Heteroaromatic and heterobicyclic aromatic derivatives for the treatment of ferroptosis-related disorders

Abstract

Heteroaromatic and heterobicyclic aromatic derivatives are provided for the treatment of ferroptosis-related disorders. This application discloses heteroaromatic and heterobicyclic aromatic derivative compounds and compositions, and methods for treating ferroptosis-related disorders and diseases in patients using the compounds and compositions disclosed herein. Described herein are compounds, compositions, and methods for treating lipid peroxidation-related degenerative diseases, excitotoxicity diseases, neurodegenerative diseases, non-apoptotic regulated cell death diseases, wasting or necrosis-related diseases, addiction-related diseases, and infectious diseases.

Description

[Technical Field]

[0001] Described herein are heteroaromatic and heterobicyclic aromatic compounds, compositions and methods of using them for the treatment of ferroptosis-associated disorders, including lipid peroxidation-associated degenerative diseases, excitotoxicity diseases, neurodegenerative diseases, non-apoptotic regulated cell death diseases, wasting or necrosis-associated diseases, poisoning-associated diseases, and infectious diseases. [Background technology]

[0002] Currently, there is no known prevention or cure for neurodegenerative diseases or disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). This application discloses compounds, compositions and methods for the treatment of such diseases or disorders. Summary of the Invention [Means for solving the problem]

[0003] Described herein are compounds, compositions and methods for the treatment of lipid peroxidation-related degenerative diseases, excitotoxicity diseases, neurodegenerative diseases, non-apoptotic regulated cell death diseases, wasting or necrosis-related diseases, addiction-related diseases, and infectious diseases.

[0004] Thus, as used herein, compounds of formula I [ka] [In the formula, R 1 is H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 1 and the N to which it is attached, taken together, form a substituted or unsubstituted C3-C6 heterocycloalkyl or heteroaryl ring (replacing the H attached to the N); R 2 and R 3 are independently H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 2 and R 3 together with the N to which they are attached form a substituted or unsubstituted C4-C6 heterocycloalkyl group; A is a bond, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 Aryl or heteroaryl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10selected from the group consisting of straight-chain or branched alkynyl, C═O, C═S, —CH—, —CH(OH)—, —NH—, —N(CH)—, —O—, —S—, and SO; R 4 is substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C1-C 10 Straight or branched alkoxy, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, substituted or unsubstituted C1-C 10 Linear or branched dialkylamino, substituted or unsubstituted C3-C 10 Cycloalkyl or heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 selected from the group consisting of heteroaryl, —CN and halo; X and Y are independently selected from the group consisting of -CH- and -N-. is described.

[0005] Also provided herein is a compound of formula II [ka] [In the formula, R 1 is H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C5-C 10 Heteroarylalkyl, substituted or unsubstituted C1-C 10Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 1 and the N to which it is attached, taken together, form a substituted or unsubstituted C3-C6 heterocycloalkyl or heteroaryl ring (replacing the H attached to the N); A is a bond, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 selected from the group consisting of straight-chain or branched alkynyl, C═O, C═S, —CH—, —CH(OH)—, —NH—, —N(CH)—, —O—, —S—, and SO; R 4 is substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C1-C 10 Straight or branched alkoxy, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, substituted or unsubstituted C1-C 10 Linear or branched dialkylamino, substituted or unsubstituted C3-C 10 Cycloalkyl or heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 selected from the group consisting of heteroaryl, —CN and halo; R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 5 and R 6 are combined to form =O, or R 7 and R 8 are combined to form =O, or R 9 and R 10 are combined to become =O, X and Y are independently selected from the group consisting of -CH- and -N-; Z is C=O, -CR 9 R 10 -, -NR 9 -, -O-, -S-, -S(O)- and -SO2-. is described.

[0006] Also described herein are pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I or II above, and a pharmaceutically acceptable excipient.

[0007] Further provided herein is a method of treating a ferroptosis-related disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula I [ka] [In the formula, R 1 is H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 1 and the N to which it is attached, taken together, form a substituted or unsubstituted C3-C6 heterocycloalkyl or heteroaryl ring (replacing the H attached to the N); R 2 and R 3 are independently H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 2 and R 3 together with the N to which they are attached form a substituted or unsubstituted C4-C6 heterocycloalkyl group; A is a bond, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 Aryl or heteroaryl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10selected from the group consisting of straight-chain or branched alkynyl, C═O, C═S, —CH—, —CH(OH)—, —NH—, —N(CH)—, —O—, —S—, and SO; R 4 is substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C1-C 10 Straight or branched alkoxy, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, substituted or unsubstituted C1-C 10 Linear or branched dialkylamino, substituted or unsubstituted C3-C 10 Cycloalkyl or heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 selected from the group consisting of heteroaryl, —CN and halo; X and Y are independently selected from the group consisting of -CH- and -N-. A method is described that includes administering

[0008] Still further provided herein is a method of treating a ferroptosis-related disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula II [ka] [In the formula, R 1 is H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C5-C10 Heteroarylalkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 1 and the N to which it is attached, taken together, form a substituted or unsubstituted C3-C6 heterocycloalkyl or heteroaryl ring (replacing the H attached to the N); A is a bond, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 selected from the group consisting of straight-chain or branched alkynyl, C═O, C═S, —CH—, —CH(OH)—, —NH—, —N(CH)—, —O—, —S—, and SO; R 4 is substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C1-C 10 Straight or branched alkoxy, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, substituted or unsubstituted C1-C 10 Linear or branched dialkylamino, substituted or unsubstituted C3-C 10 Cycloalkyl or heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 selected from the group consisting of heteroaryl, —CN and halo; R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 5 and R 6 are combined to form =O, or R 7 and R 8 are combined to form =O, or R 9 and R 10 are combined to become =O, X and Y are independently selected from the group consisting of -CH- and -N-; Z is C=O, -CR 9 R 10 -, -NR 9 -, -O-, -S-, -S(O)- and -SO2-. A method is described that includes administering

[0009] The ferroptosis-associated disease may be selected from the group consisting of lipid peroxidation-associated degenerative diseases, excitotoxicity diseases, neurodegenerative diseases, non-apoptotic regulated cell death diseases, wasting or necrosis-associated diseases, poisoning-associated diseases, and infectious diseases.

[0010] Ferroptosis-associated diseases also include atherosclerosis, ischemia-reperfusion, heart failure, Alzheimer's disease, rheumatoid arthritis, thalassemia, chronic obstructive pulmonary disease (COPD), age-related macular degeneration, aging, cancer, and immunological disorders, including, but not limited to, autoimmune diseases (e.g., diabetes mellitus, arthritis (including rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, and psoriatic arthritis), multiple sclerosis, encephalomyelitis, myasthenia gravis, systemic lupus erythematosus, and the like). tosus, autoimmune thyroiditis, dermatitis (including atopic dermatitis and eczematous dermatitis), psoriasis, Sjögren's syndrome, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, sepsis and septic shock, inflammatory bowel disorders, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, drug rash, leprosy reversal reaction, erythema nodosum leprosum, autoimmune uveitis, allergic encephalomyelitis, acute necrotizing hemorrhagic encephalopathy, idiopathic bilateral progressive Sensorineural hearing loss, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, polychondritis, Wegener's granulomatosis, chronic active hepatitis, Stevens-Johnson syndrome, glomerulonephritis, idiopathic sprue, lichen planus, Graves' disease, sarcoidosis, primary biliary cirrhosis, posterior uveitis, interstitial pulmonary fibrosis, graft-versus-host disease, transplant rejection, allergies, e.g., atopic allergy, epilepsy, kidney disease, stroke, myocardial infarction, congestive heart failure, type 1 diabetes, traumatic Brain injury (TBI), periventricular leukomalacia (PVL), Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, ataxia-telangiectasia, Rett syndrome, X-linked adrenoleukodystrophy, multiple sclerosis, Huntington's disease, transmissible spongiform encephalopathy, Charcot-Marie-Tooth disease, dementia with Lewy bodies, Menkes disease, Wilson's disease, Creutzfeldt-Jakob disease, Fahr's disease, frontotemporal dementia, amyloidosis, and Ty-Sachs diseasePeriventricular leukomalacia, corticobasal degeneration, progressive supranuclear palsy, hereditary spastic paraplegia, reduced cell proliferation, altered cell differentiation or intracellular signaling, unwanted inflammation, cell death of retinal neurons, cardiomyocytes or immune system cells, or cell death associated with renal failure, neonatal respiratory distress, respiratory arrest, incarcerated hernia, placental infarction, iron loading complications, endometriosis, congenital disease, head trauma / traumatic brain injury, liver injury, injury from environmental radiation, burns, cold injury, mechanical injury, decompression sickness, priapism, snake, scorpion or spider bite, UV damage to the skin, skin aging, hair loss, muscle wasting diseases, muscular dystrophy or related disorders (e.g., Becker muscular dystrophy) The disease may be selected from the group consisting of: Fi, Duchenne muscular dystrophy, myotonic dystrophy, limb-girdle muscular dystrophy, Landauzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy (Steinert disease), congenital myotonia, Thomsen's disease, and Pompe disease, ischemia, compartment syndrome, gangrene, pressure ulcers, sepsis, osteoarthritis, retinal necrosis, heart disease, liver, gastrointestinal or pancreatic necrotizing disease (e.g., acute necrotizing pancreatitis), avascular necrosis, diabetes, sickle cell disease, vascular alterations, cancer chemo / radiotherapy-induced cell death, and infectious diseases caused by infection with viruses, bacteria, fungi or other microorganisms. DETAILED DESCRIPTION OF THE INVENTION

[0011] Detailed Description definition Unless otherwise specifically indicated herein, the definitions of terms used are standard definitions used in the fields of organic chemistry and pharmacology. Exemplary embodiments, aspects, and variations are illustrated in the figures and drawings, and it is intended that the embodiments, aspects, and variations disclosed herein, as well as the figures and drawings, be considered illustrative and non-limiting.

[0012] While specific embodiments have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided for illustrative purposes only. Numerous variations, changes, and substitutions will now become apparent to those skilled in the art. It should be understood that various alternatives to the embodiments described herein can be used to practice the methods described herein. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patent documents and publications mentioned herein are incorporated by reference.

[0014] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0015] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein sufficient to perform the intended application, including, but not limited to, disease treatment as defined below. A therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and disease state to be treated, such as the subject's weight and age, the severity of the disease state, the mode of administration, etc., which can be readily determined by one skilled in the art. The term also applies to a dose that induces a specific response in target cells, such as reduced platelet adhesion and / or cell migration. Specific doses will vary depending on the particular compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which the compound is administered, and the physical delivery system in which the compound is carried.

[0016] The terms "treatment," "treating," "alleviating," and "alleviating" are used interchangeably herein. These terms refer to an approach to obtaining a beneficial or desired result, including, but not limited to, therapeutic benefit and / or preventative benefit. Therapeutic benefit refers to the eradication or alleviation of the underlying disorder being treated. Therapeutic benefit is also achieved in conjunction with the eradication or alleviation of one or more physiological symptoms associated with the underlying disorder, such that the patient observes improvement despite the patient still potentially suffering from the underlying disorder. For preventative benefit, the composition can be administered to a patient at risk of developing a particular disease or to a patient reporting one or more physiological symptoms of the disease, even if the disease has not yet been diagnosed.

[0017] A "therapeutic effect," as used herein, encompasses the aforementioned therapeutic and / or prophylactic benefits. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0018] The terms "co-administration," "administered in combination," and their grammatical equivalents, as used herein, encompass the administration of two or more agents to an animal such that both agents and / or their metabolites are present in the animal at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0019] "Pharmaceutically acceptable salt" refers to a salt composition that is generally considered to have the desired pharmacological activity, is considered safe and non-toxic, and is acceptable for application in animal and human medicine. Pharmaceutically acceptable salts can be derived from a variety of organic and inorganic counterions known in the art, including, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and, when the molecule contains a basic functional group, include salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0020] A "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions described herein is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0021] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds capable of inhibiting the biological function of a target protein by inhibiting the activity or expression of the target protein. Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. Antagonists herein generally specifically interact with (e.g., specifically bind to) the target, but compounds that inhibit the biological activity of a target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within the definition of "antagonist." Exemplary biological activities inhibited by antagonists are associated with the development, growth, or spread of tumors, or with undesired immune responses manifested in autoimmune diseases.

[0022] The term "agonist," as used herein, refers to a compound that has the ability to induce or enhance the biological function of a target protein by inhibiting the activity or expression of the target protein. Thus, the term "agonist" is defined in the context of the biological role of the target polypeptide. Agonists herein generally specifically interact (e.g., specifically bind) with the target, and specifically include compounds that induce or enhance the biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member.

[0023] As used herein, "drug" or "biologically active agent" refers to a biological, pharmaceutical, or chemical compound or other moiety. Non-limiting examples include simple or complex organic or inorganic molecules, peptides, proteins, oligonucleotides, antibodies, antibody derivatives, antibody fragments, vitamin derivatives, carbohydrates, toxins, or chemotherapeutic compounds. A variety of compounds, such as small molecules and oligomers (e.g., oligopeptides and oligonucleotides), as well as synthetic organic compounds based on various core structures, can be synthesized. In addition, various natural sources, such as plant or animal extracts, can provide compounds for screening. Those skilled in the art can easily recognize the limitations of the structural properties of the agents described herein.

[0024] "Signal transduction" is the process by which stimulatory or inhibitory signals are transmitted to or within a cell to induce an intracellular response. A modulator of a signal transduction pathway refers to a compound that modulates the activity of one or more cellular proteins that are mapped to the same specific signal transduction pathway. A modulator can increase (agonist) or suppress (antagonist) the activity of a signal transduction molecule.

[0025] The term "cell proliferation" refers to the phenomenon of a change in cell number as a result of division. The term also encompasses cell growth in which cell morphology changes (e.g., increases in size) in concert with proliferation signals.

[0026] The terms "selective inhibition" or "selectively inhibiting" as applied to a biologically active agent refer to the ability of the agent to selectively reduce target signaling activity relative to non-target signaling activity through direct or indirect interaction with the target.

[0027] "Subject" refers to an animal, e.g., a mammal, e.g., a human. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the patient is a mammal, and in some embodiments, the patient is human.

[0028] "Prodrug" is meant to refer to a compound that can be converted under physiological conditions or by solvolysis into a biologically active compound as described herein. Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. A prodrug may be inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference). Both are incorporated herein by reference in their entireties. The term "prodrug" is also meant to include any covalently bonded carrier that releases an active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of active compounds can be prepared by modifying functional groups present in the active compound, as described herein, in such a way that the modifications are cleaved, either routinely or in vivo, to yield the parent active compound. Prodrugs include compounds in which a hydroxy, amino, or mercapto group is bonded to any group that is cleaved to form a free hydroxy, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohols or acetamides, formamide and benzamide derivatives of amine functional groups in active compounds, and the like.

[0029] The term "in vivo" refers to an event that takes place inside a subject's body.

[0030] The term "in vitro" refers to an event that occurs outside of a subject's body. For example, an in vitro assay encompasses any assay that is performed outside of a subject's body. An in vitro assay encompasses cell-based assays in which live or dead cells are used. An in vitro assay also encompasses cell-free assays in which intact cells are not used.

[0031] As used herein, the term "lipid peroxidation-associated degenerative disease" refers to a degenerative disease, disorder or condition associated with the oxidative breakdown of fats, oils, waxes, sterols, triglycerides, and the like.

[0032] As used herein, the term "excitotoxic disease" refers to a disease, disorder, or condition associated with oxidative cell death and / or increased levels of intracellular reactive oxygen species (ROS), or a disease characterized by oxidative stress or in which oxidative stress is likely to play a substantial role or plays a substantial role.

[0033] As used herein, the term "neurodegenerative disease" refers to a disease, disorder or condition associated with degeneration of the central or peripheral nervous system.

[0034] As used herein, the term "non-apoptotic regulated cell death disease" refers to a disease, disorder or condition that is associated with non-apoptotic regulated cell death or in which non-apoptotic regulated cell death is likely to play or plays a substantial role.

[0035] As used herein, the term "wasting or necrosis associated disease" refers to a disease, disorder or condition associated with wasting or cell necrosis.

[0036] As used herein, the term "poisoning-related disease" refers to a disease, disorder, or condition associated with or characterized by intoxication of cells, tissues, organs, or organisms (e.g., nephrotoxicity), including those resulting from or associated with drug treatment, drug overdose, acute intoxication, or contrast-induced toxicity.

[0037] As used herein, the term "infectious disease" refers to a disease, disorder, or condition that is the result of, arises from, or is associated with a viral, bacterial, fungal, or other microbial form of infection.

[0038] Unless otherwise stated, structures depicted herein also include compounds which differ only in the presence of one or more isotopically enriched atoms, for example, one or more hydrogens are replaced by deuterium or tritium, or one or more carbons are replaced by 13 C- or 14It is intended to include compounds described herein that are substituted with heavier isotopes, particularly deuterium ( 2 Substitution with H or D) can confer certain therapeutic advantages resulting from greater metabolic stability, increased in vivo half-life, reduced dosage requirements, or improved therapeutic index. It is understood that deuterium, in this context, is considered a substituent of compounds of formula (I).

[0039] The compounds described herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds described herein, radioactive or not, are encompassed.

[0040] "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the way their atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(..+-..)" is used to designate a racemic mixture when appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified as either R or S. Resolved compounds of unknown absolute configuration can be designated (+) or (-) depending on the direction (dextrorotatory or levorotatory) they rotate plane-polarized light at the wavelength of the sodium D line. Some of the compounds described herein contain one or more asymmetric centers and can therefore occur as enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-. The chemical entities, pharmaceutical compositions, and methods of the present invention are meant to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. The optical activity of a compound can be analyzed by any suitable method, including, but not limited to, chiral chromatography and polarimetry, to determine the predominance of one stereoisomer over the other.

[0041] When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0042] A "substituted" or "optionally substituted" group means that the group (e.g., alkyl, aryl, heterocyclyl, cycloalkyl, hetrocyclylalkyl, arylalkyl, heteroaryl, or heteroarylalkyl), unless otherwise specifically stated, can have one, two, or three -H groups substituted by one, two, or three substituents selected from halo, trifluoromethyl, trifluoromethoxy, methoxy, -COOH, -CHO, -NH, -NO, -OH, -SH, -SMe, -NHCH, -N(CH), -CN, lower alkyl, and the like.

[0043] "Tautomers" are structurally distinct isomers that interconvert by tautomerization. "Tautomerization" is a form of isomerization that includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton-shift tautomerization" involves the migration of a proton with a change in bond order, often the interconversion of a single bond with an adjacent double bond. When tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. One example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

[0044] The compounds described herein also include crystalline and amorphous forms of the compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof. "Crystal form," "polymorph," and "novel form" can be used interchangeably herein and are meant to include all crystalline and amorphous forms of the compounds listed above, and mixtures thereof, unless a specific crystalline or amorphous form is referenced.

[0045] "Solvent," "organic solvent," and "inert solvent" each mean a solvent inert under the reaction conditions described therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N-methylpyrrolidone ("NMP"), pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions described herein are inert organic solvents. Unless specified to the contrary, 1 cc (or mL) of solvent constitutes 1 volumetric equivalent for every 1 gram of limiting reagent. composition

[0046] As used herein, compounds of formula I [ka] [In the formula, R 1 is H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C10 Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 1 and the N to which it is attached, taken together, form a substituted or unsubstituted C3-C6 heterocycloalkyl or heteroaryl ring (replacing the H attached to the N); R 2 and R 3 are independently H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 2 and R 3 together with the N to which they are attached form a substituted or unsubstituted C4-C6 heterocycloalkyl group; A is a bond, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 Aryl or heteroaryl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 selected from the group consisting of straight-chain or branched alkynyl, C═O, C═S, —CH—, —CH(OH)—, —NH—, —N(CH)—, —O—, —S—, and SO; R 4 is substituted or unsubstituted C1-C10 Straight or branched alkyl, substituted or unsubstituted C1-C 10 Straight or branched alkoxy, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, substituted or unsubstituted C1-C 10 Linear or branched dialkylamino, substituted or unsubstituted C3-C 10 Cycloalkyl or heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 selected from the group consisting of heteroaryl, —CN and halo; X and Y are independently selected from the group consisting of -CH- and -N-. is described.

[0047] In some embodiments, X=-CH- and Y=N. In some embodiments, X=Y=N.

[0048] Also provided herein is a compound of formula II [ka] [In the formula, R 1 is H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C5-C 10 Heteroarylalkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10or R is selected from the group consisting of linear or branched dialkylamino; 1 and the N to which it is attached, taken together, form a substituted or unsubstituted C3-C6 heterocycloalkyl or heteroaryl ring (replacing the H attached to the N); A is a bond, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 selected from the group consisting of straight-chain or branched alkynyl, C═O, C═S, —CH—, —CH(OH)—, —NH—, —N(CH)—, —O—, —S—, and SO; R 4 is substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C1-C 10 Straight or branched alkoxy, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, substituted or unsubstituted C1-C 10 Linear or branched dialkylamino, substituted or unsubstituted C3-C 10 Cycloalkyl or heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 selected from the group consisting of heteroaryl, —CN and halo; R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 5 and R 6 are combined to form =O, or R 7 and R 8 are combined to form =O, or R 9 and R 10 are combined to become =O, X and Y are independently selected from the group consisting of -CH- and -N-; Z is C=O, -CR 9 R 10 -, -NR 9 -, -O-, -S-, -S(O)- and -SO2-. is described.

[0049] In some embodiments, X=Y=-CH- and Z=-CH2-. In some embodiments, X=Y=-CH- and Z=O.

[0050] The following compounds in Table 1 were synthesized.

[0051] Table 1 [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

[0052] Isolation and purification of the chemical entities and intermediates described herein can be carried out, as desired, by any suitable separation or purification procedure, such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer or thick-layer chromatography, or a combination of these procedures. Specific examples of suitable separation and isolation procedures can be had by reference to the examples herein. However, other equivalent separation or isolation procedures can also be used.

[0053] If desired, the (R)- and (S)-isomers of the compounds described herein, if present, can be resolved by methods known to those skilled in the art, for example, by the formation of diastereomeric salts or complexes which can be separated by crystallization, for example, through the formation of diastereomeric derivatives which can be separated by crystallization, gas-liquid or liquid chromatography, by the selective reaction of one enantiomer with an enantiomer-specific reagent, for example, enzymatic oxidation or reduction followed by separation of the modified and unmodified enantiomers, or by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support, for example, silica, bearing an attached chiral ligand or in the presence of a chiral solvent. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

[0054] The compounds described herein can be contacted with a pharmaceutically acceptable acid, if necessary, to form the corresponding acid addition salt. Pharmaceutically acceptable forms of the compounds listed herein include pharmaceutically acceptable salts, chelates, non-covalent complexes or derivatives, prodrugs, and mixtures thereof. In certain embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. Furthermore, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts.

[0055] When ranges are used herein for physical properties, e.g., molecular weight, or chemical properties, e.g., chemical formula, all combinations and subcombinations of the ranges, as well as specific embodiments thereof, are intended to be included. The term "about," when referring to a number or numerical range, means that the referenced number or numerical range is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary, for example, by 1% to 15% of the stated number or numerical range. The term "comprising" (and "comprise" or "comprises" or "comprises") also refers to a range of values. (or related terms such as "having" or "including") are used to describe The invention includes embodiments "consisting of" or "consisting essentially of" a feature, such as any composition of matter, composition of matter, method or process.

[0056] The pharmaceutical compositions of interest are typically formulated to provide a therapeutically effective amount of a compound of Formula I or II as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. If desired, the pharmaceutical composition contains a pharmaceutically acceptable salt and / or coordination complex thereof, as well as one or more pharmaceutically acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants.

[0057] The pharmaceutical composition of interest can be administered alone or in combination with one or more other drugs, which are also typically administered in the form of pharmaceutical compositions.If desired, the compound of formula I or II and other drugs can be mixed in preparation, or both components can be formulated into separate preparations for separate or simultaneous combined use.The compound described herein can also be used in combination with other drugs for treating the diseases listed herein in subjects, for example, with the additional compound of formula I or II or not.

[0058] In some embodiments, the concentration of one or more compounds of Formula I or II in the pharmaceutical compositions herein is less than 100%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 19%, less than 18%, less than 17%, less than 16%, less than 15%, less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than 0.1%, less than 0.1% w / w, w / v or v / v. %, less than 0.09%, less than 0.08%, less than 0.07%, less than 0.06%, less than 0.05%, less than 0.04%, less than 0.03%, less than 0.02%, less than 0.01%, less than 0.009%, less than 0.008%, less than 0.007%, less than 0.006%, less than 0.005%, less than 0.004%, less than 0.003%, less than 0.002%, less than 0.001%, less than 0.0009%, less than 0.0008%, less than 0.0007%, less than 0.0006%, less than 0.0005%, less than 0.0004%, less than 0.0003%, less than 0.0002%, or less than 0.0001%.

[0059] In some embodiments, the concentration of one or more compounds of Formula I or II is greater than 90%, greater than 80%, greater than 70%, greater than 60%, greater than 50%, greater than 40%, greater than 30%, greater than 20%, greater than 19.75%, greater than 19.50%, greater than 19.25%, greater than 19%, greater than 18.75%, greater than 18.50%, greater than 18.25%, greater than 18%, greater than 17.75%, greater than 17.50%, greater than 17.25%, greater than 17%, greater than 16.75%, greater than 16.50%, greater than 16.25%, greater than 16%, greater than 15.75 ...75%, greater than 16.50%, greater than 16.25%, greater than 16%, greater than 15.75%, greater than 16.75%, greater than 16.75%, greater than 16.50%, greater than 16.25%, greater than 16%, greater than 15.75%, greater than 16.75%, greater than 16.75%, greater than 16.75%, greater than 16.25%, greater than 16%, greater than 15.75%, greater than 16.75%, greater than 16.75%, greater than 16.75 More than 15.50%, more than 15.25%, more than 15%, more than 14.75%, more than 14.50%, more than 14.25%, more than 14%, more than 13.75%, more than 13.50%, more than 13.25%, more than 13%, more than 12.75%, more than 12.50%, more than 12.25%, more than 12% , more than 11.75%, more than 11.50%, more than 11.25%, more than 11%, more than 10.75%, more than 10.50%, more than 10.25%, more than 10%, more than 9.75%, more than 9.50%, more than 9.25%, more than 9%, more than 8.75%, more than 8.50%, more than 8.25%, 8% Super, more than 7.75%, more than 7.50%, more than 7.25%, more than 7%, more than 6.75%, more than 6.50%, more than 6.25%, more than 6%, more than 5.75%, more than 5.50%, more than 5.25%, more than 5%, more than 4.75%, more than 4.50%, more than 4.25%, more than 4%, 3.75% Super, More than 3.50%, More than 3.25%, More than 3%, More than 2.75%, More than 2.50%, More than 2.25%, More than 2%, More than 1.75%, More than 1.50%, More than 125%, More than 1%, More than 0.5%, More than 0.4%, More than 0.3%, More than 0.2%, More than 0.1%, More than 0.09%, 0 greater than 0.08%, greater than 0.07%, greater than 0.06%, greater than 0.05%, greater than 0.04%, greater than 0.03%, greater than 0.02%, greater than 0.01%, greater than 0.009%, greater than 0.008%, greater than 0.007%, greater than 0.006%, greater than 0.005%, greater than 0.004%, greater than 0.003%, greater than 0.002%, greater than 0.001%, greater than 0.0009%, greater than 0.0008%, greater than 0.0007%, greater than 0.0006%, greater than 0.0005%, greater than 0.0004%, greater than 0.0003%, greater than 0.0002%, or greater than 0.0001%.

[0060] In some embodiments, the concentration of one or more compounds of Formula I or II is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 10%, from about 0.08% to about 12%, from about 0.09% to about 26%, from about 0.10% to about 12%, from about 0.11% to about 13%, from about 0.12% to about 14%, from about 0.13% to about 15%, from about 0.14% to about 16%, from about 0.15% to about 17%, from about 0.16% to about 18%, from about 0.17% to about 19%, from about 0.18% to about 22%, from about 0.19% to about 23%, from about 0.20% to about 24%, from about 0.21% to about 25%, from about 0.22% to about 26%, from about 0.23% to about 27%, from about 0.24% to about 28%, from about 0.25% to about 29%, from about 0.26% to about 28%, from about 0.27% to about 29%, from about 0.28% to about 29%, from about 0.29% to about 30%, from about 0.30% to about 30%, from about 0.31% to about 29%, from about 0.32% to about 29%, from about 0.33% to about 28%, from The ranges are approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, and approximately 1% to approximately 10%.

[0061] In some embodiments, the concentration of one or more compounds of Formula I or II ranges from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, or about 0.1% to about 0.9% w / w, w / v, or v / v.

[0062] In some embodiments, the amount of one or more compounds of Formula I or II is 10 g or less, 9.5 g or less, 9.0 g or less, 8.5 g or less, 8.0 g or less, 7.5 g or less, 7.0 g or less, 6.5 g or less, 6.0 g or less, 5.5 g or less, 5.0 g or less, 4.5 g or less, 4.0 g or less, 3.5 g or less, 3.0 g or less, 2.5 g or less. or less, 2.0g or less, 1.5g or less, 1.0g or less, 0.95g or less, 0.9g or less, 0.85g or less, 0.8g or less, 0.75g or less, 0.7g or less, 0.65g or less, 0.6g or less, 0.55g or less, 0.5g or less, 0.45g or less, 0.4g or less, 0.35g or less, 0.3g or less Less than, 0.25g or less, 0.2g or less, 0.15g or less, 0.1g or less, 0.09g or less, 0.08g or less, 0.07g or less, 0.06g or less, 0.05g or less, 0.04g or less, 0.03g or less, 0.02g or less, 0.01g or less, 0.009g or less, 0.008g or less, 0.007g or less, 0.006g or less, 0.005g or less, 0.004g or less, 0.003g or less, 0.002g or less, 0.001g or less, 0.0009g or less, 0.0008g or less, 0.0007g or less, 0.0006g or less, 0.0005g or less, 0.0004g or less, 0.0003g or less, 0.0002g or less, or 0.0001g or less.

[0063] In some embodiments, the amount of one or more compounds of Formula I or II is greater than 0.0001 g, greater than 0.0002 g, greater than 0.0003 g, greater than 0.0004 g, greater than 0.0005 g, greater than 0.0006 g, greater than 0.0007 g, greater than 0.0008 g, greater than 0.0009 g, greater than 0.001 g, greater than 0.0015 g, greater than 0.002 g, greater than 0.0025 g, greater than 0.003 g Super, over 0.0035g, over 0.004g, over 0.0045g, over 0.005g, over 0.0055g, over 0.006g, over 0.0065g, over 0.007g, 0.0075g Super, more than 0.008g, more than 0.0085g, more than 0.009g, more than 0.0095g, more than 0.01g, more than 0.015g, more than 0.02g, more than 0.025g, more than 0.03g, 0.03 More than 5g, more than 0.04g, more than 0.045g, more than 0.05g, more than 0.055g, more than 0.06g, more than 0.065g, more than 0.07g, more than 0.075g, more than 0.08g, 0.085g Super, more than 0.09g, more than 0.095g, more than 0.1g, more than 0.15g, more than 0.2g, more than 0.25g, more than 0.3g, more than 0.35g, more than 0.4g, more than 0.45g, more than 0.5g, 0. More than 55g, more than 0.6g, more than 0.65g, more than 0.7g, more than 0.75g, more than 0.8g, more than 0.85g, more than 0.9g, more than 0.95g, more than 1g, more than 1.5g, more than 2g, 2.5, 3g More than 3.5, more than 4g, more than 4.5g, more than 5g, more than 5.5g, more than 6g, more than 6.5g, more than 7g, more than 7.5g, more than 8g, more than 8.5g, more than 9g, more than 9.5g, or more than 10g.

