Quinolines that modulate SERCA and their use for treating diseases

Abstract

Provided herein are compounds of formula (I), pharmaceutical compositions thereof, and methods of their use for treating, preventing, or ameliorating one or more symptoms of a neurological disease, a neurodegenerative disorder, or diabetes.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Patent Application Serial No. 16 / 932,832, filed July 20, 2020, which is currently pending and is hereby incorporated by reference in its entirety.

[0002] Provided herein are quinoline, its pharmaceutical compositions, and methods of using them for treating, preventing, or ameliorating one or more symptoms of a neurological or neurodegenerative disorder or diabetes. Also provided herein are methods of using them for regulating the activity of sarcoplasmic / endoplasmic reticulum Ca 2+ ATPase (SERCA).

Background Art

[0003] The endoplasmic reticulum (ER) is an organelle that plays an essential role in multiple cellular processes crucial for cell survival and normal cell function. Those crucial processes include intracellular calcium homeostasis, protein secretion, and lipid biosynthesis. Anelli et al., EMBO J. 2008, 27, 315 - 327; Pizzo et al., Trends Cell Biol. 2007, 17, 511 - 517; Ma et al., J. Chem. Neuroanat. 2004, 28, 51 - 65.

[0004] Disruptions in ER homeostasis lead to the accumulation of unfolded proteins in the ER, triggering an evolutionarily conserved response known as the unfolded protein response (UPR). Ron et al., Nat. Rev. Mol. Cell Biol. 2007, 8, 519-529; Malhotra et al., Semin. Cell Dev. Biol. 2007, 18, 716-731. Perturbations that cause ER stress include, for example, disruptions in cellular redox control, glucose deprivation, abnormal calcium regulation in the ER, viral infections, high-fat diets, protein aggregation diseases (e.g., chronic neurodegenerative diseases), and inclusion body myositis. Kim et al., Nat. Rev. Drug Dis. 2008, 7, 1013-1030; Ma et al., J. Chem. Neuroanat. 2004, 28, 51-65; Ozcan et al., Science 2004, 306, 457-461; Frand et al., Trends Cell Biol. 2000, 10, 203-310. ER stress is associated with a wide range of diseases, including neurodegeneration (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, polyglutamine disease, and prion disease), stroke, bipolar disorder, heart disease, atherosclerosis, cancer, diabetes (types 1 and 2), muscle degeneration, inflammatory diseases, and autoimmune diseases. Kim et al., Nat. Rev. Drug Dis. 2008, 7, 1013-1030; Oyadomari et al., Cell Death Differ. 2004, 11, 381-389.

[0005] Sarcoplasmic / endoplasmic reticulum Ca 2+ ATPase (SERCA) is a major regulator of ER stress and glucose homeostasis in obesity. Park et al., Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 19320-19325. Obesity is associated with intracellular Ca 2+Disrupts homeostasis and induces ER stress. Fu et al., Nature 2011, 473, 528-531. Chronic activation of ER stress is involved in insulin resistance and the development of diabetes in obesity. Hotamisligil, Cell 2010, 140, 900-917; Kim et al. Nat. Rev. Drug Discov. 2008, 7, 1013-1030. ER Ca 2+ -homeostasis has been found to be altered in small cell and non-small cell lung cancer cell lines. Bergner et al., J. Exp. Clin. Cancer Res. 2009, 28, 25. Restoration of Ca 2+ homeostasis through SERCA activation has been shown to reduce dyskinesia in a model of Parkinson's disease. Dahl, Bioorg. Med. Chem. 2017, 25, 53-57. SERCA activation has also been shown to improve memory and coordination in a transgenic mouse model of Alzheimer's disease. Krajnak & Dahl, Bioorg. Med. Chem Lett. 2018, 28, 1591-1594. Therefore, there is a need for therapeutic agents capable of reducing ER stress or restoring ER homeostasis to treat diseases caused by ER stress.

Summary of the Invention

[0006] Disclosed herein are SERCA regulators. Certain SERCA regulators, such as compounds C18, C19 and C20, have significantly improved pharmacokinetic properties when measured by C MAX , AUC and F(%) compared to other SERCA regulators, such as compounds of formula I (wherein R 2 is an amino-substituted phenyl group), such as C18-C20 (see Table 6).

[0007] Disclosed herein is a method for treating, preventing, or ameliorating one or more symptoms of a disease caused by endoplasmic reticulum stress in a subject, the method comprising a compound of formula I:

Chemical formula

[0008] Also provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a disease caused by endoplasmic reticulum stress in a subject, the method comprising a compound of formula I, or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof (wherein R1 is (a) hydrogen or (b) C 1-3 alkyl; R2 is phenyl, 2-thienyl, 2-furyl, 2-benzothienyl, or 2-benzofuryl, and R2 is optionally substituted with 1 to 2 substituents independently selected from halo, cyano, -O-(C1-C4 alkyl or haloalkyl), C1-C4 alkyl or haloalkyl, -N(CH3)2, and -NH-(C1-C4 alkyl), except for F and NO2; R3 is CH3 or H; R4, R5, R6, R7, and R8 are each independently (a) hydrogen, cyano, or halo; (b) C 1-4A method is provided that includes administering to a subject an alkyl, -O-(C1-C4 alkyl), or -N(CH3)2). Another aspect is that R2 is phenyl, 2-thienyl, 2-furyl, 2-benzothienyl, or 2-benzofuryl, R2 is optionally substituted with -N(CH3)2 or -NH-(C1-C4 alkyl), and the remainder of the variable elements is as described exactly in this paragraph. In another aspect, R2 is phenyl optionally substituted with -N(CH3)2 or -NH-(C1-C4 alkyl); and the remainder of the variable elements is as described exactly in this paragraph.

[0009] Also provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a disease caused by endoplasmic reticulum stress in a subject, the method comprising a compound of formula V:

Chemical formula

[0010] Further provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by sarcoplasmic reticulum / endoplasmic reticulum calcium ATP-ase (SERCA) in a subject, the method comprising administering to the subject a compound of Formula I, or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0011] Also provided herein is a method for treating, preventing, or ameliorating one or more symptoms of diabetes in a subject, the method comprising administering to the subject a compound of Formula I, or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0012] Also provided herein is a method for increasing glucose tolerance in a subject, the method comprising administering to the subject a compound of Formula I, or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0013] Disclosed herein is a method for treating, preventing, or ameliorating one or more symptoms of Alzheimer's disease in a subject, the method comprising administering to the subject a compound of Formula I, or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0014] Disclosed herein is a method for treating, preventing, or ameliorating one or more symptoms of Parkinson's disease in a subject, the method comprising administering to the subject a compound of Formula I, or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0015] Disclosed herein is a method for reducing stress in the ER, the method comprising contacting the ER with a compound of Formula I, or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0016] Disclosed herein is a method for restoring or maintaining homeostasis in the ER, the method comprising contacting the ER with a compound of Formula I, or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0017] Disclosed herein is a method for increasing the Ca 2+ concentration in the ER, the method comprising contacting the ER with a compound of Formula I, or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0018] This specification provides a method for modulating the activity of SERCA, which comprises contacting SERCA with a compound of Formula I, or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0019]

Figure 1

Figure 2

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Figure 5

Figure 6

Figure 7

DETAILED DESCRIPTION OF THE INVENTION

[0020] To facilitate understanding of the disclosure presented herein, a number of terms are defined below.

[0021] Generally, the nomenclature used herein and the experimental procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0022] The term "subject" refers to an animal including, but not limited to, primates (e.g., humans), cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably herein, for example, in reference to mammalian subjects. In one embodiment, the subject is a human.

[0023] The terms "treating," "treatment," and "treat" mean including reducing or eliminating a disorder, disease, or condition, or one or more symptoms thereof; or reducing or removing the cause(s) of the disorder, disease, or condition itself.

[0024] The terms "prevent", "preventing", and "prevention" mean including a method of delaying and / or preventing the onset of a disorder, disease, or medical condition, and / or its attendant symptoms; preventing the subject from acquiring a disorder, disease, or medical condition; or reducing the risk that the subject will acquire a disorder, disease, or medical condition.

[0025] The term "therapeutically effective amount" means an amount of a compound that, when administered, is sufficient to prevent the onset of, or to alleviate to some extent, one or more symptoms of a disorder, disease, or medical condition being treated. The term "therapeutically effective amount" also refers to an amount of a compound sufficient to elicit a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human being sought by a researcher, veterinarian, physician, or clinician.

[0026] The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier", or "physiologically acceptable excipient" refer to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense that it is compatible with the other components of the pharmaceutical formulation and is suitable for use in contact with human and animal tissues or organs without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 7th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2012; Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; and Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009.

[0027] The term "about" or "approximately" means an acceptable error for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0028] The terms "active ingredient" and "active substance" refer to a compound that is administered to a subject, alone or in combination with one or more pharmaceutically acceptable excipients, to treat, prevent, or ameliorate one or more symptoms of a disorder, disease, or condition. As used herein, "active ingredient" and "active substance" can be optically active isomers of the compounds described herein.

[0029] The terms "drug", "therapeutic agent", and "chemotherapeutic agent" refer to a compound or a pharmaceutical composition thereof that is administered to a subject to treat, prevent, or ameliorate one or more symptoms of a disorder, disease, or condition.

[0030] The term "endoplasmic reticulum stress" or "ER stress" refers to a perturbation of endoplasmic reticulum homeostasis, e.g., a perturbation of the protein folding functionality of the endoplasmic reticulum.

[0031] The terms "ER stress disorder, disease, or condition", "disorder, disease, or condition caused by ER stress", "disorder, disease, or condition induced by ER stress", or "disorder, disease, or condition associated with ER stress" refer to a disorder, disease, or condition resulting from a perturbation of ER homeostasis. In particular, an ER stress disorder, disease, or condition is one in which a reduction of ER stress has some effect on the underlying disorder, disease, or condition, e.g., an ER stress modulator produces some improvement in at least a portion of the patients being treated.

[0032] The term "naturally occurring" or "native", when used in combination with a biological substance, e.g., a nucleic acid (e.g., DNA or RNA), polypeptide, and host cell, refers to a substance that is found in nature and has not been manipulated by man. Similarly, "non-naturally occurring" or "non-native" refers to a substance that is not found in nature or has been structurally modified or synthesized by man.

[0033] The term "SERCA" or "sarcoplasmic reticulum (endoplasmic reticulum) Ca 2+"ATPase" refers to sarcoplasmic reticulum / endoplasmic reticulum Ca 2+ ATPase or a variant thereof. The term "SERCA variant" is intended to include a protein that is substantially homologous to native SERCA, i.e., a protein having one or more naturally occurring or non-naturally occurring amino acid deletions, insertions, or substitutions (e.g., SERCA derivatives, homologs, and fragments) compared to the amino acid sequence of native SERCA. The amino acid sequence of the SERCA variant is at least about 80% identical, at least about 90% identical, or at least about 95% identical to native SERCA. SERCA enzymes are classified into at least three classes: SERCA1, SERCA2, and SERCA3. Stutzmann et al., Pharmacol. Rev. 2011, 63, 700-727; Andersen et al., Acta Physiol. Scand. Suppl. 1998, 643, 45-54. Class I includes SERCA1a and SERCA1b. Class II includes SERCA2a and SERCA2b. Class III includes SERCA3a, SERCA3b, and SERCA3c.

[0034] The terms "SERCA-mediated disorder, disease, or condition" and "disorder, disease, or condition mediated by SERCA" refer to a disorder, disease, or condition in which regulation of SERCA activity has some effect on the underlying disorder, disease, or condition, e.g., a SERCA agonist results in some improvement in at least a portion of the patient being treated.

[0035] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, where the alkyl is optionally substituted with one or more substituents Q described herein. The term "alkyl" also includes both linear and branched alkyls unless otherwise specified. In certain embodiments, alkyl is 1-20 (C 1-20 ), 1-15 (C 1-15 ), 1-10 (C 1-10 ), or 1-6 (C 1-6) a linear saturated monovalent hydrocarbon radical having from 0 carbon atoms, or a branched saturated monovalent hydrocarbon radical having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms. As used herein, linear C 1-6 and branched C 3-6 alkyl groups are also referred to as "lower alkyl". Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms). For example, C 1-6 alkyl refers to a linear saturated monovalent hydrocarbon radical having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical having 3 to 6 carbon atoms.

