Amino acid derivatives for the treatment of inflammatory diseases

Abstract

The present disclosure provides specific amino acid derivatives that inhibit NF-kB activation and, accordingly, are useful for the treatment of inflammatory diseases. Additionally, a pharmaceutical composition containing such compounds and a method for preparing such compounds are provided.

Description

Technology Field

[0001] The present disclosure provides specific amino acid derivatives that inhibit nuclear factor-kappa B (NF-kB) activation induced by inflammatory stimuli. Accordingly, the compounds of the present disclosure are useful for the treatment of inflammatory disorders, e.g., rheumatoid arthritis, multiple sclerosis, asthma, and inflammatory bowel disease. Additionally, pharmaceutical compositions containing such compounds and methods for preparing the same are provided. Background Technology

[0002] Inflammation is an important host response to infection or injury. However, dysregulation of this response caused by persistent or inappropriate inflammation results in a wide range of pathological processes. Inflammatory disorders include autoimmune diseases, allergies, asthma, chronic obstructive pulmonary disease, and sepsis, which is a major cause of disease and death. It is also becoming evident that low-grade chronic inflammation underlies many diseases, including diabetes, cancer, cardiovascular disease, and neuropathic disorders. Therefore, identifying new drugs to suppress inflammation is a major area of ​​interest.

[0003] NF-kB is a universally expressed transcription factor that regulates the expression of genes implicated in inflammation and pain. Activation of NF-kB plays a pivotal role in inflammation through its ability to induce the transcription of pro-inflammatory genes (cf. Tak et al. NF-kB: a key role in inflammatory diseases. J Clin Inv 2001; 107:7-11; and Liu et al. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017;2. pii: 17023). The synthesis of pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IL-8, is mediated by NF-kB, as is the expression of cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS), adhesion molecules (ICAM-1, E-selectin, and VCAM-1), chemokines (MCP-1, KC, MIP-1), and metalloproteinases. Conversely, cytokines produced by COX-2, such as TNF-α and IL-1β or prostaglandins, trigger NF-kB activation that generates an inflammatory cascade.

[0004] NF-kB is activated at sites of inflammation in various diseases including rheumatoid arthritis, osteoarthritis, atherosclerosis, multiple sclerosis, asthma, inflammatory bowel disease, diabetes, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, osteoporosis, systemic lupus erythematosus, chronic obstructive pulmonary disease, stroke, acute kidney injury, glomerulonephritis, psoriasis, and atopic dermatitis (Pai et al. Immune deficiency or hyperactivity-Nf-kappab illuminates autoimmunity . J Autoimmun 2008; 31:245-251; Zhang et al. NFkB in inflammation and renal diseases. Cell Bioscience 2015; 5:63; Roman-Blas et al. NF-kB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis. Osteoarthritis and Cartilage 2006; 14:839-848).

[0005] Corticosteroids were developed to treat inflammatory conditions, and particularly when used for extended periods, they have many side effects that can be mild or severe. For example, corticosteroids can cause weight gain, edema, high blood pressure, glaucoma, hypokalemia, cataracts, psychiatric disturbances, osteoporosis, and weakening of the immune system. Non-steroidal anti-inflammatory drugs (NSAIDs) that act by inhibiting cyclooxygenase (COX) isoenzymes are widely prescribed, but chronic use of NSAIDs is associated with common side effects including cardiovascular events (hypertension, myocardial infarction, stroke, and heart failure), potentially fatal gastrointestinal side effects (diffuse gastritis and discrete ulcers of both the stomach and duodenum), renal side effects (interstitial nephritis), as well as hepatic side effects (transaminitis, hepatitis). Biologics have been developed to target inflammatory cytokines. Although biological agents have been shown to improve the pathology and progression of inflammatory diseases, their use has been limited due to serious side effects and the fact that they eliminate host defenses against infection (Rider et al. Biologics for Targeting Inflammatory Cytokines, Clinical Uses, and Limitations. Int J Cell Biol. 2016; 2016:9259646).

[0006] Therefore, there is a need to develop other anti-inflammatory drugs with fewer side effects for chronic use. The present invention satisfies this and related needs.

[0007] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided:

[0008]

[0009] In the above formula,

[0010] n is 0, 1, 2, or 3, and;

[0011] The dashed line is an arbitrary combination;

[0012] Het is R independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, dialkylamino, carboxy, and alkoxycarbonyl. a , R b , and / or R c It is a heteroaryl arbitrarily substituted with;

[0013] R 1 It is hydrogen or alkyl;

[0014] R 2 is hydrogen or alkyl;

[0015] R 3 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, acylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein R itself as part of the aralkyl or heteroaralkyl is independently selected from alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, cyano, nitro, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino. d , R e , and / or R f Arbitrarily replaced with;

[0016] R 4 is hydrogen or alkyl;

[0017] R 5 is -C(O)R 6 and, here, R 6 R is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, wherein the aryl or heteroaryl itself as part of the aralkyl or heteroaralkyl is independently selected from alkyl, alkoxy, aminoalkoxy, hydroxyalkoxy, alkoxyalkoxy, cycloalkyloxy, cycloalkylalkyloxy, optionally substituted aryloxy, optionally substituted aralkyloxy, optionally substituted heteroaryloxy, optionally substituted heteroaralkyloxy, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkylalkyloxy, halo, haloalkyl, haloalkoxy, cyano, nitro, hydroxy, carboxyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, acylamino, and sulfonylamino. g , R h , and / or R i Or arbitrarily replaced with;

[0018] R 4 and R 5 They form a 5 to 7-membered heterocycloamino ring together with the nitrogen atoms to which they are bonded.

[0019] In a second aspect, the present disclosure relates to a pharmaceutical composition comprising a compound formula (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0020] In a third aspect, the present disclosure relates to a method for treating a treatable disease by inhibiting NF-kB activation, comprising administering a therapeutically effective amount of the compound of formula (I) or the pharmaceutically acceptable salt thereof to a patient in need, in a pharmaceutical composition comprising: a compound of formula (I) (or any of the embodiments described herein), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient. In one embodiment, the disease is an inflammatory disease including an autoimmune disease, pain, allergy, asthma, chronic obstructive pulmonary disease, and sepsis. In another embodiment, the disease is rheumatoid arthritis, osteoarthritis, atherosclerosis, multiple sclerosis, asthma, inflammatory bowel disease, diabetes, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, osteoporosis, systemic lupus erythematosus, chronic obstructive pulmonary disease, cystic fibrosis, stroke, acute kidney injury, glomerulonephritis, psoriasis, atopic dermatitis, Behcet's disease, tuberculosis, Crohn's disease, colitis, Pagett's disease, pancreatitis, periodontitis, inflammatory lung disease, and lupus nephritis.

[0021] In a fourth aspect, the present disclosure relates to a compound of formula (I) (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof for use as a drug. In one embodiment, the compound of formula (I) (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof is useful for the treatment of autoimmune diseases, pain, allergies, asthma, chronic obstructive pulmonary disease, and inflammatory diseases including sepsis. In another embodiment, the diseases are rheumatoid arthritis, osteoarthritis, atherosclerosis, multiple sclerosis, asthma, inflammatory bowel disease, diabetes, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, osteoporosis, systemic lupus erythematosus, chronic obstructive pulmonary disease, cystic fibrosis, stroke, acute kidney injury, glomerulonephritis, psoriasis, atopic dermatitis, Behcet's disease, pulmonary tuberculosis, Crohn's disease, colitis, Paget's disease, pancreatitis, periodontitis, inflammatory lung disease, and lupus nephritis.

[0022] In a fifth embodiment, a compound formula (I) or a pharmaceutically acceptable salt thereof (and any embodiment thereof disclosed herein) is provided for use in treating a disease in a patient in which NF-kB activation contributes to the pathology and / or symptoms of the disease. In one embodiment, the disease is an inflammatory disease including an autoimmune disease, pain, allergy, asthma, chronic obstructive pulmonary disease, and sepsis. In another embodiment, the diseases are rheumatoid arthritis, osteoarthritis, atherosclerosis, multiple sclerosis, asthma, inflammatory bowel disease, diabetes, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, osteoporosis, systemic lupus erythematosus, chronic obstructive pulmonary disease, cystic fibrosis, stroke, acute kidney injury, glomerulonephritis, psoriasis, atopic dermatitis, Behcet's disease, pulmonary tuberculosis, Crohn's disease, colitis, Paget's disease, pancreatitis, periodontitis, inflammatory lung disease, and lupus nephritis.

[0023] In the sixth embodiment, an intermediate of formula (II) is provided:

[0024]

[0025] In the above equation, dashed line, n, Het, R 1 , R 2 , and R 3 is as defined for the above chemical formula (I) (including specific examples thereof disclosed herein). In one embodiment, the intermediate has the structure (IIB):

[0026]

[0027] In the above equation, n, Het, R 1 , R 2 , and R 3 is as defined for the chemical formula (I) (including specific examples thereof disclosed herein). In another aspect, the intermediate has the structure (IIB'):

[0028]

[0029] In the above equation, R 1 , R 2 , and R 3 is as defined for chemical formula (I) (including specific examples thereof disclosed herein), and pyridyl is R a , R b , and / or R c It is arbitrarily replaced with.

[0030] In the seventh embodiment, a compound of formula (IIB),

[0031] (i) R 6 This is as defined in the above chemical formula (I), and chemical formula R in which LG is the leaving group under acylation reaction conditions. 6 A compound of COLG, or

[0032] (ii) Chemical formula R under amino acid coupling reaction conditions 6 React with a COOH compound;

[0033] (iii) optionally convert the compound of formula (IB) obtained from step (i) or (ii) into an acid addition salt;

[0034] (iv) Optionally, a method for preparing a compound of formula (IB) is provided, comprising converting the compound of formula (IB) obtained from step (i) or (ii) into a free base:

[0035]

[0036]

[0037] In the above chemical formula (IB), n, Het, R 1 , R 2 , and R 3 is as defined above, and R 4 is hydrogen or alkyl, and R 5 -COR 6 and, here, R 6 is as defined above, and

[0038] In the above chemical formula (IIB), dashed line, n, Het, R 1 , R 2 , and R 3 It is as defined above. Specific details for implementing the invention

[0039] definition:

[0040] Unless otherwise noted, the following terms used in the specification and claims are defined for this application and have the following meanings:

[0041] "Alkyl" means a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, and pentyl.

[0042] "Alkylene" means, unless otherwise noted, a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms, e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, and pentylene, etc.

[0043] "Alkylthio" means -SR radicals in which R is an alkyl as defined above, e.g., methylthio, and ethylthio.

[0044] "Alkylsulfonyl" means -SO2R radicals in which R is an alkyl as defined above, e.g., methylsulfonyl and ethylsulfonyl.

[0045] "Amino" means -NH2.

[0046] "Alkylamino" means -NHR radicals in which R is an alkyl as defined above, e.g., methylamino, ethylamino, and propylamino or 2-propylamino, etc.

[0047] "Aminoalkyl" means a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbons in which R' and R" are independently substituted with -NR'R" which is hydrogen or alkyl as defined above, e.g., aminomethyl, aminoethyl, and methylaminomethyl, etc.

[0048] "Alkoxy" means -OR radicals in which R is an alkyl as defined above, e.g., methoxy, ethoxy, propoxy or 2-propoxy, and n-, iso-, or tertiary-butoxy, etc.

[0049] "Alkoxyalkyl" means a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms substituted with at least one alkoxy group as defined above, e.g., one or two alkoxy groups, or a branched monovalent hydrocarbon radical of 3 to 6 carbons, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, and 2-ethoxyethyl, etc.

[0050] "Alkoxyalkyloxy" means -(O)R radicals where R is an alkoxyalkyl as defined above, e.g., methoxyethoxy and ethoxyethoxy.

[0051] "Aminoalkyloxy" means -O-alkylene-R radicals in which R is -NR'R" and R' and R" are independently hydrogen or alkyl as defined above, e.g., aminoethyloxy, methylaminoethyloxy, dimethylaminoethyloxy, and diethylaminoethyloxy.

[0052] "Thioalkyl" means a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms substituted with an -SH group or a branched monovalent hydrocarbon radical of 3 to 6 carbons, e.g., thioethyl, and 1-, 2-, or 3-thiopropyl.

[0053] "Alkylthioalkyl" means a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbons substituted with an alkylthio group as defined above, e.g., 2-methylthioethyl, and 1-, 2-, or 3-ethylthiopropyl, etc.

[0054] "Alkoxycarbonyl" means -C(O)OR radicals as defined above, e.g., methoxycarbonyl and ethoxycarbonyl.

[0055] "Alkoxycarbonylalkyl" means a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbons substituted with an alkoxycarbonyl group as defined above, e.g., 2-methylcarboxyethyl, methylcarboxymethyl, and 1-, 2-, or 3-ethylcarboxypropyl, etc.

[0056] "Acyl" means -C(O)R radicals in which R is an alkyl as defined above, e.g., methyl carbonyl, and ethyl carbonyl, etc.

[0057] "Acylamino" means a -NHC(O)R radical in which R is an alkyl as defined above, e.g., methylcarbonylamino and ethylcarbonylamino, etc., or R may be optionally substituted with one, two, or three substituents independently selected from substituents as disclosed herein, e.g., alkyl, hydroxyl, cycloalkyl, heterocycloalkyl, carboxyl, alkoxycarbonyl, hydroxyl, alkoxy, alkylthio, alkylsulfonyl, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, and cyano.

[0058] "Acylaminoalkyl" means a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms substituted with an acylamino group as defined above, or a branched monovalent hydrocarbon radical of 3 to 6 carbons, e.g., 2-acetylaminoethyl, and 1-, 2-, or 3-ethanoylaminopropyl, etc.

[0059] "Aminocarbonylalkyl" means a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms in which R is hydrogen or alkyl and R' is hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryl, or R and R' are substituted with a -CONRR' group that forms a heterocycloamino together with the nitrogen atom to which they are bonded, e.g., aminocarbonylethyl, methylaminocarbonylethyl, methylaminocarbonylmethyl, 1-, 2-, or 3-ethylaminocarbonylpropyl, pyrrolidinylmethyl, and piperidinylethyl, etc.

[0060] "Aryl" means monocyclic or bicyclic aromatic hydrocarbon radicals of 6 to 10 ring atoms, e.g., benzyl and phenethyl.

[0061] "Aralkyl" refers to a -(alkylene)-R radical where R is an aryl as defined above, e.g., benzyl and phenethyl, etc.

[0062] "Cycloalkyl" means a cyclic saturated monovalent hydrocarbon radical having 3 to 10 carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0063] "Cycloalkyloxy" means -OR where R is a cycloalkyl as defined above, e.g., cyclopropyloxy, cyclobutyloxy, and cyclopentyloxy.

[0064] "Cycloalkylalkyl" means -(alkylene)-R radicals in which R is a cycloalkyl as defined above, e.g., cyclopropylmethyl and cyclohexylmethyl.

[0065] "Cycloalkylalkyloxy" means -O-cycloalkylalkyl radicals as defined above, e.g., cyclopropylmethyloxy, 2-cyclopropylethyloxy, and 1-,2-,3-cyclobutylpropoxy, etc.

[0066] "Carboxy" means -COOH.

[0067] "Carboxyalkyl" means a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms substituted with a carboxyl group as defined above, or a branched monovalent hydrocarbon radical of 3 to 6 carbons, e.g., 2-carboxyethyl, and 1-, 2-, or 3-carboxypropyl, etc.

[0068] "Dialkylamino" means -NRR' radicals in which R and R' are alkyls as defined above, e.g., dimethylamino, and methylethylamino, etc.

