3-(sulfonyl or iminosulfonyl) prop-2-en-1-yl]-2-oxo-1, 2-dihydropyridine-3-carboxamide derivatives

Abstract

The present invention relates to a 3-(sulfonyl or iminosulfonyl) prop-2-en-1-yl]-2-oxo-1, 2-dihydropyridine-3-carboxamide derivative having the following formula: # imgabs0 # or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition comprising the 3-(sulfonyl or iminosulfonyl) prop-2-en-1-yl)-2-oxo-1, 2-dihydropyridine-3-carboxamide derivative. The invention further relates to the compounds according to the invention for use as a medicament and also for the treatment of cancer. The invention further relates to a method for suppressing ubiquitination of a Met1 connection. The invention also relates to a pharmaceutical composition comprising the compounds of the invention.

Description

[0001] The present invention relates to 3-(sulfonyl or imidosulfonyl)prop-2-en-1-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide derivatives or pharmaceutically acceptable salts thereof. The present invention further relates to compounds according to the present invention for use as medicaments and also for the treatment of cancer. The present invention further relates to a method for inhibiting Met1-linked ubiquitination. The present invention also relates to a pharmaceutical composition comprising a compound of the present invention.

[0002] Cellular homeostasis depends on adaptation to the environment through numerous signaling cascades that convert extrinsic and intrinsic cues and stresses into appropriate responses. Signaling is most commonly propagated through rapid and specific post-translational modifications (PTMs) of signaling proteins, leading to adaptive changes at the transcriptional and translational levels. Maladaptation may cause cell damage or cell death and may lead to disease. Methionine 1 (Met1)-linked ubiquitin (also known as linear ubiquitin) is a PTM that has been critical in the past decade to control important signaling cascades and prevent cell death. Therefore, dysregulation of Met1-linked ubiquitin modifications is associated with serious pathologies, including immune disorders, cancer, and neurodegeneration, emphasizing that the balance of a single isoform of PTM may be critical for maintaining homeostasis, preventing and treating life-threatening diseases. The linear ubiquitin (Ub) chain assembly complex (LUBAC) is the only known mammalian ubiquitin ligase that produces Met1-linked ubiquitin. Therefore, by controlling the function of LUBAC, the role and regulation of Met1-linked ubiquitin can be controlled.

[0003] LUBAC is composed of three proteins: HOIL-1 interacting protein (HOIP; also known as RNF31), heme-oxidized IRP2 Ub ligase-1 (HOIL-1; also known as RBCK1), and SHANK-related RH domain interacting protein (SHARPIN). Of the three proteins, HOIP (RNF31) was found to have remarkable specificity and exclusively assemble Met1-Ub, while HOIL-1 and SHARPIN serve as cofactors in LUBAC and are essential for HOIP activation. LUBAC was originally described to regulate signal transduction in response to activation of tumor necrosis factor (TNF) receptor 1 (TNF-R1), and has since been found to regulate signal transduction through a variety of NF-κB-activating immune receptors, including cytokine receptors, Toll-like receptors (TLRs), NOD-like receptors (NLRs), and antigen receptors. Therefore, LUBAC can be considered one of the core components of the NF-κB activation signaling pathway.

[0004] Additional detailed information on Met1-linked ubiquitin PTMs and the mechanisms and pathways involved in the subsequent control of important signaling cascades and prevention of cell death is described, for example, in Hrdinka ("The Met1-linked ubiquitin machinery: emerging themes of (De)regulation." Molecular cell 68.2 (2017): 265-280), Ning ("Structures, functions, and inhibitors of LUBAC and its related diseases." Journal of Leukocyte Biology (2022)), Jahan ("Met1-linked ubiquitin signaling in health and disease: inflammation, immunity, cancer, and beyond." Cell Death & Differentiation 28.2 (2021): 473-492) and Oikawa ("Cellular and Mathematical Analyses of LUBAC Involvement in T Cell Receptor-Mediated NF-KB Activation Pathway." Frontiers in immunology (2020): 3042).

[0005] In summary, by controlling the function of LUBAC, the role and regulation of Met1-linked ubiquitin can be controlled, and therefore, the development of diseases such as cancer can be subsequently controlled. It is believed that by providing Met1-linked ubiquitination inhibitors, particularly LUBAC-related HOIP (RNF31) inhibitors, promising candidates for the treatment of cancer can be identified. In a first aspect of the present invention, the present invention provides a compound having formula (I):

[0006]

[0007] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Both are hydrogen, or the 2-oxo-1,2-dihydropyridine moiety:

[0008]

[0009] Selected from the group consisting of the following 2-oxo-1,2-dihydropyridine moieties:

[0010]

[0011] in:

[0012] n is 1, 2, 3, or 4;

[0013] A is oxygen or nitrogen;

[0014] X is carbon or nitrogen, or wherein R 7 -X is oxygen;

[0015] Y is carbon or nitrogen;

[0016] Z is hydrogen, (C1-C6)alkyl or di-(C1-C6)alkyl;

[0017] R 3 and R 4 are each independently selected from the group consisting of hydrogen, (C1-C4) alkyl, or wherein R 3 and R 4 Together with the carbon to which they are attached they form a (C3-C6)cycloalkyl group;

[0018] R 5 Selected from the group consisting of hydrogen, halo or (C1-C6)alkyl;

[0019] R 6 Selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with one to four halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C2-C9)heterocycloalkyl, (C3-C6)cycloalkyloxy, (C6-C10)aryl, (C6-C10)aryloxy, cyano, primary, secondary or tertiary amino groups;

[0020] When X is carbon, R 7 YesR 7 ' and R 7 ”, where R 7 ' is selected from the group consisting of: hydrogen, halo or (C1-C6) alkyl, and wherein R 7" is selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, wherein the aryl and heteroaryl groups are optionally substituted with one to three (C1-C6)alkyl;

[0021] When X is nitrogen, R 7 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, wherein the aryl and heteroaryl groups are optionally substituted with one to three (C1-C6)alkyl, or wherein R 7 YesR 8 M-, where:

[0022] -R 8 M-Selected from the group consisting of: R 8 -C(O)-、R 8 -OC(O)-、R 8 -NH-C(O)- or R 8 -S(O)2-; and

[0023] -R 8 Selected from the group consisting of: (C1-C6)alkyl, (C3-C10)cycloalkyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl, (C4-C9)spiroheterocycloalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C1-C6)alkyl, (C4-C9)bicycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and bicycloalkyl groups are optionally substituted with one to four halo, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)alkoxy, cyano, oxo or hydroxyl.

[0024] The compounds of the present invention were found to exhibit promising RNF31 inhibition properties (in a cell-free HTRF-based HOIP inhibition assay), thereby providing promising candidates as Met1-linked ubiquitination inhibitors. It was further found that the compounds of the present invention down-regulate the nuclear factor kappa light-chain enhancer (NF-κB) signaling pathway of activated B cells and / or up-regulate necrosis factor alpha (TNFα)-induced cytotoxicity.

[0025] Considering the compounds of the present invention, it is found that wherein R3 , R 4 and R 5 Compounds that are hydrogen show further improved RNF31 inhibitory properties, and improved downregulation properties of the NF-κB signaling pathway and / or upregulation properties of TNFα-induced cytotoxicity.

[0026] Similarly, it is found that by selecting R from the group consisting of (C6-C10)aryl or (C2-C9)heteroaryl 6 , wherein the aryl and heteroaryl groups are optionally substituted with one to four halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C2-C9)heterocycloalkyl, (C3-C6)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, cyano, primary amino, secondary amino or tertiary amino groups, identifying more promising candidates for Met1-linked ubiquitination inhibition.

[0027] Preferably, when X is carbon, R 7 YesR 7 ' and R 7 ”, where R 7 ' is selected from the group consisting of hydrogen, halo or (C1-C6) alkyl, and wherein R 7 " is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, wherein the aryl and heteroaryl groups are optionally substituted with one to three (C1-C6)alkyl;

[0028] When X is nitrogen, R 7 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, wherein the aryl and heteroaryl groups are optionally substituted with one to three (C1-C6)alkyl, or wherein R 7 YesR 8 M-, where:

[0029] -R 8 M-Selected from the group consisting of: R 8 -OC(O)-、R 8 -NH-C(O)- or R 8 -S(O)2-; and

[0030] -R 8Selected from the group consisting of: (C1-C6)alkyl, (C3-C10)cycloalkyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl, (C4-C9)spiroheterocycloalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C1-C6)alkyl, (C4-C9)bicycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and bicycloalkyl groups are optionally substituted with one to four halo, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)alkoxy, cyano, oxo or hydroxyl.

[0031] In embodiments of the present invention, n may be 1, 2 or 3, thereby producing compounds with improved Met1-linked ubiquitination inhibition properties. It should be further noted that in preferred embodiments of the present invention, when X is nitrogen, R 7 Not hydrogen.

[0032] In a specific embodiment of the present invention, the present invention relates to a compound having formula (II):

[0033]

[0034] or a pharmaceutically acceptable salt thereof, wherein:

[0035] n is 1, 2, or 3;

[0036] A is oxygen or nitrogen; and

[0037] R' is selected from the group consisting of (C6-C10)aryl or (C2-C9)heteroaryl, wherein the aryl and heteroaryl groups are optionally substituted by one to four halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C2-C9)heterocycloalkyl, (C3-C6)cycloalkyloxy, (C6-C10)aryl, (C6-C10)aryloxy, cyano, primary amino, secondary amino or tertiary amino. Preferably, with respect to formula (II), it was found that specific active compounds are obtained, wherein (C6-C10)aryl is phenyl, or (C2-C9)heteroaryl is pyridinyl, and wherein the phenyl and pyridinyl groups are optionally substituted by one to three fluorine, chlorine, bromine or methoxy groups.

[0038] In another specific embodiment of the present invention, the present invention relates to compounds having formula (III):

[0039]

[0040] or a pharmaceutically acceptable salt thereof, wherein:

[0041] A is oxygen or nitrogen;

[0042] R" is selected from the group consisting of (C6-C10)aryl or (C2-C9)heteroaryl, wherein the aryl and heteroaryl groups are optionally substituted with one to four halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C2-C9)heterocycloalkyl, (C3-C6)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, cyano, primary amino, secondary amino or tertiary amino;

[0043] M' is carbon or -OC(O)-; and

[0044] R'' is selected from the group consisting of: (C1-C6)alkyl, (C3-C10)cycloalkyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl, (C4-C9)spiroheterocycloalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C1-C6) )alkyl, (C4-C9)bicycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and bicycloalkyl groups are optionally substituted with one to four halo, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)alkoxy, cyano, oxo or hydroxy. Preferably, with respect to formula (III), it is found that specific active compounds are obtained in which A is nitrogen.

[0045] When any group in the compounds of the present invention is described as being optionally substituted, the group may be unsubstituted or substituted with one or more substituents. Typically, such groups will be unsubstituted or substituted with one, two or three substituents (particularly one or two substituents).

[0046] For use in medicine, the salts of the compounds of the invention will be pharmaceutically acceptable salts. However, other salts may also be useful in the preparation of the compounds used in the invention or their pharmaceutically acceptable salts.

[0047] Suitable pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts, which can be formed, for example, by mixing a solution of the compound used in the present invention with a solution of a pharmaceutically acceptable acid (such as hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid). In addition, when the compound used in the present invention carries an acidic moiety (e.g., a carboxyl group), its suitable pharmaceutically acceptable salt may include an alkali metal salt, such as a sodium salt or a potassium salt; an alkaline earth metal salt, such as a calcium salt or a magnesium salt; an ammonium salt; and a salt formed with a suitable organic ligand, such as a quaternary ammonium salt and a meglumine salt.

[0048] The present invention includes solvates of the compounds of the present invention. Such solvates may be formed with common organic solvents, for example hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcohol solvents such as methanol, ethanol or isopropanol; ether solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate. Alternatively, solvates of compounds of formula (I) may be formed with water, in which case they will be hydrates.

[0049] The present invention also includes co-crystals of the compounds of the present invention. The term "co-crystal" is used to describe a situation in which neutral molecular components are present in a crystalline compound in a defined stoichiometric ratio. The preparation of pharmaceutical co-crystals enables the modification of the crystalline form of the active pharmaceutical ingredient, which in turn can change its physicochemical properties without compromising its intended biological activity. Typical examples of co-crystal formers that can be present in the co-crystal with the active pharmaceutical ingredient include L-ascorbic acid, citric acid, glutaric acid, urea and nicotinamide.

[0050] The present invention further includes prodrugs of the compounds of the present invention. In general, such prodrugs will be functional derivatives of the compounds of the present invention that are readily convertible in vivo into the desired compounds of the present invention.

[0051] Suitable alkyl groups that may be present on the compounds of the present invention include straight and branched (C1-C6) alkyl groups, such as (C1-C4) alkyl groups. Typical examples include methyl and ethyl groups, as well as straight or branched propyl, butyl and amyl groups. Specific alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3-methylbutyl. Derivative expressions (such as "(C1-C6) alkoxy" and "(C1-C6) acyl") will be explained accordingly. In addition, as used herein, the term "di-(C1-C6) alkyl" means two alkyl groups comprising 1 to 6 carbon atoms connected to the same carbon.

[0052] Suitable alkenyl groups that may be present in compounds of the present invention include straight and branched (C2-C6) alkenyl groups, including vinyl and allyl. Suitable alkynyl groups that may be present in compounds of the present invention include straight and branched (C2-C6) alkynyl groups, including ethynyl, propargyl and butynyl.

[0053] As used herein, the term "(C3-C10) cycloalkyl" refers to a monovalent group of 3 to 10 carbon atoms derived from a saturated monocyclic hydrocarbon, and may include its benzo-fused analogs. Suitable (C3-C10) cycloalkyl groups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl and cycloheptyl. As used herein, the term "(C3-C6) cycloalkyl" refers to a monovalent group of 3 to 6 carbon atoms derived from a saturated monocyclic hydrocarbon (such as including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups). The term "(C3-C10) cycloalkyl" may also refer to a cycloalkenyl group, and may include its benzo-fused analogs.

[0054] As used herein, the term "(C2-C9)heterocycloalkyl" refers to a saturated monocyclic ring containing 2 to 9 carbon atoms, preferably 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulfur and nitrogen, and may include benzo-fused analogs thereof. Suitable heterocycloalkyl groups include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, pyrrolidinyl, indolyl, isoindolyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, tetrahydrothiopyranyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl, hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazinyl, homopiperazinyl, morpholinyl, benzoxazinyl, thiomorpholinyl, azepanyl, oxazepanyl, diazepanyl, thiadiazepanyl and azocanyl groups.

[0055] As used herein, the term "(C6-C10)aryl" refers to a monovalent carbocyclic aromatic group derived from a single aromatic ring or multiple condensed aromatic rings. Suitable aryl groups include phenyl and naphthyl, preferably a phenyl group.

[0056] As used herein, the term "(C2-C9)heteroaryl" refers to a monovalent aromatic group containing at least 5 atoms derived from a single ring or multiple condensed rings, wherein one or more carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulfur and nitrogen. Suitable heteroaryl groups include furanyl, benzofuranyl, dibenzofuranyl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,4-b][1,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,4-b]pyridinyl, diazepanyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazole yl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, purinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, [1,2,4]triazolo[1,5-a]-pyrimidinyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolyl, isoquinolyl, naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl and chromenyl groups.

[0057] As used herein, the term "halo" is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine. As used herein, the term "dihalo" means two halogens attached to the same carbon.

[0058] As used herein, the term "(C4-C9)spiroheterocycloalkyl" refers to a saturated bicyclic ring system containing 4 to 9 carbon atoms and at least one heteroatom selected from oxygen, sulfur and nitrogen, wherein the two rings are linked by a common atom. Suitable spiroheterocycloalkyl groups include 5-azaspiro[2.3]hexanyl, 5-azaspiro[2.4]-heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.4]-octanyl, 2-oxa-6-azaspiro[3.5]nonanyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro-[3.5]nonanyl, 2,4,8-triazaspiro[4.5]decanyl, 1-oxaspiro[2.3]hexanyl, 2-oxaspiro[3.3]heptanyl, 1-oxaspiro[3.4]octanyl and 2-oxaspiro[3.5]nonanyl groups.

[0059] As used herein, the term "(C5-C9)bicycloalkyl" refers to a monovalent group of 5 to 9 carbon atoms derived from a saturated bicyclic hydrocarbon. Typical bicycloalkyl groups include bicyclo[3.1.0]hexyl, bicyclo[1.1.1]pentyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl and bicyclo[2.2.2]octyl. Alternatively or additionally, instead of a (C5-C9)bicycloalkyl group, a (C4-C9)heterobicycloalkyl group may also be present on the compounds of the invention, the (C4-C9)heterobicycloalkyl group corresponding to a (C5-C9)bicycloalkyl group in which one or more carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulfur and nitrogen. Typical heterobicycloalkyl groups include 3-azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, 2-oxabicyclo[2.2.2]octanyl, quinuclidine, 2-oxa-5-azabicyclo[2.2.2] octyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 3,6-diazabicyclo[3.2.2]nonyl, 3-oxa-7-azabicyclo[3.3.1]nonyl and 3,9-diazabicyclo[4.2.1]nonyl.

[0060] In addition to the terms explained above, derivative expressions (such as "(C6-C10)aryl(C1-C6)alkyl", "(C2-C9)heteroaryl(C1-C6)alkyl", "(C3-C10)cycloalkyl(C1-C6)alkyl" and "(C1-C6)alkoxy(C1-C6)alkyl") will be interpreted accordingly. For example, suitable (C6-C10)aryl(C1-6)alkyl groups include benzyl, phenethyl, phenylpropyl and naphthylmethyl groups. Suitable (C2-C9)heteroaryl(C1-C6)alkyl groups include pyridylmethyl, pyridazinylmethyl, oxadiazolylmethyl, furanylethyl, oxo-pyridylethyl and 1H-indazolylmethyl groups. Suitable (C3-C10)cycloalkyl(C1-C6)alkyl groups include cyclopropylmethyl groups. Suitable (C1-C6)alkoxy(C1-C6)alkyl groups include methoxyethyl, methoxypropyl groups.

[0061] In addition, it should be noted that the optional substituents defined in the present invention may include additional substituents themselves. For example, in the case where a particular group is optionally substituted by a (C1-C6)alkoxy group, the (C1-C6)alkoxy group may be further substituted by, for example, halo, hydroxy, cyano, oxo, primary amino, secondary amino or tertiary amino groups.

[0062] When the compounds of the present invention have one or more asymmetric centers, they may exist as enantiomers accordingly. When the compounds used in the present invention have two or more asymmetric centers, they may exist as diastereomers in addition. It should be understood that the present invention extends to the use of all such enantiomers and diastereomers, as well as mixtures thereof in any ratio, including racemates. Formula (I) and the formulas depicted below are intended to represent all individual stereoisomers and all possible mixtures thereof, unless otherwise specified or shown. In addition, the compounds of the present invention may exist as tautomers (e.g., ketone (CH2C=O) <-> enol (CH=CHOH) tautomers, amide (NHC=O) <-> hydroxyimine (N=COH) tautomers or 2-hydroxypyridine <-> 2-pyridone tautomers). Formula (I) and the formulas depicted below are intended to represent all individual tautomers and all possible mixtures thereof, unless otherwise specified or shown.

[0063] It will be understood that each individual atom present in formula (I) or the formulas depicted below may exist in virtually any of its naturally occurring isotopic forms, with the most abundant isotope being preferred. Thus, for example, each individual hydrogen atom present in formula (I) or the formulas depicted below may exist as 1 H. 2 H(deuterium) or 3 H (tritium) atoms are present, preferably 1 H. Similarly, for example, each individual carbon atom present in formula (I) or the formulas depicted below may be 12 C. 13 C or 14 C atoms are present, preferably 12 C.

[0064] In a preferred embodiment of the present invention, the compound having RNF31 activity is selected from the group consisting of:

[0065] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0066] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-benzyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0067] N-[(2Z)-3-(phenylsulfonyl)-3-fluoroprop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0068] N-[(2E)-3-(phenylsulfonyl)-3-fluoroprop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0069] N-[(2Z)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0070] tert-Butyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0071] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0072] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide;

[0073] N-[(3E)-4-(phenylsulfonyl)-2-methylbut-3-en-2-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0074] N-{1-[(E)-2-(phenylsulfonyl)vinyl]cyclopropyl}-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0075] 6-Acetyl-N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0076] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(3-methoxypropanoyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0077] N-[(3E)-4-(phenylsulfonyl)but-3-en-2-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0078] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(2-methoxyethanesulfonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0079] N-[(2E)-3-methylsulfonylprop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0080] 6-[2-(adamantan-1-yl)acetyl]-N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0081] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-[(1r,4r)-4-methoxycyclohexanecarbonyl]-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0082] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(4,4-difluorocyclohexanecarbonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0083] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-cyclopropanecarbonyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0084] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-{bicyclo[2.2.1]heptane-1-carbonyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0085] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(3,3-difluorocyclobutanecarbonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0086] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(1-cyanocyclobutanecarbonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0087] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(2-phenyl-2H-1,2,3-triazole-4-carbonyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0088] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(oxolane-3-carbonyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0089] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-{3-methylbicyclo[1.1.1]pentane-1-carbonyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0090] N-[(2E)-3-(4-Fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0091] N-[(2E)-3-(Cyclopentanesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0092] 2-Oxo-N-[(2E)-3-(propane-2-sulfonyl)prop-2-en-1-yl]-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0093] N-[(2E)-3-(3-Fluoro-4-methoxyphenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0094] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(1-methylcyclobutanecarbonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0095] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(4-cyclopropyl-1,3-thiazole-2-carbonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0096] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(2-cyclopropylacetyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0097] 2-Oxo-N-[(2Z)-3-(propane-2-sulfonyl)prop-2-en-1-yl]-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0098] N-[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0099] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(1-phenylpyrrolidine-3-carbonyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0100] 2-Methylpropyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0101] tert-Butyl 3-{[(2E)-3-(2-fluorophenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0102] N-[(2E)-3-(2-methylpropane-2-sulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0103] N-[(2E)-3-(2-Fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0104] tert-Butyl 3-{[(2E)-3-(4-fluorophenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0105] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(3,3-dimethylbutyryl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0106] tert-Butyl 3-{[(2E)-3-(3-fluoro-4-methoxyphenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0107] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-[(1-methyl-1H-indazol-4-yl)methyl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0108] 2-(4-chlorophenyl)ethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0109] tert-Butyl 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0110] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-[(pyridin-3-yl)methyl]-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0111] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-[(pyridazin-3-yl)methyl]-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0112] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(3-methoxy-3-methylbutanoyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0113] N-[(2E)-3-(4-Chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide;

[0114] 6-Benzyl-N-[(2E)-3-(4-chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0115] N-[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide;

[0116] N-[(2Z)-3-(2-Fluorophenylsulfonyl)but-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0117] N-[(2E)-3-(2-Fluorophenylsulfonyl)but-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0118] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester;

[0119] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclobutyl ester;

[0120] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid (5-methyl-1,3,4-oxadiazol-2-yl)methyl ester;

[0121] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid 1,1,1-trifluoropropan-2-yl ester;

[0122] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid (2,2-dimethylcyclopropyl)methyl ester;

[0123] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid (2,2-difluorocyclopropyl)methyl ester;

[0124] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid oxetan-3-yl ester;

[0125] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0126] 1-methoxypropan-2-yl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0127] 2-Fluoroethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0128] 2,2-difluoroethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0129] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropyl ester;

[0130] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(2-phenylcyclopropanecarbonyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0131] 2-oxaspiro[3.5]nonan-7-yl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0132] 2-Methoxyethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0133] N-[(2E)-3-(2,4-difluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0134] N-[(2E)-3-(2,4-dichlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0135] (3S)-Oxolan-3-yl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0136] (3R)-oxolan-3-yl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0137] N-[(2E)-3-(2-chloro-4-fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0138] N-[(2E)-3-(2,4-difluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide;

[0139] N-[(2E)-3-(2,4-dichlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide;

[0140] N-[(2E)-3-(2-chloro-4-fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide;

[0141] N-[(2E)-3-(2,4-difluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide;

[0142] N-[(2E)-3-(4-fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide;

[0143] N-[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide;

[0144] N-[(2Z)-3-(4-chlorobenzenesulfonyl)but-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0145] N-[(2E)-3-(4-chlorobenzenesulfonyl)but-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0146] N-[(2E)-3-(3-fluoro-4-methoxyphenylsulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide;

[0147] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide;

[0148] N-[(2Z)-3-(4-chlorobenzenesulfonyl)but-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide;

[0149] N-[(2E)-3-(4-chlorobenzenesulfonyl)but-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide;

[0150] N-[(2E)-3-(2-Chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide;

[0151] N-[(2E)-3-(3-Fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0152] N-[(2E)-3-(4-methoxyphenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0153] 2-(2-oxopiperidin-1-yl)ethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0154] N-[(2E)-3-(2-Chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0155] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopentyl ester;

[0156] 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid (2,2-dimethylcyclopropyl)methyl ester;

[0157] 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid (2,2-difluorocyclopropyl)methyl ester;

[0158] 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid oxetan-3-yl ester;

[0159] N-[(2E)-3-(4-Chlorophenylsulfonyl)-3-fluoroprop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0160] N-[(2Z)-3-(4-chlorobenzenesulfonyl)-3-fluoroprop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0161] 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester;

[0162] N-[(2E)-3-(2,4-difluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide;

[0163] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide;

[0164] 2-(Furan-2-yl)ethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0165] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclohexyl ester;

[0166] 1-(2,6-difluorophenyl)ethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0167] 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid 1-acetylpiperidin-4-yl ester;

[0168] 2-Fluoroethyl 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0169] 1-methoxypropan-2-yl 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0170] N-[(2E)-3-[(5-chloropyridin-2-yl)sulfonyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0171] 2-Oxo-N-[(2E)-3-(thiophene-2-sulfonyl)prop-2-en-1-yl]-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0172] 3-{[(2E)-3-[(5-chloropyridin-2-yl)sulfonyl]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester;