[0036] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical containing one or more, in one embodiment, 1, 2, 3, 4, or 5, in another embodiment, one carbon-carbon double bond(s). In a given embodiment, alkenyl is optionally substituted with one or more substituents Q described herein. The term "alkenyl" also encompasses radicals having "cis" and "trans" configurations, or alternatively, "Z" and "E" configurations, as understood by those skilled in the art. As used herein, the term "alkenyl" encompasses both linear and branched alkenyl unless otherwise specified. For example, C 2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical having 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical having 3 to 6 carbon atoms. In a given embodiment, alkenyl is a linear monovalent hydrocarbon radical having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 ) carbon atoms, or a branched one having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15)), 3 to 10 (C 3-10 )), or a branched monovalent hydrocarbon radical having 3 to 6 (C 3-6 ) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.

[0037] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical containing one or more, in one embodiment, 1, 2, 3, 4, or 5, and in another embodiment, 1 carbon-carbon triple bond(s). In certain embodiments, alkynyl is optionally substituted with one or more substituents Q described herein. The term "alkynyl" also encompasses both linear and branched alkynyl unless otherwise specified. In certain embodiments, alkynyl is 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 ) carbon atoms, a linear monovalent hydrocarbon radical, or 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms, a branched monovalent hydrocarbon radical. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH) and propargyl (-CH2C≡CH). For example, C 2-6 Alkynyl refers to a linear unsaturated monovalent hydrocarbon radical having 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical having 3 to 6 carbon atoms.

[0038] The term "cycloalkyl" refers to a cyclic saturated or non-aromatic unsaturated, bridged or unbridged monovalent hydrocarbon radical optionally substituted with one or more substituents Q described herein. In certain embodiments, cycloalkyl is a cyclic saturated bridged or unbridged monovalent hydrocarbon radical. In certain embodiments, cycloalkyl is 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 7 (C 3-7) has a certain number of carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.

[0039] The term "aryl" refers to monocyclic aromatic groups and / or polycyclic monovalent aromatic groups containing at least one aromatic hydrocarbon ring. In certain embodiments, aryl has 6 - 20 (C 6-20 )、6 - 15 (C 6-15 )、or 6 - 10 (C 6-10 ) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. In certain embodiments, the term "aryl" refers to bicyclic or tricyclic carbocyclic rings where one or more of the rings are aromatic and the others are saturated, partially unsaturated, or aromatic, such as dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments, aryl is optionally substituted with one or more substituents Q described herein.

[0040] The term "aralkyl" or "arylalkyl" refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, aralkyl has 7 - 30 (C 7-30 )、7 - 20 (C 7-20 )、or 7 - 16 (C 7-16 ) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, 1-phenylethyl, 2-phenylethyl, and 3-phenylpropyl. In certain embodiments, aralkyl is optionally substituted with one or more substituents Q described herein.

[0041] The term "heteroaryl" refers to a monovalent monocyclic aromatic group or a monovalent polycyclic aromatic group containing at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms, each of which is independently selected from O, S, N, and P in the ring. The heteroaryl group is attached to the remainder of the molecule through its aromatic ring. Each ring of the heteroaryl group has a total of 4 or fewer heteroatoms in each ring, and each ring contains at least one carbon atom, and may contain 1 or 2 O atoms, 1 or 2 S atoms, 1 to 4 N atoms, and / or 1 or 2 P atoms. In certain embodiments, heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl is optionally substituted with one or more substituents Q described herein.

[0042] The term "heterocyclyl" or "heterocyclic" refers to a monocyclic monovalent non-aromatic ring system or a polycyclic ring system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each of which is independently selected from O, S, N, and P; and the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. The heterocyclyl group is attached to the remainder of the molecule through its non-aromatic ring. In certain embodiments, the heterocyclyl may be spiro, fused, or bridged, and is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated or aromatic. The heterocyclyl may be attached to the main structure by any heteroatom or carbon atom that results in the formation of a stable compound.Examples of heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydrothiopyranyl, tetrahydrothienyl, thiomorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl is optionally substituted with one or more substituents Q as described herein.

[0043] The terms "halogen," "halide," or "halo" refer to fluorine, chlorine, bromine, and / or iodine.

[0044] The term "optionally substituted" means that a group or substituent, e.g., an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl group, is independently substituted with one or more substituents Q, each of which is, for example, (a) oxo (=O), cyano (-CN), halo, and nitro (-NO2); (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl (each of which is optionally further substituted with one or more, in one embodiment, 1, 2, 3, 4, or 5 substituents Q a ); and (c) -C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(NR a )NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(=NR a )NR b R c , -OS(O)R a , -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(=NR d )NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)2NR b R c , -P(O)R a R d , -P(O)(OR a )R d, -P(O)(OR a )(OR d ), -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)2NR b R c selected from, each R a , R b , R c , and R d is independently (i) hydrogen; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment 1, 2, 3, or 4 substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heteroaryl or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment 1, 2, 3, or 4 substituents Q a ). As used herein, all groups described herein that may be substituted are "optionally substituted" unless otherwise specified.

[0045] In one embodiment, each substituent Q a is independently (a) oxo, cyano, halo, and nitro; and (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R e , -C(O)OR e , -C(O)NR f Rg ,-C(NR e )NR f R g ,-OR e ,-OC(O)R e ,-OC(O)OR e ,-OC(O)NR f R g ,-OC(=NR e )NR f R g ,-OS(O)R e ,-OS(O)2R e ,-OS(O)NR f R g ,-OS(O)2NR f R g ,-NR f R g ,-NR e C(O)R h ,-NR e C(O)OR h ,-NR e C(O)NR f R g ,-NR e C(=NR h )NR f R g ,-NR e S(O)R h ,-NR e S(O)2R h ,-NR e S(O)NR f R g ,-NR e S(O)2NR f R g ,-P(O)R e R h ,-P(O)(OR e )R h ,-P(O)(OR e )(OR h ),-SR e ,-S(O)R e ,-S(O)2R e ,-S(O)NR f R g ,and -S(O)2NR f R g selected from the group consisting of; each R e ,R f ,Rg and R h are, independently, (i) hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (ii) R f and R g together with the N atom to which they are attached form heteroaryl or heterocyclyl.

[0046] In certain embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules having an enantiomeric excess of about 50% or greater, about 70% or greater, about 80% or greater, about 90% or greater, about 91% or greater, about 92% or greater, about 93% or greater, about 94% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, or about 99.8% or greater. In certain embodiments, a compound comprises about 95% or more of the desired enantiomer and about 5% or less of the less preferred enantiomer, based on the total weight of the two enantiomers of interest.

[0047] When describing an optically active compound, the prefixes R and S are used to indicate the absolute configuration of the optically active compound at its chiral center(s). (+) and (-) are used to indicate the direction of rotation of the plane of polarization by the optically active compound, i.e., the optical rotation of the optically active compound. The (-) prefix indicates that the optically active compound is levorotatory, i.e., the compound rotates the plane of polarization to the left or counterclockwise. The (+) prefix indicates that the optically active compound is dextrorotatory, i.e., the compound rotates the plane of polarization to the right or clockwise. However, the designations (+) and (-) of optical rotation are not related to the absolute configuration R and S of the compound.

[0048] The term "isotope variant" refers to a compound that contains one or more isotopes in non-natural proportions in one or more of the atoms that make up such a compound. In certain embodiments, an "isotope variant" of a compound is hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), chlorine-37 ( 37 Cl), bromine-79 ( 79 Br), bromine-81 ( 81 Br), iodine-123 ( 123 I), iodine-125 ( 125 I), iodine-127 ( 127 I), iodine-129 ( 129 I), and iodine-131 ( 131 I), and contains one or more isotopes in non-natural proportions, including but not limited to these. In certain embodiments, an "isotope variant" of a compound is in a stable form, i.e., is non-radioactive. In certain embodiments, an "isotope variant" of a compound is hydrogen ( 1 H), deuterium (2 H), carbon-12( 12 C), carbon-13( 13 C), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), fluorine-17( 17 F), phosphorus-31( 31 P), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-36( 36 S), chlorine-35( 35 Cl), chlorine-37( 37 Cl), bromine-79( 79 Br), bromine-81( 81 Br), and iodine-127( 127 I) contains one or more isotopes in non-natural proportions, including but not limited to these. In certain embodiments, the "isotope variant" of the compound is in an unstable form, i.e., radioactive. In certain embodiments, the "isotope variant" of the compound is tritium( 3 H), carbon-11( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), oxygen-14( 14 O), oxygen-15( 15 O), fluorine-18( 18 F), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-35( 35 S), chlorine-36( 36 Cl), iodine-123( 123 I), iodine-125( 125 I), iodine-129( 129 I), and iodine-131( 131 I) contains one or more isotopes in non-natural proportions, including but not limited to these. In the compounds provided herein, any hydrogen can be, for example, 2 H, or any carbon can be, for example, 13 C, or any nitrogen can be, for example,15 can be N, or any oxygen, for example, 18 can be O, and it is understood that it is feasible according to the judgment of those skilled in the art. In certain embodiments, an "isotope variant" of a compound contains non-natural proportions of deuterium (D).

[0049] The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, such as a compound provided herein, and one or more molecules of a solvent present in stoichiometric or non-stoichiometric amounts. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in crystalline form. In another embodiment, the complex or aggregate is in amorphous form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0050] The phrase "its enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotope variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof" has the same meaning as the phrase "(i) an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotope variant of the compound referred to therein; (ii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of the compound referred to therein; or (iii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotope variant of the compound referred to therein".

[0051] In one embodiment, provided herein are a compound of formula (I) or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein the variable elements are as described above. In another embodiment, provided herein are a compound of formula (V) or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein the variable elements are as described above. In yet another embodiment, provided herein are

Table 1-1

Table 1-2

Table 1-3

[0052] In another embodiment, provided herein are

Table 2

[0053] In yet another embodiment, provided herein are

Table 3-1

Table 3-2

[0054] In yet another embodiment, herein, [Table 4] Compounds selected from the group consisting of them and their isotope variants; as well as their pharmaceutically acceptable salts, solvates, hydrates, and prodrugs are provided.

[0055] In yet another embodiment, herein, [Table 5] Compounds selected from the group consisting of them and their isotope variants; as well as their pharmaceutically acceptable salts, solvates, hydrates, and prodrugs are provided.

[0056] In yet another embodiment, herein, [Table 6] Compounds selected from the group consisting of them and their isotope variants; as well as their pharmaceutically acceptable salts, solvates, hydrates, and prodrugs are provided.

[0057] In still another embodiment, herein, [Table 7] Compounds selected from the group consisting of them and their isotope variants; as well as their pharmaceutically acceptable salts, solvates, hydrates, and prodrugs are provided.

[0058] In certain embodiments, the compounds provided herein are active as agonists of SERCA. In certain embodiments, the compounds provided herein are active as allosteric SERCA modulators. In certain embodiments, the compounds provided herein are active as agonists of SERCA2b. In certain embodiments, the compounds provided herein are active as allosteric SERCA2b modulators.

[0059] In certain embodiments, the compounds provided herein are active in reducing ER stress. In certain embodiments, the compounds provided herein are active in increasing the Ca 2+ concentration of the ER.

[0060] The compounds provided herein are intended to encompass all possible stereoisomers unless a particular stereochemistry is specified. When the compounds provided herein contain an alkenyl or alkenylene group, the compounds can exist as one or a mixture of geometric cis / trans (or Z / E) isomers. When structural isomers are interconvertible, the compounds can exist as a single tautomer or a mixture of tautomers. This can take the form of, for example, proton tautomerism in compounds containing imino, keto, or oxime groups; or so-called valence tautomerism in compounds containing aromatic moieties. A single compound can exhibit multiple types of isomerism.

[0061] The compounds provided herein are enantiomerically pure and can be, for example, a single enantiomer or a single diastereomer, or a stereoisomeric mixture, for example, a mixture of enantiomers, for example, a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. Thus, one of ordinary skill in the art will recognize that administration of the (R) form of the compound is equivalent to administration of the (S) form of the compound for compounds that undergo epimerization in vivo. Conventional techniques for the preparation / isolation of individual enantiomers include synthesis from suitable optically pure precursors, asymmetric synthesis from achiral starting materials, or resolution of enantiomeric mixtures, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization to diastereomeric adducts followed by separation.

[0062] Where the compounds provided herein contain acidic or basic moieties, they may also be provided as pharmaceutically acceptable salts (see Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and “Handbook of Pharmaceutical Salts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley-VCH and VHCA, Zurich, 2002).

