Body temperature was maintained at 37 °C using a rectal temperature probe and a household heating pad.

[0196] Induction of subarachnoid hemorrhage Subarachnoid hemorrhage (SAH) was induced by injection of fresh arterial blood into the anterior optic cistern. Mice were placed in a stereotaxic frame. A hole was drilled in the skull 4.5 mm anterior to the bregma, avoiding the superior sagittal sinus. A 30-gauge needle was advanced 5 mm at a 40° angle until it touched the base of the skull. The needle was withdrawn 0.5–1 mm so that the needle tip was in the anterior optic cistern. Arterial blood was collected from the left ventricle of another anesthetized mouse using a 25-gauge needle. 100 μL of blood was manually injected with a 30-gauge needle for 15 seconds. For sham-operated animals, the needle was inserted into the anterior optic cistern and no injection was performed. For all animals, the needle was removed and the wound was closed. The animals were then allowed to recover. All mice were included in the final analysis.

[0197] Drug administration Five minutes after SAH induction, mice were given a single intraperitoneal injection with a 30-gauge needle (120 μL) of DMSO (vehicle) or test compound (e.g., ML-351) dissolved in DMSO (test compound such as ML-351 at a concentration of 12.5 mg / kg, administered at a dose of 50 mg / kg). The dose was selected by studying focal ischemia in mice. The animals were then allowed to recover. Injections were administered by a physician blinded to the treatment group, and mice were assigned to treatment groups using a predefined randomization list.

[0198] Behavioral experiments All mice, except those used for IHC 24 hours after SAH induction, were evaluated at 72 hours by assessing spontaneous activity using a 4-point neuroscore scale and an 18-point neuroscore scale. The 4-point neuroscore scale was defined as 0 = no apparent deficit; 1 = slight deficit; 2 = circling; 3 = vigorous circling or no locomotion at all; or 4 = death. The 18-point neuroscore scale assessed six parameters, each scored from 0 to 3.5. Spontaneous locomotor activity was assessed by counting horizontal movements. An open-field Plexiglas chamber was used, with four lines drawn to delineate nine fields. Mice were placed in the chamber for 5 minutes to acclimate. Videos were then recorded for 5 minutes. Videos were then analyzed by an investigator blinded to the treatment groups. The investigator manually counted the number of fields explored by the mice during the 5-minute period.

[0199] Other embodiments Although the present application has been described in connection with a detailed description thereof, it is understood that the above description is intended to illustrate, but not limit, the scope of the application, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. Compounds of formula (I) 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein: X 1 is selected from O and S; R 1 , R 2 , and R 3 each independently represents halo, CN, C 1 ~ 3 Alkyl, C 1 ~ 3 Haloalkyl, C 1 ~ 3 Alkoxy, and C 1 ~ 3 haloalkoxy; R 4 But H, C 1 ~ 3 Alkyl, and HO—C 1 ~ 3 alkylene; R 5 But C 1 ~ 6 Alkyl, C 2 ~ 6 Alkenyl, C 2 ~ 6 Alkynyl, C(O)OR a1 , C(O)N(R a1 ) 2 , P(=O)(OR a1 ) 2 , and C(O)R b1 and C is selected from 1 ~ 6 Alkyl, C 2 ~ 6 Alkenyl, and C 2 ~ 6 Each alkynyl is OR a1 and OP(=O)(OR a1 ) 2 optionally substituted with a substituent selected from Each R a1 are independent, H, C 1 ~ 6 Alkyl, C 6 ~ 10 Aryl, C 1 ~ 6 Alkyl-C 6 ~ 10 Aryl, and C 1 ~ 6 Alkyl-C 6 ~ 10 Aryl-C 1 ~ 6 alkyl, wherein C 1 ~ 6 Alkyl, C 6 ~ 10 Aryl, C 1 ~ 6 Alkyl-C 6 ~ 10 Aryl, and C 1 ~ 6 Alkyl-C 6 ~ 10 Aryl-C 16 Each of the alkyl groups is selected from amino, C 1 ~ 6 alkylamino, (C 1 ~ 6 haloalkyl)amino, di(C 1 ~ 6 alkyl)amino, (C 1 ~ 6 alkyl) (C 1 ~ 6 haloalkyl)amino, (C 6 ~ 10 aryl)amino, (C 6 ~ 10 aryl) (C 1 ~ 6 alkyl)amino, (5- to 6-membered heteroaryl)amino, (5- to 6-membered heteroaryl)(C 1 ~ 6 alkyl)amino, C 6 ~ 10 Aryl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and OR a2 and wherein said C is optionally substituted with a substituent selected from 6 ~ 10 Aryl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each selected from amino, C 1 ~ 6 Alkylamino, di(C 1 ~ 6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl), amino, carboxy, and halo; Each R a2 are independent, H, C 1 ~ 3 Alkyl, C 1 ~ 3 Haloalkyl, C 1 ~ 3 Alkoxy-C 1 ~ 3 Alkyl, 4- to 7-membered heterocycloalkyl-C 1 ~ 3 Alkyl, 5- to 6-membered heteroaryloxy-C 1 ~ 3 Alkyl, C 6 ~ 10 aryl, and 5- to 6-membered heteroaryl, 6 ~ 10 aryl and 5- to 6-membered heteroaryl are each selected from halo, C 1 ~ 3 Alkoxy, C 1 ~ 3 Haloalkoxy, C 1 ~ 3 Alkyl, and C 1 ~ 3 optionally substituted with 1, 2, or 3 substituents independently selected from haloalkyl, and R b1 But Amino, C 1 ~ 6 Alkylamino, di(C 1 ~ 6 C optionally substituted with a substituent selected from: alkyl)amino, and a 4- to 7-membered heterocycloalkyl ring containing at least one N atom 1 ~ 6 The compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

2. The compound has the formula: 【Chemistry 2】 10. The compound of claim 1, wherein R is 1 or a pharmaceutically acceptable salt thereof.