[0064] In some embodiments, the amount of one or more compounds of formula I or II ranges from 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

[0065] The compounds of Formula I or II described herein are effective over a wide dosage range. For example, in the treatment of adults, dosages of 0.01-1000 mg per day, 0.5-100 mg per day, 1-50 mg per day, and 5-40 mg per day are examples of dosages that can be used. An exemplary dosage is 10-30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound of Formula I or II is administered, the subject being treated, the subject's weight, and the preference and experience of the attending physician.

[0066] The pharmaceutical compositions described herein typically contain an active ingredient (e.g., a compound of Formula I or II, or a pharmaceutically acceptable salt and / or coordination complex thereof), and one or more pharmaceutically acceptable excipients, carriers including, but not limited to, inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants.

[0067] Below, non-limiting exemplary pharmaceutical compositions and methods for preparing the same are described. Pharmaceutical Composition for Oral Administration

[0068] As used herein, compounds of formula I [ka] [In the formula, R 1 is H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 1 and the N to which it is attached, taken together, form a substituted or unsubstituted C3-C6 heterocycloalkyl or heteroaryl ring (replacing the H attached to the N); R 2 and R 3 are independently H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 2 and R 3 together with the N to which they are attached form a substituted or unsubstituted C4-C6 heterocycloalkyl group; A is a bond, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 Aryl or heteroaryl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 selected from the group consisting of straight-chain or branched alkynyl, C═O, C═S, —CH—, —CH(OH)—, —NH—, —N(CH)—, —O—, —S—, and SO; R 4 is substituted or unsubstituted C1-C 10Straight or branched alkyl, substituted or unsubstituted C1-C 10 Straight or branched alkoxy, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, substituted or unsubstituted C1-C 10 Linear or branched dialkylamino, substituted or unsubstituted C3-C 10 Cycloalkyl or heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 selected from the group consisting of heteroaryl, —CN and halo; X and Y are independently selected from the group consisting of -CH- and -N-; and a pharmaceutical excipient suitable for oral administration.

[0069] Further provided herein is a compound of formula II [ka] [In the formula, R 1 is H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C5-C 10 Heteroarylalkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 1and the N to which it is attached, taken together, form a substituted or unsubstituted C3-C6 heterocycloalkyl or heteroaryl ring (replacing the H attached to the N); A is a bond, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 selected from the group consisting of straight-chain or branched alkynyl, C═O, C═S, —CH—, —CH(OH)—, —NH—, —N(CH)—, —O—, —S—, and SO; R 4 is substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C1-C 10 Straight or branched alkoxy, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, substituted or unsubstituted C1-C 10 Linear or branched dialkylamino, substituted or unsubstituted C3-C 10 Cycloalkyl or heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 selected from the group consisting of heteroaryl, —CN and halo; R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 5 and R 6 are combined to form =O, or R 7 and R 8 are combined to form =O, or R 9 and R 10 are combined to become =O, X and Y are independently selected from the group consisting of -CH- and -N-; Z is C=O, -CR 9 R 10 -, -NR 9 -, -O-, -S-, -S(O)- and -SO2-; and a pharmaceutical excipient suitable for oral administration.

[0070] Also described herein are solid pharmaceutical compositions for oral administration containing (i) an effective amount of a compound of Formula I or II, optionally (ii) an effective amount of a second agent, and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains (iv) an effective amount of a third agent.

[0071] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions suitable for oral administration can be presented in separate dosage forms, such as capsules, cachets, or tablets, or as liquids or aerosol sprays, each containing a predetermined amount of the active ingredient as a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any method of pharmacy, but all methods include combining the active ingredient with a carrier, which constitutes one or more necessary ingredients. Generally, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired presentation. For example, tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, mixed with excipients, such as, but not limited to, binders, lubricants, inert diluents, and / or surfactants or dispersants, as needed. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0072] Also, because water can easily degrade some compounds, anhydrous pharmaceutical compositions and dosage forms containing active ingredients are described herein. In the pharmaceutical field, water can be added (e.g., 5%) as a means of simulating long-term storage to determine characteristics such as the shelf life or stability of a formulation over time. Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low-moisture-containing ingredients and low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms containing lactose can be made anhydrous if substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous nature. Therefore, anhydrous compositions can be packaged using materials known to prevent exposure to water so that they can be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit-dose containers, blister packs, and strip packaging.

[0073] The active ingredient can be combined into a thoroughly mixed mixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. Carriers can take a variety of forms depending on the preparation form desired for administration. In preparing compositions for oral dosage forms, any of the usual pharmaceutical media can be used as a carrier, for example, for oral liquid preparations (e.g., suspensions, solutions, and elixirs) or aerosols, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., or in some embodiments that do not use lactose, for oral solid preparations, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used. For example, for solid oral preparations, suitable carriers include powders, capsules, and tablets. If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

[0074] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0075] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0076] Disintegrants can be used in the compositions described herein to provide tablets that disintegrate when exposed to an aqueous environment. Using too much disintegrant can result in tablets that may disintegrate in the bottle. Using too little can result in insufficient disintegration, which may alter the release rate and extent of the active ingredient from the dosage form. Therefore, dosage forms of the compounds disclosed herein can be formed using a sufficient amount of disintegrant that is neither too little nor too much to adversely alter the release of the active ingredient. The amount of disintegrant used can vary depending on the type of formulation and mode of administration and can be readily discerned by those skilled in the art. In pharmaceutical compositions, about 0.5 to about 15 weight percent of disintegrant or about 1 to about 5 weight percent of disintegrant can be used. Disintegrants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

[0077] Lubricants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, coagulated aerosol of synthetic silica, or mixtures thereof. Lubricants can be added as needed in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0078] When aqueous suspensions and / or elixirs are desired for oral administration, the essential active ingredient therein may be combined with a diluent such as water, ethanol, propylene glycol, glycerin, and various combinations thereof, along with various sweetening or flavoring agents, coloring substances or dyes, and, if desired, emulsifying and / or suspending agents.

[0079] Tablets can be uncoated or can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a long period of time.For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used.The preparation for oral use can also be presented as a hard gelatin capsule, in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as a soft gelatin capsule, in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.

[0080] Surfactants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof, i.e., a mixture of hydrophilic surfactants can be used, a mixture of lipophilic surfactants can be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0081] Suitable hydrophilic surfactants generally have an HLB value of at least 10, while suitable lipophilic surfactants generally have an HLB value of about 10 or less. The empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and more soluble in oil, while surfactants with higher HLB values ​​are more hydrophilic and more soluble in aqueous solutions. Hydrophilic surfactants are generally considered to be compounds with an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds to which the HLB scale is generally not applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with an HLB value of about 10 or less. However, the HLB value of a surfactant is only a rough guideline commonly used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0082] Hydrophilic surfactants can be either ionic or nonionic.Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidate salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; alkyl sulfate salts; fatty acid salts; sodium docusate; acylactylate; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citrate esters of mono- and di-glycerides; and mixtures thereof.

[0083] Among the aforementioned groups, ionic surfactants include, for example, lecithin, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl acrylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citrate esters of mono- and di-glycerides; and mixtures thereof.

[0084] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl- 2-Lactylate, Stearoyl Lactylate, Succinylated Monoglycerides, Mono / Diacetylated Tartaric Acid Esters of Mono / Diglycerides, Citrate Esters of Mono / Diglycerides, Cholesteryl Sarcosine, Caproate, Caprylate, Caprate, Laurate, Myristate, Palmitate, Oleate, Ricinoleate, Linolenate, Linolenate, Stearate, Lauryl Sulfate, Tetradecyl Sulfate, Docusate, Lauroyl Carnitine, Palmitoyl Carnitine The ionized forms of carnitine, myristoylcarnitine, and salts and mixtures thereof may also be used.

[0085] Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides; alkyl maltosides; alkyl thioglucosides; lauryl macrogol glycerides; polyoxyalkylene alkyl ethers, such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols, such as polyethylene glycol alkylphenols; polyoxyalkylene alkylphenol fatty acid esters, such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid esters; polyglycerin fatty acid esters; polyoxyalkylene sorbitan fatty acid esters, such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of polyols and at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives and analogs thereof; polyoxyethylenated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers and mixtures thereof; polyethylene glycol sorbitan fatty acid esters, and hydrophilic transesterification products of polyols and at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a sugar.

[0086] Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PE G-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Capric / Caprylic Glycerides, PEG-8 Capric / Caprylic Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Plant Sterols, PEG-30 Soy Sterols, Examples of suitable glycerin-based surfactants include PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween® 40, Tween® 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series, and poloxamer.

[0087] Suitable lipophilic surfactants include, by way of example only, fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylene sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and diglycerides; the hydrophobic transesterification product of polyols and at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof.In this group, suitable lipophilic surfactants include, but are not limited to, glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or the hydrophobic transesterification product of polyols and at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils and triglycerides.

[0088] In one embodiment, the composition can include a solubilizing agent to ensure good solubilization and / or dissolution of the compounds described herein and minimize precipitation of the compounds described herein.This may be particularly important for compositions for parenteral use, such as compositions for injection.Solubilizing agents can also be added to increase the solubility of hydrophilic drugs and / or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0089] Examples of suitable solubilizing agents include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-pyrid ... esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizing agents known in the art, such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0090] A mixture of solubilizers can also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Suitable solubilizers include, but are not limited to, sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, and propylene glycol.

[0091] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which can be easily determined by one skilled in the art. In some circumstances, it may be advantageous to include a solubilizer in an amount far in excess of the biologically acceptable amount, e.g., to maximize drug concentration, and to remove the excess solubilizer using conventional techniques, such as distillation or evaporation, before providing the composition to the patient. Thus, when present, the solubilizer can be present in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug and other excipients. If desired, very small amounts of solubilizer, e.g., 5%, 2%, 1%, or even less, can also be used. Typically, the solubilizer can be present in an amount of about 1% to about 100% by weight, more typically about 5% to about 25% by weight.

[0092] The composition may further comprise one or more pharmaceutically acceptable additives and excipients, including, but not limited to, detackifiers, antifoaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicifiers, flavors, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0093] In addition, acids or bases can be incorporated into the composition to facilitate processing, enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), etc. Also suitable are bases that are salts of pharmaceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid. Salts of polybasic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate, can also be used. When the base is a salt, the cation can be any convenient pharmaceutically acceptable cation, such as ammonium, an alkali metal, or an alkaline earth metal. Examples include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0094] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, etc. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc. Pharmaceutical compositions for injection

[0095] As used herein, compounds of formula I [ka] [In the formula, R 1 is H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 1 and the N to which it is attached, taken together, form a substituted or unsubstituted C3-C6 heterocycloalkyl or heteroaryl ring (replacing the H attached to the N); R2 and R 3 are independently H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 2 and R 3 together with the N to which they are attached form a substituted or unsubstituted C4-C6 heterocycloalkyl group; A is a bond, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 Aryl or heteroaryl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 selected from the group consisting of straight-chain or branched alkynyl, C═O, C═S, —CH—, —CH(OH)—, —NH—, —N(CH)—, —O—, —S—, and SO; R 4 is substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C1-C 10 Straight or branched alkoxy, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, substituted or unsubstituted C1-C 10 Linear or branched dialkylamino, substituted or unsubstituted C3-C 10 Cycloalkyl or heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C10 and X and Y are independently selected from the group consisting of -CH- and -N-. and a pharmaceutical excipient suitable for injection. The components and amounts of the drug in the composition are as described herein.

[0096] Also provided herein is a compound of formula II [ka] [In the formula, R 1 is H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl ), substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C5-C 10 Heteroarylalkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 1 and the N to which it is attached, taken together, form a substituted or unsubstituted C3-C6 heterocycloalkyl or heteroaryl ring (replacing the H attached to the N); A is a bond, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10Straight or branched alkenyl, substituted or unsubstituted C2-C 10 selected from the group consisting of straight-chain or branched alkynyl, C═O, C═S, —CH—, —CH(OH)—, —NH—, —N(CH)—, —O—, —S—, and SO; R 4 is substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C1-C 10 Straight or branched alkoxy, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, substituted or unsubstituted C1-C 10 Linear or branched dialkylamino, substituted or unsubstituted C3-C 10 Cycloalkyl or heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 selected from the group consisting of heteroaryl, —CN and halo; R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 5 and R 6 are combined to form =O, or R 7 and R 8are combined to form =O, or R 9 and R 10 are combined to become =O, X and Y are independently selected from the group consisting of -CH- and -N-; Z is C=O, -CR 9 R 10 -, -NR 9 and a pharmaceutical excipient suitable for injection. The components and amounts of the drug in the composition are as described herein.

[0097] Forms into which the novel compositions described herein may be incorporated for administration by injection include aqueous or oily suspensions or emulsions using sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0098] Aqueous solutions of physiological saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, by using a coating, such as lecithin, to maintain the required particle size in the case of dispersions, and by using surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0099] Sterile injectable solution is prepared by incorporating the compound of formula I or II in the required amount in a suitable solvent with various other ingredients as listed above, if necessary, and then sterile filtered.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains a basic dispersion medium and other ingredients as listed above.For sterile powders for preparing sterile injectable solution, some preferred methods are vacuum drying and freeze-drying technology, which produce powder of active ingredient and any additional desired ingredients from a previously sterile-filtered solution. Pharmaceutical compositions for topical (e.g., transdermal) delivery

[0100] Also provided herein are compounds of formula I [ka] [In the formula, R 1 is H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 1 and the N to which it is attached, taken together, form a substituted or unsubstituted C3-C6 heterocycloalkyl or heteroaryl ring (replacing the H attached to the N); R 2 and R 3are independently H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 2 and R 3 together with the N to which they are attached form a substituted or unsubstituted C4-C6 heterocycloalkyl group; A is a bond, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 Aryl or heteroaryl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 selected from the group consisting of straight-chain or branched alkynyl, C═O, C═S, —CH—, —CH(OH)—, —NH—, —N(CH)—, —O—, —S—, and SO; R 4 is substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C1-C 10 Straight or branched alkoxy, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, substituted or unsubstituted C1-C 10 Linear or branched dialkylamino, substituted or unsubstituted C3-C 10 Cycloalkyl or heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10selected from the group consisting of heteroaryl, —CN and halo; X and Y are independently selected from the group consisting of -CH- and -N-. and a pharmaceutical excipient suitable for transdermal delivery.

[0101] Also provided herein is a compound of formula II [ka] [In the formula, R 1 is H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C5-C 10 Heteroarylalkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 1 and the N to which it is attached, taken together, form a substituted or unsubstituted C3-C6 heterocycloalkyl or heteroaryl ring (replacing the H attached to the N); A is a bond, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10selected from the group consisting of straight-chain or branched alkynyl, C═O, C═S, —CH—, —CH(OH)—, —NH—, —N(CH)—, —O—, —S—, and SO; R 4 is substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C1-C 10 Straight or branched alkoxy, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, substituted or unsubstituted C1-C 10 Linear or branched dialkylamino, substituted or unsubstituted C3-C 10 Cycloalkyl or heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 selected from the group consisting of heteroaryl, —CN and halo; R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 5 and R 6 are combined to form =O, or R 7 and R 8 are combined to form =O, or R 9 and R10 are combined to become =O, X and Y are independently selected from the group consisting of -CH- and -N-; Z is C=O, -CR 9 R 10 -, -NR 9 -, -O-, -S-, -S(O)- and -SO2-. and a pharmaceutical excipient suitable for transdermal delivery.

[0102] The compositions described herein can be formulated into solid, semi-solid or liquid form preparations suitable for topical or external administration, such as gel, water-soluble jelly, cream, lotion, suspension, foam, powder, slurry, ointment, solution, oil, paste, suppository, spray, emulsion, saline solution or dimethyl sulfoxide (DMSO)-based solution.Generally, carriers with higher density can expose active ingredient to a certain area for a long time.In contrast, solution formulations can bring about more immediate exposure of active ingredient to selected area.

[0103] Pharmaceutical compositions can also contain suitable solid or gel phase carriers or excipients, which are compounds that enhance the permeability of therapeutic molecules across the stratum corneum permeability barrier of the skin or aid in their delivery.Those skilled in the art of topical formulations are familiar with many of these penetration-enhancing molecules.Examples of such carriers and excipients include, but are not limited to, moisturizers (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidone, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0104] Another exemplary formulation for use in the methods described herein employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or intermittent infusion of a compound of Formula I or II in controlled amounts, with or without additional agents.

[0105] The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches can be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Pharmaceutical Compositions for Inhalation

[0106] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions can contain suitable pharmaceutically acceptable excipients as described above. The compositions can be administered by oral or nasal respiratory routes, for example, for local or systemic effects. Compositions in pharmaceutically acceptable solvents can be nebulized by using inert gases. Nebulized solutions can be inhaled directly from the nebulizing device, or the nebulizing device can be connected to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered in any manner, such as orally or nasally, from a device that delivers the formulation in an appropriate manner. Other pharmaceutical compositions

[0107] Pharmaceutical compositions can also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural or intraspinal administration.The preparations for such pharmaceutical compositions are well known in the art. See, for example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, NY, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw-Hill, 2004; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw-Hill, 2001; Remington's Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins, 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999), which are incorporated herein by reference in their entireties.

[0108] The compound of Formula I or II or pharmaceutical composition described herein can be administered by any method that allows the compound to reach the site of action.These methods include oral route, intraduodenal route, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical administration (e.g., transdermal administration), rectal administration, local delivery by catheter or stent, or inhalation.The compound can also be administered intraadiposally or intrathecally.

[0109] The amount of a compound of Formula I or II administered will depend on the mammal being treated, the severity of the disorder or condition, the rate of administration, the nature of the compound, and the discretion of the attending physician. However, effective dosages range from about 0.001 to about 100 mg per kg of body weight per day, e.g., about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this amount may be about 0.05 to 7 g / day, e.g., about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower end of the aforementioned range may be sufficient, while in other cases, such higher doses may be used without causing any adverse side effects, e.g., by dividing the larger dose into several smaller doses to be administered throughout the day.

[0110] In some embodiments, the compound of formula I or II is administered in a single dose.Typically, such administration is carried out by injection, for example, intravenous injection, in order to rapidly introduce the drug.However, other routes can be used as appropriate.

[0111] In some embodiments, the compound of Formula I or II is administered in multiple doses. Dosing can be about once, about twice, about three times, about four times, about five times, about six times, or about seven or more times per day. Dosing can be about once a month, about once every two weeks, about once a week, or about once every two days. In another embodiment, the compound and another agent are administered together about once to about six times per day. In another embodiment, administration of the compound of Formula I or II and the agent continues for less than about seven days. In yet another embodiment, administration continues for more than about six days, more than about ten days, more than about 14 days, more than about 28 days, more than about two months, more than about six months, or more than about one year. In some cases, continuous dosing is achieved and maintained for as long as necessary.

[0112] Administration of the compound of Formula I or II can be continued as long as necessary. In some embodiments, the compound of Formula I or II is administered for more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, more than 14 days, or more than 28 days. In some embodiments, the compound of Formula I or II is administered for less than 28 days, less than 14 days, less than 7 days, less than 6 days, less than 5 days, less than 4 days, less than 3 days, less than 2 days, or less than 1 day. In some embodiments, the compound of Formula I or II is administered continuously on a long-term basis, for example, to treat chronic effects.

[0113] An effective amount of a compound of Formula I or II can be administered in either a single dose or multiple doses by any of the accepted modes of administration for pharmaceuticals of similar utility, including rectal, oral buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0114] The compositions described herein can also be delivered via impregnated or coated devices, such as stents, or arterially inserted cylindrical polymers. The compound of Formula I or II can be administered by local delivery, for example, from the struts of a stent, from a stent graft, from a graft, or from a stent cover or covering. In some embodiments, the compound of Formula I or II is mixed with a matrix. Such a matrix can be a polymer matrix and can serve to bind the compound to the stent. Suitable polymer matrices for such use include, for example, lactone-based polyesters or copolyesters, such as polylactides, polycaprolactone glycolides, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers (e.g., PEO-PLLA); polydimethylsiloxane, poly(ethylene vinyl acetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethylmethylmethacrylate, polyvinylpyrrolidinone), fluorinated polymers, such as polytetrafluoroethylene, and cellulose esters. A suitable matrix may be non-degradable or degrade over time to release one or more compounds. The compound of Formula I or II can be applied to the surface of a stent by various methods, such as dipping / spin coating, spray coating, dip coating, and / or brush coating. The compound can be applied in a solvent, and the solvent can be evaporated, thus forming a layer of the compound on the stent. Alternatively, the compound of Formula I or II can be located in the body of the stent or graft, for example, within microchannels or micropores. When implanted, the compound spreads from the stent body and contacts the arterial wall. Such a stent can be prepared by immersing a stent manufactured to contain such micropores or microchannels in a solution of the compound of Formula I or II in an appropriate solvent, followed by evaporation of the solvent.Excess drug on the surface of the stent can be removed by simple further washing with solvent. In yet another embodiment, the compound of Formula I or II can be covalently bonded to a stent or graft. A covalent linker can be used that decomposes in vivo to release the compound of Formula I. For this purpose, any biolabile linkage can be used, such as an ester, amide, or anhydride linkage. The compound of Formula I or II can also be administered intravascularly from a balloon used during angioplasty. To reduce restenosis, extravascular administration of the compound of Formula I or II can also be carried out via application of the formulations described herein to the pericardium or epicardium.

[0115] Various stent devices that can be used as described are disclosed, for example, in the following references: U.S. Pat. No. 5,451,233, U.S. Pat. No. 5,040,548, U.S. Pat. No. 5,061,273, U.S. Pat. No. 5,496,346, U.S. Pat. No. 5,292,331, U.S. Pat. No. 5,674,278, U.S. Pat. No. 3,657,744, U.S. Pat. No. 4,739,762, U.S. Pat. No. 5,195,984, U.S. Pat. No. 5,292,331, U.S. Pat. No. 5,674,278, U.S. Pat. No. 5,879,382, U.S. Pat. No. 6,344,053, all of which are incorporated herein by reference.

[0116] The compound of formula I or II can be administered in dosage.It is known to those skilled in the art that due to the intra-subject variability of the pharmacokinetics of compound, optimal treatment requires individualized dosage regimen.The dosage of the compound of formula I or II can be found by routine experiment in light of the present disclosure.

[0117] When the compound of Formula I or II is administered in a composition containing one or more drugs that have a shorter half-life than the compound of Formula I or II, the unit dosage forms of the drugs and the compound of Formula I or II may be adjusted accordingly.

[0118] The desired pharmaceutical composition may be in the form of, for example, tablets, capsules, pills, powders, sustained-release formulations, solutions, or suspensions suitable for oral administration; sterile solutions, suspensions, or emulsions suitable for parenteral injection; ointments or creams suitable for topical administration; or suppositories suitable for rectal administration. The pharmaceutical composition may be in a unit dosage form suitable for single administration of a precise dosage. The pharmaceutical composition comprises a conventional pharmaceutical carrier or excipient and a compound of Formula I or II as an active ingredient. It may also contain other drugs or pharmaceuticals, carriers, adjuvants, etc.

[0119] Exemplary parenteral dosage forms include solutions or suspensions of the active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions, which can be suitably buffered, if desired.

[0120] Kits are also described herein. The kits include one or more compounds of Formula I or II described herein in suitable packaging and materials that may include instructions for use, discussion of clinical studies, a list of side effects, and the like. Such kits can also include information such as scientific references, package inserts, clinical trial results, and / or summaries thereof, which demonstrate or establish the activity and / or benefits of the composition and / or describe dosing, administration, side effects, drug interactions, or other information useful to healthcare providers. Such information can be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. The kits can further contain another agent. In some embodiments, the compound of Formula I or II and the agent are provided as separate compositions in separate containers within the kit. In some embodiments, the compound described herein and the agent are provided as a single composition in a single container within the kit. Suitable packaging and additional items (e.g., measuring cups for liquid preparations, foil wrappers to minimize exposure to air, etc.) are known in the art and can be included in the kit. The kits described herein may be provided, marketed, and / or promoted to healthcare providers, including physicians, nurses, pharmacists, dispensing personnel, etc. The kits may also, in some embodiments, be sold directly to consumers. Treatment method

[0121] The therapeutically effective amount of the compounds and pharmaceutical compositions described herein as described above are useful in methods for treating ferroptosis-related diseases, such as lipid peroxidation-related degenerative diseases, excitotoxicity diseases, neurodegenerative diseases, non-apoptotic controlled cell death diseases, wasting or necrosis-related diseases, poisoning-related diseases, and infectious diseases.The therapeutic methods described herein comprise administering a therapeutically effective amount of a compound of formula I [ka] [In the formula, R 1 is H, substituted or unsubstituted C1-C 10Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 1 and the N to which it is attached, taken together, form a substituted or unsubstituted C3-C6 heterocycloalkyl or heteroaryl ring (replacing the H attached to the N); R 2 and R 3 are independently H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 2 and R 3 together with the N to which they are attached form a substituted or unsubstituted C4-C6 heterocycloalkyl group; A is a bond, substituted or unsubstituted C6-C 10Aryl, substituted or unsubstituted C5-C 10 Aryl or heteroaryl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 selected from the group consisting of straight-chain or branched alkynyl, C═O, C═S, —CH—, —CH(OH)—, —NH—, —N(CH)—, —O—, —S—, and SO; R 4 is substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C1-C 10 Straight or branched alkoxy, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, substituted or unsubstituted C1-C 10 Linear or branched dialkylamino, substituted or unsubstituted C3-C 10 Cycloalkyl or heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 selected from the group consisting of heteroaryl, —CN and halo; X and Y are independently selected from the group consisting of -CH- and -N-. The method includes administering

[0122] Alternatively, the methods of treatment described herein may comprise administering to a subject a therapeutically effective amount of a compound of formula II [ka] [In the formula, R 1 is H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C5-C 10 Heteroarylalkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 1 and the N to which it is attached, taken together, form a substituted or unsubstituted C3-C6 heterocycloalkyl or heteroaryl ring (replacing the H attached to the N); A is a bond, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Straight or branched alkenyl, substituted or unsubstituted C2-C 10 selected from the group consisting of straight-chain or branched alkynyl, C═O, C═S, —CH—, —CH(OH)—, —NH—, —N(CH)—, —O—, —S—, and SO; R 4 is substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C1-C 10 Straight or branched alkoxy, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, substituted or unsubstituted C1-C 10 Linear or branched dialkylamino, substituted or unsubstituted C3-C 10 Cycloalkyl or heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C5-C 10 selected from the group consisting of heteroaryl, —CN and halo; R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently H, substituted or unsubstituted C1-C 10 Straight or branched alkyl, substituted or unsubstituted C2-C 10Straight or branched alkenyl, substituted or unsubstituted C2-C 10 Straight or branched alkynyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Heteroaryl, substituted or unsubstituted C-C 10 Aryl alkyl, substituted or unsubstituted C1-C 10 Linear or branched alkylamino, and substituted or unsubstituted C1-C 10 or R is selected from the group consisting of linear or branched dialkylamino; 5 and R 6 are combined to form =O, or R 7 and R 8 are combined to form =O, or R 9 and R 10 are combined to become =O, X and Y are independently selected from the group consisting of -CH- and -N-; Z is C=O, -CR 9 R 10 -, -NR 9 -, -O-, -S-, -S(O)- and -SO2-. The method includes administering

[0123] In one embodiment, a therapeutically effective amount of the aforementioned compound is used in a method for treating a disease selected from the group consisting of atherosclerosis, ischemia-reperfusion, heart failure, Alzheimer's disease, rheumatoid arthritis, thalassemia, chronic obstructive pulmonary disease (COPD), age-related macular degeneration, aging, cancer, and immunological disorders.

[0124] In one of the foregoing aspects, the disease is an immunological disorder. Exemplary immunological disorders include autoimmune diseases (e.g., diabetes mellitus, arthritis (including rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, and psoriatic arthritis), multiple sclerosis, encephalomyelitis, myasthenia gravis, systemic lupus erythematosus, autoimmune thyroiditis, dermatitis (including atopic dermatitis and eczematous dermatitis), psoriasis, Sjogren's syndrome, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, sepsis and septic shock, inflammatory bowel disorders, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, drugs, etc.). rash, leprosy reversal reaction, erythema nodosum leprosum, autoimmune uveitis, allergic encephalomyelitis, acute necrotizing hemorrhagic encephalopathy, idiopathic bilateral progressive sensorineural hearing loss, aplastic anemia, pure cytic anemia, idiopathic thrombocytopenia, polychondritis, Wegener's granulomatosis, chronic active hepatitis, Stevens-Johnson syndrome, glomerulonephritis, idiopathic sprue, lichen planus, Graves' disease, sarcoidosis, primary biliary cirrhosis, posterior uveitis, interstitial pulmonary fibrosis, graft-versus-host disease, transplant rejection, and allergies, such as atopic allergy.

[0125] In another embodiment, a therapeutically effective amount of the aforementioned compound is used in a method for treating a disease selected from the group consisting of epilepsy, kidney disease, stroke, myocardial infarction, congestive heart failure, type I diabetes, traumatic brain injury (TBI), and periventricular leukomalacia (PVL).

[0126] In yet another embodiment, a therapeutically effective amount of the aforementioned compound is used in a method for treating a disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, ataxia-telangiectasia, Rett syndrome, X-linked adrenoleukodystrophy, multiple sclerosis, Huntington's disease, transmissible spongiform encephalopathy, Charcot-Marie-Tooth disease, dementia with Lewy bodies, Menkes disease, Wilson's disease, Creutzfeldt-Jakob disease, Fahr's disease, frontotemporal dementia, amyloidosis, Tisachs periventricular leukomalacia, corticobasal degeneration, progressive supranuclear palsy, and hereditary spastic paraplegia.

[0127] In yet another embodiment, a therapeutically effective amount of the aforementioned compound is used in a method for treating a disease selected from the group consisting of reduced cell proliferation, altered cell differentiation or intracellular signaling, unwanted inflammation, cell death of retinal neurons, cardiomyocytes or immune system cells, or cell death associated with renal failure, neonatal respiratory distress, respiratory arrest, incarcerated hernia, placental infarction, iron-loading complications, endometriosis, congenital disease, head trauma / traumatic brain injury, liver injury, environmental radiation injury, burn injury, cold injury, mechanical injury, decompression sickness, priapism, snake, scorpion or spider bite, UV damage to the skin, skin aging, and hair loss.

[0128] In further embodiments, a therapeutically effective amount of the aforementioned compound is used in a method for treating a disease selected from the group consisting of muscle wasting diseases, muscular dystrophy or related diseases (e.g., Becker muscular dystrophy, Duchenne muscular dystrophy, myotonic dystrophy, limb-girdle muscular dystrophy, Landauzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy (Steinert disease), congenital myotonia, Thomsen disease, and Pompe disease), ischemia, compartment syndrome, gangrene, pressure ulcers, sepsis, osteoarthritis, retinal necrosis, heart disease, liver, gastrointestinal or pancreatic necrotizing disease (e.g., acute necrotizing pancreatitis), avascular necrosis, diabetes, sickle cell disease, vascular alterations, and cancer chemo / radiotherapy-induced cell death.

[0129] In another embodiment, a therapeutically effective amount of the aforementioned compound is used in a method for treating an infectious disease caused by infection with a virus, bacteria, fungus or other microorganism.

