Amino acid derivatives for treating inflammatory diseases

Abstract

The present disclosure provides certain amino acid derivatives that inhibit NF-kB activation and are therefore useful in the treatment of inflammatory diseases. Pharmaceutical compositions containing such compounds and processes for preparing such compounds are also provided. The present disclosure relates to a method for treating a disease treatable by inhibiting NF-kB activation, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in a pharmaceutical composition comprising the compound of formula (I) and a pharmaceutically acceptable excipient.

Description

[Technical Field]

[0001] The present disclosure provides certain amino acid derivatives that inhibit the activation of nuclear factor kappa B (NF-kB) induced by inflammatory stimuli.Therefore, the compounds of the present disclosure are useful for treating inflammatory disorders such as rheumatoid arthritis, multiple sclerosis, asthma and inflammatory bowel disease.Pharmaceutical compositions containing such compounds and processes for preparing them are also provided. [Background technology]

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

[0003] NF-kB is a ubiquitously expressed transcription factor that regulates the expression of genes involved in inflammation and pain. NF-kB activation plays a central role in inflammation through its ability to induce the transcription of proinflammatory genes (see Tak et al., NF-kB: a key role in inflammatory diseases. J Clin Inv 2001;107:7-11; and Liu et al., NF-kB signaling in inflammation. Signal Transduct Target Ther. 2017;2.pii:17023). The synthesis of proinflammatory 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. Reciprocally, cytokines such as TNF-α and IL-1β or prostaglandins produced by COX-2 induce NF-kB activation generating an inflammatory cascade.

[0004] NF-kB is activated at sites of inflammation in a variety of 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 Biosci 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 have many side effects that can be mild or severe, especially when used for long periods of time. For example, corticosteroids can cause weight gain, edema, hypertension, glaucoma, hypokalemia, cataracts, psychiatric disorders, osteoporosis, and a weakened immune system. Nonsteroidal anti-inflammatory drugs (NSAIDs), which act through the inhibition of cyclooxygenase (COX) isoenzymes, are widely prescribed. However, 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 solitary ulcers in both the stomach and duodenum), renal side effects (interstitial nephritis), and hepatic adverse reactions (hypertransaminasemia, hepatitis). Biologics targeting inflammatory cytokines are being developed. Although biologics have been shown to ameliorate the pathology and progression of inflammatory diseases, their use is limited due to severe adverse reactions and the fact that they abrogate host defenses against infection (Rider et al. Biologics for Targeting Inflammatory Cytokines, Clinical Uses, and Limitations. Int J Cell Biol. 2016;2016:9259646). Thus, there is a need to develop other anti-inflammatory drugs with fewer side effects for chronic use. The present invention fulfills this and related needs. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Tak et al. NF-kB:a key role in inflammatory diseases.J Clin Inv 2001;107:7-11 [Non-patent document 2] Liu et al. NF-κB signaling in inflammation.Signal Transduct Target Ther.2017;2.pii:17023 [Non-patent document 3] Pai et al. Immune deficiency or hyperactivity-Nf-kappab illuminates autoimmunity.J Autoimmun 2008;31:245-251 [Non-patent document 4] Zhang et al. NFkB in inflammation and renal diseases.Cell Biosci 2015;5:63 [Non-patent document 5] Roman-Blas et al. NF-kB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis.OsteoArthritis and Cartilage 2006;14:839-848 [Non-patent document 6] Rider et al. Biologics for Targeting Inflammatory Cytokines,Clinical Uses,and Limitations.Int J Cell Biol.2016;2016:9259646 Summary of the Invention [Means for solving the problem]

[0007] overview In one embodiment, the compound of formula (I): [ka] (In the formula, n is 0, 1, 2 or 3; Dashed lines are necessary bonds; Het is an R independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, dialkylamino, carboxy, and alkoxycarbonyl. a , R b and / or R c is heteroaryl optionally substituted with; R 1 is hydrogen or alkyl; R 2 is hydrogen or alkyl; R 3 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, acylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, where aryl or heteroaryl, alone or as part of an 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 with substitution as necessary; R 4 is hydrogen or alkyl; R 5 HA-C(O)R 6 and R 6 is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, and aryl or heteroaryl, alone or as part of an 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, halo, haloalkyl, haloalkoxy, cyano, nitro, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, acylamino, and sulfonylamino.g , R h and / or R i with R 4 and R 5 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycloamino ring) or Pharmaceutically acceptable salts thereof are provided.

[0008] In a second aspect, the present disclosure relates to a pharmaceutical composition comprising the compound of formula (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0009] In a third aspect, the disclosure relates to a method of treating a disease treatable by inhibiting NF-kB activation, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in a pharmaceutical composition comprising a compound of Formula (I) (or any of the embodiments thereof described herein) and a pharmaceutically acceptable excipient. In one embodiment, the disease is an inflammatory disease, including 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, Paget's disease, pancreatitis, periodontitis, inflammatory lung disease, and lupus nephritis.

[0010] In a fourth aspect, the present disclosure relates to a compound of formula (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof for use as a pharmaceutical. In one embodiment, the compound of formula (I) (and any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof is useful for treating inflammatory diseases, including autoimmune diseases, pain, allergies, 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, Paget's disease, pancreatitis, periodontitis, inflammatory lung disease, and lupus nephritis.

[0011] In a fifth aspect, the compound of Formula (I) or a pharmaceutically acceptable salt thereof (and any of the embodiments thereof disclosed herein) is provided for use in treating a patient's disease 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 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, Behçet's disease, tuberculosis, Crohn's disease, colitis, Paget's disease, pancreatitis, periodontitis, inflammatory lung disease, and lupus nephritis.

[0012] In a sixth aspect, an intermediate of formula (II): [ka] (wherein dashed line, n, Het, R 1 , R 2 and R3 is as defined above for formula (I) (including the embodiments thereof disclosed herein). In one aspect, the intermediate has the structure (IIB): [ka] (Wherein, n, Het, R 1 , R 2 and R 3 is as defined for formula (I) (including the embodiments thereof disclosed herein). In another embodiment, the intermediate has the structure (IIB'): [ka] (In the formula, R 1 , R 2 and R 3 is as defined for formula (I) (including the embodiments thereof disclosed herein), and pyridyl is R a , R b and / or R c (substituted as necessary) It has.

[0013] In a seventh embodiment, a compound of formula (IB): [ka] (Wherein, n, Het, R 1 , R 2 and R 3 is as defined above, and R 4 is hydrogen or alkyl, and R 5 HA-COR 6 (In the formula, R 6 is as defined above) A process for producing Compound of formula (IIB): [ka] (wherein dashed line, n, Het, R1 , R 2 and R 3 is as defined above) of, (i) Under acylation reaction conditions, 6 COLG(wherein, R 6 is as defined above in formula (I), and LG is a leaving group; or (ii) a compound of formula R 6 reacting with a compound of COOH; (iii) optionally converting the compound of formula (IB) obtained from step (i) or step (ii) into an acid addition salt; or (iv) optionally converting the compound of formula (IB) obtained from step (i) or step (ii) into a free base; A process is provided that includes: In an embodiment of the present invention, for example, the following items are provided: (Item 1) Compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, n is 0, 1 or 2; Dashed lines are necessary bonds; Het is an R independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, dialkylamino, carboxy, and alkoxycarbonyl. a 、R b and / or R c is heteroaryl optionally substituted with; R 1 is hydrogen or alkyl; R 2 is hydrogen or alkyl; R 3 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, acylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, where aryl or heteroaryl, alone or as part of an 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 with substitution as necessary; R 4 is hydrogen or alkyl; R 5 HA-C(O)R 6 and R 6 is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, and aryl or heteroaryl, alone or as part of an 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, halo, haloalkyl, haloalkoxy, cyano, nitro, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, acylamino, and sulfonylamino. g 、R h and / or R i with R 4 and R 5 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycloamino ring; A compound or a pharmaceutically acceptable salt thereof. (Item 2) The compound has the structure (IA):

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[0014] Detailed Description definition Unless otherwise stated, the following terms used in the specification and claims are defined for purposes of this application and have the following meanings:

[0015] "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like.

[0016] "Alkylene," unless otherwise specified, means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[0017] "Alkylthio" means a -SR radical where R is alkyl as defined above, e.g., methylthio, ethylthio, and the like.

[0018] "Alkylsulfonyl" means a -SO2R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.

[0019] "Amino" means -NH2.

[0020] "Alkylamino" means an --NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and the like.

[0021] "Aminoalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms substituted with -NR'R", where R' and R" are independently hydrogen or alkyl as defined above, e.g., aminomethyl, aminoethyl, methylaminomethyl, and the like.

[0022] "Alkoxy" means an --OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.

[0023] "Alkoxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, substituted with at least one alkoxy group, e.g., one or two alkoxy groups as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

[0024] "Alkoxyalkyloxy" means a -(O)R radical where R is alkoxyalkyl as defined above, e.g., methoxyethoxy, ethoxyethoxy, and the like.

[0025] "Aminoalkyloxy" means an -O-alkylene-R group where R is -NR'R" and R' and R" are independently hydrogen or alkyl as defined above, e.g., aminoethyloxy, methylaminoethyloxy, dimethylaminoethyloxy, diethylaminoethyloxy, and the like.

[0026] "Thioalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms substituted with an --SH group, e.g., thioethyl, 1-, 2-, or 3-thiopropyl, and the like.

[0027] "Alkylthioalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, substituted with an alkylthio group, as defined above, e.g., 2-methylthioethyl, 1-, 2-, or 3-ethylthiopropyl, and the like.

[0028] "Alkoxycarbonyl" means a -C(O)OR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

[0029] "Alkoxycarbonylalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, substituted with an alkoxycarbonyl group as defined above, e.g., 2-methylcarboxyethyl, methylcarboxymethyl, 1-, 2-, or 3-ethylcarboxypropyl, and the like.

[0030] "Acyl" means a -C(O)R radical where R is alkyl as defined above, e.g., methylcarbonyl, ethylcarbonyl, and the like.

[0031] "Acylamino" means a -NHC(O)R group where R is alkyl as defined above, e.g., methylcarbonylamino, ethylcarbonylamino, etc., or R may be optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxyl, cycloalkyl, heterocycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfonyl, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, and cyano, as disclosed herein.

[0032] "Acylaminoalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, substituted with an acylamino group as defined above, e.g., 2-acetylaminoethyl, 1-, 2-, or 3-ethanoylaminopropyl, and the like.

[0033] "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 substituted with a -CONRR' group, where R is hydrogen or alkyl, R' is hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryl, or R and R' together with the nitrogen atom to which they are attached form a heterocycloamino, e.g., aminocarbonylethyl, methylaminocarbonylethyl, methylaminocarbonylmethyl, 1-, 2-, or 3-ethylaminocarbonylpropyl, pyrrolidinylmethyl, piperidinylethyl, and the like.

[0034] "Aryl" means a monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 ring atoms, eg, phenyl or naphthyl.

[0035] "Aralkyl" means a -(alkylene)-R radical where R is aryl as defined above, e.g., benzyl, phenethyl, and the like.

[0036] "Cycloalkyl" means a cyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0037] "Cycloalkyloxy" means --OR where R is cycloalkyl as defined above, e.g., cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and the like.

[0038] "Cycloalkylalkyl" means a -(alkylene)-R radical where R is cycloalkyl as defined above, e.g., cyclopropylmethyl, cyclohexylmethyl, and the like.

[0039] "Cycloalkylalkyloxy" means an --O-cycloalkylalkyl group as defined above, for example, cyclopropylmethyloxy, 2-cyclopropylethyloxy, 1-, 2-, 3-cyclobutylpropoxy, and the like.

[0040] "Carboxy" means --COOH.

[0041] "Carboxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, substituted with a carboxy group, as defined above, e.g., 2-carboxyethyl, 1-, 2-, or 3-carboxypropyl, and the like.

[0042] "Dialkylamino" means a --NRR' radical where R and R' are alkyl as defined above, e.g., dimethylamino, methylethylamino, and the like.

[0043] "Halo" means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.

[0044] "Haloalkyl" means an alkyl group as defined above that is substituted with one or more halogen atoms, e.g., 1 to 5 halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc. When an alkyl is substituted with only fluoro, it may be referred to in this application as fluoroalkyl. "Haloalkoxy" means an -OR radical where R is haloalkyl as defined above, e.g., -OCF, -OCHF, etc. When R is haloalkyl and the alkyl is substituted with only fluoro, it may be referred to in this Application as fluoroalkoxy.

[0045] "Hydroxyalkyl" means a linear hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms substituted with one or two hydroxy groups (provided that if two hydroxy groups are present, they are not both on the same carbon atom). Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 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.

[0046] "Hydroxyalkyloxy" means an --OR radical where R is hydroxyalkyl as defined above, e.g., hydroxymethyloxy, 2-hydroxyethyloxy, 1-, 2-, 3-hydroxypropoxy, and the like.

[0047] A "heterocycloalkyl" or "heterocyclyl" is a heterocyclic alkyl group in which one, two, or three ring atoms are N, O, or S(O). n(wherein n is an integer from 0 to 2), and the remaining ring atoms are C. Furthermore, one or two ring carbon atoms in the heterocyclyl ring may optionally be replaced by a -CO- group, and the heterocycloalkyl is optionally fused to phenyl or a 5- or 6-membered heteroaryl as defined above. More specifically, the term heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, and the like. When the heterocyclyl ring is unsaturated, it can contain one or two ring double bonds, as long as the ring is not aromatic. When a heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocycloamino, and is a subset of the heterocyclyl group. Unless otherwise specified, heterocycloalkyl rings are optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, and dialkylamino.