[0173] 2,2-difluoroethyl 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0174] 2,2,2-trifluoroethyl 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0175] N-[(2E)-3-(4-bromophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0176] N-[(2E)-3-(3,4-dimethoxybenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0177] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(prop-2-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0178] 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester;

[0179] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide;

[0180] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6,6-dimethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0181] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6,6-difluoro-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0182] N3-[(2E)-3-(4-chlorophenylsulfonyl)prop-2-en-1-yl]-N6-(cyclopropylmethyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3,6-dicarboxamide;

[0183] N3-[(2E)-3-(4-chlorophenylsulfonyl)prop-2-en-1-yl]-N6-cyclopropyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3,6-dicarboxamide;

[0184] N6-tert-butyl-N3-[(2E)-3-(4-chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3,6-dicarboxamide;

[0185] N-[(2E)-3-[(4-fluorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0186] N-[(2E)-3-(4-tert-Butylbenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0187] N-[(2E)-3-(3,4-dimethylbenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0188] N-[(2E)-3-[(3,4-dimethoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0189] N-[(2E)-3-(phenylsulfonyl)(1,1-2H2)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0190] N-[(2E)-3-[4-(Dimethylamino)benzenesulfonyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0191] N-[(2E)-3-(4-cyclopropylbenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0192] N-[(2E)-3-(4-cyanobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0193] N-[(2E)-3-[imino(4-methoxyphenyl)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0194] N-[(2E)-3-[(3,4-dimethylphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0195] 6,6-Difluoro-N-[(2E)-3-[(4-fluorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0196] 3-{[(2E)-3-[(4-fluorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester;

[0197] N-[(2E)-3-[imino(oxy)phenyl-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0198] N-[(2E)-3-[(4-tert-butylphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0199] N-[(2E)-3-[(4-ethoxyphenyl)(imino)oxy-λ 6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0200] N-[(2E)-3-[imino(4-methoxy-3,5-dimethylphenyl)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0201] N-[(2E)-3-[imino(3-methoxyphenyl)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0202] N-[(2E)-3-[Imino(oxo)[4-(trifluoromethoxy)phenyl]-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0203] N-[(2E)-3-[(4-chlorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0204] N-[(2E)-3-[(2-fluorophenyl)(imino)oxy-λ 6 -thio]propane-2-λ 6 -1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0205] N-[(2E)-3-[(3-chloro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0206] 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid 2,2-difluoroethyl ester;

[0207] N-[(2E)-3-[(3-chlorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0208] N-[(2E)-3-[(2,4-difluorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0209] N-[(2E)-3-[(4-cyanophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0210] N-[(2E)-3-[imino(4-methoxy-3-methylphenyl)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0211] N-[(2E)-3-[Imino(oxo)[4-(propan-2-yloxy)phenyl]-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0212] N-[(2E)-3-[imino(4-methoxy-2-methylphenyl)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0213] 3-{[(2E)-3-[imino(oxy)phenyl-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester;

[0214] 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid 2-fluoroethyl ester;

[0215] 3-{[(2E)-3-[imino(oxy)phenyl-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid 2-fluoroethyl ester;

[0216] 3-{[(2E)-3-[imino(oxy)phenyl-λ 6-thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid 2,2-difluoroethyl ester;

[0217] N-[(2E)-3-[imino(oxo)(4-phenoxyphenyl)-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0218] N-[(2E)-3-{[4-(dimethylamino)phenyl](imino)oxy-λ 6 -thio}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0219] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-6-methyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0220] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide;

[0221] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-6-(prop-2-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0222] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-6-methoxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0223] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-6-(2,2,2-trifluoroethyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0224] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6-thio]prop-2-en-1-yl]-2-oxo-1H,2H,5H,7H,8H-pyrano[4,3-b]pyridine-3-carboxamide;

[0225] N-[(2E)-3-[imino(oxo)(3-phenoxyphenyl)-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0226] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-6-(trifluoromethyl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0227] 6-tert-butyl-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0228] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide;

[0229] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cycloheptyl[b]pyridine-3-carboxamide;

[0230] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide;

[0231] 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid tert-butyl ester;

[0232] 6-Benzyl-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0233] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-6-[(4-methoxyphenyl)methyl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0234] 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid 4,4-difluorocyclohexyl ester;

[0235] 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclohexyl ester;

[0236] N-[(2E)-3-[Imino(oxy)[4-(trifluoromethyl)phenyl]-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0237] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-8,8-dimethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0238] 6-(Cyclopropylmethyl)-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0239] N-[(2E)-3-({[1,1'-biphenyl]-4-yl}(imino)oxy-λ 6 -thio)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0240] N-[(2E)-3-[benzyl(imino)oxy-λ 6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0241] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide;

[0242] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxamide;

[0243] 6-Fluoro-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0244] N-[(2E)-3-{imino[4-(morpholin-4-yl)phenyl]oxy-λ 6 -thio}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0245] N-[(2E)-3-{[3-cyano-4-(piperidin-1-yl)phenyl](imino)oxy-λ 6 -thio}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0246] N-[(2E)-3-[Imino(oxo)[4-(piperidin-1-yl)phenyl]-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0247] N-[(2E)-3-[Imino(oxo)[4-(pyrrolidin-1-yl)phenyl]-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0248] N-[(2E)-3-{imino[4-(methylamino)phenyl]oxy-λ 6 -thio}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0249] N-[(2E)-3-{[3-cyano-4-(morpholin-4-yl)phenyl](imino)oxy-λ 6 -thio}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0250] N-[(2E)-3-[Imino(oxo)[4-(2-oxopiperidin-1-yl)phenyl]-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0251] N-[(2E)-3-[imino(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0252] N-[(2E)-3-[(4-acetylaminophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0253] N-[(2E)-3-[(4-cyclopropyloxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0254] N-[(2E)-3-{[3-(dimethylamino)phenyl](imino)oxy-λ 6 -thio}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0255] N-[(2E)-3-[(4-cyclohexylphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0256] N-[(2E)-3-[(2,3-dihydro-1-benzofuran-5-yl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0257] N-[(2E)-3-[Imino(oxo)[3-(trifluoromethoxy)phenyl]-λ 6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; and

[0258] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide.

[0259] In particular, promising results were obtained in relation to improved RNF31 activity, wherein the compound was selected from the group consisting of:

[0260] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0261] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-benzyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0262] tert-Butyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0263] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(3-methoxypropanoyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0264] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(2-methoxyethanesulfonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0265] 6-[2-(adamantan-1-yl)acetyl]-N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0266] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-[(1r,4r)-4-methoxycyclohexanecarbonyl]-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0267] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-cyclopropanecarbonyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0268] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-{bicyclo[2.2.1]heptane-1-carbonyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0269] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(2-phenyl-2H-1,2,3-triazole-4-carbonyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0270] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(oxolane-3-carbonyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0271] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-{3-methylbicyclo[1.1.1]pentane-1-carbonyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0272] N-[(2E)-3-(4-Fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0273] N-[(2E)-3-(3-Fluoro-4-methoxyphenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0274] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(1-methylcyclobutanecarbonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0275] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(4-cyclopropyl-1,3-thiazole-2-carbonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0276] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(2-cyclopropylacetyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0277] N-[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0278] 2-Methylpropyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0279] tert-Butyl 3-{[(2E)-3-(2-fluorophenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0280] N-[(2E)-3-(2-Fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0281] tert-Butyl 3-{[(2E)-3-(4-fluorophenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0282] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(3,3-dimethylbutyryl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0283] tert-Butyl 3-{[(2E)-3-(3-fluoro-4-methoxyphenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0284] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-[(1-methyl-1H-indazol-4-yl)methyl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0285] 2-(4-chlorophenyl)ethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0286] tert-Butyl 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0287] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-[(pyridin-3-yl)methyl]-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0288] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-[(pyridazin-3-yl)methyl]-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0289] N-[(2E)-3-(4-Chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide;

[0290] 6-Benzyl-N-[(2E)-3-(4-chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0291] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester;

[0292] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclobutyl ester;

[0293] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid (5-methyl-1,3,4-oxadiazol-2-yl)methyl ester;

[0294] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid 1,1,1-trifluoropropan-2-yl ester;

[0295] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid (2,2-dimethylcyclopropyl)methyl ester;

[0296] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid (2,2-difluorocyclopropyl)methyl ester;

[0297] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid oxetan-3-yl ester;

[0298] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0299] 1-methoxypropan-2-yl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0300] 2-Fluoroethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0301] 2,2-difluoroethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0302] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropyl ester;

[0303] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(2-phenylcyclopropanecarbonyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0304] 2-oxaspiro[3.5]nonan-7-yl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0305] 2-Methoxyethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0306] N-[(2E)-3-(2,4-difluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0307] N-[(2E)-3-(2,4-dichlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0308] (3S)-Oxolan-3-yl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0309] (3R)-oxolan-3-yl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0310] N-[(2E)-3-(2-chloro-4-fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0311] N-[(2E)-3-(2,4-difluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide;

[0312] N-[(2E)-3-(2,4-dichlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide;

[0313] N-[(2E)-3-(2-chloro-4-fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide;

[0314] N-[(2E)-3-(2,4-difluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide;

[0315] N-[(2E)-3-(4-fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide;

[0316] N-[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide;

[0317] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide;

[0318] N-[(2E)-3-(2-Chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide;

[0319] N-[(2E)-3-(3-Fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0320] N-[(2E)-3-(4-methoxyphenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0321] 2-(2-oxopiperidin-1-yl)ethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0322] N-[(2E)-3-(2-Chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0323] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopentyl ester;

[0324] 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid (2,2-dimethylcyclopropyl)methyl ester;

[0325] 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid (2,2-difluorocyclopropyl)methyl ester;

[0326] 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid oxetan-3-yl ester;

[0327] 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester;

[0328] N-[(2E)-3-(2,4-difluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide;

[0329] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide;

[0330] 2-(Furan-2-yl)ethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0331] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclohexyl ester;

[0332] 1-(2,6-difluorophenyl)ethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0333] 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid 1-acetylpiperidin-4-yl ester;

[0334] 2-Fluoroethyl 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0335] 1-methoxypropan-2-yl 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0336] N-[(2E)-3-[(5-chloropyridin-2-yl)sulfonyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0337] 2-Oxo-N-[(2E)-3-(thiophene-2-sulfonyl)prop-2-en-1-yl]-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0338] 3-{[(2E)-3-[(5-chloropyridin-2-yl)sulfonyl]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester;

[0339] 2,2-difluoroethyl 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0340] 2,2,2-trifluoroethyl 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0341] N-[(2E)-3-(4-bromophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0342] N-[(2E)-3-(3,4-dimethoxybenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0343] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(prop-2-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0344] 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester;

[0345] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide;

[0346] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6,6-dimethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0347] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6,6-difluoro-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0348] N3-[(2E)-3-(4-chlorophenylsulfonyl)prop-2-en-1-yl]-N6-(cyclopropylmethyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3,6-dicarboxamide;

[0349] N3-[(2E)-3-(4-chlorophenylsulfonyl)prop-2-en-1-yl]-N6-cyclopropyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3,6-dicarboxamide;

[0350] N6-tert-butyl-N3-[(2E)-3-(4-chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3,6-dicarboxamide;

[0351] N-[(2E)-3-[(4-fluorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0352] N-[(2E)-3-(3,4-dimethylbenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0353] N-[(2E)-3-[(3,4-dimethoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0354] N-[(2E)-3-(phenylsulfonyl)(1,1- 2 H2) prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0355] N-[(2E)-3-[4-(Dimethylamino)benzenesulfonyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0356] N-[(2E)-3-(4-cyclopropylbenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0357] N-[(2E)-3-(4-cyanobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0358] N-[(2E)-3-[imino(4-methoxyphenyl)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0359] N-[(2E)-3-[(3,4-dimethylphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0360] 6,6-Difluoro-N-[(2E)-3-[(4-fluorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0361] 3-{[(2E)-3-[(4-fluorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester;

[0362] N-[(2E)-3-[imino(oxy)phenyl-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0363] N-[(2E)-3-[(4-tert-butylphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0364] N-[(2E)-3-[(4-ethoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0365] N-[(2E)-3-[imino(4-methoxy-3,5-dimethylphenyl)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0366] N-[(2E)-3-[imino(3-methoxyphenyl)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0367] N-[(2E)-3-[Imino(oxo)[4-(trifluoromethoxy)phenyl]-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0368] N-[(2E)-3-[(4-chlorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0369] N-[(2E)-3-[(2-fluorophenyl)(imino)oxy-λ 6 -thio]propane-2-λ 6 -1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0370] N-[(2E)-3-[(3-chloro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0371] 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid 2,2-difluoroethyl ester;

[0372] N-[(2E)-3-[(3-chlorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0373] N-[(2E)-3-[(2,4-difluorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0374] N-[(2E)-3-[(4-cyanophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0375] N-[(2E)-3-[imino(4-methoxy-3-methylphenyl)oxy-λ 6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0376] N-[(2E)-3-[Imino(oxo)[4-(propan-2-yloxy)phenyl]-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0377] N-[(2E)-3-[imino(4-methoxy-2-methylphenyl)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0378] 3-{[(2E)-3-[imino(oxy)phenyl-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester;

[0379] 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid 2-fluoroethyl ester;

[0380] 3-{[(2E)-3-[imino(oxy)phenyl-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid 2-fluoroethyl ester;

[0381] 3-{[(2E)-3-[imino(oxy)phenyl-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid 2,2-difluoroethyl ester;

[0382] N-[(2E)-3-[imino(oxo)(4-phenoxyphenyl)-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0383] N-[(2E)-3-{[4-(dimethylamino)phenyl](imino)oxy-λ 6 -thio}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0384] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-6-methyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0385] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide;

[0386] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-6-(prop-2-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0387] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-6-methoxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0388] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-6-(2,2,2-trifluoroethyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0389] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1H,2H,5H,7H,8H-pyrano[4,3-b]pyridine-3-carboxamide;

[0390] N-[(2E)-3-[imino(oxo)(3-phenoxyphenyl)-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0391] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-6-(trifluoromethyl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0392] 6-tert-butyl-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0393] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide;

[0394] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cycloheptyl[b]pyridine-3-carboxamide;

[0395] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide;

[0396] 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid tert-butyl ester;

[0397] 6-Benzyl-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0398] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-6-[(4-methoxyphenyl)methyl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0399] 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid 4,4-difluorocyclohexyl ester;

[0400] 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclohexyl ester

[0401] N-[(2E)-3-[Imino(oxy)[4-(trifluoromethyl)phenyl]-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0402] N-[(2E)-3-({[1,1'-biphenyl]-4-yl}(imino)oxy-λ 6 -thio)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0403] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide;

[0404] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxamide;

[0405] 6-Fluoro-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0406] N-[(2E)-3-{imino[4-(morpholin-4-yl)phenyl]oxy-λ 6 -thio}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0407] N-[(2E)-3-{[3-cyano-4-(piperidin-1-yl)phenyl](imino)oxy-λ 6 -thio}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0408] N-[(2E)-3-[Imino(oxo)[4-(piperidin-1-yl)phenyl]-λ 6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0409] N-[(2E)-3-[Imino(oxo)[4-(pyrrolidin-1-yl)phenyl]-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0410] N-[(2E)-3-{imino[4-(methylamino)phenyl]oxy-λ 6 -thio}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0411] N-[(2E)-3-{[3-cyano-4-(morpholin-4-yl)phenyl](imino)oxy-λ 6 -thio}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0412] N-[(2E)-3-[Imino(oxo)[4-(2-oxopiperidin-1-yl)phenyl]-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0413] N-[(2E)-3-[imino(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0414] N-[(2E)-3-[(4-acetylaminophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0415] N-[(2E)-3-[(4-cyclopropyloxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0416] N-[(2E)-3-{[3-(dimethylamino)phenyl](imino)oxy-λ 6 -thio}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0417] N-[(2E)-3-[(4-cyclohexylphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0418] N-[(2E)-3-[(2,3-dihydro-1-benzofuran-5-yl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0419] N-[(2E)-3-[Imino(oxo)[3-(trifluoromethoxy)phenyl]-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; and

[0420] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide.

[0421] Very promising results were obtained in relation to improved tumor necrosis factor (TNF) and / or nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) activity, wherein the compound was selected from the group consisting of:

[0422] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0423] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-benzyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0424] N-[(2E)-3-(4-Fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0425] N-[(2E)-3-(3-Fluoro-4-methoxyphenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0426] N-[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0427] 2-Methylpropyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0428] tert-Butyl 3-{[(2E)-3-(2-fluorophenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0429] N-[(2E)-3-(2-Fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0430] 6-Benzyl-N-[(2E)-3-(4-chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0431] 2-(4-chlorophenyl)ethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0432] tert-Butyl 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0433] N-[(2E)-3-(4-Chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide;

[0434] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester;

[0435] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclobutyl ester;

[0436] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid 1,1,1-trifluoropropan-2-yl ester;

[0437] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid (2,2-dimethylcyclopropyl)methyl ester;

[0438] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0439] N-[(2E)-3-(2-chloro-4-fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0440] N-[(2E)-3-(2,4-difluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide;

[0441] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide;

[0442] N-[(2E)-3-(3-Fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0443] N-[(2E)-3-(4-methoxyphenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0444] N-[(2E)-3-(2-Chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0445] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopentyl ester;

[0446] 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid (2,2-dimethylcyclopropyl)methyl ester;

[0447] 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester;

[0448] 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclohexyl ester;

[0449] 1-(2,6-difluorophenyl)ethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0450] 2-Fluoroethyl 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate;

[0451] N-[(2E)-3-[(5-chloropyridin-2-yl)sulfonyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0452] 2-Oxo-N-[(2E)-3-(thiophene-2-sulfonyl)prop-2-en-1-yl]-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0453] N-[(2E)-3-(4-bromophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0454] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(prop-2-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0455] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6,6-dimethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0456] N-[(2E)-3-(3,4-dimethylbenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0457] N-[(2E)-3-(phenylsulfonyl)(1,1-2H2)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0458] N-[(2E)-3-[4-(Dimethylamino)benzenesulfonyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0459] N-[(2E)-3-(4-cyclopropylbenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0460] N-[(2E)-3-(4-cyanobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0461] N-[(2E)-3-[imino(4-methoxyphenyl)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0462] N-[(2E)-3-[(3,4-dimethylphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0463] N-[(2E)-3-[(4-tert-butylphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0464] N-[(2E)-3-[(4-ethoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0465] N-[(2E)-3-[imino(4-methoxy-3,5-dimethylphenyl)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0466] N-[(2E)-3-[imino(3-methoxyphenyl)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0467] N-[(2E)-3-[Imino(oxo)[4-(trifluoromethoxy)phenyl]-λ 6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0468] N-[(2E)-3-[(4-chlorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0469] N-[(2E)-3-[(3-chloro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0470] N-[(2E)-3-[(3-chlorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0471] N-[(2E)-3-[imino(4-methoxy-3-methylphenyl)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0472] N-[(2E)-3-[Imino(oxo)[4-(propan-2-yloxy)phenyl]-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0473] N-[(2E)-3-[imino(4-methoxy-2-methylphenyl)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0474] N-[(2E)-3-[imino(oxo)(4-phenoxyphenyl)-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0475] N-[(2E)-3-{[4-(dimethylamino)phenyl](imino)oxy-λ 6 -thio}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0476] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-6-methyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0477] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide;

[0478] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-6-(prop-2-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0479] N-[(2E)-3-[imino(oxo)(3-phenoxyphenyl)-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0480] 6-tert-butyl-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0481] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cycloheptyl[b]pyridine-3-carboxamide;

[0482] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide;

[0483] 6-Benzyl-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0484] N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6 -thio]prop-2-en-1-yl]-6-[(4-methoxyphenyl)methyl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide;

[0485] 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclohexyl ester;

[0486] N-[(2E)-3-[Imino(oxy)[4-(trifluoromethyl)phenyl]-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0487] N-[(2E)-3-({[1,1'-biphenyl]-4-yl}(imino)oxy-λ 6 -thio)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0488] N-[(2E)-3-{imino[4-(morpholin-4-yl)phenyl]oxy-λ 6 -thio}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0489] N-[(2E)-3-{[3-cyano-4-(piperidin-1-yl)phenyl](imino)oxy-λ 6 -thio}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0490] N-[(2E)-3-[Imino(oxo)[4-(piperidin-1-yl)phenyl]-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0491] N-[(2E)-3-[Imino(oxo)[4-(pyrrolidin-1-yl)phenyl]-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0492] N-[(2E)-3-{imino[4-(methylamino)phenyl]oxy-λ 6-thio}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0493] N-[(2E)-3-[imino(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0494] N-[(2E)-3-[(4-cyclopropyloxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0495] N-[(2E)-3-{[3-(dimethylamino)phenyl](imino)oxy-λ 6 -thio}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0496] N-[(2E)-3-[(4-cyclohexylphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide;

[0497] N-[(2E)-3-[(2,3-dihydro-1-benzofuran-5-yl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; and

[0498] N-[(2E)-3-[Imino(oxo)[3-(trifluoromethoxy)phenyl]-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide.

[0499] In a second aspect, the present invention relates to a compound of the present invention for use as a medicament. In a preferred embodiment of the present invention, the use of the compound is combined with radiotherapy, targeted therapy, an agent suitable for chemotherapy (chemotherapeutic agent) and / or an agent suitable for immunotherapy (immunotherapeutic agent). Specifically, the use of the compound is combined with such therapy and an agent that causes an increase in the level of tumor necrosis factor (TNF) (e.g., tumor necrosis factor α (TNFα)), and thus treated with such chemotherapeutic agents, immunotherapeutic agents, targeted therapy and / or radiotherapy.

[0500] Examples of radiation therapy that increases TNF (e.g., TNFα) levels are described, for example, in the following publications: Rodemann, H. Peter and Marcel A. Blaese ("Responses of normal cells to ionizing radiation." Seminars in radiation oncology. Vol. 17. No. 2. WB Saunders, 2007), DiMaggio, Federica Maria et al. ("Portrait of inflammatory response to ionizing radiation treatment." Journal of inflammation 12.1 (2015): 1-11) and Meng, Guanmin et al. ("Implications for breast cancer treatment from increased autotaxin production in adipose tissue after radiotherapy." The FASEB Journal 31.9 (2017): 4064-4077).

[0501] Examples of targeted therapies that increase TNF (e.g., TNFα) levels are described, for example, in the following publications: Tabolacci, Claudio et al. ("Melanoma cell resistance to vemurafenib modifies inter-cellular communication signals." Biomedicines 9.1(2021):79), Mercogliano, María Florencia et al. ("Tumor necrosis factor αblockade:an opportunity to tackle breast cancer." Frontiers in oncology 10(2020):584), and Labrie, Marilyne et al. ("Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer." Nature Reviews Cancer 22.6(2022):323-339).

[0502] Examples of chemotherapeutic and / or immunotherapeutic agents that increase TNF (e.g., TNFα) levels are described, for example, in the following publications: Edwardson, Derek W. et al. ("Inflammatory cytokine production in tumor cells upon chemotherapy drug exposure or upon selection for drug resistance." PloS one 12.9(2017):e0183662), Mercogliano, María Florencia et al. ("Tumor necrosis factorαblockade:an opportunity to tackle breast cancer." Frontiers in oncology 10(2020):584), Vyas, Dinesh, Gieric Laput and Arpitak K. Vyas ("Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis." Onco Targets and therapy 7(2014):1015), Husain, Beate et al. ("Inflammatory markers in autoimmunity induced by checkpoint inhibitors." Journal of Cancer Research and Clinical Oncology 147.6(2021):1623-1630) and Vanneman, Matthew, and Glenn Dranoff ("Combining immunotherapy and targeted therapeutics in cancer treatment." Nature reviews cancer 12.4(2012):237-251).

[0503] In a third aspect of the invention, the invention relates to compounds of the invention for use in the treatment of cancer. Specifically, the invention relates to compounds of the invention for use in the treatment of melanoma, bladder cancer, colon cancer, pancreatic cancer, ovarian cancer, breast cancer, bone cancer, lung cancer or hematological malignancies. It has been found that compounds of the invention show particularly promising results in the treatment of ovarian cancer, lung cancer or hematological malignancies.

[0504] In a fourth aspect of the invention, the invention relates to a method for inhibiting Met1-linked ubiquitination, wherein the method comprises administering a compound according to the invention. Such methods may involve in vitro methods. However, in embodiments of the invention, the method may also involve a method for treating a subject (such as a human). Thus, the invention relates to a compound of the invention for inhibiting Met1-linked ubiquitination.

[0505] It should be noted that inhibition of Met1-linked ubiquitination includes inhibition of the linear ubiquitin (Ub) chain assembly complex (LUBAC). Inhibition of LUBAC preferably includes inhibition of RNF31 (HOIP).

[0506] In an embodiment of the invention, the invention relates to a method for inhibiting Met1-linked ubiquitination, wherein the method comprises administering a compound according to the invention, and wherein the inhibition of Met1-linked ubiquitination comprises irreversible or reversible inhibition of the linear ubiquitin (Ub) chain assembly complex (LUBAC) by covalent binding of the compound. It was found that the compounds of the invention covalently inhibit the linear ubiquitin (Ub) chain assembly complex (LUBAC), in particular covalently inhibit RNF31.

[0507] In a fifth aspect, the present invention relates to a composition comprising a compound of the present invention, wherein said composition further comprises at least one carrier.

[0508] In a sixth aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention. Such a composition may further comprise at least one pharmaceutically acceptable carrier. In an embodiment of the present invention, the pharmaceutical composition may further comprise tumor necrosis factor (TNF).

[0509] In this regard, it should be noted that the present invention also relates to formulations suitable for use as pharmaceutical compositions. Such formulations include but are not limited to tablets, powders, capsules, pills, solutions, suspensions, elixirs, emulsions, gels, creams, patches or suppositories, including rectal suppositories and urethral suppositories.

[0510] Examples

[0511] Synthetic pathway

[0512] The following reaction schemes illustrate the preparation of compounds of the present invention. Unless otherwise indicated, R in the reaction schemes is 6 , R 7 , R 8 , X and A are as defined above.