[0063] Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, -acetamidobenzoic acid, boric acid, (+)-borneolic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

[0064] Suitable bases for use in the preparation of pharmaceutically acceptable salts include inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases such as L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine, including but not limited to primary, secondary, tertiary, and quaternary aliphatic and aromatic amines.

[0065] The compounds provided in this specification can also be provided, for example, as functional derivatives of compounds of formula V and as prodrugs that can be readily converted to the parent compound in vivo. Prodrugs are often useful because in some situations they can be administered more readily than the parent compound. They can be, for example, bioavailable by oral administration while the parent compound is not. Prodrugs can also have improved solubility in pharmaceutical compositions compared to the parent compound. Prodrugs can be converted to the parent drug by various mechanisms including enzymatic processes and metabolic hydrolysis. Harper, Progress in Drug Research 1962, 4, 221 - 294; Morozowich et al. in “Design of Biopharmaceutical Properties through Prodrugs and Analogs,” Roche Ed., APHA Acad. Pharm. Sci. 1977; “Bioreversible Carriers in Drug in Drug Design, Theory and Application,” Roche Ed., APHA Acad. Pharm. Sci. 1987; “Design of Prodrugs,” Bundgaard, Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265 - 287; Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235 - 256; Mizen et al., Pharm. Biotech. 1998, 11, 345 - 365; Gaignault et al., Pract. Med. Chem. 1996, 671 - 696; Asgharnejad in “Transport Processes in Pharmaceutical Systems,” Amidon et al., Ed., Marcell Dekker, 185 - 218, 2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15, 143 - 53; Balimane and Sinko, Adv. Drug Delivery Rev.See 1999, 39, 183 - 209; Browne, Clin. Neuropharmacol. 1997, 20, 1 - 12; Bundgaard, Arch. Pharm. Chem. 1979, 86, 1 - 39; Bundgaard, Controlled Drug Delivery 1987, 17, 179 - 96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1 - 38; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115 - 130; Fleisher et al., Methods Enzymol. 1985, 112, 360 - 381; Farquhar et al., J. Pharm. Sci. 1983, 72, 324 - 325; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875 - 877; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49 - 59; Gangwar et al., Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409 - 421; Nathwani and Wood, Drugs 1993, 45, 866 - 94; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241 - 273; Stella et al., Drugs 1985, 29, 455 - 73; Tan et al., Adv. Drug Delivery Rev. 1999, 39, 117 - 151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131 - 148; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148 - 155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39, 63 - 80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497 - 507.

[0066] The compounds provided in this specification can be prepared, isolated, or obtained by any method known to those skilled in the art. The following examples are merely representative and do not exclude other relevant procedures.

[0067] In one embodiment, for example, a compound of Formula I is prepared via a coupling reaction of amine I-1 for forming Compound I with Compound I-2 having a leaving group L, optionally in the presence of a coupling reagent, as shown in Scheme I. In a given embodiment, L is hydroxyl or halo. In a given embodiment, L is hydroxyl, fluoro, chloro, bromo, or iodo.

Chemical formula

[0068] In another embodiment, for example, a compound of Formula V is prepared via a coupling reaction of amine I-1 for forming Compound V with Compound V-2 having a leaving group L, optionally in the presence of a coupling reagent, as shown in Scheme Ia. In a given embodiment, L is hydroxyl or halo. In a given embodiment, L is hydroxyl, fluoro, chloro, bromo, or iodo.

Chemical formula

[0069] Examples of suitable coupling reagents include carbodiimides (e.g., N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide (EDC), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC hydrochloride), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (EDC methiodide), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate, N,N’-diisopropylcarbodiimide (DIC), and 1,3-dicyclohexylcarbodiimide (DCC)), 1,1’-carbonyldiimidazole (CDI), bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride (BOP-Cl), 2-chloro-1,3-dimethylimidium hexafluorophosphate (CIP), bromotris(dimethylamino)phosphonium hexafluorophosphate, bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TATU), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent), N,N,N’,N’-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU), O-(benzotriazol-1-yl)-N,N,N’,N’-bis(tetramethylene)uronium hexafluorophosphate (HBPyU), O-(benzotriazol-1-yl)-N,N,N’,N'-bis(pentamethylene)uronium hexafluorophosphate, acetic anhydride, SOCl2, PCl3, POCl3, PCl5, and mixtures thereof, but not limited thereto.,

[0070] In one embodiment, provided herein are compounds of Formula I, or enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof; and pharmaceutical compositions comprising a pharmaceutically acceptable excipient.,

[0071] The disclosed compounds can be administered to a patient in a variety of forms depending on the chosen route of administration, as will be understood by those skilled in the art. The disclosed compounds can be administered, for example, orally, parenterally, buccally, sublingually, nasally, rectally, by patch, pump or transdermally and formulated pharmaceutical compositions accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, trans-epithelial, nasal, intraluminal, rectal and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time.,

[0072] The disclosed compounds can be suitably formulated into pharmaceutical compositions for administration to a subject. The pharmaceutical compositions of the present teachings optionally include one or more pharmaceutically acceptable carriers and / or diluents therefor, such as lactose, starch, cellulose and dextrose. Other excipients, such as flavoring agents; sweetening agents; and preservatives, such as methyl, ethyl, propyl and butyl parabens may also be included. A more complete list of suitable excipients is provided in the Handbook of Pharmaceutical Excipients (5 thIt can be found in Remington’s Pharmaceutical Sciences, 20th Ed., Pharmaceutical Press (2005). Those skilled in the art will know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2003 - 20th edition) and The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. Carriers, diluents and / or excipients are “acceptable” in the sense that they are compatible with the other ingredients of the pharmaceutical composition and not harmful to its recipient.

[0073] Typically, for oral therapeutic administration, the disclosed compounds can be incorporated using excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc.

[0074] Typically, for parenteral administration, solutions of the compounds used in the disclosed methods can be prepared in water, usually in suitable admixture with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and in oils. Under normal conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

[0075] Typically, for injectable use, sterile aqueous solutions or dispersions of the compounds used in the disclosed methods for the extemporaneous preparation of sterile injectable solutions or dispersions, and sterile powders are appropriate.

[0076] The pharmaceutical compositions provided herein can be administered topically to the skin, an orifice, or a mucosa. Topical administration, as used herein, includes cutaneous (intradermal), conjunctival, intracorneal, intraocular, ocular, otic, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.

[0077] The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for topical administration for local or systemic effects, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, sprays, bandages, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigation agents, sprays, suppositories, bandages, and skin patches. The topical formulations of the pharmaceutical compositions provided herein can also include liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

[0078] Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antibacterial or preservative agents against microbial growth, stabilizers, solubilizing agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, antifreeze agents, lyoprotectants, thickening agents, and inert gases.

[0079] The pharmaceutical compositions provided herein can be provided in the form of ointments, creams, and gels. Suitable ointment vehicles include oily or hydrocarbon vehicles such as lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifying or absorbent vehicles such as hydrophilic petrolatum, hydroxy stearate sulfate, and anhydrous lanolin; water-removable vehicles such as hydrophilic ointment; water-soluble ointment vehicles containing polyethylene glycols of various molecular weights; emulsion vehicles containing cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions) (see Remington: The Science and Practice of Pharmacy (supra)). These vehicles are emollients but usually require the addition of antioxidants and preservatives.

[0080] Suitable cream bases can be water-in-oil or oil-in-water. Suitable cream vehicles are washable and may contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also referred to as the "internal" phase, typically includes petrolatum and fatty alcohols such as cetyl or stearyl alcohol. The aqueous phase usually, but not necessarily, exceeds the oil phase in quantity and typically contains a humectant. Emulsifiers in cream formulations can be nonionic, anionic, cationic, or amphoteric surfactants.

[0081] Gels are semi-solid suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers such as carbomers, carboxypolyalcohols, and CARBOPOL®; hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; cellulose polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a uniform gel, a dispersant such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and / or agitation.

[0082] In one embodiment, provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by SERCA in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, such as a compound of formula I, or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0083] In certain embodiments, the disorders, diseases, or conditions mediated by SERCA are disorders, diseases, or conditions mediated by SERCA2a. In certain embodiments, the disorders, diseases, or conditions mediated by SERCA are disorders, diseases, or conditions mediated by SERCA2b.

[0084] In certain embodiments, the disorders, diseases, and conditions mediated by SERCA are cardiovascular diseases, cancer, diabetes, inflammatory diseases, metabolic diseases, or neurological diseases. In certain embodiments, the disorders, diseases, and conditions mediated by SERCA are heart diseases, strokes, stenosis, restenosis, diseases associated with vascular smooth muscle cell proliferation, diseases associated with neointimal formation, diseases associated with calcineurin PP2B, diseases associated with NFAT, arteriovenous fistula insufficiency, heart diseases, diseases associated with heart diseases, urinary incontinence, cancer, asthma, pulmonary hypertension, chronic obstructive pulmonary disease, diabetes, neurodegenerative diseases, bipolar disorder, atherosclerosis, muscle degeneration, or autoimmune diseases.

[0085] In yet another embodiment, a method for treating, preventing, or ameliorating one or more symptoms of diabetes in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, such as a compound of Formula I, or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is provided. In one embodiment, the diabetes is type 1. In one embodiment, the diabetes is type 2.

[0086] In yet another embodiment, a method for increasing glucose tolerance in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, such as a compound of Formula I, or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is provided.

[0087] In yet another embodiment, a method for treating, preventing, or ameliorating one or more symptoms of fatty liver in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, such as a compound of Formula I, or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is provided.

[0088] In yet another embodiment, a method for treating, preventing, or ameliorating one or more symptoms of obesity in a subject, the method comprising administering to the subject a compound provided herein, such as a compound of Formula I, or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is provided.

[0089] In yet another embodiment, a method for promoting thermogenesis in a subject, the method comprising administering to the subject a compound provided herein, such as a compound of Formula I, or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is provided.

[0090] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human primate, a farm animal, such as a cow, a sport animal, or a pet, such as a horse, a dog, or a cat.

[0091] Disorders, diseases, or conditions treatable with the compounds provided herein include, but are not limited to, (1) inflammatory or allergic diseases including systemic anaphylaxis and hypersensitivity disorders, atopic dermatitis, urticaria, drug allergy, insect sting allergy, food allergy (including celiac disease, etc.), and mastocytosis; (2) inflammatory bowel diseases including Crohn's disease, ulcerative colitis, ileitis, and enteritis; (3) vasculitis and Behçet's syndrome; (4) inflammatory skin diseases including psoriasis and dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, viral skin lesions including those derived from human papillomavirus, HIV or RLV infections, skin lesions of bacteria, fungi, and other parasites, and cutaneous erythematosus; (5) respiratory allergic diseases including asthma and allergic asthma, exercise-induced asthma, allergic rhinitis, otitis media, allergic conjunctivitis, hypersensitivity pneumonitis, and chronic obstructive pulmonary disease; (6) autoimmune diseases including arthritis (including rheumatoid and psoriatic), systemic lupus erythematosus, type I diabetes, myasthenia gravis, multiple sclerosis, Graves' disease, and glomerulonephritis; (7) graft rejection (including allograft rejection and graft-versus-host disease), for example, skin graft rejection, solid organ transplant rejection, bone marrow transplant rejection; (8) fever; (9) cardiovascular disorders including acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary artery disease, restenosis, and vascular stenosis; (10) cerebrovascular disorders including traumatic brain injury, stroke, ischemic reperfusion injury, and aneurysm; (11) cancers of the breast, skin, prostate, cervix, uterus, ovary, testis, bladder, lung, liver, larynx, oral cavity, colon, and gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain, thyroid, blood, and lymphatic system; (12) fibrosis, connective tissue diseases, and sarcoidosis; (13) genital and reproductive conditions including erectile dysfunction; (14) gastrointestinal disorders including gastritis, ulcers, nausea, pancreatitis, and vomiting; (15) neurological disorders including Alzheimer's disease; (16) sleep disorders including insomnia, narcolepsy, sleep apnea syndrome, and Pickwickian syndrome; (17) pain; (18) kidney disorders; (19) eye disorders including glaucoma; and (20) infectious diseases including HIV.

[0092] Depending on the disorder, disease, or condition being treated and the condition of the subject, the compounds or pharmaceutical compositions provided herein can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracapsular injection or infusion, subcutaneous injection, or implantation), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or partial) routes of administration, alone or together, formulated in suitable dosage units having pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each route of administration. Also provided is the administration of the compounds or pharmaceutical compositions provided herein in depot formulations in which the active ingredient is released over a predetermined period of time.