[0130] In one of the foregoing aspects, the infectious disease is caused by a virus. Exemplary viruses include, but are not limited to, human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), cytomegalovirus (CMV) (e.g., CMV5), human herpesvirus (HHV) (e.g., HHV6, 7, or 8), herpes simplex virus (HSV), bovine herpesvirus (BHV) (e.g., BHV4), equine herpesvirus (EHV) (e.g., EHV2), human T-cell leukemia virus (HTLV) 5, varicella-zoster virus (VZV), measles virus, papovaviruses (JC and BK), hepatitis virus (e.g., HBV or HCV), myxoma virus, adenovirus, parvovirus, polyomavirus, influenza virus, papillomavirus, and poxviruses, such as vaccinia virus, molluscum contagiosum virus (MCV), and lyssavirus. Exemplary diseases caused by viral infections include, but are not limited to, chicken pox, cytomegalovirus infection, genital herpes, hepatitis B and C, influenza, shingles, and rabies.

[0131] In another of the foregoing embodiments, the infectious disease is caused by a bacterium. Exemplary bacteria include Campylobacter jejuni, Enterobacter species, Enterococcus faecium, Enterococcus faecalis, Escherichia coli (e.g., E. coli 0157:H7), Group A Streptococcus, Haemophilus influenzae, Helicobacter pylori, listeria, Mycobacterium tuberculosis, Pseudomonas aeruginosa, S. pneumoniae, Salmonella, Shigella, Staphylococcus aureus, Staphylococcus epidermidis, Borrelia, and Rickettsia. Exemplary diseases caused by bacterial infection include anthrax, cholera, diphtheria, foodborne illness, leprosy, meningitis, peptic ulcer disease, pneumonia, sepsis, septic shock, syphilis, tetanus, tuberculosis, typhoid fever, urinary tract infections, Lyme disease, and Rocky Mountain spotted fever. [Example]

[0132] experiment All reagents were purchased from commercial suppliers and used as supplied unless otherwise indicated. Reactions were carried out in air unless otherwise indicated. 1 H NMR spectra were obtained on a JEOL AS 400 spectrometer. Low-resolution mass spectra (LRMS) were obtained on a JEOL JMS-T100LC DART / AccuTOF mass spectrometer. Protein aggregation reversal was measured using assays such as Bis-ANS fluorescence, as described, for example, in W.T. Chen et al., J. Biol. Chem, 2011, 286 (11), 9646. It may be implemented as follows. Example 1 Synthesis of fused pyrimidine ketones

[0133] General reaction scheme for fused pyrimidine ketones [ka]

[0134] Step 1. Synthesis of Cl-substituted intermediates 2-Chloro-N-cyclopentyl-pyrido[3,2-d]pyrimidin-4-amine (K-04). [ka] A 250 mL RBF was charged with 2,4-dichloropyrido[3,2-d]pyrimidine (2 g, 10 mmol), a stir bar, THF (20 mL, 0.5 M), DiPEA (1.25 equiv., 2.2 mL, 12.5 mmol), and cyclopentylamine (1 equiv., 851 mg, 10 mmol) and stirred at room temperature. The reaction mixture immediately turned milky bright yellow and stirring was continued. After 2 h, the reaction was partitioned between 50 mL of EtOAc and 50 mL of HO. The aqueous layer was back-extracted with 1 × 25 mL of EtOAc. The combined organic layers were dried over NaSO and concentrated under reduced pressure to provide 2-chloro-N-cyclopentyl-pyrido[3,2-d]pyrimidin-4-amine (K-04) as a viscous yellow oil (2.4 g, 96.5%), which was used in the next step without further purification. [ka] NOTE: The reaction can also be carried out overnight at room temperature with the same results.

[0135] 2-Chloro-4-pyrrolidin-1-yl-pyrido[3,2-d]pyrimidine (K-05). [ka] A 40 mL vial was charged with 2,4-dichloropyrido[3,2-d]pyrimidine (400 mg, 2 mmol), a stir bar, THF (4 mL, 0.5 M), DiPEA (1.25 equiv., 323 mg, 2.5 mmol), and pyrrolidine (1 equiv., 142 mg, 2 mmol) and stirred at room temperature. The reaction mixture immediately turned a warm, milky yellow color and quickly turned into a thick slurry, and stirring was continued. After 24 h, the reaction was partitioned between 25 mL of EtOAc and 25 mL of HO. The aqueous layer was back-extracted with 1 × 25 mL of EtOAc. The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 2-chloro-4-pyrrolidin-1-yl-pyrido[3,2-d]pyrimidine (K-05) as a yellow solid (422 mg, 89.9%), which was used in the next step without further purification. [ka]

[0136] N-tert-Butyl-2-chloro-pyrido[3,2-d]pyrimidin-4-amine (K-06). [ka] A 40 mL vial was charged with 2,4-dichloropyrido[3,2-d]pyrimidine (400 mg, 2 mmol), a stir bar, THF (4 mL, 0.5 M), DiPEA (1.25 equiv., 323 mg, 2.5 mmol), and tert-butylamine (1.25 equiv., 323 mg, 2.5 mmol) and stirred at room temperature. After 24 h, the reaction was partitioned between 25 mL of EtOAc and 25 mL of HO. The aqueous layer was back-extracted with 1×25 mL of EtOAc. The combined organic layers were dried over NaSO and concentrated under reduced pressure to give a yellow oil. The oil was triturated with diethyl ether to give N-tert-butyl-2-chloro-pyrido[3,2-d]pyrimidin-4-amine (K-06) as a yellow solid (246 mg, 52%), which was used in the next step without further purification. [ka]

[0137] 2-Chloro-N-(2-pyridyl)pyrido[3,2-d]pyrimidin-4-amine (K-08). [ka] A 250 mL RBF was charged with 2-aminopyridine (1 equiv., 5.0 mmol, 471 mg), tetrahydrofuran (10 mL, 0.5 M), DiPEA (1.5 equiv., 7.5 mmol, 1.31 mL), and then 2,4-dichloropyrido[3,2-d]pyrimidine (1 g, 0.5 mmol). The reaction was stirred at room temperature for 16 h and then partitioned between 50 mL of water and 50 mL of EtOAc. The aqueous layer was back-extracted with 2 × 25 mL of EtOAc, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified on SiO (40 g, 5–100% hexanes / EtOAC) to afford 2-chloro-N-(2-pyridyl)pyrido[3,2-d]pyrimidin-4-amine (K-08) as a pale yellow solid (285 mg, 22%). (APCI) m / e 258.0 (M+H).

[0138] 2-Chloro-N-prop-2-ynyl-pyrido[3,2-d]pyrimidin-4-amine (K-13). [ka] A 40 mL vial was charged with 2,4-dichloropyrido[3,2-d]pyrimidine (400 mg, 2 mmol), a stir bar, THF (4 mL, 0.5 M), DiPEA (1.5 equiv., 0.52 mL, 2.5 mmol), and prop-2-yn-1-amine (1 equiv., 110 mg, 2 mmol) and stirred at room temperature. The reaction mixture immediately turned a warm, milky yellow color and quickly turned into a thick slurry, and stirring was continued. After 2 h, the reaction was partitioned between 5 mL of EtOAc and 5 mL of H2O, and the aqueous layer was back-extracted with 1 x 5 mL of EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 350 mg (80%) of the desired product, which was used directly in the next step without further purification. (APCI) m / e 219.0 (M+H).

[0139] 2-Chloro-N-(3-methyltetrahydrofuran-3-yl)pyrido[3,2-d]pyrimidin-4-amine (N-07) [ka] A 100 mL RBF was charged with 2,4-dichloropyrido[3,2-d]pyrimidine (1 g, 5 mmol), a stir bar, THF (10 mL, 0.5 M), DiPEA (2 equiv., 1.75 mL, 10 mmol), and 3-methyltetrahydrofuran-3-amine (1 equiv., 506 mg, 5 mmol) and stirred at room temperature. After 16 h, the reaction was partitioned between 50 mL of EtOAc and 50 mL of HO. The aqueous layer was back-extracted with 1 × 25 mL of EtOAc. The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified on silica gel (80 g, 0–60% EtOAc / hexanes) to afford 1.13 g of 2-chloro-N-(3-methyltetrahydrofuran-3-yl)pyrido[3,2-d]pyrimidin-4-amine as a yellow solid (85%). (APCI) m / e 265.0 (M+H). Step 2. Synthesis of the cyano intermediate

[0140] 4-(Cyclopentylamino)pyrido[3,2-d]pyrimidine-2-carbonitrile (C-73). [ka] A solution of 2-chloro-N-cyclopentyl-pyrido[3,2-d]pyrimidin-4-amine (1.05 g, 4.2 mmol) in anhydrous DMF (15.0 mL) was degassed five times and then treated sequentially with zinc cyanide (0.993 g, 8.4 mmol, 2 equiv.) followed by tetrakis(triphenylphosphine)palladium(0) (0.735 g, 0.63 mmol, 0.15 equiv.). The reaction mixture was heated to 150 °C in a microwave for 30 minutes. LC / MS analysis of the crude reaction mixture indicated conversion to the desired product and complete consumption of the starting material. The mixture was filtered and adsorbed onto 10 g of silica. The product was purified by flash chromatography (40 g silica, 0 to 50% ethyl acetate / hexanes) to give 4-(cyclopentylamino)pyrido[3,2-d]pyrimidine-2-carbonitrile (C-73) as a yellow solid (0.784 g, 77.6%). [ka]

[0141] 4-(tert-Butylamino)pyrido[3,2-d]pyrimidine-2-carbonitrile (C-87). [ka] A solution of N-tert-butyl-2-chloro-pyrido[3,2-d]pyrimidin-4-amine (0.21 g, 0.88 mmol) in anhydrous DMF (3 mL) was degassed five times and then treated sequentially with zinc cyanide (0.21 g, 1.8 mmol, 2 equiv.) followed by tetrakis(triphenylphosphine)palladium(0) (0.153 g, 0.13 mmol, 0.15 equiv.). The reaction mixture was heated to 150 °C in a microwave for 30 min. LC / MS analysis of the crude reaction mixture indicated conversion to the desired product and complete consumption of the starting material. The mixture was filtered and adsorbed onto 1 g of silica. The product was purified by flash chromatography (12 g silica, 0-50% ethyl acetate / hexanes) to give 4-(tert-butylamino)pyrido[3,2-d]pyrimidine-2-carbonitrile (C-87) as a pale yellow solid (0.167 g, 83.2%). 12 H 13 MS (APCI) for N5: Calculated: 228.1 [M+H + ], Actual value: 228.1. Step 3. Synthesis of ketone intermediate

[0142] 1-[4-(Cyclopentylamino)pyrido[3,2-d]pyrimidin-2-yl]pentan-1-one (C-76). [ka] A solution of 4-(cyclopentylamino)pyrido[3,2-d]pyrimidine-2-carbonitrile (0.574 g, 2.4 mmol) in anhydrous THF (10 mL) was cooled to -78 °C and then treated with sodium hydroxide (0.138 g, 3.6 mmol, 1.5 equiv.), and the mixture was allowed to stir for 30 min. The mixture was then treated sequentially with copper(I) bromide (52 mg, 0.36 mmol, 0.15 equiv.) followed by butylmagnesium bromide (2 M in diethyl ether, 1.6 mL, 5.3 mmol, 2.2 equiv.). After stirring for 20 min, the reaction mixture was slowly warmed to 30 °C. LC / MS analysis after 4 h indicated partial conversion to the desired product. The mixture was then warmed to 0 °C. After an additional 4 h, LC / MS indicated complete conversion to the desired product. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and poured into ethyl acetate (50 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic extracts were dried (NaSO) and the solvent was removed in vacuo. The residual oil was purified by flash chromatography (24 g silica, 0–50% ethyl acetate / hexanes) to afford 1-[4-(cyclopentylamino)pyrido[3,2-d]pyrimidin-2-yl]pentan-1-one (C-76) as a yellow oil (0.630 g, 88.0%). [ka]

[0143] 1-[4-(Cyclopentylamino)pyrido[3,2-d]pyrimidin-2-yl]ethanone (C-89). [ka] A solution of (0.405 g, 1.7 mmol) in anhydrous THF (8 mL) was treated with copper(I) bromide (37 mg, 0.25 mmol, 0.15 equiv) and then cooled to -78 °C. After 10 min, the reaction mixture was treated dropwise with methylmagnesium bromide (3 M in diethyl ether, 1.3 mL, 3.7 mol, 2.2 equiv). After the addition was complete, the reaction was stirred for an additional 10 min and then warmed to 0 °C. After 2 h, LC / MS analysis indicated complete conversion of the starting material to the desired product. The reaction was quenched with saturated aqueous ammonium chloride (3 mL) and then warmed to room temperature. The biphasic mixture was diluted with ethyl acetate (30 mL), and the layers were separated. The aqueous layer was further extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried (NaSO) and the solvent removed in vacuo. The residual solid was purified by flash chromatography (adsorbed onto a 2 g silica precolumn, 24 g silica, 0-50% ethyl acetate / hexanes) to give 1-[4-(cyclopentylamino)pyrido[3,2-d]pyrimidin-2-yl]ethanone (C-89) as an off-white solid (0.138 g, 31.3%). 14 H 16 MS (APCI) for NO; calculated: 257.1 [M+H + ], Actual value: 257.0.

[0144] 1-[4-(Cyclopentylamino)pyrido[3,2-d]pyrimidin-2-yl]propan-1-one (C-90). [ka] A solution of 4-(cyclopentylamino)pyrido[3,2-d]pyrimidine-2-carbonitrile (0.203 g, 0.85 mmol) in THF (3 mL) was treated with copper(I) bromide (18 mg, 0.13 mmol, 0.15 equiv.) and then cooled to -78 °C. After 10 min, the reaction mixture was treated dropwise with ethylmagnesium bromide (1 M in THF, 1.3 mL, 3.7 mol, 2.2 equiv.). After the addition was complete, the reaction was stirred for an additional 10 min and then warmed to 0 °C. After 2 h, LC / MS analysis indicated complete conversion of the starting material to the desired product. The reaction was quenched with saturated aqueous ammonium chloride (3 mL) and then warmed to room temperature. The biphasic mixture was diluted with ethyl acetate (20 mL), and the layers were separated. The aqueous layer was further extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried (Na2SO4) and the solvent removed in vacuo. The residual solid was purified by flash chromatography (adsorbed onto a 1 g silica precolumn, 24 g silica, 0-50% ethyl acetate / hexanes) to give 1-[4-(cyclopentylamino)pyrido[3,2-d]pyrimidin-2-yl]propan-1-one (C-90) as an off-white solid (0.145 g, 63.2%). 15 H 18 MS (APCI) for NO; calculated: 271.1 [M+H + ], Actual value: 271.0.

[0145] [4-(Cyclopentylamino)pyrido[3,2-d]pyrimidin-2-yl]-phenyl-methanone (A-02). [ka] A solution of 4-(cyclopentylamino)pyrido[3,2-d]pyrimidine-2-carbonitrile (0.21 g, 0.88 mmol) in anhydrous THF (3 mL) was treated with copper(I) bromide (19 mg, 0.13 mmol, 0.15 equiv.) and then cooled to -78 °C. After 10 min, the mixture was then treated with phenylmagnesium chloride (2 M in THF, 1.1 mL, 2.2 mmol, 2.5 equiv.). After stirring for 10 min, the reaction mixture was slowly warmed to 0 °C. LC / MS analysis after 1 h indicated complete conversion to the desired product. The reaction mixture was quenched with saturated aqueous ammonium chloride (3 mL) and poured into ethyl acetate (10 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic extracts were dried (NaSO), and the solvent was removed in vacuo. The residual solid was purified by flash chromatography (24 g silica, 0-50% ethyl acetate / hexanes) to give [4-(cyclopentylamino)pyrido[3,2-d]pyrimidin-2-yl]-phenyl-methanone (A-02) as a pale yellow solid (0.21 g, 75.2%). 19 H 18 MS (APCI) for NO; calculated: 319.2 [M+H + ], Actual value: 319.1.

[0146] [4-(Cyclopentylamino)pyrido[3,2-d]pyrimidin-2-yl]-(4-fluorophenyl)methanone (A-03). [ka] A solution of 4-(cyclopentylamino)pyrido[3,2-d]pyrimidine-2-carbonitrile (0.21 g, 0.88 mmol) in anhydrous THF (3 mL) was treated with copper(I) bromide (19 mg, 0.13 mmol, 0.15 equiv.) and then cooled to -78 °C. After 10 min, the mixture was then treated with 4-fluorophenylmagnesium bromide (2 M in diethyl ether, 1.1 mL, 2.2 mmol, 2.5 equiv.). After stirring for 10 min, the reaction mixture was slowly warmed to 0 °C. LC / MS analysis after 1 h indicated complete conversion to the desired product. The reaction mixture was quenched with saturated aqueous ammonium chloride (3 mL) and poured onto ethyl acetate (10 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic extracts were dried (NaSO), and the solvent was removed in vacuo. The residual solid was purified by flash chromatography (24 g silica, 0-50% ethyl acetate / hexanes) to give [4-(cyclopentylamino)pyrido[3,2-d]pyrimidin-2-yl]-(4-fluorophenyl)methanone (A-03) as a pale yellow solid (0.287 g, 97.2%). 19 H 17 MS (APCI) for FNO; calculated: 337.1 [M+H + ], Actual value: 337.0.

[0147] 1-[4-(Cyclopentylamino)pyrido[3,2-d]pyrimidin-2-yl]-2,2-dimethyl-propan-1-one (A-04). [ka] A solution of 4-(cyclopentylamino)pyrido[3,2-d]pyrimidine-2-carbonitrile (0.20 g, 0.84 mmol) in anhydrous THF (3 mL) was treated with copper(I) bromide (18 mg, 0.13 mmol, 0.15 equiv.) and then cooled to −78° C. After 10 min, the mixture was then treated with tert-butylmagnesium chloride (2 M in diethyl ether, 1.1 mL, 2.2 mmol, 2.6 equiv.). After stirring for 10 min, the reaction mixture was slowly warmed to 0° C. LC / MS analysis after 1 h showed conversion to the desired product with some remaining starting material. After 2 h, no further progress was observed, and an additional 0.7 mL of tert-butylmagnesium chloride solution was added. Two hours after the second addition, LC / MS analysis showed complete consumption of the starting material and formation of the bis-tert-butyl addition product. The reaction mixture was quenched with saturated aqueous ammonium chloride (3 mL) and poured onto ethyl acetate (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were dried (Na2SO4) and the solvent removed in vacuo. The residual solid was purified by flash chromatography (24 g silica, 0-50% ethyl acetate / hexanes) to afford 1-[4-(cyclopentylamino)pyrido[3,2-d]pyrimidin-2-yl]-2,2-dimethyl-propan-1-one (A-04) as a pale yellow coating (0.080 g, 32.3%). 17 H 22 MS (APCI) for NO; calculated: 299.2 [M+H + ], Actual value: 299.1.

[0148] 1-[4-(tert-butylamino)pyrido[3,2-d]pyrimidin-2-yl]pentan-1-one (C-99). [ka] A solution of 4-(tert-butylamino)pyrido[3,2-d]pyrimidine-2-carbonitrile (0.167 g, 0.74 mmol) in anhydrous THF (3 mL) was treated with copper(I) bromide (16 mg, 0.11 mmol, 0.15 equiv.) and then cooled to -78 °C. After 10 min, the mixture was then treated with butylmagnesium chloride (2 M in diethyl ether, 1.0 mL, 1.8 mmol, 2.5 equiv.). After stirring for 10 min, the reaction mixture was slowly warmed to 0 °C. LC / MS analysis after 1 h indicated complete conversion to the desired product. The reaction mixture was quenched with saturated aqueous ammonium chloride (3 mL) and poured onto ethyl acetate (10 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic extracts were dried (NaSO), and the solvent was removed in vacuo. The residual solid was purified by flash chromatography (24 g silica, 0–50% ethyl acetate / hexanes) to afford 1-[4-(tert-butylamino)pyrido[3,2-d]pyrimidin-2-yl]pentan-1-one (C-99) as a pale yellow solid (0.167 g, 79.4%). [ka]

[0149] 1-(4-Pyrrolidin-1-ylpyrido[3,2-d]pyrimidin-2-yl)pentan-1-one (A-01). [ka] A solution of 4-pyrrolidin-1-ylpyrido[3,2-d]pyrimidine-2-carbonitrile (0.190 g, 0.84 mmol) in anhydrous THF (3 mL) was treated with copper(I) bromide (19 mg, 0.13 mmol, 0.15 equiv.) and then cooled to -78 °C. After 10 min, the mixture was then treated with butylmagnesium chloride (2 M in diethyl ether, 1.1 mL, 2.1 mmol, 2.5 equiv.). After stirring for 10 min, the reaction mixture was slowly warmed to 0 °C. LC / MS analysis after 1 h indicated complete conversion to the desired product. The reaction mixture was quenched with saturated aqueous ammonium chloride (3 mL) and poured onto ethyl acetate (10 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic extracts were dried (NaSO), and the solvent was removed in vacuo. The residual solid was purified by flash chromatography (24 g silica, 0-50% ethyl acetate / hexanes) to give 1-[4-(tert-butylamino)pyrido[3,2-d]pyrimidin-2-yl]pentan-1-one (A-01) as a pale yellow solid (0.073 g, 30.4%). 16 H 20 MS (APCI) for NO; calculated: 285.2 [M+H + ], Actual value: 285.0. Step 4. Ring reduction synthesis of the final compound 1-[4-(cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]pentan-1-one (C-82) [ka] A mixture of 1-[4-(cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]pentan-1-ol and 1-[4-(cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]pentan-1-one (0.203 g, 0.67 mmol) in methylene chloride (3 mL) was treated with Dess-Martin periodinane (0.34 g, 0.80 mmol, 1.2 equiv.). After stirring for 2 h, LC / MS analysis indicated complete conversion to the desired product. The reaction mixture was dried and the residue was purified by flash chromatography (12 g silica, 0-20% acetonitrile / ethyl acetate) to give 1-[4-(cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]pentan-1-one, 170 mg, as a yellow solid. [ka]

[0150] 2-Chloro-N-cyclopentyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine (C-80) [ka] A solution of 2-chloro-N-cyclopentyl-pyrido[3,2-d]pyrimidin-4-amine (0.60 g, 2.4 mmol) in ethanol (12 mL) was treated with TFA (0.18 mL, 2.4 mmol, 1 equiv.) and then degassed with nitrogen for five cycles. The reaction mixture was then treated with platinum(IV) oxide (0.164 g, 0.72 mmol, 0.3 equiv.), and hydrogen gas was bubbled through the solution via a balloon for 10 minutes. The needle was removed from the solution, and the reaction mixture was stirred overnight under balloon pressure of hydrogen gas. LC / MS analysis showed complete consumption of the starting material to two products: the desired major product and a minor product with the tetrahydropyridine ring replaced with hydrogen instead of chlorine. The reaction mixture was filtered through Celite, and the solvent was removed in vacuo. The residue was purified by flash chromatography (12 g silica, 0-100% ethyl acetate / hexanes) followed by 0-10% methanol / ethyl acetate) to give 2-chloro-N-cyclopentyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine (0.346 g) as an off-white solid. LCMS: (APCI) m / e 253.1 (M+H).

[0151] N-Cyclopentyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine (C-84) [ka] A by-product was isolated from C-80 (80 mg). [ka]

[0152] 1-[4-(cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]pentan-1-ol (C-79) [ka] A solution of 1-[4-(cyclopentylamino)pyrido[3,2-d]pyrimidin-2-yl]pentan-1-one (0.20 g, 0.67 mmol) in ethanol (3 mL) was treated sequentially with nickel(II) chloride (17 mg, 0.13 mmol, 0.2 equiv.) and then slowly with sodium borohydride (76 mg, 2.0 mmol, 3 equiv.). The reaction mixture slowly evolved gas and changed color to brownish-black. After stirring overnight, LC / MS analysis indicated complete conversion to the desired product. The reaction mixture was poured onto saturated aqueous sodium bicarbonate (5 mL) and then extracted with ethyl acetate (3 × 25 mL). The combined organic extracts were dried (NaSO), and the solvent was removed in vacuo. The residual solid was purified by flash chromatography (12 g silica, 0-20% methanol / methylene chloride) to give 1-[4-(cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]pentan-1-ol, 0.15 g, as a reddish-brown solid. LCMS: (APCI) m / e 305.1 (M+H).

[0153] 1-[4-(cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]ethanone (C-92) [ka] A solution of 1-[4-(cyclopentylamino)pyrido[3,2-d]pyrimidin-2-yl]ethanone (0.138 g, 0.54 mmol) in ethanol (5 mL) was treated with TFA (40 μL, 0.54 mmol, 1.0 equiv.) and then degassed by bubbling N2 through the reaction mixture. After 10 min, the reaction mixture was treated with PtO2 (25 mg, 0.11 mmol, 0.2 equiv.), and then the reaction was subjected to bubbling of H2 gas through a needle. After 20 min, the H2 gas introduction needle was elevated above the reaction, and the mixture was stirred overnight under balloon pressure. LC / MS analysis showed complete consumption of the starting material and 80% conversion to the desired product, with an additional 20% conversion to the over-reduced product, in which the ketone was also reduced to the alcohol. The reaction mixture was degassed with N2 gas, and then the reaction mixture was filtered through Celite. The solvent was removed in vacuo and the residual solid purified by flash chromatography (mixture adsorbed onto a 2 g silica precolumn, 12 g silica, 0-30% methanol / methylene chloride) to give 1-[4-(cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]ethanone, 0.123 g, as a yellow solid. LCMS: (APCI) m / e 261.1 (M+H).

[0154] 1-[4-(tert-butylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]pentan-1-ol (A-00) [ka] A solution of 1-[4-(tert-butylamino)pyrido[3,2-d]pyrimidin-2-yl]pentan-1-one (0.14 g, 0.49 mmol) in ethanol (3 mL) was treated with TFA (36 μL, 0.49 mmol, 1.0 equiv.) and then degassed by bubbling N2 through the reaction mixture. After 10 min, the reaction mixture was treated with PtO2 (22 mg, 0.098 mmol, 0.2 equiv.), and then the reaction was subjected to bubbling of H2 gas via a needle. After 20 min, the H2 gas introduction needle was lifted from the reaction, and the mixture was stirred overnight under balloon pressure. LC / MS analysis showed complete consumption of the starting material and >90% conversion to the over-reduced product, in which the ketone was also reduced to the alcohol. Crude LC / MS showed no distinct peak for the ketone product. The reaction mixture was degassed with N2 gas, and then filtered through Celite. The solvent was removed in vacuo, and the residual solid was purified by flash chromatography (12 g silica, 0-30% methanol / methylene chloride) to afford 0.107 g of 1-[4-(tert-butylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]pentan-1-ol as a viscous yellow oil. Additionally, 13 mg of the ketone was isolated as a yellow solid (D-06). LCMS: (APCI) m / e 293.1 (M+H).

[0155] 1-[4-(tert-butylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]pentan-1-one (A-06) [ka] A solution of 1-[4-(tert-butylamino)pyrido[3,2-d]pyrimidin-2-yl]pentan-1-one (0.14 g, 0.49 mmol) in ethanol (3 mL) was treated with TFA (36 μL, 0.49 mmol, 1.0 equiv.) and then degassed by bubbling N through the reaction mixture. After 10 min, the reaction mixture was treated with PtO (22 mg, 0.098 mmol, 0.2 equiv.), and then the reaction was subjected to bubbling of H gas through a needle. After 20 min, the H gas introduction needle was lifted from the reaction, and the mixture was stirred overnight under balloon pressure. LC / MS analysis showed complete consumption of the starting material and >90% conversion to the over-reduced product, in which the ketone was also reduced to the alcohol. Crude LC / MS showed no distinct peak for the ketone product. The reaction mixture was degassed with N2 gas, then filtered through Celite. The solvent was removed in vacuo, and the residual solid was purified by flash chromatography (12 g silica, 0-30% methanol / methylene chloride) to afford 13 mg of the ketone, isolated as a yellow solid. Additionally, 0.107 g of 1-[4-(tert-butylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]pentan-1-ol was obtained as a viscous yellow oil (D-00). LCMS: (APCI) m / e 291.1 (M+H); [ka]

[0156] 1-[4-(2-pyridylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]pentan-1-ol (G-63) [ka]

[0157] 1-[4-(2-pyridylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]pentan-1-ol (G-63) was prepared according to the same procedure as A-00 to give 26 mg (18%). LCMS: (APCI) m / e 314.1 (M+H).

[0158] 1-[4-(2-pyridylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]pentan-1-one (G-65) [ka]

[0159] 1-[4-(2-pyridylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]pentan-1-one (G-65) was prepared according to a similar procedure to A-06 to give 9 mg (6%). LCMS: (APCI) m / e 312.1 (M+H).

[0160] 1-(4-pyrrolidin-1-yl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)pentan-1-ol (A-09) [ka] A solution of 1-(4-pyrrolidin-1-ylpyrido[3,2-d]pyrimidin-2-yl)pentan-1-one (73 mg, 0.26 mmol) in ethanol (1 mL) was treated with TFA (19 μL, 0.26 mmol, 1.0 equiv.) and then degassed by bubbling N through the reaction mixture. After 10 min, the reaction mixture was treated with PtO (6 mg, 26 μmol, 0.1 equiv.), and then the reaction was subjected to bubbling of H gas through a needle. After 20 min, the H gas introduction needle was elevated above the reaction, and the mixture was stirred overnight under balloon pressure. LC / MS analysis showed complete consumption of the starting material, 80% conversion to the desired product, and an additional 20% conversion to the over-reduced product, in which the ketone was also reduced to the alcohol. The reaction mixture was degassed with N, and then the reaction mixture was filtered through Celite. The solvent was removed in vacuo and the residual solid purified by flash chromatography (mixture adsorbed onto a 2 g silica precolumn, 12 g silica, 0-30% methanol / methylene chloride) to give 1-(4-pyrrolidin-1-yl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)pentan-1-ol, 0.123 g, as a yellow solid. LCMS: (APCI) m / e 291.1 (M+H).

[0161] [4-(Cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]-phenyl-methanol (A-10) [ka] A solution of [4-(cyclopentylamino)pyrido[3,2-d]pyrimidin-2-yl]phenylmethanone (0.21 g, 0.66 mmol) in ethanol (3 mL) was treated with TFA (76 μL, 0.66 mmol, 1.0 equiv.) and then degassed by bubbling N through the reaction mixture. After 10 min, the reaction mixture was treated with PtO (15 mg, 0.066 mmol, 0.1 equiv.), and then the reaction was subjected to bubbling of H gas via a needle. After 20 min, the H gas introduction needle was elevated above the reaction, and the mixture was stirred under balloon pressure overnight. LC / MS analysis indicated complete consumption of the starting material and conversion to the over-reduced product. The reaction mixture was degassed with N, and then the reaction mixture was filtered through Celite. The solvent was removed in vacuo and the residual solid purified by flash chromatography (adsorb the mixture onto a 2 g silica precolumn, 12 g silica, 0-30% methanol / methylene chloride) to give [4-(cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]-phenyl-methanol, 0.185 g, as a pale yellow solid. LCMS: (APCI) m / e 325.1 (M+H).