[0069] "Halo" means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.

[0070] "Haloalkyl" means an alkyl radical as defined above that is substituted with one or more halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, and -CF(CH3)2, etc. When the alkyl is substituted with a single fluoro, it may represent a fluoroalkyl in this application.

[0071] "Haloalkoxy" means that R is a -OR radical as defined above, e.g., -OCF3, and -OCHF2, etc. If R is a haloalkyl where the alkyl is only an alkyl substituted with a fluoro, it may represent a fluoroalkoxy in this application.

[0072] "Hydroxyalkyl" means a linear hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbons substituted with one or two hydroxyl groups, provided that if two hydroxyl groups are present, they are not both present on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

[0073] "Hydroxyalkyloxy" means -OR radicals in which R is a hydroxyalkyl as defined above, e.g., hydroxymethyloxy, 2-hydroxyethyloxy, and 1-, 2-, 3-hydroxypropoxy.

[0074] "Heterocycloalkyl" or "heterocyclile" refers to one, two, or three ring atoms that are N, O, or S(O) nIt refers to a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms, wherein n is an integer from 0 to 2 and the remaining ring atoms are C. Additionally, one or two ring carbon atoms within the heterocyclile ring may optionally be replaced by a -CO- group, and the heterocycloalkyl is optionally fused to a phenyl or 5- or 6-membered heteroaryl as defined above. More particularly, the term heterocyclile includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, and thiomophorno, etc. If the heterocyclile ring is unsaturated, it may contain one or two ring double bonds, provided that the ring is not aromatic. Where the heterocyclil group contains at least one nitrogen atom, it may also be referred to herein as heterocycloamino and is a subset of the heterocyclil group. Unless otherwise noted, the heterocycloalkyl alkyl is optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, and dialkylamino.

[0075] "Heterocycloalkyl" means -(alkylene)-R radicals in which R is a heterocycloalkyl ring as defined above, e.g., tetrahydrofuranylmethyl, piperazinylmethyl, and morpholionylethyl.

[0076] "Heterocycloamino" is a group in which one or two ring atoms are N, O, or S(O) nIt refers to a saturated or unsaturated monocyclic group of 4 to 8 ring atoms, wherein n is an integer from 0 to 2 and the remaining ring atoms are C, provided that, unless otherwise noted, at least one of the ring atoms is N. Additionally, one or two ring carbon atoms within the heterocycloamino ring may optionally be replaced by a -CO- group. The heterocycloamino is optionally fused to a phenyl or 5- or 6-membered heteroaryl as defined above. More specifically, the term heterocyclil includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopipperidinyl, morpholino, piperazino, and thiomophorpolino, etc. Unless otherwise noted, the heterocycloamino ring may optionally be substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, or aminoalkyl as defined herein.

[0077] "Heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, wherein, unless otherwise noted, one or more (in one embodiment, one, two, or three) ring atoms are heteroatoms selected from N, O, or S, and the remaining ring atoms are carbons. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, and tetrazolyl. The terms "heteroaryl" and "aryl" as defined herein are mutually exclusive. When a heteroaryl ring contains 5 or 6 ring atoms, it is also referred to herein as a 5- or 6-membered heteroaryl.

[0078] "Heteroaralkyl" means a -(alkylene)-R radical in which R is a heteroaryl as defined above, e.g., pyridinylmethyl, etc. If the heteroaryl ring within the heteroaralkyl contains a 5- or 6-ring atom, it is also referred to herein as a 5- or 6-membered heteroaralkyl.

[0079] "Patient" means a mammal, preferably a human.

[0080] The present disclosure also includes protected derivatives of compound (I) of the present disclosure. For example, if the compound of the present disclosure contains groups such as hydroxyl, carboxyl, thiol, or any group containing nitrogen atom(s), these groups may be protected by suitable protecting groups. A comprehensive list of suitable protecting groups is available in the literature [TW Greene, Protective Groups in Organic Synthesis It may be found in John Wiley & Sons, Inc. (1999), the entire contents of which are incorporated herein by reference. Protected derivatives of the chemical of the present disclosure can be prepared by methods well known in the art.

[0081] The present disclosure also includes polymorphic forms and deuteriumized forms of the compounds of the present disclosure or pharmaceutically acceptable salts thereof.

[0082] "Pharmaceuticalally acceptable salt" of a compound means a salt that is pharmaceutically acceptable and possesses the desirable pharmaceutical activity of the parent compound. Such a salt is,

[0083] Formed by inorganic acids, e.g., hydrochloric acid, hydrobromide, nitric acid, phosphoric acid, etc.; Organic acids, e.g., formic acid, acetic acid, propanoic acid, hexanoic acid, cyclopentanepropanoic acid, glycolic acid, pyruvate, laxic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropanoic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, Acid addition salts formed of gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylan, stearic acid, and muconic acid, etc.; or

[0084] It includes salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, alkaline earth ion, or aluminum ion; or coordinates with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, and N-methylglucarmine. Pharmaceutically acceptable salts are understood to be non-toxic. For further information on pharmaceutically acceptable salts, see the literature [ Remington's Pharmaceutical Sciences It can be found in , 17th ed., Mack Publishing Company, Easton, PA, 1985, the entire contents of which are incorporated herein by reference.

[0085] The compounds of the present disclosure may have asymmetric centers. Compounds of the present disclosure containing asymmetrically substituted atoms may be separated into optically active or ceramiform forms. For example, methods for producing optically active forms by separation of materials are well known in the art. Unless otherwise specifically indicated, all chiral, diastereomers, all mixtures of chiral or diastereomer forms, and racemic forms are within the scope of the present disclosure. Furthermore, when a compound is indicated as an (R) or (S) stereoisomer, it will be understood by those skilled in the art that it may contain the corresponding (S) or (R) stereoisomer as an impurity, preferably in an amount of about 10%, preferably less than 5% w / w, of an unwanted enantiomer. "About" means + or -10% of the initial value.

[0086] Certain compounds of the present disclosure may exist as tautomers and / or geometric isomers. As individual forms and mixtures thereof, all possible tautomers and cis and trans isomers are within the scope of the present disclosure. Additionally, the term alkyl as used herein includes all possible isomer forms of said alkyl group, although only a few examples are described. Similarly, when a cyclic group, e.g., aryl, heteroaryl, or heterocyclil, is substituted, additionally, all hydrates of the chemical compounds of the present disclosure are within the scope of the present disclosure.

[0087] "Oxo" or "carbonyl" means the =(O) group.

[0088] "Optionally substituted alkyl" means an alkyl as defined above optionally substituted with one, two, or three substituents independently selected from, for example, alkyl, hydroxyl, cycloalkyl, heterocycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfonyl, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, and cyano.

[0089] "Optionally substituted aryl" means an aryl as defined above that is optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfonyl, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, and cyano.

[0090] "Optionally substituted aryloxy" means -O-alkylene-R radicals in which R is an optionally substituted aryl as defined above, e.g., benzyloxy, methoxybenzyloxy, halobenzyloxy, and 2-phenethyloxy.

[0091] "Optionally substituted aralkyl" means -alkylene-R where R is an optionally substituted aryl as defined above. "Optionally substituted aralkyloxy" means -O-alkylene-R radical where R is an optionally substituted aryl as defined above, e.g., benzyloxy, methoxybenzyloxy, halobenzyloxy, and 2-phenethyloxy.

[0092] "Optionally substituted heteroaryl" means a heteroaryl as defined above optionally substituted with one, two, or three substituents independently selected from alkyl, alkylthio, alkylsulfonyl, hydroxyl, cycloalkyl, carboxycarbonyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and cyano.

[0093] "Optionally substituted heteroaryloxy" means -OR radicals in which R is an optionally substituted heteroaryl as defined above, e.g., pyridinyloxy, furanyloxy, and thienyloxy, etc.

[0094] "Optionally substituted heteroaralkyloxy" means an -O-alkylene-R radical where R is an optionally substituted heteroaryl as defined above.

[0095] "Optionally substituted heterocycloalkyl" means a heterocycloalkyl as defined above that is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylthio, alkylsulfonyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, halo, haloalkyl, haloalkoxy, and cyano.

[0096] "Optionally substituted heterocycloalkyl" means an -alkylene-R radical in which R is an optionally substituted heterocycloalkyl as defined above, e.g., piperidinylmethyl, pyrrolidinylethyl, and piperazine-1-ylethyl, etc.

[0097] "Optionally substituted heterocycloalkyloxy" means -OR radicals in which R is an optionally substituted heterocycloalkyl as defined above, e.g. piperidinyloxy, pyrrolidinyloxy, and tetrahydrofuranyloxy.

[0098] "Optionally substituted heterocycloalkylalkyloxy" means -O-alkylene-R radicals in which R is an optionally substituted heterocycloalkyl as defined above, e.g., piperidinylmethyloxy, pyrrolidinylethyloxy, and piperazine-1-ylethyloxy, etc.

[0099] "Optional" or "optional" means that the event or situation described in relation may occur but does not need to occur, and that the description includes examples where the event or situation occurs and examples where it does not occur. For example, "a heterocyclyl group arbitrarily substituted with an alkyl group" means that an alkyl may be present but does not need to be present, and that the description includes situations where the heterocyclyl group is substituted with an alkyl group and situations where the heterocyclyl group is not substituted with an alkyl group.

[0100] "Pharmaceuticalally acceptable carriers or excipients" generally means carriers or excipients that are safe, non-toxic, and useful for producing biologically or otherwise desirable pharmaceutical compositions, and include carriers or excipients that are acceptable for human pharmaceutical use as well as veterinary use. As used herein in the specification and claims, "pharmaceuticalally acceptable carriers / excipients" includes one or more of both of such excipients.

[0101] "Sulfonylamino" means a -NRSO2R' radical in which, as defined above, R is hydrogen or alkyl and R' is alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl.

[0102] "Treating" a disease or "treatment" of a disease is,

[0103] (1) Preventing disease, that is, preventing clinical symptoms of disease from occurring in mammals that may be exposed to or have a predisposition to disease but do not yet have disease or show symptoms of disease;

[0104] (2) Suppressing the disease, that is, suppressing or reducing the occurrence of the disease or its clinical symptoms;

[0105] (3) Alleviation of the disease, that is, inducing regression of the disease or its clinical symptoms.

[0106] "Therapeutic effective dose" means an amount of the compound of the present disclosure and / or a pharmaceutically acceptable salt thereof sufficient to perform such treatment of the disease when administered to a patient to treat the disease. The "therapeutic effective dose" may vary depending on the compound, the disease and its severity, and the age, body weight, etc., of the mammal to be treated.

[0107] Specific example:

[0108] Specific Example 1:

[0109] In Example 1, a compound of formula (I) as defined in the content of the invention.

[0110] Specific Example 2:

[0111] In Example 2, the compound of formula (I) has structure (IA):

[0112]

[0113] In the above equation, Het, R 1 , R 2 , R 3 , R 4 , R 5 , and n are as defined in the content of the invention.

[0114] Specific Example 3:

[0115] In Example 3, the compound of formula (I) has structure (IB):

[0116]

[0117] In the above equation, Het, R 1 , R 2 , R 3 , R 4 , R 5 , and n are as defined in the content of the invention.

[0118] Specific Example 4:

[0119] In Example 4, the compound of any one of Examples 1, 2 and 3 is one in which n is 1, 2, or 3.

[0120] Specific Example 5:

[0121] In Example 5, the compounds of any one of Examples 1, 2, 3 and 4 are those in which n is 1.

[0122] Specific Example 6:

[0123] In Example 6, the compounds of any one of Examples 1, 2, and 3 are those in which n is 0 or 1. In one subembodiment of Example 6, the compounds of any one of Examples 1, 2, and 3 are those in which n is 0. In the second subembodiment of Example 6, the compounds of any one of Examples 1, 2, and 3 are those in which n is 2.

[0124] Specific Example 7:

[0125] In Example 7, the compound of any one of Examples 1 to 6 and the sub-examples contained therein is R 4 ga is hydrogen or an alkyl group, R 5 -C(O)R 6 and R 6 R is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, and aryl or heteroaryl is independently selected from alkyl, alkoxy, aminoalkoxy, hydroxyalkoxy, alkoxyalkoxy, cycloalkyloxy, cycloalkylalkyloxy, optionally substituted aryloxy, optionally substituted aralkyloxy, optionally substituted heteroaryloxy, optionally substituted heteroaralkyloxy, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylalkyloxy, optionally substituted heterocycloalkylalkyloxy, halo, haloalkyl, haloalkoxy, cyano, nitro, hydroxy, carboxyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, acylamino, and sulfonylamino, either as itself or as part of aralkyl or heteroaralkyl. g , R h , and / or R iThese are those that are arbitrarily substituted with. In one sub-specification of Example 7, the compound of any one of Examples 1 to 6 is R 6 R as defined above (wherein "above" means Example 7). g , R h , and / or R i These are aryl or heteroaryls optionally substituted with (e.g., thienyl, furanyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, indolyl, or indazolyl). In the second sub-specification of Example 7, the compound of any one of Examples 1 to 6 is R 6 R as defined above g , R h , and / or R i They are aralkyl or heteroaralkyl alkyls optionally substituted with . In the third sub-specification of Example 7, the compound of any one of Examples 1 to 6 is R 6 R as defined above g , R h , and / or R i They are phenyls optionally substituted with R. In the fourth sub-specification of Example 7, the compound of any one of Examples 1 to 6 is R 6 R as defined above g , R h , and / or R i These are heteroaryls optionally substituted with (e.g., thienyl, furanyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, indolyl, or indazolyl). In the fifth sub-specification of Example 7, the compound of any one of Examples 1 to 6 and the compounds in Sub-specifications 1 to 4 within Example 7 are R g ga is alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, or cyano, and R h and R iThese are independently selected from alkyl, alkoxy, aminoalkoxy, hydroxyalkoxy, alkoxyalkoxy, cycloalkyloxy, cycloalkylalkyloxy, optionally substituted aralkyloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkylalkyloxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, acylamino, and sulfonylamino. In the sixth sub-specification of Example 7, the compound of any one of Examples 1 to 6 and the compound in Sub-specifications 1 to 5 within Example 7 are R g , R h and / or R i The compounds are independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, acylamino, preferably methyl, ethyl, methoxy, ethoxy, chloro, fluoro, trifluoromethyl, trifluoromethoxy, hydroxy, acetylamino, butanoylamino, and pentanoyamino.

[0126] Specific Example 8:

[0127] In Example 8, the compound of any one of Examples 1 to 6 and the sub-specifications contained therein is R 4 and R 5 These are those that form a 5 to 7-membered heterocycloamino ring together with the nitrogen atoms to which they are bonded. In one sub-specification of Example 8, the heterocycloamino ring is pyrrolidino, piperidino, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, thiomophorpolino, isoindolinyl, or 1,3-dioxoisoindolin-2-yl, optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxyl, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl.

[0128] Specific Example 9:

[0129] In Example 9, the compound of any one of Examples 1 to 8 and the sub-examples contained therein is R 1 and R 2 These are independently hydrogen or methyl, preferably hydrogen.

[0130] Specific Example 10:

[0131] In Example 10, the compound of any one of Examples 1 to 9 and the sub-examples contained therein is R 1 and R 2 Both of them are alkyls, and they are not bonded to the same ring carbon.