[0513] Solution 1

[0514]

[0515] exist Solution 1 In reaction 1, diethyl (tosyloxy) methylphosphonate is converted to the corresponding thioether of formula III by treating the tosylate with a thiol in N,N-dimethylformamide in the presence of an inorganic base (e.g., anhydrous potassium carbonate). The reaction mixture is stirred at room temperature for a period of time in the range of 8 h to 72 h, preferably 12 h.

[0516] exist Solution 1 In reaction 2, by using an oxidizing agent (such as The compound of formula III is oxidized to the corresponding sulfone of formula IV by treating III with a mixture of monopersulfate or sodium tungstate and hydrogen peroxide in water and a polar solvent (such as ethyl acetate) or an alcohol solvent (such as methanol). The reaction mixture is stirred at room temperature for a period of 8 h to 72 h, preferably 12 h. When R 5 When it is not hydrogen, the molecule is reacted with an electrophile (e.g., Or treating the compound of formula IV with iodomethane. The reaction mixture is stirred at room temperature for a period of 8 hmin to 24 h, preferably 16 h.

[0517] exist Solution 1 In reaction 3, the compound of formula IV is converted to the compound of formula V by reacting IV with tert-butyl (2-oxoethyl)carbamate in a polar aprotic solvent (e.g., tetrahydrofuran) in the presence of an organic base (such as potassium tert-butoxide). The reaction mixture is stirred for a period of 1 h to 24 h, preferably 1.5 h.

[0518] exist Solution 1 In reaction 4, the protecting group is removed from the compound of formula V by treating V with an acid such as hydrogen chloride in an aprotic polar solvent such as 1,4-dioxane or diethyl ether. The reaction mixture is stirred at room temperature for a period of 10 min to 3 h, preferably 1 h.

[0519] exist Solution 1 In reaction 5, by using a stoichiometric amount of an oxidizing agent such as The compound of formula III is oxidized to the corresponding sulfoxide of general formula VI by treating III with a mixture of 1,2-dihydro- ...

[0520] exist Solution 1In reaction 6, in the presence of rhodium acetate (II) dimer and magnesium oxide, the compound of formula VI is converted to the compound of formula VII by treating sulfoxide with tert-butyl carbamate and iodobenzene diacetate in an aprotic solvent such as dichloromethane. The reaction mixture is stirred at a temperature between 10° C. and 70° C., preferably 40° C., for a period of 6 h to 72 h, preferably 12 h.

[0521] exist Solution 1 In reaction 7, the compound of formula VII is converted to the compound of formula VIII by reacting VII with tert-butyl (2-oxoethyl)carbamate in a polar aprotic solvent such as tetrahydrofuran in the presence of an organic base such as potassium tert-butoxide. The reaction mixture is stirred for a period of 1 h to 24 h, preferably 1.5 h.

[0522] exist Solution 1 In reaction 8, the protecting group is removed from the compound of formula VIII by treating VIII with an acid such as hydrogen chloride in an aprotic polar solvent such as 1,4-dioxane or diethyl ether. The reaction mixture is stirred at room temperature for a period of 10 min to 3 h, preferably 1 h.

[0523] Solution 2

[0524]

[0525] exist Solution 2 In reaction 1, 1,3-bis(1,1-dimethylethyl)2-(2-propyn-1-yl)iminodicarbonate is converted to the corresponding vinyl thioether of formula IX by treating the alkyne with a thiol in an aprotic solvent (preferably DCE) in the presence of a rhodium catalyst, preferably tris(triphenylphosphine)rhodium chloride (I). The reaction mixture is stirred at a temperature of -10°C to about 50°C, preferably 0°C, for a period of 12h to 80h, preferably 24h.

[0526] exist Solution 2 In reaction 2, the compound of formula IX is oxidized to the corresponding sulfinyl imine of formula X by treating IX with ammonium carbonate and iodobenzene diacetate in an alcohol solvent such as methanol. The reaction mixture is stirred at a temperature of -10°C to about 50°C, preferably 0°C, for a period of 10 min to 3 h, preferably 30 min.

[0527] exist Solution 2 In reaction 3, the protecting group is removed from the compound of formula X by treating X with an acid such as hydrogen chloride in an aprotic polar solvent such as 1,4-dioxane or diethyl ether. The reaction mixture is stirred at room temperature for a period of 10 min to 3 h, preferably 30 min.

[0528] Solution 3

[0529]

[0530] exist Solution 3 In reaction 1, amines of general structures I and II are converted to the corresponding amides of general structure XII by treatment with an acid of general structure XI in a polar solvent such as N,N-dimethylformamide or acetonitrile in the presence of an amide coupling agent such as T3P (n-propanephosphonic anhydride) or HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium cation 3-oxide hexafluorophosphate) and an organic base such as triethylamine or diisopropylethylamine. The reaction mixture is stirred at room temperature for a period of 8 to 72 h, preferably 16 h.

[0531] exist Solution 3 In reaction 2, when X is tert-butyloxycarbonyl (Boc), the Boc protecting group is removed by treating XII with an acid (such as hydrogen chloride) in an aprotic polar solvent (such as 1,4-dioxane or diethyl ether). The reaction mixture is stirred at room temperature for a period of 10 min to 4 h, preferably 2 h.

[0532] Solution 4

[0533]

[0534] exist Solution 4 In the reaction 1, in the presence of an organic base (such as pyridine), by treating the chloroformate with an alcohol in an aprotic chlorinated solvent (such as dichloromethane), 4-nitrophenyl chloroformate is converted into the corresponding carbonate of formula XIII. The reaction mixture is stirred at room temperature for a period of 8h to 72h, preferably 12h.

[0535] exist Solution 4 In the reaction 2, in the presence of an inorganic base (such as sodium bicarbonate), by treating XIII with an amine of formula XII (wherein X is nitrogen) in a mixture of a polar aprotic solvent and a protic solvent (such as water and tetrahydrofuran), the compound of formula XIII is converted into a carbamate of the corresponding formula structure XVI. The reaction mixture is stirred at room temperature for a period of 1 h to 12 h, preferably 2 h.

[0536] exist Solution 4In the reaction 3, in the presence of an inorganic base (such as sodium bicarbonate), by treating XIII with 1,2,5,6,7,8-hexahydro-2-oxo-1,6-naphthyridine-3-carboxylic acid ethyl ester in a mixture of a polar aprotic solvent and a protic solvent (such as water and tetrahydrofuran), the compound of formula XIII is converted into the corresponding carbamate of formula structure XIV. The reaction mixture is stirred at room temperature for a period of 1 h to 12 h, preferably 2 h.

[0537] exist Solution 4 In reaction 4, the compound of formula XII is converted to the corresponding acid XIII by treating XII with a 1.0 molar aqueous solution of an inorganic base such as lithium hydroxide in a polar aprotic solvent such as tetrahydrofuran. The reaction mixture is stirred at room temperature for a period of 8 h to 72 h, preferably 12 h.

[0538] exist Solution 4 In reaction 5, using Solution 3 The same procedure as described in reaction 1.

[0539] Solution 5

[0540]

[0541] exist Solution 5 In the reaction 1, in the presence of an organic base (such as pyridine), by treating the chloroformate with an amine in an aprotic chlorinated solvent (such as dichloromethane), 4-nitrophenyl chloroformate is converted into the corresponding carbamate of formula XVII. The reaction mixture is stirred at room temperature for a period of 8h to 72h, preferably 12h.

[0542] exist Solution 5 In the reaction 2, in the presence of an inorganic base (such as sodium bicarbonate), by treating XVII with an amine (wherein X is nitrogen) of formula XII in a mixture of a polar aprotic solvent and a protic solvent (such as water and tetrahydrofuran), the compound of formula XVII is converted into the urea of ​​corresponding formula XVIII. The reaction mixture is stirred at room temperature for a period of 1 h to 12 h, preferably 2 h.

[0543] Solution 6

[0544]

[0545] exist Solution 6In reaction 1, in the presence of an amide coupling agent (such as T3P or HATU) and an organic base (such as triethylamine or diisopropylethylamine), by treating XII with an acid in a polar solvent (such as N,N-dimethylformamide or acetonitrile), the compound of formula XII (wherein X is nitrogen) is converted into the corresponding amide of formula structure XIX. The reaction mixture is stirred at room temperature for a period of 8h to 72h, preferably 16h.

[0546] exist Solution 6 In the reaction 2, in the presence of an organic base (such as triethylamine or diisopropylethylamine), by treating XII with an organic sulfonyl chloride in a polar solvent (such as N,N-dimethylformamide or acetonitrile), the compound of formula XII (wherein X is nitrogen) is converted into the corresponding sulfonamide of formula structure XX. The reaction mixture is stirred at room temperature for a period of 8h to 72h, preferably 16h.

[0547] exist Solution 6 In reaction 3, in the presence of an inorganic base (such as potassium carbonate), by treating XII with an organic bromide or chloride in a polar solvent (such as N,N-dimethylformamide), a compound of formula XII (wherein X is nitrogen) is converted into the corresponding aminoalkyl group of formula XXI. The reaction mixture is stirred at room temperature for a period of 2h to 24h, preferably 4h.

[0548] Compound

[0549] The following examples illustrate the preparation of compounds of the present invention, but are not limited to their details. NMR data are reported in parts per million (δ) and referenced to the deuterium lock signal from the sample solvent (deuterated chloroform, unless otherwise specified). All commercial reagents were used without further purification. THF refers to tetrahydrofuran, DMF refers to N,N-dimethylformamide, MeOH refers to methanol, and DCM refers to dichloromethane. Room temperature refers to 20-25°C.

[0550] Example 1: Preparation of (2E)-3-(4-bromophenylsulfonyl)prop-2-en-1-amine hydrochloride (Scheme 1)

[0551] Scheme 1, Reaction 1: Diethyl {[(4-bromophenyl)thio]methyl}phosphonate

[0552] Diethyl (toluenesulfonyloxy) methylphosphonate (3.0g, 9.1mmol, 1.0eq) and anhydrous potassium carbonate (3.15g, 22.8mmol, 2.5eq) are suspended in anhydrous DMF (24.0ml, 8.0vol), then mixed with 4-bromothiophenol (1.91g, 9.6mmol, 1.05eq) once and stirred at room temperature, UPLC after stirring for 12h shows that the starting material is completely consumed to obtain the desired product. The reaction mixture is concentrated under reduced pressure and distributed between ethyl acetate (20mL) and distilled water (30mL) with saturated NaCl solution (10mL). Separate the layers, and extract the water layer with ethyl acetate (3x10mL). The combined organic layer is dried with MgSO4, filtered and concentrated under reduced pressure to obtain a light yellow oil (3.39g). The oil is dissolved in minimal DCM and purified by flash chromatography, eluted with hexane / ethyl acetate (0 to 55%). The fractions containing the product were collected and concentrated under reduced pressure to give the desired product, diethyl {[(4-bromophenyl)thio]methyl}phosphonate (3.02 g, Y: 97%) as a colorless oil. UPLC and 1 H NMR (CDCl3, 300 MHz) confirmed the structure and purity of the product.

[0553] UPLC Rt: 2.02, m / z: 341.0 [M+1]; purity (254 nm): 99%; 1H NMR (300 MHz, chloroform-d) δ 7.47–7.37 (m, 2H), 7.36–7.27 (m, 2H), 4.14 (dqd, J = 8.2, 7.0, 1.0 Hz, 4H), 3.17 (s, 1H), 3.13 (s, 1H), 1.31 (td, J = 7.1, 0.5 Hz, 6H).

[0554] Scheme 1, Reaction 2: Diethyl [(4-bromobenzenesulfonyl)methyl]phosphonate

[0555] Diethyl {[(4-bromophenyl)thio]methyl}phosphonate (0.4 g, 1.18 mmol, 1.0 eq.) was dissolved in anhydrous MeOH (4.0 ml, 10.0 vol) and then added The monopersulfate compound (0.91 g, 2.95 mmol, 2.5 eq.) was added to a distilled water solution (4.0 ml, 10.0 vol), and the light yellow solution was immediately turned into a bright white mixture. After stirring for 12 h, UPLC analysis showed complete conversion to the desired product. The mixture was filtered through diatomaceous earth, washed with MeOH and concentrated to a small volume under reduced pressure. The reduced filtrate was distributed between ethyl acetate (20 mL) and water (25 mL) with a saturated NaCl solution (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give the desired product [(4-bromobenzenesulfonyl)methyl]phosphonic acid diethyl ester (448 mg, Y: 99%) as a yellow oil. The product was used in the next step without any further purification. UPLC and 1 H NMR (CDCl3, 300 MHz) confirmed the structure and purity of the product.

[0556] UPLC Rt:1.99,m / z:373.0[M+1]; 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.92–7.80 (m, 2H), 7.77–7.66 (m, 2H), 4.17 (dq, J=8.3, 7.1 Hz, 4H), 3.77 (s, 1H), 3.72 (s, 1H), 1.36–1.27 (m, 6H).

[0557] Scheme 1, Reaction 3: tert-Butyl N-[(2E)-3-(4-bromophenylsulfonyl)prop-2-en-1-yl]carbamate

[0558] Potassium tert-butoxide (0.13 g, 1.18 mmol, 1.0 eq.) was suspended in anhydrous THF (9.0 ml) and cooled to 0° C. in 5 min. Diethyl [(4-bromobenzenesulfonyl)methyl]phosphonate (0.45 g, 1.18 mmol, 1.0 eq.) was added dropwise as a solution in anhydrous THF (2.83 ml), immediately forming a yellow solution which was stirred at 0° C. under argon for 30 min. Tert-butyl N-(2-oxoethyl)carbamate (0.20 g, 1.24 mmol, 1.05 eq.) was added as a solution in anhydrous THF (2.37 ml, 0.5 M) over 1 min, and the reaction was stirred under argon and then allowed to reach room temperature. After 90 min, the reaction was concentrated under reduced pressure to give a yellow oil which was distributed between ethyl acetate (10 mL) and saturated aqueous NaHCO3 (20 mL). The layers were separated and the organic layer was washed with saturated NaCl solution (20 mL). The combined aqueous layer was extracted with ethyl acetate (3x10 mL), and the combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow oil. The oil was dissolved in minimal DCM and purified by flash chromatography, eluting with hexane / ethyl acetate (0 to 36%). The fractions containing the pure product were collected and concentrated under reduced pressure to give the desired product, tert-butyl N-[(2E)-3-(4-bromobenzenesulfonyl)prop-2-en-1-yl]carbamate (211 mg, Y: 47%) as a light yellow oil. UPLC and 1 H NMR (DMSO-d6, 300 MHz) confirmed the structure and purity of the product as the (E)-isomer.

[0559] UPLC Rt: 1.87, m / z: 376.0 [M+Na]; purity (254 nm): 99%; 1 H NMR (300MHz, DMSO-d6) δ7.91–7.83(m,2H),7.83–7.73(m,2H),7.18(t,J=5.2Hz,1H),6. 86(dt,J=15.1,4.4Hz,1H), 6.68(d,J=15.2Hz,1H), 3.78(d,J=6.0Hz,2H), 1.36(s,9H).

[0560] Scheme 1, Reaction 4: (2E)-3-(4-bromophenylsulfonyl)prop-2-en-1-amine hydrochloride

[0561] Chilled 4N HCl in dioxane 3.7-4.3N (1.40 ml, 5.61 mmol, 10.0 eq.) was added to tert-butyl N-[(2E)-3-(4-bromobenzenesulfonyl)prop-2-en-1-yl]carbamate (0.21 g, 0.56 mmol, 1.0 eq.) and the solution was stirred at room temperature. A white solid began to form within the first 10 min, and after stirring for 1 h, the reaction was concentrated under reduced pressure to give the desired product (2E)-3-(4-bromobenzenesulfonyl)prop-2-en-1-amine hydrochloride (161 mg, Y: 92%) as a white solid, which was used in the next reaction without further purification. UPLC and 1 H NMR (DMSO-d6, 300 MHz) confirmed the structure and purity of the product.

[0562] UPLC Rt: 1.41min, m / z: 276.0 [M+1], Br mode; purity (254nm): 99%; 1 H NMR(300MHz,DMSO-d6)δ8.23(s,3H),7.96–7.86(m,2H),7.84–7.75(m,2H),7.0 8(dt,J=15.3,1.6Hz,1H), 6.90(dt,J=15.3,5.2Hz,1H), 3.72(d,J=5.7Hz,2H).

[0563] Example 2: [(1E)-3-aminoprop-1-en-1-yl](4-fluorophenyl)imino-λ 6 Preparation of -thioketone dihydrochloride (Solution 1)

[0564] Scheme 1, Reaction 1: Diethyl {[(4-fluorophenyl)thio]methyl}phosphonate

[0565] Diethyl (tosyloxy) methylphosphonate (9.86g, 30mmol, 1.0eq.) and anhydrous potassium carbonate (10.4g, 75mmol, 2.5eq.) are suspended in anhydrous DMF (79ml, 8.0vol), then mixed with 4-fluorothiophenol (4.04g, 31.5mmol, 1.05eq) and stirred at room temperature. UPLC after stirring overnight shows that the starting material is completely consumed and the desired product is formed. The reaction is concentrated to a small volume under reduced pressure and distributed between ethyl acetate (20mL) and distilled water (70mL) with saturated NaCl solution (10mL). Separate the layers, and extract the water layer with ethyl acetate (5x20mL). The combined organic layer is dried with MgSO4, filtered and concentrated under reduced pressure to obtain a yellow oil. The oil is dissolved in minimal DCM and purified by flash chromatography, eluted with hexane / ethyl acetate (0 to 50%). The fractions containing the product were collected and concentrated under reduced pressure to give the desired product, diethyl {[(4-fluorophenyl)thio]methyl}phosphonate (8.19 g, Y: 98%) as a pale yellow oil. UPLC and 1 H NMR (CDCl3, 300 MHz) confirmed the structure and purity of the product.

[0566] UPLC Rt: 1.76, m / z: 279.10 [M+1]; purity (254 nm): 94%; 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.55–7.41 (m, 2H), 7.07–6.95 (m, 2H), 4.13 (dqd, J = 8.4, 7.0, 1.3 Hz, 4H), 3.15 (s, 1H), 3.10 (s, 1H), 1.31 (t, J = 7.1 Hz, 6H).

[0567] Scheme 1, Reaction 5: Diethyl [(4-fluorobenzenesulfinyl)methyl]phosphonate

[0568] Diethyl {[(4-fluorophenyl)thio]methyl}phosphonate (8.19 g, 29.4 mmol, 1.0 eq) was dissolved in anhydrous MeOH (81.9 ml, 10.0 vol) and cooled to 0°C within 20 min, then added Monopersulfate compound (9.50g, 31mmol, 1.05eq.) distilled water solution (82ml, 10.0vol), immediately turns the light yellow solution into a bright white mixture, which is stirred at 0°C for 30min and then allowed to reach room temperature. After stirring overnight, UPLC shows that the desired product is completely formed as the starting material is consumed. The reaction is filtered through diatomaceous earth, washed with MeOH (5x20mL) and concentrated to a small volume under reduced pressure. The concentrated filtrate is distributed between ethyl acetate (40mL) and distilled water (80mL) with a saturated solution of NaCl (20mL). The layers are separated, and the aqueous layer is extracted with ethyl acetate (5x20mL). The combined organic layers are dried with MgSO4, filtered and concentrated under reduced pressure to obtain the desired product [(4-fluorobenzenesulfinyl)methyl] diethyl phosphonate (8.754g) as a yellow oil, which is suitable for purification in the next step. UPLC and 1 H NMR (CDCl3, 300 MHz) confirmed the structure and purity of the product.

[0569] UPLC Rt: 1.53, m / z: 295.00 [M+1]; purity (254 nm): 99%; 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.83–7.71 (m, 2H), 7.28–7.20 (m, 2H), 4.26–4.00 (m, 4H), 3.42 (t, J = 14.7 Hz, 1H), 3.28 (t, J = 14.9 Hz, 1H), 1.31 (dt, J = 10.5, 7.0 Hz, 6H).

[0570] Scheme 1, Reaction 6: N-{[(diethoxyphosphoryl)methyl](4-fluorophenyl)oxy-λ 6 -sulfylidene}aminomethyl Acid esters

[0571] By [(4-fluorobenzenesulfinyl) methyl] diethyl phosphonate (1.0g, 3.4mmol, 1.0eq) with the solution form in anhydrous DCM (20ml, 0.17M) add in the bottle containing rhodium acetate (II) dimer (0.045g, 0.10mmol, 0.03eq), t-butyl carbamate (0.80g, 6.8mmol, 2.0eq) and magnesium oxide (0.55g, 13.6mmol, 4.0eq).By mixture argon degassed 20min, then add iodobenzene diacetate (1.642g, 5.097mmol, 1.5eq).Heating front sealed bottle, and after stirring 12h at 50 ℃, UPLC shows that starting material is close to complete consumption.Reaction mixture is filtered through diatomite, washed with DCM (6x10mL) and concentrated under reduced pressure, to obtain yellow oil (3.458g). The oil was dissolved in minimal DCM and purified by flash chromatography eluting with hexane / ethyl acetate (0 to 65%). The product-containing fractions were collected and concentrated under reduced pressure to give the desired product, N-{[(diethoxyphosphoryl)methyl](4-fluorophenyl)oxy-λ, as a yellow oil. 6 -sulfydene}carbamic acid tert-butyl ester (825 mg, Y: 59%). UPLC and 1 H NMR (CDCl3, 300 MHz) confirmed the purity and structure of the product.

[0572] UPLC Rt: 1.78, m / z: 432.3 [M+Na]; purity (254 nm): 99%; 1 H NMR (300 MHz, CHLOROFORM-d) δ 8.14–8.04 (m, 2H), 7.31–7.20 (m, 2H), 4.39 (dd, J = 16.3, 15.4 Hz, 1H), 4.21–4.07 (m, 4H), 4.07–3.96 (m, 1H), 1.43 (s, 9H), 1.27 (dtd, J = 12.5, 7.1, 0.7 Hz, 6H).

[0573] Scheme 1, Reaction 7: N-[(2E)-3-({[(tert-butyloxy)carbonyl]imino}(4-fluorophenyl)oxy-λ 6 -sulfur tert-butyl]prop-2-en-1-yl]carbamate

[0574] Potassium tert-butoxide (0.14 g, 1.22 mmol, 1.0 eq) was suspended in anhydrous THF (9.0 ml), and the mixture was degassed with argon while cooling at 0° C. for 20 min. N-{[(diethoxyphosphoryl)methyl](4-fluorophenyl)oxy-λ- 6-sulfylin} carbamate (0.5g, 1.22mmol, 1.0eq), the mixture is formed into a yellow solution. It is stirred at 0 ° C for 30min, then N-(2-oxoethyl) tert-butyl carbamate (0.20g, 1.28mmol, 1.05eq) is added as a solution in anhydrous THF (2.44ml, 0.5M), and the reaction is allowed to reach room temperature and stirred under argon. After 90min, the reaction is concentrated to dryness under reduced pressure, then distributed between ethyl acetate (20mL) and saturated NaHCO3 aqueous solution (20mL). Separate each layer, and wash the organic layer with saturated NaCl solution (10mL). The water layer is extracted with ethyl acetate (2x10mL), and the combined organic layer is dried with MgSO4, filtered and concentrated under reduced pressure to obtain a yellow oil (589mg). The oil is dissolved in a minimum of DCM and purified by flash chromatography, eluted with DCM / ethyl acetate (0 to 12%). The fractions containing the product were collected and concentrated under reduced pressure to give the desired product, N-{[(1E)-3-{[(tert-butoxy)carbonyl]amino}prop-1-en-1-yl](4-fluorophenyl)oxy-λ as a yellow oil. 6 -sulfydene}carbamic acid tert-butyl ester (225 mg, Y: 44%). UPLC and 1 H NMR (DMSO-d6, 300 MHz) confirmed the structure and purity of the (E)-isomer product.

[0575] UPLC Rt: 1.87, m / z: 437.1 [M+Na]; purity (254 nm): 99%; 1H NMR (300 MHz, DMSO-d6) δ 8.00–7.86 (m, 2H), 7.57–7.44 (m, 2H), 7.21 (t, J = 5.2 Hz, 1H), 6.84 (dt, J = 14.9, 4.2 Hz, 1H), 6.72 (d, J = 15.1 Hz, 1H), 3.80 (s, 2H), 1.36 (s, 9H), 1.25 (s, 9H).

[0576] Scheme 1, Reaction 8: [(1E)-3-aminoprop-1-en-1-yl](4-fluorophenyl)imino-λ 6 -Thione dihydrochloride

[0577] Chilled 4N HCl in dioxane 3.7-4.3N (1.36 ml, 5.4 mmol, 10.0 eq.) was added to N-[(2E)-3-({[(tert-butyloxy)carbonyl]imino}(4-fluorophenyl)oxy-λ 6-sulfuryl)prop-2-en-1-yl]tert-butyl carbamate (0.23 g, 0.54 mmol, 1.0 eq.) was added and the solution was stirred at room temperature. A white solid formed within the first 10 min. After 1 h, the reaction was concentrated under reduced pressure to give the desired product [(1E)-3-aminoprop-1-en-1-yl](4-fluorophenyl)imino-λ as a light brown solid. 6 -thioketone dihydrochloride (198 mg) was used in the next reaction without further purification. 1 HNMR (DMSO-d6, 300 MHz) confirmed the structure of the product.

[0578] UPLC Rt: 0.66, m / z = 215.1 [M + 1]; Purity (254 nM): 71% (sum of 3 peaks); 1 H NMR (300MHz, DMSO-d6) δ8.29 (s, 6H), 8.06–7.91 (m, 5H), 7.55–7.43 (m, 4H), 6.96 (d, J = 15.1Hz, 1H), 6.78 (dt, J = 15.1, 5.3Hz, 1H).