[0048] "Heterocycloalkylalkyl" means a -(alkylene)-R radical where R is a heterocycloalkyl ring as defined above, e.g., tetraydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.

[0049] "Heterocycloamino" refers to a heterocyclic group in which one or two ring atoms are N, O, or S(O). n(wherein n is an integer from 0 to 2), the remaining ring atoms are C, with the proviso that, unless otherwise specified, at least one ring atom is N. Furthermore, one or two ring carbon atoms in the heterocycloamino ring may optionally be replaced by a -CO- group. The heterocycloamino is optionally fused to a phenyl or a 5- or 6-membered heteroaryl as defined above. More specifically, the term heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, thiomorpholino, and the like. Unless otherwise specified, 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, each as defined herein.

[0050] "Heteroaryl," unless otherwise specified, refers to a monovalent monocyclic or bicyclic aromatic group of 5 to 10 ring atoms in which 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 carbon. 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, tetrazolyl, and the like. As defined herein, the terms "heteroaryl" and "aryl" are mutually exclusive. When a heteroaryl ring contains five or six ring atoms, it is also referred to herein as a five- or six-membered heteroaryl.

[0051] "Heteroaralkyl" means a -(alkylene)-R group, where R is heteroaryl as defined above, e.g., pyridinylmethyl, and the like. When the heteroaryl ring in the heteroaralkyl contains 5 or 6 ring atoms, it is also referred to herein as a 5- or 6-membered heteroaralkyl.

[0052] "Patient" means a mammal, preferably a human.

[0053] The present disclosure also includes protected derivatives of Compound (I) of the present disclosure. For example, when the compounds of the present disclosure contain groups such as hydroxy, carboxy, thiol, or any group containing one or more nitrogen atoms, these groups can be protected with suitable protecting groups. A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (1999), the entire disclosure of which is incorporated herein by reference. Protected derivatives of the compounds of the present disclosure can be prepared by methods well known in the art.

[0054] The present disclosure also includes polymorphic forms and deuterated forms of the disclosed compounds or pharmaceutically acceptable salts thereof.

[0055] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include:

[0056] Acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic 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, salts formed with organic acids such as benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid; or

[0057] Salts are formed when the acidic proton present in the parent compound is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion or an aluminum ion, or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. Pharmaceutically acceptable salts are understood to be non-toxic. Further information about suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety.

[0058] The compounds of the present disclosure may have asymmetric centers. Compounds of the present disclosure containing asymmetrically substituted atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms, such as by resolution of materials, are well known in the art. Unless a specific stereochemistry or isomeric form is specifically indicated, all chiral, diastereomeric, and all mixtures of chiral or diastereomeric forms, as well as racemic forms, are within the scope of the present disclosure. When a compound is designated as an (R) or (S) stereoisomer, it is also understood by those skilled in the art that it may contain the corresponding (S) or (R) stereoisomer as an impurity, preferably present at less than about 10%, preferably less than 5% w / w, of the undesired enantiomer. About means + or -10% of the initial value.

[0059] Certain compounds of the present disclosure may exist as tautomers and / or geometric isomers. All possible tautomers, as individual forms and mixtures thereof, and cis and trans isomers are within the scope of the present disclosure. Furthermore, as used herein, the term alkyl includes all possible isomeric forms of said alkyl group, although only a few examples are set forth. Similarly, when cyclic groups such as aryl, heteroaryl, and heterocyclyl are substituted, they include all positional isomers, although only a few examples are set forth. Furthermore, all hydrates of compounds of the present disclosure are within the scope of the present disclosure.

[0060] "Oxo" or "carbonyl" refers to the =(O) group.

[0061] "Optionally substituted alkyl" means 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.

[0062] "Optionally substituted aryl" means aryl as defined above 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. "Optionally substituted aryloxy" means an -O-alkylene-R radical where R is an optionally substituted aryl as defined above, e.g., benzyloxy, methoxybenzyloxy, halobenzyloxy, 2-phenethyloxy, and the like.

[0063] "Optionally substituted aralkyl" means -alkylene-R, where R is an optionally substituted aryl, each as defined above. "Optionally substituted aralkyloxy" means an -O-alkylene-R group, where R is an optionally substituted aryl, each as defined above, such as benzyloxy, methoxybenzyloxy, halobenzyloxy, 2-phenethyloxy, and the like.

[0064] "Optionally substituted heteroaryl" means heteroaryl as defined above optionally substituted with one, two, or three substituents independently selected from alkyl, alkylthio, alkylsulfonyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and cyano.

[0065] "Optionally substituted heteroaryloxy" means an --OR radical where R is an optionally substituted heteroaryl as defined above, e.g., pyridinyloxy, furanyloxy, thienyloxy, and the like.

[0066] "Optionally substituted heteroaralkyloxy" means an -O-alkylene-R group, where R is an optionally substituted heteroaryl as defined above.

[0067] "Optionally substituted heterocycloalkyl" means heterocycloalkyl as defined above 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.

[0068] "Optionally substituted heterocycloalkylalkyl" means an -alkylene-R radical where R is an optionally substituted heterocycloalkyl as defined above, e.g., piperidinylmethyl, pyrrolidinylethyl, piperazin-1-ylethyl, and the like.

[0069] "Optionally substituted heterocycloalkyloxy" means an -OR radical where R is an optionally substituted heterocycloalkyl as defined above, e.g., piperidinyloxy, pyrrolidinyloxy, tetrahydrofuranyloxy, and the like.

[0070] "Optionally substituted heterocycloalkylalkyloxy" means an -O-alkylene-R radical where R is an optionally substituted heterocycloalkyl as defined above, e.g., piperidinylmethyloxy, pyrrolidinylethyloxy, piperazin-1-ylethyloxy, and the like.

[0071] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl may, but need not, be present, and the description includes instances where the heterocyclyl group is substituted with an alkyl group and instances where the heterocyclyl group is not substituted with an alkyl group.

[0072] A "pharmaceutically acceptable carrier or excipient" generally means a carrier or excipient that is safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes carriers or excipients that are acceptable for veterinary and human pharmaceutical use. As used in this specification and claims, "pharmaceutically acceptable carrier / excipient" includes both one such excipient and more than one such excipient.

[0073] "Sulfonylamino" means the group -NRSO2R', where R is hydrogen or alkyl and R' is alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl, each as defined above.

[0074] "Treating" or "treatment" of a disease includes: (1) To prevent disease, i.e., to prevent the development of clinical symptoms of disease in mammals that may be exposed to or predisposed to the disease but that have not yet experienced or exhibited symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or (3) Relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

[0075] A "therapeutically effective amount" means the amount of a compound of the present disclosure and / or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0076] Embodiments: Embodiment 1: In embodiment 1, a compound of formula (I) as defined in the summary above.

[0077] Embodiment 2: In embodiment 2, the compound of formula (I) has the structure (IA): [ka] (Wherein, Het, R 1 , R 2 , R 3 , R 4 , R 5 and n is as defined in the overview). It has.

[0078] Embodiment 3: In embodiment 3, the compound of formula (I) has the structure (IB): [ka] (Wherein, Het, R 1 , R 2 , R 3 , R 4 , R 5 and n is as defined in the overview). It has.

[0079] Embodiment 4: In embodiment 4, the compound of any one of embodiments 1, 2, and 3 is a compound where n is 1, 2, or 3.

[0080] Embodiment 5: In embodiment 5, the compound of any one of embodiments 1, 2, 3, and 4 is a compound where n is 1.

[0081] Embodiment 6: In embodiment 6, the compound of any one of embodiments 1, 2, and 3 is a compound where n is 0 or 2. In one subembodiment of embodiment 6, the compound of any one of embodiments 1, 2, and 3 is a compound where n is 0. In a second subembodiment of embodiment 6, the compound of any one of embodiments 1, 2, and 3 is a compound where n is 2.

[0082] Embodiment 7: In embodiment 7, the compound of any one of embodiments 1 to 6 and subembodiments therein comprises R 4 is hydrogen or alkyl, and R 5 -C(O)R 6 and R 6 is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, and aryl or heteroaryl, alone or as part of an 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, halo, haloalkyl, haloalkoxy, cyano, nitro, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, acylamino, and sulfonylamino; g , R h and / or R i In one subembodiment of embodiment 7, the compound of any one of embodiments 1 to 6 is a compound optionally substituted with R 6 R is defined above g , R hand / or R i (As used herein, the above refers to embodiment 7.) In a second subembodiment of embodiment 7, the compound of any one of embodiments 1 to 6 is a compound wherein R is an aryl or heteroaryl optionally substituted with R 6 R is defined above g , R h and / or R i In a third subembodiment of embodiment 7, the compound of any one of embodiments 1 to 6 is a compound that is an aralkyl or heteroaralkyl optionally substituted with R 6 R is defined above g , R h and / or R i In a fourth subembodiment of embodiment 7, the compound of any one of embodiments 1 to 6 is a compound that is phenyl optionally substituted with R 6 R is defined above g , R h and / or R i In a fifth subembodiment of embodiment 7, the compound of any one of embodiments 1 to 6 and subembodiments 1 to 4 within embodiment 7 is a compound that is optionally substituted with R g is alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, or cyano, and R h and R iis 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, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, acylamino, and sulfonylamino. In a sixth subembodiment of embodiment 7, the compound of any one of embodiments 1 to 6 and the compounds of the first through fifth subembodiments within embodiment 7 are compounds wherein R g , R h and / or R i are compounds 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 pentanoylamino.

[0083] Embodiment 8: In embodiment 8, the compound of any one of embodiments 1 to 6 and subembodiments therein comprises R 4 and R 5 taken together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycloamino ring. In one subembodiment of embodiment 8, the heterocycloamino ring is pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, thiomorpholino, 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.

[0084] Embodiment 9: In embodiment 9, the compound of any one of embodiments 1 to 8 and subembodiments therein comprises R 1 and R 2 are independently hydrogen or methyl, preferably hydrogen.

[0085] Embodiment 10: In embodiment 10, the compound of any one of embodiments 1 to 9 and subembodiments therein comprises R 1 and R 2 When both are alkyl, they are not attached to the same ring carbon.

[0086] Embodiment 11: In embodiment 11, the compound of any one of embodiments 1 through 10 and subembodiments therein is further characterized in that Het is pyridinyl, pyrimidinyl, pyrazinyl, furanyl, thienyl, quinolinyl, isoquinolinyl, pyrazolyl, or indolyl, and each ring is independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, dialkylamino, carboxy, and alkoxycarbonyl. a , R b and / or R c R is preferably independently selected from methyl, ethyl, methoxy, ethoxy, chloro, fluoro, trifluoromethyl, trifluoromethoxy, cyano, amino, methylamino, and dimethylamino; a , R b and / or R c In one subembodiment, Het is pyridin-2-yl.

[0087] Embodiment 12: In embodiment 12, the compound of any one of embodiments 1 to 11 and subembodiments therein comprises R 3is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, acylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, where aryl or heteroaryl, alone or in aralkyl and heteroaralkyl, are independently selected from alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, cyano, nitro, carboxy, alkoxycarbonyl, amino, alkylamino, or dialkylamino; d , R e and / or R f In one subembodiment of embodiment 12, the compound of any one of embodiments 1 to 11 is optionally substituted with R 3 is hydrogen or alkyl, preferably methyl, ethyl, propyl, isopropyl, sec-propyl, n-, sec, iso or tert-butyl.

[0088] In a second subembodiment of embodiment 12, the compound of any one of embodiments 1 to 11 comprises R 3 R is defined above d , R e and / or R f and optionally substituted aralkyl, preferably R 3 is benzyl or phenethyl, more preferably R as defined above d , R e and R f and even more preferably benzyl optionally substituted with

[0089] In a third subembodiment of embodiment 12, the compound of any one of embodiments 1 to 11 is R 3 R is defined above d , R e and / or R f cycloalkylalkyl optionally substituted with, preferably R as defined above d, R e and R f and n is 0 or 1. The compounds are cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl optionally substituted with

[0090] In a fourth subembodiment of embodiment 12, the compound of any one of embodiments 1 to 11 is R 3 R is defined above d , R e and / or R f and optionally substituted heteroaralkyl (eg, thienylmethyl, furanylmethyl, pyridinylmethyl, quinolinylmethyl, isoquinolinylmethyl, indolylmethyl, or indazolylmethyl).

[0091] In a fifth subembodiment of embodiment 12, the compound of any one of embodiments 1 to 11 comprises R 3 is a hydroxyalkyl, alkoxyalkyl or aminoalkyl, preferably hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, aminomethyl or aminobutyl.

[0092] In one embodiment, R 3 The stereochemistry at the carbon to which is attached is (S).

[0093] In another embodiment, R 3 The stereochemistry at the carbon to which is attached is (R).

[0094] R 1 and R 2 Representative compounds of formula (I) where is H, n is 1, and other groups are as shown in Table 1 below are: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0095] Further contemplated compounds of formula (I) are provided in Table 2 below: [Table 2-1] [Table 2-2]

[0096] General synthetic scheme The compounds of the present disclosure can be prepared by the methods illustrated in the reaction schemes shown below.

[0097] The starting materials and reagents used in the preparation of these compounds are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrance, California) or Sigma (St. Louis, Missouri), or are prepared by methods known to those skilled in the art according to procedures set forth in references such as 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 Supplements (Elsevier Science Publishers, 1989); 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 schemes are merely illustrative of some of the methods by which the compounds of the present disclosure can be synthesized; various modifications to these schemes can be made and will be suggested to those skilled in the art upon reading this disclosure. The starting materials and intermediates of the reactions, as well as the final products, can be isolated and purified, if desired, using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data. Unless otherwise specified, the reactions described herein are carried out over a temperature range of about -78°C to about 150°C, e.g., about 0°C to about 125°C, further e.g., at about room (or ambient) temperature, e.g., about 20°C, at atmospheric pressure.