[0132] Specific Example 11:

[0133] In Example 11, the compound of any one of Examples 1 to 10 and the sub-examples contained therein is Het which is pyridinyl, pyrimidinyl, pyrazinyl, furanyl, thienyl, quinolinyl, isoquinolinyl, pyrazolyl, or indolyl, and each ring is R independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, dialkylamino, carboxy, and alkoxycarbonyl. a , R b , and / or R c R; preferably, independently selected from methyl, ethyl, methoxy, ethoxy, chloro, fluoro, trifluoromethyl, trifluoromethoxy, cyano, amino, methylamino, and dimethylamino. a , R b , and / or R c These are things that are arbitrarily substituted. In one sub-specific example, Het is pyridine-2-yl.

[0134] Specific Example 12:

[0135] In Example 12, the compound of any one of Examples 1 to 11 and the sub-examples contained therein is R 3This is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, acylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein R is independently selected from alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, cyano, nitro, carboxy, alkoxycarbonyl, amino, alkylamino, or dialkylamino, either itself or from aralkyl and heteroaralkyl. d , R e , and / or R f These are those that are arbitrarily substituted with. In one sub-specification of Example 12, the compound of any one of Examples 1 to 11 is R 3 This is hydrogen or alkyl, preferably methyl, ethyl, propyl, isopropyl, secondary-propyl, n-, secondary, iso, or tertiary-butyl.

[0136] In the second sub-specification of Example 12, the compound of any one of Examples 1 to 11 is R 3 R as defined above d , R e , and / or R f It is an aralkyl optionally substituted with , preferably R 3 This benzyl or phenethyl, more preferably R as defined above d , R e , and / or R f These are benzyl arbitrarily substituted with benzyl, more preferably benzyl.

[0137] In the third sub-specification of Example 12, the compound of any one of Examples 1 to 11 is R 3 R as defined above d , R e , and / or R f A cycloalkylalkyl optionally substituted with , preferably R as defined above. d, R e , and / or R f These are cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl that are arbitrarily substituted.

[0138] In the fourth sub-specification of Example 12, the compound of any one of Examples 1 to 11 is R 3 R as defined above d , R e , and / or R f These are heteroaralkyls (e.g., thienylmethyl, furanylmethyl, pyridinylmethyl, quinolinylmethyl, isoquinolinylmethyl, indolylmethyl, or indazolylmethyl) arbitrarily substituted with .

[0139] In the fifth sub-specification of Example 12, the compound of any one of Examples 1 to 11 is R 3 These are hydroxyalkyl, alkoxyalkyl, or aminoalkyl, preferably hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, aminomethyl, or aminobutyl.

[0140] In one specific example, R 3 The stereochemistry at this bonding carbon is (S).

[0141] In another specific example, R 3 The stereochemistry at this bonded carbon is (R).

[0142] R 1 and R 2 Representative compounds of chemical formula (I), where α is H, n is 1, and other groups are as shown in Table 1 below, are as follows:

[0143] Table 1

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151] Compounds additionally considered for chemical formula (I) are provided in Table 2 below:

[0152] Table 2

[0153]

[0154]

[0155]

[0156] General composite diagram

[0157] The compounds of the present disclosure can be prepared by the method illustrated in the reaction schematic described below.

[0158] The starting materials and reagents used to prepare these compounds are available for purchase from commercial sources, e.g., Aldrich Chemical Co. (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.), or from references, e.g., Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); The compounds are prepared by methods known to those skilled in the art, in accordance with the following procedures described in Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schematics merely illustrate some of the methods by which the compounds of the present disclosure may be synthesized, and various modifications to these schematics may be made and will be suggested to those skilled in the art who read these disclosures. The starting materials and intermediates of the reaction, and the final products, may be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, and chromatography, if required. Such materials may be characterized using conventional means, including physical constants and spectral data.Unless otherwise specified, the reactions described herein are carried out under atmospheric pressure in a temperature range of about -78°C to about 150°C, e.g., about 0°C to about 125°C, and additionally, e.g., at approximately room temperature (or ambient temperature), e.g., about 20°C.

[0159] R 1 , R 2 , R 3 , Het as defined in the content of this invention, and R 4 ga is hydrogen or alkyl, and R 5 a -COR 6 and R 6 Compounds of chemical formulas (IA) and (IB) as defined in the content of this invention can be prepared as described in Schematic 1 below.

[0160] Diagram 1

[0161]

[0162] R prepared as described in Schematic 2 below using an aqueous hydrazine solution 4 and R 5 Treatment of a compound (I') that forms a phthalimido ring with a nitrogen atom yields an amino compound of Formula 1. The reaction can be carried out in an alcohol solvent, such as methanol, ethanol, or isopropyl alcohol.

[0163] At room temperature in the presence of an organic solvent, e.g., dichloromethane, and a coupling agent, e.g., HOBt and EDC, etc., in chloroform, and a non-nucleophilic base, e.g., triethylamine, diisopropylamine, and i-Pr2NEt, R 6 The coupling of a compound of Formula 1 with an acid of Formula 2 as defined in the content of this invention provides compound (I).

[0164] Alternatively, the compound of formula (I) is, under acylation reaction conditions, an LG-halo, preferably a chloro-based formula R 6It can be prepared by the reaction of CO(LG) with the acetyl of the compound of Chemical Formula 1.

[0165] The compounds of Formula 2 may be commercially available, or they may be prepared from readily available starting materials by methods well known in the art. For example, benzoic acid, o-, m-, and p-nitrobenzoic acid, phenylacetic acid, trifluorobenzoic acid, picolinic acid, nicotinic acid, methoxybenzoic acid, fluorobenzoic acid, chlorobenzoic acid, hydroxybenzoic acid, 3-fluoro-5-methoxybenzoic acid, 3-aminobenzoic acid, acetic acid, propanoic acid, cyclopropanecarboxylic acid, and cyclopentanecarboxylic acid are commercially available. The compounds of Formula 2 may also be prepared from commercially available compounds. For example, R 6 The compound of Formula 2, which is a hydroxyl-substituted aryl, aralkyl, heteroaryl, or heteroaralkyl, reacts under alkylation reaction conditions with an optionally substituted aralkyl halide, an optionally substituted heterocycloalkyl halide, and an optionally substituted heterocycloalkylalkyl halide, so that R 6 This can produce corresponding compounds of Formula 2 that are each substituted with an optionally substituted aralkyloxy, an optionally substituted heterocycloalkyloxy, and an optionally substituted heterocycloalkylalkyloxy. Similarly, R 6 The compound of Formula 2 substituted with this amino group reacts with an acid halide or a sulfonyl halide under acylation and sulfonylation reaction conditions, R 6 Each of these can produce a corresponding compound of Formula 2 substituted with an acylamino or sulfonylamino group.

[0166] Alternatively, the above variation is also R 6 This can be done for compounds of formula (I'') or (I''') which are aryl, aralkyl, heteroaryl, or heteroaralkyl substituted with a hydroxyl or amino group.

[0167] Dashed line, R1 , R 2 , R 3 , Het is as defined in the description of the invention, and R 4 and R 5 Compounds of chemical formulas (IA) and (IB) that form a phthalimido ring together with the nitrogen atoms to which they are bonded can be prepared as described in Schematic 2 below.

[0168] Diagram 2

[0169]

[0170] R 3 The compound of Formula 4 as defined in the content of this invention is, under basic conditions at elevated temperatures (see J.C. Sheehan, D.W. Chapman, and RW. Roth, J. Am. Chem. Soc. , 74, 3822 (1952)), or acidic conditions (see R. Mahboub, int. J. Chem. Sci, Under 7(1), 2009, 28-36), the compound of Formula 3 can be prepared by reacting it with phthalic anhydride. When basic conditions are used, the reaction is carried out in an aromatic organic solvent, e.g., benzene and toluene, in the presence of an organic base, e.g., Et3N and iPr2Net. The compound of Formula 3 is commercially available or can be easily prepared by methods known in the art.

[0171] Compound (I) can be prepared by adding a solution of the compound of Formula 6 together with the acid chloride of Formula 5 under acylation reaction conditions. Suitable solvents include aromatic or halogenated organic solvents, such as benzene, toluene, or DCM in their anhydrous forms.

[0172] The compound of Formula 5 can be prepared by reacting the compound of Formula 4 with a chlorinating agent, such as SOCl2, (COCl)2, or PCl5, under conditions well known in the art. The compounds of Formula 6, such as (R)-2-(piperidin-2-yl)pyridine and S-2-(piperidin-2-yl)pyridine, are commercially available or can be prepared by methods well known in the art.

[0173] Dashed line, R 1 , R 2 , R 3 , Het is as defined in the description of the invention, and R 4 and R 5 Compounds of chemical formulas (IA) and (IB) that form pyrrolidinyl, piperidinyl, or homopiperidinyl together with the nitrogen atoms to which they are bonded can be prepared as described in Schematic 3 below.

[0174] Diagram 3

[0175]

[0176] After protecting the amino group in the compound of Formula 1 with a suitable amino protecting group, e.g., Boc, benzyl, or Ns, treatment of the resulting compound of Formula 7 with a compound of Formula 8, in which each X is a leaving group, e.g., halo (e.g., chloro or bromo), tosylate, or mesylate, and m is 0 to 2, provides the compound of Formula 9. The reaction is carried out in the presence of NaH in THF. After removing the amino protecting group, crystallization of the resulting amine in the presence of a base, e.g., potassium hydroxide or sodium hydroxide, in a suitable organic solvent, e.g., dichloromethane, provides the compound of Formula (I).

[0177] Proceed as described above, but by replacing compound 8 with other starting materials, e.g., bis(2-chloroethyl)amine, oxybis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate), (Z)-1,4-dichlorobut-2-ene, 2-(bromomethyl)benzoic acid, 2-(2-bromoethyl)benzoic acid, 2-(bromomethyl)-5-methoxybenzoic acid, and 2-(bromomethyl)-4-fluorobenzoic acid, NR 4 R 5 It will be recognized by a person skilled in the art that a compound of formula (I) forming a different heterocycloamino ring can be synthesized.

[0178] Administration and pharmaceutical composition

[0179] Generally, the compounds of the present disclosure may be administered at a therapeutically effective dose by any of the acceptable modes of administration for agents providing similar availability. The therapeutically effective dose of the compounds of the present disclosure may be in the range of about 0.01 to about 500 mg per kg of patient body weight per day, which may be administered as a single or multiple doses. Suitable dose levels may be about 0.1 to about 250 mg / kg per day; or about 0.5 to about 100 mg / kg per day. Suitable dose levels may be about 0.01 to about 250 mg / kg per day, about 0.05 to about 100 mg / kg per day, or about 0.1 to about 50 mg / kg per day. Within these ranges, the dose may be about 0.05 to about 0.5, about 0.5 to about 5, or about 5 to about 50 mg / kg per day. In the case of oral administration, the composition may be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, in particular about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The substantial amount of the compound of the present disclosure, i.e., the active ingredient, will depend on many factors, e.g., the severity of the disease being treated, the age and relative health of the patient, the efficacy of the compound used, the route and form of administration, and other factors.

[0180] Generally, the compounds of the present disclosure may be administered as a pharmaceutical composition by any one of the following routes: oral, systemic (e.g., transdermal, intranasal, or suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous). A preferred mode of administration is oral administration using a standard daily dosage regimen that may be adjusted according to the degree of pain. The composition may be in the form of tablets, pills, capsules, semi-solids, powders, sustained-release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition.

[0181] The selection of a formulation depends on various factors, such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules, including enteric-coated or delayed-release tablets, pills, or capsules, are preferred) and the bioavailability of the drug. Recently, pharmaceutical formulations have been developed, particularly for drugs exhibiting poor bioavailability, based on the principle that bioavailability can be increased by increasing the surface area, that is, by reducing the particle size. For example, U.S. Patent No. 4,107,288 describes a pharmaceutical formulation having particles in the size range of 10 to 1,000 nm in which an active substance is supported on a cross-linked matrix of a macromolecule. U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which a drug is pulverized into nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to produce a pharmaceutical formulation exhibiting remarkably high bioavailability.

[0182] The composition generally consists of the compound of the present disclosure in combination with at least one pharmaceutically acceptable excipient. The acceptable excipient is a non-toxic dosing adjuvant and does not adversely affect the therapeutic benefit of the compound of the present disclosure. Such excipient may be any solid, liquid, or semi-solid, or, in the case of an aerosol composition, a gaseous excipient generally available to a person skilled in the art.

[0183] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, magnesium stearate, glycerol monostearate, sodium chloride, and dried skim milk, etc. Liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol, and petroleum, or various oils including those of animal, vegetable, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. In particular, preferred liquid carriers for injectable solutions include water, brine, aqueous dextrose, and glycol.

[0184] The compounds of the present disclosure can be dispersed in aerosol form using a compressed gas. Inert gases suitable for this purpose include nitrogen, carbon dioxide, etc.

[0185] Other suitable pharmaceutical excipients and their formulations are described in the literature [Remington's Pharmaceutical Sciences, edited by EW Martin (Mack Publishing Company, 20th ed., 2000)].

[0186] The levels of the compound within the formulation may vary within the full range used by a person skilled in the art. Typically, the formulation will contain, on a weight percentage basis (weight%), about 0.01 to 99.99 weight percent of the compound of the present disclosure based on the total formulation, and the remainder is one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1 to 80 weight percent.

[0187] The compound of the present disclosure may be used in combination with one or more other drugs in the treatment of a disease or condition for which the compound of the present disclosure or other drugs may be useful. Such other drug(s) may be administered simultaneously or sequentially with the compound of the present disclosure by a commonly used route and in such amounts. When the compound of the present disclosure is used simultaneously with one or more other drugs, a pharmaceutical composition in the form of a unit dose containing such other drugs and the compound of the present disclosure is preferred. However, combination therapy may also include a regimen in which the compound of the present disclosure and one or more other drugs are administered on different overlapping schedules. Additionally, when used in combination with one or more other active ingredients, the compound of the present disclosure and the other active ingredients may be used at lower doses than when each is used alone.

[0188] Examples

[0189] The following methods of preparing the compound of formula (I) are provided to enable a person skilled in the art to more clearly understand and practice the present disclosure. These should not be construed as limiting the scope of the present disclosure, but merely as illustrative or representative methods of preparation.

[0190] Synthesis Examples

[0191] Example 1

[0192] Synthesis of 2-((2S)-1-oxo-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)isoindolin-1,3-dione (Compound 1)

[0193]

[0194] Step 1

[0195] L-alanine (17.9 g, 0.2 mole), phthalic anhydride (29.6 g, 0.2 mole), toluene (300 mL), and Et3N (2.6 mL) were filled in this order into a 1-neck round-bottom flask (1 L) equipped with a condenser and a Dean-Stark apparatus. The resulting mixture was refluxed for 16 hours until no more H2O was produced. H2O (300 mL) was added to the cooled solution, and the layers were separated. The organic layer was further washed with brine, dried, and concentrated. The unrefined material was crystallized from EtOAc / hexane (80 mL / 200 mL) to obtain (S)-2-(1,3-dioxoisoindoline-2-yl)propanoic acid (34.5 g, 79%) as a white solid.

[0196] Step 2

[0197] Oxalyl chloride (1.7 mL, 20 mmol) was added dropwise to a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (2.3 g, 10 mmol) in a mixture of hexane / benzene (20 mL / 20 mL), followed by the addition of DMF (0.01 mL). After 4 hours, all volatile substances were completely removed using a rotary evaporator. The resulting (S)-2-(1,3-dioxoisoindolin-2-yl)propanoyl chloride as an unpurified substance was used in the next step without further purification.