[0162] [4-(cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]-(4-fluorophenyl)methanol (A-11) [ka] A solution of [4-(cyclopentylamino)pyrido[3,2-d]pyrimidin-2-yl]-(4-fluorophenyl)methanone (0.287 g, 0.85 mmol) in ethanol (3 mL) was treated with TFA (98 μL, 0.85 mmol, 1.0 equiv.) and then degassed by bubbling N through the reaction mixture. After 10 min, the reaction mixture was treated with PtO (20 mg, 0.085 mmol, 0.1 equiv.), and then the reaction was subjected to bubbling of H gas via a needle. After 20 min, the H gas introduction needle was elevated above the reaction, and the mixture was stirred overnight under balloon pressure. LC / MS analysis indicated complete consumption of the starting material and conversion to the alcohol. The reaction mixture was degassed with N gas, and then the reaction mixture was filtered through Celite. The solvent was removed in vacuo and the residual solid purified by flash chromatography (mixture adsorbed onto a 2 g silica precolumn, 12 g silica, 0-30% methanol / methylene chloride) to give [4-(cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]-(4-fluorophenyl)methanol, 0.245 g, as a pale yellow solid. LCMS: (APCI) m / e 343.1 (M+H).

[0163] [4-(Cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]-phenyl-methanone (A-16) [ka] A solution of 1-[4-(cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]phenyl-methanol (0.069 g, 24 mmol) in methylene chloride (1 mL) was treated with Dess-Martin periodinane (0.12 g, 0.28 mmol, 1.2 equiv.). After stirring for 2 h, LC / MS analysis indicated complete conversion to the desired product. The reaction mixture was dried, and the residue was purified by flash chromatography (12 g silica, 0–20% acetonitrile / ethyl acetate) to afford 1-[4-(cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]phenyl-methanone, 170 mg, as a yellow solid. [ka]

[0164] [4-(Cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]-(4-fluorophenyl)methanone (A-17) [ka] A solution of [4-(cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]-(4-fluorophenyl)methanol (0.069 g, 24 mmol) in methylene chloride (1 mL) was treated with Dess-Martin periodinane (0.12 g, 0.28 mmol, 1.2 equiv.). After stirring for 2 h, LC / MS analysis indicated complete conversion to the desired product. The reaction mixture was dried, and the residue was purified by flash chromatography (12 g silica, 0–20% acetonitrile / ethyl acetate) to afford [4-(cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]-(4-fluorophenyl)methanone, 170 mg, as a yellow solid. [ka]

[0165] 1-(4-Pyrrolidin-1-yl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)pentan-1-ol (A-18) [ka] A solution of 1-(4-pyrrolidin-1-yl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)pentan-1-ol (43 mg, 0.15 mmol) in acetone (1 mL) was subsequently treated with Dess-Martin reagent (63 mg, 0.15 mmol, 1.0 equiv.). After stirring for 2 h, LC / MS analysis indicated complete and complete conversion to the desired ketone. The solvent was removed in vacuo, and the residual solid was purified by flash chromatography (12 g silica, 0-10% methanol / methylene chloride) to afford 1-(4-pyrrolidin-1-yl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl)pentan-1-one, mg, as a yellow gum. LCMS: (APCI) m / e 289.1 (M+H); [ka]

[0166] 1-[4-(cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]-2,2-dimethyl-propan-1-one (A-35) [ka] A solution of 1-[4-(cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]-2,2-dimethyl-propan-1-ol (33 mg, 0.11 mmol) in acetone (1 mL) was treated with Dess-Martin periodinane (51 mg, 0.12 mmol, 1.1 equiv.) and the reaction was stirred at room temperature. After 16 h, the reaction was complete by crude LCMS. The reaction mixture was partitioned between 20 mL of DCM and 20 mL of 1 M NaOH(aq); stirred for 10 min. The aqueous layer was extracted with DCM (3 × 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified on silica gel (40 g, 0-30% EtOAc / hexanes) to give 30 mg of 1-[4-(cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-2-yl]-2,2-dimethyl-propan-1-one (91%). LCMS: (APCI) m / e 303.1 (M+H).

[0167] N-Cyclopentyl-2-pentyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine (A-63) [ka] A solution of 1-[4-(tert-butylamino)pyrido[3,2-d]pyrimidin-2-yl]pentan-1-one (0.14 g, 0.49 mmol) in ethanol (3 mL) was treated with TFA (36 μL, 0.49 mmol, 1.0 equiv.) and then degassed by bubbling N through the reaction mixture. After 10 min, the reaction mixture was treated with PtO (22 mg, 0.098 mmol, 0.2 equiv.), and then the reaction was subjected to bubbling of H gas via a needle. After 20 min, the H gas introduction needle was elevated above the reaction, and the mixture was stirred under balloon pressure overnight. LC / MS analysis showed complete consumption of the starting material and >90% conversion to the over-reduced product, in which the ketone was also reduced to the alcohol. Crude LC / MS showed no distinct peak for the ketone product. The reaction mixture was degassed with N2 gas, and then filtered through Celite. The solvent was removed in vacuo, and the residual solid was purified by flash chromatography (12 g silica, 0-30% methanol / methylene chloride) to give N-cyclopentyl-2-pentyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine (A-63), 0.107 g, as a viscous yellow oil. LCMS: (APCI) m / e 289.1 (M+H).

[0168] 4-(Cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidine-2-carbonitrile (F-38) [ka] A solution of 2-chloro-N-cyclopentyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine (0.75 g, 2.97 mmol), zinc cyanide (0.7 g, 5.93 mmol, 2 equiv.), and benzaldehyde (0.332 mL, 3.26 mmol, 1.2 equiv.) in anhydrous DMF (10 mL) in a 25 mL microwave vial was degassed 4x (until no more bubbling occurred) and then treated with tetrakis(triphenylphosphine)palladium(0) (0.686 g, 0.593 mmol, 0.2 equiv.). The reaction mixture was heated to 150 °C in a microwave for 45 min. LC / MS analysis of the crude reaction mixture indicated conversion to the desired product and complete consumption of the starting material. The mixture was filtered and adsorbed onto silica. The product was purified by flash chromatography to give 4-(cyclopentylamino)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidine-2-carbonitrile, 0.62 g, as a yellow / beige solid. LCMS: (APCI) m / e 244.1 (M+H). Example 2 Synthesis of fused pyrimidine alkynes

[0169] General reaction scheme 2 for fused pyrimidine alkynes [ka] Synthesis of the final compound

[0170] N-Cyclopentyl-2-(2-phenylethynyl)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine (C-91) [ka] A slurry of 2-chloro-N-cyclopentyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine (0.15 g, 0.59 mmol) in triethylamine (2.0 mL) was treated with phenylacetylene (0.1 mL, 0.89 mmol, 1.5 equiv.) and then degassed by bubbling nitrogen through. After 10 min, the reaction mixture was subsequently treated with palladium(II) acetate (35 mg, 0.15 mmol, 0.25 equiv.) followed by triphenylphosphine (82 mg, 0.31 mmol, 0.52 equiv.). The reaction mixture was then microwaved at 100 °C for 1 h. LC / MS analysis indicated that approximately 10% of the desired product had formed. The reaction mixture was diluted with methylene chloride, filtered through Celite®, and the solvent was removed in vacuo. The residue was purified by flash chromatography (12 g silica, 0-100% ethyl acetate / hexanes) to give N-cyclopentyl-2-(2-phenylethynyl)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine, 6.2 mg, as a yellowish-red film. LCMS: (APCI) m / e 319.1 (M+H).

[0171] N-Cyclopentyl-2-prop-1-ynyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine (A-12) [ka] A solution of 2-chloro-N-cyclopentyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine (0.1 g, 0.48 mmol) in acetonitrile (0.75 mL) and water (1.5 mL) was treated successively with 4,4,5,5-tetramethyl-2-prop-1-ynyl-1,3,2-dioxaborolane (0.085 mL, 0.48 mmol, 1.2 equiv.) and cesium carbonate (0.387 g, 1.2 mmol, 3.0 equiv.), then degassed by bubbling nitrogen through. After 10 minutes, the reaction mixture was treated sequentially with palladium(II) acetate (9 mg, 40 μmol, 0.1 equiv) and triphenylphosphine-3,3′,3″-trisulfonic acid trisodium salt (90 mg, 1.6 mmol, 0.4 equiv). The reaction mixture was then microwaved at 160° C. for 1 hour. LC / MS analysis showed 50% product formation. The reaction mixture was diluted with methylene chloride, filtered through Celite®, and the solvent was removed in vacuo. The residue was purified by flash chromatography (12 g silica, 0-10% methanol / methylene chloride) to afford N-cyclopentyl-2-prop-1-ynyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine, 14 mg, as a yellow film. LCMS: (APCI) m / e 257.1 (M+H).

[0172] N-Cyclopentyl-2-pent-1-ynyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine (A-27) [ka] A solution of 2-chloro-N-cyclopentyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine (0.12 g, 0.48 mmol) in 1,4-dioxane (2.0 mL) was subsequently treated with 4,4,5,5-tetramethyl-2-prop-1-ynyl-1,3,2-dioxaborolane (0.8 mL, 0.48 mmol, 1.0 equiv.) and sodium carbonate (0.13 g, 1.2 mmol, 2.5 equiv.) and then degassed by bubbling nitrogen through. After 10 min, the reaction mixture was subsequently treated with tetrakis(triphenylphosphine)palladium (0.11 g, 95 µmol, 0.2 equiv.). The reaction mixture was then microwaved at 160 °C for 1 h. LC / MS analysis indicated that approximately 10% of the desired product had formed. The reaction mixture was diluted with methylene chloride, filtered through Celite®, and the solvent removed in vacuo. The residue was purified by flash chromatography (12 g silica, 0-100% ethyl acetate / hexanes) to afford N-cyclopentyl-2-(2-phenylethynyl)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine, 6.2 mg, as a yellowish-red film. LCMS: (APCI) m / e 285.1 (M+H). Example 3 Synthesis of fused pyrimidine aromatics

[0173] Schematic reaction scheme 3 for fused pyrimidine aromatics [ka] Synthesis of the final compound

[0174] N-Cyclopentyl-2-(4-phenyltriazol-1-yl)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine (A-31) [ka] A solution of 2-azido-N-cyclopentyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine (75 mg, 2.9 mmol) in DMSO (1 mL) was degassed by bubbling N through a balloon for 20 minutes. The reaction mixture was then treated with phenylacetylene (48 μL, 4.3 mmol, 1.5 equiv.) followed by copper(I) iodide (12 mg, 58 μmol, 0.2 equiv.), and the reaction mixture was then warmed to 60 °C. After 1 h, LC / MS analysis indicated complete conversion to the desired product. The reaction mixture was diluted with 10 mL of water, and the mixture was extracted with ethyl acetate (4 × 10 mL). The combined organic extracts were dried (NaSO), and the solvent was removed in vacuo. The residual solid was purified by flash chromatography (12 g silica, 0-10% methylene chloride / methanol) to give N-cyclopentyl-2-(4-phenyltriazol-1-yl)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine, 44 mg, as a yellow solid. LCMS: (APCI) m / e 362.1 (M+H).

[0175] N-Cyclopentyl-2-(p-tolyl)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine (A-32) [ka] A microwave tube containing 2-chloro-N-cyclopentyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine (0.2 g, 0.79 mmol), cesium carbonate (1.0 g, 3.2 mmol, 4 equiv), p-tolylboronic acid (0.27 g, 2.0 mmol, 2.5 equiv), palladium(II) acetate (18 mg, 79 μmol, 0.1 equiv), and triphenylphosphine-3,3′,3″-trisulfonic acid trisodium salt (0.18 g, 3.2 mmol, 0.4 equiv) was purged with N gas for 2 minutes and then sealed. The mixture was then diluted with water (1.5 mL) and acetonitrile (0.75 mL). The reaction mixture was microwaved at 175 °C for 2 hours. LC / MS analysis indicated approximately 50% of the desired product had formed. The reaction mixture was diluted with methylene chloride (5 mL) and the layers were separated. The aqueous phase was extracted with methylene chloride (2 × 10 mL), the combined organic extracts were dried (NaSO), and the solvent was removed in vacuo. The residue was purified by flash chromatography (12 g silica, 0-10% methanol / methylene chloride) to afford N-cyclopentyl-2-(p-tolyl)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine, 19.6 mg, as a yellowish solid. LCMS: (APCI) m / e 309.1 (M+H); [ka]

[0176] N-Cyclopentyl-2-(4-pyridyl)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine (A-34) [ka] A microwave tube containing 2-chloro-N-cyclopentyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine (0.2 g, 0.79 mmol), cesium carbonate (1.0 g, 3.2 mmol, 4 equiv.), 4-pyridylboronic acid (0.24 g, 2.0 mmol, 2.5 equiv.), palladium(II) acetate (18 mg, 79 µmol, 0.1 equiv.), and triphenylphosphine-3,3',3"-trisulfonic acid trisodium salt (0.18 g, 3.2 mmol, 0.4 equiv.) was purged with N gas for 2 min and then sealed. The mixture was then diluted with water (1.5 mL) and acetonitrile (0.75 mL). The reaction mixture was then microwaved at 150 °C for 2 h. LC / MS analysis indicated approximately 50% of the desired product had formed. The reaction mixture was diluted with methylene chloride (5 mL) and the layers were separated. The aqueous phase was extracted with methylene chloride (2 × 10 mL), the combined organic extracts were dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by flash chromatography (12 g silica, 0–10% methanol / methylene chloride) to afford N-cyclopentyl-2-(4-pyridyl)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine, 47.5 mg, as a yellowish solid. LCMS: (APCI) m / e 296.1 (M+H); [ka] Example 4 Synthesis of aromatic pyrimidines

[0177] Schematic reaction scheme 4 for pyrimidine aromatics [ka] Step 1. Synthesis of Cl-substituted intermediates

[0178] N-Benzyl-2-chloro-N-cyclopentyl-5-nitro-pyrimidin-4-amine (K-39). [ka] A 250 mL RBF was charged with 2,4-dichloro-5-nitro-pyrimidine (500 mg, 2.58 mmol), THF (25 mL, 0.1 M) and cooled to -78 °C in a dry ice bath. The cooled reaction mixture was then carefully treated with DiPEA (3 equiv., 7.74 mmol, 1.4 mL). The reaction mixture was then treated with N-benzylcyclopentanamine; hydrochloride salt (1 equiv., 2.58 mmol, 546 mg) as a solid. The reaction was purged with nitrogen and allowed to warm gradually to room temperature. After 16 h, the reaction was diluted with water (50 mL) and EtOAc ( The mixture was partitioned between 100 ml of ethyl acetate (50 mL), the aqueous layer was back-extracted with 3 x 50 mL of EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a red oil (850 mg, 99%) that was used directly in the next step. (APCI) m / e 333.0 (M+H). Step 2. Synthesis of the final analogue

[0179] N 4 -Cyclopentyl-2-(p-tolyl)-N 5 -sec-butyl-pyrimidine-4,5-diamine (F-69) [ka] In a 40 mL vial fitted with a stir bar, add N 4A mixture of 1,2-cyclopentyl-2-(p-tolyl)pyrimidine-4,5-diamine (F-68, 0.065 g, 0.242 mmol), MEK (1.3 equiv., 0.028 mL, 0.315 mmol), TFA (2 equiv., 0.036 mL, 2.47 mmol), and isopropyl acetate (3.25 mL) was added. The reaction was stirred at room temperature for 15 minutes, carefully treated with sodium triacetoxyborohydride (0.0565 g, 0.266 mmol), purged with N2, and stirred at room temperature for 3 days. The reaction mixture was partitioned between saturated NaHCO4 (10 mL) and EtOAc (10 mL). The aqueous layer was back-extracted with 3 x 10 mL of EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel (24 g, hexanes / ethyl acetate). LCMS: (APCI) m / e 325.1 (M+H); [ka]

[0180] N 4 -Cyclopentyl-2-(3-pyridyl)-N 5 -sec-butyl-pyrimidine-4,5-diamine (F-78) [ka] In a 40 mL vial equipped with a stir bar, add N 4A mixture of 1,2-cyclopentyl-2-(3-pyridyl)pyrimidine-4,5-diamine (F-76, 0.150 g, 0.588 mmol), MEK (3 equiv., 0.158 mL, 1.76 mmol), TFA (2 equiv., 0.0873 mL, 1.18 mmol), and isopropyl acetate (7.5 mL) was added. The reaction was stirred at room temperature for 15 minutes, carefully treated with sodium triacetoxyborohydride (1.1 equiv., 0.138 g, 0.646 mmol), purged with N2, and stirred at room temperature for 3 days. The reaction mixture was partitioned between saturated NaHCO4 (10 mL) and EtOAc (10 mL). The aqueous layer was back-extracted with 3 x 10 mL of EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel (24 g, hexanes / ethyl acetate). LCMS: (APCI) m / e 312.1 (M+H); [ka]

[0181] N 4 -Cyclopentyl-2-pyrimidin-5-yl-N 5 -sec-butyl-pyrimidine-4,5-diamine (F-81) [ka] In a 40 mL vial equipped with a stir bar, add N 4-Cyclopentyl-2-pyrimidin-5-yl-pyrimidine-4,5-diamine (F-79, 0.300 g, 1.17 mmol), MEK (3 equiv., 0.315 mL, 3.51 mmol), TFA (2 equiv., 0.174 mL, 2.34 mmol), and isopropyl acetate (15 mL) were charged. The reaction was stirred at room temperature for 15 minutes, carefully treated with sodium triacetoxyborohydride (1.1 equiv., 0.273 g, 1.29 mmol), purged with N2, and stirred at room temperature for 3 days. The reaction mixture was partitioned between saturated NaHCO4 (10 mL) and EtOAc (10 mL). The aqueous layer was back-extracted with 3 x 10 mL of EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel (24 g, hexanes / ethyl acetate). LCMS: (APCI) m / e 313.1 (M+H); [ka]

[0182] N 4 -Cyclopentyl-N 5 -(Oxetan-3-yl)-2-pyrimidin-5-yl-pyrimidine-4,5-diamine (F-82) [ka] In a 40 mL vial equipped with a stir bar, add N 4A mixture of 1,2-cyclopentyl-2-pyrimidin-5-yl-pyrimidine-4,5-diamine (F-79, 0.300 g, 1.17 mmol), oxetanone (3 equiv., 0.206 mL, 3.51 mmol), TFA (2 equiv., 0.174 mL, 2.34 mmol), and isopropyl acetate (15 mL) was added. The reaction was stirred at room temperature for 15 minutes, carefully treated with sodium triacetoxyborohydride (1.1 equiv., 0.273 g, 1.29 mmol), purged with N2, and stirred at room temperature for 3 days. The reaction mixture was partitioned between saturated NaHCO4 (10 mL) and EtOAc (10 mL). The aqueous layer was back-extracted with 3 x 10 mL of EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel (24 g, DCM / methanol). LCMS: (APCI) m / e 313.1 (M+H).

[0183] N 4 -Cyclopentyl-2-(4-pyridyl)-N 5 -sec-butyl-pyrimidine-4,5-diamine (F-88) [ka] In a 40 mL vial equipped with a stir bar, add N 4 A mixture of 4-cyclopentyl-2-(4-pyridyl)pyrimidine-4,5-diamine (F-84, 0.123 g, 0.482 mmol), MEK (3 equiv., 0.13 mL, 1.45 mmol), TFA (2 equiv., 0.072 mL, 0.964 mmol), and isopropyl acetate (6.5 mL) was added. The reaction was stirred at room temperature for 15 minutes, carefully treated with sodium triacetoxyborohydride (1.1 equiv., 0.112 g, 0.53 mmol), purged with N2, and stirred at room temperature for 24 hours. The reaction mixture was partitioned between saturated NaHCO4 (10 mL) and EtOAc (10 mL). The aqueous layer was back-extracted with 3 x 10 mL of EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified on silica gel (24 g, hexanes / ethyl acetate). LCMS: (APCI) m / e 312.1 (M+H); [ka]

[0184] N 4 -Cyclopentyl-2-methyl-6-(2-methylprop-1-enyl)pyrimidine-4,5-diamine (F-99) [ka] In a 20 mL microwave vial equipped with a stir bar, add 6-chloro-N 4 A mixture of 1-cyclopentyl-2-methyl-pyrimidine-4,5-diamine (F-98, 1 g, 4.41 mmol), n-butanol (12 mL), water (1.2 mL), 2,2-dimethylethenylboronic acid (2.5 equiv., 1.1 g, 11 mmol), and potassium acetate (3.5 equiv., 1.52 g, 15.4 mmol) was added. The vial was then evacuated, backfilled with nitrogen (2x), treated with tetrakis(triphenylphosphine)palladium(0) (0.01 equiv.; 35 mg, 0.0441 mmol), sealed, and heated in a microwave oven for 15 min at 110 °C. LC showed primarily the desired product with traces of starting material. The reaction mixture was filtered through a PTFE 0.45 μm syringe filter into a 250 mL RBF and concentrated under reduced pressure. The residue was dissolved in 3 mL of DCM, absorbed onto silica gel, concentrated under reduced pressure, and the solid material was heated at 100° C. overnight. The solid was directly purified on silica gel (50 g, hexane / ethyl acetate) to give the desired product (F-99). LCMS: (APCI) m / e 247.1 (M+H). Example 5 Synthesis of aromatic pyridines

[0185] Schematic reaction scheme 5 for pyridine aromatics [ka] Step 1. Synthesis of Cl-substituted intermediates

[0186] 6-Chloro-N-cyclopentyl-3-nitro-pyridin-2-amine (H-40) [ka] In a 40 mL vial equipped with a stir bar, 2,6-dichloro-3-nitro-pyridine (0.500 g, 2.59 mmol) was dissolved in THF (5 mL). To this was added DIEA (0.554 mL, 3.24 mmol, 1.25 equiv.), followed by cyclopentylamine (0.256 mL, 2.59 mmol, 1 equiv.). The reaction was stirred at room temperature for 2 hours, at which time LCMS analysis indicated the formation of the desired product. The reaction mixture was poured into water (approximately 20 mL) and extracted with ethyl acetate (3 x approximately 25 mL). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and rotary evaporated. The resulting orange oil was purified via flash chromatography (hexanes / EtOAc). The desired product fractions were combined, rotary evaporated, and dried under vacuum at 40° C. overnight to give 6-chloro-N-cyclopentyl-3-nitro-pyridin-2-amine as an orange oil (375 mg, 60.0%). [ka]

[0187] N-tert-Butyl-6-chloro-3-nitro-pyridin-2-amine (K-57). [ka] A 250 mL RBF was charged with 2,6-dichloro-3-nitro-pyridine (1.0 g, 5.18 mmol), a stir bar, THF (10 mL, 0.5 M), DiEA (2 equiv., 1.8 mL, 10.4 mmol), 2-methylpropan-2-amine (1 equiv., 5.18 mmol, 380 mg) in 4 mL of THF (1 equiv., 5.18 mmol, 380 mg), and the reaction was stirred at room temperature overnight. The reaction was then partitioned between 75 mL of water and 75 mL of EtOAc. The aqueous layer was extracted with 3 x 50 mL of EtOAc, and the combined organic layers were dried over NaSO and concentrated under reduced pressure to give an oil of 1.15 g that was >70% pure by LCMS, which was purified on silica gel (40 g, 0-50% EtOAc / hexanes) to give 550 mg as a yellow oil (46%). LCMS: (APCI) m / e 230.1 (M+H).

[0188] 6-Chloro-N-(3-methyloxetan-3-yl)-3-nitro-pyridin-2-amine (K-58). [ka] A 250 mL RBF was charged with 2,6-dichloro-3-nitro-pyridine (1.0 g, 5.18 mmol), a stir bar, THF (8 mL, 0.5 M), DiEA (2 equiv., 1.8 mL, 10.4 mmol), and 3-methyloxetan-3-amine in 2 mL of THF (1 equiv., 5.18 mmol, 451 mg), and the reaction was stirred at room temperature overnight. The reaction was then partitioned between 75 mL of water and 75 mL of EtOAc. The aqueous layer was extracted with 3 × 50 mL of EtOAc, and the combined organic layers were dried over NaSO and concentrated under reduced pressure to give an oil of 1.5% purity by LCMS. Purification on silica gel (80 g, 0–50% EtOAc / hexanes) yielded 740 mg as a yellow solid (58%). LCMS: (APCI) m / e 244.0 (M+H).

[0189] N-Benzyl-6-chloro-N-cyclopentyl-3-nitro-pyridin-2-amine (K-64). [ka] A 40 mL vial was charged with 2-chloro-6-methyl-3-nitro-pyridine (1.0 g, 5.79 mmol), a stir bar, DMF (5 mL, 1 M), DiEA (3 equiv., 3.1 mL, 17.4 mmol), and N-benzylcyclopentanamine hydrochloride (1.1 equiv., 6.37 mmol, 1.35 g) at 80 °C overnight. After 16 h, the starting material was consumed and the desired product was confirmed by crude LCMS. The reaction mixture was partitioned between 75 mL of water and 75 mL of EtOAc. The aqueous layer was back-extracted with 3 × 50 mL of EtOAc, and the combined organic layers were dried over NaSO. The residue was purified on silica gel (80 g, 0–30% EtOAc / hexanes) to give 1.2 g (85%) as a yellow solid. LCMS: (APCI) m / e 312.1 (M+H).

[0190] 6-Chloro-N-(3,3-difluorocyclobutyl)-3-nitro-pyridin-2-amine (K-60). [ka] A 40 mL vial was charged with 2-chloro-6-methyl-3-nitro-pyridine (1.0 g, 5.79 mmol), a stir bar, DMF (5 mL, 1 M), DiEA (3 equiv., 3.1 mL, 17.4 mmol), and 3,3-difluorocyclobutanamine hydrochloride (1 equiv., 5.79 mmol, 937 mg), and the reaction was stirred at 80 °C overnight. The reaction was then heated at 75 °C for 24 h, and the THF was evaporated under reduced pressure. The residue was directly purified on silica gel (80 g, 0-30% EtOAc / hexanes) to give 1.2 g (85%) as a yellow solid. LCMS: (APCI) m / e 244.1 (M+H).

[0191] 6-Chloro-N-(3,3-difluoro-1-methyl-cyclobutyl)-3-nitro-pyridin-2-amine (K-89). [ka] A 250 mL RBF was charged with 2,6-dichloro-3-nitro-pyridine (1.0 g, 5.18 mmol), a stir bar, DMF (8 mL, 0.5 M), DiEA (3 equiv., 2.7 mL, 15.5 mmol), and 3,3-difluoro-1-methyl-cyclobutanamine hydrochloride (1 equiv., 5.18 mmol, 817 mg), and the reaction was stirred at room temperature for 3 days. The reaction was then partitioned between 75 mL of water and 75 mL of EtOAc. The aqueous layer was extracted with 3 x 50 mL of EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give an oil that was >70% pure by LCMS and purified on silica gel (80 g, 0-40% EtOAc / hexanes) to give 1.07 g of 6-chloro-N-(3,3-difluoro-1-methyl-cyclobutyl)-3-nitro-pyridin-2-amine as a yellow solid (74%). LCMS: (APCI) m / e 278.1 (M+H).

[0192] 6-Chloro-N-(3-methyltetrahydrofuran-3-yl)-3-nitro-pyridin-2-amine (K-86). [ka] A 250 mL RBF was charged with 2,6-dichloro-3-nitro-pyridine (1.0 g, 5.18 mmol), a stir bar, THF (8 mL, 0.5 M), DiEA (2 equiv., 1.8 mL, 10.4 mmol), and 3-methyltetrahydrofuran-3-amine in 2 mL of THF (1 equiv., 5.18 mmol, 524 mg), and the reaction was stirred at room temperature for 3 days. The reaction was then partitioned between 75 mL of water and 75 mL of EtOAc. The aqueous layer was extracted with 3 x 50 mL of EtOAc, and the combined organic layers were dried over NaSO and concentrated under reduced pressure to give an oil that was >70% pure by LCMS. Purification on silica gel (80 g, 0-40% EtOAc / hexanes) yielded 770 mg as a yellow solid (48%). LCMS: (APCI) m / e 358.0 (M+H). Step 2. Synthesis of Suzuki coupling intermediate

[0193] N-Cyclopentyl-3-nitro-6-(p-tolyl)pyridin-2-amine (H-54) (represents the general procedure followed for all boronic acid couplings in this series) [ka] In a 2.0-5.0 mL microwave vial, 6-chloro-N-cyclopentyl-3-nitro-pyridin-2-amine (0.750 g, 3.10 mmol) was dissolved in DMF (5 mL). To this was added cesium carbonate (2.53 g, 7.76 mmol, 2.5 equiv.) and p-tolylboronic acid (0.844 g, 6.20 mmol, 2 equiv.). The mixture was then purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.538 g, 0.466 mmol, 0.15 equiv.) was added. The vial was sealed and heated in a microwave reactor for 20 min at 120 °C. The reaction mixture was then filtered, loaded onto silica, and purified by flash chromatography (hexane / EtOAc). The desired product fractions 13-21 were combined, rotary evaporated, and dried at 40 °C overnight to give N-cyclopentyl-3-nitro-6-(p-tolyl)pyridin-2-amine as a yellow-orange solid (354 mg, 38.3%). LCMS: (APCI) m / e 298 (M+H).

[0194] N-(3,3-Difluoro-1-methyl-cyclobutyl)-3-nitro-6-(3-pyridyl)pyridin-2-amine (M-03). [ka] In a 40 mL vial, 6-chloro-N-(3,3-difluoro-1-methyl-cyclobutyl)-3-nitro-pyridin-2-amine (0.400 g, 1.44 mmol), 3-pyridylboronic acid (0.354 g, 2.88 mmol, 2 equiv.), and potassium carbonate (0.597 g, 4.32 mmol, 3 equiv.) were stirred in THF (4 mL) and water (2 mL). Tetrakis(triphenylphosphine)palladium(0) (0.166 g, 0.144 mmol, 0.1 equiv.) was added, the vial was capped, and the mixture was stirred at 60 °C. After overnight reaction, LCMS analysis of the crude reaction mixture indicated that the desired product was primarily formed. The reaction mixture was poured onto water (approximately 25 mL) and extracted with EtOAc (4 x approximately 30 mL). The organic extracts were combined, dried over anhydrous magnesium sulfate, and rotary evaporated to give a deep red oil, which was subsequently dried under vacuum for approximately 1 hour at 40 °C. The resulting mass was higher than the expected yield, likely due to the presence of tetrakis by-product(s) (also suggested by LCMS). This material was used in the next step (H-71) without further purification, assuming a quantitative yield. LCMS: (APCI) m / e 321.0 (M+H).

[0195] 6-(4-Fluorophenyl)-N-(3-methyltetrahydrofuran-3-yl)-3-nitro-pyridin-2-amine (K-99). [ka] A 40 mL vial was charged with 6-chloro-N-(3-methyltetrahydrofuran-3-yl)-3-nitro-pyridin-2-amine (518 mg, 2.01 mmol), THF (4 mL), water (2 mL), (4-fluorophenyl)boronic acid (2 equiv., 563 mg, 4.02 mmol), and sodium carbonate (4 equiv., 852 mg, 8.04 mmol), then fitted with a stir bar and septum. The solution was degassed for 10 minutes using a stream of nitrogen directly into the solution and an outlet needle. The reaction mixture was then treated with tetrakis(triphenylphosphine)palladium(0) (0.1 equiv., 232 mg, 0.201 mmol), fitted with a nitrogen balloon, and stirred at 60 °C. After 2 h, crude LCMS confirmed complete consumption of the starting material, and the major product showed the correct MS for the desired product. The reaction mixture was allowed to cool to room temperature and then partitioned between 20 mL of EtOAc and 20 mL of water. The aqueous layer was back-extracted with 2 x 20 mL of EtOAc, and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure, and the resulting residue was purified on silica gel (80 g, 0-30% EtOAc / hexanes) to give 6-(4-fluorophenyl)-N-(3-methyltetrahydrofuran-3-yl)-3-nitro-pyridin-2-amine as a confirmed yellow solid (500 mg, 78%). LCMS: (APCI) m / e 318.1 (M+H).