[0579] Example 3: Preparation of (2E)-3-(4-chlorobenzenesulfonyl)-3-fluoroprop-2-en-1-amine hydrochloride (Scheme 1)

[0580] Scheme 1, Reaction 1: Diethyl {[(4-chlorophenyl)thio]methyl}phosphonate

[0581] By (tosyloxy) methylphosphonic acid diethyl ester (11.2g, 34.3mmol, 1.0eq) and anhydrous potassium carbonate (11.8g, 85.7mmol, 2.5eq) suspended in anhydrous N, N-dimethylformamide (90.2ml, 8.0vol), then with 4-bromobenzenethiol (5.6g, 37.7mmol, 1.1eq) disposable mixing and stirring at room temperature, UPLC after stirring 12h shows that starting material is completely consumed, to obtain the desired product. The reaction mixture is concentrated under reduced pressure and distributed between ethyl acetate (50mL) and distilled water (750mL) with saturated NaCl solution (50mL). Separate each layer, and extract the water layer with ethyl acetate (4x50mL). The organic layer MgSO4 combined is dried, filtered and concentrated under reduced pressure, to obtain a light yellow oil (12.896g). The oil was dissolved in minimal dichloromethane and purified by flash chromatography eluting with hexane / ethyl acetate (0 to 75%). The product-containing fractions were collected and concentrated under reduced pressure to give the desired product, diethyl {[(4-chlorophenyl)thio]methyl}phosphonate (9.88 g, Y: 97%) as a light yellow oil. UPLC and 1 H NMR (CDCl3, 300 MHz) confirmed the structure and purity of the product.

[0582] UPLC Rt: 1.84, m / z: 295.1 [M+1] Cl mode; purity (254 nm): 99%; 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.44–7.37 (m, 2H), 7.33–7.26 (m, 2H), 4.25–4.07 (m, 4H), 3.20 (s, 1H), 3.15 (s, 1H), 1.33 (t, J = 7.1 Hz, 6H).

[0583] Scheme 1, Reaction 2: Diethyl [(4-chlorobenzenesulfonyl)(fluoro)methyl]phosphonate

[0584] Diethyl {[(4-bromophenyl)thio]methyl}phosphonate (9.8 g, 33.5 mmol, 1.0 eq.) was dissolved in anhydrous methanol (59.3 ml, 6.0 vol), and then added The monopersulfate compound (22.6 g, 73.7 mmol, 2.2 eq.) was added to a distilled water solution (59.3 ml, 6.0 vol), and the light yellow solution was immediately turned into a bright white mixture. After stirring for 12 h, UPLC analysis showed complete conversion to the desired product. The mixture was filtered through diatomaceous earth, washed with MeOH and concentrated to a small volume under reduced pressure. The reduced filtrate was distributed between ethyl acetate (30 mL) and water (90 mL) with a saturated NaCl solution (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3x20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give the desired product [(4-chlorobenzenesulfonyl)methyl]phosphonic acid diethyl ester (10.76 g, Y: 98%) as a yellow oil. The product was used in the next step without any further purification. UPLC and 1 H NMR (CDCl3, 300 MHz) confirmed the structure and purity of the product. UPLC Rt: 1.68, m / z: 325.1 [M-1], Cl mode; purity (254 nm): 98%.

[0585] Potassium tert-butoxide (0.34g, 3.06mmol, 1.0eq) is added to a dry flask and suspended in anhydrous tetrahydrofuran (25.0ml), cooled to 0°C in 10min. [(4-chlorobenzenesulfonyl)methyl] diethyl phosphonate (1.0g, 3.06mmol, 1.0eq) is added dropwise as a solution in anhydrous tetrahydrofuran (5.6ml) to form a yellow solution, which is stirred at 0°C for 30min under argon. F-TEDA-BF4 (1.14g, 3.21mmol, 1.05eq) is added dropwise as a solution in anhydrous N,N-dimethylformamide (4.1ml, 4.1vol) in 1min, and the reaction is allowed to reach rt and stirred for 16h under argon atmosphere. The reaction is quenched with saturated NH4Cl aqueous solution (50mL) and stirred for 10min, then concentrated to a small volume under reduced pressure and distributed with EtOAc (20mL). The layers were separated and the aqueous layer was extracted with EtOAc (3x20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow oil (1.27 g). The oil was dissolved in minimal DCM and purified by flash chromatography, eluting with hexane / ethyl acetate (0-40%). The fractions containing the product were collected and concentrated under reduced pressure to give diethyl [(4-chlorobenzenesulfonyl)(fluoro)methyl]phosphonate (758 mg, Y: 72%) as a light yellow oil. UPLC and 1 HNMR (CDCl3, 300 MHz) confirmed the structure and purity of the product.

[0586] UPLC Rt: 1.79, m / z: 367.0 [M+Na], Cl mode; purity (254 nm): 98%; 1 H NMR (300 MHz, CHLOROFORM-d) δ 8.02–7.89 (m, 2H), 7.63–7.51 (m, 2H), 5.37 (dd, J = 45.4, 6.7 Hz, 1H), 4.43–4.17 (m, 4H), 1.36 (tdd, J = 7.1, 3.7, 0.7 Hz, 6H).

[0587] Scheme 1, Reaction 3: tert-Butyl N-[(2E)-3-(phenylsulfonyl)-3-fluoroprop-2-en-1-yl]carbamate

[0588] Potassium tert-butoxide (0.247 g, 2.2 mmol, 1.0 eq.) was suspended in anhydrous tetrahydrofuran (17.0 ml) and cooled to 0° C. over 5 min. Diethyl [(4-chlorobenzenesulfonyl)(fluoro)methyl]phosphonate (0.758 g, 2.2 mmol, 1.0 eq.) was added dropwise as a solution in anhydrous tetrahydrofuran (4.9 ml), immediately forming a yellow solution which was stirred at 0° C. under argon for 30 min. Tert-butyl N-(2-oxoethyl)carbamate (0.368 g, 2.31 mmol, 1.05 eq.) was added as a solution in anhydrous tetrahydrofuran (4.6 ml, 0.5 M) over 1 min, and the reaction was stirred under argon and then allowed to reach room temperature. After 90min, the reaction was concentrated under reduced pressure to give a yellow oil, which was distributed between ethyl acetate (10mL) and saturated NaHCO3 aqueous solution (20mL). The layers were separated and the organic layer was washed with saturated NaCl solution (20mL). The combined aqueous layer was extracted with ethyl acetate (4x5mL), and the combined organic layer was dried with MgSO4, filtered and concentrated under reduced pressure to give a yellow oil. Next, the oil was dissolved in minimal DCM and purified by flash chromatography, eluting with hexane / ethyl acetate (0 to 15%). The fractions containing the pure product with the E-isomer and the fractions containing the Z-isomer were collected separately and concentrated under reduced pressure to give tert-butyl N-[(2E)-3-(4-chlorobenzenesulfonyl)-3-fluoroprop-2-ene-1-yl]carbamate (170mg, Y: 22%) as a white solid. UPLC and 1 H NMR confirmed the structure and purity of the molecule as the (E)-isomer, coupling constants and geometry.

[0589] UPLC Rt: 1.91, m / z: 372.0 [M+Na], Cl mode; purity (254 nm): 94%; 1H NMR (300 MHz, DMSO-d6) δ7.96 (d, J=8.7 Hz, 2H), 7.87–7.74 (m, 2H), 7.22 (t, J=5.2 Hz, 1H), 6.28 (dt, J=33.7, 6.5 Hz, 1H), 3.75 (s, 2H), 1.37 (s, 9H).

[0590] Scheme 1, Reaction 4: (2E)-3-(4-Chlorophenylsulfonyl)-3-fluoroprop-2-en-1-amine hydrochloride

[0591] Chilled 4N HCl in dioxane 3.7-4.3N (1.21 ml, 4.86 mmol, 10.0 eq.) was added to tert-butyl N-[(2E)-3-(4-chlorobenzenesulfonyl)-3-fluoroprop-2-en-1-yl]carbamate (0.17 g, 0.48 mmol, 1.0 eq.) and the solution was stirred at room temperature. A white solid began to form within the first 10 min, and after stirring for 1 h, the reaction was concentrated under reduced pressure to give the desired product (2E)-3-(4-chlorobenzenesulfonyl)-3-fluoroprop-2-en-1-amine hydrochloride (138 mg, Y: 99%) as a white solid, which was used in the next reaction without further purification. UPLC and 1 H NMR (DMSO-d6, 300 MHz) confirmed the structure and purity of the product.

[0592] UPLC Rt: 1.41, m / z: 249.9 [M+1], Cl mode; purity (254 nm): 99%; 1 H NMR (300MHz, DMSO-d6) δ8.24 (s, 3H), 8.04–7.95 (m, 2H), 7.90–7.80 (m, 2H), 6.50 (dt, J = 33.0, 6.9Hz, 1H), 3.70 (s, 2H).

[0593] Example 4: [(1E)-3-aminoprop-1-en-1-yl](imino)[4-(trifluoromethoxy)phenyl]-λ 6 -Thione Preparation of hydrochloride salt (Scheme 2)

[0594] Scheme 2, Reaction 1: N-[(tert-Butyloxy)carbonyl]-N-[(2E)-3-{[4-(trifluoromethoxy)phenyl]thio} tert-Butyl]prop-2-en-1-ylcarbamate

[0595] 1,3-bis(1,1-dimethylethyl)2-(2-propyn-1-yl)iminodicarbonate (0.3g, 1.12mmol, 1.0eq.), tri(triphenylphosphine)rhodium chloride (I) (0.03g, 0.033mmol, 0.03eq.) and 1,2-dichloroethane (4.0ml) were degassed with argon for 30min while cooling to 0°C. Next, 4-(trifluoromethoxy)thiophenol (0.24g, 1.23mmol, 1.1eq.) was added dropwise as a solution in 1,2-dichloroethane (1.6ml) over 10min to form a dark brown solution. The reaction was stirred at room temperature under argon overnight and then concentrated to a dark brown oil under reduced pressure. UPLC of the crude material showed that the desired product was formed. The oil was dissolved in minimal DCM and purified by flash chromatography, eluting with hexane / ethyl acetate (0 to 90%). The fractions containing the product were collected and concentrated under reduced pressure to give a light yellow oil (428 mg). UPLC and 1H NMR (CDCl3, 300 MHz) confirmed the formation of the desired product, tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2E)-3-{[4-(trifluoromethoxy)phenyl]thio}prop-2-en-1-yl]carbamate, as an approximately 93:7 mixture with the ortho-olefin side product formed by the addition of thiophenol to the other side of the triple bond. The mixture was used in the next step without further purification.

[0596] UPLC Rt: 2.31, m / z: 472.1 [M+Na]; purity (NMR): 93%; 1H NMR (300 MHz, chloroform-d) δ 7.38–7.31 (m, 2H), 7.15 (dq, J = 7.7, 1.0 Hz, 2H), 6.32 (dt, J = 15.0, 1.2 Hz, 1H), 5.92 (dt, J = 15.0, 6.3 Hz, 1H), 4.23 (dd, J = 6.3, 1.3 Hz, 2H), 1.50 (s, 18H).

[0597] Scheme 2, Reaction 2: N-[(tert-butyloxy)carbonyl]-N-[(2E)-3-[imino(oxo)[4-(trifluoromethoxy) Phenyl]-λ 6 -thio]prop-2-en-1-yl]carbamic acid tert-butyl ester

[0598] N-[(tert-Butyloxy)carbonyl]-N-[(2E)-3-{[4-(trifluoromethoxy)phenyl]-thio}prop-2-en-1-yl]-carbamic acid tert-butyl ester (0.43 g, 0.89 mmol, 1.0 eq.) was dissolved in MeOH (17.1 ml, 40 vol) and cooled to 0°C over 10 min before adding ammonium carbamate (0.28 g, 3.5 mmol, 4.0 eq.). The mixture was stirred at 0°C for 30 min before adding iodobenzene diacetate (0.71 g, 2.2 mmol, 2.5 eq.) in three portions with 10 min intervals. After the last portion was added, the mixture was allowed to reach room temperature. After 30 min, UPLC indicated complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to a small volume before being dissolved in minimal MeOH, adsorbed onto celite and purified by flash chromatography eluting with hexane / ethyl acetate (0 to 60%). The fractions containing the product were collected and concentrated under reduced pressure to give the desired product, N-[(tert-butoxy)carbonyl]-N-[(2E)-3-[imino(oxo)[4-(trifluoromethoxy)phenyl]-λ as a white solid. 6 -thio]prop-2-en-1-yl]carbamic acid tert-butyl ester (336 mg, Y: 77%). UPLC and 1 H NMR (CDCl3, 300 MHz) confirmed the structure and purity of the product.

[0599] UPLC Rt: 1.98, m / z: 481.00 [M+1]; purity (NMR): 99%;1 H NMR (300 MHz, CHLOROFORM-d) δ 8.08 (d, J = 8.9 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.01 (dt, J = 15.0, 5.1 Hz, 1H), 6.62 (d, J = 15.0 Hz, 1H), 4.42 (dd, J = 5.2, 1.6 Hz, 2H), 1.41 (s, 18H).

[0600] Scheme 2, Reaction 3: [(1E)-3-aminoprop-1-en-1-yl](imino)[4-(trifluoromethoxy)phenyl]-λ 6 - Thiothione dihydrochloride

[0601] Chilled 4N HCl in dioxane (1.7 ml, 6.9 mmol, 10.0 eq.) was added to N-[(tert-butyloxy)carbonyl]-N-[(2E)-3-[imino(oxo)[4-(trifluoromethoxy)phenyl]-λ 6 -sulfuryl]prop-2-en-1-yl]carbamate (0.34 g, 0.69 mmol, 1.0 eq.) and the solution was stirred at room temperature. A white solid formed within the first 10 min. After 30 min, the reaction was concentrated under reduced pressure and the resulting solid was triturated with diethyl ether (10 mL) and dried under vacuum to give the desired product [(1E)-3-aminoprop-1-en-1-yl](imino)[4-(trifluoromethoxy)phenyl]-λ as a white solid. 6 -thioketone dihydrochloride (258 mg, Y: 85%) was used in the next reaction without further purification. UPLC and 1 H NMR (DMSO-d6, 300 MHz) confirmed the structure and purity of the product.

[0602] UPLC Rt: 1.39, m / z: 281.00 [M+1]; purity (254): 75%; 1 H NMR(300MHz,DMSO-d6)δ8.43–8.22(m,5H),8.11–7.96(m,3H),7.69–7.59( m,3H),7.04–6.93(m,1H),6.82(dt,J=15.2,5.3Hz,1H),3.76–3.63(m,2H).

[0603] Example 5: N-[(2E)-3-(4-bromophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline Preparation of 3-oxo-1-pyridine carboxamide (Scheme 3)

[0604] 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid (0.025 g, 0.13 mmol, 1.0 eq.) and T3P (50+% w / w solution in acetonitrile (0.17 g, 0.26 mmol, 2.0 eq.)) were dissolved in anhydrous DMF (1.3 ml, 0.1 M). N,N-diisopropylethylamine (0.09 ml, 0.52 mmol, 4.0 eq.) was added and the yellow mixture was stirred for 10 min. (2E)-3-(4-bromophenylsulfonyl)prop-2-en-1-amine hydrochloride (0.038 g, 0.14 mmol, 1.1 eq.) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between water and DCM and the organic layer was collected, washed with saturated NaHCO3 solution, saturated NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC eluting with DCM / MeOH 5% to give N-[(2E)-3-(4-bromobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide (13 mg, Y: 18%) as a yellow solid.

[0605] LCMS Rt=3.34min, m / z=451 / 453[M+1]; Purity: 98.31% (254nm); 1H NMR(300MHz, DMSO-d6)δ12.26(s,1H),10.01(t,J=5.9Hz,1H),8.03(s,1H),7.91–7.83(m,2H),7.83–7.75(m,2H), 6.97(dt,J=15.1,4.3Hz,1H),6.68(dt,J=15.1,1.8Hz,1H),4.23–4.13(m,2H),2.58(s,2H),1.68(d,J=5.6Hz,4H).

[0606] Example 6: N-[(2E)-3-[(4-fluorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo- Preparation of 1,2,5,6,7,8-hexahydroquinoline-3-carboxamide (Scheme 3)

[0607] 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid (0.023 g, 0.12 mmol, 1.0 eq) and HATU (0.059 g, 0.16 mmol, 1.0 eq) were dissolved in anhydrous DMF (0.5 mL). N,N-diisopropylethylamine (0.11 ml, 0.62 mmol, 4.0 eq) was added and the yellow mixture was stirred for 10 min. [(1E)-3-aminoprop-1-en-1-yl](4-fluorophenyl)imino-λ was added. 6-thioketone dihydrochloride (0.042g, 0.14mmol, 0.9eq), and the mixture was stirred at room temperature for 2h. The reaction mixture was distributed between water and DCM, and the organic layer was collected, washed with saturated NaHCO3 solution, saturated NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC, eluted with ethyl acetate / MeOH 10% to obtain N-[(2E)-3-[(4-fluorophenyl)(imino)oxo-λ as an off-white solid 6 -thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide (0.012 g, 0.028 mmol, 18%).

[0608] LCMS Rt=1.85m / z=390.10[M+1]388.09[M-1];Purity: 92.5%(254nm); 1 H NMR (300MHz, DMSO-d6) δ12.28(s,1H),10.02(t,J=5.9Hz,1H),8.03(s,1H),7.98–7.85(m,2H),7.48–7.36(m,2H),6.79(dt ,J=14.9,4.6Hz,1H),6.57–6.43(m,1H),4.67(s,1H),4.21–4.07(m,2H),2.59(d,J=5.6Hz,2H),1.70(p,J=7.3,6.8Hz,4H).

[0609] The title compounds of Examples 7-65, 126-177 and 186 were prepared by methods similar to those described in Example 5 or 6.

[0610] Example 7: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline- 3-Formamide

[0611] LCMS Rt=2.27 min, m / z=372.98 [M+1]; purity: 98% (254 nm); 1 H NMR(400MHz, DMSO-d6)12.26(s,1H),10.02(t,J=6.0Hz,1H),8.03(s,1H),7.90–7.82(m,2H),7.78–7.70(m,1H),7.69–7.60(m,2H),6.9 5(dt,J=15.2,4.5Hz,1H), 6.66(dt,J=15.0,1.8Hz,1H), 4.18(ddd,J=6.3,4.5,2.0Hz,2H), 2.58(t,J=5.9Hz,2H), 1.69(q,J=8.2Hz,4H).

[0612] Example 8: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-benzyl-2-oxo-1,2,5,6,7,8-hexa Hydrogen-1,6-naphthyridine-3-carboxamide

[0613] RT = 2.29 min, m / z = 463.90 [M+1]; Purity: 95% (254 nm); 1 H NMR (300 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.98 (t, J = 5.9 Hz, 1H), 8.01 (s, 1H), 7.91–7.82 (m, 2H), 7.79–7.70 (m, 1H), 7.69–7.58 (m, 2H), 7.40–7.22 (m, 5H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.67 (dt, J = 15.1, 1.8 Hz, 1H), 4.26–4.10 (m, 2H), 3.66 (s, 2H), 3.39 (s, 2H), 2.67 (s, 4H).

[0614] Example 9: N-[(2Z)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline- 3-Formamide

[0615] Purity: 97.2% (254 nm); RT = 2.91 min, m / z = 373.79 [M+1], 371.22 [M-1]; 1 H NMR (400 MHz, DMSO-d6) 12.26 (s, 1H), 10.06 (t, J = 5.8 Hz, 1H), 8.05 (s, 1H), 8.02–7.95 (m, 2H), 7.79–7.73 (m, 1H), 7.72–7.64 (m, 2H), 6.59 (dt, J = 11.2, 2.0 Hz, 1H), 6.38 (dt, J = 11.5, 6.0 Hz, 1H), 4.52 (td, J = 5.9, 2.0 Hz, 2H), 2.58 (t, J = 6.0 Hz, 2H), 1.69 (q, J = 8.0 Hz, 4H).

[0616] Example 10: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, tert-Butyl 7,8-hexahydro-1,6-naphthyridine-6-carboxylate

[0617] Purity: 96.8% (254 nm); RT = 3.15 min, m / z = 473.69 [M+1], 471.72 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 9.95 (t, J = 5.9 Hz, 1H), 8.12 (s, 1H), 7.90 - 7.83 (m, 2H), 7.78 - 7.69 (m, 1H), 7.64 (dd, J = 8.3, 6.8 Hz, 2H), 6.95 (dt, J = 15.2, 4.4 Hz, 1H), 6.67 (dt, J = 15.1, 1.9 Hz, 1H), 4.31 (s, 2H), 4.24 - 4.14 (m, 2H), 3.56 (t, J = 5.8 Hz, 2H), 2.65 (t, J = 5.8 Hz, 2H), 1.42 (s, 9H).

[0618] Example 11: N-[(2E)-3-[(5-chloropyridin-2-yl)sulfonyl]prop-2-en-1-yl]-2-oxo-1,2,5,6, 7,8-Hexahydroquinoline-3-carboxamide

[0619] Purity: 97.9% (254 nm); RT = 2.23 min, m / z = 408.09 [M+1], 406.04 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 10.04 (t, J = 5.9 Hz, 1H), 8.85 (d, J = 2.3 Hz, 1H), 8.28 (dd, J = 8.4, 2.4 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 8.05 (s, 1H), 7.06 (dt, J = 15.2, 4.3 Hz, 1H), 6.71 (dt, J = 15.2, 1.9 Hz, 1H), 4.23 (ddd, J = 6.1, 4.4, 2.0 Hz, 2H), 2.58 (t, J = 5.9 Hz, 2H), 1.69 (q, J = 8.0 Hz, 4H).

[0620] Example 12: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine- 3-Formamide

[0621] Purity: 94.6%; RT = 2.56 min, m / z = 395.18 [M+1], 392.97 [M-1], 1 1H NMR (300 MHz, DMSO-d6) δ 12.66 (s, 1H), 10.00 (t, J = 5.9 Hz, 1H), 8.60 (d, J = 2.9 Hz, 1H), 8.06 (d, J = 2.9 Hz, 1H), 7.92 - 7.81 (m, 2H), 7.80 - 7.56 (m, 5H), 7.53 - 7.40 (m, 2H), 7.40 - 7.29 (m, 1H), 6.98 (dt, J = 15.1, 4.3 Hz, 1H), 6.75 (dt, J = 15.1, 1.8 Hz, 1H), 4.23 (tt, J = 4.6, 1.9 Hz, 2H).

[0622] Example 13: 6-acetyl-N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8- Hexahydro-1,6-naphthyridine-3-carboxamide

[0623] Purity: 98.3%; Rt = 2.17 min, m / z = 416.17 [M+1], 414.14 [M-1]; 1 H NMR (300 MHz, DMSO-d6) 12.49 (s, 1H), 9.95 (t, J = 6.0 Hz, 1H), 8.14 (d, J = 5.9 Hz, 1H), 7.91–7.81 (m, 2H), 7.79–7.69 (m, 1H), 7.64 (dd, J = 8.2, 6.6 Hz, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.73–6.59 (m, 1H), 4.43 (d, J = 22.9 Hz, 2H), 4.19 (d, J = 5.3 Hz, 2H), 3.66 (q, J = 5.5 Hz, 2H), 2.80–2.58 (m, 2H), 2.06 (d, J = 8.0 Hz, 3H).

[0624] Example 14: N-[(3E)-4-(phenylsulfonyl)but-3-en-2-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline- 3-Formamide

[0625] Purity: 97.6%; RT = 1.96 min, m / z = 387.21 [M+1] 385.20 [M-1]; 1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 10.00 (d, J = 7.7 Hz, 1H), 8.02 (s, 1H), 7.91–7.81 (m, 2H), 7.78–7.68 (m, 1H), 7.65 (dd, J = 8.4, 6.9 Hz, 2H), 6.98 (dd, J = 15.1, 4.7 Hz, 1H), 6.72 (dd, J = 15.2, 1.7 Hz, 1H), 4.83–4.69 (m, 1H), 2.62–2.55 (m, 2H), 1.77–1.59 (m, 4H), 1.31 (d, J = 7.0 Hz, 3H).

[0626] Example 15: N-[(2E)-3-methylsulfonylprop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3- Formamide

[0627] Purity: 93.1%; Rt = 2.02 min, m / z = 311.19 [M+1] 309.22 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 10.06 (t, J = 6.0 Hz, 1H), 8.08 (s, 1H), 6.80 (dt, J = 15.2, 4.3 Hz, 1H), 6.69–6.55 (m, 1H), 4.29–4.08 (m, 2H), 3.01 (s, 3H), 2.65–2.56 (m, 2H), 1.70 (q, J = 7.9 Hz, 4H).

[0628] Example 16: N-[(2E)-3-(4-fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro Quinoline-3-carboxamide

[0629] Purity: 97.7%; RT = 1.90 min, m / z = 391.14 [M+1], 389.10 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) 12.28 (s, 1H), 10.01 (t, J = 5.9 Hz, 1H), 8.03 (s, 1H), 7.98–7.89 (m, 2H), 7.54–7.45 (m, 2H), 6.96 (dt, J = 15.1, 4.4 Hz, 1H), 6.68 (dt, J = 15.1, 1.8 Hz, 1H), 4.18 (ddd, J = 6.1, 4.4, 1.9 Hz, 2H), 2.58 (t, J = 6.0 Hz, 2H), 1.68 (q, J = 8.4, 7.5 Hz, 4H).

[0630] Example 17: N-[(2E)-3-(cyclopentanesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro Quinoline-3-carboxamide

[0631] Purity: 98.6%; RT = 1.52 min, m / z = 365.21 [M+1], 363.18 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) 12.29 (s, 1H), 10.05 (t, J = 5.9 Hz, 1H), 8.07 (s, 1H), 6.79 (dt, J = 15.2, 4.5 Hz, 1H), 6.52 (dt, J = 15.2, 1.8 Hz, 1H), 4.19 (ddd, J = 6.2, 4.6, 1.9 Hz, 2H), 3.52 (tt, J = 8.9, 6.7 Hz, 1H), 2.59 (t, J = 6.0 Hz, 2H), 1.94–1.47 (m, 12H).