[0198] Step 3

[0199] (+ / -)-anatabin (1.4 g, 9 mmol) and Et3N (1.7 mL, 12 mmol) were added to a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)propanoyl chloride (~10 mmol) in anhydrous DCM (60 mL). The resulting solution was stirred at room temperature for 20 hours and quenched with H2O (60 mL). The layers were separated, and the aqueous layer was extracted with DCM (60 mL x 3). The combined organic layer was washed with 2N HCl, saturated NaHCO3, and brine, dried, and concentrated. Flash chromatography using a normal phase column (hexane / EtOAc = 50 / 50) produced the title compound (1.0 g, 31%) as white foam. MS (ESI, pos. ion) m / z: 362.1 (M+1).

[0200] Example 2

[0201] Synthesis of 2-((S)-1-oxo-1-((S)-6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)isoindolin-1,3-dione (Compound 2)

[0202]

[0203] (+ / -)-anatabin (3.0 g, 19 mmol) was slowly added to a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)propanoyl chloride (4.5 g, 20 mmol) in anhydrous benzene (120 mL). The resulting solution was stirred at room temperature for 20 hours and quenched with saturated NaHCO3 (100 mL). The layers were separated, the benzene layer was washed with brine, dried, and concentrated. Unpurified substance 2-((2S)-1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propane-2-yl)isoindolin-1,3-dione (4.7 g, 68%) was prepared into two diastereomers: (A) 2-((S)-1-oxo-1-((S)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propane-2-yl)isoindolin-1,3-dione; (B) A mixture of 2-((S)-1-oxo-1-((R)-6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)isoindolin-1,3-dione was obtained as a pale yellow foam and separated using CombiFlash® with an HP C18 Aq GOLD column with MeCN / buffered H2O as the elution mobile phase. Designation was based on hydrolysis experiments. Diastereomer A produces S-anatabin, and distereomer B produces R-anatabin.

[0204] Example 3

[0205] Synthesis of 2-((S)-3-methyl-1-oxo-1-((S)-6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)butane-2-yl)isoindolin-1,3-dione (Compound 3) and 2-((S)-3-methyl-1-oxo-1-((R)-6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)butane-2-yl)isoindolin-1,3-dione (Compound 4)

[0206]

[0207] Step 1

[0208] L-valine (23.4 g, 0.2 mole), phthalic anhydride (29.6 g, 0.2 mole), toluene (300 mL), and Et3N (2.6 mL) were filled in this order into a 1-neck round-bottom flask (1 L) equipped with a condenser and a Dean-Stark apparatus. The resulting mixture was refluxed for 16 hours until no more H2O was produced. H2O (300 mL) was added to the cooled solution, and the layers were separated. The organic layer was further washed with brine, dried, and concentrated. The unrefined material was crystallized from EtOAc / hexane (80 mL / 200 mL) to obtain (S)-2-(1,3-dioxoisoindolin-2-yl)-3-methylbutanoic acid (39.0 g, 80%) as a white solid.

[0209] Step 2

[0210] Oxalyl chloride (3.5 mL, 40 mmol) was added dropwise to a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-methylbutanoic acid (5.0 g, 20 mmol) in a mixture of hexane / benzene (40 mL / 40 mL), followed by the addition of DMF (0.02 mL). After 4 hours, all volatile matter was completely removed using a rotary evaporator. The resulting (S)-2-(1,3-dioxoisoindolin-2-yl)-3-methylbutanoyl chloride as an unpurified substance was used in the next step without further purification.

[0211] Step 3

[0212] (+ / -)-anatabin (3.0 g, 19 mmol) was slowly added to a solution of ((S)-2-(1,3-dioxoisoindolin-2-yl)-3-methylbutanoyl chloride (20 mmol) in anhydrous benzene (120 mL). The resulting solution was stirred at room temperature for 20 hours and quenched with saturated NaHCO3 (100 mL). The layers were separated, the benzene layer was washed with brine, dried, and concentrated. The unrefined material was purified by CombiFlash® using an HP C18 Aq GOLD column with MeCN / buffered H2O as the elution mobile phase. (A): First peak, 2-((S)-3-methyl-1-oxo-1-((S)-6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)butane-2-yl)isoindolin-1,3-dione (1.2 g, 15%), white foam. MS (ESI, pos. ion) m / z: 390.1 (M+1); (B): Second peak, 2-((S)-3-methyl-1-oxo-1-((R)-6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)butane-2-yl)isoindolin-1,3-dione (1.0 g, 12%), white foam. MS (ESI, pos. ion) m / z: 390.1 (M+1).

[0213] Example 4

[0214] A mixture of 2-((S)-1-oxo-1-((S)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)butane-2-yl)isoindolin-1,3-dione and 2-((R)-1-oxo-1-((R)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)butane-2-yl)isoindolin-1,3-dione (Compound 5) and 2-((S)-1-oxo-1-((R)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)butane-2-yl)isoindolin-1,3-dione and Synthesis of a mixture of 2-((R)-1-oxo-1-((S)-6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)butane-2-yl)isoindolin-1,3-dione (Compound 6)

[0215]

[0216] Step 1

[0217] DL-2-aminobutanoic acid (3.5 g, 34 mmol), phthalic anhydride (5.0 g, 33.8 mmol), and glacial acetic acid (75 mL) were filled in that order into a 1-neck round-bottom flask (200 mL) equipped with a condenser. The resulting mixture was refluxed for 6 hours. The solvent was completely removed under vacuum to obtain 2-(1,3-dioxoisoindoline-2-yl)butanoic acid (7.3 g, 92%) as a clear oil.

[0218] Step 2

[0219] Oxalyl chloride (5.1 mL, 58.6 mmol) was added dropwise to a solution of 2-(1,3-dioxoisoindolin-2-yl)butanoic acid (7.0 g, 29.3 mmol) in a mixture of hexane / benzene (100 mL / 100 mL), followed by the addition of DMF (0.02 mL). After 4 hours, all volatile substances were completely removed using a rotary evaporator. The resulting 2-(1,3-dioxoisoindolin-2-yl)butanoyl chloride as an unpurified substance was used in the next step without further purification.

[0220] Step 3

[0221] (+ / -)-anatabin (4.2 g, 27 mmol) was slowly added to a solution of 2-(1,3-dioxoisoindolin-2-yl)butanoyl chloride (29 mmol) in anhydrous benzene (120 mL). The resulting solution was stirred at room temperature for 20 hours and quenched with saturated NaHCO3 (100 mL). The layers were separated, the benzene layer was washed with brine, dried, and concentrated to obtain 2-(1-oxo-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)butane-2-yl)isoindolin-1,3-dione as an unpurified substance (5.5 g, 54%). Racemic diastereomers were separated by CombiFlash® using an HP C18 Aq GOLD column with MeCN / buffered H2O as the elution mobile phase. (A): Peak 1, 2-((S)-1-oxo-1-((S)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)butane-2-yl)isoindolin-1,3-dione and 2-((R)-1-oxo-1-((R)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)butane-2-yl)isoindolin-1,3-dione, white foam. MS (ESI, pos. ion) m / z: 376.1 (M+1); (B): Second peak, 2-((S)-1-oxo-1-((R)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)butane-2-yl)isoindolin-1,3-dione and 2-((R)-1-oxo-1-((S)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)butane-2-yl)isoindolin-1,3-dione, white foam. MS (ESI, pos. ion) m / z: 376.1 (M+1).

[0222] Example 5

[0223] Synthesis of 2-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)isoindolin-1,3-dione (Compound 7)

[0224]

[0225] Step 1

[0226] DL-phenylalanine (5.6 g, 34 mmol), phthalic anhydride (5.0 g, 33.8 mmol), and glacial acetic acid (100 mL) were filled in that order into a 1-neck round-bottom flask (200 mL) equipped with a condenser. The resulting mixture was refluxed for 6 hours. The solvent was completely removed under vacuum, and the residue was precipitated from a mixture of ethyl acetate and hexane to obtain 2-(1,3-dioxoisoindoline-2-yl)-3-phenylpropanoic acid (7.0 g, 70%) as a white solid.

[0227] Step 2

[0228] Oxalyl chloride (3.5 mL, 40.2 mmol) was added dropwise to a solution of 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid (5.0 g, 16.9 mmol) in a mixture of hexane / benzene (100 mL / 100 mL), followed by the addition of DMF (0.02 mL). After 4 hours, all volatile substances were completely removed using a rotary evaporator. The resulting 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride, as an unpurified substance, was used in the next step without further purification.

[0229] Step 3

[0230] (+ / -)-anatabin (2.4 g, 15.7 mmol) was slowly added to a solution of 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride (16.9 mmol) in anhydrous benzene (100 mL). The resulting solution was stirred at room temperature for 20 hours and quenched with saturated NaHCO3 (100 mL). The layers were separated, the benzene layer was washed with brine, dried, and concentrated. After purification by CombiFlash® using an HP C18 Aq GOLD column with MeCN / buffered H2O as the elution mobile phase, 2-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)isoindolin-1,3-dione (4.5 g, 65%) was obtained as a white foam as a mixture of two diastereomers. MS (ESI, pos. ion) m / z: 438.1 (M+1).

[0231] Example 6

[0232] Synthesis of 2-(2-oxo-2-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)ethyl)isoindolin-1,3-dione (Compound 8)

[0233]

[0234] Step 1

[0235] Glycine (5.1 g, 68 mmol), phthalic anhydride (10.0 g, 67.5 mmol), and glacial acetic acid (120 mL) were filled in that order into a 1-neck round-bottom flask (200 mL) equipped with a condenser. The resulting mixture was refluxed for 6 hours. The solvent was completely removed under vacuum, and the residue was precipitated from the mixture of ethyl acetate and hexane to obtain 2-(1,3-dioxoisoindolin-2-yl)acetic acid (10.8 g, 80%) as a white solid.

[0236] Step 2

[0237] Oxalyl chloride (3.5 mL, 40 mmol) was added dropwise to a solution of 2-(1,3-dioxoisoindolin-2-yl)acetic acid (4.1 g, 20 mmol) in a mixture of hexane / benzene (40 mL / 40 mL), followed by the addition of DMF (0.02 mL). After 4 hours, all volatile substances were completely removed using a rotary evaporator. The resulting 2-(1,3-dioxoisoindolin-2-yl)acetyl chloride as an unrefined substance was used in the next step without further purification.

[0238] Step 3

[0239] (+ / -)-anatabin (2.9 g, 19.0 mmol) was slowly added to a solution of 2-(1,3-dioxoisoindolin-2-yl)acetyl chloride (20 mmol) in anhydrous benzene (120 mL). The resulting solution was stirred at room temperature for 20 hours and quenched with saturated NaHCO3 (100 mL). The layers were separated, the benzene layer was washed with brine, dried, and concentrated. After purification by CombiFlash® using an HP C18 Aq GOLD column with MeCN / buffered H2O as the elution mobile phase, 2-(2-oxo-2-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)ethyl)isoindolin-1,3-dione (3.8 g, 58%) was obtained as white foam. MS (ESI, pos. ion) m / z: 348.1 (M+1).

[0240] Example 7

[0241] Synthesis of 2-((2R)-1-oxo-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)isoindolin-1,3-dione (Compound 17)

[0242]

[0243] Step 1

[0244] D-alanine (5.0 g, 56.2 mmol), phthalic anhydride (18.2 g, 56.2 mmol), and glacial acetic acid (100 mL) were filled in that order into a 1-neck round-bottom flask (200 mL) equipped with a condenser. The resulting mixture was refluxed for 3 hours. The solvent was completely removed under vacuum, and the residue was precipitated from a mixture of ethyl acetate and hexane to obtain (R)-2-(1,3-dioxoisoindoline-2-yl)propanoic acid (8.0 g, 64%) as a white solid.

[0245] Step 2

[0246] PCl5 (7.6 g, 36.5 mmol) was added in portions to a solution of (R)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (7.5 g, 33.3 mmol) in anhydrous DCM (120 mL). The resulting reaction mixture was stirred at room temperature for 3 hours. All volatile products were completely removed using a rotary evaporator. The residue (R)-2-(1,3-dioxoisoindolin-2-yl)propanoyl chloride, which was a clear oil, was used in the next step without further purification.

[0247] Step 3

[0248] (+ / -)-anatabin (5.3 g, 34.7 mmol) was slowly added to a solution of (R)-2-(1,3-dioxoisoindolin-2-yl)propanoyl chloride (33 mmol) in anhydrous benzene (120 mL). The resulting solution was stirred at room temperature for 20 hours and quenched with saturated NaHCO3 (100 mL). The layers were separated, the benzene layer was washed with brine, dried, and concentrated to obtain 2-((2R)-1-oxo-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)isoindolin-1,3-dione (9.7 g, 81%) as foam, as a mixture of two diastereomers. MS (ESI, pos. ion) m / z: 362.1 (M+1).

[0249] Example 8

[0250] Synthesis of 3-nitro-N-((2S)-(1-oxo-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (Compound 9)

[0251]

[0252] Step 1

[0253] PCl5 (11.4 g, 55 mmol) was added in small amounts to a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (11.2 g, 50.0 mmol) in anhydrous DCM (150 mL). The resulting reaction mixture was stirred at room temperature for 5 hours. All volatile products were completely removed using a rotary evaporator. The residue (S)-2-(1,3-dioxoisoindolin-2-yl)propanoyl chloride, which was a clear oil, was used in the next step without further purification.

[0254] Step 2

[0255] (+ / -)-anatabin (7.6 g, 50 mmol) was slowly added to a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)propanoyl chloride (~50 mmol) in anhydrous benzene (120 mL). The resulting solution was stirred at room temperature for 20 hours and quenched with saturated NaHCO3 (100 mL). The layers were separated, the benzene layer was washed with brine, dried, and concentrated to obtain (S)-2-(1-oxo-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)isoindolin-1,3-dione (13.5 g, 74%) as an unpurified substance, as a mixture of two diastereomers. MS (ESI, pos. ion) m / z: 362.4 (M+1).

[0256] Step 3

[0257] Hydrazine monohydrate (3.6 mL) was added to a solution of (S)-2-(1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindolin-1,3-dione (13.5 g, 37 mmol) in EtOH (200 mL). The reaction solution was refluxed for 2 hours, and the resulting suspension was filtered at room temperature. The filtrate was concentrated to obtain (S)-2-amino-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-1-one (9.0 g, 77% from step 2) as an unpurified substance, as a mixture of two diastereomers.

[0258] Step 4

[0259] EDC hydrochloride (0.72 g, 3.8 mmol) and i-Pr2NEt (0.70 mL, 3.9 mmol) in DCM (10 mL) were added to a solution of 3-nitrobenzoic acid (0.50 g, 3.0 mmol) and (S)-2-amino-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-1-one (0.7 g, 3.0 mmol). The reaction mixture was stirred overnight at room temperature and quenched with H2O (10 mL). The layers were separated, the organic layer was washed with brine, dried, and concentrated to obtain 3-nitro-N-(1-oxo-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.2 g, 17%) as a film in a flask existing as a mixture of two diastereomers. MS (ESI, pos. ion) m / z: 381.3 (M+1).

[0260] The compounds of Examples 9 to 13 were prepared through a process similar to Example 8, starting with the corresponding benzoic acid.

[0261] Example 9: 3-methoxy-N-((2S)-1-oxo-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.5 g, 46%). (Compound 10)

[0262]

[0263] MS (ESI, pos. ion) m / z: 366.1 (M+1).

[0264] Example 10: 3,4-diethoxy-N-((2S)-1-oxo-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.6 g, 47%). (Compound 11)

[0265]

[0266] MS (ESI, pos. ion) m / z: 424.2 (M+1).