[0196] N,N-Dimethyl-4-[6-[(3-methyltetrahydrofuran-3-yl)amino]-5-nitro-2-pyridyl]benzamide (N-02). [ka] A 40 mL vial was charged with 6-chloro-N-(3-methyltetrahydrofuran-3-yl)-3-nitro-pyridin-2-amine (550 mg, 2.13 mmol), THF (4 mL), water (2 mL), [4-(dimethylcarbamoyl)phenyl]boronic acid (2 equiv., 824 mg, 4.27 mmol), and sodium carbonate (4 equiv., 905 mg, 8.54 mmol), then fitted with a stir bar and septum. The solution was degassed for 10 minutes using a stream of nitrogen directly into the solution and an outlet needle. The reaction mixture was then treated with tetrakis(triphenylphosphine)-palladium(0) (0.1 equiv., 247 mg, 0.213 mmol), fitted with a nitrogen balloon, and stirred at 60 °C. After 4 h, crude LCMS confirmed complete consumption of the starting material, and the major product showed the correct MS for the desired product. The reaction mixture was allowed to cool to room temperature and then partitioned between 20 mL of EtOAc and 20 mL of water. The aqueous layer was back-extracted with 2 × 20 mL of EtOAc, and the combined organic layers were dried over NaSO. The solvent was removed under reduced pressure, and the resulting residue was purified on silica gel (80 g, 0–30% EtOAc / hexanes) to afford N,N-dimethyl-4-[6-[(3-methyltetrahydrofuran-3-yl)amino]-5-nitro-2-pyridyl]benzamide as a yellow solid (700 mg, 85%). LCMS: (APCI) m / e 371.1 (M+H).

[0197] 4-[6-[(3,3-difluoro-1-methyl-cyclobutyl)amino]-5-nitro-2-pyridyl]-N,N-dimethyl-benzamide (N-06) [ka] A 40 mL vial was charged with 6-chloro-N-(3,3-difluoro-1-methyl-cyclobutyl)-3-nitro-pyridin-2-amine (550 mg, 2.33 mmol), THF (4 mL), water (2 mL), [4-(dimethylcarbamoyl)phenyl]boronic acid (2 equiv., 898 mg, 4.65 mmol), and sodium carbonate (4 equiv., 986 mg, 9.31 mmol), then fitted with a stir bar and septum. The solution was degassed for 10 minutes using a direct stream of nitrogen and an outlet needle. The reaction mixture was then treated with tetrakis(triphenylphosphine)-palladium(0) (0.1 equiv., 269 mg, 0.233 mmol), fitted with a nitrogen balloon, and stirred at 60 °C. After 16 h, crude LCMS confirmed complete consumption of the starting material, and the major product showed the correct MS for the desired product. The reaction mixture was cooled to room temperature and then partitioned between 50 mL of EtOAc and 50 mL of water. The aqueous layer was back-extracted with 2 x 50 mL of EtOAc, and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure, and the resulting residue was purified on silica gel (80 g, 0-40% EtOAc / hexanes) to give 4-[6-[(3,3-difluoro-1-methyl-cyclobutyl)amino]-5-nitro-2-pyridyl]-N,N-dimethyl-benzamide as a yellow solid (830 mg, 91%). LCMS: (APCI) m / e 391.1 (M+H). Step 3. Synthesis of nitro-reduced intermediate

[0198] N 2 -Cyclopentyl-6-(p-tolyl)pyridine-2,3-diamine (H-59) (represents the general procedure followed for all nitro reduction reactions in this series) [ka] In a 40 mL vial equipped with a stir bar, N-cyclopentyl-3-nitro-6-(p-tolyl)pyridin-2-amine (0.354 g, 1.19 mmol), ammonium chloride (0.0636 g, 1.19 mmol), and iron powder (0.332 g, 5.95 mmol) were stirred in 5 mL of 4:1 ethanol:water. The vial was sealed, and the mixture was stirred in a reaction block at 80 °C. After 2 h, LCMS indicated complete conversion to the desired product. The reaction was cooled to room temperature, and the iron was filtered off. The filtrate was poured into water and extracted with ethyl acetate (x3). The combined organic extracts were dried over magnesium sulfate, filtered, rotary evaporated, and dried under vacuum at 40 °C overnight. 2 -Cyclopentyl-6-(p-tolyl)pyridine-2,3-diamine was obtained as a dark brown solid (0.3032 g, 95.3%). LCMS: (APCI) m / e 268 (M+H).

[0199] N 2 -(3,3-Difluoro-1-methyl-cyclobutyl)-6-(3-pyridyl)pyridine-2,3-diamine (M-05). [ka] In a 40 mL vial equipped with a stir bar, N-(3,3-difluoro-1-methyl-cyclobutyl)-3-nitro-6-(3-pyridyl)pyridin-2-amine (M-03, 0.299 g, 0.933 mmol), ammonium chloride (0.0499 g, 0.933 mmol), and iron powder (0.260 g, 4.66 mmol) were dissolved in 5 mL of ethanol:water. The mixture was stirred in a 4:1 ethanol / hexanes mixture. The vial was sealed and the mixture was stirred in a reaction block at 80° C. for 8 hours. LC-MS indicated that the reaction had gone to completion. The reaction was cooled to room temperature, diluted with methanol, and filtered through a plug of Celite®. The filtrate was rotary evaporated and dried under vacuum at 40° C. overnight to give a quantitative yield. The material was used directly in the next step without further purification. LCMS: (APCI) m / e 291.1 (M+H).

[0200] 4-[5-amino-6-[(3-methyltetrahydrofuran-3-yl)amino]-2-pyridyl]-N,N-dimethyl-benzamide (N-03) [ka] A 20 mL microwave vial was charged with N,N-dimethyl-4-[6-[(3-methyltetrahydrofuran-3-yl)amino]-5-nitro-2-pyridyl]benzamide (700 mg, 1.89 mmol), EtOH (5 mL), water (1.25 mL), ammonium chloride (1 equiv., 1.89 mmol, 102 mg), and iron filings (5 equiv., 9.45 mmol, 528 mg), fitted with a stir bar, purged with nitrogen, sealed, and stirred at 80 °C. After 16 h, the reaction was cooled to room temperature and filtered using an ISCO sample cartridge containing wet Celite® (MeOH), washing several times with MeOH. The yellow solution was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 850 mg. The residue was dissolved in 50 mL of 0.1 M HCl and 50 mL of EtOAc. The aqueous layer was extracted with 2 x 50 mL of EtOAc, and the combined organic layers were discarded. The acidic layer was brought to pH 12 by the addition of 5N NaOH, then extracted with 4 x 50 mL of DCM, dried over Na2SO4, and concentrated under reduced pressure to give 590 mg of 4-[5-amino-6-[(3-methyltetrahydrofuran-3-yl)amino]-2-pyridyl]-N,N-dimethyl-benzamide (91%) as a light green solid. The material was pure by LCMS and used directly in the next step. LCMS: (APCI) m / e 341.1 (M+H).

[0201] 6-(4-fluorophenyl)-N 2 -(3-methyltetrahydrofuran-3-yl)pyridine-2,3-diamine (N-01) [ka] A 20 mL microwave vial was charged with 6-(4-fluorophenyl)-N-(3-methyltetrahydrofuran-3-yl)-3-nitro-pyridin-2-amine (500 mg, 1.58 mmol), EtOH (4 mL), water (1 mL), ammonium chloride (1 equiv., 1.58 mmol, 86 mg), and iron filings (5 equiv., 7.88 mmol, 440 mg), fitted with a stir bar, purged with nitrogen, sealed, and stirred at 80 °C. After 3 h, the reaction was cooled to room temperature and filtered using an ISCO sample cartridge equipped with wet Celite® (MeOH), washing several times with MeOH. The yellow solution was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 950 mg. The residue was dissolved in 50 mL of 0.1 M HCl and 50 mL of EtOAc. The aqueous layer was extracted 2 × 50 mL with EtOAc, and the combined organic layers were discarded. The acidic layer was brought to pH 12 by addition of 5N NaOH, extracted with 4 x 50 mL of DCM, dried over Na2SO4, and concentrated under reduced pressure to give 420 mg of 6-(4-fluorophenyl)-N 2 -(3-methyltetrahydrofuran-3-yl)pyridine-2,3-diamine (92%) was obtained as a grey solid. The material was pure by LCMS and used directly in the next step. LCMS: (APCI) m / e 288.1 (M+H). Step 4. Synthesis of the final compound

[0202] N 2 -Cyclopentyl-6-(p-tolyl)-N 3 -sec-butyl-pyridine-2,3-diamine (H-61) [ka] N 2To a vial containing 2-cyclopentyl-6-(p-tolyl)pyridine-2,3-diamine (0.3032 g, 1.13 mmol) and a stir bar was added 2-butanone (0.112 mL, 1.25 mmol, 1.1 equiv.), TFA (0.168 mL, 2 equiv.), and isopropyl acetate (4 mL). To this was added sodium triacetoxyborohydride (0.288 g, 1.36 mmol, 1.2 equiv.) over approximately 5 minutes. An additional 1 mL of isopropyl acetate was added to facilitate mixing. The reaction was then stirred at room temperature for 1.5 hours. The reaction mixture was then filtered, and the filtrate was poured into water and extracted with EtOAc (×3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated on a rotary evaporator. The material was then loaded onto silica and purified by flash chromatography (24 g column, hexane / EtOAc). Combine the desired product fractions, dry down, and evaporate under N 2 -Cyclopentyl-6-(p-tolyl)-N 3 -sec-Butyl-pyridine-2,3-diamine was obtained as a reddish-brown oil (42.2 mg, 11.5%). [ka]

[0203] N 3 -tert-Butyl-N 2 -Cyclopentyl-6-(p-tolyl)pyridine-2,3-diamine (A-98) [ka] N 2A solution of 1,3-cyclopentyl-6-(p-tolyl)pyridine-2,3-diamine (0.238 g, 0.89 mmol) in dichloromethane (2.5 mL) was treated with tert-butyl 2,2,2-trichloroethaneimidate (0.39 g, 1.8 mmol, 2 equiv.) followed by boron trifluoride etherate (22 μL, 0.18 mmol, 0.2 equiv.). After stirring for 3 h, LC / MS analysis indicated partial conversion to the desired product with significant amounts of starting material. The reaction mixture was treated with additional tert-butyl 2,2,2-trichloroethaneimidate (0.39 g, 1.8 mmol, 2 equiv.) and boron trifluoride etherate (22 μL, 0.18 mmol, 0.2 equiv.). After stirring overnight, LC / MS analysis showed 50% conversion to the desired product and 50% starting material. Purification on silica gel gave 23 mg (8%) of N 3 -tert-Butyl-N 2 -cyclopentyl-6-(p-tolyl)pyridine-2,3-diamine (A-98). LCMS: (APCI) m / e 324.1 (M+H).

[0204] N 2 -Cyclopentyl-6-pentyl-N 3 -sec-butyl-pyridine-2,3-diamine (H-72) [ka] N 2To a vial containing 6-cyclopentyl-6-pentyl-pyridine-2,3-diamine (0.268 g, 1.08 mmol) and a stir bar was added 2-butanone (0.107 mL, 1.19 mmol, 1.1 equiv.), TFA (0.161 mL, 2.17 mmol, 2 equiv.), and isopropyl acetate (5 mL). To this was added sodium triacetoxyborohydride (0.276 g, 1.30 mmol, 1.2 equiv.) over approximately 5 minutes. The reaction was then allowed to stir at room temperature. After 45 minutes of reaction time, LCMS indicated conversion to the desired product. The reaction was filtered, and the filtrate was poured into water and extracted with EtOAc (×3). The combined organic extracts were dried over anhydrous magnesium sulfate, rotary evaporated, loaded onto silica, and purified by column chromatography (40 g column, hexane / EtOAc). Combine the desired product fractions, dry down, and evaporate under N 2 -Cyclopentyl-6-pentyl-N 3 To the obtained solution was added 40.3 mg (12.3%) of sec-butyl-pyridine-2,3-diamine. [ka]

[0205] N 2 -Cyclopentyl-6-(3-pyridyl)-N 3 -sec-butyl-pyridine-2,3-diamine (H-74) [ka] N 2To a vial containing 2-cyclopentyl-6-(3-pyridyl)pyridine-2,3-diamine (0.316 g, 1.24 mmol) and a stir bar was added 2-butanone (0.122 mL, 1.37 mmol, 1.1 equiv.), TFA (0.185 mL, 2.48 mmol, 2 equiv.), and isopropyl acetate (5 mL). To this was added sodium triacetoxyborohydride (0.316 g, 1.49 mmol, 1.2 equiv.) over approximately 5 minutes. The reaction was then allowed to stir at room temperature. After 45 minutes, LCMS indicated conversion to the desired product. The reaction was filtered, and the filtrate was poured into water and extracted with EtOAc (×3). The combined organic extracts were dried over anhydrous magnesium sulfate, rotary evaporated, and loaded onto silica. The product was purified by column chromatography (hexanes / ethyl acetate). Combine the desired product fractions, dry down, and evaporate under N 2 -Cyclopentyl-6-pentyl-N 3 -sec-butyl-pyridine-2,3-diamine (0.1443 g, 37.4%) was obtained as a light brown solid. [ka]

[0206] N 2 -Cyclopentyl-N 3 -(Oxetan-3-yl)-6-(3-pyridyl)pyridine-2,3-diamine (H-75) [ka] N 2To a vial containing -cyclopentyl-6-(3-pyridyl)pyridine-2,3-diamine (0.316 g, 1.24 mmol) and a stir bar was added oxetan-3-one (0.087 mL, 1.37 mmol, 1.1 equiv.), TFA (0.185 mL, 2.48 mmol, 2 equiv.), and isopropyl acetate (5 mL). To this was added sodium triacetoxyborohydride (0.316 g, 1.49 mmol, 1.2 equiv.) over approximately 5 minutes. The reaction was then allowed to stir at room temperature. After 45 minutes of reaction time, LCMS indicated conversion to the desired product. The reaction mixture was poured into water and extracted with EtOAc (×3). The combined organic extracts were dried over anhydrous magnesium sulfate, rotary evaporated, loaded onto silica, and purified by column chromatography (hexanes / ethyl acetate). The desired product fractions were combined, dried down, and purified by N 2 -Cyclopentyl-N 3 -(oxetan-3-yl)-6-(3-pyridyl)pyridine-2,3-diamine was obtained as an off-white solid (89 mg, 23.1%). [ka]

[0207] N 2 -Cyclopentyl-6-(4-pyridyl)-N 3 -sec-butyl-pyridine-2,3-diamine (H-76) [ka] N 2To a vial containing 4-cyclopentyl-6-(4-pyridyl)pyridine-2,3-diamine (0.1391 g, 0.547 mmol) and a stir bar was added 2-butanone (0.108 mL, 1.204 mmol), TFA (0.081 mL, 1.09 mmol), and isopropyl acetate (5 mL). To this was added sodium triacetoxyborohydride (0.139 g, 0.656 mmol) over approximately 2 minutes. The reaction was then allowed to stir overnight at room temperature. The resulting reaction mixture was then poured into water and extracted with ethyl acetate (×3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, rotary evaporated, loaded onto silica, and purified by column chromatography (24 g column, hexane / EtOAc). The desired product fractions were combined, dried down, and purified by N 2 -Cyclopentyl-6-(4-pyridyl)-N 3 -sec-Butyl-pyridine-2,3-diamine was obtained as a brown solid (39.6 mg, 23.3%). [ka]

[0208] N 2 -Cyclopentyl-N 3 -(Oxetan-3-yl)-6-(4-pyridyl)pyridine-2,3-diamine (H-77) [ka] N 2To a vial containing 4-cyclopentyl-6-(4-pyridyl)pyridine-2,3-diamine (0.1375 g, 0.541 mmol) and a stir bar was added oxetan-3-one (0.076 mL, 1.19 mmol), TFA (0.080 mL, 1.08 mmol), and isopropyl acetate (5 mL). To this was added sodium triacetoxyborohydride (0.137 g, 0.649 mmol) over approximately 2 minutes. The reaction was then allowed to stir overnight at room temperature. The resulting reaction mixture was poured into water and extracted with ethyl acetate (×3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, rotary evaporated, and loaded onto silica. The material was purified by column chromatography (24 g column, DCM / MeOH). The desired product fractions were combined, dried down, and purified by N 2 -Cyclopentyl-N 3 4 mg (5.01%) of 4-pyridyl-6-pyridine-2,3-diamine was obtained as a pale yellow solid (8.4 mg, 5.01%). [ka]

[0209] N 2 -Cyclopentyl-6-pyrimidin-5-yl-N 3 -sec-butyl-pyridine-2,3-diamine (H-80) [ka] In a 2.0-5.0 mL microwave vial equipped with a stir bar, 2 -Cyclopentyl-N 3Sec-butyl-pyridine-2,3-diamine (by-product recovered from H-72, 0.1559 g), potassium acetate (0.171 g, 3 equiv.), and pyrimidin-5-ylboronic acid (0.159 g, 2.2 equiv.) were combined in n-butanol (3 mL) and water (0.3 mL). The reaction mixture was flushed with nitrogen. Dichlorobis{[4-(N,N-dimethylamino)phenyl]di-t-butylphenylphosphino}palladium(II) (8.2 mg, 0.02 equiv.) was then added and the vial was sealed. The vial was then placed in a microwave reactor at 110 °C for 20 minutes. The resulting mixture was poured into water and extracted with ethyl acetate (×3). The organic extracts were combined and dried over anhydrous magnesium sulfate. The material was then filtered, concentrated, loaded onto silica, and purified via flash chromatography (hexanes / ethyl acetate). Combine the desired product fractions, dry down, and evaporate under N 2 -Cyclopentyl-6-pyrimidin-5-yl-N 3 -sec-butyl-pyridine-2,3-diamine was obtained as a light brown solid (73.8 mg, 40.7%). [ka]

[0210] N 2 -Cyclopentyl-N 3 -(Oxetan-3-yl)-6-(p-tolyl)pyridine-2,3-diamine (H-81) [ka] N 2To a vial containing -cyclopentyl-6-(p-tolyl)pyridine-2,3-diamine (0.278 g, 1.04 mmol) and a stir bar was added oxetan-3-one (0.100 mL, 1.56 mmol, 1.5 equiv), TFA (0.154 mL, 2.08 mmol, 2 equiv), and isopropyl acetate (5 mL). To this was added sodium triacetoxyborohydride (0.331 g, 1.56 mmol, 1.5 equiv) over approximately 2 minutes. The reaction was then allowed to stir at room temperature. After 2 hours, the reaction mixture was poured into water and extracted with EtOAc (×3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated on a rotary evaporator. The material was then loaded onto silica and purified by flash chromatography (24 g column, hexanes / EtOAc). The desired product fractions were combined, dried down, and purified by N 2 -Cyclopentyl-N 3 -(oxetan-3-yl)-6-(p-tolyl)pyridine-2,3-diamine was obtained as a pale purple solid (59.6 mg, 17.7%). [ka]

[0211] N 2 -Cyclopentyl-N 3 -(Oxetan-3-yl)-6-pyrimidin-5-yl-pyridine-2,3-diamine (H-84) [ka] N 2To a vial containing -cyclopentyl-6-pyrimidin-5-yl-pyridine-2,3-diamine (0.213 g, 0.834 mmol) and a stir bar was added oxetan-3-one (0.081 mL, 1.25 mmol, 1.5 equiv.), TFA (0.124 mL, 1.67 mmol, 2 equiv.), and isopropyl acetate (5 mL). To this was added sodium triacetoxyborohydride (0.212 g, 1.00 mmol, 1.2 equiv.) over approximately 2 minutes. The reaction was then allowed to stir overnight at room temperature. The reaction was quenched, poured into water, and extracted with ethyl acetate (×4). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, concentrated on a rotary evaporator, and loaded onto silica. The material was purified by column chromatography (hexanes / ethyl acetate). The desired product fractions were combined, dried down, and purified by N 2 -Cyclopentyl-N 3 -(Oxetan-3-yl)-6-pyrimidin-5-yl-pyridine-2,3-diamine was obtained as a yellow oil (21.4 mg, 8.24%). [ka]

[0212] N 2 -Cyclopentyl-6-(4-methoxyphenyl)-N 3 -sec-butyl-pyridine-2,3-diamine (H-86) [ka] N 2To a vial containing 1,3-cyclopentyl-6-(4-methoxyphenyl)pyridine-2,3-diamine (0.250 g, 0.882 mmol) and a stir bar was added isopropyl acetate (5 mL), TFA (0.131 mL, 1.76 mmol), and 2-butanone (0.119 mL, 1.32 mmol). To the stirred mixture was added sodium triacetoxyborohydride (0.224 g, 1.06 mmol) over approximately 2 minutes. The reaction was then stirred at room temperature. After 45 minutes, saturated sodium bicarbonate (aq) was added, and the organic layer was isolated and loaded onto silica. The material was then purified by column chromatography (hexanes / EtOAc). The desired product fractions were combined and concentrated by rotary evaporation to give N 2 -Cyclopentyl-6-(4-methoxyphenyl)-N 3 -sec-Butyl-pyridine-2,3-diamine was obtained as a viscous brown oil (0.2594 g, 86.6%). [ka]

[0213] N 2 -Cyclopentyl-6-(4-methoxyphenyl)-N 3 -(Oxetan-3-yl)pyridine-2,3-diamine (H-87) [ka] N 2To a vial containing 1,3-cyclopentyl-6-(4-methoxyphenyl)pyridine-2,3-diamine (0.250 g, 0.882 mmol) and a stir bar was added isopropyl acetate (5 mL), TFA (0.131 mL, 1.76 mmol), and oxetanone (0.0851 mL, 1.32 mmol). To the stirred mixture was added sodium triacetoxyborohydride (0.224 g, 1.06 mmol) over approximately 2 minutes. The reaction was then stirred at room temperature for 3 hours. At this time, saturated sodium bicarbonate (aq) was added, and the organic layer was isolated and loaded onto silica. The material was purified by column chromatography (hexanes / EtOAc). The desired product fractions were combined, rotary evaporated, dried under vacuum at 40° C., and purified by N 2 -Cyclopentyl-6-(4-methoxyphenyl)-N 3 -(oxetan-3-yl)pyridine-2,3-diamine was obtained as a fluffy brown solid (169.3 mg, 56.5%). [ka]

[0214] N 2 -tert-butyl-6-(p-tolyl)-N 3 -sec-butyl-pyridine-2,3-diamine (L-02) [ka] N 2A solution of tert-butyl-6-(p-tolyl)pyridine-2,3-diamine (0.147 g, 0.58 mmol) in isopropyl acetate (3.0 mL) was treated sequentially with 2-butanone (63 mg, 0.86 mmol, 1.5 equiv.) and then TFA (85 μL, 1.1 mmol, 2.0 equiv.). After 30 min, the reaction was then treated with sodium triacetoxyborohydride (0.147 g, 0.68 mmol, 1.2 equiv.). After 1 h, LC / MS analysis indicated complete conversion to the desired product. The reaction mixture was quenched with saturated aqueous NaCl (5 mL) and extracted with ethyl acetate (3 × 10 mL). The combined extracts were dried (NaSO), and the solvent was removed in vacuo. The residue was purified by flash chromatography (12 g silica, 0–100% ethyl acetate / hexanes) to afford N 2 -tert-butyl-6-(p-tolyl)-N 3 -sec-butyl-pyridine-2,3-diamine (0.154 g, 86%) was obtained as a blue oil. LCMS: (APCI) m / e 312.2 (M+H).

[0215] N 2 ,N 3 -Di-tert-butyl-6-(p-tolyl)pyridine-2,3-diamine (L-03) [ka] N 2A solution of 1,3-cyclopentyl-6-(p-tolyl)pyridine-2,3-diamine (0.238 g, 0.89 mmol) in dichloromethane (2.5 mL) was treated with tert-butyl 2,2,2-trichloroethaneimidate (0.39 g, 1.8 mmol, 2 equiv.) followed by boron trifluoride etherate (22 μL, 0.18 mmol, 0.2 equiv.). After stirring for 3 h, LC / MS analysis indicated partial conversion to the desired product with significant amounts of starting material. The reaction mixture was treated with additional tert-butyl 2,2,2-trichloroethaneimidate (0.39 g, 1.8 mmol, 2 equiv.) and boron trifluoride etherate (22 μL, 0.18 mmol, 0.2 equiv.). After stirring overnight, LC / MS analysis showed 50% conversion to the desired product and 50% starting material. After stirring overnight, LC / MS showed only a slight increase in conversion to the desired product. The reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL), and the mixture was extracted with methylene chloride (3 x 15 mL). The combined organic extracts were dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by flash chromatography (12 g silica, 0-100% ethyl acetate / hexanes) to give N 2 ,N 3 -di-tert-butyl-6-(p-tolyl)pyridine-2,3-diamine (0.229 g, 56%) was obtained as a blue solid. LCMS: (APCI) m / e 312.2 (M+H); [ka]

[0216] N 3 -tert-Butyl-N 2 -Cyclopentyl-6-(4-pyridyl)pyridine-2,3-diamine (L-04) [ka] N 2A solution of 1,3-cyclopentyl-6-(p-tolyl)pyridine-2,3-diamine (0.238 g, 0.89 mmol) in dichloromethane (2.5 mL) was treated with tert-butyl 2,2,2-trichloroethaneimidate (0.39 g, 1.8 mmol, 2 equiv.) followed by boron trifluoride etherate (22 μL, 0.18 mmol, 0.2 equiv.). After stirring for 3 h, LC / MS analysis indicated partial conversion to the desired product with significant amounts of starting material. The reaction mixture was treated with additional tert-butyl 2,2,2-trichloroethaneimidate (0.39 g, 1.8 mmol, 2 equiv.) and boron trifluoride etherate (22 μL, 0.18 mmol, 0.2 equiv.). After stirring overnight, LC / MS analysis showed 50% conversion to the desired product and 50% starting material. The reaction was quenched with saturated aqueous ammonium chloride (5 mL), and the mixture was extracted with ethyl acetate (3 x 15 mL methylene chloride). The combined organic extracts were dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by flash chromatography (0-100% ethyl acetate / hexanes). The product coeluted with an impurity from an unknown source. The product was repurified by RP-HPLC to give N 3 -tert-Butyl-N 2 -Cyclopentyl-6-(4-pyridyl)pyridine-2,3-diamine (7 mg, 4%) was obtained as a red solid. LCMS: (APCI) m / e 311.1 (M+H).

[0217] 6-(2-pyridyl)-N 3 -sec-Butyl-N 2 -Tetrahydrofuran-3-yl-pyridine-2,3-diamine (L-19) [ka] 6-(2-pyridyl)-N 2A solution of 2-tetrahydrofuran-3-yl-pyridine-2,3-diamine (87 mg, 0.34 mmol) in methanol (1 mL) was treated sequentially with 2-butanone (38 mg, 0.51 mmol, 1.5 equiv.) and then acetic acid (40 μL, 0.68 mmol, 2.0 equiv.). After stirring for 30 minutes, the reaction mixture was treated with sodium cyanoborohydride (33 mg, 0.51 mmol, 1.5 equiv.). After stirring overnight, LC / MS analysis indicated partial conversion to the desired product. An additional 1.5 equiv. of 2-butanone and sodium cyanoborohydride were added to drive the reaction toward product. LC / MS analysis indicated complete conversion to the desired product. The reaction mixture was adsorbed onto a 12 g cartridge and purified by flash chromatography (12 g silica, 0–100% ethyl acetate / hexanes) to afford 6-(2-pyridyl)-N,N-dimethylformamide. 3 -sec-Butyl-N 2 -Tetrahydrofuran-3-yl-pyridine-2,3-diamine (0.101 g, 95%) was obtained as an orange-yellow solid. LCMS: (APCI) m / e 313.1 (M+H).