[0098] R 1 , R 2 , R 3 , Het is as defined in the overview, and R 4 is hydrogen or alkyl, and R5 Ga-COR 6 (In the formula, R 6 Compounds of formula (IA) and (IB), where R is as defined in the Summary, can be prepared as described in Scheme 1 below. [ka]

[0099] R is prepared as described in Scheme 2 below. 4 and R 5 Treatment of compound (I') with aqueous hydrazine, in which (I') forms a phthalimide ring together with the nitrogen atom, provides the amino compound of formula 1. The reaction can be carried out in an alcohol solvent such as methanol, ethanol, or isopropyl alcohol.

[0100] The compound of formula 1 is reacted with R 6 is as defined in the Summary with an acid of formula 2, in the presence of a coupling agent such as HOBt, EDC, and a non-nucleophilic base such as triethylamine, diisopropylamine, i-PrNEt, at room temperature in an organic solvent such as dichloromethane, chloroform, to give compound (I'').

[0101] Alternatively, compounds of formula (I) can be prepared by converting a compound of formula 1 under acylation reaction conditions to a compound of formula R 6 It can be prepared by reacting CO(LG) with acetyl.

[0102] The compound of formula 2 is commercially available or can 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, propionic acid, cyclopropanecarboxylic acid, and cyclopentanecarboxylic acid are commercially available. The compound of formula 2 can also be prepared from commercially available compounds. For example, R 6 is reacted with an optionally substituted aralkyl halide, an optionally substituted heterocycloalkyl halide, and an optionally substituted heterocycloalkylalkyl halide under alkylation reaction conditions to form a compound of formula 2, wherein R is a hydroxy-substituted aryl, aralkyl, heteroaryl, or heteroaralkyl; 6 is substituted with optionally substituted aralkyloxy, optionally substituted heterocycloalkyloxy, or optionally substituted heterocycloalkylalkyloxy, respectively. 6 A compound of formula 2 in which R is substituted with an amino group is reacted with an acid halide or sulfonyl halide under acylation and sulfonylation reaction conditions to form R 6 can be obtained the corresponding compounds of formula 2, in which each is substituted with an acylamino group or a sulfonylamino group.

[0103] Alternatively, the above transformation can be done in R 6 It can also be performed on compounds of formula (I") or (I'"), where is an aryl, aralkyl, heteroaryl or heteroaralkyl substituted with a hydroxy or amino group.

[0104] dashed line, R 1 , R 2 , R 3 , Het is as defined in the overview, and R 4 and R 5However, compounds of formula (IA) and (IB), which together with the nitrogen atom to which they are attached form a phthalimide ring, can be prepared as described in Scheme 2 below. [ka]

[0105] R 3 Compounds of formula 4, where R is as defined in the summary, can be prepared by reacting compounds of formula 3 with phthalic anhydride under basic conditions (see J.C. Sheehan, D.W. Chapman, and R.W. Roth, J. Am. Chem. Soc., 74, 3822 (1952)) or acidic conditions (see R. Mahboub, int. J. Chem. Sci., 7(1), 2009, 28-36) at elevated temperatures. When basic reaction conditions are used, the reaction is carried out in an aromatic organic solvent such as benzene or toluene in the presence of an organic base such as EtN or iPrNet. Compounds of formula 3 are commercially available or readily prepared by methods known in the art.

[0106] Compound (I) can be prepared by adding under acylation reaction conditions a solution of a compound of formula 6 and an acid chloride of formula 5. Suitable solvents include aromatic or halogenated organic solvents such as anhydrous benzene, toluene or DCM.

[0107] Compounds of formula 5 can be prepared by reacting compounds of formula 4 with a chlorinating agent such as SOCl, (COCl), or PCl under conditions well known in the art. 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.

[0108] dashed line, R 1 , R 2 , R 3 , Het is as defined in the overview, and R 4 and R5 which, taken together with the nitrogen atom to which they are attached, form pyrrolidinyl, piperidinyl, or homopiperidinyl, can be prepared as described in Scheme 3 below. [ka]

[0109] Protection of the amino group in a compound of formula 1 with a suitable amino-protecting group such as Boc, benzyl, or Ns, followed by treatment of the resulting compound of formula 7 with a compound of formula 8, in which each X is a leaving group such as halo (e.g., chloro or bromo), tosylate, or mesylate, and m is 0-2, provides a compound of formula 9. The reaction is carried out in the presence of NaH in THF. Removal of the amino-protecting group followed by cyclization of the resulting amine in the presence of a base such as potassium hydroxide or sodium hydroxide in a suitable organic solvent such as dichloromethane provides a compound of formula (I).

[0110] By proceeding as above but substituting compound 8 with other starting materials such as 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 appreciated by those skilled in the art that compounds of formula (I) can be synthesized in which form other heterocycloamino rings.

[0111] Administration and Pharmaceutical Compositions In general, compounds of the present disclosure are administered in therapeutically effective amounts by any of the accepted modes of administration for agents that perform similar utilities. Therapeutically effective amounts of compounds of the present disclosure can range from about 0.01 to about 500 mg per kg of patient body weight per day, and can be administered in single or multiple doses. Suitable dosage levels can be from about 0.1 to about 250 mg / kg / day; or from about 0.5 to about 100 mg / kg / day. Suitable dosage levels can be from about 0.01 to about 250 mg / kg / day, from about 0.05 to about 100 mg / kg / day, or from about 0.1 to about 50 mg / kg / day. Within this range, dosages can be from about 0.05 to about 0.5, from about 0.5 to about 5, or from about 5 to about 50 mg / kg / day. For oral administration, the composition may be provided in the form of a tablet containing about 1.0 to about 1000 milligrams of active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of active ingredient. The actual amount of a compound of the present disclosure, i.e., active ingredient, will depend on numerous factors, including the severity of the disease being treated, the age and relative health of the patient, the potency of the compound utilized, the route and form of administration, and other factors.

[0112] Generally, the compounds of the present disclosure are administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal, or suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. The preferred mode of administration is oral, using a convenient daily dosing regimen, which can be adjusted according to the severity of the affliction. The compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained-release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable compositions.

[0113] The choice of 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 active ingredient. Recently, pharmaceutical formulations have been developed specifically for drugs exhibiting low bioavailability, based on the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing the particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range of 10 to 1,000 nm, in which the active substance is supported on a crosslinked matrix of polymers. U.S. Pat. No. 5,145,684 describes the preparation of a pharmaceutical formulation in which the active ingredient is milled into nanoparticles (average particle size 400 nm) in the presence of a surface modifier, which is then dispersed in a liquid medium to obtain a pharmaceutical formulation exhibiting significantly higher bioavailability.

[0114] Composition is generally comprised of the compound of the present disclosure combined with at least one pharmaceutically acceptable excipient.Acceptable excipient is non-toxic, aids administration, and does not adversely affect the therapeutic benefits of the compound of the present disclosure.This excipient can be any solid, liquid, semi-solid, or gaseous excipient that is generally available to those skilled in the art in the case of aerosol compositions.

[0115] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, nonfat dry milk, etc. Liquid and semisolid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0116] Compressed gases can be used to disperse the compounds of the present disclosure in aerosol form. Suitable inert gases for this purpose include nitrogen, carbon dioxide, and the like.

[0117] Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by EW Martin (Mack Publishing Company, 20th ed., 2000).

[0118] The level of the compound in the formulation can vary within the range used by those skilled in the art. Typically, the formulation contains, by weight percent (wt%), about 0.01 to 99.99 wt% of the compound of the present disclosure, based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1 to 80 wt%.

[0119] The compounds of the present disclosure can be used in combination with one or more other drugs in the treatment of diseases or symptoms for which the compounds of the present disclosure or other drugs can be useful.One or more such other drugs can be administered simultaneously or sequentially with the compounds of the present disclosure, by the route and amount commonly used therefor.When the compounds of the present disclosure are used simultaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compounds of the present disclosure is preferred.However, combination therapy can also include therapy in which the compounds of the present disclosure and one or more other drugs are administered on different overlapping schedules.It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present disclosure and other active ingredients can be used in lower doses than when each is used alone. [Example]

[0120] The following preparations of compounds of formula (I) are given to enable those skilled in the art to more clearly understand and to practice the present disclosure, and should not be construed as limiting the scope of the disclosure, but merely as illustrative and representative. Synthesis Examples Example 1 Synthesis of 2-((2S)-1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindoline-1,3-dione (Compound 1) [ka]

[0121] Step 1 A one-neck round-bottom flask (1 L) equipped with a condenser and a Dean-Stark apparatus was charged with L-alanine (17.9 g, 0.2 mol), phthalic anhydride (29.6 g, 0.2 mol), toluene (300 mL), and EtN (2.6 mL) in that order. The resulting mixture was refluxed for 16 h until no more HO was produced. HO (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 crude product was crystallized from EtOAc / hexane (80 mL / 200 mL) to give (S)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (34.5 g, 79%) as a white solid.

[0122] Step 2 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), oxalyl chloride (1.7 mL, 20 mmol) was added dropwise, followed by DMF (0.01 mL). After 4 h, all volatiles were completely removed by rotary evaporation. The crude (S)-2-(1,3-dioxoisoindolin-2-yl)propanoyl chloride obtained was used in the next step without further purification.

[0123] Step 3 To a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)propanoyl chloride (approximately 10 mmol) in anhydrous DCM (60 mL) was added (+ / -)-anatabine (1.4 g, 9 mmol) and EtN (1.7 mL, 12 mmol). The resulting solution was stirred at room temperature for 20 h and quenched with HO (60 mL). The layers were separated, and the aqueous layer was extracted with DCM (60 mL × 3). The combined organic layers were washed with saturated 2 N HCl, saturated NaHCO, and brine, dried, and concentrated. Flash chromatography using a normal-phase column (hexane / EtOAc = 50 / 50) afforded the title compound (1.0 g, 31%) as a white foam. MS (ESI, pos. ion) m / z: 362.1 (M+1).

[0124] Example 2 Synthesis of 2-((S)-1-oxo-1-((S)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindoline-1,3-dione (compound 2) [ka] To a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)propanoyl chloride (4.5 g, 20 mmol) in anhydrous benzene (120 mL) was slowly added (+ / -)-anatabine (3.0 g, 19 mmol). The resulting solution was stirred at room temperature for 20 hours and quenched with saturated NaHCO (100 mL). The layers were separated, and the benzene layer was washed with brine, dried, and concentrated. Crude 2-((2S)-1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindoline-1,3-dione (4.7 g, 68%) was obtained as a slightly yellow foam, a mixture of two diastereomers: (A) 2-((S)-1-oxo-1-((S)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindoline-1,3-dione; (B) 2-((S)-1-oxo-1-((R)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindoline-1,3-dione, which was purified by HPLC using MeCN / buffered HO as the eluting mobile phase. Separation was performed on a CombiFlash® column using a C18 Aq GOLD column. Assignments are based on hydrolysis experiments: the A diastereomer gives S-anatabine and the B diastereomer gives R-anatabine.

[0125] Example 3 Synthesis of 2-((S)-3-methyl-1-oxo-1-((S)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)butan-2-yl)isoindoline-1,3-dione (Compound 3) and 2-((S)-3-methyl-1-oxo-1-((R)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)butan-2-yl)isoindoline-1,3-dione (Compound 4) [ka]

[0126] Step 1 A one-neck round-bottom flask (1 L) equipped with a condenser and a Dean-Stark apparatus was charged with L-valine (23.4 g, 0.2 mol), phthalic anhydride (29.6 g, 0.2 mol), toluene (300 mL), and EtN (2.6 mL) in that order. The resulting mixture was refluxed for 16 h until no more HO was produced. HO (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 crude product was crystallized from EtOAc / hexane (80 mL / 200 mL) to give (S)-2-(1,3-dioxoisoindolin-2-yl)-3-methylbutanoic acid (39.0 g, 80%) as a white solid.

[0127] Step 2 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), oxalyl chloride (3.5 mL, 40 mmol) was added dropwise, followed by DMF (0.02 mL). After 4 h, all volatiles were completely removed by rotary evaporation. The resulting crude (S)-2-(1,3-dioxoisoindolin-2-yl)-3-methylbutanoyl chloride was used in the next step without further purification.

[0128] Step 3 To a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-methylbutanoyl chloride (20 mmol) in anhydrous benzene (120 mL) was slowly added (+ / -)-anatabine (3.0 g, 19 mmol). The resulting solution was stirred at room temperature for 20 h and quenched with saturated NaHCO3 (100 mL). The layers were separated, and the benzene layer was washed with brine, dried, and concentrated. The crude product was purified by HPLC using MeCN / buffered HO as the eluting mobile phase. Purification by CombiFlash® using a GOLD column. (A): First peak, 2-((S)-3-methyl-1-oxo-1-((S)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)butan-2-yl)isoindoline-1,3-dione (1.2 g, 15%) as a white foam. MS (ESI, pos. ion) m / z: 390.1 (M+1); (B): Second peak, 2-((S)-3-methyl-1-oxo-1-((R)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)butan-2-yl)isoindoline-1,3-dione (1.0 g, 12%) as a white foam. MS (ESI, pos. ion) m / z: 390.1 (M+1).