[0267] Example 11: 3,4-dimethoxy-N-((2S)-1-oxo-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.7 g, 59%). (Compound 12)

[0268]

[0269] MS (ESI, pos. ion) m / z: 396.1 (M+1).

[0270] Example 12: 4-nitro-N-((2S)-1-oxo-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.1 g, 8%), which was crystallized from MeCN. (Compound 13)

[0271]

[0272] MS (ESI, pos. ion) m / z: 381.1 (M+1).

[0273] Example 13. 4-chloro-N-((2S)-1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propane-2-yl)benzamide (150 mg, 13%), which was crystallized from MeCN. (Compound 14)

[0274]

[0275] MS (ESI, pos. ion) m / z: 370.1 (M+1).

[0276] Example 14

[0277] Synthesis of 3-nitro-N-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (Compound 15)

[0278]

[0279] Step 1

[0280] DL-phenylalanine (11.2 g, 68 mmol), phthalic anhydride (10.0 g, 67.6 mmol), and glacial acetic acid (200 mL) were filled in that order into a 1-neck round-bottom flask (200 mL) equipped with a condenser. The resulting mixture was refluxed for 2 hours. The solvent was completely removed under vacuum, and the residue was precipitated from a mixture of ethyl acetate and hexane to obtain 2-(1,3-dioxoisoindoline-2-yl)-3-phenylpropanoic acid (18.1 g, 90%) as a white solid.

[0281] Step 2

[0282] PCl5 (15.3 g, 73.8 mmol) was added in small amounts to a solution of 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid (19.8 g, 67.1 mmol) in anhydrous DCM (300 mL). The reaction mixture was stirred at room temperature for 3 hours. All volatile substances were completely removed using a rotary evaporator to obtain 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride as an unpurified substance, which was used in the next step without further purification.

[0283] Step 3

[0284] (+ / -)-anatabin (12.0 g, 75.0 mmol) was slowly added to a solution of 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride (67 mmol) in anhydrous benzene (300 mL). The resulting solution was stirred overnight at room temperature and quenched with saturated NaHCO3 (300 mL). The layers were separated, the benzene layer was washed with brine, dried, and concentrated to obtain 2-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)isoindolin-1,3-dione (25.0 g, 86%) as a foam as a mixture of two diastereomers without further purification.

[0285] Step 4

[0286] Hydrazine monohydrate (5.0 mL) was added to a solution of 2-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propane-2-yl)isoindolin-1,3-dione (25.0 g) in EtOH (300 mL). The reaction solution was refluxed for 3 hours, and the resulting suspension was filtered at room temperature. The filtrate was dissolved in a mixture of EtOAc and hexane and left to stand overnight. The resulting solid was filtered, and the filtrate was concentrated to obtain 2-amino-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propane-1-one (16.7 g, 54%) as an unpurified substance, as a mixture of two diastereomers.

[0287] Step 5

[0288] To a solution of 3-nitrobenzoic acid (0.5 g, 3.0 mmol) and 2-amino-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propan-1-one (0.9 g, 3.0 mmol), EDC hydrochloride (0.7 g, 3.8 mmol) and i-Pr2NEt (0.7 mL, 3.9 mmol) in DCM (10 mL) were added. The reaction mixture was stirred overnight at room temperature and quenched with H2O (10 mL). The layers were separated, the organic layer was washed with brine, dried, and concentrated to obtain 3-nitro-N-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.6 g, 43%) as a film in the flask, which existed as a mixture of two diastereomers after purification by CombiFlash® using an HP C18 Aq GOLD column with MeCN / buffered H2O as the elution mobile phase. MS (ESI, pos. ion) m / z: 457.1 (M+1).

[0289] Alternative Step 5

[0290] PCl5 (1.2 g) was added to a solution of 3-nitrobenzoic acid (0.8 g, 5 mmol) in DCM (20 mL). The reaction mixture was stirred at room temperature for 2 hours, concentrated, diluted with anhydrous DCM, and transferred to a solution of 2-amino-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-1-one (1.5 g, 5 mmol) and Et3N (7.5 mmol). Post-treatment and purification yield the title product as described in step 5 above.

[0291] Example 15

[0292] Synthesis of 3-methoxy-N-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (Compound 16)

[0293]

[0294] EDC hydrochloride (0.72 g, 3.8 mmol) and i-Pr2NEt (0.70 mL, 3.9 mmol) in DCM (10 mL) were added to a solution of 3-methoxybenzoic acid (0.46 g, 3.0 mmol) and 2-amino-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-1-one (0.92 g, 3.0 mmol). The reaction mixture was stirred overnight at room temperature and quenched with H2O (10 mL). The layers were separated, the organic layer was washed with brine, dried, and concentrated to obtain 3-methoxy-N-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.60 g, 45%) as a film in the flask, which existed as a mixture of two diastereomers after purification with a CombiFlash® normal phase Silcargel column using EtOAc and hexane as the elution mobile phase. MS (ESI, pos. ion) m / z: 442.2 (M+1).

[0295] Example 16

[0296] Synthesis of 3-chloro-N-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (Compound 18)

[0297]

[0298] Step 1

[0299] A solution of 3-chlorobenzaldehyde (3.5 g, 25 mmol) in MeOH (100 mL) was added dropwise at room temperature to a purple solution of KMnO4 (4.0 g, 25.0 mmol) and Na2HPO4 (6.7 g, 25 mmol) in H2O (100 mL). The reaction mixture was stirred for about 30 minutes until a brown suspension was formed. The resulting suspension was filtered through a Celite® pad, the filtrate was concentrated using a rotary evaporator, and diluted with H2O (100 mL). The diluted filtrate was oxidized with 1N HCl until the pH reached 3 to 4. The resulting precipitate was filtered and dried overnight under vacuum at 76 °C to obtain 3-chlorobenzoic acid (3.5 g, 90%) as a white solid.

[0300] Step 2

[0301] EDC hydrate (0.75 g, 3.8 mmol) and i-Pr2NEt (0.72 mL, 3.9 mmol) in DCM (10 mL) were added to a solution of 3-chlorobenzoic acid (0.47 g, 3.0 mmol) and 2-amino-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-1-one (0.92 g, 3.0 mmol). The reaction mixture was stirred overnight at room temperature and quenched with H2O (10 mL). The layers were separated, the organic layer was washed with brine, dried, and concentrated to obtain 3-chloro-N-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.30 g, 20%) as a film in the flask, which existed as a mixture of two diastereomers after purification by CombiFlash® using an HP C18 Aq GOLD column with MeCN / buffered H2O as the elution mobile phase. MS (ESI, pos. ion) m / z: 446.1 (M+1).

[0302] Example 17

[0303] Synthesis of 3-fluoro-N-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (Compound 19)

[0304]

[0305] Step 1

[0306] A solution of 3-fluorobenzaldehyde (3.1 g, 25 mmol) in MeOH (100 mL) was added dropwise at room temperature to a purple solution of KMnO4 (4.0 g, 25.0 mmol) and Na2HPO4 (6.7 g, 25 mmol) in H2O (100 mL). The reaction mixture was stirred for about 30 minutes until a brown suspension was formed. The resulting suspension was filtered through a Celite® pad, the filtrate was concentrated using a rotary evaporator, and diluted with H2O (100 mL). The diluted filtrate was oxidized with 1N HCl until the pH reached 3 to 4. The resulting precipitate was filtered and dried overnight under vacuum at 76 °C to obtain 3-fluorobenzoic acid (2.0 g, 57%) as a white solid.

[0307] Step 2

[0308] EDC hydrochloride (0.72 g, 3.8 mmol) and i-Pr2NEt (0.70 mL, 3.9 mmol) in DCM (10 mL) were added to a solution of 3-fluorobenzoic acid (0.46 g, 3.0 mmol) and 2-amino-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-1-one (0.92 g, 3.0 mmol). The reaction mixture was stirred overnight at room temperature and quenched with H2O (10 mL). The layers were separated, the organic layer was washed with brine, dried, and concentrated to obtain 3-fluoro-N-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.50 g, 39%) as a film in the flask, which existed as a mixture of two diastereomers after purification by CombiFlash® using an HP C18 Aq GOLD column with MeCN / buffered H2O as the elution mobile phase. MS (ESI, pos. ion) m / z: 430.1 (M+1).

[0309] Example 18

[0310] Synthesis of 3-ethoxy-N-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (Compound 20)

[0311]

[0312] Step 1

[0313] Ethyl iodide (9.4 g, 60 mmol) and K2CO3 (10.3 g, 75 mmol) were added in that order to a solution of 3-hydroxybenzaldehyde (6.1 g, 50 mmol) in DMF (200 mL). The resulting suspension was heated at 120°C for 4 hours and cooled to room temperature. The reaction mixture was quenched with H2O (200 mL) and extracted with ether (200 mL). The ether layer was washed with H2O (200 mL x 3), dried, and concentrated to obtain 3-ethoxybenzaldehyde (6.2 g, 83%) as a clear oil.

[0314] Step 2

[0315] A solution of 3-ethoxybenzaldehyde (5.8 g) in MeOH (150 mL) was added dropwise at room temperature to a purple solution of KMnO4 (6.2 g, 39.0 mmol) and Na2HPO4 (10.5 g, 39 mmol) in H2O (150 mL). The reaction mixture was stirred for about 30 minutes until a brown suspension was formed. The resulting suspension was filtered through a Celite® pad, the filtrate was concentrated using a rotary evaporator, and diluted with H2O (100 mL). The diluted filtrate was oxidized with 1N HCl until the pH reached 3 to 4. The resulting precipitate was filtered and dried overnight under vacuum at 76 °C to obtain 3-ethoxybenzoic acid (2.9 g, 50%) as a white solid.

[0316] Step 3

[0317] To a solution of 3-ethoxybenzoic acid (0.55 g, 3.0 mmol) and 2-amino-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propan-1-one (0.92 g, 3.0 mmol), EDC hydrochloride (0.72 g, 3.8 mmol) and i-Pr2NEt (0.70 mL, 3.9 mmol) in DCM (10 mL) were added. The reaction mixture was stirred overnight at room temperature and quenched with H2O (10 mL). The layers were separated, the organic layer was washed with brine, dried, and concentrated to obtain 3-ethoxy-N-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.66 g, 48%) as a film in the flask, which existed as a mixture of two diastereomers after purification by CombiFlash® using an HP C18 Aq GOLD column with MeCN / buffered H2O as the elution mobile phase. MS (ESI, pos. ion) m / z: 456.2 (M+1).

[0318] The compounds in Examples 19 to 22 were synthesized using correspondingly prepared or commercial benzoic acid, proceeding similarly to Example 18.

[0319] Example 19: 3,4-dimethoxy-N-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.35 g, 25%). (Compound 21)

[0320]

[0321] MS (ESI, pos. ion) m / z: 472.2 (M+1).

[0322] Example 21: N-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)-3-(trifluoromethyl)benzamide (0.55 g, 38%). (Compound 23)

[0323]

[0324] MS (ESI, pos. ion) m / z: 480.1 (M+1).

[0325] Example 22: 3-fluoro-5-methoxy-N-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.57 g, 41%). (Compound 24)

[0326]

[0327] MS (ESI, pos. ion) m / z: 460.2 (M+1).

[0328] Example 23

[0329] Synthesis of 3-methoxy-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (Compound 25)

[0330]

[0331] Step 1

[0332] D-phenylalanine (25.0 g, 151.3 mmol), phthalic anhydride (22.2 g, 151.3 mmol), and glacial acetic acid (300 mL) were filled in that order into a 1-neck round-bottom flask (500 mL) equipped with a condenser. The resulting mixture was refluxed for 4 hours. The solvent was completely removed under vacuum, and the residue was precipitated from a mixture of ethyl acetate and hexane to obtain (R)-2-(1,3-dioxoisoindoline-2-yl)-3-phenylpropanoic acid (38.4 g, 86%) as a white solid.

[0333] Step 2

[0334] PCl5 (29.4 g, 141.0 mmol) was added in small amounts to a solution of (R)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid (37.9 g, 128.0 mmol) in anhydrous DCM (500 mL). The reaction mixture was stirred at room temperature for 3 hours. All volatile substances were completely removed using a rotary evaporator to obtain (R)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride as an unpurified substance, which was used in the next step without further purification.

[0335] Step 3

[0336] (+ / -)-anatabin (20.6 g, 128.7 mmol) was slowly added to a solution of (R)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride (128 mmol) in anhydrous benzene (500 mL). The resulting solution was stirred overnight at room temperature and quenched with saturated NaHCO3 (500 mL). The layers were separated, the benzene layer was washed with brine, dried, and concentrated to obtain 2-((2R)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)isoindolin-1,3-dione (43.3 g, 79%) as a mixture of two diastereomers in foam without further purification.

[0337] Step 4

[0338] Hydrazine monohydrate (8.7 mL) was added to a solution of 2-((2R)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)isoindolin-1,3-dione (43.3 g) in EtOH (500 mL). The reaction solution was refluxed for 3 hours, and the resulting suspension was filtered at room temperature. The filtrate was dissolved in a mixture of EtOAc and hexane and left to stand overnight. The resulting solid was filtered, and the filtrate was concentrated to obtain (2R)-2-amino-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-1-one (32.3 g, 82%) as an unpurified substance, as a mixture of two diastereomers.

[0339] Step 5

[0340] EDC hydrochloride (0.72 g, 3.8 mmol) and i-Pr2NEt (0.70 mL, 3.9 mmol) in DCM (10 mL) were added to a solution of 3-methoxybenzoic acid (0.46 g, 3.0 mmol) and (2R)-2-amino-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-1-one (0.92 g, 3.0 mmol). The reaction mixture was stirred overnight at room temperature and quenched with H2O (10 mL). The layers were separated, the organic layer was washed with brine, dried, and concentrated to obtain 3-methoxy-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.73 g, 55%) as a film in the flask, which existed as a mixture of two diastereomers after purification by CombiFlash® using an HP C18 Aq GOLD column with MeCN / buffered H2O as the elution mobile phase. MS (ESI, pos. ion) m / z: 442.2 (M+1).

[0341] Example 24

[0342] Synthesis of 3-ethoxy-4-methoxy-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (Compound 26)

[0343]

[0344] Step 1

[0345] To a solution of 3-ethoxy-4-hydroxybenzaldehyde (8.6 g, 50 mmol) in DMF (200 mL), NaH (3.0 g, 75 mmol, 60 wt%) was added gradually at 0°C, followed by the addition of MeI (3.35 mL, 60 mmol). The reaction mixture was stirred overnight at room temperature and quenched with water. Extraction with ether (100 mL x 3) was performed. The ether layer was washed, dried, and concentrated to obtain 3-ethoxy-4-methoxybenzaldehyde (5.9 g, 66%) as an unpurified material.

[0346] Step 2

[0347] A solution of 3-ethoxy-4-methoxybenzaldehyde (5.6 g) in MeOH (120 mL) was added dropwise at room temperature to a purple solution of KMnO4 (5.1 g, 32.0 mmol) and Na2HPO4 (8.4 g, 32 mmol) in H2O (120 mL). The reaction mixture was stirred for about 30 minutes until a brown suspension was formed. The resulting suspension was filtered through a Celite® pad, the filtrate was concentrated using a rotary evaporator, and diluted with H2O (100 mL). The diluted filtrate was oxidized with 1N HCl until the pH reached 3 to 4. The resulting precipitate was filtered and dried overnight under vacuum at 76 °C to obtain 3-ethoxy-4-methoxybenzoic acid (4.0 g, 66%) as a white solid.