[0218] 6-(2-pyridyl)-N 2 ,N 3 -Di(tetrahydrofuran-3-yl)pyridine-2,3-diamine (L-21) [ka] 6-(2-pyridyl)-N 2A solution of 2-tetrahydrofuran-3-yl-pyridine-2,3-diamine (77 mg, 0.30 mmol) in methanol (1 mL) was treated sequentially with tetrahydrofuran-3-one (39 mg, 0.45 mmol, 1.5 equiv.) and then acetic acid (35 μL, 0.60 mmol, 2.0 equiv.). After stirring for 30 minutes, the reaction mixture was treated with sodium cyanoborohydride (29 mg, 0.45 mmol, 1.5 equiv.). After stirring overnight, LC / MS analysis showed partial conversion to the desired product. An additional 1.5 equiv. of tetrahydrofuran-3-one and sodium cyanoborohydride were added to drive the reaction toward product. LC / MS analysis showed complete conversion to the desired product. The reaction mixture was adsorbed onto a 12 g cartridge and purified by flash chromatography (12 g silica, 0–100% ethyl acetate / hexanes) to afford 6-(2-pyridyl)-N,N-dimethylformamide. 2 ,N 3 -Di(tetrahydrofuran-3-yl)pyridine-2,3-diamine (0.047 g, 48%) was obtained as a brown solid. LCMS: (APCI) m / e 327.1 (M+H); [ka]

[0219] N 2 -(3-methyltetrahydrofuran-3-yl)-6-(2-pyridyl)-N 3 -sec-butyl-pyridine-2,3-diamine (L-22) [ka] N 2A solution of -(3-methyltetrahydrofuran-3-yl)-6-(2-pyridyl)pyridine-2,3-diamine (79 mg, 0.29 mmol) in methanol (1 mL) was treated sequentially with 2-butanone (32 mg, 0.44 mmol, 1.5 equiv.) and then acetic acid (33 μL, 0.58 mmol, 2.0 equiv.). After stirring for 30 minutes, the reaction mixture was then treated with sodium cyanoborohydride (28 mg, 0.44 mmol, 1.5 equiv.). After stirring overnight, LC / MS analysis indicated partial conversion to the desired product. An additional 1.5 equiv. of 2-butanone and sodium cyanoborohydride were added to drive the reaction toward product. LC / MS analysis indicated complete conversion to the desired product. The reaction mixture was adsorbed onto a 12 g cartridge and purified by flash chromatography (12 g silica, 0–100% ethyl acetate / hexanes) to obtain N-methyl-N ... 2 -(3-methyltetrahydrofuran-3-yl)-6-(2-pyridyl)-N 3 -sec-butyl-pyridine-2,3-diamine (0.079 g, 83%) was obtained as an orange-yellow solid. LCMS: (APCI) m / e 327.2 (M+H); [ka]

[0220] N 2 -(3-methyltetrahydrofuran-3-yl)-6-(2-pyridyl)-N 3 -Tetrahydrofuran-3-yl-pyridine-2,3-diamine (L-23) [ka] N 2A solution of -(3-methyltetrahydrofuran-3-yl)-6-(2-pyridyl)pyridine-2,3-diamine (83 mg, 0.31 mmol) in methanol (1 mL) was treated sequentially with tetrahydrofuran-3-one (40 mg, 0.46 mmol, 1.5 equiv.) and then acetic acid (35 μL, 0.61 mmol, 2.0 equiv.). After stirring for 30 minutes, the reaction mixture was then treated with sodium cyanoborohydride (29 mg, 0.46 mmol, 1.5 equiv.). After stirring overnight, LC / MS analysis indicated partial conversion to the desired product. An additional 1.5 equiv. of tetrahydrofuran-3-one and sodium cyanoborohydride were added to drive the reaction toward the product. LC / MS analysis indicated complete conversion to the desired product. The reaction mixture was adsorbed onto a 12 g cartridge and purified by flash chromatography (12 g silica, 0-100% ethyl acetate / hexanes) to obtain N 2 -(3-methyltetrahydrofuran-3-yl)-6-(2-pyridyl)-N 3 -Tetrahydrofuran-3-yl-pyridine-2,3-diamine (0.082 g, 79%) was obtained as a brown solid. LCMS: (APCI) m / e 341.1 (M+H); [ka]

[0221] N 3 -(3,3-difluorocyclobutyl)-N 2 -(3,3-Difluoro-1-methyl-cyclobutyl)-6-(3-pyridyl)pyridine-2,3-diamine (M-09) [ka] In a 40 mL vial, 2-(3,3-Difluoro-1-methyl-cyclobutyl)-6-(3-pyridyl)pyridine-2,3-diamine (0.271 g, 0.933 mmol) was added. A stir bar, 3,3-difluorocyclobutanone (1.6 equiv., 0.158 g, 1.49 mmol), TFA (1.2 equiv., 0.083 mL, 1.12 mmol), and isopropyl acetate (6 mL) were added. To this was added sodium triacetoxyborohydride (1.5 equiv., 0.297 g, 1.40 mmol). The reaction was stirred at 25 °C overnight, after which LCMS analysis indicated that the majority of the material had been converted to the desired product. The reaction was partitioned between water and ethyl acetate. The organic layer was isolated, and the aqueous layer was extracted three times with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated on a rotary evaporator. The resulting concentrate was loaded onto silica and purified by column chromatography (hexane / ethyl acetate) to give N 3 -(3,3-difluorocyclobutyl)-N 2 -(3,3-Difluoro-1-methyl-cyclobutyl)-6-(3-pyridyl)pyridine-2,3-diamine (58.7 mg, 16.5%) was obtained as a pale pink solid. LCMS: (APCI) m / e 381 (M+H); [ka]

[0222] N 3 -(3,3-difluorocyclobutyl)-6-(4-fluorophenyl)-N 2 -(3-methyltetrahydrofuran-3-yl)pyridine-2,3-diamine (M-10) [ka] In a 40 mL vial, add 6-(4-fluorophenyl)-N 2-(3-Methyltetrahydrofuran-3-yl)pyridine-2,3-diamine (0.200 g, 0.696 mmol) was added. A stir bar, 3,3-difluorocyclobutanone (1.2 eq., 0.089 g, 0.835 mmol), TFA (1.2 eq., 0.062 mL, 0.835 mmol), and isopropyl acetate (6 mL) were added. To this was added sodium triacetoxyborohydride (1.5 eq., 0.221 g, 1.04 mmol). The reaction was stirred at 25° C. overnight. LCMS after overnight reaction indicated conversion to the desired product. The reaction was partitioned between water and ethyl acetate. The organic layer was isolated, and the aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated on a rotary evaporator. The resulting concentrate was loaded onto silica and purified by column chromatography (hexane / ethyl acetate) to give N 3 -(3,3-difluorocyclobutyl)-6-(4-fluorophenyl)-N 2 -(3-methyltetrahydrofuran-3-yl)pyridine-2,3-diamine (102 mg, 38.8%) was obtained as a pale brown solid. LCMS: (APCI) m / e 378 (M+H); [ka]

[0223] 4-[5-[(3,3-difluorocyclobutyl)amino]-6-[(3-methyltetrahydrofuran-3-yl)amino]-2-pyridyl]-N,N-dimethyl-benzamide (N-04) [ka] A 40 mL vial was charged with 4-[5-amino-6-[(3-methyltetrahydrofuran-3-yl)amino]-2-pyridyl]-N,N-dimethyl-benzamide (279 g, 0.820 mmol) and a stir bar, and 3,3-difluorocyclobutanone (1.2 equiv., 104 mg, 0.983 mmol), TFA (1.2 equiv., 0.74 mL, 0.983 mmol), and isopropyl acetate (5 mL, 0.2 M) were added. To this was added sodium triacetoxyborohydride (1.5 equiv., 261 mg, 1.23 mmol) over approximately 2 minutes. The reaction was then stirred at room temperature. After 16 hours, the reaction was complete by LCMS and partitioned between 25 mL of water and 25 mL of EtOAc. The aqueous layer was extracted 3 x 25 mL of EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (40 g, 0-50% EtOAc / hexanes) to give 110 mg of 4-[5-[(3,3-difluorocyclobutyl)amino]-6-[(3-methyltetrahydrofuran-3-yl)amino]-2-pyridyl]-N,N-dimethyl-benzamide (31%) as a yellow film: LCMS (APCI) m / e 431.1 (M+H); [ka] Example 6 Synthesis of gem-dimethylpyrimidine compounds

[0224] Reaction Scheme 6 for gem-dimethylpyrimidine compounds [ka]

[0225] Ethyl 2-chloro-6-(cyclopentylamino)-5-nitro-pyrimidine-4-carboxylate (K-19). [ka] A 100 mL 14 / 22 RBF was charged with ethyl 2,6-dichloro-5-nitro-pyrimidine-4-carboxylate (500 mg, 1.88 mmol), THF (4 mL), attached with a balloon of nitrogen, and cooled to -78 °C. The reaction was then treated with DiPEA (1.5 equiv., 2.8 mmol, 0.5 mL) followed by a solution of cyclopentanamine (1.0 equiv., 1.88 mmol, 160 mg) in THF (3 mL) dropwise over a 15 minute period. The reaction mixture was allowed to gradually warm to room temperature overnight. After 16 h, the reaction was partitioned between 25 mL of EtOAc and 25 mL of HO, the aqueous layer was back-extracted with 2×25 mL of EtOAc, and the combined organic layers were dried over NaSO and concentrated under reduced pressure to afford ethyl 2-chloro-6-(cyclopentylamino)-5-nitro-pyrimidine-4-carboxylate (K-19) as a viscous yellow oil (450 mg, 76%), which was used in the next step without further purification. [ka]

[0226] Ethyl 6-(cyclopentylamino)-5-nitro-2-(p-tolyl)pyrimidine-4-carboxylate (K-20). [ka] A 40 mL vial was charged with chloropyrimidine (500 mg, 1.6 mmol), THF (3 mL), water (1.5 mL), p-tolylboronic acid (2 equiv., 432 mg, 3.2 mmol), and sodium carbonate (4 equiv., 674 mg, 6.4 mmol), then fitted with a stir bar and septum. The solution was degassed for 20 minutes using a direct stream of nitrogen and an outlet needle. The reaction mixture was then treated with tetrakis(triphenylphosphine)palladium(0) (0.1 equiv., 184 mg, 0.159 mmol), fitted with a nitrogen balloon, and stirred at 60 °C. After 0.5 h, LCMS confirmed complete conversion of the starting material, and the major product showed the correct MS for the desired product. The reaction mixture was allowed to cool to room temperature and then partitioned between 20 mL of EtOAc and 20 mL of water. The aqueous layer was back-extracted with 2 × 20 mL of EtOAc, and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure, and the resulting residue was purified on silica gel (40 g, 0–30% EtOAc / hexanes) to afford ethyl 6-(cyclopentylamino)-5-nitro-2-(p-tolyl)pyrimidine-4-carboxylate (K-20) as a yellow solid (400 mg, 68%). [ka]

[0227] Ethyl 5-amino-6-(cyclopentylamino)-2-(p-tolyl)pyrimidine-4-carboxylate (K-33). [ka] A 40 mL vial was charged with ethyl 6-(cyclopentylamino)-5-nitro-2-(p-tolyl)pyrimidine-4-carboxylate (520 mg, 1.4 mmol), EtOH (8 mL), water (2 mL), ammonium chloride (1 equiv., 1.4 mmol, 75 mg), and iron powder (5 equiv., 7 mmol, 392 mg), fitted with a stir bar, purged with nitrogen, sealed, and stirred at 80 °C. After 16 h, the reaction was cooled to room temperature and filtered using a syringe filter. The reaction residue was washed with 3 × 5 mL of EtOH, settled, and filtered. The yellow solution was concentrated under reduced pressure to give ethyl 5-amino-6-(cyclopentylamino)-2-(p-tolyl)pyrimidine-4-carboxylate (K-33) (270 mg, 55%) as a brown powder. The material was pure by LCMS and used directly in the hydrolysis step. LCMS(APCI) m / e 341.1(M+H).

[0228] 5-Amino-6-(cyclopentylamino)-2-(p-tolyl)pyrimidine-4-carboxylic acid (K-35). [ka] A 20 mL vial was charged with ethyl 5-amino-6-(cyclopentylamino)-2-(p-tolyl)pyrimidine-4-carboxylate (118 mg, 0.9347 mmol), THF (1 mL), methanol (0.5 mL), HO (0.5 mL), and LiOH-HO (1.5 equiv., 0.52 mmol, 22 mg), attached with a stir bar, and stirred at room temperature. After 3 days, crude LCMS confirmed complete consumption of the starting ethyl ester. The reaction mixture was partitioned between 25 mL of water and 25 mL of EtOAc. The aqueous layer was back-extracted with 2×25 mL of EtOAc, but remained yellow at pH=8. The aqueous layer was treated with 1 mL of 1 N HCl, and a precipitate formed at pH=4. The acidic aqueous layer was extracted with 3 × 20 mL of DCM, and the combined organic layers were dried over NaSO and concentrated under reduced pressure to give 5-amino-6-(cyclopentylamino)-2-(p-tolyl)pyrimidine-4-carboxylic acid (K-35) as a reddish solid (40 mg, 37%). The material was pure by LCMS and used directly in the amide coupling step. LCMS (APCI) m / e 313.1 (M+H).

[0229] 5-Amino-6-(cyclopentylamino)-N-methyl-2-(p-tolyl)pyrimidine-4-carboxamide (K-31). [ka] A 4 mL vial was charged with 5-amino-6-(cyclopentylamino)-2-(p-tolyl)pyrimidine-4-carboxylic acid (40 mg, 0.128 mmol), DMF (1 mL), DiPEA (3 equiv., 0.384 mmol, 50 mg), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 1.5 equiv., 0.192 mmol, 73 mg), and the reaction was stirred at room temperature for 20 minutes. The reaction was then treated with methylamine hydrochloride (1.5 equiv., 0.192 mmol, 13 mg), and the reaction was stirred at room temperature. After 16 hours, crude LCMS showed complete consumption of the starting carboxylic acid. The reaction mixture was treated with 2 mL of water to give 5-amino-6-(cyclopentylamino)-N-methyl-2-(p-tolyl)pyrimidine-4-carboxamide (K-31) as an off-white precipitate, which was isolated by filtration (40.0 mg, 96%). The material was pure by LCMS and used directly in the crystallization step. LCMS (APCI) m / e 326.1 (M+H). Step 2. Synthesis of the final compound

[0230] 9-Cyclopentyl-N,8,8-trimethyl-2-(p-tolyl)-5,7-dihydro-4H-purine-6-carboxamide (K-34). [ka] A 20 mL microwave vial was charged with a solution of 5-amino-6-(cyclopentylamino)-N-methyl-2-(p-tolyl)pyrimidine-4-carboxamide in acetone, p-toluenesulfonic acid monohydrate (0.25 equiv, 190.22 MW, 0.031 mmol, 69 mg), and glacial acetic acid (1 mL), sealed, and heated to 70 °C. After 16 h, the starting material was consumed, and a major and minor amount of product with the correct M+H+ were observed by crude LCMS. The reaction mixture was cooled to room temperature and partitioned between 15 mL of water and 15 mL of EtOAc. There was a precipitate in the EtOAc layer. The aqueous layer was back-extracted with 2 × 10 mL of EtOAc, and the combined organic layers were concentrated under reduced pressure without drying over Na2SO4, affording 45 mg of a yellow solid. The solid was triturated with 5 × 3 mL of ether to give a yellow powder, which was dried under reduced pressure to give 9-cyclopentyl-N,8,8-trimethyl-2-(p-tolyl)-5,7-dihydro-4H-purine-6-carboxamide (K-34) (23.0 mg, 50.9%). LCMS (APCI) m / e 366.1 (M+H). The ether layer was further purified as described for K-36.

[0231] 8-(Cyclopentylamino)-2,2,3-trimethyl-6-(p-tolyl)-1H-pyrimido[5,4-d]pyrimidin-4-one (K-36). [ka] The combined ether layers from K-34 were concentrated under reduced pressure to give 12 mg of a 1:1 mixture of the major and minor products from K-34. A 5-inch pipette was plugged with cotton and three-quarters filled with silica gel. The silica gel was washed with three column volumes of 10% EtOAc / hexane. The crude residue was dissolved in the minimum amount of DMC possible and loaded onto the column. The material was eluted using 12 column volumes of 10% EtOAc / hexane via a pipette valve, collecting two fractions per column volume, and then 8 column volumes of 50% EtOAc / hexane were flushed through the column, resulting in the elution of 8-(cyclopentylamino)-2,2,3-trimethyl-6-(p-tolyl)-1H-pyrimido[5,4-d]pyrimidin-4-one (K-36) as the residue (2 mg, 3.7%). LCMS (APCI) m / e 366.1 (M+H). Example 7 Synthesis of pyridine ketones

[0232] General reaction scheme 7 for pyridine ketones [ka] Synthesis of pyridine ketone analogue 1

[0233] N-Benzyl-N-cyclopentyl-6-methyl-3-nitro-pyridin-2-amine (K-64). [ka] A 40 mL vial was charged with 2-chloro-6-methyl-3-nitro-pyridine (1.0 g, 5.79 mmol), a stir bar, DMF (5 mL, 1 M), DiEA (3 equiv., 3.1 mL, 17.4 mmol), and N-benzylcyclopentanamine hydrochloride (1.1 equiv., 6.37 mmol, 1.35 g) at 80 °C overnight. After 16 h, the starting material was consumed and the desired product was confirmed by crude LCMS. The reaction mixture was partitioned between 75 mL of water and 75 mL of EtOAc. The aqueous layer was back-extracted with 3 × 50 mL of EtOAc, and the combined organic layers were dried over NaSO. The residue was purified on silica gel (80 g, 0–30% EtOAc / hexanes) to afford 1.2 g of N-benzyl-N-cyclopentyl-6-methyl-3-nitro-pyridin-2-amine (85%) as a yellow solid. LCMS(APCI) m / e 312.1(M+H).

[0234] 6-[Benzyl(cyclopentyl)amino]-5-nitro-pyridine-2-carbaldehyde (L-20). [ka] A solution of N-benzyl-N-cyclopentyl-6-methyl-3-nitro-pyridin-2-amine (0.69 g, 2.2 mmol) in 1,4-dioxane (10 mL) was treated with selenium dioxide (0.370 g, 3.3 mmol, 1.5 equiv.) and then warmed to 100 °C. After stirring overnight, LC / MS analysis indicated partial conversion to the desired product. Additional selenium dioxide was added, and the reaction was allowed to proceed for an additional 8 h. LC / MS analysis indicated no further progress of the reaction. The mixture was dried onto silica (10 g) and purified by flash chromatography (24 g silica, 0–50% methylene chloride / hexanes) to give 6-[benzyl(cyclopentyl)amino]-5-nitro-pyridine-2-carbaldehyde (0.498 g, 69%) as an orange-yellow solid. LCMS(APCI) m / e 326.1(M+H).

[0235] 1-[6-[benzyl(cyclopentyl)amino]-5-nitro-2-pyridyl]but-3-en-1-ol (L-24). [ka] A solution of 6-[benzyl(cyclopentyl)amino]-5-nitro-pyridine-2-carbaldehyde (0.243 g, 0.75 mmol) in anhydrous dichloromethane (3 mL) was cooled to -78 °C and then treated sequentially with allyltrimethylsilane (0.142 mL, 90 mmol, 1.2 equiv.), followed by the dropwise addition of titanium tetrachloride (40 μL, 0.37 mmol, 0.5 equiv.). After 1 h, LC / MS analysis showed complete and complete conversion to the desired product as two peaks, one consistent with the Ti-conjugated product and the other with the unconjugated product. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and then diluted with methylene chloride (10 mL). The layers were separated, and the aqueous layer was further extracted with methylene chloride (2 × 15 mL). The combined organic extracts were dried (NaSO), and the solvent was removed in vacuo. The residue was purified by flash chromatography (12 g silica, 0-100% ethyl acetate / hexanes) to give 1-[6-[benzyl(cyclopentyl)amino]-5-nitro-2-pyridyl]but-3-en-1-ol (0.20 g, 73%) as a yellow solid in two distinct peaks: LCMS (APCI) m / e 368.1 (M+H).

[0236] 1-[5-amino-6-[benzyl(cyclopentyl)amino]-2-pyridyl]butan-1-ol (L-26). [ka] A solution of 1-[6-[benzyl(cyclopentyl)amino]-5-nitro-2-pyridyl]but-3-en-1-ol (0.20 g, 0.54 mmol) in methanol (2 mL) was degassed with a nitrogen balloon for 15 minutes. The reaction mixture was then treated with Pd / C (58 mg, 54 μmol, 0.1 equiv.), followed by introduction of hydrogen via balloon. After stirring overnight, LC / MS analysis showed only reduction of the nitro and olefin, with retention of the benzyl moiety. The sample was filtered through Celite®, and 1-[5-amino-6-[benzyl(cyclopentyl)amino]-2-pyridyl]butan-1-ol (0.16 g, 87%) was carried forward without further purification. LCMS (APCI) m / e 340.1 (M+H).

[0237] 1-[6-[benzyl(cyclopentyl)amino]-5-(sec-butylamino)-2-pyridyl]butan-1-ol (L-29). [ka] A solution of 1-[5-amino-6-[benzyl(cyclopentyl)amino]-2-pyridyl]butan-1-ol (0.16 g, 0.47 mmol) in anhydrous methanol (2 mL) was treated with 2-butanone (68 mg, 0.94 mmol, 2.0 equiv.) followed by acetic acid (57 μL, 0.94 mmol, 2.0 equiv.). After 1 h, the reaction was treated with sodium cyanoborohydride (45 mg, 0.71 mmol, 1.5 equiv.). After stirring overnight, LC / MS analysis showed conversion to the desired product. Additionally, the mixture contained two peaks consistent with the formation of the product from acetone and acetaldehyde. The mixture was dissolved on silica and purified by flash chromatography (12 g silica, 0-100% ethyl acetate / hexanes) to give 1-[6-[benzyl(cyclopentyl)amino]-5-(sec-butylamino)-2-pyridyl]butan-1-ol (44 mg, 24%) as a red oil: LCMS (APCI) m / e 396.1 (M+H).

[0238] 1-[6-[benzyl(cyclopentyl)amino]-5-(sec-butylamino)-2-pyridyl]butan-1-one (L-32). [ka] A solution of 1-[6-[benzyl(cyclopentyl)amino]-5-(sec-butylamino)-2-pyridyl]butan-1-ol (45 mg, 0.11 mmol) in acetone (0.5 mL) was treated with Dess-Martin reagent (58 mg, 0.14 mmol, 1.2 equiv.). After stirring overnight, LC / MS analysis showed complete conversion to the desired ketone. The reaction mixture was filtered through a plug of silica (1 g, ethyl acetate), and the filtrate was dried in vacuo. The residue was carried forward without further purification. LCMS (APCI) m / e 394.1 (M+H).

[0239] 1-[6-(cyclopentylamino)-5-(sec-butylamino)-2-pyridyl]butan-1-one (L-34). [ka] A solution of 1-[6-[benzyl(cyclopentyl)amino]-5-(sec-butylamino)-2-pyridyl]butan-1-ol (44 mg, 0.11 mmol) in anhydrous methanol (0.5 mL) was degassed with a N balloon. After 15 min, the reaction was treated with 20% palladium hydroxide on carbon (50% wet, 32 mg, 23 μmol, 0.2 equiv.). The reaction mixture was then subjected to bubbling of H via a balloon and allowed to react. After stirring overnight, LC / MS analysis indicated conversion to the desired product and the formation of some by-products. The sample was filtered through Celite and dried under vacuum. The sample was then purified by RP-HPLC to give 1-[6-(cyclopentylamino)-5-(sec-butylamino)-2-pyridyl]butan-1-one (5.5 mg, 16%) as a yellow film. LCMS(APCI) m / e 304.1(M+H). Synthesis of pyridine ketone analogue 2

[0240] N-Benzyl-N-(3,3-difluorocyclobutyl)-6-methyl-3-nitro-pyridin-2-amine (K-87). [ka] A 40 mL vial was charged with 2-chloro-6-methyl-3-nitro-pyridine (400 mg, 2.32 mmol), a stir bar, DMF (5 mL, 0.5 M), DiPEA (2 equiv., 0.8 mL, 4.64 mmol), and N-benzyl-3,3-difluoro-cyclobutanamine (2 equiv., 4.64 mmol, 0.914 g) and stirred at 80 °C for 72 h. Crude LCMS confirmed the reaction was complete. The reaction mixture was partitioned between 50 mL of water and 50 mL of EtOAc. The aqueous layer was back-extracted with 3 x 50 mL of EtOAc, and the combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified on silica gel (80 g, 0-30% EtOAc / hexanes) to give 700 mg of N-benzyl-N-(3,3-difluorocyclobutyl)-6-methyl-3-nitro-pyridin-2-amine (90%) as a yellow solid: LCMS (APCI) m / e 334.1 (M+H).

[0241] 6-[Benzyl-(3,3-difluorocyclobutyl)amino]-5-nitro-pyridine-2-carbaldehyde (K-91). [ka] A 40 mL vial was charged with N-benzyl-N-(3,3-difluorocyclobutyl)-6-methyl-3-nitro-pyridin-2-amine (700 mg, 2.10 mmol), dioxane (0.4 M, 5 mL), and SeO (2 equiv., 4.2 mmol, 466 mg), purged with nitrogen, and stirred at 100 °C. After 16 h, the reaction was complete by LCMS and purified directly on silica gel (40 g, 0-50% EtOAc / hexanes) to afford 540 mg of 6-[benzyl-(3,3-difluorocyclobutyl)amino]-5-nitro-pyridine-2-carbaldehyde (74%) as a yellow oil. LCMS (APCI) m / e 348.1 (M+H).

[0242] 1-[6-[benzyl-(3,3-difluorocyclobutyl)amino]-5-nitro-2-pyridyl]but-3-en-1-ol (K-92). [ka] A solution of 6-[benzyl-(3,3-difluorocyclobutyl)amino]-5-nitro-pyridine-2-carbaldehyde (540 mg, 1.55 mmol) in anhydrous dichloromethane (6 mL, 0.25 M) was cooled to -78 °C and then treated sequentially with allyltrimethylsilane (0.25 mL, 1.86 mmol, 1.2 equiv.), followed by the dropwise addition of titanium tetrachloride (85 μL, 0.78 mmol, 0.5 equiv.). After 2 h, LC / MS analysis showed complete and complete conversion to the desired product as two peaks, one consistent with the Ti-complexed product and the other with the uncomplexed product. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL) and then diluted with methylene chloride (20 mL). The layers were separated, and the aqueous layer was further extracted with methylene chloride (2 × 30 mL). The combined organic extracts were dried (NaSO) and the solvent removed in vacuo. The residue was purified by flash chromatography (80 g silica, 0-40% ethyl acetate / hexanes) to give 11-[6-[benzyl-(3,3-difluorocyclobutyl)amino]-5-nitro-2-pyridyl]but-3-en-1-ol (0.320 g, 52%) as a yellow oil. LCMS (APCI) m / e 390.1 (M+H). Synthesis of the final compound

[0243] 1-[6-[benzyl-(3,3-difluorocyclobutyl)amino]-5-nitro-2-pyridyl]but-3-en-1-one (K-96). [ka] A 40 mL vial was charged with 1-[6-[benzyl-(3,3-difluorocyclobutyl)amino]-5-nitro-2-pyridyl]but-3-en-1-ol (320 mg, 0.822 mmol), DCM (8 mL, 0.1 M), and sodium bicarbonate (10 equiv., 8.22 mmol, 690 mg) and stirred for 5 minutes. The reaction mixture was then treated with Dess-Martin periodinane (1.5 equiv., 1.23 mmol, 523 mg) and stirred at room temperature. After 3 hours, the reaction was 50% complete. The reaction was treated with Dess-Martin periodinane (1.5 equiv., 1.23 mmol, 523 mg) and stirred at room temperature overnight. After 16 hours, the reaction was complete by crude LCMS. The reaction mixture was partitioned between 20 mL of DCM and 20 mL of 1 M NaOH(aq); stirred for 10 minutes. The aqueous layer was extracted with DCM (3 × 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified on silica gel (40 g, 0–30% EtOAc / hexanes) to afford 156 mg of 1-[6-[benzyl-(3,3-difluorocyclobutyl)amino]-5-nitro-2-pyridyl]but-3-en-1-one (318 mg, 49%) as a yellow solid. LCMS (APCI) m / e 388.1 (M+H).

[0244] 1-[5-amino-6-[(3,3-difluorocyclobutyl)amino]-2-pyridyl]butan-1-one (P-46). [ka] 156 mg of 1-[6-[benzyl-(3,3-difluorocyclobutyl)amino]-5-nitro-2-pyridyl]but-3-en-1-one (K-96) was dissolved in 10 ml of MeOH. The solution was degassed and flushed with nitrogen. 50 mg of 20% Pd(OH)2 on carbon was added to the solution, followed by a hydrogen balloon. The reaction was stirred at room temperature for 18 hours. LC-MS showed one peak with the mass of the desired product. There was no evidence of any starting material. The reaction was worked up by filtration. Evaporation of the MeOH gave 97 mg (90%) of a brown solid. LC-MS and NMR confirmed the structure and purity. LCMS (APCI) m / e 270.1 (M+H); [ka]

[0245] 1-[5,6-bis[(3,3-difluorocyclobutyl)amino]-2-pyridyl]butan-1-one (P-47). [ka] 1-[5,6-bis[(3,3-difluorocyclobutyl)amino]-2-pyridyl]butan-1-one (P-47) was prepared using standard reductive amination conditions (similar to L-29). LCMS (APCI) m / e 360.1 (M+H); [ka] Example 8 Synthesis of heterocycloalkyl aromatic compounds

[0246] Intermediate 1: 2-chloro-N-cyclopentyl-6,7-dihydro-5H-pyrimido[4,5-b][1,4]oxazin-4-amine [ka] 2-Chloro-4-(cyclopentylamino)-5H-pyrimido[4,5-b][1,4]oxazin-6-one (550 mg, 2.05 mmol) was dissolved in dry THF under argon. A 1 M solution of BH3-THF complex (10.0 equiv.) was slowly added. The mixture was stirred for 1 hour. The mixture was diluted with water. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (hexane / ethyl acetate as eluent) to give the title compound as a solid (350 mg, 67.1%). LC-MS m / z: ES+ [M+H] + :255.1;t R =2.23 minutes.

[0247] Intermediate 2, Step 1: Ethyl 8-chloro-1,7-naphthyridine-6-carboxylate [ka] A mixture of ethyl 8-hydroxy-1,7-naphthyridine-6-carboxylate (300 mg) in POCl3 (7 ml) was stirred at 110 °C for 30 min. Once all starting material was converted to the product, the mixture was cooled and concentrated. The resulting residue was then poured onto crushed ice and stirred for 15 min. The pH of the aqueous mixture was basified to pH 8 at 0 °C by careful addition of saturated aqueous sodium carbonate solution. The product was extracted three times with DCM, and the organic phases were combined, washed with brine, dried, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (12 g) using a 0-50% gradient of ethyl acetate in hexane. The desired product was isolated in 58% yield (189 mg). LC-MS m / z: ES+ [M+H] + :237.1;(B05)t R =1.99 minutes.

[0248] Intermediate 2, Step 2: 2,4-Dichloropyrido[3,2-d]pyrimidine [ka] A mixture of pyrido[3,2-d]pyrimidine-2,4-diol (1 g), POCl3 (10 mL), and PCl5 (5.11 g) was heated at 120 °C under argon for 12 h. The reaction mixture was cooled to room temperature, POCl3 was evaporated under reduced pressure, and the resulting residue was taken up in DCM. Ice and water were added, the mixture was cooled to 0 °C, and the pH was adjusted to 8 by slow addition of saturated aqueous NaHCO3. The aqueous phase was extracted three times with DCM, and the organic phases were combined and then washed successively with water and brine. The organic phase was filtered and concentrated, and the resulting residue was purified by silica gel column chromatography (40 g) using a 0-20% gradient of EtOAc in hexane to give 2,4-dichloropyrido[3,2-d]pyrimidine in 42% yield (510 mg). [ka] Synthesis of the final compound

[0249] 4-[(oxolan-3-yl)amino]-2-[(1E)-pent-1-en-1-yl]-5H,6H,7H-pyrimido[4,5-b][1,4]oxazin-6-one (B-603) [ka] A mixture of 2-chloro-4-(tetrahydrofuran-3-ylamino)-5H-pyrimido[4,5-b][1,4]oxazin-6-one (45.0 mg, 0.166 mmol), [(E)-pent-1-enyl]boronic acid (56.8 mg, 0.498 mmol), and potassium carbonate (68.9 mg, 0.499 mmol) in toluene (0.800 mL), ethanol (0.20 mL), and water (0.20 mL) was degassed by bubbling argon through it for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (38.4 mg, 0.0332 mmol) was added, the vial was sealed, and the mixture was stirred at 100 °C for 16 hours. The mixture was cooled to room temperature and diluted with ethyl acetate and saturated aqueous NaHCO3. The organic phase was separated, and the aqueous phase was further extracted twice with EtOAc. The organic phases were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography using a gradient of 0-10% MeOH in DCM to give the title compound (23.0 mg, 46%). LC-MS m / z: ES+ [M+H]+: 305.2, LCMS; R =4.14 minutes (10 minute run).

[0250] N-Cyclopentyl-2-pentyl-5H,6H,7H-pyrimido[4,5-b][1,4]thiazin-4-amine (B-601) [ka] Under argon, BH3·THF (0.405 g, 4.71 mmol) was added dropwise to a solution of 4-(cyclopentylamino)-2-[(E)-pent-1-enyl]-5H-pyrimido[4,5-b][1,4]thiazin-6-one (150 mg, 0.471 mmol) in dry tetrahydrofuran (10.0 mL). The mixture was then stirred for 1 h at room temperature, diluted with water and ethyl acetate, and the organic phase was separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography using a gradient of 0–100% ethyl acetate in hexane as the eluent to give the title compound (102 mg, 71%). [ka] LC-MS m / z: ES+ [M+H]+: 307.2;t R =3.70 minutes.

[0251] 4-(Cyclopentylamino)-2-[(1E)-pent-1-en-1-yl]-5H,6H,7H-pyrimido[4,5-b][1,4]thiazin-6-one (B-600) [ka] A mixture of 2-chloro-4-(cyclopentylamino)-5H-pyrimido[4,5-b][1,4]thiazin-6-one (250 mg), 1-pentenylboronic acid (100 mg), and potassium carbonate (364 mg) in toluene (1.5 mL), ethanol (0.7 mL), and water (0.7 mL) was degassed by bubbling argon through it for 10 minutes. Pd(PPh3)4 was added, the vial was sealed, and the mixture was stirred at 100 °C for 12 hours. The mixture was cooled to room temperature, and the product was partitioned between saturated aqueous NaHCO3 and EtOAc. The separated organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography using a 0-100% gradient of EtOAc in hexane as the eluent to give the title compound (155 mg, 56%). [ka] LC-MS m / z:ES+[M+H]+:319.2;tR=4.82 min.

[0252] 1-{8-[(pyridin-2-yl)amino]-1,2,3,4-tetrahydroquinolin-6-yl}pentan-1-one (B-249) [ka] To a solution of 1-[1-benzyl-8-(2-pyridylamino)-3,4-dihydro-2H-quinolin-6-yl]pentan-1-one in anhydrous EtOAc (5 mL) was carefully added Pd—C under an argon atmosphere. The flask was connected to a H balloon. The resulting suspension was stirred at room temperature for 6 h, after which time the reaction was stopped and the mixture was filtered through Celite®. The solvent was evaporated under reduced pressure to give the crude reaction product, which was purified by flash chromatography (0–50% EtOAc / hexanes). [ka] LC-MS m / z:ES+[M+H]+:310.2, tR:3.29 min.