[0129] Example 4 A mixture of 2-((S)-1-oxo-1-((S)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)butan-2-yl)isoindoline-1,3-dione and 2-((R)-1-oxo-1-((R)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)butan-2-yl)isoindoline-1,3-dione (compound 5), and Synthesis of a mixture of 2-((S)-1-oxo-1-((R)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)butan-2-yl)isoindoline-1,3-dione and 2-((R)-1-oxo-1-((S)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)butan-2-yl)isoindoline-1,3-dione (Compound 6) [ka]

[0130] Step 1 DL-2-aminobutanoic acid (3.5 g, 34 mmol), phthalic anhydride (5.0 g, 33.8 mmol), and glacial acetic acid (75 mL) were added to a 200 mL, single-necked round-bottom flask equipped with a condenser. The resulting mixture was refluxed for 6 hours. The solvent was completely removed in vacuo to give 2-(1,3-dioxoisoindolin-2-yl)butanoic acid (7.3 g, 92%) as a clear oil.

[0131] Step 2 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), oxalyl chloride (5.1 mL, 58.6 mmol) was added dropwise, followed by DMF (0.02 mL). After 4 h, all volatiles were completely removed by rotary evaporation. The crude product, 2-(1,3-dioxoisoindolin-2-yl)butanoyl chloride, was used in the next step without further purification.

[0132] Step 3 To a solution of 2-(1,3-dioxoisoindolin-2-yl)butanoyl chloride (29 mmol) in anhydrous benzene (120 mL) was slowly added (+ / -)-anatabine (4.2 g, 27 mmol). The resulting solution was stirred at room temperature for 20 hours and quenched with saturated NaHCO (100 mL). The layers were separated, and the benzene layer was washed with brine, dried, and concentrated to give 2-(1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)butan-2-yl)isoindoline-1,3-dione as a crude product (5.5 g, 54%). The racemic diastereomers were separated by CombiFlash® using a HP C 18 Aq GOLD column with MeCN / buffered HO as the eluting mobile phase. (A): First peak, 2-((S)-1-oxo-1-((S)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)butan-2-yl)isoindoline-1,3-dione and 2-((R)-1-oxo-1-((R)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)butan-2-yl)isoindoline-1,3-dione as a 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)butan-2-yl)isoindoline-1,3-dione and 2-((R)-1-oxo-1-((S)-6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)butan-2-yl)isoindoline-1,3-dione as a white foam. MS (ESI, pos. ion) m / z: 376.1 (M+1).

[0133] Example 5 Synthesis of 2-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindoline-1,3-dione (compound 7) [ka] Step 1 DL-Phenylalanine (5.6 g, 34 mmol), phthalic anhydride (5.0 g, 33.8 mmol), and glacial acetic acid (100 mL) were added to a 200 mL, single-necked round-bottom flask equipped with a condenser in that order. The resulting mixture was refluxed for 6 hours. The solvent was completely removed in vacuo, and the residue was precipitated from a mixture of ethyl acetate and hexane to give 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid (7.0 g, 70%) as a white solid.

[0134] Step 2 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), oxalyl chloride (3.5 mL, 40.2 mmol) was added dropwise, followed by DMF (0.02 mL). After 4 h, all volatiles were completely removed by rotary evaporation. The resulting crude 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride was used in the next step without further purification.

[0135] Step 3 To a solution of 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride (16.9 mmol) in anhydrous benzene (100 mL) was slowly added (+ / -)-anatabine (2.4 g, 15.7 mmol). The resulting solution was stirred at room temperature for 20 hours and quenched with saturated NaHCO (100 mL). The layers were separated, and the benzene layer was washed with brine, dried, concentrated, and purified by CombiFlash® using an HP C 18 Aq GOLD column with MeCN / buffered HO as the eluent to give 2-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindoline-1,3-dione (4.5 g, 65%) as a white foam as a mixture of two diastereomers. MS (ESI, post. ion) m / z: 438.1 (M+1).

[0136] Example 6 Synthesis of 2-(2-oxo-2-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethyl)isoindoline-1,3-dione (compound 8) [ka] Step 1 A single-necked round-bottom flask (200 mL) equipped with a condenser was charged with glycine (5.1 g, 68 mmol), phthalic anhydride (10.0 g, 67.5 mmol), and glacial acetic acid (120 mL) in that order. The resulting mixture was refluxed for 6 hours. The solvent was completely removed in vacuo, and the residue was precipitated from a mixture of ethyl acetate and hexane to give 2-(1,3-dioxoisoindolin-2-yl)acetic acid (10.8 g, 80%) as a white solid.

[0137] Step 2 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), oxalyl chloride (3.5 mL, 40 mmol) was added dropwise, followed by DMF (0.02 mL). After 4 h, all volatiles were completely removed by rotary evaporation. The resulting crude 2-(1,3-dioxoisoindolin-2-yl)acetyl chloride was used in the next step without further purification.

[0138] Step 3 To a solution of 2-(1,3-dioxoisoindolin-2-yl)acetyl chloride (20 mmol) in anhydrous benzene (120 mL) was slowly added (+ / -)-anatabine (2.9 g, 19.0 mmol). The resulting solution was stirred at room temperature for 20 hours and quenched with saturated NaHCO (100 mL). The layers were separated, and the benzene layer was washed with brine, dried, concentrated, and purified by CombiFlash® using an HP C 18 Aq GOLD column with MeCN / buffered HO as the eluting mobile phase to give 2-(2-oxo-2-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethyl)isoindoline-1,3-dione (3.8 g, 58%) as a white foam. MS (ESI, pos. ion) m / z: 348.1 (M+1).

[0139] Example 7 Synthesis of 2-((2R)-1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindoline-1,3-dione (compound 17) [ka] Step 1 D-alanine (5.0 g, 56.2 mmol), phthalic anhydride (18.2 g, 56.2 mmol), and glacial acetic acid (100 mL) were added to a 200 mL, single-necked round-bottom flask equipped with a condenser. The resulting mixture was refluxed for 3 hours. The solvent was completely removed in vacuo, and the residue was precipitated from a mixture of ethyl acetate and hexane to give (R)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (8.0 g, 64%) as a white solid.

[0140] Step 2 To a solution of (R)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (7.5 g, 33.3 mmol) in anhydrous DCM (120 mL) was added PCl5 (7.6 g, 36.5 mmol) in small portions. The resulting reaction mixture was stirred at room temperature for 3 h. All volatiles were completely removed by rotary evaporation. The residual (R)-2-(1,3-dioxoisoindolin-2-yl)propanoyl chloride as a clear oil was used in the next step without further purification.

[0141] Step 3 To a solution of (R)-2-(1,3-dioxoisoindolin-2-yl)propanoyl chloride (33 mmol) in anhydrous benzene (120 mL) was slowly added (+ / -)-anatabine (5.3 g, 34.7 mmol). The resulting solution was stirred at room temperature for 20 h and quenched with saturated NaHCO (100 mL). The layers were separated, and the benzene layer was washed with brine, dried, and concentrated to give 2-((2R)-1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindoline-1,3-dione (9.7 g, 81%) as a foam in a mixture of two diastereomers. MS (ESI, pos. ion) m / z: 362.1 (M+1).

[0142] Example 8 Synthesis of 3-nitro-N-((2S)-(1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (Compound 9) [ka] Step 1 To a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (11.2 g, 50.0 mmol) in anhydrous DCM (150 mL) was added PCl5 (11.4 g, 55 mmol) in small portions. The resulting reaction mixture was stirred at room temperature for 5 h. All volatiles were completely removed by rotary evaporation. The residual (S)-2-(1,3-dioxoisoindolin-2-yl)propanoyl chloride as a clear oil was used in the next step without further purification.

[0143] Step 2 To a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)propanoyl chloride (approximately 50 mmol) in anhydrous benzene (120 mL) was slowly added (+ / -)-anatabine (7.6 g, 50 mmol). The resulting solution was stirred at room temperature for 20 h and quenched with saturated NaHCO (100 mL). The layers were separated, and the benzene layer was washed with brine, dried, and concentrated to give crude (S)-2-(1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindoline-1,3-dione (13.5 g, 74%) as a mixture of two diastereomers. MS (ESI, pos. ion) m / z: 362.4 (M+1).

[0144] Step 3 To a solution of (S)-2-(1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindoline-1,3-dione (13.5 g, 37 mmol) in EtOH (200 mL) was added hydrazine monohydrate (3.6 mL). The reaction solution was refluxed for 2 hours, and the resulting suspension was filtered at room temperature. The filtrate was concentrated to give crude (S)-2-amino-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-1-one (9.0 g, 77% yield from Step 2) as a mixture of two diastereomers.

[0145] Step 4 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) in DCM (10 mL) was added EDC hydrochloride (0.72 g, 3.8 mmol) and i-PrNEt (0.70 mL, 3.9 mmol). The reaction mixture was stirred at room temperature overnight and quenched with HO (10 mL). The layers were separated, and the organic layer was washed with brine, dried, and concentrated to give 3-nitro-N-(1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.2 g, 17%), present as a mixture of two diastereomers, as a film in the flask. MS (ESI, pos. ion) m / z: 381.3 (M+1).

[0146] The compounds of Examples 9-13 were prepared by a procedure similar to that of Example 8, starting from the corresponding benzoic acid. Example 9: 3-Methoxy-N-((2S)-1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.5 g, 46%). (Compound 10) [ka] MS (ESI, pos. ion) m / z: 366.1 (M+1).

[0147] Example 10: 3,4-Diethoxy-N-((2S)-1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.6 g, 47%). (Compound 11) [ka] MS (ESI, pos. ion) m / z: 424.2 (M+1).

[0148] Example 11: 3,4-Dimethoxy-N-((2S)-1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.7 g, 59%). (Compound 12) [ka] MS (ESI, pos. ion) m / z: 396.1 (M+1).

[0149] Example 12: 4-Nitro-N-((2S)-1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.1 g, 8%) was crystallized from MeCN. (Compound 13) [ka] MS (ESI, pos. ion) m / z: 381.1 (M+1).

[0150] Example 13. 4-Chloro-N-((2S)-1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (150 mg, 13%) crystallized from MeCN. (Compound 14) [ka] MS (ESI, pos. ion) m / z: 370.1 (M+1).

[0151] Example 14 Synthesis of 3-nitro-N-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (Compound 15) [ka] Step 1 DL-Phenylalanine (11.2 g, 68 mmol), phthalic anhydride (10.0 g, 67.6 mmol), and glacial acetic acid (200 mL) were added to a single-necked round-bottom flask (200 mL) equipped with a condenser in that order. The resulting mixture was refluxed for 2 hours. The solvent was completely removed in vacuo, and the residue was precipitated from a mixture of ethyl acetate and hexane to give 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid (18.1 g, 90%) as a white solid.

[0152] Step 2 To a solution of 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid (19.8 g, 67.1 mmol) in anhydrous DCM (300 mL) was added PCl5 (15.3 g, 73.8 mmol) in small portions. The reaction mixture was stirred at room temperature for 3 h. All volatiles were completely removed by rotary evaporation to give 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride as a crude product, which was used in the next step without further purification.

[0153] Step 3 To a solution of 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride (67 mmol) in anhydrous benzene (300 mL) was slowly added (+ / -)-anatabine (12.0 g, 75.0 mmol). The resulting solution was stirred at room temperature overnight and quenched with saturated NaHCO (300 mL). The layers were separated, and the benzene layer was washed with brine, dried, and concentrated to afford 2-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindoline-1,3-dione (25.0 g, 86%) as a foam as a mixture of two diastereomers without further purification.

[0154] Step 4 To a solution of 2-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindoline-1,3-dione (25.0 g) in EtOH (300 mL) was added hydrazine monohydrate (5.0 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 allowed to stand overnight. The resulting solid was filtered off, and the filtrate was concentrated to give 2-amino-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-1-one (16.7 g, 54%) as a crude product, a mixture of two diastereomers.

[0155] Step 5 To a solution of 3-nitrobenzoic acid (0.5 g, 3.0 mmol) and 2-amino-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-1-one (0.9 g, 3.0 mmol) in DCM (10 mL) was added EDC hydrochloride (0.7 g, 3.8 mmol) and i-PrNEt (0.7 mL, 3.9 mmol). The reaction mixture was stirred at room temperature overnight and quenched with HO (10 mL). The layers were separated, and the organic layer was washed with brine, dried, concentrated, and purified by CombiFlash® using a HP C 18 Aq GOLD column with MeCN / buffered HO as the eluting mobile phase to give 3-nitro-N-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.6 g, 43%), present as a mixture of two diastereomers, as a film in a flask. MS (ESI, pos. ion) m / z: 457.1 (M+1).

[0156] Alternative Step 5 To a solution of 3-nitrobenzoic acid (0.8 g, 5 mmol) in DCM (20 mL) was added PCl5 (1.2 g). 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). Workup and purification as described in Step 5 above gave the title product.

[0157] Example 15 Synthesis of 3-methoxy-N-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (Compound 16) [ka] 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) in DCM (10 mL) was added EDC hydrochloride (0.72 g, 3.8 mmol) and i-PrNEt (0.70 mL, 3.9 mmol). The reaction mixture was stirred at room temperature overnight and quenched with HO (10 mL). The layers were separated, and the organic layer was washed with brine, dried, concentrated, and purified by CombiFlash® using a normal-phase silica gel column with EtOAc and hexanes as the eluting mobile phase to give 3-methoxy-N-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.60 g, 45%), present as a mixture of two diastereomers, as a film in a flask. MS (ESI, pos. ion) m / z: 442.2 (M+1).