3. The compound has the formula: 【Chemistry 3】 10. The compound of claim 1, wherein:

4. R 1 , R 2 , and R 3 The compound of claim 1 , wherein each is halo.

5. 2. The compound of claim 1 , R 2 and R 3 are each halos, and R 1 But C 1 ~ 3 Alkyl, C 1 ~ 3 Alkoxy, and C 1 ~ 3 The compound is selected from haloalkoxy.

6. 2. The compound of claim 1 , R 1 and R 3 are each halos, and R 2 But C 1 ~ 3 Alkyl, C 1 ~ 3 Alkoxy, and C 1 ~ 3 The compound is selected from haloalkyl.

7. 2. The compound of claim 1 , R 1 and R 2 are each halos, and R 3 But C 1 ~ 3 Alkyl, C 1 ~ 3 haloalkyl, and CN.

8. The compound has the formula: 【Chemistry 4】 10. The compound of claim 1, wherein R is 1 or a pharmaceutically acceptable salt thereof.

9. R 5 But C 1 ~ 3 The compound of claim 1 , wherein the aryl group is alkyl.

10. R 5 But OR a1 C optionally substituted with 2 ~ 6 The compound of claim 1 which is alkenyl.

11. R 5 But OR a1 C optionally substituted with 2 ~ 6 The compound of claim 1 which is alkynyl.

12. R 5 But OR a1 C optionally substituted with 1 ~ 6 The compound of claim 1, wherein the compound is alkyl.

13. R 5 OP(=O)(OR a1 ) 2 C optionally substituted with 1 ~ 6 The compound of claim 1 , wherein the aryl group is alkyl.

14. R a1 The compound of claim 1 , wherein is H.

15. R a1 But C 6 ~ 10 Aryl or OR a2 C optionally substituted with 1 ~ 6 The compound of claim 1 , wherein the aryl group is alkyl.

16. R 4 The compound of claim 1 , wherein is H.

17. R 5 But C(O)OR a1 2. The compound of claim 1, wherein:

18. R a1 But Amino, C 1 ~ 6 Alkylamino, and di(C 1 ~ 6 C optionally substituted with a substituent selected from: 1 ~ 6 18. The compound of claim 17, wherein the compound is alkyl.

19. R 5 But C(O)OR b1 2. The compound of claim 1, wherein:

20. 2. The compound of claim 1 , R 4 But H, C 1 ~ 3 Alkyl, and HO—C 1 ~ 3 alkylene, and R 5 But C 1 ~ 6 Alkyl, C 2 ~ 6 Alkenyl, and C 2 ~ 6 alkynyl, each of which is selected from OR a1 and OP(=O)(OR a1 ) 2 and Each R a1 are independently H and C 1 ~ 6 alkyl, wherein said C 1 ~ 6 The alkyl is C 6 ~ 10 Aryl and OR a2 The compound is optionally substituted with a substituent selected from:

21. 2. The compound of claim 1 , R 4 But C(O)OR a1 and C(O)R b1 is selected from R 5 But C 1 ~ 3 alkyl, and R a1 But Amino, C 1 ~ 6 Alkylamino, and di(C 1 ~ 6 C optionally substituted with a substituent selected from: 1 ~ 6 The compound is alkyl.

22. The compound of formula (I) is any one of the following compounds: 【Chemistry 5-1】 【Chemistry 5-2】 【Chemistry 5-3】 【Chemistry 5-4】 【Chemistry 5-5】 【Chemistry 5-6】 【Chemistry 5-7】 【Chemistry 5-8】 or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising the compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

24. 24. The pharmaceutical composition of claim 23, which is used to treat or prevent a disease or disorder in which 12 / 15-lipoxygenase (LOX) is involved in the pathology.

25. The disease or disorder may be stroke, diabetes, obesity, asthma, glomerulonephritis, osteoporosis, periventricular leukomalacia, resuscitation cardiac arrest, atherosclerosis, neurodegenerative or neuroinflammatory disorders (e.g., Parkinson's disease, Alzheimer's disease, or dementia), cancer, brain injury, diseases involving hypoxia or anoxia, myocardial infarction, cardiovascular disease, heart failure (e.g., chronic or congestive heart failure), ischemia (e.g., cerebral ischemia, retinal ischemia, myocardial ischemia, or postoperative cognitive dysfunction), inflammatory diseases (e.g., arterial inflammation, inflammatory bowel disease, Crohn's disease, kidney disease, asthma, allergic rhinitis, gout, cardiopulmonary inflammation, 25. The pharmaceutical composition of claim 24, wherein the therapeutic agent is selected from the group consisting of: rheumatoid arthritis, osteoarthritis, muscle fatigue, acne, dermatitis, or psoriasis), chronic bronchitis, mucus hypersecretion, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (including fibrosis caused by chemotherapy), idiopathic pulmonary fibrosis, cystic fibrosis, adult respiratory distress syndrome, central nervous system disorders, psychiatric disorders (e.g., anxiety or depression), peripheral neuropathy (e.g., spinal cord injury, head injury, or surgical trauma), graft rejection of allogeneic tissue or organ transplants, autoimmune disorders (e.g., eczema), and disorders involving bone loss or bone formation.

Images