[0253] Additional synthetic schemes for heterocycloalkylaromatics [ka] [ka] Example 9 Synthesis of aromatic pyridines Schematic reaction scheme 9 for CF3-pyridine [ka]

[0254] N-Cyclopentyl-3-nitro-6-(trifluoromethyl)pyridin-2-amine (K-61). [ka] A 40 mL vial was charged with 2-chloro-3-nitro-6-(trifluoromethyl)pyridine (0.5 g, 2.21 mmol), a stir bar, THF (3 mL, 0.5 M), DiEA (2 equiv., 0.8 mL, 4.41 mmol), and cyclopentanamine in 2 mL of THF (1 equiv., 2.21 mmol, 188 mg), and the reaction was stirred at room temperature. After 2 h, the reaction was complete by LCMS and then partitioned between 50 mL of water and 50 mL of EtOAc. The aqueous layer was extracted with 3 × 30 mL of EtOAc, and the combined organic layers were dried over NaSO and concentrated under reduced pressure to give 370 mg of an oil (60%) with a purity of >90% by LCMS, which was used in the next step without further purification. LCMS: (APCI) m / e 276.0 (M+H).

[0255] N-(3-Methyltetrahydrofuran-3-yl)-3-nitro-6-(trifluoromethyl)pyridin-2-amine (K-63). [ka] A 40 mL vial was charged with 2-chloro-3-nitro-6-(trifluoromethyl)pyridine (0.5 g, 2.21 mmol), a stir bar, THF (3 mL, 0.5 M), DiEA (2 equiv., 0.8 mL, 4.41 mmol), and 3-methyltetrahydrofuran-3-amine in 2 mL of THF (1.1 equiv., 2.43 mmol, 246 mg), and the reaction was stirred at room temperature. After 24 h, the reaction was approximately 60% complete, and an additional 0.5 equiv. of amine was added (1.22 mmol, 123 mg). After 48 h, the reaction was complete by LCMS, and then the reaction was partitioned between 50 mL of water and 50 mL of EtOAc. The aqueous layer was extracted with 3 x 30 mL of EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a yellow residue which was purified on silica gel (80 g, 0-30% EtOAc / hexanes) to give 410 mg of N-(3-methyltetrahydrofuran-3-yl)-3-nitro-6-(trifluoromethyl)pyridin-2-amine as a yellow oil (63%). LCMS: (APCI) m / e 292.0 (M+H).

[0256] N 2 -Cyclopentyl-6-(trifluoromethyl)pyridine-2,3-diamine (K-62). [ka] A 20 mL microwave vial was charged with N-cyclopentyl-3-nitro-6-(trifluoromethyl)pyridin-2-amine (370 mg, 1.34 mmol), EtOH (8 mL), water (2 mL), ammonium chloride (1 equiv., 1.34 mmol, 72 mg), and iron filings (5 equiv., 6.72 mmol, 375 mg), fitted with a stir bar, bubbled with nitrogen for 10 minutes, sealed, and stirred at 80 °C. After 4 h, the reaction was cooled to room temperature and filtered using an ISCO sample cartridge equipped with Celite® (MeOH), washing several times with MeOH. The yellow solution was dried over Na2SO4 and concentrated under reduced pressure to give 320 mg (97%) of a yellow oil. The material was pure by LCMS and used directly in the next step. LCMS: (APCI) m / e 246.1 (M+H).

[0257] N 2 -(3-Methyltetrahydrofuran-3-yl)-6-(trifluoromethyl)pyridine-2,3-diamine (K-66). [ka] A 20 mL microwave vial was charged with N-(3-methyltetrahydrofuran-3-yl)-3-nitro-6-(trifluoromethyl)pyridin-2-amine (410 mg, 1.41 mmol), EtOH (8 mL), water (2 mL), ammonium chloride (1 equiv., 1.41 mmol, 75 mg), and iron filings (5 equiv., 7.042 mmol, 393 mg), fitted with a stir bar, purged with nitrogen, sealed, and stirred at 80 °C. After 3 h, the reaction was cooled to room temperature and filtered using an ISCO sample cartridge with wet Celite® (MeOH), washing several times with MeOH. The yellow solution was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 350 mg (95%) of N 2 -(3-methyltetrahydrofuran-3-yl)-6-(trifluoromethyl)pyridine-2,3-diamine was obtained as an orange film. The material was pure by LCMS and used directly in the next step. LCMS: (APCI) m / e 262.1 (M+H).

[0258] N 2 -Cyclopentyl-N 3 -sec-Butyl-6-(trifluoromethyl)pyridine-2,3-diamine (K-65). [ka] In a 40 mL vial, 2 To a solution of 1,3-cyclopentyl-6-(trifluoromethyl)pyridine-2,3-diamine (320 g, 1.30 mmol) and a stir bar was added 2-butanone (1.1 equiv., 103 mg, 1.44 mmol), TFA (2 equiv., 0.194 mL, 2.61 mmol), and isopropyl acetate (4 mL, 0.3 M). To this was added sodium triacetoxyborohydride (1.2 equiv., 332 mg, 1.57 mmol) over approximately 2 minutes. The reaction was then allowed to stir at room temperature. After 2 hours, the reaction was complete by LCMS and partitioned between 25 mL of water and 25 mL of EtOAc. The aqueous layer was extracted with 3 x 25 mL of EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (40 g, 0-50% EtOAc / hexanes) to give 276 mg (70%) of a yellow oil. [ka]

[0259] N 2 -(3-methyltetrahydrofuran-3-yl)-N 3 -Tetrahydrofuran-3-yl-6-(trifluoromethyl)pyridine-2,3-diamine (K-67). [ka] In a 40 mL vial, 2To a solution of -(3-methyltetrahydrofuran-3-yl)-6-(trifluoromethyl)pyridine-2,3-diamine (350 mg, 1.34 mmol) and a stir bar was added tetrahydrofuran-3-one (1.1 equiv., 127 mg, 1.47 mmol), TFA (2 equiv., 0.306 mL, 2.68 mmol), and isopropyl acetate (4 mL, 0.3 M). To this was added sodium triacetoxyborohydride (1.2 equiv., 341 mg, 1.61 mmol). The reaction was then allowed to stir at room temperature. After 1 hour, the reaction was completed by LCMS and partitioned between 25 mL of water and 25 mL of EtOAc. The aqueous layer was extracted with 3 x 25 mL of EtOAc, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (40 g, 0-100% EtOAc / hexanes) to give 270 mg (61%) of N 2 -(3-methyltetrahydrofuran-3-yl)-N 3 -Tetrahydrofuran-3-yl-6-(trifluoromethyl)pyridine-2,3-diamine was obtained as an orange foam. LCMS: (APCI) m / e 232.1 (M+H); [ka] Example 10 Synthesis of intermediates

[0260] Intermediate 1: 2-chloro-N-cyclopentyl-6,7-dihydro-5H-pyrimido[4,5-b][1,4]oxazin-4-amine [ka] To a solution of 2-chloro-4-(cyclopentylamino)-5H-pyrimido[4,5-b][1,4]oxazin-6-one (550 mg, 2.05 mmol) in dry THF (10 mL) under argon, a 1 M solution of BH3·THF (20.5 mL, 20.5 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with water, and the aqueous layer was extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, and then concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a 0-100% gradient of EtOAc in hexanes to give the title compound (350 mg, 67%) as a solid. LCMS m / z: ES+ [M+H] + =255.1;t R =2.23 minutes.

[0261] Intermediate 2, Step 1: Ethyl 8-chloro-1,7-naphthyridine-6-carboxylate [ka] A mixture of ethyl 8-hydroxy-1,7-naphthyridine-6-carboxylate (300 mg, 1.37 mmol) in POCl (7 mL) was stirred at 110 °C for 30 min. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was poured onto crushed ice and stirred for 15 min. The pH was adjusted to 8 at 0 °C by careful addition of aqueous saturated sodium carbonate solution. The aqueous layer was extracted with DCM, and the combined organic layers were washed with brine, then dried (Na SO ), filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (12 g) using a 0-50% gradient of EtOAc in hexanes to afford the title compound (189 mg, 58%) as a solid. [ka] LCMS m / z:ES+[M+H] + =237.1;(B05)t R =1.99 minutes.

[0262] Intermediate 3, Step 1: 2,4-Dichloropyrido[3,2-d]pyrimidine [ka] A mixture of pyrido[3,2-d]pyrimidine-2,4-diol (1.0 g, 6.13 mmol), POCl3 (10.1 mL, 110 mmol), and PCl5 (5.11 g, 24.5 mmol) was heated at 120 °C under argon for 12 h. The mixture was cooled to room temperature, and the volatiles were evaporated under reduced pressure. The residue was diluted with DCM, ice and water were added, and the mixture was cooled to 0 °C. The pH was adjusted to 8 by slow addition of aqueous saturated NaHCO3 solution. The aqueous layer was extracted with DCM, and the combined organic layers were washed with water and brine. The organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel (40 g) using a 0-20% gradient of EtOAc in hexanes to give the title compound (510 mg, 42%) as a solid. [ka] LCMS m / z: ES+ [M+H] + = 200.1; t R = 2.00 minutes. Example 11 Synthesis of B-647 [ka]

[0263] Step 1: Synthesis of N-tert-butyl-3-methyl-pyridine-2-carboxamide [ka] To a suspension of 3-methylpyridine-2-carbonitrile (10 g, 84.6 mmol) in tert-butanol (30 mL) at 70 °C, sulfuric acid (10 mL, 186 mmol) was added dropwise. The mixture was stirred at 75 °C for 30 minutes, diluted with water (150 mL), and then cooled to room temperature. The volatiles were evaporated and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel (120 g) using 0.5% EtOAc in hexane to give the title compound (10.44 g, 64%) as a solid. [ka] LCMS m / z:ES+[M+H] + =193.2;t R =2.00 minutes.

[0264] Step 2: Synthesis of ethyl 3-[2-(tert-butylcarbamoyl)-3-pyridyl]-2-oxo-propanoate [ka] A solution of n-BuLi in hexanes (1.6 M in hexanes, 23.6 mL, 37.8 mmol) was added dropwise to a stirred solution of N-tert-butyl-3-methylpyridine-2-carboxamide (3.3 g, 17.2 mmol) in THF (48 mL) at −78 °C under argon. N,N,N',N'-tetramethylethylenediamine (2.57 mL, 17.2 mmol) was then added dropwise, and the resulting solution was stirred at −78 °C for 30 min. A solution of diethyl oxalate (4.65 mL, 34.3 mmol) in THF (48 mL) was added dropwise to the reaction mixture, and the resulting solution was stirred at −78 °C for 1 h. The reaction was diluted with saturated aqueous NH4Cl, and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to give the title compound (5.5 g) as a solid, which was used in the next step without further purification. LCMS m / z: ES+ [M+H] + =293.2;t R =2.45 minutes.

[0265] Step 3: Synthesis of ethyl 8-hydroxy-1,7-naphthyridine-6-carboxylate [ka] A mixture of ethyl 3-[2-(tert-butylcarbamoyl)-3-pyridyl]-2-oxo-propanoate (5.30 g, 18.1 mmol) and ammonium acetate (2.88 g, 36.3 mmol) in acetic acid (50 mL) was stirred at 110° C. The mixture was concentrated in vacuo and the material was purified by column chromatography on silica gel using a gradient of 0 to 4% MeOH in DCM to give the title compound (2.17 g, 55%, over two steps) as a solid. [ka] LC-MS m / z:ES+[M+H] + =219.1;t R=1.65 minutes.

[0266] Step 4: Synthesis of ethyl 8-chloro-1,7-naphthyridine-6-carboxylate [ka] A mixture of ethyl 8-hydroxy-1,7-naphthyridine-6-carboxylate (300 mg, 1.37 mmol) in POCl (7 mL) was stirred at 110 °C for 30 min. The mixture was cooled to room temperature, concentrated, and then poured onto crushed ice and stirred for 15 min. The pH of the aqueous mixture was basified to pH 8 at 0 °C by careful addition of saturated aqueous NaHCO solution. The aqueous layer was extracted with DCM (3 × 15 mL), and the combined organic layers were washed with brine, then dried (NaSO), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel (12 g) using a gradient of 0–50% EtOAc in hexanes to give the title compound (189 mg, 58%) as a solid. LCMS m / z: ES+ [M+H] + =237.1;t R =1.99 minutes.

[0267] Step 5: Synthesis of ethyl 8-(cyclopentylamino)-1,7-naphthyridine-6-carboxylate [ka] Under argon, a mixture of ethyl 8-chloro-1,7-naphthyridine-6-carboxylate (350 mg, 1.48 mmol), cyclopentylamine (126 mg, 1.48 mmol), and CsCO (482 mg, 1.48 mmol) in anhydrous DMF (3 mL) was sealed and heated at 100 °C for 12 h. The mixture was cooled to room temperature, diluted with water (10 mL), and the aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–100% EtOAc in hexanes to afford the title compound (255 mg, 54%) as a solid. LCMS m / z: ES+ [M+H] + =286.2;t R =2.24 minutes.

[0268] Step 6: Synthesis of 8-(cyclopentylamino)-N-methoxy-N-methyl-1,7-naphthyridine-6-carboxamide [ka]

[0269] A) To a solution of ethyl 8-(cyclopentylamino)-1,7-naphthyridine-6-carboxylate (350 mg, 1.22 mmol) in a mixture of THF:MeOH:HO (15 mL, 3:1:1), LiOH (59 mg, 2.45 mmol) was added, and the mixture was stirred at room temperature for 4 h. The volatiles were evaporated, the aqueous layer was washed once with EtOAc, and the pH was adjusted to 2 by adding 1N HCl. The aqueous layer was extracted with EtOAc (3 × 15 mL), and the combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure to give 8-(cyclopentylamino)-1,7-naphthyridine-6-carboxylic acid as a solid, which was used in the next step without further purification. LCMS m / z: ES+ [M+H] + =258.1;t R =1.61 minutes.

[0270] B) To a solution of the above material (200 mg, 0.77 mmol) in anhydrous DMF (10 mL) was added N,O-dimethylhydroxylamine, HCl (91 mg, 0.933 mmol), HATU (355 mg, 0.933 mmol), and DIPEA (0.314 mL, 2.31 mmol) successively, and the resulting mixture was stirred at room temperature for 8 hours. The mixture was diluted with EtOAc (15 mL) and 0.1 N HCl (3 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with brine, then dried (Na2SO4), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a 0-60% gradient of EtOAc in hexanes to afford the title compound (190 mg, 82%) as a solid. LCMS m / z: ES+[M+H]+=301.2;t R =1.95 minutes.

[0271] Step 7: Synthesis of 1-[8-(cyclopentylamino)-1,7-naphthyridin-6-yl]pentan-1-one [ka] To a solution of 8-(cyclopentylamino)-N-methoxy-N-methyl-1,7-naphthyridine-6-carboxamide (145 mg, 0.483 mmol) in THF (10 mL) was added n-BuMgCl (2 M in THF, 0.3 mL, 0.579 mmol) at 0 °C, and the reaction mixture was warmed to room temperature and stirred for 2 h. The mixture was quenched with saturated aqueous NH4Cl, and the aqueous layer was then extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-20% EtOAc in hexanes to afford the title compound (70 mg, 50%) as an oil. LCMS m / z: ES+ [M+H] + =298.2, t R =2.83 minutes.

[0272] Step 8: Synthesis of 1-[8-(cyclopentylamino)-1,2,3,4-tetrahydro-1,7-naphthyridin-6-yl]pentan-1-one [ka] A mixture of 1-[8-(cyclopentylamino)-1,7-naphthyridin-6-yl]pentan-1-one (40 mg, 0.135 mmol) and PtO (15 mg, 0.068 mmol) in anhydrous EtOH (10 mL) and TFA (1 drop) was hydrogenated under a hydrogen atmosphere at room temperature for 6 h. The mixture was filtered through Celite, washed with EtOH (2 × 20 mL), and the filtrate was concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–100% EtOAc in hexanes to afford the title compound (22 mg, 54%) as a solid. [ka] LCMS m / z: ES+ [M+H]+ = 302.3, t R =3.63 minutes. Example 12 Synthesis of S-168 [ka]

[0273] Step 1: Synthesis of 8-(tert-butylamino)-1,7-naphthyridine-6-carboxylic acid [ka] A solution of ethyl 8-chloro-1,7-naphthyridine-6-carboxylate (900 mg, 3.80 mmol), DIPEA (2 mL, 11.68 mmol), and 2-methylpropan-2-amine (3.2 mL, 30.4 mmol) in dry DMF (4.0 mL) was heated in a microwave at 170 °C for 2 h. Note: The reaction was performed five times for a total of 4.5 g. The vials were combined, and the volatiles were evaporated under reduced pressure, then used in the next step without further purification. To the above material in a mixture of THF / MeOH / water (125 mL, 3:1:1) at room temperature, LiOH·HO (1.6 g, 38 mmol) was added, and the reaction mixture was stirred at room temperature for 18 h. The volatiles were evaporated under reduced pressure, and then water (250 mL) was added. The mixture was acidified to pH 1 using 1 N aqueous HCl, and the aqueous layer was then extracted with CHCl (3 × 150 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The material was triturated with ether (25 mL), and the resulting precipitate was filtered and then dried to give the title compound (2 g, 43%) as a solid. LCMS m / z: ES+ [M+H] + =246.1.t R =1.63 minutes.

[0274] Step 2: Synthesis of 8-(tert-butylamino)-N-methoxy-N-methyl-1,7-naphthyridine-6-carboxamide [ka] To a solution of 8-(tert-butylamino)-1,7-naphthyridine-6-carboxylic acid (1.00 g, 4.08 mmol) and HATU (1.66 g, 4.36 mmol) in acetonitrile (10 mL) at room temperature, DIPEA (1.40 mL, 8.15 mmol) was added, followed by N-methoxymethanamine hydrochloride (0.437 g, 4.48 mmol), and the resulting mixture was stirred for 1 h. The mixture was diluted with EtOAc (50 mL) and 0.1 N aqueous HCl (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine, then dried (MgSO), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel (40 g) using a gradient of 0–60% EtOAc in hexanes to afford the title compound (652 mg, 56%) as a solid. LCMS m / z:ES+[M+H] + =289.5. t R =2.31 minutes.

[0275] Step 3: Synthesis of 1-[8-(tert-butylamino)-1,7-naphthyridin-6-yl]pentan-1-one [ka] To a solution of 8-(tert-butylamino)-N-methoxy-N-methyl-1,7-naphthyridine-6-carboxamide 3 (452 ​​mg, 1.57 mmol) in THF (10.0 mL) was added n-BuMgCl (2N in THF, 3.14 mL, 6.27 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with water (20 mL), and the pH was adjusted to 3 using 1N aqueous HCl. The aqueous layer was extracted with EtO (2 × 25 mL), and the combined organic layers were dried (MgSO), filtered, and concentrated under reduced pressure to give the title compound 4 (290 mg, 65%) as a solid. [ka] LCMS m / z:ES+[M+H]+ =287.8. t R =2.94 minutes.

[0276] Step 4: Synthesis of 1-[8-(tert-butylamino)-1,2,3,4-tetrahydro-1,7-naphthyridin-6-yl]pentan-1-one [ka] A solution of 1-[8-(tert-butylamino)-1,7-naphthyridin-6-yl]pentan-1-one (180 mg, 0.63 mmol), PtO (14.3 mg, 0.06 mmol), and TFA (0.23 mL, 3.15 mmol) in EtOH (7.00 mL) was hydrogenated under a hydrogen atmosphere at room temperature for 3 h. The mixture was filtered over Celite, washed, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel (12 g) using a gradient of 0–100% EtOAc in hexanes and further purified by preparative HPLC (BEH C18 30 × 100; 66–86% 10 mM aqueous ammonium formate and MeCN) to give the title compound (31.0 mg, 17%) as a solid. [ka] LCMS m / z:ES+[M+H] + =290.3. t R =1.89 minutes. Example 13 Synthesis of R-830 [ka]

[0277] Step 1: Synthesis of ethyl 2-cyano-2-[2-cyano-5-(trifluoromethyl)-3-pyridyl]acetate [ka] To a mixture of NaH (60.0%, 9.28 g, 242 mmol) in DMF (130.0 mL) at 0° C., a solution of ethyl 2-cyanoacetate (17.4 mL, 163 mmol) in DMF (20.0 mL) was slowly added, and the mixture was stirred for 15 minutes. A solution of 3-chloro-5-(trifluoromethyl)pyridine-2-carbonitrile (25.0 g, 121 mmol) in DMF (20.0 mL) was slowly added, and the reaction mixture was then heated to 70° C. and stirred for 2 hours. The mixture was cooled to room temperature and diluted with EtOAc and 1N aqueous HCl. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, then dried (Na2SO4), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel (330 g) using a gradient of 0-100% EtOAc in hexanes to give the title compound (31.0 g, 91%) as an oil. LCMS m / z: ES-[MH]-=282.6; t R =2.38 minutes.

[0278] Step 2: Synthesis of 3-(cyanomethyl)-5-(trifluoromethyl)pyridine-2-carbonitrile [ka] To a solution of ethyl 2-cyano-2-[2-cyano-5-(trifluoromethyl)-3-pyridyl]acetate (31.0 g, 109 mmol) in DMSO (100 mL) was added a solution of lithium sulfate (20.1 g, 183 mmol) and NaOH (0.438 g, 10.9 mmol) in water (28 mL), and the resulting mixture was stirred at 135 °C for 1 h. The mixture was cooled to room temperature and diluted with water (100 mL). The aqueous layer was extracted with EtOAc (3 × 350 mL), and the combined organic layers were washed with brine, then dried (NaSO), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a mixture of DCM / ethyl acetate / hexanes (1:1:6) to give the title compound (9.60 g, 42%) as an oil. [ka] LCMS: m / z: ES-[MH]-=210.1; t R =2.21 minutes.

[0279] Step 3: Synthesis of 8-bromo-3-(trifluoromethyl)-1,7-naphthyridin-6-amine [ka] To a solution of 3-(cyanomethyl)-5-(trifluoromethyl)pyridine-2-carbonitrile (4.00 g, 18.9 mmol) in DCM (100.0 mL) at 0 °C, HBr (5.00 M, 11.4 mL, 56.8 mmol, 30% in AcOH) was added dropwise, and the reaction mixture was warmed to room temperature and stirred for 30 min. The mixture was diluted with water and stirred vigorously for 15 min. The layers were separated, and the aqueous layer was extracted with DCM (75.0 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (2 x 60.0 mL), then dried (Na2SO4), filtered, and concentrated to give the title compound (4.50 g, 82%) as a solid. LCMS m / z: ES+ [M+H]+ = 292.0; t R =2.41 minutes.

[0280] Step 4: Synthesis of 6,8-dichloro-3-(trifluoromethyl)-1,7-naphthyridine [ka] To 8-bromo-3-(trifluoromethyl)-1,7-naphthyridin-6-amine (360 mg, 1.23 mmol) at 0 °C was slowly added concentrated HCl (12.0 M, 3.39 mL, 40.7 mmol), and the resulting mixture was stirred at 0 °C for 30 minutes. NaNO (0.170 g, 2.47 mmol) was then slowly added, and the mixture was stirred for an additional 10 minutes at 0 °C, then at room temperature for 1.5 hours. The mixture was diluted with DCM and water at 0 °C. Saturated aqueous NaCO solution was slowly added, and the layers were separated. The aqueous layer was extracted with DCM (2 ×), and the combined organic layers were washed with saturated aqueous NaHCO, then dried (NaSO), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-20% EtOAc in hexanes to afford the title compound (105 mg, 32%) as a solid. [ka] LCMS m / z:ES+[M+H]+=267.0, LCMS;t R =2.61 minutes.

[0281] Step 5: Synthesis of N-tert-butyl-6-chloro-3-(trifluoromethyl)-1,7-naphthyridin-8-amine [ka] A solution of 6,8-dichloro-3-(trifluoromethyl)-1,7-naphthyridine (2.10 g, 7.86 mmol), tert-butylamine (0.690 g, 9.44 mmol), and DIPEA (1.62 mL, 9.44 mmol) in anhydrous DMF (10.2 mL) was heated in a microwave for 1 h at 170 °C. The mixture was diluted with EtOAc (150 mL), and the organic layer was washed with saturated aqueous NaHCO (50 mL) and brine (50 mL), then dried (NaSO), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–100% DCM in hexanes to afford the title compound (2.05, 86%) as a solid. [ka] LCMS m / z: ES+ [M+H]+ = 304.1;t R =3.36 minutes.

[0282] Step 6: Synthesis of 8-(tert-butylamino)-3-(trifluoromethyl)-1,7-naphthyridine-6-carboxamide [ka] A mixture of N-tert-butyl-6-chloro-3-(trifluoromethyl)-1,7-naphthyridin-8-amine (1.75 g, 5.76 mmol), Zn(CN) (1.27 g, 10.8 mmol), and BrettPhos (0.579 g, 1.08 mmol) in DMF (23.1 mL) was degassed by bubbling argon through it for 10 minutes. (Note: The mixture was transferred to three microwave vials under argon. Each vial was treated as follows: Pd(dba) (0.166 g, 0.180 mmol) was added, and the mixture was degassed for 5 minutes afterward. The vials were then sealed and heated in a microwave oven at 160 °C for 1 hour.) The mixture was combined and diluted with EtOAc (100 mL) and saturated aqueous NaHCO (50 mL). The layers were separated, and the organic layer was washed with brine, then dried (NaSO), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel (40 g) using a gradient of 0 to 100% DCM in hexanes to afford the title compound (1.65 g, 92%) as a solid. [ka] LCMS m / z:ES+[M+H]+=314.1, LCMS;t R =2.56 minutes.

[0283] Step 7: Synthesis of 8-(tert-butylamino)-3-(trifluoromethyl)-1,7-naphthyridine-6-carboxamide [ka] To a solution of 8-(tert-butylamino)-3-(trifluoromethyl)-1,7-naphthyridine-6-carbonitrile (1.54 g, 5.23 mmol) in ethanol (120.0 mL) was added aqueous NaOH (5.00 M, 41.9 mL, 209 mmol), and the reaction mixture was heated at 100 °C for 2 h and then cooled to room temperature. The volatiles were evaporated under reduced pressure, the residue was diluted with water, and the aqueous layer was washed with EtOAc. The aqueous layer was acidified to pH 2-4 by slow addition of 1 N aqueous HCl (ca. 250 mL). The aqueous layer was extracted with EtOAc (3 × 150.0 mL). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure to give the title compound (1.03 g, 63%) as a solid. [ka] LCMS m / z:ES+[M+H]+=314.1, LCMS;t R =2.56 minutes.

[0284] Step 8: Synthesis of 8-(tert-butylamino)-3-(trifluoromethyl)-1,2,3,4-tetrahydro-1,7-naphthyridine-6-carboxylic acid [ka] To a solution of 8-(tert-butylamino)-3-(trifluoromethyl)-1,7-naphthyridine-6-carboxylic acid (1030 mg, 3.29 mmol) in ethanol (41.0 mL) was added TFA (0.122 mL, 1.64 mmol), platinum(IV) oxide (0.224 g, 0.986 mmol), and the resulting mixture was hydrogenated under a hydrogen atmosphere for 10 h. The mixture was filtered over Celite, washed, and the filtrate was concentrated under reduced pressure to give the title compound (976 mg, 94%) as a solid, which was used in the next step without further purification. [ka] LCMS m / z:ES+[M+H]+=318.2, LCMS;t R =1.91 minutes.

[0285] Step 9: Synthesis of 8-(tert-butylamino)-3-(trifluoromethyl)-1,2,3,4-tetrahydro-1,7-naphthyridine-6-carboxylic acid [ka] To a solution of 8-(tert-butylamino)-3-(trifluoromethyl)-1,2,3,4-tetrahydro-1,7-naphthyridine-6-carboxylic acid (1.03 g, 3.25 mmol) in DMF (17.6 mL) was added morpholine (0.341 mL, 3.90 mmol), followed by bis(dimethylamino), methylene-(triazolo[4,5-b]pyridin-3-yl)oxonium; hexafluorophosphate (1.48 g, 3.90 mmol), and DIPEA (1.67 mL, 9.74 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with brine (10 mL), and the aqueous layer was extracted with EtOAc (3 × 50.0 mL). The combined organic layers were washed with saturated aqueous NaHCO (10 mL) and brine (10.0 mL), then dried (NaSO), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0 to 100% EtOAc in hexanes to afford the title compound (850 mg, 68%) as a solid. [ka] LCMS m / z:ES+[M+H]+=387.2, LCMS;t R =2.48 minutes.

[0286] Step 10: Synthesis of 3-[8-(tert-butylamino)-3-(trifluoromethyl)-1,2,3,4-tetrahydro-1,7-naphthyridin-6-yl]pentan-1-one [ka] At 0° C., n-BuLi (2.50 M in hexanes, 0.121 mL, 0.303 mmol) was added to a solution of [8-(tert-butylamino)-3-(trifluoromethyl)-1,2,3,4-tetrahydro-1,7-naphthyridin-6-yl]-morpholino-methanone (39.0 mg, 0.101 mmol) in anhydrous THF (0.767 mL). The mixture was stirred at 0° C. for 15 minutes, then warmed to room temperature and stirred for 1 hour. The mixture was cooled to 0° C. and then diluted with water (0.3 mL), EtOAc (1.0 mL), and 1 M aqueous HCl (0.2 mL). The layers were separated, and the organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The material was purified by reverse-phase chromatography on C18 (5.5 g) using a gradient of 10 to 100% acetonitrile in water (containing 0.1% formic acid) and further purified by column chromatography on silica gel using a gradient of 0 to 100% EtOAc in hexanes to give the title compound (9.5 mg, 27%) as a solid. [ka] LCMS m / z:ES+[M+H]+=358.2, LCMS;t R =6.20 minutes (10 minute run). Example 14 Synthesis of R-812 [ka]

[0287] Step 1: 8-(tert-butylamino)-N-methoxy-N-methyl-3-(trifluoromethyl)-1,7-naphthyridine-6-carboxamide [ka] To a solution of 8-(tert-butylamino)-3-(trifluoromethyl)-1,7-naphthyridine-6-carboxylic acid (0.880 g, 2.81 mmol) in anhydrous DMF (15.0 mL) was added N,O-dimethylhydroxylamine hydrochloride (0.329 g, 3.37 mmol), HATU (674 mg, 1.77 mmol), and DIPEA (0.77 mL, 4.43 mmol), successively. The mixture was stirred at room temperature for 8 hours and then diluted with EtOAc (100 mL) and 0.1 N aqueous HCl (6 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine, then dried (NaSO), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-60% EtOAc in hexanes to afford the title compound (850 mg, 85%) as a solid. LCMS m / z: ES+ [M+H]+ = 357.2; R =2.69 minutes.

[0288] Step 2: Synthesis of 1-[8-(tert-butylamino)-3-(trifluoromethyl)-1,7-naphthyridin-6-yl]pentan-1-one [ka] To a solution of 8-(tert-butylamino)-N-methoxy-N-methyl-3-(trifluoromethyl)-1,7-naphthyridine-6-carboxamide (850 mg, 2.39 mmol) in THF (15.0 mL) at −78° C., n-butylmagnesium chloride (2.00 M, 4.77 mL, 9.54 mmol) was added, and the reaction mixture was stirred at −78° C. for 5 minutes, then warmed to room temperature and stirred for 1 hour. The reaction was diluted with saturated aqueous NH4Cl (50 mL) at −78° C., warmed to room temperature, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–100% DCM in hexanes to afford the title compound (350 mg, 42%) as a solid. LCMS m / z: ES+[M+H]+=354.2;t R =3.43 minutes.