[0158] Example 16 Synthesis of 3-chloro-N-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (Compound 18) [ka] Step 1 To a purple solution of KMnO4 (4.0 g, 25.0 mmol) and Na2HPO4 (6.7 g, 25 mmol) in HO (100 mL) was added dropwise a solution of 3-chlorobenzaldehyde (3.5 g, 25 mmol) in MeOH (100 mL) at room temperature. The reaction mixture was stirred for approximately 30 minutes until a brown suspension formed. The resulting suspension was filtered through a Celite® pad, and the filtrate was concentrated by rotary evaporation and diluted with HO (100 mL). The diluted filtrate was acidified with 1 N HCl until a pH of 3–4 was reached. The resulting precipitate was filtered and dried overnight in vacuo at 76 °C to give 3-chlorobenzoic acid (3.5 g, 90%) as a white solid.

[0159] Step 2 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) in DCM (10 mL) was added EDC hydrate (0.75 g, 3.8 mmol) and i-PrNEt (0.72 mL, 3.9 mmol). The reaction mixture was stirred at room temperature overnight and quenched with HO (10 mL). The layers were separated, and the organic layer was washed with brine, dried, concentrated, and purified by CombiFlash® using a HP C 18 Aq GOLD column with MeCN / buffered HO as the eluting mobile phase to give 3-chloro-N-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.30 g, 20%), present as a mixture of two diastereomers, as a film in a flask. MS (ESI, pos. ion) m / z: 446.1 (M+1).

[0160] Example 17 Synthesis of 3-fluoro-N-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (Compound 19) [ka] Step 1 To a purple solution of KMnO4 (4.0 g, 25.0 mmol) and Na2HPO4 (6.7 g, 25 mmol) in HO (100 mL) was added dropwise a solution of 3-fluorobenzaldehyde (3.1 g, 25 mmol) in MeOH (100 mL) at room temperature. The reaction mixture was stirred for approximately 30 minutes until a brown suspension formed. The resulting suspension was filtered through a Celite® pad, and the filtrate was concentrated by rotary evaporation and diluted with HO (100 mL). The diluted filtrate was acidified with 1 N HCl until a pH of 3-4 was reached. The resulting precipitate was filtered and dried overnight in vacuo at 76 °C to give 3-fluorobenzoic acid (2.0 g, 57%) as a white solid.

[0161] Step 2 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) in DCM (10 mL) was added EDC hydrochloride (0.72 g, 3.8 mmol) and i-PrNEt (0.70 mL, 3.9 mmol). The reaction mixture was stirred at room temperature overnight and quenched with HO (10 mL). The layers were separated, and the organic layer was washed with brine, dried, concentrated, and purified by CombiFlash® using a HP C 18 Aq GOLD column with MeCN / buffered HO as the eluting mobile phase to give 3-fluoro-N-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.50 g, 39%), present as a mixture of two diastereomers, as a film in a flask. MS (ESI, pos. ion) m / z: 430.1 (M+1).

[0162] Example 18 Synthesis of 3-ethoxy-N-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (Compound 20) [ka] Step 1 To a solution of 3-hydroxybenzaldehyde (6.1 g, 50 mmol) in DMF (200 mL) were added ethyl iodide (9.4 g, 60 mmol) and K2CO3 (10.3 g, 75 mmol) in that order. The resulting suspension was heated to 120 °C for 4 h and cooled to room temperature. The reaction was quenched with HO (200 mL) and extracted with ether (200 mL). The ether layer was washed with HO (200 mL × 3), dried, and concentrated to give 3-ethoxybenzaldehyde (6.2 g, 83%) as a clear oil.

[0163] Step 2 To a purple solution of KMnO4 (6.2 g, 39.0 mmol) and Na2HPO4 (10.5 g, 39 mmol) in HO (150 mL) was added dropwise a solution of 3-ethoxybenzaldehyde (5.8 g) in MeOH (150 mL) at room temperature. The reaction mixture was stirred for approximately 30 minutes until a brown suspension was formed. The resulting suspension was filtered through a Celite® pad, and the filtrate was concentrated by rotary evaporation and diluted with HO (100 mL). The diluted filtrate was acidified with 1 N HCl until a pH of 3-4 was reached. The resulting precipitate was filtered and dried overnight in vacuo at 76 °C to give 3-ethoxybenzoic acid (2.9 g, 50%) as a white solid.

[0164] Step 3 To a solution of 3-ethoxybenzoic acid (0.55 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) in DCM (10 mL) was added EDC hydrochloride (0.72 g, 3.8 mmol) and i-PrNEt (0.70 mL, 3.9 mmol). The reaction mixture was stirred at room temperature overnight and quenched with HO (10 mL). The layers were separated, and the organic layer was washed with brine, dried, concentrated, and purified by CombiFlash® using a HP C 18 Aq GOLD column with MeCN / buffered HO as the eluting mobile phase to give 3-ethoxy-N-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.66 g, 48%), present as a mixture of two diastereomers, as a film in a flask. MS (ESI, pos. ion) m / z: 456.2 (M+1).

[0165] Proceeding similarly to Example 18 above, the compounds of Examples 19-22 were synthesized using the corresponding prepared or commercially available benzoic acids.

[0166] Example 19: 3,4-Dimethoxy-N-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.35 g, 25%). (Compound 21) [ka] MS (ESI, pos. ion) m / z: 472.2 (M+1).

[0167] Example 21: N-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)-3-(trifluoromethyl)benzamide (0.55 g, 38%). (Compound 23) [ka] MS (ESI, pos. ion) m / z: 480.1 (M+1).

[0168] Example 22: 3-Fluoro-5-methoxy-N-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.57 g, 41%). (Compound 24) [ka] MS (ESI, pos. ion) m / z: 460.2 (M+1).

[0169] Example 23 Synthesis of 3-methoxy-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (Compound 25) [ka] Step 1 D-Phenylalanine (25.0 g, 151.3 mmol), phthalic anhydride (22.2 g, 151.3 mmol), and glacial acetic acid (300 mL) were added to a 500 mL, single-necked round-bottom flask equipped with a condenser. The resulting mixture was refluxed for 4 hours. The solvent was completely removed in vacuo, and the residue was precipitated from a mixture of ethyl acetate and hexane to give (R)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid (38.4 g, 86%) as a white solid.

[0170] Step 2 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) was added PCl5 (29.4 g, 141.0 mmol) in small portions. The reaction mixture was stirred at room temperature for 3 h. All volatiles were completely removed by rotary evaporation to give (R)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride as a crude product, which was used in the next step without further purification.

[0171] Step 3 To a solution of (R)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride (128 mmol) in anhydrous benzene (500 mL) was slowly added (+ / -)-anatabine (20.6 g, 128.7 mmol). The resulting solution was stirred at room temperature overnight and quenched with saturated NaHCO (500 mL). The layers were separated, and the benzene layer was washed with brine, dried, and concentrated to afford 2-((2R)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindoline-1,3-dione (43.3 g, 79%) as a foam as a mixture of two diastereomers without further purification.

[0172] Step 4 To a solution of 2-((2R)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindoline-1,3-dione (43.3 g) in EtOH (500 mL) was added hydrazine monohydrate (8.7 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 allowed to stand overnight. The resulting solid was filtered off, and the filtrate was concentrated to give crude (2R)-2-amino-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-1-one (32.3 g, 82%) as a mixture of two diastereomers.

[0173] Step 5 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) in DCM (10 mL) was added EDC hydrochloride (0.72 g, 3.8 mmol) and i-PrNEt (0.70 mL, 3.9 mmol). The reaction mixture was stirred at room temperature overnight and quenched with HO (10 mL). The layers were separated, and the organic layer was washed with brine, dried, concentrated, and purified by CombiFlash® using a HP C 18 Aq GOLD column with MeCN / buffered HO as the eluting mobile phase to give 3-methoxy-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.73 g, 55%), present as a mixture of two diastereomers, as a film in a flask. MS (ESI, pos. ion) m / z: 442.2 (M+1).

[0174] Example 24 Synthesis of 3-ethoxy-4-methoxy-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (Compound 26) [ka] Step 1 To a solution of 3-ethoxy-4-hydroxybenzaldehyde (8.6 g, 50 mmol) in DMF (200 mL) was added NaH (3.0 g, 75 mmol, 60 wt%) in small portions at 0 °C, followed by MeI (3.35 mL, 60 mmol). The reaction mixture was stirred overnight at room temperature and quenched with water. Extraction was performed with ether (100 mL x 3). The ether layer was washed, dried, and concentrated to give 3-ethoxy-4-methoxybenzaldehyde (5.9 g, 66%) as a crude product.

[0175] Step 2 To a purple solution of KMnO (5.1 g, 32.0 mmol) and NaHPO (8.4 g, 32 mmol) in HO (120 mL) was added dropwise a solution of 3-ethoxy-4-methoxybenzaldehyde (5.6 g) in MeOH (120 mL) at room temperature. The reaction mixture was stirred for approximately 30 minutes until a brown suspension formed. The resulting suspension was filtered through a Celite® pad, and the filtrate was concentrated by rotary evaporation and diluted with HO (100 mL). The diluted filtrate was acidified with 1 N HCl until a pH of 3-4 was reached. The resulting precipitate was filtered and dried overnight in vacuo at 76 °C to give 3-ethoxy-4-methoxybenzoic acid (4.0 g, 66%) as a white solid.

[0176] Step 3 To a solution of 3-ethoxy-4-methoxybenzoic acid (0.59 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) in DCM (10 mL) was added EDC hydrochloride (0.72 g, 3.8 mmol) and i-PrNEt (0.70 mL, 3.9 mmol). The reaction mixture was stirred at room temperature overnight and quenched with HO (10 mL). The layers were separated, and the organic layer was washed with brine, dried, concentrated, and purified by CombiFlash® using a HP C 18 Aq GOLD column with MeCN / buffered HO as the eluting mobile phase to give 3-ethoxy-4-methoxy-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide, present as a mixture of two diastereomers, as a film in a flask. MS (ESI, pos. ion) m / z: 486.2 (M+1).

[0177] Proceeding similarly as described in Example 24 above, and substituting synthesized or commercially available benzoic acid, the compounds of Examples 25-30 were prepared.

[0178] Example 25: 2-chloro-5-methoxy-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.76 g, 53%). (Compound 27) [ka] MS (ESI, pos. ion) m / z: 476.1 (M+1).

[0179] Example 26: 3,5-Dimethoxy-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.86 g, 61%). (Compound 28) [ka] MS (ESI, pos. ion) m / z: 472.2 (M+1).

[0180] Example 27: 5-Methoxy-2-methyl-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.76 g, 56%). (Compound 29) [ka] MS (ESI, pos. ion) m / z: 456.2 (M+1).

[0181] Example 28: 4-chloro-2-methoxy-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.56 g, 41%). (Compound 30) [ka] MS (ESI, pos. ion) m / z: 476.1 (M+1).

[0182] Example 29: 4-Fluoro-3-methoxy-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.65 g, 47%). (Compound 31) [ka] MS (ESI, pos. ion) m / z: 460.2 (M+1).

[0183] Example 30: 2-Methoxy-N-((2R)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide. (Compound 32) [ka] MS (ESI, pos. ion) m / z: 442.3 (M+1).

[0184] Example 31 Synthesis of 3-ethoxy-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (Compound 33) [ka] Step 1 A single-necked round-bottom flask (500 mL) equipped with a condenser was charged with L-phenylalanine (25.0 g, 151.3 mmol), phthalic anhydride (22.2 g, 151.3 mmol), and glacial acetic acid (300 mL) in that order. The resulting mixture was refluxed for 4 hours. The solvent was completely removed in vacuo, and the residue was precipitated from a mixture of ethyl acetate and hexane to give (S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid (42.8 g, 96%) as a white solid.

[0185] Step 2 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) was added PCl5 (32.8 g, 157.0 mmol) in small portions. The reaction mixture was stirred at room temperature for 3 h. All volatiles were completely removed by rotary evaporation to give (S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride as a crude product, which was used in the next step without further purification.

[0186] Step 3 To a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride (142 mmol) in anhydrous benzene (550 mL) was slowly added (+ / -)-anatabine (23.0 g, 142.9 mmol). The resulting solution was stirred overnight at room temperature and quenched with saturated NaHCO (550 mL). The layers were separated, and the benzene layer was washed with brine, dried, and concentrated to afford 2-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindoline-1,3-dione (57.7 g, 100%) as a foam as a mixture of two diastereomers without further purification.

[0187] Step 4 To a solution of 2-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindoline-1,3-dione (57.7 g) in EtOH (500 mL) was added hydrazine monohydrate (11.6 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 allowed to stand overnight. The resulting solid was filtered off, and the filtrate was concentrated to give (2S)-2-amino-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-1-one (39.0 g, 99%) as a crude product, a mixture of two diastereomers.

[0188] Step 5 To a solution of 3-ethoxybenzoic acid (0.83 g, 5.0 mmol) and (2S)-2-amino-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-1-one (1.5 g, 5.0 mmol) in DCM (30 mL) was added EDC hydrochloride (1.2 g, 6.3 mmol) and i-PrNEt (1.1 mL, 6.5 mmol). The reaction mixture was stirred at room temperature overnight and quenched with HO (30 mL). The layers were separated, and the organic layer was washed with brine, dried, concentrated, and purified by CombiFlash® using a HP C 18 Aq GOLD column with MeCN / buffered HO as the eluting mobile phase to give 3-ethoxy-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (1.3 g, 63%), present as a mixture of two diastereomers, as a film in a flask. MS (ESI, pos. ion) m / z: 456.2 (M+1).

[0189] Proceeding similarly as described in Example 31 above, by substituting synthesized or commercially available benzoic acid, the compounds of Examples 32-33 were prepared.