[0348] Step 3

[0349] To a solution of 3-ethoxy-4-methoxybenzoic acid (0.59 g, 3.0 mmol) and (2R)-2-amino-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propan-1-one (0.92 g, 3.0 mmol), EDC hydrochloride (0.72 g, 3.8 mmol) and i-Pr2NEt (0.70 mL, 3.9 mmol) in DCM (10 mL) were added. The reaction mixture was stirred overnight at room temperature and quenched with H2O (10 mL). The layers were separated, the organic layer washed with brine, dried, and concentrated to obtain 3-ethoxy-4-methoxy-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide as a film in the flask, which existed as a mixture of two diastereomers after purification by CombiFlash® using an HP C18 Aq GOLD column with MeCN / buffered H2O as the elution mobile phase. MS (ESI, pos. ion) m / z: 486.2 (M+1).

[0350] Compounds in Examples 25 to 30 were prepared by proceeding similarly to that described in Example 24 above, by synthesizing or replacing commercially available benzoic acid.

[0351] Example 25: 2-chloro-5-methoxy-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.76 g, 53%). (Compound 27)

[0352]

[0353] MS (ESI, pos. ion) m / z: 476.1 (M+1).

[0354] Example 26: 3,5-dimethoxy-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.86 g, 61%). (Compound 28)

[0355]

[0356] MS (ESI, pos. ion) m / z: 472.2 (M+1).

[0357] Example 27: 5-methoxy-2-methyl-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.76 g, 56%). (Compound 29)

[0358]

[0359] MS (ESI, pos. ion) m / z: 456.2 (M+1).

[0360] Example 28: 4-chloro-2-methoxy-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.56 g, 41%). (Compound 30)

[0361]

[0362] MS (ESI, pos. ion) m / z: 476.1 (M+1).

[0363] Example 29: 4-fluoro-3-methoxy-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.65 g, 47%). (Compound 31)

[0364]

[0365] MS (ESI, pos. ion) m / z: 460.2 (M+1).

[0366] Example 30: 2-methoxy-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide. (Compound 32)

[0367]

[0368] MS (ESI, pos. ion) m / z: 442.3 (M+1).

[0369] Example 31

[0370] Synthesis of 3-ethoxy-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (Compound 33)

[0371]

[0372] Step 1

[0373] L-phenylalanine (25.0 g, 151.3 mmol), phthalic anhydride (22.2 g, 151.3 mmol), and glacial acetic acid (300 mL) were filled in that order into a 1-neck round-bottom flask (500 mL) equipped with a condenser. The resulting mixture was refluxed for 4 hours. The solvent was completely removed under vacuum, and the residue was precipitated from a mixture of ethyl acetate and hexane to obtain (S)-2-(1,3-dioxoisoindoline-2-yl)-3-phenylpropanoic acid (42.8 g, 96%) as a white solid.

[0374] Step 2

[0375] PCl5 (32.8 g, 157.0 mmol) was added in small amounts to a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid (42.3 g, 142.0 mmol) in anhydrous DCM (550 mL). The reaction mixture was stirred at room temperature for 3 hours. All volatile products were completely removed using a rotary evaporator to obtain (S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride as an unpurified material, which was used in the next step without further purification.

[0376] Step 3

[0377] (+ / -)-anatabin (23.0 g, 142.9 mmol) was slowly added to a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride (142 mmol) in anhydrous benzene (550 mL). The resulting solution was stirred overnight at room temperature and quenched with saturated NaHCO3 (550 mL). The layers were separated, the benzene layer was washed with brine, dried, and concentrated to obtain 2-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)isoindolin-1,3-dione (57.7 g, 100%) as a mixture of two diastereomers in foam without further purification.

[0378] Step 4

[0379] Hydrazine monohydrate (11.6 mL) was added to a solution of 2-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)isoindolin-1,3-dione (57.7 g) in EtOH (500 mL). The reaction solution was refluxed overnight, and the resulting suspension was filtered at room temperature. The filtrate was dissolved in a mixture of EtOAc and hexane and left to stand overnight. The resulting solid was filtered, and the filtrate was concentrated to obtain (2S)-2-amino-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-1-one (39.0 g, 99%) as an unpurified substance, as a mixture of two diastereomers.

[0380] Step 5

[0381] To a solution of 3-ethoxybenzoic acid (0.83 g, 5.0 mmol) and (2S)-2-amino-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propan-1-one (1.5 g, 5.0 mmol), EDC hydrochloride (1.2 g, 6.3 mmol) and i-Pr2NEt (1.1 mL, 6.5 mmol) in DCM (30 mL) were added. The reaction mixture was stirred overnight at room temperature and quenched with H2O (30 mL). The layers were separated, the organic layer was washed with brine, dried, and concentrated to obtain 3-ethoxy-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (1.3 g, 63%) as a film in the flask, which existed as a mixture of two diastereomers after purification by CombiFlash® using an HP C18 Aq GOLD column with MeCN / buffered H2O as the elution mobile phase. MS (ESI, pos. ion) m / z: 456.2 (M+1).

[0382] Compounds in Examples 32 to 33 were prepared by proceeding similarly to that described in Example 31 above, by synthesizing or replacing commercially available benzoic acid.

[0383] Example 32: 4-fluoro-3-methoxy-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.4 g, 29%). (Compound 34)

[0384]

[0385] MS (ESI, pos. ion) m / z: 460.2 (M+1).

[0386] Example 33: 3-methoxy-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (0.8 g, 36%). (Compound 35)

[0387]

[0388] MS (ESI, pos. ion) m / z: 442.2 (M+1).

[0389] The compounds in Examples 40 to 56 were prepared by proceeding similarly to that described in Example 31 above, by replacing a commercially available carboxylic acid or a carboxylic acid that can be easily prepared from aminobenzoic acid and a corresponding acid chloride using a coupling reaction.

[0390] Example 40: 3-(3-methylbutanamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide, yellowish-brown solid (0.90 g, 60%). (Compound 42)

[0391]

[0392] MS (ESI, pos, ion) m / z: 511.2 (M+1).

[0393] Example 41: N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)-3-pivalamidobenzamide, gray solid (0.93 g, 62%). (Compound 43)

[0394]

[0395] MS (ESI, pos, ion) m / z: 511.2 (M+1).

[0396] Example 42: 3-(cyclopropanecarboxamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide, white solid (1.01 g, 69%). (Compound 44)

[0397]

[0398] MS (ESI, pos, ion) m / z: 495.2 (M+1).

[0399] Example 43: 3-(cyclobutanecarboxamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide, orange solid (1.05 g, 69%). (Compound 45)

[0400]

[0401] MS (ESI, pos, ion) m / z: 509.2 (M+1).

[0402] Example 44: 3-(cyclopentanecarboxamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide, white solid (0.69 g, 64%). (Compound 46)

[0403]

[0404] MS (ESI, pos, ion) m / z: 523.2 (M+1).

[0405] Example 45: 2-butyramido-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide, white solid (0.12 g, 12%). (Compound 47)

[0406]

[0407] MS (ESI, pos, ion) m / z: 497.2 (M+1).

[0408] Example 46: 4-butyramido-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide, white solid (0.45 g, 45%). (Compound 48)

[0409]

[0410] MS (ESI, pos, ion) m / z: 497.2 (M+1).

[0411] Example 47: N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)quinoline-2-carboxamide, white solid (0.50 g, 53%). (Compound 49)

[0412]

[0413] MS (ESI, pos, ion) m / z: 463.2 (M+1).

[0414] Example 48: N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)pyrazine-2-carboxamide, yellow solid (0.50 g, 61%). (Compound 50)

[0415]

[0416] MS (ESI, pos, ion) m / z: 414.1 (M+1).

[0417] Example 49: N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)nicotinamide, white solid (0.41 g, 50%). (Compound 51)

[0418]

[0419] MS (ESI, pos, ion) m / z: 413.1 (M+1).

[0420] Example 50: N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)furan-2-carboxamide, white solid (0.50 g, 63%). (Compound 52)

[0421]

[0422] MS (ESI, pos, ion) m / z: 402.1 (M+1).

[0423] Example 51: N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)-1H-pyrrole-2-carboxamide, pale yellow solid (0.20 g, 25%). (Compound 56)

[0424]

[0425] MS (ESI, pos, ion) m / z: 401.1 (M+1).

[0426] Example 52: 3-((S)-2-methylbutanamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide, pale yellow solid (0.60 g, 56%). (Compound 57)

[0427]

[0428] MS (ESI, pos, ion) m / z: 511.2 (M+1).

[0429] Example 53: 3-((R)-2-methylbutanamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide, pale yellow solid (0.67 g, 65%). (Compound 58)

[0430]

[0431] MS (ESI, pos, ion) m / z: 511.2 (M+1).

[0432] Example 54: 3-(N-methylbutyramido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide, pale yellow solid (0.80 g, 78%). (Compound 59)

[0433]

[0434] MS (ESI, pos, ion) m / z: 511.2 (M+1).

[0435] Example 55: 3-(butylamino)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide, pale yellow solid (0.82 g, 85%). (Compound 60)

[0436]

[0437] MS (ESI, pos, ion) m / z: 483.2 (M+1).

[0438] Example 56: 1-butyl-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propane-2-yl)-1H-pyrrole-2-carboxamide, yellow oil (0.21 g, 23%). (Compound 61)

[0439]

[0440] MS (ESI, pos, ion) m / z: 457.2 (M+1).

[0441] Example 34

[0442] Synthesis of N-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)-3-pentamidobenzamide (Compound 36)

[0443]

[0444] Step 1

[0445] Pyridine (6.5 mL) and valeroyl chloride (5.5 mL, 45.6 mmol) were added in that order at 0°C to a suspension of 3-aminobenzoic acid (5.0 g, 36.5 mmol) in DCM (120 mL). The resulting solution was stirred overnight at room temperature and quenched with water. The layers were separated, the organic layer was washed, dried, and concentrated to obtain 3-pentamidobenzoic acid (7.2 g, 90%) as a white solid.

[0446] Step 2

[0447] EDC hydrochloride (0.72 g, 3.8 mmol) and i-Pr2NEt (0.70 mL, 3.9 mmol) in DCM (10 mL) were added to a solution of 3-pentamidobenzoic acid (0.66 g, 3.0 mmol) and 2-amino-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-1-one (0.92 g, 3.0 mmol). The reaction mixture was stirred overnight at room temperature and quenched with H2O (10 mL). The layers were separated, the organic layer was washed with brine, dried, and concentrated to obtain N-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)-3-pentamidobenzamide (0.81 g, 59%) as a film in the flask, which existed as a mixture of two diastereomers after purification by CombiFlash® using an HP C18 Aq GOLD column with MeCN / buffered H2O as the elution mobile phase. MS (ESI, pos. ion) m / z: 511.2 (M+1).

[0448] Compounds in Examples 35 to 37 were prepared by proceeding similarly to that described in Example 34 above, by replacing synthetic or commercially available benzoic acid.

[0449] Example 35: 3-butyramido-N-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide. (Compound 37)

[0450]

[0451] MS (ESI, pos. ion) m / z: 497.2 (M+1).

[0452] Example 36: 3-amino-N-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide. (Compound 38)

[0453]

[0454] MS (ESI, pos. ion) m / z: 427.2 (M+1).

[0455] Example 37: 3-acetamido-N-(1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (169 mg, 12%). (Compound 39)

[0456]

[0457] MS (ESI, pos. ion) m / z: 469.2 (M+1).

[0458] Example 38

[0459] Synthesis of 3-butyramido-N-(1-oxo-3-phenyl-1-(2-(quinoline-3-yl)-3,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (Compound 40)

[0460]

[0461] Synthesis scheme for 3-butyramido-N-(1-oxo-3-phenyl-1-(2-(quinoline-3-yl)-3,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (1,2-combo compound):

[0462]

[0463] Step 1

[0464] Synthesis of N-phenylacetamide

[0465]

[0466] Acetyl chloride (4.63 g, 59.07 mmol, 1.1 equivalents) in 40.3 mL of dichloromethane was added dropwise in an ice bath for 1 hour to a suspension of aniline (5 g, 53.7 mmol) in 2N NaOH (40.3 mL). The resulting mixture was stirred at room temperature for an additional time. The organic layer was washed with dilute ice, NaHCO3, and brine. The organic layer was concentrated under reduced pressure to obtain the desired product as crude acetanilide. The crude acetanilide was recrystallized by dissolution in distilled water to obtain pure, dry acetanilide as a white crystalline solid (6.3 g, 87% separated yield).

[0467] Step 2

[0468] Synthesis of 2-chloroquinoline-3-carbaldehyde

[0469]

[0470] Phosphorus oxychloride (63.5 g, 414.13 mmol, 7 equivalents) was added dropwise to DMF (10.82 g, 148 mmol, 2.5 equivalents) and cooled in an ice bath (30 min). The mixture was stirred at 0 °C for another 30 minutes, and then acetanilide (8 g, 59.18 mmol, 1 equivalent) was added all at once. The white suspension turned into a greenish solution, which was heated overnight. The mixture was poured over ice. The yellow precipitate was filtered and dried to obtain a yellowish-orange solid (6.8 g, 60% separated yield).

[0471] Step 3

[0472] Synthesis of quinoline-3-carbaldehyde

[0473]

[0474] 19.05 g of triethylamine (188.28 mmol, 12 equivalents), tetrakis(triphenylphosphine)palladium (0) (0.9 g, 0.78 mmol, 5 mol%), and formic acid (3.9 g, 84.72 mmol, 5.4 equivalents) were added to 2-chloroquinoline-3-carbaldehyde (3 g, 15.69 mmol, 1 equivalent) in DMF (18 mL) under a nitrogen atmosphere at 23 °C. After stirring at 110 °C for 3 hours, the reaction mixture was cooled to 23 °C and extracted with water (90 mL) and ethyl acetate (3 x 60 mL). The combined organic phase was washed with brine (50 mL), dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum to obtain an unpurified product, which was purified by flash chromatography using 50% EtOAc / hexane to obtain the desired product as a reddish-brown solid (1.5 g, 60.8% separated yield).

[0475] Step 4

[0476] Synthesis of (E)-N-allyl-1-(quinoline-3-yl)methaneimine

[0477]

[0478] In a 250 mL round-bottom flask, allylamine (1.3 g, 22.92 mmol, 1.2 equivalents) was activated 4 o A mixture of quinoline-3-carbaldehyde (3 g, 19.1 mmol, 1 equivalent) in anhydrous dichloromethane (96 mL) containing MS (5 g) was added to a stirred solution. The resulting mixture was then stirred at room temperature for 24 hours. Subsequently, the mixture was filtered through a molecular sieve, washed with DCM, and after solvent evaporation, the imine product was obtained as a brown solid (4.3 g, 95% separated yield).

[0479] Step 5

[0480] (Synthesis of N-allyl-1-(quinoline-3-yl)but-3-en-1-amine

[0481]

[0482] In a 250 mL 2-neck flask, allyl bromide (3.95 g, 32.63 mmol, 2 equivalents) was added dropwise to a cold (0 °C) anhydrous ethanol (83 mL) solution of (E)-N-allyl-1-(quinoline-3-yl)methaneimine (3.2 g, 16.31 mmol, 1 equivalent) and indium powder (2.79 g, 24.46 mmol, 1.5 equivalents). The resulting mixture was stirred at the same temperature for 30 minutes. Afterward, the temperature was allowed to reach room temperature, and the system was stirred for an additional 3.5 hours. Subsequently, the solvent was evaporated under vacuum, the residue was dissolved in EtOAc (60 mL), and treated with saturated aqueous NaHCO3 (40 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layer was dried using anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by column chromatography using 50% EtOAc / hexane as the eluent to obtain a pure product, a yellowish-brown oil (3.4 g, 88% separated yield).