[0289] Step 3: Synthesis of 1-[8-(tert-butylamino)-3-(trifluoromethyl)-1,2,3,4-tetrahydro-1,7-naphthyridin-6-yl]pentan-1-ol [ka] To a solution of 1-[8-(tert-butylamino)-3-(trifluoromethyl)-1,7-naphthyridin-6-yl]pentan-1-one (60.0 mg, 0.170 mmol) in ethanol (3.0 mL) was added platinum(IV) oxide (0.0416 g, 0.170 mmol) and 3 drops of TFA, and the reaction mixture was hydrogenated under a hydrogen atmosphere for 50 minutes. The mixture was diluted with EtOAc and filtered through Celite. The volatiles were evaporated under reduced pressure, and the material was purified by reverse-phase chromatography on a C18 column using a gradient of 10–100% MeCN in water to afford the title compound (61 mg, 25%) as a solid. [ka] LCMS: m / z:ES+[M+H]+=360.3;t R =2.37 minutes. Example 15 Synthesis of B-917 [ka]

[0290] Step 1: Synthesis of ethyl (E)-4-(tert-butoxycarbonylamino)-4-methyl-pent-2-enoate [ka] Triphenylcarbethoxymethylenephosphorane (558 mg, 1.60 mmol) was added in one portion to a solution of tert-butyl N-(1,1-dimethyl-2-oxo-ethyl)carbamate (150 mg, 0.80 mmol) in anhydrous THF (2.5 mL) at room temperature under an argon atmosphere, and the reaction mixture was stirred at room temperature for 5 h. The mixture was diluted with saturated aqueous NH4Cl, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, then dried (Na2SO4), filtered, and concentrated under reduced pressure. The material was purified by reverse-phase chromatography on a C18 column using a gradient of 10–100% MeCN in water (containing 0.1% formic acid) to afford the title compound (173 mg, 84%) as an oil. [ka] LCMS m / z: ES+ [M+Na] + 280.1;t R = 2.42 minutes.

[0291] Step 2: Synthesis of ethyl (E)-4-amino-4-methyl-pent-2-enoate; 2,2,2-trifluoroacetic acid [ka] To a solution of ethyl (E)-4-(tert-butoxycarbonylamino)-4-methyl-pent-2-enoate (510 mg, 1.98 mmol) in DCM (5.0 mL) was added TFA (637 μL, 9.91 mmol), and the mixture was stirred at room temperature for 3 h. The volatiles were concentrated under reduced pressure to give the title compound (538 mg) as a solid, which was used in the next step without further purification. [ka] LCMS(ES+):m / z[M+H] + 158.5;t R =0.86 minutes.

[0292] Step 3: Synthesis of ethyl (E)-4-[(2-ethoxy-2-oxo-ethyl)amino]-4-methyl-pent-2-enoate [ka] To a solution of ethyl (E)-4-amino-4-methyl-pent-2-enoate; 2,2,2-trifluoroacetic acid (4.14 g; 8.06 mmol) in anhydrous acetonitrile (25.0 mL) at room temperature under argon, CsCO (9.19 g, 1.6 mmol, 28.2 mmol) was added, followed by ethyl 2-bromoacetate (1.34 mL, 12.1 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-100% EtOAc in hexanes to afford the title compound (0.874 g, 45%) as an oil. LCMS (ES+): m / z [M+H] + 244.7;t R =1.44 minutes.

[0293] Step 4: Synthesis of ethyl (E)-4-[(2-ethoxy-2-oxo-ethyl)-(2,2,2-trifluoroacetyl)amino]-4-methyl-pent-2-enoate [ka] To a solution of ethyl (E)-4-[(2-ethoxy-2-oxo-ethyl)amino]-4-methyl-pent-2-enoate (0.878 g, 3.61 mmol) in anhydrous DCM (3.0 mL) at 0 °C under argon, anhydrous pyridine (3.81 mL, 72.2 mmol) was added, followed by trifluoroacetic anhydride (0.752 mL, 5.41 mmol), and the reaction mixture was stirred at 0 °C for 30 min. The mixture was diluted with water, and the aqueous layer was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with 1 M aqueous HCl and brine, then dried (Na SO ), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–50% EtOAc in hexanes to give the title compound (60%, 733 mg) as an oil. [ka] LCMS(ES+):m / z[M+H] + 339.7;t R =2.62 minutes.

[0294] Step 5: Synthesis of ethyl 4-[(2-ethoxy-2-oxo-ethyl)-(2,2,2-trifluoroacetyl)amino]-4-methyl-pentanoate [ka] A mixture of ethyl (E)-4-[(2-ethoxy-2-oxo-ethyl)-(2,2,2-trifluoroacetyl)amino]-4-methyl-pent-2-enoate (0.743 g, 2.19 mmol) and Pd / C (0.233 g, 0.219 mmol) in EtOAc (5.0 mL) was hydrogenated under a hydrogen atmosphere at room temperature for 2 hours. The mixture was filtered through Celite, washed with EtOAc, and the filtrate was concentrated under reduced pressure to give the title compound (0.787 g, 100%) as an oil, which was used in the subsequent step without further purification. [ka] LCMS(ES+):m / z[M+H] + 342.8;t R =2.70 minutes.

[0295] Step 6: Synthesis of ethyl 6,6-dimethyl-3-oxo-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate [ka] To a solution of ethyl 4-[(2-ethoxy-2-oxo-ethyl)-(2,2,2-trifluoroacetyl)amino]-4-methyl-pentanoate (0.454 g, 1.33 mmol) in anhydrous THF (5.0 mL) was added NaH (61.2 mg, 1.60 mmol) at 0 °C, and the reaction mixture was warmed to room temperature and stirred for 1 h. The mixture was diluted with water (5.0 mL), and the aqueous layer was extracted with EtOAc (3 × 15.0 mL). The combined organic layers were washed with water and brine, then dried (NaSO), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–50% EtOAc in hexanes to afford the title compound (0.115 g, 29%) as a solid. LCMS (ES+): m / z [M+H] + 296.1;t R =2.71 minutes.

[0296] Step 7: Synthesis of 6,6-dimethyl-2-pentyl-7,8-dihydro-5H-pyrido[3,2-d]pyrimidin-4-ol [ka] To a solution of ethyl 6,6-dimethyl-3-oxo-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (255 mg, 0.86 mmol) in MeOH (2.0 mL) was added hexaneamidine hydrochloride (195 mg, 1.3 mmol), and the reaction mixture was heated at 110° C. for 48 h. The mixture was concentrated, and the material was purified by column chromatography on silica gel using a gradient of 0 to 20% MeOH in DCM to afford the title compound (23 mg, 11%) as a solid. [ka] LCMS(ES+):m / z[M+H] + 250.2;t R =1.67 minutes.

[0297] Step 8: Synthesis of N-cyclopentyl-6,6-dimethyl-2-pentyl-5H,6H,7H,8H-pyrido[3,2-d]pyrimidin-4-amine [ka] To a solution of 4-chloro-6,6-dimethyl-2-pentyl-7,8-dihydro-5H-pyrido[3,2-d]pyrimidine (11.0 mg, 0.041 mmol) and cyclopentanamine (16.0 μL, 0.16 mmol) in anhydrous n-butanol (1.0 mL) was added DIPEA (28.0 μL, 0.16 mmol), and the reaction mixture was heated to 95° C. for 16 h. The mixture was concentrated under reduced pressure, and the material was purified by reverse-phase chromatography on a C18 column using a gradient of 10 to 60% acetonitrile in water (containing 0.1% formic acid) to afford the title compound (1.8 mg, 14%) as a solid. [ka] LCMS(ES+):m / z[M+H] + 317.3;t R =3.31 minutes.

[0298] (Example B-647) Step x: 1-[8-(cyclopentylamino)-1,2,3,4-tetrahydro-1,7-naphthyridin-6-yl]pentan-1-one [ka] To a suspension of 1-[8-(cyclopentylamino)-1,7-naphthyridin-6-yl]pentan-1-one (40.0 mg, 0.135 mmol) in anhydrous EtOH (10.0 mL) under argon, platinum oxide (0.0189 g, 0.161 mmol) and one drop of TFA were added and hydrogenated under a hydrogen atmosphere for 6 h at room temperature. The mixture was filtered over Celite, and the filtrate was evaporated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–50% EtOAc in hexanes to afford the title compound (22 mg, 54%) as a solid. [ka] LCMSm / z:ES+[M+H]+=302.3, LCMS;t R =3.66 minutes.

[0299] (Example B-626) Step x: 1-[8-(cyclopentylamino)-1,2,3,4-tetrahydro-1,7-naphthyridin-6-yl]pentan-1-one [ka] B-626, FER-1 were purchased from Combi Blocks, San Diego, WZ9339. Example 16 Synthesis of B-604 [ka]

[0300] Step 1: Synthesis of 2,6-dichloro-5-nitro-N-tetrahydrofuran-3-yl-pyrimidin-4-amine [ka] To a solution of 2,4,6-trichloro-5-nitro-pyrimidine (100 mg, 0.438 mmol) in iPrOH (2.0 mL) at −78° C. under argon, a solution of tetrahydrofuran-3-amine (38.1 mg, 0.438 mmol) in iPrOH (1.0 mL) was added over 15 min. The reaction mixture was stirred at −78° C. for 30 min, then warmed to room temperature and stirred for 1 h. DIPEA (0.150 mL, 0.876 mmol) was then added, and the resulting mixture was stirred at room temperature for 2 h. The volatiles were evaporated under reduced pressure, and the material was purified by column chromatography on silica gel using a gradient of 0–100% EtOAc in hexanes to give the title compound (80 mg, 66%) as a solid.

[0301] [ka] LCMS m / z: ES+ [M+H]+ = 279.5;t R =2.27 minutes.

[0302] Step 2: Synthesis of methyl 2-[2-chloro-5-nitro-6-(tetrahydrofuran-3-ylamino)pyrimidin-4-yl]oxyacetate [ka] To a solution of 2,6-dichloro-5-nitro-N-tetrahydrofuran-3-yl-pyrimidin-4-amine (0.205 g, 0.734 mmol) and methyl 2-hydroxyacetate (99 mg, 1.10 mmol) in iPrOH (8.0 mL) and DCM (2.0 mL) was added sodium tert-butoxide (2.00 M, 0.404 mL, 8.08 mmol) in THF (0.50 mL) at 0 °C under argon, and the reaction mixture was stirred for 1 h at room temperature. The mixture was diluted with water, and the aqueous layer was extracted with DCM (3 × 20.0 mL). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–100% EtOAc in hexanes to afford the title compound (158 mg, 64%) as a solid. LCMS m / z: ES+ [M+H]+ = 331.1, t R :2.27 minutes.

[0303] Step 3: Synthesis of 2-chloro-4-(tetrahydrofuran-3-ylamino)-5H-pyrimido[4,5-b][1,4]oxazin-6-one [ka] To a solution of methyl 2-[2-chloro-5-nitro-6-(tetrahydrofuran-3-ylamino)pyrimidin-4-yl]oxyacetate (150 mg, 0.451 mmol) in THF (6.0 mL) and 10% aqueous HCl (3.0 mL) was added Zn (88.5 mg, 1.35 mmol), and the reaction mixture was heated to 70 °C for 30 min. The mixture was diluted with saturated aqueous NaHCO and the aqueous layer was extracted with EtOAc (3 × 20.0 mL). The combined organics were dried (NaSO), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–100% EtOAc in hexanes to afford the title compound (50.0 mg, 41%) as a solid. LCMS m / z: ES+ [M+H]+ = 271.1, t R :1.80 minutes.

[0304] Step 4: Synthesis of 4-[(oxolan-3-yl)amino]-2-[(1E)-pent-1-en-1-yl]-5H,6H,7H-pyrimido[4,5-b][1,4]oxazin-6-one [ka] A mixture of 2-chloro-4-(tetrahydrofuran-3-ylamino)-5H-pyrimido[4,5-b][1,4]oxazin-6-one (45.0 mg, 0.166 mmol), [(E)-pent-1-enyl]boronic acid (56.8 mg, 0.498 mmol), and potassium carbonate (68.9 mg, 0.500 mmol) in toluene (0.80 mL), ethanol (0.20 mL), and water (0.20 mL) was degassed by bubbling argon through it for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (38.4 mg, 0.0332 mmol) was added, the vial was sealed, and then stirred at 100 °C for 16 hours. The mixture was cooled to room temperature and diluted with EtOAc and saturated aqueous NaHCO3. The layers were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, then dried (Na2SO4), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-10% MeOH in DCM to give the title compound (23.0 mg, 46%) as a solid. LCMS m / z: ES+ [M+H]+ = 305.2, LCMS; t R =4.14 minutes (10 minute run).

[0305] Step 5: Synthesis of 2-pentyl-N-tetrahydrofuran-3-yl-6,7-dihydro-5H-pyrimido[4,5-b][1,4]oxazin-4-amine [ka] To a solution of 2-[(E)-pent-1-enyl]-4-(tetrahydrofuran-3-ylamino)-5H-pyrimido[4,5-b][1,4]oxazin-6-one (19.0 mg, 0.0624 mmol) in THF (0.25 mL) at 0 °C, BH THF (1.00 M, 0.624 mL, 0.624 mmol) was added, and the reaction mixture was warmed and stirred at room temperature for 2 h. The mixture was diluted with saturated aqueous NaHCO, and the aqueous layer was extracted with EtOAc (3 × 2.0 mL). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–10% MeOH in DCM to afford the title compound (8.0 mg, 44%) as a solid. [ka] LCMS m / z:ES+[M+H]+=293.2, LCMS;t R =2.96 minutes. Example 17 Synthesis of B-322 [ka]

[0306] Step 1: Synthesis of 2-chloro-N-cyclopentyl-pyrido[3,2-d]pyrimidin-4-amine [ka] To a solution of 2,4-dichloropyrido[3,2-d]pyrimidine (125 mg, 0.625 mmol) in THF (5.0 mL) and water (3.0 mL) was added cyclopentanamine (62 μL, 0.625 mmol), followed by CHCOONa (0.0513 g, 0.625 mmol), and the reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with EtOAc, and the layers were separated. The organic layer was washed with water (3×), then dried (NaSO), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a mixture of 20% EtOAc in hexanes to afford the title compound (130 mg, 84%) as a solid. [ka] LCMS m / z: ES+[M+H]+=249.1;t R =2.44 minutes. Example 18 Synthesis of B-456 [ka]

[0307] Step 1: Synthesis of 2-(cyclopenten-1-yl)-N-cyclopentyl-pyrido[3,2-d]pyrimidin-4-amine [ka] A solution of 2-chloro-N-cyclopentyl-pyrido[3,2-d]pyrimidin-4-amine (90 mg, 0.362 mmol), 1-cyclopentylboronic acid (122 mg, 1.09 mmol), and potassium carbonate (150 mg, 1.09 mmol) in toluene (1.5 mL), ethanol (0.35 mL), and water (0.35 mL) was degassed by bubbling argon through it for 10 minutes. Pd(PPh3)4 (83 mg, 0.724 mmol) was then added, the vial was sealed, and heated at 100 °C for 8 hours. The mixture was cooled to room temperature, and the mixture was diluted with saturated aqueous NaHCO3 and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, then dried (Na2SO4), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-70% EtOAc in hexanes to afford the title compound (35 mg, 35%) as a solid. [ka] LCMS m / z: ES+ [M+H]+ = 281.2.;t R =1.91 minutes.

[0308] Step 2: Synthesis of N,2-dicyclopentyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine [ka] To a solution of 2-(cyclopenten-1-yl)-N-cyclopentyl-pyrido[3,2-d]pyrimidin-4-amine (30 mg, 0.107 mmol) in ethanol (2.0 mL) under argon, PtO (7.2 mg, 0.0321 mmol) was added, followed by three drops of TFA, and the reaction mixture was hydrogenated under a hydrogen atmosphere at room temperature for 2 h. The mixture was filtered over Celite, washed, and the filtrate was concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–30% MeOH in DCM to afford the title compound (30 mg, 97%) as a solid. [ka] LCMS m / z: ES+ [M+H]+ = 287.3;t R =3.45 minutes. Example 19 Synthesis of B-349 [ka]

[0309] Step 1: Synthesis of N-cyclopentyl-2-[(E)-pent-1-enyl]pyrido[3,2-d]pyrimidin-4-amine [ka] A solution of 2-chloro-N-cyclopentyl-pyrido[3,2-d]pyrimidin-4-amine (50 mg, 0.201 mmol), 1-pentenylboronic acid (30 mg, 0.261 mmol), and potassium carbonate (84 mg, 0.603 mmol) in toluene (1.5 mL), ethanol (0.35 mL), and water (0.35 mL) was degassed by bubbling argon through it for 10 minutes. Pd(dppf)Cl2 (30 mg, 0.0402 mmol) and PPh3 (21 mg, 0.0804 mmol) were added, the vial was sealed, and heated at 100 °C overnight. The mixture was cooled to room temperature and diluted with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (2 × 15.0 mL), and the combined organic layers were washed with brine, then dried (Na2SO4), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-70% EtOAc in hexanes to afford the title compound (35 mg, 62%) as a solid. LCMS m / z: ES+ [M+H]+ = 283.3; t R =2.00 minutes.

[0310] Step 2: Synthesis of N-cyclopentyl-2-pentyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine [ka] To a mixture of N-cyclopentyl-2-[(E)-pent-1-enyl]pyrido[3,2-d]pyrimidin-4-amine (30 mg, 0.105 mmol) and PtO (7 mg, 0.0315 mmol) in ethanol (2.0 mL) was added TFA (15.6 μL, 0.0210 mmol), and the resulting mixture was hydrogenated under a hydrogen atmosphere at room temperature for 2 h. The mixture was filtered over Celite, washed, and the filtrate was concentrated under reduced pressure. The material was purified by reverse-phase chromatography on C18 (5.5 g) using a gradient of 10–100% MeCN in water (containing 0.1% formic acid) to afford the title compound (30 mg, 99%) as a solid. [ka] LCMS m / z: ES+ [M+H]+ = 289.3;t R =3.89 minutes (10 minute run). Example 20 Synthesis of B-323 [ka]

[0311] Step 1: Synthesis of 2-butoxy-N-cyclopentyl-pyrido[3,2-d]pyrimidin-4-amine [ka] To a solution of 1-butanol (55 mg, 0.754 mmol) in anhydrous THF (10.0 mL) under argon at 0°C, NaH (48 mg, 2.01 mmol) was added, and the mixture was stirred at room temperature for 10 min. A solution of 2-chloro-N-cyclopentyl-pyrido[3,2-d]pyrimidin-4-amine (125 mg, 0.502 mmol) in THF (2.0 mL) was then added, and the resulting mixture was stirred at 65°C for 30 min. The mixture was cooled to room temperature and diluted with saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc (3 × 10.0 mL), and the combined organic layers were washed with brine, then dried (Na2SO4), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–30% methanol in DCM to afford the title compound (73 mg, 50%) as a solid. LCMS m / z: ES+ [M+H]+ = 287.2.;t R =1.78 minutes.

[0312] Step 2: Synthesis of 2-butoxy-N-cyclopentyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine [ka] Under an argon atmosphere, a mixture of 2-butoxy-N-cyclopentyl-pyrido[3,2-d]pyrimidin-4-amine (50 mg, 0.175 mmol) and PtO (3.97 mg, 0.0175 mmol) in anhydrous EtOH (10.0 mL) was added with TFA (13 μL, 0.0175 mmol), and the resulting mixture was hydrogenated under a hydrogen atmosphere for 6 h at room temperature. The mixture was filtered over Celite, washed, and the filtrate was concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–30% MeOH in DCM to give the title compound (15 mg, 30%) as a solid. [ka] LCMS m / z: ES+ [M+H]+ = 291.3;t R =3.59 minutes. Example 21 Synthesis of B-433 [ka]

[0313] Step 1: Synthesis of N2-butyl-N4-cyclopentyl-pyrido[3,2-d]pyrimidine-2,4-diamine [ka] To a solution of 2-chloro-N-cyclopentyl-pyrido[3,2-d]pyrimidin-4-amine (100 mg, 0.402 mmol) in anhydrous 1,4-dioxane (8.0 mL) was added n-butylamine (52 μL, 0.523 mmol), followed by triethylamine (0.112 mL, 0.804 mmol), and the reaction mixture was stirred under reflux for 12 h. The mixture was cooled to room temperature and then diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 20.0 mL). The combined organic layers were washed with brine, then dried (NaSO), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–25% MeOH in DCM to afford the title compound (42 mg, 37%) as a solid. [ka] LCMS m / z: ES+ [M+H]+ = 286.3;t R =1.87 minutes.

[0314] Step 2: Synthesis of N2-butyl-N4-cyclopentyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidine-2,4-diamine [ka] To a mixture of N-cyclopentyl-2-[(E)-pent-1-enyl]pyrido[3,2-d]pyrimidin-4-amine (10 mg, 0.0350 mmol) and PtO (3 mg, 0.0105 mmol) in ethanol (5.0 mL) was added three drops of TFA, and the resulting mixture was hydrogenated under a hydrogen atmosphere at room temperature for 2 h. The mixture was filtered over Celite, washed, and the filtrate was concentrated under reduced pressure. The material was purified by reverse-phase chromatography on C18 (5.5 g) using a gradient of 10 to 100% MeCN in water (containing 0.1% formic acid) to afford the title compound (3 mg, 99%) as a solid. [ka] LCMS m / z:ES+[M+H]+=290.3.;t R =3.45 minutes. Example 22 Synthesis of B-434 [ka]

[0315] Step 1: Synthesis of N2-butyl-N4-cyclopentyl-N2-methyl-pyrido[3,2-d]pyrimidine-2,4-diamine [ka] To a solution of 2-chloro-N-cyclopentyl-pyrido[3,2-d]pyrimidin-4-amine (150 mg, 0.603 mmol) in anhydrous DMF was added N-methylbutylamine (52.6 mg, 0.603 mmol), followed by CsCO (393 mg, 1.21 mmol), and the mixture was degassed by bubbling N for 5 minutes. Xantphos (41.9 mg, 0.0724 mmol) was then added, followed by Pddba (69.4 mg, 0.121 mmol), and the resulting mixture was degassed for 5 minutes and then heated to 100 °C for 12 hours. The mixture was diluted with water (10.0 mL), and the organic layer was extracted with EtOAc (2x). The combined organic layers were dried (NaSO), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-100% EtOAc in hexanes to give the title compound (90 mg, 49.8%) as a solid. LCMS m / z: ES+ [M+H]+ = 300.3, t R =1.90 minutes.

[0316] Step 2: Synthesis of N2-butyl-N4-cyclopentyl-N2-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidine-2,4-diamine [ka] To a mixture of 2-butoxy-N-cyclopentyl-pyrido[3,2-d]pyrimidin-4-amine (50 mg, 0.167 mmol) and PtO (3.80 mg, 0.0167 mmol) in anhydrous EtOH (10.0 mL) was added three drops of TFA, and the resulting mixture was hydrogenated under a hydrogen atmosphere at room temperature for 6 h. The mixture was filtered over Celite, washed, and the filtrate was concentrated under reduced pressure. The material was purified by flash chromatography on silica gel using a gradient of 0 to 100% EtOAc in hexanes to afford the title compound (15 mg, 29%) as a solid. [ka] LCMS m / z: ES+ [M+H]+ = 304.3;t R =3.62 minutes. Example 23 Synthesis of B-495 [ka]

[0317] Step 1: Synthesis of N-cyclopentyl-2-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-amine [ka] To a solution of 2-methoxyethanol (0.0594 mL, 0.754 mmol) in anhydrous THF (10.0 mL) at 0°C, NaH (60% oil dispersion, 77 mg, 2.01 mmol) was added, and the mixture was stirred at room temperature for 10 min. 2-Chloro-N-cyclopentyl-pyrido[3,2-d]pyrimidin-4-amine (125 mg, 0.503 mmol) was then added, and the resulting mixture was stirred at 65°C for 30 min. The mixture was cooled to room temperature and diluted with saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, then dried (Na2SO4), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-30% methanol in DCM to afford the title compound (130 mg, 90%) as a solid. LCMS m / z: ES+ [M+H] + =289.2.;t R =1.73 minutes.

[0318] Step 2: Synthesis of N-cyclopentyl-2-(2-methoxyethoxy)-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-amine [ka] To a mixture of N-cyclopentyl-2-(2-methoxyethoxy)pyrido[3,2-d]pyrimidin-4-amine (30 mg, 0.104 mmol) and PtO (7.1 mg, 0.0312 mmol) in ethanol (2 mL) was added TFA (1.55 μL, 0.0208 mmol), and the resulting mixture was hydrogenated under a hydrogen atmosphere at room temperature for 2 h. The mixture was filtered over Celite, rinsed with EtOH, and the filtrate was concentrated under reduced pressure. The material was purified by column chromatography on C18 (5.5 g) using a gradient of 10 to 100% MeCN in water (containing 0.1% formic acid) to afford the title compound (30 mg, 99%) as a solid. [ka] LCMS m / z:ES+[M+H] + =293.2.;t R =2.72 minutes. Example 24 Synthesis of B-710 [ka]

[0319] Step 1: Synthesis of 1-[8-(tert-butylamino)-3-(trifluoromethyl)-1,2,3,4-tetrahydro-1,7-naphthyridin-6-yl]pentan-1-one [ka] A mixture of 2-chloro-N-cyclopentyl-6,7-dihydro-5H-pyrimido[4,5-b][1,4]oxazin-4-amine (150 mg, 0.589 mmol), 1-pentenylboronic acid (67.1 mg, 0.589 mmol), and potassium carbonate (244 mg, 1.77 mmol) in toluene (1.5 mL), ethanol (0.7 mL), and water (0.7 mL) was degassed by bubbling argon through it for 10 minutes. Pd(PPh) (136 mg, 0.118 mmol) was then added, and the resulting mixture was heated at 100 °C for 12 hours. The mixture was cooled to room temperature and diluted with saturated aqueous NaHCO and EtOAc. The layers were separated, and the organic layer was dried (NaSO), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-100% EtOAc in hexanes to afford the title compound (25 mg, 15%) as a solid. [ka] LCMS m / z: ES+ [M+H]+ = 289.2; QC t R =3.63 minutes. Example 25 Synthesis of B-711 [ka]

[0320] Step 1: Synthesis of N-cyclopentyl-2-pentyl-5H,6H,7H-pyrimido[4,5-b][1,4]oxazin-4-amine [ka] A mixture of N-cyclopentyl-2-[(E)-pent-1-enyl]-6,7-dihydro-5H-pyrimido[4,5-b][1,4]oxazin-4-amine (150 mg, 0.520 mmol) and Pd / C (20% wt, 55 mg, 0.520 mmol) in MeOH (10 mL) was hydrogenated under a hydrogen atmosphere for 2 h at room temperature. The mixture was filtered over Celite, washed, and the filtrate was concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0 to 100% EtOAc in hexanes to afford the title compound (155 mg, 99%) as a solid. [ka] LCMS m / z:ES+[M+H] + =291.2;t R =1.94 minutes. Example 26 Synthesis of B-763 [ka]

[0321] Step 1: Synthesis of 4-(cyclopentylamino)-6,7-dihydro-5H-pyrimido[4,5-b][1,4]oxazine-2-carbonitrile [ka] To a solution of 2-chloro-N-cyclopentyl-6,7-dihydro-5H-pyrimido[4,5-b][1,4]oxazin-4-amine (150 mg, 0.589 mmol) in DMF (10.0 mL) was added Zn(CN) (0.138 g, 1.18 mmol), followed by Pd(PPh 3)4 (204 mg, 0.177 mmol) was added, and the mixture was degassed by bubbling argon through it for 5 minutes, then heated at 100° C. for 12 hours. The mixture was cooled to room temperature, saturated aqueous NH4Cl was added, and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, then dried (Na2SO4), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-100% EtOAc in hexanes to give the title compound (100 mg, 69%) as a solid. LCMS (ES+): m / z [M+H] + 246.1;t R =2.23 minutes.

[0322] Step 2: Synthesis of 1-[4-(cyclopentylamino)-5H,6H,7H-pyrimido[4,5-b][1,4]oxazin-2-yl]pentan-1-one [ka] To a solution of 4-(cyclopentylamino)-6,7-dihydro-5H-pyrimido[4,5-b][1,4]oxazine-2-carbonitrile (40.0 mg, 0.163 mmol) in THF (1.5 mL) was added n-butylmagnesium chloride solution (2 M in THF, 0.16 mL, 0.326 mmol) at 0 °C, and the reaction mixture was warmed to room temperature and stirred for 2 h. The mixture was diluted with saturated aqueous NH4Cl, and the aqueous layer was extracted with EtOAc (3 × 20.0 mL). The combined organic layers were washed with brine, then dried (Na2SO4), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-100% EtOAc in hexanes to afford the title compound (2.5 mg, 5%) as a solid. LCMS m / z: ES+ [M+H] + =305.2;t R =4.74 minutes. Example 27 Synthesis of B-602 [ka]

[0323] Step 1: Synthesis of 2,6-dichloro-N-cyclopentyl-5-nitro-pyrimidin-4-amine [ka] To a solution of 2,4,6-trichloro-5-nitro-pyrimidine (100 mg, 0.438 mmol) in 2-propanol (3 mL) at −78° C., a solution of cyclopentanamine (43 μL, 0.438 mmol) in 2-propanol (1 mL) was added over 15 min. The resulting mixture was stirred at −78° C. for 30 min, then warmed to room temperature and stirred for 1 h. DIPEA (0.15 mL, 0.876 mmol) was then added dropwise, and the mixture was stirred at room temperature for 2 h. The volatiles were evaporated under reduced pressure, and the material was purified by column chromatography on silica gel (12 g) using a gradient of 0–100% EtOAc in hexanes to afford the title compound (100 mg, 83%) as a solid. [ka] LCMS m / z:ES+[M+H] + =277.5.;t R =2.72 minutes.

[0324] Step 2: Synthesis of methyl 2-[2-chloro-6-(cyclopentylamino)-5-nitro-pyrimidin-4-yl]sulfanyl acetate [ka] To a solution of 2,6-dichloro-N-cyclopentyl-5-nitro-pyrimidin-4-amine (500 mg, 1.80 mmol) in THF (15.0 mL) at 0 °C, methyl thioglycolate (0.192 g, 1.80 mmol) was added, followed by DIPEA (0.309 mL, 1.80 mmol), and the reaction mixture was stirred at 0 °C for 1 h. The mixture was diluted with water (10 mL) and EtOAc (25 mL). The separated organic layer was dried (Na SO ), filtered, and concentrated under reduced pr...

Claims

1. below 【Chemistry 440】 The compound is selected from compounds having the formula:

2. below 【Chemistry 441】 A compound having the formula:

3. below 【Chemical 442】 A compound having the formula:

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 3 and a pharma- ceutically acceptable excipient.

5. A composition for treating a ferroptosis-associated disease in a patient in need of such treatment, comprising: 【Chemistry 461】 A composition comprising a compound selected from compounds having the formula:

6. The composition of claim 5, wherein the ferroptosis-related disease is selected from the group consisting of lipid peroxidation-related degenerative diseases, excitotoxicity diseases, neurodegenerative diseases, non-apoptotic regulated cell death diseases, wasting or necrosis-related diseases, poisoning-related diseases, and infectious diseases.

Images