[0190] Example 32: 4-Fluoro-3-methoxy-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.4 g, 29%). (Compound 34) [ka] MS (ESI, pos. ion) m / z: 460.2 (M+1).

[0191] Example 33: 3-Methoxy-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.8 g, 36%). (Compound 35) [ka] MS (ESI, pos. ion) m / z: 442.2 (M+1).

[0192] Proceeding similarly as described in Example 31 above, the compounds of Examples 40-56 were prepared by substituting either commercially available carboxylic acids or carboxylic acids that can be readily prepared from aminobenzoic acids and the corresponding acid chlorides or acids using coupling reactions.

[0193] Example 40: 3-(3-methylbutanamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.90 g, 60%) as a tan solid. (Compound 42) [ka] MS (ESI, pos, ion) m / z: 511.2 (M+1).

[0194] Example 41: N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)-3-pivalamidobenzamide (0.93 g, 62%) as a gray solid. (Compound 43) [ka] MS (ESI, pos, ion) m / z: 511.2 (M+1).

[0195] Example 42: 3-(cyclopropanecarboxamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (1.01 g, 69%) as a white solid. (Compound 44) [ka] MS (ESI, pos, ion) m / z: 495.2 (M+1).

[0196] Example 43: 3-(cyclobutanecarboxamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (1.05 g, 69%) as an orange solid. (Compound 45) [ka] MS (ESI, pos, ion) m / z: 509.2 (M+1).

[0197] Example 44: 3-(Cyclopentanecarboxamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.69 g, 64%) as a white solid. (Compound 46) [ka] MS (ESI, pos, ion) m / z: 523.2 (M+1).

[0198] Example 45: 2-Butylamido-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.12 g, 12%) as a white solid. (Compound 47) [ka] MS (ESI, pos, ion) m / z: 497.2 (M+1).

[0199] Example 46: 4-Butylamido-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.45 g, 45%) as a white solid. (Compound 48) [ka] MS (ESI, pos, ion) m / z: 497.2 (M+1).

[0200] Example 47: N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)quinoline-2-carboxamide (0.50 g, 53%) as a white solid. (Compound 49) [ka] MS (ESI, pos, ion) m / z: 463.2 (M+1).

[0201] Example 48: N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)pyrazine-2-carboxamide (0.50 g, 61%) as a yellow solid. (Compound 50) [ka] MS (ESI, pos, ion) m / z: 414.1 (M+1).

[0202] Example 49: N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)nicotinamide (0.41 g, 50%) as a white solid. (Compound 51) [ka] MS (ESI, pos, ion) m / z: 413.1 (M+1).

[0203] Example 50: N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)furan-2-carboxamide (0.50 g, 63%) as a white solid. (Compound 52) [ka] MS (ESI, pos, ion) m / z: 402.1 (M+1).

[0204] Example 51: N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)-1H-pyrrole-2-carboxamide (0.20 g, 25%) as a pale yellow solid. (Compound 56) [ka] MS (ESI, pos, ion) m / z: 401.1 (M+1).

[0205] Example 52: 3-((S)-2-methylbutanamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.60 g, 56%) as a pale yellow solid. (Compound 57) [ka] MS (ESI, pos, ion) m / z: 511.2 (M+1).

[0206] Example 53: 3-((R)-2-methylbutanamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.67 g, 65%) as a pale yellow solid. (Compound 58) [ka] MS (ESI, pos, ion) m / z: 511.2 (M+1).

[0207] Example 54: 3-(N-methylbutyramido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.80 g, 78%) as a pale yellow solid. (Compound 59) [ka] MS (ESI, pos, ion) m / z: 511.2 (M+1).

[0208] Example 55: 3-(butylamino)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.82 g, 85%) as a pale yellow solid. (Compound 60) [ka] MS (ESI, pos, ion) m / z: 483.2 (M+1).

[0209] Example 56: 1-butyl-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)-1H-pyrrole-2-carboxamide (0.21 g, 23%) as a yellow oil. (Compound 61) [ka] MS (ESI, pos, ion) m / z: 457.2 (M+1).

[0210] Example 34 Synthesis of N-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)-3-pentanamidobenzamide (compound 36) [ka] Step 1 To a suspension of 3-aminobenzoic acid (5.0 g, 36.5 mmol) in DCM (120 mL) were added pyridine (6.5 mL) and valeroyl chloride (5.5 mL, 45.6 mmol), in that order, at 0° C. The resulting solution was stirred at room temperature overnight and quenched with water. The layers were separated, and the organic layer was washed, dried, and concentrated to give 3-pentanamidobenzoic acid (7.2 g, 90%) as a white solid.

[0211] Step 2 To a solution of 3-pentanamidobenzoic 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) in DCM (10 mL) was added EDC hydrochloride (0.72 g, 3.8 mmol) and i-PrNEt (0.70 mL, 3.9 mmol). The reaction mixture was stirred at room temperature overnight and quenched with HO (10 mL). The layers were separated, and the organic layer was washed with brine, dried, concentrated, and purified by CombiFlash® using a HP C 18 Aq GOLD column with MeCN / buffered HO as the eluting mobile phase to give N-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)-3-pentanamidobenzamide (0.81 g, 59%), present as a mixture of two diastereomers, as a film in a flask. MS (ESI, pos. ion) m / z: 511.2 (M+1).

[0212] Proceeding similarly as described in Example 34 above, and substituting synthesized or commercially available benzoic acid, the compounds of Examples 35-37 were prepared.

[0213] Example 35: 3-Butylamido-N-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide. (Compound 37) [ka] MS (ESI, pos. ion) m / z: 497.2 (M+1).

[0214] Example 36: 3-amino-N-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide. (Compound 38) [ka] MS (ESI, pos. ion) m / z: 427.2 (M+1).

[0215] Example 37: 3-acetamido-N-(1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (169 mg, 12%). (Compound 39) [ka] MS (ESI, pos. ion) m / z: 469.2 (M+1).

[0216] Example 38 Synthesis of 3-butylamido-N-(1-oxo-3-phenyl-1-(2-(quinolin-3-yl)-3,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (Compound 40) [ka] Synthesis scheme of 3-butylamido-N-(1-oxo-3-phenyl-1-(2-(quinolin-3-yl)-3,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (1,2-combo compound): [ka] Step 1 Synthesis of N-phenylacetamide [ka] To a suspension of aniline (5 g, 53.7 mmol) in 2 N NaOH (40.3 mL) was added acetyl chloride (4.63 g, 59.07 mmol, 1.1 equiv.) in 40.3 mL of dichloromethane dropwise over 1 h in an ice bath. The resulting mixture was stirred at room temperature for an additional 1 h. The organic layer was washed with dilute ice-NaHCO3 and brine. The organic layer was concentrated under reduced pressure to give the desired product as crude acetanilide. The crude acetanilide was recrystallized by dissolving in distilled water to give pure dry acetanilide as a white crystalline solid (6.3 g, 87% isolated yield).

[0217] Step 2 Synthesis of 2-chloroquinoline-3-carbaldehyde [ka] To DMF (10.82 g, 148 mmol, 2.5 equiv.) was added dropwise (30 min) phosphorus oxychloride (63.5 g, 414.13 mmol, 7 equiv.) cooled in an ice bath. The mixture was stirred at 0° C. for an additional 30 min, and then acetanilide (8 g, 59.18 mmol, 1 equiv.) was added in one portion. The white suspension became a greenish solution, which was heated overnight. The mixture was poured onto ice. The yellow precipitate was filtered and dried to give a yellow-orange solid (6.8 g, 60% isolated yield).

[0218] Step 3 Synthesis of quinoline-3-carbaldehyde [ka] To 2-chloroquinoline-3-carbaldehyde (3 g, 15.69 mmol, 1 equiv.) in DMF (18 mL) at 23 °C and under a nitrogen atmosphere were added triethylamine (19.05 g, 188.28 mmol, 12 equiv.), tetrakis(triphenylphosphine)palladium(0) (0.9 g, 0.78 mmol, 5 mol%), and formic acid (3.9 g, 84.72 mmol, 5.4 equiv.). After stirring at 110 °C for 3 h, the reaction mixture was cooled to 23 °C and diluted with water (90 mL) and ethyl acetate (3 × 60 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give the crude product, which was purified by flash chromatography using 50% EtOAc / hexanes to give the desired product as a reddish-brown solid (1.5 g, 60.8% isolated yield).

[0219] Step 4 Synthesis of (E)-N-allyl-1-(quinolin-3-yl)methanimine [ka] In a 250 mL round-bottom flask, allylamine (1.3 g, 22.92 mmol, 1.2 equiv.) was added to a stirred solution of quinoline-3-carbaldehyde (3 g, 19.1 mmol, 1 equiv.) in anhydrous dichloromethane (96 mL) containing activated 4 Å MS (5 g). The resulting mixture was then stirred at room temperature for 24 h. Subsequently, the molecular sieves were filtered off and washed with DCM, affording the imine product as a brown solid after solvent evaporation (4.3 g, 95% isolated yield).

[0220] Step 5 Synthesis of N-allyl-1-(quinolin-3-yl)but-3-en-1-amine [ka] In a 250 mL two-neck flask, allyl bromide (3.95 g, 32.63 mmol, 2 equiv.) was added dropwise to a cold (0 °C) absolute ethanolic solution (83 mL) of (E)-N-allyl-1-(quinolin-3-yl)methanimine (3.2 g, 16.31 mmol, 1 equiv.) and indium powder (2.79 g, 24.46 mmol, 1.5 equiv.). The resulting mixture was stirred at the same temperature for 30 min. The temperature was then allowed to reach room temperature, and the system was stirred for an additional 3.5 h. Subsequently, the solvent was evaporated under vacuum, and the residue was dissolved in EtOAc (60 mL) and treated with saturated aqueous NaHCO3 solution (40 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by column chromatography using 50% EtOAc / hexanes as the eluent to give the pure product as a tan oil (3.4 g, 88% isolated yield).

[0221] Step 6 Synthesis of 3-(1,2,3,6-tetrahydropyridin-2-yl)quinoline [ka] In a 100 mL two-necked pear-shaped flask equipped with a magnetic stirrer, N-allyl-1-(quinolin-3-yl)but-3-en-1-amine (1.56 g, 6.55 mmol, 1 equiv.) was dissolved in anhydrous dichloromethane (64 mL). p-Toluenesulfonic acid monohydrate (2.74 g, 14.41 mmol, 2.2 equiv.) was added, and the mixture was stirred for 10 min. Grubbs' solution 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, and a second-generation catalyst (0.555 g, 0.65 mmol, 10 mol%) was added. The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was neutralized using 50 mL of 2 N NaOH and stirred for 20 min. The organic layer was collected and washed with water (3 × 50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was dissolved in 100 mL of EtOAc, and then 30 mL of 6N HCl, 70 mL of deionized water, and 20 mL of brine solution were added, and the mixture was stirred for 20 minutes. The aqueous layer was collected and further extracted with EtOAc (3 x 50 mL). 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 anhydrous potassium carbonate, and the mixture was subjected to column chromatography using a 20:1 mixture of hexane and ammonium hydroxide and 4% methanol / chloroform as the eluent to obtain the pure product as a reddish-brown oil (0.325 g, 28% isolated yield).

[0222] Step 7 Synthesis of 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride [ka] Step 7(i) DL-phenylalanine (20 g, 121 mmol, 1 equiv.), phthalic anhydride (17.9 g, 121 mmol, 1 equiv.), toluene (180 mL), and EtN (1.6 mL) were added to an oven-dried, one-necked, round-bottom flask (500 mL) equipped with a condenser and a Dean-Stark apparatus, in that order. The resulting mixture was refluxed for 16 h until no more water was produced. HO (180 mL) was added to the cooled solution to precipitate the product. The product was filtered and dried overnight under high vacuum. The dried product, 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid, was recovered as a white solid (29.5 g, 82.6% isolated 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.

[0223] Step 7(ii) To a solution of 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid (2.5 g, 8.47 mmol, 1 equiv.) in anhydrous DCM (32 mL) was added PCl5 (1.93 g, 9.28 mmol, 1.09 equiv.) in small portions. The resulting reaction mixture was stirred at room temperature for 3 h. All volatiles were completely removed under reduced pressure. The residual 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.

[0224] Step 8 Synthesis of 2-(1-oxo-3-phenyl-1-(2-(quinolin-3-yl)-3,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindoline-1,3-dione [ka] To a solution of 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride (6.78 mmol) in anhydrous benzene (25 mL) was slowly added 3-(1,2,3,6-tetrahydropyridin-2-yl)quinoline (1.5 g, 7.13 mmol, 1.05 equiv.). The resulting solution was stirred at room temperature for 20 h and quenched with saturated NaHCO (20 mL). The layers were separated, and the benzene layer was washed with brine, dried, and concentrated to give 3-(1,2,3,6-tetrahydropyridin-2-yl)quinoline as crude product. The crude product was purified by column chromatography using a 50% EtOAc / hexane mixture as eluent to give the desired product as a mixture of diastereomers as a white solid (1.4 g, 42.3%). MS (ESI, pos. ion) m / z: 488.2 (M+1).