[0093] In the treatment, prevention, or amelioration of one or more symptoms of the disorders, diseases, or conditions described herein, suitable dosage levels are generally in the range of about 0.001 to 100 mg per kg of subject body weight per day (mg / kg per day), about 0.01 to about 75 mg / kg per day, about 0.1 to about 50 mg / kg per day, about 0.5 to about 25 mg / kg per day, or about 1 to about 20 mg / kg per day, which can be administered in single or multiple doses. Within this range, the dosage can be about 0.005 to about 0.05, about 0.05 to about 0.5, about 0.5 to about 5.0, about 1 to about 15, about 1 to about 20, or about 1 to about 50 mg / kg per day.

[0094] For oral administration, the pharmaceutical compositions provided herein can be formulated in the form of tablets containing from about 1.0 to about 1,000 mg of the active ingredient, in one embodiment, about 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900, and about 1,000 mg of the active ingredient for symptomatic adjustment of the dosage for the patient being treated. The pharmaceutical compositions can be administered in a regimen of 1 to 4 times per day, including 1, 2, 3, and 4 times per day.

[0095] However, the specific dosage levels and frequencies of dosing for any particular patient can vary and depend on a variety of factors including the activity of the specific compound used, the metabolic stability and duration of action of that compound, age, weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combinations, the severity of the particular medical condition, and the host undergoing therapy.

[0096] In one embodiment, provided herein is a method for reducing stress in the ER, the method comprising contacting the ER with an effective amount of a compound provided herein, such as a compound of Formula I, or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the ER stress is due to 2+ perturbation of ER Ca

[0097] In yet another embodiment, provided herein is a method for restoring or maintaining homeostasis in the ER, the method comprising contacting the ER with an effective amount of a compound provided herein, such as a compound of Formula I, or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0098] In yet another embodiment, provided herein is a method for increasing the Ca 2+ concentration of the ER, the method comprising contacting the ER with an effective amount of a compound provided herein, such as a compound of Formula I, or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0099] In yet another embodiment, provided herein is a method for modulating the activity of SERCA, the method comprising contacting SERCA with an effective amount of a compound provided herein, such as a compound of Formula I, or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0100] In certain embodiments, SERCA is SERCA1. In certain embodiments, SERCA is SERCA2. In certain embodiments, SERCA is SERCA3.

[0101] In certain embodiments, SERCA is SERCA1a. In certain embodiments, SERCA is SERCA1b. In certain embodiments, SERCA is SERCA2a. In certain embodiments, SERCA is SERCA2b. In certain embodiments, SERCA is SERCA3a. In certain embodiments, SERCA is SERCA3b. In certain embodiments, SERCA is SERCA3c.

[0102] The compounds provided herein, such as a compound of Formula I or an enantiomer thereof, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof may also be combined with, or used in combination with, other agents or therapies useful in the treatment, prevention, or amelioration of one or more symptoms of a disorder, disease, or condition for which the compounds provided herein are useful.

[0103] Other suitable therapeutic agents include: (1) alpha - adrenergic agonists; (2) anti - arrhythmic agents; (3) anti - atherosclerotic agents, such as ACAT inhibitors; (4) antibiotics, such as anthracyclines, bleomycin, mitomycin, dactinomycin, and plicamycin; (5) anti - cancer agents and cytotoxic agents, such as alkylating agents, such as nitrogen mustard, alkyl sulfonates, nitrosoureas, ethyleneimines, and triazenes; (6) anticoagulants, such as acenocoumarol, argatroban, bivalirudin, repirudin, fondaparinux, heparin, phenindione, warfarin, and ximelagatran; (7) anti - diabetic agents, such as biguanides (e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulin, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glipyride, and glypidide), thiazolidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), and PPAR - gamma agonists; (8) antifungal agents, such as amorolfin, amphotericin B, anidulafungin, bifonazole, butenafine, butoconazole, caspofungin, ciclopirox, clotrimazole, econazole, fenticonazole, filipin, fluconazole, isoconazole, itraconazole, ketoconazole, micafungin, miconazole, naftifine, natamycin, nystatin, oxiconazole, ravuconazole, posaconazole, rimocidin, sertaconazole, sulconazole, terbinafine, terconazole, ticonaazole, and voriconazole;(9) Anti-inflammatory agents, for example, non-steroidal anti-inflammatory agents such as aceclofenac, acemetacin, amoxiprin, aspirin, azapropazone, benorylate, bromfenac, carprofen, celecoxib, choline magnesium salicylate, diclofenac, diflunisal, etodolac, etoricoxib, feslamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicyl salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam, tiaprofenic acid, and tolmetin; (10) Metabolic antagonists, for example, folic acid antagonists, purine analogs, and pyrimidine analogs; (11) Antiplatelet agents, for example, GPIIb / IIIa blockers (such as abciximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (such as clopidogrel, ticlopidine and CS-747), cilostazol, dipyridamole, and aspirin; (12) Antiproliferative agents, for example, methotrexate, FK506 (tacrolimus), and mycophenolate mofetil; (13) Anti-TNF antibodies or soluble TNF receptors, for example, etanercept, rapamycin, and leflunomide; (14) aP2 inhibitors; (15) Beta-adrenergic agonists, for example, carvedilol and metoprolol; (16) Bile acid sequestrants, for example, cholestyramine; (17) Calcium channel blockers, for example, amlodipine besylate; (18) Chemotherapeutic agents; (19) Cyclooxygenase-2 (COX-2) inhibitors, for example, celecoxib and rofecoxib; (20) Cyclosporine; (21) Cytotoxic agents, for example, azathioprine and cyclophosphamide;(22) Diuretics, for example, chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzothiazide, ethacrynic acid, ticrynafen, chlorthalidone, furosemide, muzolimine, bumetanide, triamterene, amiloride, and spironolactone; (23) Endothelin-converting enzyme (ECE) inhibitors, for example, phosphoramidon; (24) Enzymes, for example, L-asparaginase; (25) Factor VIIa inhibitors and Factor Xa inhibitors; (26) Farnesyl-protein transferase inhibitors; (27) Fibric acids; (28) Growth factor inhibitors, for example, regulators of PDGF activity; (29) Growth hormone secretagogues; (30) HMG CoA reductase inhibitors, for example, pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (also known as itavastatin, nisvastatin, or nisvastatin), and ZD-4522 (also known as rosuvastatin, atavasin, or bisvastatin); neutral endopeptidase (NEP) inhibitors; (31) Hormonal agents, for example, glucocorticoids (for example, cortisone), estrogen / anti-estrogen agents, androgen / anti-androgen agents, progestins, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; (32) Immunosuppressants; (33) Mineralocorticoid receptor antagonists, for example, spironolactone and eplerenone; (34) Microtubule disruptors, for example, ecteinascidin; (35) Microtubule stabilizers, for example, paclitaxel, docetaxel, and epothilones A-F; (36) MTP inhibitors; (37) Niacin; (38) Phosphodiesterase inhibitors, for example, PDEIII inhibitors (for example, cilostazol) and PDE V inhibitors (for example, sildenafil, tadalafil, and vardenafil); (39) Plant-derived products, for example, vinca alkaloids, epipodophyllotoxins, and taxanes; (40) Platelet-activating factor (PAF) antagonists; (41) Platinum coordination complexes, for example, cisplatin, satraplatin, and carboplatin; (42) Potassium channel openers; (43) Prenyl-protein transferase inhibitors;(44) Protein tyrosine kinase inhibitor; (45) Renin inhibitor; (46) Squalene synthase inhibitor; (47) Steroids, such as aldosterone, beclomethasone, betamethasone, desoxycorticosterone acetate, fludrocortisone, hydrocortisone (cortisol), prednisolone, prednisone, methylprednisolone, dexamethasone, and triamcinolone; (48) TNF-alpha inhibitor, such as tenidap; (49) Thrombin inhibitor, such as hirudin; (50) Thrombolytic agents, such as anisoylated plasminogen streptokinase activator complex (APSAC); (51) Thromboxane receptor antagonist, such as ifetroban; (52) Topoisomerase inhibitor; (53) Vasopeptidase inhibitor (dual NEP-ACE inhibitor), such as omapatrilat and gemopatrilat; and (54) Various other agents, such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine, and gold compounds, may be included but are not limited thereto.;

[0104] In certain embodiments, other therapies that may be used in combination with the compounds provided herein include, but are not limited to, surgery, endocrine therapy, biological response modifiers (e.g., interferons, interleukins, and tumor necrosis factor (TNF)), hyperthermia and cryotherapy, and agents for attenuating any adverse effects (e.g., antiemetics).

[0105] Such other agents, or drugs, can be administered simultaneously or sequentially with the compounds provided herein, such as compounds of Formula I, or enantiomers thereof, mixtures of enantiomers, mixtures of two or more diastereomers, or isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof, in the routes and amounts commonly used therefor. When the compounds provided herein are used in combination with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compounds provided herein can, but need not, be utilized. Thus, pharmaceutical compositions provided herein include those that contain, in addition to the compounds provided herein, one or more other active ingredients or therapeutic agents.

Example

[0106] The present disclosure is further understood by the following non-limiting examples.

[0107] As used herein, the symbols and conventions used in these processes, schemes and examples are consistent with those used in modern scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry, whether or not specific abbreviations are specifically defined. Specifically, but not limited to, the following abbreviations can be used in the examples and throughout the specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); M (molarity); mM (millimolarity); μM (micromolarity); mol (mole); mmol (millimole); hr or hrs (hour or hours); and min (minute).

[0108] For all of the following examples, standard procedures and methods known to those of ordinary skill in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in °C (degrees Celsius). All procedures are carried out at room temperature unless otherwise described.

[0109] Biological assay ER stress cell survival assay CSM14.1 cells were maintained in complete medium at 32°C; the complete medium contained Dulbecco's Modified Eagle Medium (DMEM) with 10% fetal bovine serum (FBS), 1% L-glutamine, 100 IU / mL penicillin, and 100 μg / mL streptomycin. The cells were then recovered from the culture by trypsinization and seeded at a concentration of 1,000 cells / well in 20 μL of DMEM assay medium in a 384-well plate (Greiner #781098). The DMEM assay medium contained 2% FBS, 100 IU / mL penicillin, and 100 μg / mL streptomycin. Seeding was performed using a MultiDrop Combi reagent broadcaster. The plate was incubated overnight at 32°C.

[0110] The test compounds were prepared by two-fold serial dilution in 100% DMSO using a BIOMEK® 2000 liquid handler (Beckman Coulter). A dose-response curve containing 10 concentrations of the test compounds was obtained. Using a BIOMEK® FX liquid handler (Beckman Coulter), 2.5 μL of the test compound was transferred from the 100% DMSO serial dilution plate to an intermediate plate containing 47.5 μL of DMEM assay medium containing 2% FBS, 100 IU / mL penicillin, and 100 μg / mL streptomycin and mixed. To reduce or eliminate interference from compound precipitation, 6 μL of the diluted compound was immediately transferred to the assay plate to achieve a high compound concentration of 100 μM in 99% DMEM assay medium and 1% DMSO. After incubating the assay plate for 2 hours, 4 μL of 112.5 μM thapsigargin (TG) (DMSO stock diluted in assay TC medium) was dispensed into each test well using a MultiDrop Combi reagent broadcaster for a final concentration of approximately 15 μM TG. Tissue culture medium containing vehicle only (4 μL) was manually transferred to each control cell using a 16-channel electronic pipette. After incubating the plate overnight (about 16 - 24 hours), CELLTITER-GLO® (Promega) (16 μL) was added to all wells and luminescence was measured. High luminescence indicates cell survival.

[0111] Alternatively, the test compounds were tested at a single compound concentration (e.g., 2 μM) to determine the effect of the compound on cell survival compared to the vehicle.

[0112] The biological results of testing each compound at 2 μM are summarized in Table 1, where A represents values greater than 50%, B represents values from 10% to 50%, C represents values from 1% to 10%, and D represents values less than or equal to 1%.