[0632] Example 18: 2-Oxo-N-[(2E)-3-(propane-2-sulfonyl)prop-2-en-1-yl]-1,2,5,6,7,8-hexahydro Quinoline-3-carboxamide

[0633] Purity: 97.0%; RT = 1.76 m / z = 339.23 [M+1], 337.16 [M-1]; 11H NMR (400 MHz, DMSO-d6): δ 12.28 (s, 1H), 10.06 (t, J = 5.9 Hz, 1H), 8.07 (s, 1H), 6.79 (dt, J = 15.2, 4.5 Hz, 1H), 6.48 (dt, J = 15.2, 1.8 Hz, 1H), 4.19 (ddd, J = 6.3, 4.4, 1.9 Hz, 2H), 3.18 (p, J = 6.8 Hz, 1H), 2.59 (t, J = 6.0 Hz, 2H), 1.68 (d, J = 12.8 Hz, 4H), 1.18 (d, J = 6.8 Hz, 6H).

[0634] Example 19: N-[(2E)-3-(3-fluoro-4-methoxyphenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6, 7,8-Hexahydroquinoline-3-carboxamide

[0635] Purity: 99.8%; RT = 1.97 min, m / z = 421.33 [M+1], 419.12 [M-1]; 1 1H NMR (400 MHz, DMSO-d6): δ 12.28 (s, 1H), 10.01 (t, J = 5.9 Hz, 1H), 8.03 (s, 1H), 7.74–7.63 (m, 2H), 7.40 (t, J = 8.3 Hz, 1H), 6.91 (dt, J = 15.1, 4.4 Hz, 1H), 6.64 (dt, J = 15.1, 1.8 Hz, 1H), 4.17 (ddd, J = 6.2, 4.4, 1.9 Hz, 2H), 3.94 (s, 3H), 2.58 (t, J = 5.7 Hz, 2H).

[0636] Example 20: 2-Oxo-N-[(2Z)-3-(propane-2-sulfonyl)prop-2-en-1-yl]-1,2,5,6,7,8-hexahydro Quinoline-3-carboxamide

[0637] Purity: 88.9%; RT = 5.45 min, m / z = 339.22 [M+1], 337.20 [M-1]; 1 1H NMR (300 MHz, DMSO-d6): δ 12.27 (s, 1H), 10.04 (t, J = 5.9 Hz, 1H), 8.06 (s, 1H), 6.53–6.39 (m, 2H), 4.41 (t, J = 5.5 Hz, 2H), 2.57 (d, J = 6.0 Hz, 2H), 1.69 (d, J = 5.1 Hz, 4H), 1.26 (d, J = 6.8 Hz, 6H).

[0638] Example 21: N-[(2E)-3-(4-chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro Quinoline-3-carboxamide

[0639] Purity: 97.0%; RT = 5.25 min, m / z = 407.17 [M+1], 405.15 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 10.02 (t, J = 5.9 Hz, 1H), 8.03 (s, 1H), 7.91–7.84 (m, 2H), 7.75–7.68 (m, 2H), 6.97 (dt, J = 15.1, 4.4 Hz, 1H), 6.68 (dt, J = 15.1, 1.9 Hz, 1H), 4.18 (ddd, J = 6.2, 4.5, 2.0 Hz, 2H), 2.58 (t, J = 6.0 Hz, 2H), 1.69 (h, J = 6.7, 6.2 Hz, 4H).

[0640] Example 22: 3-{[(2E)-3-(2-fluorophenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2, tert-Butyl 5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate

[0641] Purity: 93.6%; RT = 2.19 min, m / z = 492.40 [M+1]; 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.99 (t, J = 6.0 Hz, 1H), 8.14 (s, 1H), 7.88 (td, J = 7.5, 1.8 Hz, 1H), 7.85–7.76 (m, 1H), 7.55–7.42 (m, 2H), 7.05 (dt, J = 15.0, 4.4 Hz, 1H), 6.72 (d, J = 15.1 Hz, 1H), 4.32 (s, 2H), 4.27–4.15 (m, 2H), 3.57 (t, J = 5.8 Hz, 2H), 2.66 (s, 2H), 1.42 (s, 9H).

[0642] Example 23: N-[(2E)-3-(2-methylpropane-2-sulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7, 8-Hexahydroquinoline-3-carboxamide

[0643] Purity: 97.5%; RT = 1.39 min, m / z = 353.30 [M+1], 351.20 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 10.07 (t, J = 5.8 Hz, 1H), 8.06 (s, 1H), 6.79 (dt, J = 15.2, 4.6 Hz, 1H), 6.50 (dt, J = 15.1, 1.8 Hz, 1H), 4.20 (ddd, J = 6.3, 4.6, 1.9 Hz, 2H), 2.62–2.55 (m, 2H), 1.77–1.62 (m, 4H), 1.24 (s, 9H).

[0644] Example 24: N-[(2E)-3-(2-Fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro Quinoline-3-carboxamide

[0645] Purity: 91.6%; RT = 2.07 m / z = 391.20 [M+1] 389.10 [M-1]; 1 H NMR (400MHz, DMSO-d6) δ12.29(s,1H),10.05(t,J=5.9Hz,1H),8.04(s,1H),7.88(td,J=7.6,1.8Hz,1H),7.84–7.76(m,1H),7.55–7.40(m ,2H),7.05(ddd,J=15.1,5.1,3.9Hz,1H),6.76–6.63(m,1H),4.22(ddd,J=6.3,4.5,2.0Hz,2H),2.58(t,J=6.0Hz,2H),1.76–1.59(m,4H).

[0646] Example 25: 3-{[(2E)-3-(4-fluorophenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2, tert-Butyl 5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate

[0647] Purity: 95.0%; RT = 1.66 m / z = 492.42 [M+1] 490.18 [M-1]; 1 H NMR(400MHz, DMSO-d6)12.48(s,1H),10.03(s,1H),8.11(s,1H),7.97–7.91(m,2H),7.53–7.44(m,2H),6.96(dt,J=15.1,4.3Hz,1H),6 .68(dt,J=15.1,1.9Hz,1H),4.31(s,2H),4.18(ddd,J=6.4,4.5,1.9Hz,2H),3.56(t,J=5.8Hz,2H),2.65(t,J=6.1Hz,2H),1.42(s,9H).

[0648] Example 26: 3-{[(2E)-3-(3-Fluoro-4-methoxyphenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2- Oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid tert-butyl ester

[0649] Purity: 97.9%; RT = 2.72min, m / z = 522.17 [M+1] 520.41 [M-1]; 11H NMR (300 MHz, DMSO-d6): δ 12.49 (s, 1H), 9.95 (t, J = 5.9 Hz, 1H), 8.16 (d, J = 19.0 Hz, 1H), 7.92–7.82 (m, 2H), 7.77–7.69 (m, 1H), 7.64 (dd, J = 8.2, 6.6 Hz, 2H), 6.95 (dt, J = 15.2, 4.4 Hz, 1H), 6.66 (d, J = 15.1 Hz, 1H), 4.54 (s, 1H), 4.42 (s, 1H), 4.18 (s, 2H), 3.72 (d, J = 6.1 Hz, 2H), 2.66 (d, J = 30.6 Hz, 2H), 2.30 (d, J = 4.0 Hz, 2H), 0.98 (d, J = 11.6 Hz, 9H).

[0650] Example 27: 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2, tert-Butyl 5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate

[0651] Purity: 94.7%; RT = 3.15 min, m / z = 508.12 [M+1], 505.87 [M-1]; 1H NMR (400 MHz, DMSO-d6): δ 12.48 (s, 1H), 10.00 (d, J = 6.3 Hz, 1H), 8.12 (s, 1H), 7.92–7.83 (m, 2H), 7.77–7.68 (m, 2H), 6.98 (dt, J = 15.2, 4.3 Hz, 1H), 6.69 (dt, J = 15.1, 1.9 Hz, 1H), 4.32 (s, 2H), 4.24–4.14 (m, 2H), 3.56 (t, J = 5.9 Hz, 2H), 2.65 (t, J = 6.0 Hz, 2H), 1.42 (s, 9H).

[0652] Example 28: N-[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2-dihydroquinolin-3-yl Amide

[0653] Purity: 96.2%; RT = 3.30 min, m / z = 403.12 [M+1], 400.92 [M-1]; 1 1H NMR (400 MHz, DMSO-d6): δ 12.48 (s, 1H), 9.97 (d, J = 6.2 Hz, 1H), 8.82 (s, 1H), 7.94 (dd, J = 8.2, 1.4 Hz, 1H), 7.91–7.85 (m, 2H), 7.75–7.70 (m, 2H), 7.66 (ddd, J = 8.5, 7.1, 1.4 Hz, 1H), 7.01 (dt, J = 15.2, 4.3 Hz, 1H), 6.81 (dt, J = 15.0, 1.9 Hz, 1H), 4.24 (ddd, J = 6.2, 4.4, 1.9 Hz, 2H).

[0654] Example 29: 6-Benzyl-N-[(2E)-3-(4-chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7, 8-Hexahydro-1,6-naphthyridine-3-carboxamide

[0655] Purity: 82.9%; RT = 2.04 min, m / z = 497.84 [M+1] 495.97 [M-1]; 1 H NMR (400 MHz, DMSO-d6) 12.45 (s, 1H), 10.02 (d, J = 6.5 Hz, 1H), 8.00 (s, 1H), 7.90–7.84 (m, 2H), 7.76–7.68 (m, 2H), 7.39–7.24 (m, 5H), 6.97 (dt, J = 15.2, 4.5 Hz, 1H), 6.69 (dt, J = 14.9, 1.9 Hz, 1H), 4.17 (q, J = 3.8, 1.9 Hz, 2H), 3.65 (s, 2H), 2.66 (d, J = 2.7 Hz, 4H).

[0656] Example 30: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0657] Purity: 97.7%; RT = 2.18 min, m / z = 420.11 [M+1] 418.09 [M-1]; 1 H NMR (400 MHz, DMSO-d6) δ12.26 (s, 1H), 9.99 (t, J = 6.0 Hz, 1H), 8.04 (s, 1H), 7.68–7.59 (m, 2H), 7.35 (t, J = 8.4 Hz, 1H), 6.76 (dt, J = 14.9, 4.6 Hz, 1H), 6.48 (dt, J = 14.9, 1.8 Hz, 1H), 4.59 (s, 1H), 4.17–4.08 (m, 2H), 3.92 (s, 3H), 2.58 (t, J = 6.0 Hz, 2H), 1.69 (q, J = 7.7, 6.9 Hz, 4H).

[0658] Example 31: N-[(2E)-3-(2,4-dichlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8- Hexahydroquinoline-3-carboxamide

[0659] Purity: 92.6%; RT = 2.46 min, m / z = 407.27 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 10.04 (t, J = 5.9 Hz, 1H), 8.05 (s, 1H), 7.95 (td, J = 8.7, 6.3 Hz, 1H), 7.62 (ddd, J = 10.6, 9.2, 2.5 Hz, 1H), 7.42–7.31 (m, 1H), 7.11–6.99 (m, 1H), 6.75–6.64 (m, 1H), 4.22 (ddd, J = 6.2, 4.4, 1.9 Hz, 2H), 2.58 (t, J = 6.0 Hz, 2H), 1.79–1.59 (m, 4H).

[0660] Example 32: N-[(2E)-3-(2,4-dichlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8- Hexahydroquinoline-3-carboxamide

[0661] Purity: 97.1%; RT = 2.88 min, m / z = 443.00 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 10.05 (t, J = 5.9 Hz, 1H), 8.12–8.01 (m, 2H), 7.94 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.6, 2.1 Hz, 1H), 7.09 (dt, J = 15.1, 4.4 Hz, 1H), 6.73 (dt, J = 15.1, 1.9 Hz, 1H), 4.23 (ddd, J = 6.2, 4.5, 1.9 Hz, 2H), 2.58 (t, J = 6.0 Hz, 2H), 1.69 (q, J = 8.4, 8.0 Hz, 4H).

[0662] Example 33: N-[(2E)-3-(2-chloro-4-fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8- Hexahydroquinoline-3-carboxamide

[0663] Purity: 97.5%; RT = 2.17 min, m / z = 425.20 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 10.05 (t, J = 5.9 Hz, 1H), 8.12 (dd, J = 8.9, 6.0 Hz, 1H), 8.04 (s, 1H), 7.78 (dd, J = 8.7, 2.5 Hz, 1H), 7.51 (ddd, J = 8.9, 8.0, 2.6 Hz, 1H), 7.08 (dt, J = 15.1, 4.5 Hz, 1H), 6.73 (dt, J = 15.0, 1.9 Hz, 1H), 4.23 (ddd, J = 6.3, 4.5, 2.0 Hz, 2H), 2.58 (t, J = 5.9 Hz, 2H), 1.78–1.60 (m, 4H).

[0664] Example 34: N-[(2E)-3-(2,4-difluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H, 7H,8H,9H-Cycloheptyl[b]pyridine-3-carboxamide

[0665] Purity: 97.0%; RT = 2.24 min, m / z = 423.15 [M+1], 421.10 [M-1]; 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 10.03 (t, J = 5.9 Hz, 1H), 8.10 (s, 1H), 7.94 (td, J = 8.6, 6.2 Hz, 1H), 7.62 (ddd, J = 11.3, 9.2, 2.4 Hz, 1H), 7.36 (td, J = 8.6, 2.5 Hz, 1H), 7.05 (ddd, J = 15.0, 4.9, 3.8 Hz, 1H), 6.71 (dd, J = 15.1, 2.2 Hz, 1H), 4.21 (ddd, J = 6.3, 4.5, 1.9 Hz, 2H), 2.83–2.73 (m, 2H), 2.66–2.59 (m, 2H), 1.82–1.71 (m, 2H), 1.65–1.44 (m, 4H).

[0666] Example 35: N-[(2E)-3-(4-fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H, 8H,9H-Cycloheptyl[b]pyridine-3-carboxamide

[0667] Purity: 93.4%; RT = 2.16 min, m / z = 405.15 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.00 (t, J = 5.8 Hz, 1H), 8.09 (s, 1H), 7.99–7.88 (m, 2H), 7.54–7.43 (m, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.68 (dt, J = 15.0, 1.9 Hz, 1H), 4.17 (ddd, J = 6.2, 4.5, 1.9 Hz, 2H), 2.83–2.75 (m, 2H), 2.66–2.57 (m, 2H), 1.82–1.70 (m, 2H), 1.62–1.45 (m, 4H).

[0668] Example 36: N-[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H, 8H,9H-Cycloheptyl[b]pyridine-3-carboxamide

[0669] Purity: 92.0%; RT = 2.45 min, m / z = 421.15 [M+1] 419.21 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.09–9.97 (m, 1H), 8.08 (s, 1H), 7.91–7.83 (m, 2H), 7.76–7.69 (m, 2H), 6.97 (dt, J = 15.1, 4.3 Hz, 1H), 6.69 (dt, J = 15.1, 1.9 Hz, 1H), 4.18 (q, J = 5.2, 3.6 Hz, 2H), 2.77 (d, J = 9.9 Hz, 2H), 2.62 (d, J = 8.3 Hz, 2H), 1.74 (d, J = 10.8 Hz, 2H), 1.54 (d, J = 23.5 Hz, 4H).

[0670] Example 37: N-[(2E)-3-(3-fluoro-4-methoxyphenylsulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H, 5H,6H,7H,8H,9H-Cycloheptyl[b]pyridine-3-carboxamide

[0671] Purity: 95% (254 nm); RT = 2.94 min, m / z = 435.14 [M+1] 433.12 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.04 (s, 1H), 8.08 (s, 1H), 7.76–7.64 (m, 2H), 7.40 (t, J = 8.3 Hz, 1H), 6.92 (dt, J = 15.2, 4.4 Hz, 1H), 6.65 (dt, J = 15.0, 1.9 Hz, 1H), 4.22–4.13 (m, 2H), 3.94 (s, 3H), 2.84–2.71 (m, 2H), 2.66–2.58 (m, 2H), 1.83–1.70 (m, 2H), 1.64–1.45 (m, 4H).

[0672] Example 38: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H- Cyclohepta[b]pyridine-3-carboxamide

[0673] Purity: 85% (254 nm); RT = 2.01 min, m / z = 387.18 [M+1] 385.34 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 10.02 (t, J = 5.8 Hz, 1H), 8.09 (s, 1H), 7.89–7.83 (m, 2H), 7.77–7.70 (m, 1H), 7.69–7.61 (m, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.66 (dt, J = 15.1, 1.8 Hz, 1H), 4.18 (ddd, J = 6.2, 4.5, 1.9 Hz, 2H), 2.82–2.75 (m, 2H), 2.66–2.59 (m, 2H), 1.81–1.70 (m, 2H), 1.61–1.46 (m, 4H).

[0674] Example 39: N-[(2E)-3-(3-fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro Quinoline-3-carboxamide

[0675] Purity: 96.1% (254 nm); RT = 1.97 min, m / z = 391.16 [M+1], 389.14 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 10.02 (t, J = 5.9 Hz, 1H), 8.04 (s, 1H), 7.76–7.67 (m, 3H), 7.61 (ddd, J = 9.5, 5.5, 2.4 Hz, 1H), 7.01 (dt, J = 15.1, 4.3 Hz, 1H), 6.72 (dt, J = 15.1, 1.9 Hz, 1H), 4.19 (ddd, J = 6.1, 4.4, 1.9 Hz, 2H), 2.58 (t, J = 5.9 Hz, 2H), 1.76–1.62 (m, 4H).

[0676] Example 40: N-[(2E)-3-(4-methoxyphenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8- Hexahydroquinoline-3-carboxamide

[0677] Purity: 98.5% (254 nm); RT = 2.37 min, m / z = 403.16 [M+1], 400.89 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 10.00 (t, J = 6.0 Hz, 1H), 8.03 (s, 1H), 7.77 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 6.86 (dt, J = 15.1, 4.4 Hz, 1H), 6.59 (d, J = 15.1 Hz, 1H), 4.16 (d, J = 5.8 Hz, 2H), 3.85 (s, 3H), 2.58 (t, J = 5.9 Hz, 2H), 1.69 (q, J = 8.1 Hz, 4H).

[0678] Example 41: N-[(2E)-3-(2-chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro Quinoline-3-carboxamide

[0679] Purity: 96.3% (254 nm); RT = 2.01 min, m / z = 407.10 [M+1], 405.38 [M-1]; 1 H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 10.06 (t, J = 5.9 Hz, 1H), 8.12–7.97 (m, 2H), 7.81–7.66 (m, 2H), 7.63 (ddd, J = 7.9, 6.8, 1.8 Hz, 1H), 7.08 (dt, J = 15.1, 4.5 Hz, 1H), 6.75 (dt, J = 15.1, 1.9 Hz, 1H), 4.23 (ddd, J = 6.3, 4.6, 1.9 Hz, 2H), 2.58 (t, J = 5.9 Hz, 2H), 1.78–1.59 (m, 4H).

[0680] Example 42: N-[(2E)-3-(2,4-difluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H, 7H-Cyclopenta[b]pyridine-3-carboxamide

[0681] Purity: 82.2% (254 nm); RT = 2.26 min, m / z = 395.11 [M+1] 393.30 [M-1]; 1 H NMR (300 MHz, DMSO-d6) δ 12.76 (s, 1H), 10.09 (t, J = 5.9 Hz, 1H), 8.22 (s, 1H), 7.95 (td, J = 8.6, 6.2 Hz, 1H), 7.62 (ddd, J = 11.2, 9.3, 2.5 Hz, 1H), 7.36 (td, J = 8.6, 2.5 Hz, 1H), 7.14–6.97 (m, 1H), 6.78–6.64 (m, 1H), 4.22 (ddd, J = 6.3, 4.4, 2.0 Hz, 2H), 2.84 (q, J = 7.7 Hz, 2H), 2.76–2.67 (m, 2H), 2.05 (p, J = 7.5 Hz, 2H).

[0682] Example 43: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H-cyclopentadienyl Oleno[b]pyridine-3-carboxamide

[0683] Purity: 92.0% (254 nm); Rt = 2.06 min, m / z = 359.14 [M+1], 357.26 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 10.07 (t, J = 5.9 Hz, 1H), 8.21 (s, 1H), 7.90–7.83 (m, 2H), 7.78–7.70 (m, 1H), 7.68–7.61 (m, 2H), 6.95 (dt, J = 15.1, 4.5 Hz, 1H), 6.66 (dt, J = 15.1, 1.9 Hz, 1H), 4.18 (ddd, J = 6.2, 4.5, 1.9 Hz, 2H), 2.82 (t, J = 7.6 Hz, 2H), 2.71 (t, J = 7.4 Hz, 2H), 2.05 (p, J = 7.8 Hz, 2H).

[0684] Example 44: 2-Oxo-N-[(2E)-3-(thiophene-2-sulfonyl)prop-2-en-1-yl]-1,2,5,6,7,8-hexahydro Quinoline-3-carboxamide

[0685] Purity: 96.3% (254 nm); RT = 2.59 min, m / z = 379.09 [M+1], 393.30 [M-1]; 1 1H NMR (300 MHz, DMSO-d6) δ 12.25 (s, 1H), 10.02 (t, J = 6.0 Hz, 1H), 8.10 (dd, J = 5.0, 1.4 Hz, 1H), 8.04 (s, 1H), 7.75 (dd, J = 3.8, 1.4 Hz, 1H), 7.26 (dd, J = 5.0, 3.8 Hz, 1H), 6.93 (dt, J = 15.1, 4.5 Hz, 1H), 6.73 (dt, J = 15.1, 1.8 Hz, 1H), 4.18 (ddd, J = 6.2, 4.5, 1.9 Hz, 2H), 2.58 (t, J = 5.9 Hz, 2H), 1.76–1.62 (m, 4H).

[0686] Example 45: N-[(2E)-3-(3,4-dimethoxyphenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6, 7,8-Hexahydroquinoline-3-carboxamide

[0687] Purity: 98.5% (254 nm); Rt = 2.20 min, m / z = 433.14 [M+1], 431.36 [M-1]; 11H NMR (300 MHz, DMSO-d6) δ 12.26 (s, 1H), 10.00 (t, J = 5.9 Hz, 1H), 8.03 (s, 1H), 7.43 (dd, J = 8.5, 2.2 Hz, 1H), 7.29 (d, J = 2.2 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 6.87 (dt, J = 15.1, 4.5 Hz, 1H), 6.63 (dt, J = 15.1, 1.8 Hz, 1H), 4.16 (ddd, J = 6.4, 4.5, 1.9 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 2.63–2.55 (m, 2H), 1.68 (q, J = 6.6 Hz, 4H).

[0688] Example 46: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(prop-2-yl)-1,2,5,6, 7,8-Hexahydroquinoline-3-carboxamide

[0689] Purity: 95.0% (254 nm); Rt = 2.70 min, m / z = 415.12 [M+1], 413.12 [M-1]; 1 1H NMR (300 MHz, DMSO-d6) δ 12.27 (s, 1H), 10.01 (t, J = 5.9 Hz, 1H), 8.05 (s, 1H), 7.90–7.83 (m, 2H), 7.79–7.70 (m, 1H), 7.69–7.60 (m, 2H), 6.95 (dt, J = 15.1, 4.3 Hz, 1H), 6.71–6.60 (m, 1H), 4.18 (t, J = 4.7 Hz, 2H), 2.61 (d, J = 13.5 Hz, 2H), 2.25–2.15 (m, 1H), 1.87 (d, J = 11.7 Hz, 1H), 1.53 (p, J = 6.3 Hz, 1H), 1.47–1.21 (m, 3H), 0.91 (d, J = 6.7 Hz, 6H).

[0690] Example 47: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2-dihydro-1,8-naphthyridine-3- Formamide

[0691] Purity: 89.7% (254 nm); Rt = 2.01 min, m / z = 370.10 [M+1], 368.11 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 9.81 (t, J = 6.0 Hz, 1H), 8.84 (s, 1H), 8.67 (dd, J = 4.7, 1.8 Hz, 1H), 8.41 (dd, J = 7.8, 1.9 Hz, 1H), 7.90–7.84 (m, 2H), 7.76–7.70 (m, 1H), 7.68–7.61 (m, 2H), 7.37 (dd, J = 7.8, 4.7 Hz, 1H), 6.98 (dt, J = 15.1, 4.3 Hz, 1H), 6.80 (dt, J = 15.1, 1.9 Hz, 1H), 4.24 (ddd, J = 6.1, 4.3, 1.9 Hz, 2H).

[0692] Example 48: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6,6-dimethyl-2-oxo-1,2,5,6,7, 8-Hexahydroquinoline-3-carboxamide

[0693] Purity: 99.9% (254 nm); Rt = 2.74 min, m / z = 401.16 [M+1], 398.85 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 10.01 (t, J = 5.9 Hz, 1H), 8.00 (s, 1H), 7.89–7.82 (m, 2H), 7.76–7.70 (m, 1H), 7.67–7.61 (m, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.66 (dt, J = 15.1, 1.8 Hz, 1H), 4.17 (ddd, J = 6.2, 4.4, 1.9 Hz, 2H), 2.59 (t, J = 6.7 Hz, 2H), 2.30 (s, 2H), 1.50 (t, J = 6.6 Hz, 2H), 0.93 (s, 6H).

[0694] Example 49: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6,6-difluoro-2-oxo-1,2,5,6,7,8- Hexahydroquinoline-3-carboxamide

[0695] Purity: 99.9% (254 nm); Rt = 2.32 min, m / z = 409.13 [M+1], 407.15 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.93 (t, J = 5.9 Hz, 1H), 8.11 (s, 1H), 7.89–7.83 (m, 2H), 7.76–7.70 (m, 1H), 7.68–7.61 (m, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.67 (dt, J = 15.1, 1.9 Hz, 1H), 4.18 (ddd, J = 6.1, 4.4, 1.9 Hz, 2H), 3.13 (t, J = 14.6 Hz, 2H), 2.83 (t, J = 6.9 Hz, 2H), 2.25 (tt, J = 14.0, 6.8 Hz, 2H).

[0696] Example 50: N-[(2E)-3-(4-tert-butylbenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8- Hexahydroquinoline-3-carboxamide

[0697] Purity: 99.8% (254 nm); Rt = 2.34 min, m / z = 429.18 [M+1] 427.41 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 10.00 (t, J = 5.9 Hz, 1H), 8.03 (s, 1H), 7.81–7.72 (m, 2H), 7.70–7.61 (m, 2H), 6.92 (dt, J = 15.1, 4.4 Hz, 1H), 6.62 (dt, J = 15.0, 1.9 Hz, 1H), 4.23–4.11 (m, 2H), 2.58 (t, J = 6.0 Hz, 2H), 1.78–1.61 (m, 4H), 1.31 (s, 9H).