[0225] Step 9 Synthesis of 2-amino-3-phenyl-1-(2-(quinolin-3-yl)-3,6-dihydropyridin-1(2H)-yl)propan-1-one [ka] To a solution of 2-(1-oxo-3-phenyl-1-(2-(quinolin-3-yl)-3,6-dihydropyridin-1(2H)-yl)propan-2-yl)isoindoline-1,3-dione (1.4 g, 2.9 mmol) in EtOH (20 mL) was added hydrazine monohydrate (0.45 mL). The reaction solution was refluxed at 85° C. overnight, and the resulting suspension was filtered at room temperature. The filtrate was concentrated and further dissolved in 20 mL of a 1:1 mixture of EtOAc / hexanes and kept at 0° C. overnight. The mixture was filtered, and the filtrate was concentrated to give 2-amino-3-phenyl-1-(2-(quinolin-3-yl)-3,6-dihydropyridin-1(2H)-yl)propan-1-one (0.8 g, 77%) as a brown oil, a mixture of diastereomers. MS (ESI, pos. ion) m / z: 358.19 (M+1).

[0226] Step 10 Synthesis of 2-amino-3-phenyl-1-(2-(quinolin-3-yl)-3,6-dihydropyridin-1(2H)-yl)propan-1-one [ka] To a solution of 3-butylamidobenzoic acid (0.47 g, 2.15 mmol, 1 equiv.) and 2-amino-3-phenyl-1-(2-(quinolin-3-yl)-3,6-dihydropyridin-1(2H)-yl)propan-1-one (0.47 g, 2.15 mmol, 1 equiv.) in DCM (10 mL) was added EDC hydrochloride (0.56 g, 2.8 mmol, 1.3 equiv.) and i-PrNEt (0.5 mL, 2.80 mmol, 1.3 equiv.). The reaction mixture was stirred at room temperature overnight and quenched with HO (10 mL). The layers were separated, and the organic layer was washed with brine, dried, and concentrated to give the crude product, which was crystallized using acetonitrile as the solvent. The crystals were filtered and collected as a white mass (0.45 g, 38.3%) present as a mixture of diastereomers. MS (ESI, pos. ion) m / z: 547.5 (M+1).

[0227] Proceeding similarly as described in Example 38 above, starting from the corresponding amino acid, the compounds of Examples 65-66 were prepared.

[0228] Example 65: 3-Butylamido-N-(1-(2-(2-chloroquinolin-3-yl)-3,6-dihydropyridin-1(2H)-yl)-1-oxo-3-phenylpropan-2-yl)benzamide (0.05 g, 17.2%) as a pale yellow solid. (Compound 67) [ka] MS (ESI, pos, ion) m / z: 581.3 (M+1).

[0229] Example 66: 3-Butylamido-N-(1-oxo-1-(2-(quinolin-3-yl)-3,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.13 g, 38.6%) as a creamy white solid. (Compound 68) [ka] MS (ESI, pos, ion) m / z: 471.4 (M+1).

[0230] Example 39 Synthesis of 3-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamide}-N-[(2S)-1-oxo-3-phenyl-1-{1,2,3,6-tetrahydro-[2,3'-bipyridin]-1-yl}propan-2-yl]benzamide (Compound 41) [ka] Step 1 To a solution of 3-nitrobenzoic acid (8.4 g, 50 mmol) in MeOH (150 mL) was added SOCl (7.1 mL, 100 mmol) slowly at room temperature. The reaction mixture was refluxed for 2 hours. All solvent was removed to give methyl 3-nitrobenzoate (9.1 g, 100%) as a crude product.

[0231] Step 2 To a solution of methyl 3-nitrobenzoate (9.1 g, 50 mmol) in EtOH (150 mL) was added SnCl 2H O (22.5 g, 100 mmol) in one portion. The reaction mixture was refluxed for 2 h, and then the solvent was removed. The residue was extracted with EtOAc. The organic layer was washed, dried, and concentrated to give methyl 3-aminobenzoate (8.4 g, 100%) as a brown oil.

[0232] Step 3 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) was added EDC (1.3 g, 7.0 mmol) and i-PrNEt (1.2 mL, 7.5 mmol). The reaction mixture was stirred at room temperature overnight and quenched with HO (10 mL). The layers were separated, and the organic layer was washed with brine, dried, and concentrated to give methyl 3-(5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)benzoate (1.13 g, 52%).

[0233] Step 4 To a solution of methyl 3-(5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)benzoate (1.13 g, 2.9 mmol) in a mixture of THF (15 mL) and HO (15 mL), LiOH (0.36 g, 14 mmol) was added in one portion and stirred at room temperature overnight. The reaction was further diluted with 1 N NaOH, and the aqueous layer was washed with EtOAc and neutralized with 1 N HCl. The resulting solid was collected to give 3-(5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)benzoic acid (0.7 g, 83%) as crude product.

[0234] Step 5 To a solution of 3-(5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)benzoic acid (0.7 g, 1.9 mmol) and (2S)-2-amino-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-1-one (0.6 g, 1.9 mmol) in DCM (20 mL) was added EDC hydrochloride (0.5 g, 2.4 mmol) and i-PrNEt (0.4 mL, 2.5 mmol). The reaction mixture was stirred at room temperature overnight and quenched with HO (30 mL). The layers were separated, and the organic layer was washed with brine, dried, concentrated, and purified by CombiFlash® using a HP C 18 Aq GOLD column with MeCN / buffered HO as the eluting mobile phase to give 3-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamide}-N-[(2S)-1-oxo-3-phenyl-1-{1,2,3,6-tetrahydro-[2,3'-bipyridin]-1-yl}propan-2-yl]benzamide (80 mg, 7%) as a powder. MS (ESI, pos. ion) m / z: 653.5 (M+1).

[0235] Example 57 Synthesis of 3-(3-aminopropanamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide hydrochloride (Compound 54) [ka] Synthesis scheme of 3-(3-aminopropanamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide hydrochloride: [ka] 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-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-1-one (0.62 g, 2.0 mmol) in DCM (10 mL) was added EDC hydrochloride (0.57 g, 2.9 mmol) and i-PrNEt (0.47 mL, 3.9 mmol). The reaction mixture was stirred at room temperature overnight and quenched with HO (10 mL). The layers were separated, and the organic layer was washed with brine, dried, concentrated, and purified by CombiFlash® using a HP C 18 Aq GOLD column with MeCN / buffered HO as the eluting mobile phase to give 3-(3-aminopropanamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide as a film in a flask, present as a mixture of two diastereomers. The benzamide was converted to the benzamide hydrochloride salt by dissolving it in 5 ml of 1,4-dioxane and stirring with 2 equivalents of 4N HCl in 1,4-dioxane for 1 h, followed by concentration of the reaction mixture to give 3-(3-aminopropanamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide hydrochloride as a brown solid (0.89 g, 84%) MS (ESI, pos, ion) m / z: 498.2 (M+1).

[0236] Proceeding similarly to Example 57 above, the compounds of Examples 58-59 were prepared starting from the corresponding benzoic acids.

[0237] Example 58: 3-(2-aminoacetamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide hydrochloride (0.83 g, 83%) as a beige solid. (Compound 53) [ka] MS (ESI, pos, ion) m / z: 484.2 (M+1).

[0238] Example 59: 3-(4-aminobutanamido)-N-((2S)-1-oxo-3-phenyl-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide hydrochloride (0.40 g, 36%) as a beige solid. (Compound 55) [ka] MS (ESI, pos, ion) m / z: 512.2 (M+1).

[0239] Example 61 Synthesis of 3-butylamido-N-((2S)-1-oxo-3-phenyl-1-(2-(pyridin-3-yl)piperidin-1-yl)propan-2-yl)benzamide (Compound 63) [ka] Synthesis scheme of 3-butylamido-N-((2S)-1-oxo-3-phenyl-1-(2-(pyridin-3-yl)piperidin-1-yl)propan-2-yl)benzamide: [ka] Step 1 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) was added PCl5 (1.0 g, 4.8 mmol) in small portions. The reaction mixture was stirred at room temperature for 3 h. All volatiles were completely removed by rotary evaporation to give (S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride, which was used in the next step without further purification.

[0240] Step 2 To a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl chloride (4.8 mmol) in anhydrous benzene (20 mL) was slowly added (+ / -)-anabasine (0.8 g, 4.9 mmol). The resulting solution was stirred at room temperature overnight and quenched with saturated NaHCO (20 mL). The layers were separated, and the benzene layer was washed with brine, dried, and concentrated to give 2-((2S)-1-oxo-3-phenyl-1-(2-(pyridin-3-yl)-piperidin-1-yl)propan-2-yl)isoindoline-1,3-dione, present as a mixture of two diastereomers, as a foam (1.5 g), which was used in the next step without further purification.

[0241] Step 3 To a solution of 2-((2S)-1-oxo-3-phenyl-1-(2-(pyridin-3-yl)-piperidin-1-yl)propan-2-yl)isoindoline-1,3-dione (1.5 g) in EtOH (30 mL) was added hydrazine monohydrate (0.3 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 allowed to stand overnight. The resulting solid was filtered off, and the filtrate was concentrated to give (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.

[0242] Step 4 To a solution of 3-butylamidobenzoic 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) in DCM (20 mL) was added EDC hydrochloride (0.78 g, 4.0 mmol) and i-PrNEt (0.65 mL, 4.1 mmol). The reaction mixture was stirred at room temperature overnight and quenched with HO (20 mL). The layers were separated and the organic layer was washed with brine, dried and concentrated to give 3-butylamido-N-((2S)-1-oxo-3-phenyl-1-(2-(pyridin-3-yl)piperidin-1-yl)propan-2-yl)benzamide, present as a mixture of two diastereomers, as a pale yellow solid (0.64 g, 32%) MS (ESI, pos. ion) m / z: 499.2 (M+1), after purification by CombiFlash® using a HP C 18 Aq GOLD column with MeCN / buffered HO as the eluting mobile phase.

[0243] Example 62 Synthesis of 3-butylamido-N-((2S)-3-(naphthalen-1-yl)-1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (Compound 64) [ka] Step 1 A single-necked round-bottom flask (100 mL) equipped with a condenser was charged with 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) in that order. The resulting mixture was refluxed for 4 hours. The solvent was completely removed in vacuo, and the residue was precipitated from a mixture of ethyl acetate and hexane to give (S)-2-(1,3-dioxoisoindolin-2-yl)-3-(naphthalen-1-yl)propanoic acid (0.52 g) as a beige solid.

[0244] Step 2 To a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-(naphthalen-1-yl)propanoic acid (0.52 g, 1.4 mmol) in anhydrous DCM (10 mL) was added PCl5 (0.32 g, 1.6 mmol) in small portions. The reaction mixture was stirred at room temperature for 3 h. All volatiles were completely removed by rotary evaporation to give (S)-2-(1,3-dioxoisoindolin-2-yl)-3-(naphthalen-1-yl)propanoyl chloride, which was used in the next step without further purification.

[0245] Step 3 To a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-(naphthalen-1-yl)propanoyl chloride (0.5 g, 1.3 mmol) in anhydrous benzene (10 mL) was slowly added (+ / -)-anatabine (0.2 g, 1.3 mmol). The resulting solution was stirred at room temperature overnight and quenched with saturated NaHCO (10 mL). The layers were separated, and the benzene layer was washed with brine, dried, and concentrated to give 2-((2S)-1-oxo-3-phenyl-1-(2-(pyridin-3-yl)piperidin-1-yl)propan-2-yl)isoindoline-1,3-dione, present as a mixture of two diastereomers, as a brown solid (0.33 g), which was used in the next step without further purification.

[0246] Step 4 To a solution of 2-((2S)-1-(3,6-dihydro-[2,3'-bipyridin]-1(2H)-yl)-3-(naphthalen-1-yl)-1-oxopropan-2-yl)isoindoline-1,3-dione (0.33 g) in EtOH (10 mL) was added hydrazine monohydrate (0.1 mL). The reaction solution was refluxed for 3 h, and the resulting suspension was filtered at room temperature. The filtrate was dissolved in a mixture of EtOAc and hexane and allowed to stand overnight. The resulting solid was filtered off, and the filtrate was concentrated to give (2S)-2-amino-1-(3,6-dihydro-[2,3'-bipyridin]-1(2H)-yl)-3-(naphthalen-1-yl)propan-1-one, present as a mixture of two diastereomers, as a brown oil (0.38 g), which was used in the next step without further purification.

[0247] Step 5 To a solution of 3-butylamidobenzoic acid (0.21 g, 1.0 mmol) and (2S)-2-amino-1-(3,6-dihydro-[2,3'-bipyridin]-1(2H)-yl)-3-(naphthalen-1-yl)propan-1-one (0.36 g, 1.0 mmol) in DCM (10 mL) was added EDC hydrochloride (0.28 g, 1.4 mmol) and i-PrNEt (0.23 mL, 1.4 mmol). The reaction mixture was stirred at room temperature overnight and quenched with HO (10 mL). The layers were separated and the organic layer was washed with brine, dried and concentrated to give 3-butylamido-N-((2S)-3-(naphthalen-1-yl)-1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide, present as a mixture of two diastereomers, as a yellow solid (0.19 g) MS (ESI, pos. ion) m / z: 547.2 (M+1), after purification by CombiFlash® using a HP C 18 Aq GOLD column with MeCN / buffered HO as the eluting mobile phase.

[0248] Proceeding similarly to Example 62 above, the compounds of Examples 63-64 were prepared starting from the corresponding benzoic acids.

[0249] Example 63: 3-Butylamido-N-((2S)-3-(naphthalen-2-yl)-1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.35 g) as a yellow solid. (Compound 65) [ka] MS (ESI, pos, ion) m / z: 547.2 (M+1).

[0250] Example 64: 3-Butylamido-N-((2S)-3-cyclohexyl-1-oxo-1-(6-(pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)propan-2-yl)benzamide (0.06 g) as a yellow solid. (Compound 66) [ka] MS (ESI, pos, ion) m / z: 503.3 (M+1).