Table 8

[0113] Cell recovery assay Protection against thapsigargin (TG)-induced cell death. Human embryonic kidney (HEK293) cells were grown in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS) and 1% antibiotic-antimycotic solution (ABAM). Mouse neuroblastoma (N2a) cells were grown in a 1:1 DMEM:OPTI-MEM® containing 5% FBS and 1% ABAM. All cells were grown in 10% CO2 in a humidified environment of an incubator. Cells grown in 96-well plates were exposed to a test compound (20 μM) for 2 hours, and then thapsigargin (15 μM for HEK293 cells and 1 μM for N2a cells) was added to induce ER stress. After incubation in a cell culture incubator for 24 hours, ALAMARBLUE® reagent (10% v / v) was added to the wells. Fluorescence readings were taken 2 hours after the addition of the ALAMARBLUE® reagent. Cell viability was calculated as the percentage of relative fluorescence units (RFU) compared to the control. Vehicle-treated control cells showed similar viability to that of untreated cells.

[0114] Protection against hydrogen peroxide-induced cell death. N2a cells grown in 96-well plates were exposed to a test compound (40 μM) for 2 hours, and then hydrogen peroxide (200 μM) was added. After incubation with hydrogen peroxide for 40 minutes, ALAMARBLUE® reagent (10% v / v) was added to the wells. Fluorescence readings were taken 2 hours after the addition of the ALAMARBLUE® reagent. Cell viability was calculated as the percentage of relative fluorescence units (RFU) compared to the control. Vehicle-treated control cells showed similar viability to that of untreated cells.

[0115] The results are summarized in Table 2, where A represents values of more than 50% cell recovery, B represents values of 10% - 50% cell recovery, C represents values of 1% - 10% cell recovery, and D represents values of 1% or less cell recovery.

[0116] Ca 2+ -ATPase assay In contrast, microsomal preparations from HEK293 cells were used at a series of calcium concentrations corresponding to physiological ranges for the Ca 2+ -ATPase assay relative to the control. The NADH-linked enzyme-coupled ATPase assay adapted for 96-well microplates was used to measure the ATP hydrolysis rate over a variety of calcium concentrations in the presence of test compounds, and V max was determined by fitting the ATPase calcium-dependence to a Hill function. Each well contained 2 μg or 7 μg of SR vesicles (optimized for skeletal or cardiac SR, respectively), 50 mM MOPS (pH 7.0), 100 mM KCl, 5 mM MgCl2, 1 mM EGTA, 0.2 mM NADH, 1 mM phosphoenolpyruvate pyruvate, 5 IU pyruvate kinase, 5 IU lactate dehydrogenase, and 3.5 μg / mL A23187 (calcium ionophore). CaCl2 was added to set the free [Ca 2+ to a specific value. The assay was initiated by adding ATP at a final concentration of 5 mM and read on a SpectraMax Plus microplate spectrophotometer. Compounds A12, A13, and C19 increased the baseline ATPase activity by 10 - 15%; compounds C18 and C20 increased the ATPase activity by more than 15%.

Table 9

[0117] [Ca 2+ ER Determination of the effect of SERCA agonists on HeLa cells expressing BI-1 mimicking the diabetic state and having reduced [Ca 2+ ER were used to evaluate the effect of test compound Compound A12 on [Ca 2+ ER . To directly measure the ER Ca 2+ content, genetically encoded Ca 2+ ​​​The ER chameleon, which is an indicator, was used. HeLa cells were transfected with a plasmid encoding ER-chameleon for two days before analysis. The cells were treated with the test compound for 24 hours, and thapsigargin was added to deplete ER stores, followed by Ca 2+ Imaged with free HBSS. Ratiometric imaging of the ER chameleon was achieved using a 430 / 24 excitation filter, a 450-nm dichroic mirror, and two emission filters (475 / 40 for CFP and 535 / 25 for YFP). The fluorescence ratio of YFP / CFP is an indicator of the relative ERCa 2+ level. Compound A12 significantly restored [Ca 2+ ER .

[0118] Determination of the effect of SERCA agonists on blood glucose levels ob / ob mice (10 weeks old, n = 3) were intraperitoneally (i.p.) injected once a day for a total of 5 days with 100 μL of a solution containing 0 (vehicle), 10 or 50 mg / kg of a test compound (selected from compound A12, C18, C19, or C20). The protocol for evaluating the effect of the test compound is shown in Figure 3. Fasting glucose was measured at baseline and 10 hours after administration of the test compound. Glucose levels were measured in blood samples collected from the tail vein using a OneTouch Ultra 2 Meter (LifeScan, Inc.). Compounds A12, C18, C19, and C20 significantly decreased blood glucose as early as day 2; ob / ob mice maintained lower glucose levels to the same level as lean mice for more than one week after the last injection of the test compound.

[0119] Determination of the effect of SERCA agonists on improving glucose and insulin tolerance ​Baseline blood glucose measurements were taken before the start of the experiment, and both glucose (GTT) and insulin (ITT) tolerance tests were performed after a 10-hour fast and an additional 2 hours after A12 injection. For the GTT, D-glucose dissolved in 0.9% NaCl was delivered intraperitoneally at a dose of 1 g / kg. Blood glucose levels were measured at 0, 15, 30, 60, 90, and 120 minutes after glucose administration. For the ITT, insulin was administered intraperitoneally at a dose of 1 IU / kg. Blood glucose levels were measured at 0, 15, 30, 60, 90, and 120 minutes after insulin administration. Glucose levels were measured in blood samples collected from the tail vein using a OneTouch Ultra 2 Meter (LifeScan, Inc.). The glucose tolerance test (GTT) on day 7 after injection in ob / ob mice showed that the hyperglycemic response to an i.p. glucose load was significantly decreased in compound A12-treated ob / ob mice compared to the vehicle; the insulin tolerance test (ITT) on day 10 after injection showed that insulin-stimulated glucose disposal was strongly improved in compound A12-treated ob / ob mice compared to the vehicle.

[0120] Determination of the effects of SERCA agonists on improving glucose and lipid metabolism The expression of important genes involved in gluconeogenesis and lipogenesis was measured. RNA was isolated from liver samples of ob / ob mice, and the mRNA expression of the genes shown by real-time PCR using iTaq Fast SYBR Green Supermix with ROX (Bio-Rad) in a 7500 Real-Time PCR System (Applied Biosystems) with mouse-specific primers was quantified. Gene expression was normalized to 18s. RNA was isolated using Trizol (Invitrogen). cDNA was generated using a High Capacity cDNA Reverse Transcription kit (Applied Biosystems). Real-time PCR was performed using iTaq Fast SYBR Green Supermix with ROX (Bio-Rad) in a 7500 Real-Time PCR System (Applied Biosystems) with mouse-specific primers. Gene expression was normalized to 18s. The isolated liver tissue was homogenized in RIPA buffer (Roche) containing protease inhibitors and phosphatase inhibitors. Protein samples were equalized for their protein concentrations, and 30 micrograms of each sample was applied to SDS-PAGE and transferred onto nitrocellulose membranes. The membranes were then incubated with the corresponding fluorescent or total primary antibody specific to the desired protein, followed by incubation with an appropriate secondary antibody conjugated to horseradish peroxidase (Pierce), and the signal intensity was visualized by chemiluminescence (Pierce). Membranes from at least four independent experiments were scanned, and the density of immunoreactive bands was evaluated using NIH Image software. GAPDH (Santa Cruz Biotechnology) was used as a loading control.

[0121] Compound A12 significantly decreased the mRNA expression of glucose 6-phosphatase (G6PAse) and phosphoenolpyruvate carboxykinase (PEPCK), which are known candidates involved in glucose homeostasis. Compound A12 also significantly decreased the mRNA expression of a number of lipid synthesis genes, such as stearoyl-CoA desaturase-1 (SCD1), diacylglycerol acyltransferase 2 (DGAT2), fatty acid synthase (FASn), as well as acetyl co-A and sterol regulatory element-binding protein 1c (SREBP1c). Compound A12 increased the expression of the transcription factors peroxisome proliferator-activated receptor α (PPARα) and its target peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α), which are known to be involved in lipid oxidation and mitochondrial biogenesis. These data demonstrate that Compound A12 affects glucose and lipid homeostasis and thus implicates the compound in mediating energy homeostasis in the liver of obese mice.

[0122] Protection of Human Islets under Type 1 Diabetes-Related Stress Human islet microtissues treated with cytokines were used to model the pathology of type 1 diabetes in vitro. This study tested the effect of compounds on β-cell viability in human islets under cytokine stress. The model consisted of human islet microtissues from HLA-A2 positive donors grown and isolated in 96-well plates (one microtissue per well). The microtissues were treated for 7 days with a cocktail of cytokines (IL1-β 5 ng / mL, IFN-γ 25 ng / mL, TNF-α 25 ng / mL) and compound (5 μM) or vehicle. Six microtissues per compound or vehicle were treated. On day 7, the total ATP content was measured using CellTiter-Glo (Promega). Compound A17 increased viability by 10 - 20% over baseline; Compounds A12, A13, A19, C19, and C20 increased viability by 20 - 50%; Compound C18 increased viability by more than 50%.

[0123] Determination of the Effect of SERCA Agonists on the Reduction of ER Stress Protein samples were prepared from the livers of ob / ob mice treated with vehicle (ob) or ob / ob mice treated with 50 mg / kg of a test compound (Compound A12). The proteins were analyzed and quantified by Western blot. The bands were normalized to GAPDH and represented as 100% of ob / ob + vehicle (ob). Liver tissues were homogenized in ice-cold tissue lysis buffer with a tabletop homogenizer. The homogenized samples were centrifuged at 8,000×g for 20 minutes at 4°C. The lipid layer was removed, and the supernatant was transferred to an Eppendorf tube. After centrifugation at 16,000×g for 60 minutes at 4°C, the supernatant was normalized to the same concentration and boiled in 1× Laemmli buffer at 100°C for 5 minutes. The lysate was cooled to room temperature before loading for Western blot analysis. The protein lysate was resolved on an SDS polyacrylamide gel and transferred onto a PVDF membrane at 100 V for 2 hours at 4°C. The membrane was blocked in 10% blocking reagent and incubated overnight at 4°C with a primary antibody in Tris-buffered saline / Tween (TBST) / 10% blocking reagent. After incubation, the membrane was washed three times with TBST for 20 minutes each and incubated with a secondary antibody in TBST / 10% blocking reagent for 1 hour at room temperature. The membrane was washed three times for 20 minutes each and developed using a chemiluminescence assay system. To strip the membrane for another primary antibody, the membrane was stirred in stripping buffer (2% SDS and 100 mM 2-mercaptoethanol in TBS, pH 7.5) in a box at 50°C for 20 minutes. The membrane was washed three times for 20 minutes each before blocking and incubation with the primary antibody.

[0124] Administration of the test compound as a SERCA agonist resulted in improved ER function, as demonstrated by the expression protein markers of ER stress. Compounds A12 and C18 significantly decreased the phosphorylation of PKR-like ER kinase (PERK) and elF2α. The dephosphorylation of PERK and elF2α indicates the alleviation of the ER stress response. The test compound also significantly decreased the expression of the pro-apoptotic transcription factor C / EBP homologous protein (CHOP), suggesting that the test compound may also be involved in attenuating ER stress-induced apoptosis.

[0125] Activation of SERCA The test compound was characterized over a range of concentrations using a NADH-linked enzyme-coupled ATPase assay. Each well contained 2 mg or 7 mg of SR vesicles (optimized for skeletal or cardiac SR, respectively), 50 mM MOPS (pH 7.0), 100 mM KCl, 5 mM MgCl2, 1 mM EGTA, 0.2 mM NADH, 1 mM phosphoenolpyruvate pyruvate, 5 IU pyruvate kinase, 5 IU lactate dehydrogenase, and 3.5 mg / mL A23187 (calcium ionophore), and CaCl2 was added to set the free [Ca2+] to a specific value. The assay was initiated by adding ATP at a final concentration of 5 mM, read on a SpectraMax Plus microplate spectrophotometer, and the ATPase activity was fitted using the Hill function. The concentration of the test compound required for 50% activation of the maximum V max was determined as the EC 50 value.

[0126] The biological results are summarized in Table 3, and for the EC 50 value, A represents a value less than 20 μM, B represents a value of 20 μM to 100 μM, and C represents a value greater than 100 μM; for the increase in V max at 10 μM, A' represents an increase greater than 50%, B' represents an increase of 20 to 50%, and C' represents an increase of 20% or less.

[0127] Selectivity determination Compound A12 was tested in duplicate at 10 μM against a panel of 164 biological targets commonly assayed in the pharmaceutical and biotechnology industries. The methods used here for each target were adapted from the scientific literature to maximize reliability and reproducibility. A reference standard was run as an integral part of each assay to ensure the validity of the results obtained. Of the 164 targets, compound A12 showed significant responses only against human adenosine A 2A 、human serotonin (5-hydroxytryptamine) 5-HT 2B 、rabbit monoamine transporter, and human norepinephrine (NET) transporter.