[0698] Example 51: N-[(2E)-3-(3,4-dimethylbenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7, 8-Hexahydroquinoline-3-carboxamide

[0699] Purity: 99.6% (254 nm); RT = 2.70 min, m / z = 401.15 [M+1] 399.31 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 10.01 (s, 1H), 8.03 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 7.9, 2.1 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 6.88 (dt, J = 15.2, 4.4 Hz, 1H), 6.58 (dt, J = 15.0, 1.9 Hz, 1H), 4.23–4.10 (m, 2H), 2.58 (t, J = 5.9 Hz, 2H), 2.30 (s, 6H), 1.77–1.61 (m, 4H).

[0700] Example 52: N-[(2E)-3-[(3,4-dimethoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0701] Purity: 92.2% (254nm); RT = 6.51min, m / z = 432.15 [M+1] 430.19 [M-1]; 1 H NMR (400MHz, DMSO-d6) δ12.26 (s, 1H), 9.99 (t, J = 5.9Hz, 1H), 8.04 (s, 1H), 7.4 3(dd,J=8.5,2.2Hz,1H),7.32(d,J=2.2Hz,1H),7.12(d,J=8.6Hz,1H),6.72(d t,J=14.9,4.7Hz,1H),6.48(dt,J=14.9,1.8Hz,1H),4.41(s,1H),4.12(t,J=5 .3Hz,2H),3.83(s,3H),3.80(s,3H),2.58(t,J=5.9Hz,2H),1.76–1.61(m,4H).

[0702] Example 53: N-[(2E)-3-(phenylsulfonyl)(1,1-2H2)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8- Hexahydroquinoline-3-carboxamide

[0703] Purity: 97.6% (254nm); Rt = 2.27min, m / z = 375.20 [M+1], 372.96 [M-1]; 1 H NMR(400MHz,DMSO-d6)δ12.26(s,1H),10.00(s,1H),8.03(s,1H),7.91–7.81(m,2H),7.77–7.69(m,1H),7. 69–7.59(m,2H),6.94(d,J=15.1Hz,1H),6.67(d,J=15.1Hz,1H),2.58(t,J=6.0Hz,2H),1.77–1.59(m,4H).

[0704] Example 54: N-[(2E)-3-[4-(dimethylamino)benzenesulfonyl]prop-2-en-1-yl]-2-oxo-1,2,5, 6,7,8-Hexahydroquinoline-3-carboxamide

[0705] Purity: 97.3% (254 nm); RT = 2.97 min, m / z = 416.17 [M+1], 414.16 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.98 (t, J = 6.0 Hz, 1H), 8.03 (s, 1H), 7.60–7.49 (m, 2H), 6.84–6.68 (m, 3H), 6.48 (dt, J = 15.0, 1.8 Hz, 1H), 4.18–4.03 (m, 2H), 3.01 (s, 6H), 2.58 (t, J = 6.0 Hz, 2H), 1.78–1.58 (m, 4H).

[0706] Example 55: N-[(2E)-3-(4-cyclopropylbenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8- Hexahydroquinoline-3-carboxamide

[0707] Purity: 94.8% (254 nm); RT = 3.33 min, m / z = 413.3 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.99 (t, J = 5.9 Hz, 1H), 6.89 (dt, J = 15.1, 4.4 Hz, 1H), 6.64–6.55 (m, 1H), 4.22–4.10 (m, 2H), 2.58 (t, J = 5.9 Hz, 2H), 2.04 (tt, J = 8.6, 4.9 Hz, 1H), 1.78–1.59 (m, 4H), 1.12–1.02 (m, 2H), 0.84–0.75 (m, 2H).

[0708] Example 56: N-[(2E)-3-(4-cyanobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexa Hydroquinoline-3-carboxamide

[0709] Purity: 95.6% (254 nm); RT = 2.91 min, m / z = 398.20 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 10.04 (t, J = 5.6 Hz, 1H), 8.16–8.10 (m, 2H), 8.08–8.01 (m, 3H), 7.06 (dt, J = 15.2, 4.3 Hz, 1H), 6.75 (dt, J = 15.1, 1.9 Hz, 1H), 4.25–4.17 (m, 2H), 2.58 (t, J = 5.8 Hz, 2H), 1.78–1.61 (m, 4H).

[0710] Example 57: N-[(2E)-3-[imino(4-methoxyphenyl)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxy 1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0711] Purity: 90.6% (254 nm); RT = 2.58 min, m / z = 402.20 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 10.04 (s, 1H), 8.03 (s, 1H), 7.82–7.73 (m, 2H), 7.15–7.04 (m, 2H), 6.71 (dt, J=15.1, 4.7 Hz, 1H), 6.44 (d, J=14.8 Hz, 1H), 4.42 (s, 1H), 4.15–4.07 (m, 2H), 3.83 (s, 3H), 2.58 (s, 3H), 1.69 (s, 4H).

[0712] Example 58: N-[(2E)-3-[(3,4-dimethylphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]- 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0713] Purity: 93.8% (254 nm); RT = 2.58 min, m / z = 400.30 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 10.00 (s, 1H), 8.03 (s, 1H), 7.62 (d, J=2.1 Hz, 1H), 7.57 (dd, J=7.9, 2.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 6.73 (dt, J=14.9, 4.6 Hz, 1H), 6.49–6.39 (m, 1H), 4.43 (s, 1H), 4.12 (t, J=5.3 Hz, 2H), 2.58 (s, 2H), 2.29 (s, 6H), 1.69 (d, J=7.4 Hz, 4H).

[0714] Example 59: 6,6-difluoro-N-[(2E)-3-[(4-fluorophenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0715] Purity: 97.3% (254 nm); RT = 1.88 min, m / z = 426.20 [M+1], 424.15 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 10.04–9.93 (m, 1H), 8.10 (s, 1H), 7.96–7.87 (m, 2H), 7.47–7.36 (m, 2H), 6.79 (dt, J=14.9, 4.6 Hz, 1H), 6.56–6.47 (m, 1H), 4.67 (s, 1H), 4.14 (s, 2H), 3.18–3.07 (m, 2H), 2.83 (t, J=6.9 Hz, 2H), 2.25 (tt, J=13.0, 6.5 Hz, 2H).

[0716] Example 60: N-[(2E)-3-[imino(oxy)phenyl-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2, 5,6,7,8-Hexahydroquinoline-3-carboxamide

[0717] Purity: 97.9% (254 nm); RT = 2.25 min, m / z = 372.22 [M+1], 370.19 [M-1]; 1 H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 10.00 (t, J = 5.9 Hz, 1H), 8.04 (s, 1H), 7.91–7.79 (m, 2H), 7.69–7.52 (m, 3H), 6.79 (dt, J = 15.0, 4.7 Hz, 1H), 6.54–6.46 (m, 1H), 4.58 (s, 1H), 4.20–4.05 (m, 2H), 2.58 (t, J = 5.9 Hz, 2H), 1.69 (q, J = 7.8 Hz, 4H).

[0718] Example 61: N-[(2E)-3-[(4-tert-butylphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2- Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0719] Purity: 84.1% (254 nm); RT = 2.25 min, m / z = 427.97 [M+1] 426.28 [M-1]; 1 H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 10.02 (s, 1H), 8.03 (d, J = 5.0 Hz, 1H), 7.87–7.73 (m, 2H), 7.60 (dq, J = 9.0, 2.4, 2.0 Hz, 2H), 6.77 (dt, J = 15.0, 4.7 Hz, 1H), 6.47 (dt, J = 14.9, 1.8 Hz, 1H), 4.48 (s, 1H), 4.13 (t, J = 5.4 Hz, 2H), 2.57 (d, J = 6.0 Hz, 2H), 1.74–1.63 (m, 4H), 1.30 (d, J = 1.8 Hz, 9H).

[0720] Example 62: N-[(2E)-3-[(4-ethoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2- Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0721] Purity: 92.3% (254 nm): RT = 1.93 min, m / z = 416.18 [M+1] 414.23 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.99 (t, J = 5.9 Hz, 1H), 8.04 (s, 1H), 7.79–7.72 (m, 2H), 7.11–7.03 (m, 2H), 6.71 (dt, J = 14.9, 4.7 Hz, 1H), 6.44 (dd, J = 14.9, 1.9 Hz, 1H), 4.41 (s, 1H), 4.11 (q, J = 6.8 Hz, 4H), 2.57 (d, J = 6.3 Hz, 2H), 1.78–1.61 (m, 4H), 1.34 (t, J = 7.0 Hz, 3H).

[0722] Example 63: N-[(2E)-3-[imino(4-methoxy-3,5-dimethylphenyl)oxy-λ 6 -thio]propan-2- [1-enyl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0723] Purity: 92.7% (254 nm): RT = 2.42 min, m / z = 430.25 [M+1] 428.25 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.99 (t, J = 5.9 Hz, 1H), 8.04 (s, 1H), 7.54 (s, 2H), 6.74 (dt, J = 15.0, 4.6 Hz, 1H), 6.45 (d, J = 15.0 Hz, 1H), 4.42 (s, 1H), 4.13 (t, J = 5.3 Hz, 2H), 3.70 (s, 3H), 2.58 (t, J = 5.9 Hz, 2H), 2.28 (s, 6H), 1.74–1.63 (m, 4H).

[0724] Example 64: N-[(2E)-3-[imino(3-methoxyphenyl)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxy 1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0725] Purity: 94.6% (254 nm); RT = 2.11 min, m / z = 402.23 [M+1] 400.20 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 10.05–9.95 (m, 1H), 8.04 (s, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.42 (dt, J = 7.8, 1.3 Hz, 1H), 7.37–7.33 (m, 1H), 7.19 (ddd, J = 8.1, 2.6, 1.0 Hz, 1H), 6.79 (dt, J = 14.9, 4.6 Hz, 1H), 6.54–6.46 (m, 1H), 4.58 (s, 1H), 4.21–4.09 (m, 2H), 2.58 (t, J = 5.8 Hz, 2H), 1.78–1.60 (m, 4H).

[0726] Example 65: N-[(2E)-3-[Imino(oxo)[4-(trifluoromethoxy)phenyl]-λ 6 -thio]prop-2-ene-1- 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0727] Purity: 92.3% (254 nm); Rt = 2.90 min, m / z = 456.15 [M+1], 454.17 [M-1]; 1 H NMR (400MHz, DMSO-d6) δ12.27(s,1H),10.10–9.99(m,1H),8.03(s,1H),8.02–7.95(m,2H),7.62–7.53(m,2H),6.84(dt,J=1 5.0,4.6Hz,1H),6.54(dt,J=14.9,1.8Hz,1H),4.77(s,1H),4.15(t,J=5.4Hz,2H),2.58(t,J=5.9Hz,2H),1.77–1.62(m,4H).

[0728] Example 66: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6- Preparation of naphthyridine-3-carboxamide hydrochloride (Scheme 3)

[0729] Tert-butyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate (1.16 g, 2.4 mmol, 1.0 eq) was suspended in dioxane (5 mL, 0.5 M) and cooled to 0°C. Dioxane containing HCl 4.0 M (6.0 ml, 24 mmol, 10 eq) was added to the reaction mixture and stirred for 2 h. The solution was concentrated to dryness, and the residue was triturated with diethyl ether and dried to obtain N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide hydrochloride (980 mg, Y: 98%).

[0730] UPLC Rt=1.20min, m / z=374.2[M+1]; Purity: 95% (NMR); 1H NMR(300MHz, DMSO-d6)12.67(s,1H),9.87(t,J=5.9Hz,1H),9.61(s,2H),8. 20(s,1H),7.92–7.81(m,2H),7.79–7.69(m,1H),7.64(dd,J=8.2,6.6Hz,2H ),6.95(dt,J=15.1,4.4Hz,1H),6.74–6.61(m,1H),4.19(ddd,J=6.2,4.4,1 .9Hz, 2H), 4.06 (d, J = 4.6Hz, 2H), 3.42–3.27 (m, 2H), 2.89 (t, J = 6.2Hz, 2H).

[0731] Example 67: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, Preparation of 7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid oxetan-3-yl ester (Scheme 4)

[0732] Scheme 4, Reaction 1: 4-Nitrophenyloxetane-3-yl carbonate

[0733] 4-Nitrophenyl chloroformate (0.30 g, 1.48 mmol, 1.1 eq) was added to a solution of oxetane-3-ol (0.1 g, 1.35 mmol, 1.0 eq) and pyridine (0.164 ml, 2.03 mmol, 1.5 eq) in DCM (3.47 ml, 0.4 M) in batches at 0 ° C. The reaction was allowed to reach room temperature and stirred for 2 h. The reaction was diluted with DCM, washed with 1 M HCl and saturated NaHCO3 aqueous solution, dried over MgSO4, filtered and then concentrated under reduced pressure to give oxetane-3-ylcarbonic acid 4-nitrophenyl ester (0.281 g, Y: 74%) as a light yellow oil, which was used in the next step without any further purification. 1 H NMR (DMSO-d6, 400 MHz) confirmed the structure of the product.

[0734] 1 H NMR (400MHz, DMSO-d6) δ8.37–8.29(m,2H),7.64–7.55(m,2H),5.53(tt,J=6.2,4 .7Hz, 1H), 4.85 (ddd, J=7.5, 6.2, 1.1Hz, 2H), 4.67 (ddd, J=7.8, 4.7, 1.1Hz, 2H).

[0735] Scheme 4, Reaction 2: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2, 5,6,7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid oxetan-3-yl ester

[0736] N-[(2E)-3-(benzenesulfonyl)prop-2-ene-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide (0.050g, 0.12mmol, 1.0eq) is dissolved in tetrahydrofuran (1mL). Next, a solution of NaHCO3aqueous solution (0.020g, 0.23mmol, 2.0eq, 1mL) and oxetane-3-ylcarbonic acid 4-nitrophenyl ester (0.036g, 0.128mmol, 1.1eq) in tetrahydrofuran (0.5mL) is added, and the reaction is stirred at room temperature for 2h. The reaction mixture is concentrated under reduced pressure and dissolved in DCM. The organic layer is washed with saturated NaHCO3aqueous solution until the yellow color disappears. The organic layer is collected, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC eluting with DCM / MeOH 10% to give (2,2-difluorocyclopropyl)methyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate (21 mg, Y: 37%) as a white solid.

[0737] Rt: 2.38 min, m / z = 474.3 [M + 1]; purity: 97.79% (254 nm); 1 H NMR(400MHz,DMSO-d6)δ12.50(s,1H),9.95(t,J=5.9Hz,1H),8.15(s,1H),7.90–7.82(m,2H),7.7 7–7.69(m,1H),7.64(dd,J=8.3,6.8Hz,2H),6.95(dt,J=15.2,4.4Hz,1H),6.66(dt,J=15.1,1.9Hz ,1H),5.31(p,J=5.6Hz,1H),4.77(dd,J=7.5,6.3Hz,2H),4.52(dd,J=7.6,5.1Hz,2H),4.49–4.41( m,1H),4.40–4.29(m,1H),4.18(td,J=5.1,4.2,2.0Hz,2H),3.78–3.54(m,2H),2.77–2.68(m,2H).

[0738] Example 68: 3-{[(2E)-3-[(4-fluorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]aminomethyl Preparation of cyclopropylmethyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate (Scheme 4)

[0739] Scheme 4, Reaction 1: 4-Nitrophenyl Cyclopropyl Methyl Carbonate

[0740] Nitrophenyl chloroformate (1.0 g, 5.0 mmol, 1.0 eq) was added to a solution of cyclopropylmethanol (0.32 g, 4.5 mmol, 0.9 eq) and pyridine (0.6 ml, 7.4 mmol, 1.5 eq) in DCM (12.4 ml, 0.4 M) in batches at 0 ° C. The reaction was allowed to reach room temperature and stirred for 2 h. The reaction was diluted with DCM, washed with 1 M HCl and saturated NaHCO3 aqueous solution, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give 4-nitrophenyl cyclopropylmethyl carbonate (0.998 g, Y: 75%) as a light yellow oil, which was used for the next step without any further purification. 1 H NMR (DMSO-d6, 300 MHz) confirmed the structure and purity of the product.

[0741] 1 H NMR (300MHz, DMSO-d6) δ8.37–8.27(m,2H),7.64–7.50(m,2H),4.10(d,J=7.5Hz, 2H), 1.21 (pt, J=7.7, 4.7Hz, 1H), 0.68–0.52 (m, 2H), 0.37 (qd, J=4.6, 2.0Hz, 2H).

[0742] Scheme 4, Reaction 3: 6-cyclopropyl 3-ethyl 2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3,6-dicarboxylate Methyl ester

[0743] 1,2,5,6,7,8-hexahydro-2-oxo-1,6-naphthyridine-3-carboxylic acid ethyl ester (0.67g, 2.6mmol, 1.0eq) was dissolved in THF (11mL). Next, a solution of NaHCO3 aqueous solution (0.433g, 5.157mmol, 2.0eq) and 4-nitrophenyl cyclopropyl methyl carbonate (0.70g, 2.6mmol, 1.0eq) in THF (2mL) was added, and the reaction was stirred at room temperature for 2h. The mixture was concentrated under reduced pressure and dissolved in DCM. The organic layer was washed with saturated NaHCO3 aqueous solution until the yellow color disappeared. The organic layer was collected, dried over MgSO4, filtered and concentrated under reduced pressure to obtain 3-ethyl 2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3,6-dicarboxylic acid 6-cyclopropyl methyl ester (0.625g, Y: 72%) as a yellow solid. 1 H NMR (DMSO-d6, 300 MHz) confirmed the structure of the product.

[0744] Purity: 90%( 1 H-NMR); 1H NMR (300MHz, DMSO-d6) δ12.01(s,1H),7.93(s,1H),4.32(s,2H),4.19(q,J=7.1Hz,2H),3.88(d,J=7.1Hz,2H),3.61(t,J=5 .8Hz,2H),2.63(t,J=5.9Hz,2H),1.26(t,J=7.1Hz,3H),1.11(pt,J=7.2,4.7Hz,1H),0.58–0.43(m,2H),0.33–0.21(m,2H).

[0745] Scheme 4, Reaction 4: 6-[(cyclopropylmethoxy)carbonyl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine- 3-Formic acid

[0746] 6-Cyclopropylmethyl 3-ethyl 2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3,6-dicarboxylate (0.63 g, 1.9 mmol, 1.0 eq) was dissolved in tetrahydrofuran (7.4 ml, 0.25 M) and the solution was cooled to 0 ° C. Next, 1.0 M aqueous LiOH (4.64 ml, 2.5 eq) was added and the mixture was stirred at room temperature for 12 h. Tetrahydrofuran was evaporated under reduced pressure, 0.5 HCl was added until ~ pH 3, and the resulting precipitate was filtered, washed with water and dried under reduced pressure to give 6-[(cyclopropylmethoxy)carbonyl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxylic acid (0.425 g, Y: 78%) as a solid. 1 H NMR (DMSO-d6, 300 MHz) confirmed the structure of the product.

[0747] UPLC: Rt: 1.15min, m / z: 293.8 [M+1]; purity (254): 90%; 1 H NMR(300MHz,DMSO-d6)δ14.80(s,1H),13.28(s,1H),8.29(s,1H),4.44(s,2H),3.89(d,J=7.1Hz,2H), 3.66(t,J=5.9Hz,2H), 2.78(t,J=5.9Hz,2H), 1.20–1.03(m,1H), 0.58–0.43(m,2H), 0.37–0.21(m,2H).

[0748] Scheme 4, Reaction 5: 3-{[(2E)-3-[(4-fluorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl] Carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropyl methyl ester

[0749] 6-[(Cyclopropylmethoxy)carbonyl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxylic acid (0.036 g, 0.122 mmol, 1.0 eq) and HATU (0.046 g, 0.122 mmol, 1.0 eq) were dissolved in anhydrous DMF (0.4 mL). Next, N,N-diisopropylethylamine (0.085 ml, 0.49 mmol, 4.0 eq) was added and the yellow mixture was stirred for 10 min. [(1E)-3-aminoprop-1-en-1-yl](4-fluorophenyl)imino-λ 6 -thioketone dihydrochloride (0.033 g, 0.11 mmol, 0.9 eq), and the mixture was stirred at room temperature for 2 h. The reaction mixture was distributed between water and DCM, and the organic layer was collected, washed with saturated NaHCO3 solution, saturated NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC, eluted with DCM / MeOH 10% to give 3-{[(2E)-3-[(4-fluorophenyl)(imino)oxo-λ as a yellow solid. 6 -thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester (0.005 g, Y: 7%).

[0750] Rt: 2.03 min, m / z = 489.14 [M+1]; purity (254): 90.3%; 1 H NMR(400MHz,DMSO-d6)δ12.48(s,1H),10.07–9.95(m,1H),8.14(s,1H),7.96–7.8 8(m,2H),7.46–7.37(m,2H),6.80(dt,J=15.0,4.6Hz,1H),6.56–6.47(m,1H),4.67 (s,1H),4.42–4.33(m,2H),4.18–4.12(m,2H),3.89(d,J=7.1Hz,2H),3.66–3.59(m ,2H),2.70–2.64(m,2H),1.15–1.07(m,1H),0.55–0.46(m,2H),0.32–0.24(m,2H).

[0751] The title compounds of Examples 69-98 and 178-184 were prepared by methods analogous to those described in Example 67 or 68.

[0752] Example 69: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, 7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropyl methyl ester

[0753] Purity: 95.6% (254 nm); RT = 1.94 min, m / z = 471.94 [M+1] 470.20 [M-1]; 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.96 (t, J = 6.1 Hz, 1H), 8.15 (s, 1H), 7.91–7.82 (m, 2H), 7.78–7.69 (m, 1H), 7.69–7.58 (m, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.67 (dt, J = 15.0, 1.8 Hz, 1H), 4.37 (s, 2H), 4.24–4.12 (m, 2H), 3.88 (d, J = 7.1 Hz, 2H), 3.72–3.53 (m, 2H), 2.73–2.62 (m, 2H), 1.19–1.03 (m, 1H), 0.55–0.44 (m, 2H), 0.32–0.21 (m, 2H).

[0754] Example 70: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, 7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid cyclobutyl ester

[0755] Purity: 97.9% (254 nm); RT = 1.97 min, m / z = 472.20 [M+1] 469.91 [M-1]; 1 H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.96 (t, J = 5.9 Hz, 1H), 8.13 (s, 1H), 7.90–7.80 (m, 2H), 7.79–7.68 (m, 1H), 7.68–7.56 (m, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.66 (dt, J = 15.1, 1.8 Hz, 1H), 4.92–4.79 (m, 1H), 4.48–4.25 (m, 2H), 4.24–4.13 (m, 2H), 3.68–3.52 (m, 2H), 2.73–2.62 (m, 2H), 2.30–2.18 (m, 2H), 2.09–1.94 (m, 2H), 1.72 (q, J = 10.4 Hz, 1H), 1.64–1.48 (m, 1H).

[0756] Example 71: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, 7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid (5-methyl-1,3,4-oxadiazol-2-yl) methyl ester

[0757] Purity: 99.0% (254 nm); RT = 1.81 min, m / z = 514.18 [M+1] 512.21 [M-1]; 11H NMR (300 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.95 (t, J = 5.9 Hz, 1H), 8.15 (s, 1H), 7.92–7.80 (m, 2H), 7.79–7.68 (m, 1H), 7.64 (dd, J = 8.2, 6.6 Hz, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.66 (d, J = 15.2 Hz, 1H), 5.30 (s, 2H), 4.40 (s, 2H), 4.18 (t, J = 4.9 Hz, 2H), 3.64 (s, 2H), 2.70 (s, 1H).

[0758] Example 72: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, 7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid 1,1,1-trifluoropropan-2-yl ester

[0759] Purity: 97.5% (254 nm); RT = 2.70 min, m / z = 512.00 [M - 1]; 1 1H NMR (300 MHz, DMSO-d6) δ 12.52 (s, 1H), 9.97 (d, J = 6.0 Hz, 1H), 8.16 (s, 1H), 7.91–7.80 (m, 2H), 7.79–7.69 (m, 1H), 7.64 (dd, J = 8.2, 6.6 Hz, 2H), 6.95 (dt, J = 15.2, 4.3 Hz, 1H), 6.66 (d, J = 15.1 Hz, 1H), 5.36 (p, J = 6.8 Hz, 1H), 4.48–4.32 (m, 2H), 4.25–4.09 (m, 2H), 3.73–3.57 (m, 2H), 2.77–2.64 (m, 2H), 1.38 (d, J = 6.6 Hz, 3H). 1H NMR (300 MHz, DMSO-d6) δ 12.52 (s, 1H), 9.97 (d, J = 6.0 Hz, 1H), 8.16 (s, 1H), 7.91–7.80 (m, 2H), 7.79–7.69 (m, 1H), 7.64 (dd, J = 8.2, 6.6 Hz, 2H), 6.95 (dt, J = 15.2, 4.3 Hz, 1H), 6.66 (d, J = 15.1 Hz, 1H), 5.36 (p, J = 6.8 Hz, 1H), 4.48–4.32 (m, 2H), 4.25–4.09 (m, 2H), 3.73–3.57 (m, 2H), 2.77–2.64 (m, 2H), 1.38 (d, J = 6.6 Hz, 3H).

[0760] Example 73: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, 7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid (2,2-dimethylcyclopropyl) methyl ester

[0761] Purity: 94.5% (254 nm); RT = 2.22 min, m / z = 500.2 [M+1] 498.40 [M-1]; 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.95 (t, J = 5.9 Hz, 1H), 8.15 (s, 1H), 7.90–7.82 (m, 2H), 7.78–7.70 (m, 1H), 7.65 (dd, J = 8.4, 6.9 Hz, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.67 (dt, J = 15.1, 1.8 Hz, 1H), 4.45–4.29 (m, 2H), 4.29–4.13 (m, 3H), 3.88 (dd, J = 11.6, 8.8 Hz, 1H), 3.71–3.56 (m, 2H), 2.74–2.63 (m, 2H), 1.08 (s, 3H), 1.04 (s, 3H), 0.99–0.84 (m, 1H), 0.50 (dd, J = 8.6, 4.3 Hz, 1H), 0.25 (t, J = 4.8 Hz, 1H).