[0251] Biological Examples Example 1 Determination of inhibition of TNFα-induced NF-kB activation...in vitro assay The ability of the compounds disclosed herein to inhibit TNFα-induced NFkB activation was determined using a TNFα luciferase assay. The HEK 293 / NF-kB luciferase cell line was obtained by cotransfecting the pNFkB-luc vector with pHyg (Panomics, CA, USA) followed by hygromycin selection. HEK 293 / 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 selection agents. HEK293 NFkB luciferase cells were grown in T75 flasks (Nunc™ Cell Culture Treated EasyFlasks™) in a 37°C, 5% CO2 cell culture incubator.

[0252] Confluent T75 cell culture flasks (approximately 8-10 million cells per flask) were washed with 10 ml of sterile PBS (calcium- and magnesium-free) under a safety cabinet. After aspirating the PBS with a sterile glass pipette, the cell layer (for each T75 flask) was covered with 1 ml of phenol red-free TrypLE™ Express (Gibco) at room temperature. After a 1-minute incubation, the HEK293 cells were mechanically resuspended in TrypLE by tapping the side of the flask. The cells were then resuspended in 10 ml of prewarmed complete culture medium and transferred to a conical tube. The cells were centrifuged at 4000 rpm (1000 g) for 5 minutes at room temperature. The cell pellet was resuspended in 24 ml of prewarmed cell culture medium, and 200 ml of the cell suspension (approximately 80,000 cells per well) was seeded per well into a 96-well cell culture plate (Costar #3599, Corning, NY, USA) using a multichannel pipette and a reverse pipette to prevent bubble formation. After seeding, the cells were maintained overnight in a cell culture incubator before treatment. For each 96-well cell culture plate, 8 wells were used as "control wells" (culture medium only) and 8 wells were added with TNFα only. The NF-kB luciferase reporter cell line was exposed to 25 ng / ml of TNFα for 4 hours in the presence and absence (control condition) of a range of doses of various compounds to be tested. For each compound, a range of concentrations was tested in quadruplicate, and the IC 50 was used to determine

[0253] Luciferase activity was monitored by chemiluminescence using the Luc-Screen® Extended-Glow Luciferase Reporter Gene Assay System and a BioTek Synergy HT plate reader (BioTek Instruments, VT, USA) according to the manufacturer's instructions. IC values, the concentrations at which NF-kB activation was reduced by 50%, for a representative number of compounds were calculated. 50 are shown in Table 3 below. [Table 3]

[0254] Example 2 Determining anti-inflammatory activity using an acute LPS model of inflammation in mice...in vivo model The ability of compounds disclosed herein to reduce inflammation was determined in vivo using the mouse model described above. The effect of the compounds on LPS-induced proinflammatory cytokine production can be evaluated in various tissues (e.g., plasma, brain, intestine, spleen, lung, etc.). Adult C57B16 / J wild-type mice were used to evaluate the effect of compounds disclosed herein ("test" compounds) on cytokine production induced by intraperitoneal injection of LPS (lipopolysaccharide) [LPS:B4 from Escherichia coli O111, Sigma-Aldrich No. L4391]. Prior to treatment with LPS (1 mg / kg (ip) dissolved in sterile PBS), mice were randomized 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 (receiving 20 mg / kg of test compound IP). Mice were injected with test compound or vehicle 15 minutes before LPS injection.

[0255] Mice were then 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 1500 g for 4 minutes, and 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.

[0256] Tissue homogenates were prepared by sonication in ice-cold M-PER Reagent (Pierce Biotechnology, Rockford, IL, USA) containing 1 mM phenylmethanesulfonyl fluoride, 1× protease cocktail inhibitor (Roche, Inc., USA), and 1 mM sodium orthovanadate (Sigma-Aldrich, MO, USA). Cytokines were quantified by electrochemiluminescence using the multi-spot plate of the V-Plex Assay Kit Pro-Inflammatory Panel 1 (Mouse) Kit (Mesoscale discovery, USA). All LPS-treated samples were diluted 10-fold with diluent 41 from the kit, and control samples were assayed undiluted. The amounts of the proinflammatory cytokines interferon-gamma, IL-1β, and TNFα produced were lower in the treated group compared to the control group.

[0257] Formulation Examples The following are representative pharmaceutical formulations containing compounds of the present disclosure.

[0258] Tablet formulation The following ingredients are intimately mixed and compressed into single scored tablets: Ingredients Amount per tablet mg Compound 400 of the present disclosure 50g cornstarch Croscarmellose sodium 25 Lactose 120 Magnesium stearate 5

[0259] Capsule formulation The following ingredients are intimately mixed and filled into a hard-shell gelatin capsule: Ingredients Amount per capsule mg Compound 200 of the present disclosure Spray-dried lactose 148 Magnesium stearate 2

[0260] Injectable preparations Compound of the disclosure (e.g., Compound 1) in 2% HPMC, 1% Tween® 80 in DI, pH 2.2 with MSA, appropriate amount to at least 20 mg / mL

[0261] Inhalation composition To prepare the pharmaceutical composition for inhalation delivery, 20mg of the compound disclosed herein is mixed with 50mg of anhydrous citric acid and 100mL of 0.9% sodium chloride solution.This mixture is incorporated into the inhalation delivery unit, such as a nebulizer, that is suitable for inhalation administration.

[0262] Topical gel compositions 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 placed into a container, such as a tube, suitable for topical administration.

[0263] eye drop composition To prepare pharmaceutical eye drop composition, 100mg of the compound disclosed herein is mixed with 0.9g of NaCl in 100mL of purified water, and filtered through a 0.2 micron filter.The resulting isotonic solution is then incorporated into an eye delivery unit, such as an eye dropper, suitable for ocular administration.

[0264] nasal solution To prepare a pharmaceutical nasal solution, 10 g of a compound disclosed herein is mixed with 30 mL of 0.05 M phosphate buffer (pH 4.4). The solution is placed in a nasal administration device designed to deliver 100 μl of spray per application. (Item 1) A compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, n is 0, 1 or 2; Dashed lines are necessary bonds; Het is an R independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, dialkylamino, carboxy, and alkoxycarbonyl. a , R b and / or R c is heteroaryl optionally substituted with; R 1 is hydrogen or alkyl; R 2 is hydrogen or alkyl; R 3 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, acylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, where aryl or heteroaryl, alone or as part of an 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 with substitution as necessary; R 4 is hydrogen or alkyl; R 5 HA-C(O)R 6 and R 6is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, and aryl or heteroaryl, alone or as part of an 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, halo, haloalkyl, haloalkoxy, cyano, nitro, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, acylamino, and sulfonylamino. g , R h and / or R i with R 4 and R 5 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycloamino ring; A compound or a pharmaceutically acceptable salt thereof. (Item 2) The compound has the structure (IA): [ka] Item 1. The compound according to item 1, having the formula: (Item 3) The above compound has structure (IB): [ka] Item 1. The compound according to item 1, having the formula: (Item 4) The compound according to any one of items 1 to 3, wherein n is 1, 2 or 3. (Item 5) The compound according to any one of items 1 to 4, wherein n is 1. (Item 6) The compound according to any one of Items 1 to 3, wherein n is 0 or 2. (Item 7) The compound according to any one of items 1 to 3, wherein n is 0. (Item 8) The compound according to any one of items 1 to 3, wherein n is 2. (Item 9) R 4 is hydrogen or alkyl, and R 5 -C(O)R 6 and R 6 is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or heterocycloalkyl, and the aryl or heteroaryl, alone or as part of an aralkyl or heteroaralkyl, is 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, nitro, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, acylamino, and sulfonylamino; g , R h and / or R i 9. The compound according to any one of items 1 to 8, optionally substituted with (Item 10) R 5 But R g , R h and / or R i Item 10. The compound according to item 9, wherein R is an optionally substituted aryl or heteroaryl. (Item 11) R 5 But R g , R h and / or R i 10. The compound according to item 9, wherein the aryl group is an aralkyl or heteroaralkyl optionally substituted with (Item 12) R 5 But R g , Rh and / or R i Item 10. The compound according to item 9, wherein R is phenyl optionally substituted with R. (Item 13) R g is alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, or cyano, and R h and R i is 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, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, acylamino, or sulfonylamino. (Item 14) R g , R h and R i is 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 pentanoylamino. (Item 15) R 4 and R 5 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycloamino ring. (Item 16) R 1 and R 2 16. The compound according to any one of items 1 to 15, wherein is independently hydrogen or methyl, preferably hydrogen. (Item 17) R 1 and R 217. The compound according to any one of items 1 to 16, wherein when both of are alkyl, they are not attached to the same ring carbon. (Item 18) Het is pyridinyl, pyrimidinyl, pyrazinyl, furanyl, thienyl, quinolinyl, isoquinolinyl, pyrazolyl or indolyl, and each ring is independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, dialkylamino, carboxy and alkoxycarbonyl. a , R b and R c 18. The compound according to any one of items 1 to 17, optionally substituted with (Item 19) R a , R b and R c is independently selected from methyl, ethyl, methoxy, ethoxy, chloro, fluoro, trifluoromethyl, trifluoromethoxy, cyano, amino, methylamino or dimethylamino. (Item 20) The compound according to any one of items 1 to 17, wherein Het is pyridin-2-yl. (Item 21) R 3 R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, acylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, where aryl or heteroaryl, alone or in aralkyl and heteroaralkyl, are independently selected from alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, cyano, nitro, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino; d , R e and / or R f 21. The compound according to any one of items 1 to 20, optionally substituted with (Item 22) R 321. Compounds according to any one of items 1 to 20, wherein is hydrogen or alkyl, preferably methyl, ethyl, propyl, isopropyl, sec-propyl, n-, sec, iso, tert-butyl. (Item 23) R 3 R d , R e and / or R f and optionally substituted aralkyl, preferably R 3 is benzyl or phenethyl, more preferably R d , R e and / or R f and even more preferably R is optionally substituted benzyl. 3 21. The compound according to any one of items 1 to 20, wherein is benzyl. (Item 24) R 3 R d , R e and / or R f is cycloalkylalkyl optionally substituted with, preferably R 3 R d , R e and / or R f 21. The compound according to any one of items 1 to 20, wherein the aryl group is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl, optionally substituted with (Item 25) R 3 R d , R e and / or R f 21. The compound according to any one of items 1 to 20, wherein the heteroaralkyl optionally substituted with (e.g., thienylmethyl, furanylmethyl, pyridinylmethyl, quinolinylmethyl, isoquinolinylmethyl, indolylmethyl or indazolylmethyl). (Item 26) R 3 is hydroxyalkyl, alkoxyalkyl, aminoalkyl, preferably R 3 21. The compound according to any one of items 1 to 20, wherein is hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, aminomethyl or aminobutyl. (Item 27) R 3 27. The compound according to any one of items 1 to 26, wherein the stereochemistry at the carbon to which is attached is (S). (Item 28) R 3 27. The compound according to any one of items 1 to 26, wherein the stereochemistry at the carbon to which is attached is (R). (Item 29) A pharmaceutical composition comprising the compound according to any one of items 1 to 28 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. (Item 30) A method for treating a disease treatable by inhibiting NF-kB activation, comprising administering the pharmaceutical composition of Item 29 to a patient in need thereof. (Item 31) The method according to Item 30, wherein the disease is an inflammatory disease. (Item 32) The method according to Item 31, wherein the disease is selected from the group consisting of autoimmune diseases, pain, allergies, asthma, chronic obstructive pulmonary disease, and sepsis. (Item 33) The method according to Item 30, wherein the disease is selected from the group consisting of 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, Paget's disease, pancreatitis, periodontitis, inflammatory lung disease, and lupus nephritis.

Claims

1. Compound of formula (IA): 【Chemistry 92】 Or a compound of formula (IB): 【Chemistry 93】 or a pharmaceutically acceptable salt thereof, During the ceremony, n is 1; Het is pyridin-3-yl; R １ is hydrogen or alkyl; R ２ is hydrogen or alkyl; R ３ is methyl, ethyl, propyl, or benzyl; R ４ is hydrogen; R ５ Ha-C(O)R ６ and R ６ is phenyl, furanyl, pyrrolyl, pyridinyl, pyrazinyl, or quinolinyl, and phenyl is selected from methyl, methoxy, ethoxy, chloro, fluoro, trifluoromethyl, nitro, amino, alkylamino, and acylamino; ｇ and / or R ｈ and pyrrolyl is optionally substituted with alkyl; A compound or a pharmaceutically acceptable salt thereof.

2. R １ and R ２ The compound of claim 1 , wherein is independently hydrogen or methyl.

3. R １ and R ２ The compound of claim 2 , wherein is independently hydrogen.

4. R １ and R ２ 10. The compound of claim 1, wherein when both are alkyl, they are not attached to the same ring carbon.

5. R ３ 5. The compound of claim 1, wherein the stereochemistry at the carbon to which is attached is (S).

6. R ３ 5. The compound of claim 1, wherein the stereochemistry at the carbon to which is attached is (R).

7. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

8. 8. The pharmaceutical composition of claim 7 for treating a disease treatable by inhibiting NF-kB activation in a patient in need thereof.

9. The pharmaceutical composition of claim 8, wherein the disease is an inflammatory disease.

10. 9. The pharmaceutical composition of claim 8, wherein the disease is selected from the group consisting of autoimmune diseases, pain, allergies, asthma, chronic obstructive pulmonary disease, and sepsis.

11. 11. The pharmaceutical composition of claim 10, wherein the disease is selected from the group consisting of 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, Paget's disease, pancreatitis, periodontitis, inflammatory lung disease, and lupus nephritis.

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