Table 10

[0128] Treatment of Alzheimer's disease (AD) and Parkinson's disease (PD) Mouse model: PS1 / APP mice (PS1M146V and APPSWE) (Howlett et al., Brain Res. 2004, 1017, 130-136) were used. Age-matched NTg controls were of the same background strain (C57bl6 / J9).

[0129] Drug dosing: (2) For TASTPM, compound A12 (10 mg / kg in sterile water) was administered intraperitoneally (IP) to AD-Tg and NonTg mice at 5 months (coinciding with the onset of moderate plaque formation and cognitive impairment) and for 4 weeks of daily injections. Control mice were administered 0.9% saline daily.

[0130] Brain section preparation: Mice were deeply anesthetized with halothane and the head was rapidly removed. The brain was quickly extracted and transverse hippocampal slices 300 or 400 μm thick were cut using a vibrating microtome in ice-cold oxygenated artificial cerebrospinal fluid (aCSF) with the following composition (mM): 125 NaCl, 2.5 KCl, 1.25 KH2PO4, 1.2 MgSO4, 2 CaCl2, 10 dextrose, and 25 NaHCO3.

[0131] Alzheimer's disease model behavioral test: Compound A12 was administered intraperitoneally (IP, 10 mg / kg) to APPswe / PSEN1dE9 double transgenic mice starting at 4 months and daily for 4 weeks (5 days per week). Mice were tested after the last administration of A12 or vehicle solution according to the dosing schedule. Briefly, mice were shown a visible platform, which was then removed. The distance the mice swam while searching for the platform was measured. Shorter distances indicate increased memory. As shown in Figure 6(A), in the hidden platform test, mice treated with A12 showed a decrease in total distance compared to mice treated with vehicle. Motor coordination, strength, and balance were evaluated using the rotarod test (Figure 6, B). Mice were first trained to stay on a rotarod rotating at 16 rpm in three consecutive 120-second trials until they could do so. The next day, the mice were returned to the rotarod for a single trial at 18 rpm (maximum duration 120 seconds). The period during which the mice could stay on the rotarod was recorded, and then the mice were returned to their home cages. The speed of the rotarod was then increased to 21 rpm, and all mice were subjected to another test trial. This process was repeated for rotarod speeds of 24, 27, 30, 33, and 36 rpm. All speeds were repeated twice at 30-minute intervals for mice in different groups. The average values of the two tests were analyzed. Mice were maintained on the rotarod for a longer time with more ability in motor coordination, strength, and balance.

[0132] Ca 2+ Imaging: Ca in individual neurons in brain slice preparations was imaged using a custom video-rate multiphoton imaging system based on an upright Olympus BX51 microscope frame. 2+ Individual neurons were loaded with Ca via a patch pipette. 2+Loaded with the indicator bis-fura-2 (50 μM). Laser excitation was provided by 100 fs pulses at 780 nm (80 MHz) from a Ti:sapphire laser (Mai Tai Broadband, Spectra-Physics). To provide a full-frame scan speed of 30 frames / s, the laser beam was scanned by a resonant galvanometer (General Scanning Lumonics) enabling rapid (7.9 kHz) bidirectional scanning along the x-axis and by a conventional linear galvanometer along the y-axis. The laser beam was focused onto the tissue through an Olympus 40x water immersion objective lens (numerical aperture 0.8). The emitted fluorescence was detected by a wide-field photomultiplier tube (Electron Tubes) to induce a video signal, which was captured and analyzed by Video Savant 5.0 software (IO Industries). Further analysis of the background-corrected images was performed using MetaMorph software. For clarity, the results are presented as an inverse ratio such that increases in [Ca 2+ correspond to increases in the ratio of increase. The % change was calculated as [(F / ΔF) - 1] x 100, where F is the mean resting fluorescence at baseline and ΔF is the decrease in fluorescence reflecting Ca release. The difference between the drug-treated group and the saline-treated group was evaluated for significance (p < 0.05) using two-way ANOVA and Scheffe's post hoc analysis. For the dataset measuring somatic Ca 2+ responses, nuclei were excluded.

[0133] Aβ deposition Mice were perfused transcardially with ice-cold PBS (3 mL), followed by 4% paraformaldehyde (5 mL). Brains were extracted and fixed overnight in 30% sucrose-antifreeze solution. 40-μm-thick coronal hippocampal sections were cut on a cryostat and collected in TBS (0.1 M Tris, 0.9% saline, pH 7.4).

[0134] Thioflavin S staining: Floating hippocampal slices were washed with TBS (4×3 min). The slices were immersed in 0.5% Thioflavin S (50 / 50 ethyl alcohol / distilled water, Sigma - Aldrich) for 10 min, followed by washing with 50% ethyl alcohol for 2×3 min. The slices were washed again with TBS (2×3 min), minimally dried, mounted, and coverslipped with the anti - fade mounting agent PVA - DABCO for microscopy.

[0135] Confocal images of immunolabeled tissue were obtained using a 4X and 10X objective lens on an Olympus Fluoview confocal microscope. The density of amyloid plaques was quantified by averaging the percentage of stained positive area (threshold above background staining determined by software parameters and experimenter confirmation) within the hippocampus and cortex from 3 - 5 slices from each experimental animal using MetaMorph software (Molecular Devices). There was no significant difference in the intensity of the background threshold across animal strains or treatment conditions (p>0.05). The experimenter was blinded to the animal strain and treatment condition.

[0136] In vivo treatment with compound A12 restored ER Ca 2+ signaling in AD mice. A). Pseudocolored two - photon images show Ca2+ responses to caffeine (10 mM, 60 s) in CA1 pyramidal neurons of saline - treated PS1 / APP (lower figure, left) and compound A12 - treated PS1 / APP (center). The right image is the caffeine response from NonTg control neurons. B). The bar graph of the peak Ca 2+ responses shows the normalized RyR - Ca2+ responses in compound A12 - treated PS1 / APP (red) compared to saline - treated PS1 / APP (black) and NonTg - saline - treated neurons.

[0137] The results are shown in Figures 4 and 5. Figure 4 shows that in vivo treatment with compound A12 (RD163) restored ER Ca 2+It shows that signal transduction has been restored. Figure 5 shows that amyloid plaques stained with thioflavin S are reduced in APP-PS1 mice treated with compound A12 (RD163) for 4 weeks (10 mg / kg, ip) compared to saline-treated APP-PS1 mice. The mice were approximately 6 months old.

[0138] Behavioral tests in a 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson's disease. Male Wistar rats were trained for both the stepping test and the initial time (IT) test 6 days before treatment with 6-OHDA or NaCl (-6 days). Five days before treatment with 6-OHDA, animals from groups 1-3 were given a vehicle [a mixture of NaCl or DMSO (10%) / tween80 (10%) / water (80%)] once a day for 16 days. Animals from group 4 were administered A12 (10 mg / kg) once a day. All treatments were given once a day, except on Sundays, via the IP route. Surgery was performed at D0 under ketamine (50 mg / kg) and xylazine (10 mg / kg). The animals received a unilateral injection of 6 μl of 6-OHDA (sigma Aldrich) in the left substantia nigra pars compacta. During surgery, local anesthesia was achieved using subcutaneous injection of lidocaine. At the end of the surgery, the animals were treated with buprenorphine (0.05 mg / kg, S.C.). At D11, the animals were given L-DOPA + benserazide or A12 and then the akinesia test was performed. For the IT test, only one of the two forelimbs was left free to move, and 180 seconds was used as the break-off point to record the time required to initiate movement in the planar direction. As seen in Figure 7(A), the animals lesioned with 6-OHDA had an increase in initial time that was reduced by A12. In the stepping test, the rat was held by the experimenter and only one of the two forelimbs was left free to move on the plane. The other hand fixed the non-monitored forelimb while touching one limb to the table. Then the experimenter slowly moved the animal forward. The number of adjusted steps was counted for the right limb. Figure 7(B) shows the results of the stepping test with L-DOPA and A12. The lesioned animals had a dramatic decrease in the number of adjusted steps increased by A12. In the cylinder test, the animal was placed in a Plexiglas cylinder and immediately video-recorded for 15 minutes. During this time, the number of contacts of the ipsilateral limb, the contralateral limb, and both limbs simultaneously (double contact) with the wall of the cylinder was recorded and then expressed as a percentage of the total number of contacts. Figure 7(C) details the results of the treatment with A12 in the cylinder test.6-OHDA animals show a decreased number of contacts that is increased by A12.

[0139] Pharmacokinetics in Sprague Dawley Rats The pharmacokinetics of test compound Compound A12 was evaluated in Dawley rats. The compound was formulated at 1 mg / mL in DMSO / Tween80 / water (10 / 10 / 80, vol / vol / vol) and dosed in triplicate by intravenous (i.v.) at 1 mg / kg or by oral gavage (P.O.) at 2 mg / kg. Blood was collected into EDTA-containing tubes at 5, 15, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours, and plasma was collected by centrifugation. Plasma (25 μL) was treated with acetonitrile (125 μL) containing internal standard. The samples were then centrifuged at 4,000 rpm for 5 minutes in a tabletop centrifuge and the filtrate was collected. The filtrate was injected into a Thermo Betasil C18 HPLC column 5 μ (50 × 2.1 mm). Mobile phase A was water with 0.1% formic acid. Mobile phase B was acetonitrile with 0.1% formic acid. Separation was achieved using a gradient from 90% A / 10% B to 5% A / 95% B over 7 minutes. API Sciex 4000 equipped with a turbo ion spray source was used for all analytical measurements. A positive ion MRM method was developed. The peak area of the product ion was measured relative to the peak area of the internal standard. The data was fitted using WinNonLin (Pharsight Corporation, Mountain View, CA). The oral pharmacokinetic characteristics of Compound A12 were T 1 / 2 : 1.17 hr; C max : 0.26 μM; AUC last 0.41 μM·hr; CL obs : 251 mL / min / kg; and F%: 13.22.

[0140] The brain barrier penetration of Compound A12 was also determined similarly by IP at a dose of 10 mg / kg in mice. The brains of the mice were collected 1 hour after dosing. The brain / plasma ratio was 2.6.

[0141] The pharmacokinetics of compounds A13, A17, and A19 were evaluated in Sprague Dawley rats. Compound A13 was formulated in 0.2% DMA / 0.5% SOLUTOL® / 99.3% saline. Compounds A17 and A18 were formulated in 0.2% DMA / 2% SOLUTOL® / 97.8% saline. The results are summarized in Table 4.

[0142] The pharmacokinetics of compound A13 were evaluated in dogs. Compound A13 was formulated in 0.2% DMA / 0.5% SOLUTOL® / 99.3% saline. The results are summarized in Table 5. For pharmacokinetic evaluation, the test compound was dosed intravenously (IV) (1 mg / kg body weight) to three male beagle dogs and orally (PO) (10 mg / kg body weight) to three male beagle dogs. Blood (approximately 1.0 mL) was collected via the femoral vein into tubes containing K3EDTA anticoagulant at 0, 0.017, 0.083, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing. Plasma samples were analyzed by LC-MS / MS. Quality control samples were used to confirm the analytical results due to within-assay variation. >66% accuracy of the quality control samples was between 80 - 120% of the known value(s). From the concentration data, a standard set of pharmacokinetic parameters including area under the curve (AUC 0-t and AUC 0-inf ), elimination half-life, clearance, volume of distribution, and bioavailability (based on AUC0-t), maximum plasma concentration (C0; C max ), and time to reach maximum plasma concentration (T max ) was generated.

Table 11

Table 12

[0143] Pharmacokinetics in CD-1 mice The pharmacokinetics of the test compound were evaluated in CD-1 mice. The compound was formulated at 1 mg / mL in DMSO / Tween80 / water (10 / 10 / 80, vol / vol / vol) and dosed in triplicate by intravenous (i.v.) injection at 2 mg / kg or oral gavage (P.O.) at 10 mg / kg. Blood was collected into EDTA-containing tubes at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h time points, and plasma was obtained by centrifugation. Plasma (10 μL) containing 50% acetonitrile in water (5 μL) was added to 200 μL of ACN containing the internal standard. The samples were vortexed for 30 seconds. After centrifugation at 4°C and 4,000 rpm for 15 minutes, the supernatant was diluted three times with water. Then, 20 μL of the diluted supernatant was injected into the LC / MS / MS system for quantitative analysis. Samples were injected onto an Agilent ZORBAX XDB-Phenyl 5 μ column (50 × 2.10 mm). Mobile phase A was water with 0.1% formic acid. Mobile phase B was acetonitrile with 0.1% formic acid. Separation was achieved using a gradient from 70% A / 30% B to 0% A / 100% B over 2.10 minutes. A Shimadzu LCMS-8050 equipped with a turbo ion spray source was used for all analytical measurements. A positive ion MRM method was developed. The peak area of the product ion was measured relative to the peak area of the internal standard. The data were fitted using WinNonLin (Pharsight Corporation, Mountain View, CA). The results are shown in Table 6.