[0762] Example 74: (2,2-Difluorocyclopropyl)methyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl 2-Oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate

[0763] Purity: 99.2% (254 nm); RT = 2.47 min, m / z = 508.41 [M+1] 506.11 [M-1]; 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.96 (t, J = 5.8 Hz, 1H), 8.15 (s, 1H), 7.91–7.81 (m, 2H), 7.76–7.69 (m, 1H), 7.69–7.59 (m, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.67 (dt, J = 15.1, 1.8 Hz, 1H), 4.44–4.31 (m, 2H), 4.25–4.13 (m, 3H), 4.05–3.94 (m, 1H), 3.62 (t, J = 6.7 Hz, 2H), 2.74–2.64 (m, 2H), 2.11 (ddt, J = 20.2, 14.3, 7.4 Hz, 1H), 1.67 (tdd, J = 12.2, 7.8, 4.8 Hz, 1H), 1.53–1.37 (m, 1H).

[0764] Example 75: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, 7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid 1-methoxypropan-2-yl ester

[0765] Purity: 98.0% (254 nm); RT = 2.11 min, m / z = 490.18 [M+1], 487.92 [M-1]; 1 H NMR (300 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.95 (t, J = 5.9 Hz, 1H), 8.14 (s, 1H), 7.96–7.81 (m, 2H), 7.77–7.70 (m, 1H), 7.69–7.55 (m, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.66 (dt, J = 15.1, 1.8 Hz, 1H), 4.86 (td, J = 6.4, 4.1 Hz, 1H), 4.35 (s, 2H), 4.17 (d, J = 5.6 Hz, 2H), 3.61 (t, J = 5.8 Hz, 2H), 3.48–3.36 (m, 2H), 3.26 (s, 3H), 2.71–2.61 (m, 2H), 1.16 (d, J = 6.4 Hz, 3H).

[0766] Example 76: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, 7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid 2-fluoroethyl ester

[0767] Purity: 99.3% (254 nm); RT = 2.04 min, m / z = 464.15 [M+1], 462.12 [M-1]; 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.96 (t, J = 5.9 Hz, 1H), 8.15 (s, 1H), 7.92–7.82 (m, 2H), 7.78–7.70 (m, 1H), 7.65 (dd, J = 8.2, 6.8 Hz, 2H), 6.95 (dt, J = 15.2, 4.4 Hz, 1H), 6.67 (dt, J = 15.1, 1.9 Hz, 1H), 4.72–4.66 (m, 1H), 4.60–4.54 (m, 1H), 4.39 (s, 2H), 4.35–4.31 (m, 1H), 4.25 (dd, J = 4.7, 3.2 Hz, 1H), 4.19 (ddd, J = 6.3, 4.6, 2.0 Hz, 2H), 3.64 (s, 2H), 2.73–2.65 (m, 2H).

[0768] Example 77: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, 2,2-Difluoroethyl 7,8-hexahydro-1,6-naphthyridine-6-carboxylate

[0769] Purity: 99.7% (254 nm); RT = 2.25 min, m / z = 481.93 [M+1], 480.251 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 9.95 (t, J = 5.8 Hz, 1H), 8.16 (s, 1H), 7.93–7.81 (m, 2H), 7.78–7.69 (m, 1H), 7.69–7.56 (m, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.67 (dt, J = 15.0, 1.8 Hz, 1H), 6.45–6.09 (m, 1H), 4.46–4.28 (m, 2H), 4.23–4.14 (m, 2H), 3.65 (s, 2H), 2.75–2.65 (m, 2H).

[0770] Example 78: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, 7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropyl ester

[0771] Purity: 96.3% (254 nm); RT = 2.16 min, m / z = 458.10 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.95 (t, J = 5.9 Hz, 1H), 8.12 (s, 1H), 7.94–7.80 (m, 2H), 7.80–7.68 (m, 1H), 7.68–7.58 (m, 2H), 6.95 (dt, J = 15.2, 4.4 Hz, 1H), 6.66 (dt, J = 15.1, 1.8 Hz, 1H), 4.40–4.26 (m, 2H), 4.22–4.13 (m, 2H), 4.06–3.98 (m, 1H), 3.66–3.48 (m, 2H), 2.72–2.60 (m, 3H), 0.69–0.60 (m, 4H).

[0772] Example 79: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, 7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid 2-oxaspiro[3.5]nonan-7-yl ester

[0773] Purity: 96.4% (254 nm); RT = 2.19 min, m / z = 542.4 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.96 (t, J = 5.8 Hz, 1H), 8.14 (s, 1H), 7.91–7.82 (m, 2H), 7.77–7.69 (m, 1H), 7.69–7.59 (m, 2H), 6.95 (dt, J = 15.2, 4.4 Hz, 1H), 6.66 (dt, J = 15.1, 1.8 Hz, 1H), 4.64–4.53 (m, 1H), 4.40–4.31 (m, 2H), 4.28 (s, 2H), 4.26 (s, 2H), 4.22–4.14 (m, 2H), 3.66–3.53 (m, 2H), 2.72–2.60 (m, 2H), 1.98–1.84 (m, 2H), 1.76–1.56 (m, 4H), 1.51–1.35 (m, 2H).

[0774] Example 80: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, 2-Methoxyethyl 7,8-hexahydro-1,6-naphthyridine-6-carboxylate

[0775] Purity: 98.0% (254 nm); RT = 1.91 min, m / z = 476.10 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.97 (t, J = 5.8 Hz, 1H), 8.14 (s, 1H), 7.93–7.80 (m, 2H), 7.79–7.69 (m, 1H), 7.69–7.56 (m, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.67 (dt, J = 15.1, 1.9 Hz, 1H), 4.37 (s, 2H), 4.27–4.08 (m, 4H), 3.62 (t, J = 5.7 Hz, 2H), 3.58–3.50 (m, 2H), 3.27 (s, 3H), 2.68 (t, J = 5.6 Hz, 2H).

[0776] Example 81: (3S)-oxolan-3-yl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl 2-Oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate

[0777] Purity: 99.0% (254 nm); RT = 1.89 min, m / z = 488.30 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.96 (t, 1H), 8.14 (s, 1H), 7.90–7.81 (m, 2H), 7.77–7.69 (m, 1H), 7.64 (dd, J = 8.4, 6.9 Hz, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.66 (dt, J = 14.9, 1.8 Hz, 1H), 5.22–5.10 (m, 1H), 4.44–4.29 (m, 2H), 4.23–4.13 (m, 2H), 3.84–3.75 (m, 2H), 3.75–3.67 (m, 2H), 3.60 (t, J = 5.9 Hz, 2H), 2.72–2.63 (m, 2H), 2.10 (dt, J = 14.7, 7.4 Hz, 1H), 1.93 (dt, J = 12.4, 5.2 Hz, 1H).

[0778] Example 82: (3R)-oxolan-3-yl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl 2-Oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate

[0779] Purity: 98.9% (254 nm); RT = 1.89 min, m / z = 488.30 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.96 (t, J = 5.9 Hz, 1H), 8.14 (s, 1H), 7.91–7.82 (m, 2H), 7.78–7.69 (m, 1H), 7.69–7.59 (m, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.67 (dt, J = 15.1, 1.8 Hz, 1H), 5.21–5.11 (m, 1H), 4.45–4.28 (m, 2H), 4.25–4.13 (m, 2H), 3.86–3.76 (m, 2H), 3.76–3.68 (m, 2H), 3.61 (t, J = 5.9 Hz, 2H), 2.73–2.63 (m, 2H), 2.11 (dt, 1H), 1.95 (dt, 1H).

[0780] Example 83: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, 7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid 2-(2-oxopiperidin-1-yl)ethyl ester

[0781] Purity: 97.2% (254 nm); RT = 2.17 min, m / z = 543.30 [M+1], 541.16 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.96 (t, J = 6.0 Hz, 1H), 8.13 (s, 1H), 7.90–7.82 (m, 2H), 7.78–7.70 (m, 1H), 7.70–7.58 (m, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.66 (d, J = 15.1 Hz, 1H), 4.35 (s, 2H), 4.26–4.06 (m, 4H), 3.60 (t, J = 5.8 Hz, 2H), 3.56–3.43 (m, 2H), 3.31–3.24 (m, 2H), 2.73–2.61 (m, 2H), 2.23–2.07 (m, 2H), 1.77–1.56 (m, 4H).

[0782] Example 84: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, 7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropyl ester

[0783] Purity: 98.8% (254 nm); RT = 2.22 min, m / z = 486.03 [M+1], 484.30 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.97 (t, J = 5.7 Hz, 1H), 8.14 (s, 1H), 7.91–7.82 (m, 2H), 7.78–7.69 (m, 1H), 7.69–7.58 (m, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.67 (dt, J = 15.2, 1.8 Hz, 1H), 5.02 (tt, J = 5.6, 2.6 Hz, 1H), 4.34 (s, 2H), 4.23–4.11 (m, 2H), 3.59 (t, J = 5.9 Hz, 2H), 2.72–2.61 (m, 3H), 1.86–1.74 (m, 2H), 1.74–1.60 (m, 5H), 1.60–1.46 (m, 2H).

[0784] Example 85: 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2, 5,6,7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid (2,2-dimethylcyclopropyl) methyl ester

[0785] Purity: 94.3% (254 nm); RT = 2.89 min, m / z = 534.16 [M+1], 532.15 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.96 (t, J = 5.9 Hz, 1H), 8.15 (s, 1H), 7.93–7.82 (m, 2H), 7.76–7.67 (m, 2H), 6.98 (dt, J = 15.1, 4.4 Hz, 1H), 6.75–6.64 (m, 1H), 4.37 (s, 2H), 4.30–4.12 (m, 3H), 3.88 (dd, J = 11.6, 8.8 Hz, 1H), 3.71–3.56 (m, 2H), 2.68 (t, J = 5.9 Hz, 2H), 1.08 (s, 3H), 1.04 (s, 3H), 0.98–0.86 (m, 1H), 0.49 (dd, J = 8.6, 4.3 Hz, 1H), 0.25 (t, J = 4.7 Hz, 1H).

[0786] Example 86: 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2, 5,6,7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid (2,2-difluorocyclopropyl) methyl ester

[0787] Purity: 97.4% (254 nm); RT = 2.41 min, m / z = 542.34 [M+1], 540.06 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.96 (t, 1H), 8.15 (s, 1H), 7.93–7.83 (m, 2H), 7.77–7.67 (m, 2H), 6.98 (dt, J = 15.2, 4.4 Hz, 1H), 6.70 (dt, J = 15.0, 1.8 Hz, 1H), 4.38 (s, 2H), 4.28–4.13 (m, 3H), 4.01 (dd, J = 11.9, 8.3 Hz, 1H), 3.63 (d, 2H), 2.74–2.64 (m, 2H), 2.18–2.02 (m, 1H), 1.74–1.60 (m, 1H), 1.53–1.40 (m, 1H).

[0788] Example 87: 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2, 5,6,7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid oxetan-3-yl ester

[0789] Purity: 97.5% (254 nm); RT = 1.66 min, m / z = 508.12 [M+1], 506.27 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 9.95 (t, J = 5.9 Hz, 1H), 8.16 (s, 1H), 7.94–7.81 (m, 2H), 7.79–7.65 (m, 2H), 6.98 (dt, J = 15.2, 4.4 Hz, 1H), 6.70 (dd, J = 15.2, 1.9 Hz, 1H), 5.32 (p, J = 5.7 Hz, 1H), 4.77 (dd, J = 7.5, 6.3 Hz, 2H), 4.52 (dd, J = 7.6, 5.1 Hz, 2H), 4.48 (s, 1H), 4.39–4.29 (m, 1H), 4.23–4.14 (m, 2H), 3.77–3.54 (m, 2H), 2.76–2.69 (m, 2H).

[0790] Example 88: 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2, 5,6,7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropyl methyl ester

[0791] Purity: 99.2% (254 nm); RT = 2.77 min, m / z = 506.10 [M+1], 503.80 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.96 (t, J = 5.8 Hz, 1H), 8.15 (s, 1H), 7.92–7.83 (m, 2H), 7.77–7.67 (m, 2H), 6.98 (dt, J = 15.2, 4.4 Hz, 1H), 6.70 (dt, J = 15.1, 1.9 Hz, 1H), 4.49–4.28 (m, 2H), 4.28–4.12 (m, 2H), 3.89 (d, J = 7.2 Hz, 2H), 3.71–3.54 (m, 2H), 2.74–2.63 (m, 2H), 1.19–1.04 (m, 1H), 0.57–0.44 (m, 2H), 0.34–0.22 (m, 2H).

[0792] Example 89: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, 2-(Furan-2-yl)ethyl 7,8-hexahydro-1,6-naphthyridine-6-carboxylate

[0793] Purity: 95.3% (254 nm); RT = 2.55 min, m / z = 512.16 [M+1], 509.89 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.98 (t, 1H), 8.14 (s, 1H), 7.91–7.82 (m, 2H), 7.74 (t, J = 7.4 Hz, 1H), 7.65 (t, J = 7.6 Hz, 2H), 7.61–7.55 (m, 1H), 7.55–7.48 (m, 1H), 6.96 (dt, J = 15.1, 4.5 Hz, 1H), 6.67 (d, J = 15.1 Hz, 1H), 6.44 (s, 1H), 4.36 (s, 2H), 4.18 (q, J = 6.9, 6.2 Hz, 4H), 3.60 (t, J = 5.9 Hz, 2H), 2.72 (t, J = 6.6 Hz, 2H), 2.70–2.60 (m, 2H).

[0794] Example 90: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, 7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid cyclohexyl ester

[0795] Purity: 99.8% (254 nm); RT = 2.89 min, m / z = 500.20 [M+1], 498.33 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.96 (t, J = 5.9 Hz, 1H), 8.15 (s, 1H), 7.93–7.80 (m, 2H), 7.77–7.68 (m, 1H), 7.68–7.57 (m, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.67 (dt, J = 15.1, 1.8 Hz, 1H), 4.60 (dt, J = 8.3, 4.6 Hz, 1H), 4.36 (s, 2H), 4.27–4.12 (m, 2H), 3.70–3.55 (m, 2H), 2.67 (t, J = 5.7 Hz, 2H), 1.84–1.72 (m, 2H), 1.72–1.60 (m, 2H), 1.53–1.23 (m, 6H).

[0796] Example 91: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, 7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid 1-(2,6-difluorophenyl)ethyl ester

[0797] Purity: 98.5% (254 nm); RT = 2.976 min, m / z = 558.13 [M+1] 556.14 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.94 (t, J = 5.9 Hz, 1H), 8.12 (s, 1H), 7.90–7.80 (m, 2H), 7.79–7.69 (m, 1H), 7.69–7.57 (m, 2H), 7.41 (ddd, J = 15.0, 8.5, 6.5 Hz, 1H), 7.10 (t, J = 8.4 Hz, 2H), 6.95 (dt, J = 15.2, 4.4 Hz, 1H), 6.67 (d, J = 15.2 Hz, 1H), 6.02 (q, J = 6.7 Hz, 1H), 4.49–4.27 (m, 2H), 4.22–4.13 (m, 2H), 3.70–3.51 (m, 2H), 2.74–2.59 (m, 2H), 1.60 (d, J = 6.8 Hz, 3H).

[0798] Example 92: 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2, 5,6,7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid 1-acetylpiperidin-4-yl ester

[0799] Purity: 94.6% (254 nm); RT = 2.14 min, m / z = 577.15 [M+1] 575.08 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.97 (s, 1H), 8.16 (s, 1H), 7.92–7.83 (m, 2H), 7.77–7.68 (m, 2H), 6.98 (dt, J = 15.2, 4.4 Hz, 1H), 6.70 (d, J = 15.2 Hz, 1H), 4.84 (s, 1H), 4.40 (d, J = 22.8 Hz, 2H), 4.19 (t, J = 4.9 Hz, 2H), 3.71–3.53 (m, 4H), 3.51–3.37 (m, 2H), 2.73–2.64 (m, 2H), 2.01 (s, 3H), 1.91–1.80 (m, 1H), 1.80–1.70 (m, 1H), 1.65–1.56 (m, 1H), 1.56–1.44 (m, 1H).

[0800] Example 93: 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2, 2-Fluoroethyl 5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate

[0801] Purity: 99.0% (254 nm); RT = 2.39 min, m / z = 498.10 [M+1] 496.10 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.96 (t, J = 5.7 Hz, 1H), 8.15 (s, 1H), 7.91–7.83 (m, 2H), 7.75–7.68 (m, 2H), 6.98 (dt, J = 15.1, 4.4 Hz, 1H), 6.70 (dt, J = 15.1, 1.8 Hz, 1H), 4.72–4.65 (m, 1H), 4.61–4.54 (m, 1H), 4.50–4.35 (m, 2H), 4.35–4.30 (m, 1H), 4.28–4.22 (m, 1H), 4.22–4.13 (m, 2H), 3.71–3.58 (m, 2H), 2.75–2.64 (m, 2H).

[0802] Example 94: 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2, 5,6,7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid 1-methoxypropan-2-yl ester

[0803] Purity: % (254 nm); RT = 1.98 min, m / z = 523.80 [M+1], 522.20 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.95 (t, J = 5.9 Hz, 1H), 8.14 (s, 1H), 7.92–7.83 (m, 2H), 7.76–7.66 (m, 2H), 6.98 (dt, J = 15.1, 4.3 Hz, 1H), 6.70 (dt, J = 15.0, 1.8 Hz, 1H), 4.86 (td, J = 6.4, 4.0 Hz, 1H), 4.36 (s, 2H), 4.19 (dq, J = 4.6, 2.2 Hz, 2H), 3.61 (t, J = 5.9 Hz, 2H), 3.46–3.35 (m, 2H), 3.26 (s, 3H), 2.71–2.63 (m, 2H), 1.16 (d, J = 6.5 Hz, 3H).

[0804] Example 95: 3-{[(2E)-3-[(5-chloropyridin-2-yl)sulfonyl]prop-2-en-1-yl]carbamoyl}-2- Oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropyl methyl ester

[0805] Purity: 90.5% (254 nm); RT = 2.42 min, m / z = 507.14 [M+1], 505.20 [M-1]; 11H NMR (300 MHz, DMSO-d6) δ 12.49 (s, 1H), 10.00 (d, J = 5.9 Hz, 1H), 8.86 (dd, J = 2.5, 0.7 Hz, 1H), 8.28 (dd, J = 8.4, 2.4 Hz, 1H), 8.16 (s, 1H), 8.08 (dd, J = 8.5, 0.7 Hz, 1H), 7.06 (dt, J = 15.3, 4.4 Hz, 1H), 6.80–6.66 (m, 1H), 4.38 (s, 2H), 4.23 (s, 2H), 3.88 (d, J = 7.2 Hz, 2H), 3.63 (s, 2H), 2.69 (s, 2H), 1.10 (dd, J = 13.4, 5.8 Hz, 1H), 0.58–0.45 (m, 2H), 0.34–0.23 (m, 2H).

[0806] Example 96: 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2, 2,2-Difluoroethyl 5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate

[0807] Purity: 89.3% (254 nm); RT = 2.89 min, m / z = 516.10 [M+1], 514.38 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 10.00 (s, 1H), 8.14 (s, 1H), 7.91–7.84 (m, 2H), 7.76–7.68 (m, 2H), 6.98 (dt, J = 15.2, 4.4 Hz, 1H), 6.70 (d, J = 15.1 Hz, 1H), 6.27 (t, J = 54.6 Hz, 1H), 4.46–4.29 (m, 4H), 4.19 (s, 2H), 3.65 (s, 2H), 2.75–2.68 (m, 2H).

[0808] Example 97: 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2, 5,6,7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid 2,2,2-trifluoroethyl ester

[0809] Purity: 92.1% (254 nm); RT = 2.43 min, m / z = 534.25 [M+1] 532.24 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 9.98 (s, 1H), 8.16 (s, 1H), 7.91–7.83 (m, 2H), 7.75–7.67 (m, 2H), 6.98 (dt, J = 15.1, 4.4 Hz, 1H), 6.69 (d, J = 15.1 Hz, 1H), 4.75 (q, J = 9.0 Hz, 2H), 4.48–4.37 (m, 2H), 4.22–4.15 (m, 2H), 3.70–3.62 (m, 2H), 2.74–2.69 (m, 2H).

[0810] Example 98: 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropyl methyl ester

[0811] Purity: 87.0% (254 nm); RT = 2.09 min, m / z = 519.20 [M+1], 517.30 [M-1]; 1 1H NMR (300 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.99 (s, 1H), 8.14 (s, 1H), 7.70–7.58 (m, 2H), 7.35 (t, J = 8.6 Hz, 1H), 6.77 (dt, J = 14.9, 4.6 Hz, 1H), 6.49 (d, J = 15.0 Hz, 1H), 4.60 (s, 1H), 4.38 (s, 2H), 4.13 (d, J = 5.8 Hz, 2H), 3.92 (s, 3H), 3.88 (d, J = 7.1 Hz, 2H), 3.63 (s, 2H), 2.69 (d, J = 6.4 Hz, 2H), 1.17–1.06 (m, 1H), 0.56–0.46 (m, 2H), 0.33–0.23 (m, 2H).

[0812] Example 99: N6-tert-butyl-N3-[(2E)-3-(4-chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5, Preparation of 6,7,8-hexahydro-1,6-naphthyridine-3,6-dicarboxamide (Scheme 5)

[0813] Scheme 5, Reaction 1: 4-Nitrophenyl N-tert-butylcarbamate

[0814] Nitrophenyl chloroformate (0.14 g, 0.68 mmol, 1.0 eq) was added to a solution of tert-butylamine (0.072 ml, 0.68 mmol, 1.0 eq) and pyridine (0.083 ml, 1.03 mmol, 1.5 eq) in DCM (12.4 ml, 0.4 M) in batches at 0 ° C. The reaction mixture was allowed to reach room temperature and stirred for 2 h. The reaction was diluted with DCM, washed with 1 M HCl and saturated NaHCO3 aqueous solution, dried over MgSO4, filtered and then concentrated under reduced pressure to obtain 4-nitrophenyl N-tert-butylcarbamate (0.137 g, Y: 70%) as a light yellow solid, which was used for the next step without any further purification. 1 H NMR (DMSO-d6, 400 MHz) confirmed the structure and purity of the product.

[0815] 1 H NMR (400MHz, DMSO-d6) δ8.30–8.22(m,2H),7.88(s,1H),7.42–7.33(m,2H),1.31(s,9H).

[0816] Scheme 5, Reaction 2: N6-tert-butyl-N3-[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo- 1,2,5,6,7,8-Hexahydro-1,6-naphthyridine-3,6-dicarboxamide

[0817] N-[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide hydrochloride (0.04 g, 0.086 mmol, 1.0 eq) was dissolved in THF (1 mL), NaHCO aqueous solution (0.014 g, 0.17 mmol, 2.0 eq), and a solution of 4-nitrophenyl N-tert-butylcarbamate (0.027 g, 0.094 mmol, 1.1 eq) in anhydrous THF (0.86 ml, 0.1 M) was added and the reaction was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and dissolved in DCM. The organic layer was washed with saturated NaHCO aqueous solution until the yellow color disappeared. The organic layer was collected, dried over MgSO, filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC eluting with DCM / MeOH 10% to give N6-tert-butyl-N3-[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3,6-dicarboxamide (0.005 g, Y: 12%) as a white solid.

[0818] Rt = 2.55 min, m / z = 507.10 [M+1], 505.10 [M-1]; purity: 99.6% (254 nm); 1H NMR (400MHz, DMSO-d6) δ12.44(s,1H),9.99(s,1H),8.07(s,1H),7.94–7.82(m,2H),7.78–7.66(m,2H),6.98(dt,J=15.1,4.3Hz,1 H), 6.75–6.61 (m, 1H), 5.89 (s, 1H), 4.26 (s, 2H), 4.19 (d, J = 5.0Hz, 2H), 3.53 (t, J = 5.8Hz, 2H), 2.62 (t, J = 5.6Hz, 2H), 1.26 (s, 9H).

[0819] The title compounds of Examples 100 and 101 were prepared by methods analogous to those described in Example 99.

[0820] Example 100: N3-[(2E)-3-(4-chlorophenylsulfonyl)prop-2-en-1-yl]-N6-(cyclopropylmethyl)-2-oxo 1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3,6-dicarboxamide

[0821] Purity: 99.6 (254 nm); RT = 3.24 min, m / z = 505.1 [M+1]; 1 H NMR(400MHz,DMSO-d6)δ12.29(s,1H),9.99(s,1H),8.07(s,1H),7.92–7.82( m,2H),7.77–7.65(m,2H),6.98(dt,J=15.1,4.4Hz,1H),6.75–6.65(m,2H),4. 30(s,2H),4.22–4.15(m,2H),3.57(t,J=5.8Hz,2H),2.92(t,J=6.1Hz,2H),2. 63(t,J=5.8Hz,2H),0.98–0.86(m,1H),0.41–0.33(m,2H),0.18–0.10(m,2H).

[0822] Example 101: N3-[(2E)-3-(4-chlorophenylsulfonyl)prop-2-en-1-yl]-N6-cyclopropyl-2-oxo-1,2, 5,6,7,8-Hexahydro-1,6-naphthyridine-3,6-dicarboxamide

[0823] Purity: 98.4% (254nm) RT = 2.11min, m / z = 491.10 [M+1], 489.23 [M-1]; 1H NMR (400MHz, DMSO-d6) δ12.45(s,1H),9.98(s,1H),8.05(s,1H),7.92–7.82(m,2H),7.76–7.67(m,2H),6.98(dt,J=15.1,4.4Hz,1H),6.74–6.64 (m,2H),4.25(s,2H),4.18(dq,J=4.3,2.1Hz,2H),3.53(t,J=5.8Hz,2H),2.61(t,J=5.8Hz,2H),0.55(td,J=6.9,4.6Hz,2H),0.42–0.32(m,2H).