[0483] Step 6

[0484] Synthesis of 3-(1,2,3,6-tetrahydropyridine-2-yl)quinoline

[0485]

[0486] In a 100 mL 2-wood pear-shaped flask equipped with a magnetic rod, N-allyl-1-(quinoline-3-yl)but-3-en-1-amine (1.56 g, 6.55 mmol, 1 equivalent) was dissolved in anhydrous dichloromethane (64 mL). p-toluenesulfonic acid monohydrate (2.74 g, 14.41 mmol, 2.2 equivalents) was added, and the mixture was stirred for 10 minutes. Grubb's catalyst was added until the solution pH was found to be 9-10. The organic layer was separated, dried using anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified, a second-generation catalyst (0.555 g, 0.65 mmol, 10 mol%) was added, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was neutralized with 50 mL of 2N NaOH and stirred for 20 minutes. The organic layer was collected and washed with water (3 x 50 mL). The organic layer was dried using anhydrous Na2SO4 and concentrated under reduced pressure. The residue was dissolved in 100 mL of EtOAc, followed by the addition of 30 mL of 6N HCl, 70 mL of deionized water, and 20 mL of a brine solution, and the mixture was stirred for 20 minutes. The aqueous layer was collected and further extracted with 3 x 50 mL of EtOAc. The aqueous layer was transferred to a 500 mL round-bottom flask and cooled to 0 °C. 120 mL of methyl tert-butyl ether was added to the aqueous layer, and potassium anhydrous carbonate was packed into a column chromatograph with a mixture of hexane and ammonium hydroxide in a ratio of 20:1, and 4% methanol / chloroform was used as the eluent to obtain a pure product as a reddish-brown oil (0.325 g, 28% separated yield).

[0487] Step 7

[0488] Synthesis of 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride

[0489]

[0490] Step 7(i)

[0491] DL-phenylalanine (20 g, 121 mmole, 1 equivalent), phthalic anhydride (17.9 g, 121 mmole, 1 equivalent), toluene (180 mL), and Et3N (1.6 mL) were filled in that order into an oven-dried 1-neck round-bottom flask (500 mL) equipped with a condenser and a Dean-Stark apparatus. The resulting mixture was refluxed for 16 hours until no more water was produced. H2O (180 mL) was added to the cooled solution, and the product was precipitated. The product was filtered and dried overnight under high vacuum. The dried product, 2-(1,3-dioxoisoindoline-2-yl)-3-phenylpropanoic acid, was collected as a white solid (29.5 g, 82.6% separated yield). 1 H NMR (CDCl3): 7.80-7.78 (m, 2H), 7.70 -7.69 (m, 2H), 7.27-7.13 (m, 5H), 5.23 (t, J = 8.2 Hz, 1H), 3.61 (d, J = 7.5 Hz, 2H); 13 C NMR (CDCl3): 174.1, 167.3, 136.4, 134.1, 131.4, 128.8, 128.5, 126.9, 123.5, 53.0, 34.4.

[0492] Step 7(ii)

[0493] PCl5 (1.93 g, 9.28 mmol, 1.09 equivalents) was aliquoted into a solution of 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid (2.5 g, 8.47 mmol, 1 equivalent) in anhydrous DCM (32 mL). The resulting reaction mixture was stirred at room temperature for 3 hours. All volatile products were completely removed under reduced pressure. The residue, 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride (2.12 g), as a white solid, was used in the next step without further purification.

[0494] Step 8

[0495] Synthesis of 2-(1-oxo-3-phenyl-1-(2-(quinoline-3-yl)-3,6-dihydropyridine-1(2H)-yl)propane-2-yl)isoindolin-1,3-dione

[0496]

[0497] 3-(1,2,3,6-tetrahydropyridine-2-yl)quinoline (1.5 g, 7.13 mmo, 1.05 equivalents) was slowly added to a solution of 2-(1,3-dioxoisoindoline-2-yl)-3-phenylpropanoyl chloride (6.78 mmol) in anhydrous benzene (25 mL). The resulting solution was stirred at room temperature for 20 hours and quenched with saturated NaHCO3 (20 mL). The layers were separated, the benzene layer was washed with brine, dried, and concentrated to obtain 3-(1,2,3,6-tetrahydropyridine-2-yl)quinoline as an unpurified product. The crude product was purified by column chromatography using a 50% EtOAc / hexane mixture as the eluent, and the desired product was obtained as a mixture of diastereomers as a white solid (1.4 g, 42.3%). MS (ESI, pos. ion) m / z: 488.2 (M+1).

[0498] Step 9

[0499] Synthesis of 2-amino-3-phenyl-1-(2-(quinoline-3-yl)-3,6-dihydropyridine-1(2H)-yl)propan-1-one

[0500]

[0501] Hydrazine monohydrate (0.45 mL) was added to a solution of 2-(1-oxo-3-phenyl-1-(2-(quinoline-3-yl)-3,6-dihydropyridine-1(2H)-yl)propane-2-yl)isoindolin-1,3-dione (1.4 g, 2.9 mmol) in EtOH (20 mL). The reaction solution was refluxed overnight at 85 °C, and the resulting suspension was filtered at room temperature. The filtrate was concentrated, further dissolved in a 20 mL 1:1 mixture of EtOAc / hexane, and maintained overnight at 0 °C. The mixture was filtered, and the filtrate was concentrated to obtain 2-amino-3-phenyl-1-(2-(quinoline-3-yl)-3,6-dihydropyridine-1(2H)-yl)propan-1-one (0.8 g, 77%) as a brown oil, as a mixture of diastereoisomers. MS (ESI, pos. ion) m / z: 358.19 (M+1).

[0502] Step 10

[0503] Synthesis of 2-amino-3-phenyl-1-(2-(quinoline-3-yl)-3,6-dihydropyridine-1(2H)-yl)propan-1-one

[0504]

[0505] To a solution of 3-butyramidobenzoic acid (0.47 g, 2.15 mmol, 1 equivalent) and 2-amino-3-phenyl-1-(2-(quinoline-3-yl)-3,6-dihydropyridine-1(2H)-yl)propan-1-one (0.47 g, 2.15 mmol, 1 equivalent), EDC hydrochloride (0.56 g, 2.8 mmol, 1.3 equivalents) and i-Pr2NEt (0.5 mL, 2.80 mmol, 1.3 equivalents) in DCM (10 mL) were added. The reaction mixture was stirred overnight at room temperature and quenched with H2O (10 mL). The layers were separated, the organic layer was washed with brine, dried, and concentrated to obtain an unpurified product, and the unpurified product was crystallized using acetonitrile as a solvent. The crystals were filtered and collected as a white residue (0.45 g, 38.3%) existing as a mixture of diastereomers. MS (ESI, pos. ion) m / z: 547.5 (M+1).

[0506] Compounds in Examples 65 to 66 were prepared by proceeding similarly to that described in Example 38 above, starting with the corresponding amino acids.

[0507] Example 65: 3-butyramido-N-(1-(2-(2-chloroquinoline-3-yl)-3,6-dihydropyridine-1(2H)-yl)-1-oxo-3-phenylpropane-2-yl)benzamide, pale yellow solid (0.05 g, 17.2%). (Compound 67)

[0508]

[0509] MS (ESI, pos, ion) m / z: 581.3(M+1).

[0510] Example 66: 3-butyramido-N-(1-oxo-1-(2-(quinoline-3-yl)-3,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide, creamy-white solid (0.13 g, 38.6%). (Compound 68)

[0511]

[0512] MS (ESI, pos, ion) m / z: 471.4 (M+1).

[0513] Example 39

[0514] Synthesis of 3-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazole-4-yl]pentamido}-N-[(2S)-1-oxo-3-phenyl-1-{1,2,3,6-tetrahydro-[2,3'-bipyridine]-1-yl}propane-2-yl]benzamide (Compound 41)

[0515]

[0516] Step 1

[0517] SOCl2 (7.1 mL, 100 mmol) was slowly added at room temperature to a solution of 3-nitrobenzoic acid (8.4 g, 50 mmol) in MeOH (150 mL). The reaction mixture was refluxed for 2 hours. All solvent was removed to obtain methyl 3-nitrobenzoate (9.1 g, 100%) as an unpurified substance.

[0518] Step 2

[0519] SnCl2·2H2O (22.5 g, 100 mmol) was added all at once to a solution of methyl 3-nitrobenzoate (9.1 g, 50 mmol) in EtOH (150 mL). The reaction mixture was refluxed for 2 hours, and then the solvent was removed. The residue was extracted with EtOAc. The organic layer was washed, dried, and concentrated to obtain methyl 3-aminobenzoate (8.4 g, 100%) as a brown oil.

[0520] Step 3

[0521] EDC (1.3 g, 7.0 mmol) and i-Pr2NEt (1.2 mL, 7.5 mmol) were added to a solution of methyl 3-aminobenzoate (0.87 g, 5.7 mmol) and biotin (1.4 g, 5.7 mmol) in DCM (15 mL). The reaction mixture was stirred overnight at room temperature and quenched with H2O (10 mL). The layers were separated, the organic layer was washed with brine, dried, and concentrated to obtain methyl 3-(5-(2-oxohexahydro-1H-thieno[3,4-d]imidazole-4-yl)pentamido)benzoate (1.13 g, 52%).

[0522] Step 4

[0523] LiOH (0.36 g, 14 mmol) was added all at once to a solution of methyl 3-(5-(2-oxohexahydro-1H-thieno[3,4-d]imidazole-4-yl)pentamido)benzoate (1.13 g, 2.9 mmol) in a mixture of THF (15 mL) and H2O (15 mL), and stirred overnight at room temperature. The reaction mixture was further diluted with 1N NaOH, the aqueous layer was washed with EtOAc, and neutralized with 1N HCl. The resulting solid was collected, and 3-(5-(2-oxohexahydro-1H-thieno[3,4-d]imidazole-4-yl)pentamido)benzoic acid (0.7 g, 83%) was obtained as an unpurified material.

[0524] Step 5

[0525] To a solution of 3-(5-(2-oxohexahydro-1H-thieno[3,4-d]imidazole-4-yl)pentamido)benzoic acid (0.7 g, 1.9 mmol) and (2S)-2-amino-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propan-1-one (0.6 g, 1.9 mmol), EDC hydrochloride (0.5 g, 2.4 mmol) and i-Pr2NEt (0.4 mL, 2.5 mmol) in DCM (20 mL) were added. The reaction mixture was stirred overnight at room temperature and quenched with H2O (30 mL). The layers were separated, the organic layer was washed with brine, dried, and concentrated to obtain 3-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazole-4-yl]pentamido}-N-[(2S)-1-oxo-3-phenyl-1-{1,2,3,6-tetrahydro-[2,3'-bipyridine]-1-yl}propane-2-yl]benzamide (80 mg, 7%) as a powder after purification using CombiFlash® with an HP C18 Aq GOLD column via MeCN / buffered H2O as the elution mobile phase. MS (ESI, pos. ion) m / z: 653.5 (M+1).

[0526] Example 57

[0527] Synthesis of 3-(3-aminopropaneamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide hydrochloride (Compound 54)

[0528]

[0529] Synthesis scheme for 3-(3-aminopropaneamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide hydrochloride:

[0530]

[0531] To a solution of 3-(3-((tert-butoxycarbonyl)amino)propanamido)benzoic acid (0.62 g, 2.0 mmol) and (2S)-2-amino-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propan-1-one (0.62 g, 2.0 mmol), EDC hydrochloride (0.57 g, 2.9 mmol) and i-Pr2NEt (0.47 mL, 3.9 mmol) in DCM (10 mL) were added. The reaction mixture was stirred overnight at room temperature and quenched with H2O (10 mL). The layers were separated, the organic layers were washed with brine, dried, and concentrated to obtain 3-(3-aminopropaneamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide as a film in a flask, which existed as a mixture of two diastereomers after purification by CombiFlash® using an HP C18 Aq GOLD column with MeCN / buffered H2O as the elution mobile phase. Benzamide was dissolved in 5 mL of 1,4-dioxane and converted to benzamide hydrochloride by stirring with 2 equivalents of 4N HCl in 1,4-dioxane; afterward, the reaction mixture was concentrated to obtain 3-(3-aminopropaneamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide hydrochloride as a brown solid (0.89 g, 84%). MS (ESI, pos, ion) m / z: 498.2 (M+1).

[0532] Similar to Example 57 above, the compounds in Examples 58 and 59 were prepared by starting with the corresponding benzoic acid.

[0533] Example 58: 3-(2-aminoacetamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide hydrochloride, beige solid (0.83 g, 83%). (Compound 53)

[0534]

[0535] MS (ESI, pos, ion) m / z: 484.2 (M+1).

[0536] Example 59: 3-(4-aminobutanamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide hydrochloride, beige solid (0.40 g, 36%). (Compound 55)

[0537]

[0538] MS (ESI, pos, ion) m / z: 512.2 (M+1).

[0539] Example 61

[0540] Synthesis of 3-butyramido-N-((2S)-1-oxo-3-phenyl-1-(2-(pyridine-3-yl)piperidine-1-yl)propane-2-yl)benzamide (Compound 63)

[0541]

[0542] Synthesis scheme for 3-butyramido-N-((2S)-1-oxo-3-phenyl-1-(2-(pyridine-3-yl)piperidine-1-yl)propane-2-yl)benzamide:

[0543]

[0544] Step 1

[0545] PCl5 (1.0 g, 4.8 mmol) was added in small amounts to a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid (1.3 g, 4.4 mmol) in anhydrous DCM (20 mL). The reaction mixture was stirred at room temperature for 3 hours. All volatile products were completely removed using a rotary evaporator to obtain (S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride, which was used in the next step without further purification.

[0546] Step 2

[0547] (+ / -)-anabasine (0.8 g, 4.9 mmol) was slowly added to a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride (4.8 mmol) in anhydrous benzene (20 mL). The resulting solution was stirred overnight at room temperature and quenched in saturated NaHCO3 (20 mL). The layers were separated, the benzene layers were washed with brine, dried, and concentrated to obtain 2-((2S)-1-oxo-3-phenyl-1-(2-(pyridine-3-yl)-piperidine-1-yl)propane-2-yl)isoindolin-1,3-dione as a foam (1.5 g) existing as a mixture of two diastereomers, which was used in the next step without further purification.

[0548] Step 3

[0549] Hydrazine monohydrate (0.3 mL) was added to a solution of 2-((2S)-1-oxo-3-phenyl-1-(2-(pyridin-3-yl)-piperidin-1-yl)propan-2-yl)isoindolin-1,3-dione (1.5 g) in EtOH (30 mL). The reaction solution was refluxed overnight, and the resulting suspension was filtered at room temperature. The filtrate was dissolved in a mixture of EtOAc and hexane and left to stand overnight. The resulting solid was filtered, and the filtrate was concentrated to obtain (2S)-2-amino-3-phenyl-1-(2-(pyridin-3-yl)piperidin-1-yl)propan-1-one (0.82 g) as a mixture of two diastereomers, which was used in the next step without further purification.