Table 13

[0144] Compound Synthesis 3-Methyl-N-(2-methylquinolin-8-yl)butanamide A1 3-Methylbutanoyl chloride (120 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A1. ESI-MS: m / z 243 [M+H] + 。

[0145] N-(2-Methylquinolin-8-yl)pivalamide A2 2,2-Dimethylpropanoyl chloride (120 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A2. ESI-MS: m / z 243 [M+H] + 。

[0146] 3,3-Dimethyl-N-(2-methylquinolin-8-yl)butanamide A3 3,3-Dimethylbutyryl chloride (134 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A3. ESI-MS: m / z 257 [M+H] + .

[0147] 4-(tert-Butyl)-N-(2-methylquinolin-8-yl)benzamide A4 4-tert-Butylbenzoyl chloride (197 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A4. ESI-MS: m / z 319 [M+H] + .

[0148] 4-Butyl-N-(2-methylquinolin-8-yl)benzamide A5 4-Butyrylbenzoyl chloride (197 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A5. ESI-MS: m / z 319 [M+H] + 。

[0149] 4-Fluoro-N-(quinolin-8-yl)benzamide A6 4-Fluorobenzoyl chloride (158 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinoline (144 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A6. ESI-MS: m / z 267 [M+H] + 。

[0150] 3-Fluoro-N-(quinolin-8-yl)benzamide A7 3-Fluorobenzoyl chloride (158 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinoline (144 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A7. ESI-MS: m / z 267 [M+H] + .

[0151] 4-Methoxy-N-(2-methylquinolin-8-yl)benzamide A8 4-Methoxybenzoyl chloride (171 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A8. ESI-MS: m / z 293 [M+H] + .

[0152] 2-Methoxy-N-(2-methylquinolin-8-yl)benzamide A9 2-Methoxybenzoyl chloride (171 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A9. ESI-MS: m / z 293 [M+H] + .

[0153] 2-Ethoxy-N-(2-methylquinolin-8-yl)benzamide A10 2-Ethoxybenzoyl chloride (185 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A10. ESI-MS: m / z 307 [M+H] + .

[0154] 4-Isopropoxy-N-(quinolin-8-yl)benzamide A11 4-Isopropoxybenzoic acid (180 mg, 1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (260 μL, 1.5 mmol) was added and the solution was stirred for 10 minutes. 8-Aminoquinoline (144 mg, 1.0 mmol) was added to this solution and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A11. ESI-MS: m / z 307 [M+H] + 。

[0155] 4-Isopropoxy-N-(2-methylquinolin-8-yl)benzamide A12 4-Isopropoxybenzoic acid (180 mg, 1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (260 μL, 1.5 mmol) was added and the solution was stirred for 10 minutes. 8-Aminoquinazoline (158 mg, 1.0 mmol) was added to this solution and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A12. ESI-MS: m / z 321 [M+H] + 。

[0156] 3-Isopropoxy-N-(2-methylquinolin-8-yl)benzamide A13 3-Isopropoxybenzoic acid (180 mg, 1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (260 μL, 1.5 mmol) was added, and the solution was stirred for 10 minutes. 8-Aminochinaldine (158 mg, 1.0 mmol) was added to this solution, and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected, and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain compound A13. ESI-MS: m / z 321 [M+H] + 。

[0157] 2-((5-Methoxyquinolin-8-yl)carbamoyl)benzoic acid A14 Phthalic anhydride (148 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 5-methoxyquinolin-8-amine (174 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected, and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain compound A14. ESI-MS: m / z 323 [M+H] + 。

[0158] 2,6-Difluoro-N-(2-methylquinolin-8-yl)benzamide A15 2,6-Difluorobenzoyl chloride (177 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A15. ESI-MS: m / z 299 [M+H] + .

[0159] 4-Cyano-2-fluoro-N-(2-methylquinolin-8-yl)benzamide A16 4-Cyano-2-fluorobenzoic acid (165 mg, 1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (260 μL, 1.5 mmol) was added and the solution was stirred for 10 min. 8-Aminoquinazoline (158 mg, 1.0 mmol) was added to this solution and the mixture was stirred for 20 h. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A16. ESI-MS: m / z 306 [M+H] + .

[0160] 2-Chloro-4-methyl-N-(2-methylquinolin-8-yl)benzamide A17 2-Chloro-4-methylbenzoic acid (171 mg, 1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (260 μL, 1.5 mmol) was added and the solution was stirred for 10 minutes. 8-Aminochinaldine (158 mg, 1.0 mmol) was added to this solution and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A17. ESI-MS: m / z 311 [M+H] + 。

[0161] 3-Chloro-4-methoxy-N-(2-methylquinolin-8-yl)benzamide A18 3-Chloro-4-methoxybenzoic acid (187 mg, 1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (260 μL, 1.5 mmol) was added and the solution was stirred for 10 minutes. 8-Aminochinaldine (158 mg, 1.0 mmol) was added to this solution and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A18. ESI-MS: m / z 327 [M+H] + 。

[0162] 2-Methoxy-3-methyl-N-(2-methylquinolin-8-yl)benzamide A19 2-Methoxy-3-methylbenzoic acid (166 mg, 1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (260 μL, 1.5 mmol) was added and the solution was stirred for 10 minutes. 8-Aminoquinazoline (158 mg, 1.0 mmol) was added to this solution and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain Compound A19. ESI-MS: m / z 307 [M+H] + 。

[0163] 2,3,4-Trifluoro-N-(2-methylquinolin-8-yl)benzamide A20 2,3,4-Trifluorobenzoyl chloride (195 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 hours. The mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain Compound A20. ESI-MS: m / z 317 [M+H] + 。

[0164] N-(Quinolin-8-yl)-1-naphthamide A21 1-Naphthoyl chloride (191 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinoline (144 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A21. ESI-MS: m / z 299 [M+H] + .

[0165] 2-(4-Chlorophenyl)-N-(2-methylquinolin-8-yl)acetamide A22 4-Chlorophenylacetyl chloride (189 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A22. ESI-MS: m / z 311 [M+H] + .

[0166] 3-(4-Methoxyphenyl)-N-(2-methylquinolin-8-yl)propanamide A23 3-(4-Methoxyphenyl)propanoyl chloride (199 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A23. ESI-MS: m / z 321 [M+H] + 。

[0167] 5-(4-Methoxyphenyl)-N-(2-methylquinolin-8-yl)isoxazole-3-carboxamide A24 5-(4-Methoxyphenyl)isoxazole-3-carboxylic acid (219 mg, 1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (260 μL, 1.5 mmol) was added and the solution was stirred for 10 min. 8-Aminoquinazoline (158 mg, 1.0 mmol) was added to this solution and the mixture was stirred for 20 h. The mixture was diluted with water and extracted with two volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A24. ESI-MS: m / z 360 [M+H] + 。

[0168] 6-Chloro-N-(2-methylquinolin-8-yl)nicotinamide A25 6-Chloronicotinoyl chloride (176 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A25. ESI-MS: m / z 298 [M+H] + .

[0169] 3-Chloro-N-(2-methylquinolin-8-yl)benzo[b]thiophene-2-carboxamide A26 3-Chlorobenzothiophene-2-carbonyl chloride (231 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A26. ESI-MS: m / z 353 [M+H] + .

[0170] N-(2-Methylquinolin-8-yl)benzofuran-2-carboxamide A27 Method 1. Benzofuran-2-carbonyl chloride (181 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A27. ESI-MS: m / z 303 [M+H] + 。

[0171] Method 2. Benzofuran-2-carboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 min. To this solution, 8-aminoquinazoline (1.0 mmol) was added and the mixture was stirred for 20 h. The mixture was diluted with water and extracted with two volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give the desired product A27. ESI-MS: m / z 303 [M+H] + 。

[0172] 2-(Quinolin-8-yl)-2,3-dihydrophthalazine-1,4-dione A28 Phthalic anhydride (148 mg, 1.0 mmol) was dissolved in acetic acid (5 mL). To this solution, quinolin-8-yl-hydrazine (159 mg, 1.0 mmol) was added and the solution was heated to 80 °C. After heating with stirring for 8 h, the mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound A28. ESI-MS: m / z 290 [M+H] + 。

[0173] 2-(Quinolin-8-yl)isoindoline-1,3-dione A29 Phthalic anhydride (148 mg, 1.0 mmol) was dissolved in acetic acid (5 mL). 8-Aminoquinoline (144 mg, 1.0 mmol) was added to this solution, and the solution was heated to 110 °C. After heating with stirring for 20 hours, the mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected, and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain compound A29. ESI-MS: m / z 275 [M+H] + 。

[0174] 5-Bromo-N-(2-methylquinolin-8-yl)thiophene-2-carboxamide B1 Method 1. 5-Bromo-2-thiophenecarbonyl chloride (1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 hours. The mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected, and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain compound B1. ESI-MS: m / z 348 [M+H] + 。

[0175] Method 2. 2-Thiophenecarboxylic acid, 5-bromo- (1.0 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 8-aminoquinazoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product B1. ESI-MS: m / z 348 [M+H] + 。

[0176] N-(2-Methylquinolin-8-yl)benzo[b]thiophene-2-carboxamide B2 Method 1. Benzo[b]thiophene-2-carbonyl chloride (196 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 hours. The mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain compound B2. ESI-MS: m / z 319 [M+H] + 。

[0177] Method 2.1 - Benzo[b]thiophene-2-carboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 8-aminoquinazoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product B2. ESI-MS: m / z 319 [M+H]. + 。

[0178] 3-Cyano-N-(quinolin-8-yl)benzamide B3 3-Cyanobenzoyl chloride (1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinoline (144 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 hours. The mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain compound B3. ESI-MS: m / z 274 [M+H]+.

[0179] 4-Cyano-N-(2-methylquinolin-8-yl)benzamide B4 4-Cyanobenzoyl chloride (1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give Compound B4. ESI-MS: m / z 288 [M+H] + 。

[0180] 4-Bromo-N-(2-methylquinolin-8-yl)benzamide C1 4-Bromobenzoyl chloride (219 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give Compound C1. ESI-MS: m / z 342 [M+H] + 。

[0181] 2-Fluoro-N-(2-methylquinolin-8-yl)benzamide C2 2-Fluorobenzoyl chloride (159 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C2. ESI-MS: m / z 281 [M+H] + 。

[0182] 2-Nitro-N-(2-methylquinolin-8-yl)benzamide C3 2-Nitrobenzoyl chloride (186 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C3. ESI-MS: m / z 308 [M+H] + 。

[0183] 3-(Trifluoromethoxy)-N-(2-methylquinolin-8-yl)benzamide C4 3-Trifluoromethoxybenzoyl chloride (225 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C4. ESI-MS: m / z 347 [M+H] + 。

[0184] 2-Trifluoromethyl-N-(2-methylquinolin-8-yl)benzamide C5 2-Trifluoromethylbenzoyl chloride (209 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C5. ESI-MS: m / z 331 [M+H] + 。

[0185] 3-Fluoro-N-(2-methylquinolin-8-yl)benzamide C6 3-Fluorobenzoyl chloride (159 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C6. ESI-MS: m / z 281 [M+H] + 。

[0186] 3-Nitro-N-(2-methylquinolin-8-yl)benzamide C7 3-Nitrobenzoyl chloride (186 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C7. ESI-MS: m / z 308 [M+H] + 。

[0187] 4-Nitro-N-(2-methylquinolin-8-yl)benzamide C8 4-Nitrobenzoyl chloride (186 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C8. ESI-MS: m / z 308 [M+H] + 。

[0188] 2-Chloro-N-(2-methylquinolin-8-yl)benzamide C9 2-Chlorobenzoyl chloride (175 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C9. ESI-MS: m / z 297 [M+H] + 。

[0189] 4-(Trifluoromethyl)-N-(2-methylquinolin-8-yl)benzamide C10 4-Trifluoromethylbenzoyl chloride (209 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C10. ESI-MS: m / z 331 [M+H] + .