[0550] Step 4

[0551] EDC hydrochloride (0.78 g, 4.0 mmol) and i-Pr2NEt (0.65 mL, 4.1 mmol) in DCM (20 mL) were added to a solution of 3-butyramidobenzoic acid (0.56 g, 2.7 mmol) and (2S)-2-amino-3-phenyl-1-(2-(pyridin-3-yl)piperidin-1-yl)propan-1-one (0.82 g, 2.7 mmol). The reaction mixture was stirred overnight at room temperature and quenched with H2O (20 mL). The layers were separated, the organic layer was washed with brine, dried, and concentrated to obtain 3-butyramido-N-((2S)-1-oxo-3-phenyl-1-(2-(pyridine-3-yl)piperidin-1-yl)propane-2-yl)benzamide as a pale yellow solid (0.64 g, 32%) MS (ESI, pos. ion) m / z: 499.2 (M+1), which existed as a mixture of two diastereomers after purification by CombiFlash® using an HP C18 Aq GOLD column with MeCN / buffered H2O as the elution mobile phase.

[0552] Example 62

[0553] Synthesis of 3-butyramido-N-((2S)-3-(naphthalene-1-yl)-1-oxo-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide (Compound 64)

[0554]

[0555] Step 1

[0556] 3-(1-naphthyl)-L-alanine (1.0 g, 4.6 mmol), phthalic anhydride (0.7 g, 4.6 mmol), and glacial acetic acid (10 mL) were filled in that order into a 1-neck round-bottom flask (100 mL) equipped with a condenser. The resulting mixture was refluxed for 4 hours. The solvent was completely removed under vacuum, and the residue was precipitated from the mixture of ethyl acetate and hexane to obtain (S)-2-(1,3-dioxoisoindoline-2-yl)-3-(naphthalene-1-yl)propanoic acid (0.52 g) as a beige solid.

[0557] Step 2

[0558] PCl5 (0.32 g, 1.6 mmol) was added in small amounts to a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-(naphthalene-1-yl)propanoic acid (0.52 g, 1.4 mmol) in anhydrous DCM (10 mL). The reaction mixture was stirred at room temperature for 3 hours. All volatile products were completely removed using a rotary evaporator to obtain (S)-2-(1,3-dioxoisoindolin-2-yl)-3-(naphthalene-1-yl)propanoyl chloride, which was used in the next step without further purification.

[0559] Step 3

[0560] (+ / -)-anatabin (0.2 g, 1.3 mmol) was slowly added to a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-(naphthalene-1-yl)propanoyl chloride (0.5 g, 1.3 mmol) in anhydrous benzene (10 mL). The resulting solution was stirred overnight at room temperature and quenched with saturated NaHCO3 (10 mL). The layer was separated, the benzene layer was washed with brine, dried, and concentrated to obtain 2-((2S)-1-oxo-3-phenyl-1-(2-(pyridine-3-yl)-piperidine-1-yl)propane-2-yl)isoindolin-1,3-dione as a brown solid (0.33 g) existing as a mixture of two diastereomers, which was used in the next step without further purification.

[0561] Step 4

[0562] Hydrazine monohydrate (0.1 mL) was added to a solution of 2-((2S)-1-(3,6-dihydro-[2,3'-bipyridine]-1(2H)-yl)-3-(naphthalene-1-yl)-1-oxopropane-2-yl) isoindolin-1,3-dione (0.33 g) in EtOH (10 mL). The reaction solution was refluxed for 3 hours, and the resulting suspension was filtered at room temperature. The filtrate was dissolved in a mixture of EtOAc and hexane and left to stand overnight. The resulting solids were filtered, and the filtrate was concentrated to obtain (2S)-2-amino-1-(3,6-dihydro-[2,3'-bipyridine]-1(2H)-yl)-3-(naphthalene-1-yl)propan-1-one as a brown oil (0.38 g) existing as a mixture of two diastereomers, which was used in the next step without further purification.

[0563] Step 5

[0564] EDC hydrochloride (0.28 g, 1.4 mmol) and i-Pr2NEt (0.23 mL, 1.4 mmol) in DCM (10 mL) were added to a solution of 3-butyramidobenzoic acid (0.21 g, 1.0 mmol) and (2S)-2-amino-1-(3,6-dihydro-[2,3'-bipyridine]-1(2H)-yl)-3-(naphthalene-1-yl)propan-1-one (0.36 g, 1.0 mmol). The reaction mixture was stirred overnight at room temperature and quenched with H2O (10 mL). The layers were separated, the organic layer was washed with brine, dried, and concentrated to obtain 3-butyramido-N-((2S)-3-(naphthalene-1-yl)-1-oxo-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide as a yellow solid (0.19 g) MS (ESI, pos. ion) m / z: 547.2 (M+1), which existed as a mixture of two diastereomers after purification by CombiFlash® using an HP C18 Aq GOLD column with MeCN / buffered H2O as the elution mobile phase.

[0565] Similar to Example 62 above, the compounds in Examples 63 and 64 were prepared by starting with the corresponding benzoic acid.

[0566] Example 63: 3-butyramido-N-((2S)-3-(naphthalene-2-yl)-1-oxo-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide, yellow solid (0.35 g). (Compound 65)

[0567]

[0568] MS (ESI, pos, ion) m / z: 547.2 (M+1).

[0569] Example 64: 3-butyramido-N-((2S)-3-cyclohexyl-1-oxo-1-(6-(pyridine-3-yl)-5,6-dihydropyridine-1(2H)-yl)propane-2-yl)benzamide, yellow solid (0.06 g). (Compound 66)

[0570]

[0571] MS (ESI, pos, ion) m / z: 503.3 (M+1).

[0572] Biological Examples

[0573] Example 1

[0574] Measurement of inhibition of TNFα-induced NF-kB activation... In vitro analysis

[0575] The properties of the compounds disclosed herein that inhibit TNFα-induced NFkB activation were measured using a TNFα luciferase assay. HEK293 / NF-kB luciferase cell lines were obtained by hygromycin selection following co-transfection with the pNFkB-luc vector by pHyg (Panomics, CA, USA). HEK293 / NFkB luciferase cells were grown in DMEM medium supplemented with 10% fetal bovine serum, 100 U / mL penicillin, 100 μg / mL streptomycin / Fungizone, and 100 μg / mL hygromycin B as a selecting agent. HEK293 NFkB luciferase cells were grown in T75 flasks (Nunc™ Cell Culture Treated EasYFlasks™) in a cell culture incubator at 37°C and 5% CO2. Confluent T75 cell culture flasks (approximately 8 to 10 million cells per flask) were washed with 10 mL of sterile PBS (without calcium and magnesium) under a biosafety cabinet. After aspirating the PBS with a sterile glass pipette, the layer of cells (for each T75 flask) was covered with 1 mL of TrypLE™ Express without phenol red (Gibco) at room temperature. After 1 minute of incubation, HEK293 was mechanically resuspended in TrypLE by tapping the side of the flask. Subsequently, the cells were resuspended in 10 mL of pre-warmed complete culture medium and transferred to a conical tube. The cells were centrifuged at 4000 rpm (1000 g) at room temperature for 5 minutes.The cell pellet was resuspended in 24 mL of pre-warmed cell culture medium, and 200 mL of the cell suspension (approximately 80,000 cells per well) was plated per well into 96-well cell culture plates (Costar #3599, Corning, NY, USA) using a multi-channel pipette, with reverse pipetting to inhibit bubble formation. After plating, the cells were kept overnight in a cell culture incubator prior to treatment. For each 96-well cell culture plate, 8 wells were used as control wells (containing only culture medium), and 8 wells were added only to TNFα. NF-kB luciferase receptor cell lines were challenged with 25 ng / mL TNFα for 4 hours in the presence and absence of the different compounds tested within the dose range (control conditions). For each compound, the dose range concentration was IC. 50 It was tested and used in 4 stages to measure.

[0576] Luciferase activity was monitored using the Luc-Screen® Extended-Glow Luciferase Reporter Gene Assay System via chemiluminescence according to the manufacturer's (Invitrogen) instructions and a BioTek Synergy HT plate reader (BioTek Instruments, VT, USA). IC 50 That is, for a representative number of compounds, the concentration at which NF-kB activation decreases by up to 50% is provided in Table 3 below.

[0577] Table 3

[0578]

[0579]

[0580] Example 2

[0581] Measurement of anti-inflammatory activity using an acute LPS model of inflammation in mice... In vivo model

[0582] The properties of the compounds disclosed herein for reducing inflammation were measured in vivo using the mouse model described above. The effect of the compounds on the production of pro-inflammatory cytokines induced by LPS can be evaluated in various tissues (e.g., plasma, brain, intestine, spleen, lung, etc.). Using mature C57Bl6 / J wild-type mice, the effect of the compounds disclosed herein ("test" compounds) on cytokine production induced by intraperitoneal injection of LPS (lipopolysaccharide) [LPS from Escherichia coli O111:B4, Sigma-Aldrich # L4391] was evaluated. Prior to treatment with LPS (1 mg / kg dissolved in sterile PBS (intraperitoneal injection)), mice were randomly divided into a placebo / control group receiving an intraperitoneal (IP) injection of the vehicle used to dissolve the test compound (50% PEG4000 / 50% DMSO) and a treatment group (IP administration of 20 mg / kg of the test compound). Mice were injected with either the test compound or the vehicle 15 minutes prior to the LPS injection.

[0583] Subsequently, mice were humanely euthanized 4 hours after intraperitoneal injection of LPS. After euthanasia, blood was collected by intracardiac puncture using EDTA as an anticoagulant. The blood was immediately centrifuged at 1500g for 4 hours, plasma was collected, and flash-frozen in liquid nitrogen. All other tissues were rapidly dissected and flash-frozen in liquid nitrogen. Samples were stored at -80°C.

[0584] Tissue homogenates were prepared by sonication in ice-cold M-PER reagent (Pierce Biotechnology, Rockford, IL, USA) containing 1 mM phenylmethanesulfonyl fluoride, 1X protease cocktail inhibitor (Roche, Inc., USA), and 1 mM sodium orthovanadate (Sigma-Aldrich, MO, USA). Cytokines were quantified by electrochemiluminescence using MULTI-SPOT plates from the V-Plex assay kit pro-inflammatory panel 1 (mouse) kit (Mesoscale discovery, USA). All LPS-treated samples were diluted 10X with diluent 41 from the kit, while control samples were analyzed without dilution. The amounts of the generated pro-inflammatory cytokines interferon-gamma, IL-1β, and TNFα were lower in the treatment groups compared to the control group.

[0585] Formulation Examples

[0586] Representative pharmaceutical formulations containing the compounds of the present disclosure are described below.

[0587] Tablet formulation

[0588] The following ingredients were closely mixed and compressed into a single-engraved tablet.

[0589] Amount of ingredients in tablets

[0590] mg

[0591] Compound 400 of the present disclosure

[0592] 50 corn starch

[0593] Croscarmellose sodium 25

[0594] Lactose 120

[0595] Magnesium Stearate 5

[0596] Capsule formulation

[0597] The following ingredients were tightly mixed and placed in a hard-shell gelatin capsule.

[0598] Amount per capsule of ingredients

[0599] mg

[0600] Compound 200 of the present disclosure

[0601] Spray-dried lactose 148

[0602] Magnesium stearate 2

[0603] Injectable formulation

[0604] A compound of the present disclosure (e.g., Compound 1) in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 according to MSA, and an appropriate amount up to 20 mg / mL.

[0605] Inhalation composition

[0606] To prepare a pharmaceutical composition for inhalation delivery, 20 mg of the compound disclosed herein is mixed with 50 mg of anhydrous citric acid and 100 mL of a 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery device suitable for inhalation administration, such as a nebulizer.

[0607] Topical gel composition

[0608] To prepare a pharmaceutical topical gel composition, 100 mg of the compound disclosed herein is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate, and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into a container suitable for topical administration, such as a tube.

[0609] ophthalmic solution composition

[0610] To prepare a pharmaceutical ophthalmic solution composition, 100 mg of the compound disclosed herein was mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. Subsequently, the resulting isotonic solution was incorporated into an ophthalmic delivery device suitable for ophthalmic administration, such as an ophthalmic container.

[0611] Nasal spray solution

[0612] To prepare a pharmaceutical nasal spray solution, 10 g of the compound disclosed herein is mixed with 30 mL of 0.05 M phosphate buffer solution (pH 4.4). The solution is placed in a nasal dispenser designed to deliver 100 µl of spray for each application.

Claims

Claim 1 Compound of formula (IA) or formula (IB) or a pharmaceutically acceptable salt thereof: In the above formula, n is 1 or 2; Het is pyridine-3-yl; and R 1 is hydrogen or alkyl; R 2 is hydrogen or alkyl and;R 3 is methyl, ethyl, isopropyl, benzyl, cyclohexylmethyl, or naphthylmethyl; R 4 is hydrogen or alkyl and;R 5 is -C(O)R 6 and, here, R 6 is phenyl, furanyl, pyrrolyl, pyridinyl, pyrazinyl, or quinolinyl, wherein the phenyl is independently selected from C1-C2 alkyl, C1-C2 alkoxy, halo, trifluoromethyl, nitro, amino, C4 alkylamino, and -NHC(O)R. g and / or R h It is optionally substituted with, where R is a C1-C4 alkyl, C3-C6 cycloalkyl, C1-C3 alkylamino, or 4-(4λ 3 -butyl)tetrahydro-1 H -Tieno[3,4- d ]Imidazole-2(3 H )-one, and the pyrrolyl is optionally substituted with an alkyl group. Claim 2 In claim 1, the compound having the structure (IA): . Claim 3 In claim 1, the compound having the structure (IB): . Claim 4 A compound in which n is 1, in any one of claims 1 to 3. Claim 5 A compound in which n is 2, in any one of claims 1 to 3. Claim 6 In any one of paragraphs 1 to 3, R 6 This R g and / or R h A compound of phenyl phosphate arbitrarily substituted with . Claim 7 In any one of paragraphs 1 to 3, R 1 and R 2 A compound in which is independently hydrogen or methyl. Claim 8 In Paragraph 7, R 1 and R 2 A compound in which is independently hydrogen. Claim 9 In any one of paragraphs 1 to 3, R 1 and R 2 A compound in which all are alkyls and are not bonded to the same ring carbon. Claim 10 In any one of paragraphs 1 to 3, R 3 This benzyl compound. Claim 11 In any one of paragraphs 1 to 3, R 3 A compound in which the stereochemistry of the bonded carbon is (S). Claim 12 In any one of paragraphs 1 to 3, R 3 A compound in which the stereochemistry of the bonded carbon is (R). Claim 13 A pharmaceutical composition for treating a disease treatable by inhibiting NF-kB activation, comprising a compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the disease is an inflammatory disease. Claim 14 A pharmaceutical composition for treating a disease treatable by inhibiting NF-kB activation, comprising a compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the disease is selected from the group consisting of autoimmune diseases, pain, allergy, asthma, chronic obstructive pulmonary disease, and sepsis. Claim 15 A pharmaceutical composition according to claim 14, wherein the disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, atherosclerosis, multiple sclerosis, asthma, inflammatory bowel disease, diabetes mellitus, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, osteoporosis, systemic lupus erythematosus, chronic obstructive pulmonary disease, cystic fibrosis, stroke, acute renal injury, glomerulonephritis, psoriasis, atopic dermatitis, Behcet's disease, pulmonary tuberculosis, Crohn's disease, colitis, Paget's disease, pancreatitis, periodontitis, inflammatory lung disease, and lupus nephritis. Claim 16 delete Claim 17 delete Claim 18 delete Claim 19 delete Claim 20 delete Claim 21 delete Claim 22 delete Claim 23 delete Claim 24 delete Claim 25 delete Claim 26 delete Claim 27 delete Claim 28 delete Claim 29 delete Claim 30 delete Claim 31 delete Claim 32 delete Claim 33 delete Claim 34 delete

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