[0190] 4-Trifluoromethoxy-N-(2-methylquinolin-8-yl)benzamide C11 4-Trifluoromethoxybenzoyl chloride (225 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C11. ESI-MS: m / z 347 [M+H] + .

[0191] 3-Trifluoromethyl-N-(2-methylquinolin-8-yl)benzamide C12 3-Trifluoromethylbenzoyl chloride (209 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C12. ESI-MS: m / z 331 [M+H] + 。

[0192] 4-Ethoxy-N-(2-methylquinolin-8-yl)benzamide C13 4-Ethoxybenzoyl chloride (185 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C13. ESI-MS: m / z 307 [M+H] + 。

[0193] 4-Fluoro-N-(2-methylquinolin-8-yl)benzamide C14 4-Fluorobenzoyl chloride (159 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 hours. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C14. ESI-MS: m / z 281 [M+H] + 。

[0194] 3-Chloro-N-(2-methylquinolin-8-yl)benzamide C15 3-Chlorobenzoyl chloride (175 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 hours. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C15. ESI-MS: m / z 297 [M+H] + 。

[0195] 3-Bromo-N-(2-methylquinolin-8-yl)benzamide C16 3-Bromobenzoyl chloride (219 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C16. ESI-MS: m / z 342 [M+H] + 。

[0196] 4-Chloro-N-(2-methylquinolin-8-yl)benzamide C17 4-Chlorobenzoyl chloride (175 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C17. ESI-MS: m / z 297 [M+H] + 。

[0197] 4-N,N-Dimethylamino-N-(2-methylquinolin-8-yl)benzamide C18 N,N-Dimethylaminobenzoyl chloride (1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C18. ESI-MS: m / z 306 [M+H] + .

[0198] 4-(Ethylamino)-N-(2-methylquinolin-8-yl)benzamide C19 4-(Ethylamino)benzoyl chloride (1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C19. ESI-MS: m / z 306 [M+H] + .

[0199] 4-(Isopropylamino)-N-(2-methylquinolin-8-yl)benzamide C20 4-(Isopropylamino)benzoyl chloride (1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C20. ESI-MS: m / z 320 [M+H] + .

[0200] 4-(Isopropylthio)-N-(2-methylquinolin-8-yl)benzamide C21 4-(Isopropylthio)benzoyl chloride (1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound C21. ESI-MS: m / z 337 [M+H] + .

[0201] 4-(Ethylthio)-N-(2-methylquinolin-8-yl)benzamide C22 4-(Ethylthio)benzoyl chloride (1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinazoline (158 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give Compound C22. ESI-MS: m / z 323 [M+H] + 。

[0202] 8-(4-Isopropoxybenzamido)quinoline-2-carboxylic acid E1 4-Isopropoxybenzoic acid (180 mg, 1.0 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (260 μL, 1.5 mmol) was added and the solution was stirred for 10 min. 8-Aminoquinoline-2-carboxylic acid (188 mg, 1.0 mmol) was added to this solution and the mixture was stirred for 20 h. The mixture was diluted with water and extracted with two volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give Compound E1. ESI-MS: m / z 351 [M+H] + 。

[0203] 8-(3-Isopropoxybenzamido)quinoline-2-carboxylic acid E2 3-Isopropoxybenzoic acid (180 mg, 1.0 mmol) and N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (260 μL, 1.5 mmol) was added and the solution was stirred for 10 minutes. 8-Aminoquinoline-2-carboxylic acid (188 mg, 1.0 mmol) was added to this solution and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain Compound E2. ESI-MS: m / z 351 [M+H] + 。

[0204] 8-(5-Bromothiophene-2-carboxamido)quinoline-2-carboxylic acid E3 5-Bromo-2-thiophenecarbonyl chloride (1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinoline-2-carboxylic acid (188 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 hours. The mixture was diluted with water and extracted with 2 volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain Compound E3. ESI-MS: m / z 378 [M+H] + 。

[0205] 8-(Benzo[b]thiophene-2-carboxamido)quinoline-2-carboxylic acid E4 Benzothieno[2,3-b]thiophene-2-carbonyl chloride (196 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 8-aminoquinoline-2-carboxylic acid (188 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 hours. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give Compound E4. ESI-MS: m / z 349 [M+H] + .

[0206] N-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)quinolin-8-yl)-3-isopropoxybenzamide F1 3-Isopropoxybenzoic acid (180 mg, 1.0 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (260 μL, 1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution was added 2-(3,5-dimethyl-1H-pyrazol-1-yl)quinolin-8-amine (238 mg, 1.0 mmol) and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with two volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give Compound F1. ESI-MS: m / z 401 [M+H] + .

[0207] N-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)quinolin-8-yl)-4-isopropoxybenzamide F2 4-Isopropoxybenzoic acid (180 mg, 1.0 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (260 μL, 1.5 mmol) was added and the solution was stirred for 10 minutes. 2-(3,5-Dimethyl-1H-pyrazol-1-yl)quinolin-8-amine (238 mg, 1.0 mmol) was added to this solution and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with two volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain Compound F2. ESI-MS: m / z 401 [M+H] + 。

[0208] 5-Bromo-N-(2-(3,5-dimethyl-1H-pyrazol-1-yl)quinolin-8-yl)thiophene-2-carboxamide F3 5-Bromo-2-thiophenecarbonyl chloride (1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 2-(3,5-dimethyl-1H-pyrazol-1-yl)quinolin-8-amine (238 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 hours. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain Compound F3. ESI-MS: m / z 428 [M+H] + 。

[0209] N-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)quinolin-8-yl)benzo[b]thiophene-2-carboxamide F4 Benzothiophene-2-carbonyl chloride (196 mg, 1.0 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. This solution was added dropwise to a cooled (0 °C) solution of 2-(3,5-dimethyl-1H-pyrazol-1-yl)quinolin-8-amine (238 mg, 1.0 mmol) and N,N-diisopropylethylamine (260 μL, 1.5 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for 2.5 h. The mixture was diluted with water and extracted with two volumes of dichloromethane. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give compound F4. ESI-MS: m / z 399 [M+H] + .

[0210] N-(2-Methylquinolin-8-yl)thiophene-2-carboxamide G1 2-Thiophenecarboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 min. 8-Aminoquinazoline (1.0 mmol) was added to this solution and the mixture was stirred for 20 h. The mixture was diluted with water and extracted with two volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to give the desired product G1. ESI-MS: m / z 269 [M+H] + .

[0211] 5-Methyl-N-(2-methylquinolin-8-yl)thiophene-2-carboxamide G2 5-Methyl-2-thiophenecarboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 8-aminoquinazoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product G2. ESI-MS: m / z 283 [M+H] + 。

[0212] 3-Methyl-N-(2-methylquinolin-8-yl)thiophene-2-carboxamide G3 3-Methyl-2-thiophenecarboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 8-aminoquinazoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product G3. ESI-MS: m / z 283 [M+H] + 。

[0213] 5-Chloro-N-(2-methylquinolin-8-yl)thiophene-2-carboxamide G4 5-Chloro-2-thiophenecarboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 8-aminoquinazoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product G4. ESI-MS: m / z 303 [M+H] + 。

[0214] 5-Acetyl-N-(2-methylquinolin-8-yl)thiophene-2-carboxamide G5 5-Acetyl-2-thiophenecarboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 8-aminoquinazoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product G5. ESI-MS: m / z 311 [M+H] + 。

[0215] 3,5-Dibromo-N-(2-methylquinolin-8-yl)thiophene-2-carboxamide G6 3,5-Dibromothiophene-2-carboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 8-aminoquinazoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product G6. ESI-MS: m / z 427 [M+H] + 。

[0216] 4,5-Dibromo-N-(2-methylquinolin-8-yl)thiophene-2-carboxamide G7 4,5-Dibromothiophene-2-carboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 8-aminoquinazoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product G7. ESI-MS: m / z 427 [M+H] + 。

[0217] 4-Bromo-N-(2-methylquinolin-8-yl)thiophene-2-carboxamide G8 4-Bromo-2-thiophenecarboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 8-aminoquinazoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product G8. ESI-MS: m / z 348 [M+H] + 。

[0218] 5-Bromo-N-(quinolin-8-yl)thiophene-2-carboxamide H1 5-Bromo-2-thiophenecarboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 6-aminoquinoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product H1. ESI-MS: m / z 334 [M+H] + 。

[0219] N-(quinolin-8-yl)thiophene-2-carboxamide H2 2-Thiophenecarboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 8-aminoquinoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product H2. ESI-MS: m / z 255 [M+H] + 。

[0220] 5-Methyl-N-(quinolin-8-yl)thiophene-2-carboxamide H3 5-Methyl-2-thiophenecarboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 8-aminoquinazoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product H3. ESI-MS: m / z 269 [M+H] + 。

[0221] 3-Methyl-N-(quinolin-8-yl)thiophene-2-carboxamide H4 3-Methyl-2-thiophenecarboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 8-aminoquinoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product H4. ESI-MS: m / z 269 [M+H] + 。

[0222] 5-Chloro-N-(quinolin-8-yl)thiophene-2-carboxamide H5 5-Chloro-2-thiophenecarboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 8-aminoquinoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product H5. ESI-MS: m / z 289 [M+H] + 。

[0223] 5-Acetyl-N-(quinolin-8-yl)thiophene-2-carboxamide H6 5-Acetyl-2-thiophenecarboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 8-aminoquinoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product H6. ESI-MS: m / z 297 [M+H] + 。

[0224] N-(Quinolin-8-yl)benzofuran-2-carboxamide H7 Benzofuran-2-carboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 8-aminoquinoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product H7. ESI-MS: m / z 289 [M+H] + 。

[0225] 5-Nitro-N-(quinolin-8-yl)thiophene-2-carboxamide H8 5-Nitro-2-thiophenecarboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 6-aminoquinoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product H8. ESI-MS: m / z 300 [M+H] + 。

[0226] 4-Bromo-N-(quinolin-8-yl)thiophene-2-carboxamide H9 4-Bromo-2-thiophenecarboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 8-aminoquinoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product H9. ESI-MS: m / z 334 [M+H] + 。

[0227] 3,5-Dibromo-N-(quinolin-8-yl)thiophene-2-carboxamide H10 3,5-Dibromothiophene-2-carboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 8-aminoquinoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product H10. ESI-MS: m / z 413 [M+H] + 。

[0228] 4,5-Dibromo-N-(quinolin-8-yl)thiophene-2-carboxamide H11 4,5-Dibromothiophene-2-carboxylic acid (1.0 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution, 8-aminoquinoline (1.0 mmol) was added and the mixture was stirred for 20 hours. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layer was collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to obtain the desired product H11. ESI-MS: m / z 413 [M+H] + 。 * * * * *

[0229] The examples shown above are provided to give those skilled in the art a complete disclosure and description of how to make and use the claimed embodiments and are not intended to limit the scope of what is disclosed herein. Modifications that are obvious to those skilled in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference as if each such publication, patent, or patent application had been specifically and individually indicated to be incorporated by reference herein.

Claims

1. A compound represented by a formula selected from i) 【Chemical 1】 or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and ii) a pharmaceutically acceptable carrier, excipient, or diluent A pharmaceutical composition comprising.

2. The compound is represented by the following formula: 【Chemical 2】 Or a pharmaceutically acceptable salt, solvate, or hydrate thereof. The pharmaceutical composition according to Claim 1.

3. The compound is represented by the following formula: 【Chemical Formula 3】 Or a pharmaceutically acceptable salt, solvate, or hydrate thereof. The pharmaceutical composition according to Claim 1.

4. The compound is represented by the following formula: 【Chemical Formula 4】 Or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to Claim 1.

5. The pharmaceutical composition is in solid form. The pharmaceutical composition according to any one of Claims 1 to 4.

6. The pharmaceutical composition according to any one of Claims 1 to 5, for treating Alzheimer's disease.

7. The pharmaceutical composition according to any one of Claims 1 to 5, for treating diabetes.

8. The diabetes is type 1. The pharmaceutical composition according to Claim 7.

9. The diabetes is type 2. The pharmaceutical composition according to Claim 7.

10. The pharmaceutical composition according to any one of Claims 1 to 5, for treating Parkinson's disease.

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