[0824] Example 102: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(3,3-difluorocyclobutanecarbonyl)-2-oxo Preparation of 1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide (Scheme 6, Reaction 1)

[0825] 4,4-difluorocyclohexanecarboxylic acid (13mg, 0.08mmol, 1.1eq) was dissolved in DMF (0.8mL). Then, N,N-diisopropylethylamine (0.051mL, 0.29mmol, 4eq) and T3P (50% w / w solution in DMF (0.092mL, 0.15mmol, 2eq)) were added and the solution was shaken for 10min, followed by addition of N-[(2E)-3-(benzenesulfonyl)prop-2-ene-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide (30mg, 0.07mmol, 1eq). The reaction mixture was shaken for another 2h, and the control performed by UPLC showed the consumption of the starting material. Next, saturated NaHCO3 solution and DCM were added, the two phases were separated, the organic phase was collected and concentrated to dryness. The residue was purified by preparative TLC eluting with DCM / MeOH 6%. The desired product was collected and concentrated to dryness to give N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(3,3-difluorocyclobutanecarbonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide (1.68 mg, Y: 4%) as a white solid.

[0826] Rt = 2.24 min, m / z = 492.17 [M+1], 490.16 [M-1]; purity: 95% (254 nm); 1H NMR (400MHz, DMSO-d6) δ12.47(s,1H),9.96(s,1H),8.17(d,J=13.6Hz,1H),7.86(dd, J=7.3,1.7Hz,2H),7.76–7.70(m,1H),7.67–7.61(m,2H),6.95(dt,J=15.3,4.4Hz,1H ),6.66(dd,J=15.2,2.6Hz,1H),4.43(d,J=6.2Hz,2H),4.19(s,2H),3.72(t,J=5.9Hz ,1H),3.62(t,J=5.8Hz,1H),2.89–2.75(m,4H),2.75–2.70(m,2H),2.69–2.62(m,1H).

[0827] Example 103: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(2-methoxyethanesulfonyl)-2-oxo Substituted-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide (Scheme 6, reaction 2)

[0828] N-[(2E)-3-(benzenesulfonyl)prop-2-ene-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide (30mg, 0.072mmol, 1eq) is dissolved in DMF (0.72mL), and N,N-diisopropylethylamine (0.038mL, 0.22mmol, 3eq) and 2-methoxyethane-1-sulfonyl chloride (0.010mL, 0.087mmol, 1.2eq) are added. The reaction mixture is stirred at room temperature for 2h. LCMS shows that the starting material is completely consumed. Next, the mixture is poured into water and extracted with DCM. The organic phase is collected, concentrated to half of its volume, and passed through a silica NH2 column, eluted with MeOH. The filtrate was collected and concentrated under reduced pressure and purified by preparative TLC eluting with DCM / MeOH 6% to give N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(2-methoxyethanesulfonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide (4.5 mg, Y: 12%) as a white solid.

[0829] RT = 2.07 min, m / z = 496.10 [M+1], 493.93 [M-1]; purity: 94% (254 nm); 1H NMR(400MHz,DMSO-d6)δ12.52(s,1H),9.96(s,1H),8.13(s,1H),7.90–7.82(m, 2H),7.76–7.70(m,1H),7.68–7.61(m,2H),6.95(dt,J=15.1,4.4Hz,1H),6.67(d t,J=15.0,1.9Hz,1H),4.22(s,2H),4.21–4.16(m,2H),3.65(t,J=5.9Hz,2H),3 .47(t,J=5.9Hz,2H), 3.41(t,J=5.9Hz,2H), 3.23(s,3H), 2.75(t,J=5.9Hz,2H).

[0830] Example 104: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-[(pyridin-3-yl)methyl]- 1,2,5,6,7,8-Hexahydro-1,6-naphthyridine-3-carboxamide (Scheme 6, Reaction 3)

[0831] N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide (0.03 g, 0.07 mmol, 1.0 eq) was dissolved in DMF (0.24 ml, 0.3 M). Next, Na2CO3 (0.022 g, 0.21 mmol, 3.0 eq) and 3-(bromomethyl)pyridine (0.021 g, 0.08 mmol, 1.0 eq) were added and the reaction was stirred at room temperature for 4 h. Water was added to the reaction mixture and the solid precipitate was filtered, collected and then dissolved in minimal DCM and purified by preparative TLC eluting with DCM / MeOH 5% to give N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-[(pyridin-3-yl)methyl]-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide (14 mg, Y: 42%) as a white solid.

[0832] Rt = 1.75 min, m / z = 464.96 [M+1]; purity: 97.54% (210 nm); 1H NMR(400MHz, DMSO-d6)12.42(s,1H),10.02(s,1H),8.53(d,J=2.2Hz,1H),8.49(dd,J =4.8,1.7Hz,1H),8.01(s,1H),7.86(t,J=1.3Hz,1H),7.84(d,J=1.6Hz,1H),7.77–7.6 9(m,2H),7.67–7.61(m,2H),7.40–7.35(m,1H),6.94(dt,J=15.1,4.4Hz,1H),6.65(dt ,J=15.0,1.8Hz,1H),4.21–4.13(m,2H),3.68(s,2H),3.39(s,2H),2.71–2.63(m,4H).

[0833] The title compounds of Examples 105-125 and 185 were prepared by methods analogous to those described in Examples 102-104.

[0834] Example 105: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(3-methoxypropanoyl)-2-oxo- 1,2,5,6,7,8-Hexahydro-1,6-naphthyridine-3-carboxamide

[0835] Purity: 96.0 (254 nm); RT = 2.26 min, m / z = 460.48 [M+1], 458.16 [M-1]; 1 H NMR (300MHz, DMSO-d6)12.48(s,1H),9.95(t,J=5.9Hz,1H),8.15(d,J=6.7Hz,1H) ,7.90–7.81(m,2H),7.78–7.69(m,1H),7.64(dd,J=8.2,6.6Hz,2H),6.95(dt,J=15 .1,4.3Hz,1H),6.66(d,J=15.6Hz,1H),4.45(d,J=25.7Hz,2H),4.18(s,2H),3.69 (t,J=5.8Hz,2H),3.56(d,J=2.7Hz,2H),3.21(d,J=6.1Hz,3H),2.77–2.58(m,4H).

[0836] Example 106: 6-[2-(Adamantane-1-yl)acetyl]-N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]- 2-Oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0837] Purity: 99.3% (254 nm); RT = 1.50 min, m / z = 550.3 [M+1]; 11H NMR (300 MHz, DMSO-d6) δ 12.46 (s, 1H), 9.96 (t, J = 5.8 Hz, 1H), 8.17 (d, J = 22.4 Hz, 1H), 7.92–7.79 (m, 2H), 7.80–7.68 (m, 1H), 7.69–7.57 (m, 2H), 6.95 (dt, J = 15.2, 4.3 Hz, 1H), 6.73–6.58 (m, 1H), 4.48 (d, J = 37.8 Hz, 2H), 4.26–4.07 (m, 2H), 3.72 (dt, J = 11.2, 5.7 Hz, 2H), 2.77–2.57 (m, 2H), 2.17 (d, J = 2.8 Hz, 2H), 1.99–1.78 (m, 4H), 1.71–1.47 (m, 11H).

[0838] Example 107: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-[(1r,4r)-4-methoxy [cyclohexanecarbonyl]-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0839] Purity: 98.7% (254 nm); RT = 1.97 min, m / z = 514.4 [M+1]; 1 1H NMR (300 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.96 (t, J = 5.8 Hz, 1H), 8.17 (d, J = 25.3 Hz, 1H), 7.97–7.80 (m, 2H), 7.80–7.52 (m, 3H), 6.96 (dt, J = 15.2, 4.4 Hz, 1H), 6.66 (d, J = 15.1 Hz, 1H), 4.55 (s, 1H), 4.39 (s, 1H), 4.18 (d, J = 6.9 Hz, 2H), 3.70 (dt, J = 12.1, 6.0 Hz, 2H), 3.23 (s, 3H), 3.14–2.99 (m, 1H), 2.74 (s, 1H), 2.66–2.57 (m, 2H), 2.09–1.91 (m, 2H), 1.79–1.58 (m, 2H), 1.53–1.27 (m, 2H), 1.28–1.05 (m, 2H).

[0840] Example 108: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(4,4-difluorocyclohexanecarbonyl)-2-oxo 1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0841] Purity: 94% (254 nm); RT = 1.90 min, m / z = 520.24 [M+1], 518.36 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 10.14–9.77 (m, 1H), 8.24–8.07 (m, 1H), 7.93–7.83 (m, 2H), 7.77–7.57 (m, 3H), 7.14–6.80 (m, 1H), 6.66 (d, J = 15.5 Hz, 1H), 4.58 (s, 1H), 4.41 (s, 1H), 4.19 (s, 2H), 3.83–3.62 (m, 2H), 2.95–2.74 (m, 2H), 2.12–1.69 (m, 6H), 1.64–1.51 (m, 2H), 1.24 (s, 1H).

[0842] Example 109: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-cyclopropanecarbonyl-2-oxo-1,2,5, 6,7,8-Hexahydro-1,6-naphthyridine-3-carboxamide

[0843] Purity: 96.0% (254 nm); RT = 1.33 min, m / z = 442.23 [M+1], 440.16 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.96 (t, J = 6.0 Hz, 1H), 8.16 (d, J = 18.4 Hz, 1H), 7.90–7.83 (m, 2H), 7.78–7.70 (m, 1H), 7.65 (dd, J = 8.4, 7.0 Hz, 2H), 6.96 (dt, J = 15.2, 4.4 Hz, 1H), 6.67 (dt, J = 15.1, 1.8 Hz, 1H), 4.73 (s, 1H), 4.42 (s, 1H), 4.20 (d, J = 5.6 Hz, 2H), 3.92 (s, 1H), 3.71 (s, 1H), 2.78 (s, 1H), 2.64 (s, 1H), 2.07 (d, J = 8.4 Hz, 1H), 1.37–1.27 (m, 2H), 0.86 (t, J = 6.0 Hz, 1H).

[0844] Example 110: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-{bicyclo[2.2.1]heptane-1-carbonyl}- 2-Oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0845] Purity: 97.7% (254 nm); RT = 1.99 min, m / z = 496.20 [M+1], 494.20 [M-1]; 11H NMR (300 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.96 (t, J = 5.9 Hz, 1H), 8.37–8.09 (m, 1H), 7.86 (d, J = 7.6 Hz, 2H), 7.80–7.53 (m, 3H), 6.95 (dt, J = 15.1, 4.3 Hz, 1H), 6.67 (d, J = 15.3 Hz, 1H), 4.48 (s, 2H), 4.18 (d, J = 5.5 Hz, 2H), 3.74 (t, J = 5.5 Hz, 2H), 2.64 (t, J = 5.6 Hz, 2H), 2.11 (s, 1H), 1.93–1.74 (m, 2H), 1.73–1.51 (m, 5H), 1.44–1.27 (m, 2H), 1.14 (t, J = 7.2 Hz, 1H).

[0846] Example 111: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(1-cyanocyclobutanecarbonyl)-2-oxo 1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0847] Purity: 97.0 (254 nm); RT = 2.19 min, m / z = 481.18 [M+1], 479.19 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 9.96 (s, 1H), 8.24 (d, J = 43.4 Hz, 1H), 7.91–7.82 (m, 2H), 7.77–7.69 (m, 1H), 7.68–7.59 (m, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.67 (d, J = 15.1 Hz, 1H), 4.48 (s, 1H), 4.41 (s, 1H), 4.19 (t, J = 5.2 Hz, 2H), 3.77 (d, J = 6.0 Hz, 1H), 3.62 (d, J = 6.1 Hz, 1H), 2.83–2.62 (m, 6H), 2.20–2.10 (m, 1H), 1.97–1.81 (m, 1H).

[0848] Example 112: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(2-phenyl-2H-1,2,3- Triazole-4-carbonyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0849] Purity: 94% (254 nm); RT = 2.24 min, m / z = 545.19 [M+1], 543.18 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 10.00 (s, 1H), 8.44 (d, J = 18.4 Hz, 1H), 8.20 (d, J = 22.4 Hz, 1H), 8.09 (t, J = 7.4 Hz, 2H), 7.85 (t, J = 8.5 Hz, 2H), 7.72 (d, J = 7.6 Hz, 1H), 7.69–7.58 (m, 4H), 7.51 (t, J = 7.5 Hz, 1H), 7.00–6.86 (m, 1H), 6.77–6.57 (m, 1H), 4.92 (s, 1H), 4.65 (s, 1H), 4.22–4.15 (m, 2H), 4.14–4.05 (m, 1H), 3.98–3.83 (m, 1H), 2.90–2.81 (m, 1H), 2.82–2.71 (m, 1H).

[0850] Example 113: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(oxacyclopentane-3-carbonyl)- 1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0851] Purity: 99% (254 nm); RT = 1.68 min, m / z = 472.20 [M+1], 470.31 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.97 (s, 1H), 8.17 (d, J = 19.5 Hz, 1H), 7.91–7.83 (m, 2H), 7.78–7.69 (m, 1H), 7.68–7.61 (m, 2H), 6.96 (dt, J = 15.1, 4.4 Hz, 1H), 6.74–6.58 (m, 1H), 4.55 (d, J = 3.8 Hz, 1H), 4.43 (s, 1H), 4.22–4.14 (m, 2H), 3.89 (q, J = 7.9 Hz, 1H), 3.71 (ddt, J = 13.6, 9.9, 6.7 Hz, 5H), 3.42 (dt, J = 14.1, 7.3 Hz, 1H), 2.77–2.71 (m, 1H), 2.66–2.60 (m, 1H), 2.12–1.90 (m, 2H).

[0852] Example 114: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-{3-methylbicyclo[1.1.1]pentane-1-yl Carbonyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0853] Purity: 99.4% (254 nm); RT = 2.31 min, m / z = 482.21 [M+1]; 11H NMR (300 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.96 (q, J = 6.4 Hz, 1H), 8.37–8.04 (m, 1H), 7.92–7.80 (m, 2H), 7.78–7.55 (m, 3H), 7.04–6.85 (m, 1H), 6.67 (dd, J = 15.1, 1.9 Hz, 1H), 4.55 (s, 1H), 4.37 (s, 1H), 4.18 (d, J = 5.0 Hz, 2H), 3.79 (t, J = 5.7 Hz, 1H), 3.65 (t, J = 5.9 Hz, 1H), 2.76–2.56 (m, 2H), 1.97 (s, 6H), 1.16 (d, J = 2.4 Hz, 3H).

[0854] Example 115: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(1-methylcyclobutanecarbonyl)-2-oxo 1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0855] Purity: 98.9% (254 nm); RT = 2.16 min, m / z = 470.22 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.97 (t, J = 5.9 Hz, 1H), 8.18 (d, J = 27.0 Hz, 1H), 7.89–7.83 (m, 2H), 7.78–7.69 (m, 1H), 7.69–7.59 (m, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.67 (dt, J = 15.0, 1.8 Hz, 1H), 4.46–4.23 (m, 2H), 4.19 (ddd, J = 6.3, 4.4, 2.0 Hz, 2H), 3.76–3.42 (m, 2H), 2.80–2.56 (m, 2H), 2.46–2.26 (m, 2H), 2.03–1.78 (m, 3H), 1.69–1.53 (m, 1H), 1.45–1.23 (m, 3H).

[0856] Example 116: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(4-cyclopropyl-1,3-thiazole-2-carbonyl)- 2-Oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0857] Purity: 92.2% (254 nm); RT = 2.61 min, m / z = 525.15 [M+1], 523.22 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 9.98 (s, 1H), 8.14 (d, J = 45.1 Hz, 1H), 8.01–7.81 (m, 2H), 7.77–7.69 (m, 1H), 7.67–7.58 (m, 3H), 6.96 (dt, J = 15.1, 4.4 Hz, 1H), 6.67 (d, J = 15.2 Hz, 1H), 5.28–5.11 (m, 1H), 4.65–4.55 (m, 1H), 4.44–4.29 (m, 1H), 4.26–4.13 (m, 2H), 3.95–3.81 (m, 1H), 2.92–2.74 (m, 2H), 2.22–2.11 (m, 1H), 1.02–0.93 (m, 2H), 0.91–0.80 (m, 2H).

[0858] Example 117: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(2-cyclopropylacetyl)-2-oxo- 1,2,5,6,7,8-Hexahydro-1,6-naphthyridine-3-carboxamide

[0859] Purity: 97.9% (254 nm); RT = 1.99 min, m / z = 456.22 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.96 (t, J = 5.9 Hz, 1H), 8.15 (d, J = 5.1 Hz, 1H), 7.92–7.81 (m, 2H), 7.79–7.69 (m, 1H), 7.69–7.54 (m, 2H), 6.95 (dt, J = 15.2, 4.4 Hz, 1H), 6.72–6.60 (m, 1H), 4.44 (d, J = 19.8 Hz, 2H), 4.18 (t, J = 4.7 Hz, 2H), 3.68 (dt, J = 15.1, 5.8 Hz, 2H), 2.81–2.55 (m, 2H), 2.33 (dd, J = 9.7, 6.7 Hz, 2H), 1.05–0.87 (m, 1H), 0.51–0.35 (m, 2H), 0.19–0.03 (m, 2H).

[0860] Example 118: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(1-phenylpyrrolidine-3-carbonyl)- 1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0861] Purity: 95.9% (254 nm); RT = 2.73 min, m / z = 547.20 [M+1]; 11H NMR (300 MHz, DMSO-d6) δ 12.51 (s, 1H), 9.98 (t, 1H), 8.18 (d, J = 17.5 Hz, 1H), 7.93–7.81 (m, 2H), 7.78–7.69 (m, 1H), 7.69–7.58 (m, 2H), 7.15 (t, J = 7.7 Hz, 2H), 6.96 (dt, J = 15.1, 4.4 Hz, 1H), 6.72–6.49 (m, 4H), 4.64 (s, 1H), 4.45 (s, 1H), 4.28–4.09 (m, 2H), 3.87–3.78 (m, 1H), 3.78–3.68 (m, 1H), 3.67–3.54 (m, 1H), 3.49 (t, J = 8.5 Hz, 1H), 3.30–3.18 (m, 3H), 2.85–2.76 (m, 1H), 2.70–2.61 (m, 1H), 2.25–1.99 (m, 2H).

[0862] Example 119: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, 7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid 2-methylpropyl ester

[0863] Purity: 96.9% (254 nm); RT = 2.58 min, m / z = 474.2 [M+1], 472.19 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.96 (t, J = 6.0 Hz, 1H), 8.16 (s, 1H), 7.92–7.80 (m, 2H), 7.78–7.69 (m, 1H), 7.69–7.59 (m, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.67 (dt, J = 15.1, 1.8 Hz, 1H), 4.50–4.27 (m, 2H), 4.24–4.13 (m, 2H), 3.82 (d, J = 6.6 Hz, 2H), 3.71–3.53 (m, 2H), 2.69–2.65 (m, 2H), 1.88 (dq, J = 13.3, 6.6 Hz, 1H), 0.91 (d, J = 6.7 Hz, 6H).

[0864] Example 120: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(3,3-dimethylbutanoyl)-2-oxo 1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0865] Purity: 91.9% (254 nm); RT = 2.34 min, m / z = 472.24 [M+1], 470.47 [M-1]; 11H NMR (300 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.95 (t, J = 5.9 Hz, 1H), 8.16 (d, J = 19.0 Hz, 1H), 7.92–7.82 (m, 2H), 7.77–7.69 (m, 1H), 7.64 (dd, J = 8.2, 6.6 Hz, 2H), 6.95 (dt, J = 15.2, 4.4 Hz, 1H), 6.66 (d, J = 15.1 Hz, 1H), 4.54 (s, 1H), 4.42 (s, 1H), 4.18 (s, 2H), 3.72 (d, J = 6.1 Hz, 2H), 2.66 (d, J = 30.6 Hz, 2H), 2.30 (d, J = 4.0 Hz, 2H), 0.98 (d, J = 11.6 Hz, 9H).

[0866] Example 121: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-[(1-methyl-1H-indazol-4-yl)methyl 2-Oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0867] Purity: 82.1% (254 nm); RT = 3.42 min, m / z = 518.18 [M+1], 516.17 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 10.02 (s, 1H), 8.18 (d, J = 1.0 Hz, 1H), 7.98 (s, 1H), 7.93–7.82 (m, 2H), 7.77–7.69 (m, 1H), 7.69–7.52 (m, 3H), 7.35 (ddd, J = 8.5, 6.9, 2.2 Hz, 1H), 7.10 (t, J = 5.4 Hz, 1H), 6.94 (dt, J = 15.1, 4.4 Hz, 1H), 6.65 (dt, J = 15.1, 1.9 Hz, 1H), 4.21–4.13 (m, 2H), 4.04 (d, J = 1.2 Hz, 3H), 3.96 (s, 2H), 3.44 (s, 2H), 2.70 (dd, J = 8.5, 4.3 Hz, 4H).

[0868] Example 122: 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6, 7,8-Hexahydro-1,6-naphthyridine-6-carboxylic acid 2-(4-chlorophenyl)ethyl ester

[0869] Purity: 90.0% (254 nm); RT = 2.07 min, m / z = 556.12 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 9.97 (s, 1H), 8.12 (s, 1H), 7.90–7.83 (m, 2H), 7.77–7.69 (m, 1H), 7.64 (tt, J = 6.6, 1.5 Hz, 2H), 7.29 (s, 4H), 6.96 (dt, J = 15.2, 4.4 Hz, 1H), 6.66 (dt, J = 15.1, 1.9 Hz, 1H), 4.31 (s, 2H), 4.25–4.16 (m, 4H), 3.56 (t, J = 5.7 Hz, 2H), 2.90 (t, J = 6.5 Hz, 2H), 2.65–2.59 (m, 2H).

[0870] Example 123: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-[(pyridazin-3-yl)methyl]- 1,2,5,6,7,8-Hexahydro-1,6-naphthyridine-3-carboxamide

[0871] Purity: 96.1% (254 nm); RT = 1.80 min, m / z 465.81 [M+1], 464.04 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) 12.44 (s, 1H), 10.02 (t, J = 5.7 Hz, 1H), 9.16 (dd, J = 4.8, 1.8 Hz, 1H), 8.01 (s, 1H), 7.89–7.83 (m, 2H), 7.77–7.60 (m, 5H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.66 (dt, J = 15.1, 1.8 Hz, 1H), 4.17 (ddd, J = 6.3, 4.5, 1.9 Hz, 2H), 3.98 (s, 2H), 3.47 (s, 2H), 2.72 (dd, J = 12.9, 4.7 Hz, 4H).

[0872] Example 124: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(3-methoxy-3-methylbutanoyl)- 2-Oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0873] Purity: 79.2% (254 nm); RT = 1.93 min, m / z = 488.11 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 9.98 (s, 1H), 8.15 (d, J = 15.8 Hz, 1H), 7.89–7.84 (m, 2H), 7.77–7.71 (m, 1H), 7.68–7.57 (m, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.66 (dd, J = 15.2, 1.9 Hz, 1H), 4.55 (s, 1H), 4.42 (s, 1H), 4.19 (s, 2H), 3.72 (dt, J = 14.2, 5.9 Hz, 2H), 3.08 (d, J = 27.1 Hz, 3H), 2.72 (t, J = 6.9 Hz, 1H), 2.62 (d, J = 5.7 Hz, 1H), 2.57 (d, J = 3.9 Hz, 2H), 1.20 (d, J = 13.5 Hz, 6H).

[0874] Example 125: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(2-phenylcyclopropanecarbonyl)- 1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0875] Purity: 91% (254 nm); RT = 2.21 min, m / z = 518.09 [M+1], 516.04 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 10.06 (s, 1H), 8.12 (s, 1H), 7.88–7.83 (m, 2H), 7.76–7.70 (m, 1H), 7.67–7.61 (m, 2H), 7.31–7.25 (m, 2H), 7.23–7.16 (m, 3H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.70–6.61 (m, 1H), 4.84–4.60 (m, 1H), 4.45 (s, 1H), 4.25–4.06 (m, 2H), 3.89–3.61 (m, 2H), 2.78–2.61 (m, 2H), 2.44 (dt, J = 8.8, 4.9 Hz, 1H), 2.36–2.30 (m, 1H), 1.48–1.36 (m, 1H), 1.29–1.12 (m, 1H).

[0876] Example 126: N-[(2E)-3-(2,4-dichlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2- Dihydropyridine-3-carboxamide

[0877] Purity: 94% (254 nm); Rt = 2.27 min, m / z = 462.83 [M+1], 461.02 [M-1]; 1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 10.04 (t, J = 5.9 Hz, 1H), 8.60 (d, J = 2.9 Hz, 1H), 8.09–8.03 (m, 2H), 7.95 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 8.5, 2.1 Hz, 1H), 7.65–7.60 (m, 2H), 7.50–7.40 (m, 2H), 7.39–7.31 (m, 1H), 7.12 (dt, J = 15.1, 4.4 Hz, 1H), 6.81 (dt, J = 15.1, 1.8 Hz, 1H), 4.33–4.24 (m, 2H).

[0878] Example 127: N-[(2E)-3-(2,4-difluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2- Dihydropyridine-3-carboxamide

[0879] Purity: 93% (254 nm); Rt = 2.36 min, m / z = 429.20 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 10.02 (t, J = 5.9 Hz, 1H), 8.60 (d, J = 2.9 Hz, 1H), 8.07 (d, J = 2.9 Hz, 1H), 7.95 (td, J = 8.6, 6.2 Hz, 1H), 7.70–7.58 (m, 3H), 7.53–7.40 (m, 2H), 7.41–7.30 (m, 2H), 7.15–7.01 (m, 1H), 6.85–6.72 (m, 1H), 4.27 (ddd, J = 6.2, 4.4, 1.9 Hz, 2H).

[0880] Example 128: N-[(2E)-3-(2-chloro-4-fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2- Dihydropyridine-3-carboxamide

[0881] Purity: 95% (254 nm); Rt = 1.94 min, m / z = 447.1 [M+1], 445.08 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 10.03 (t, J = 5.9 Hz, 1H), 8.60 (d, J = 2.9 Hz, 1H), 8.13 (dd, J = 8.9, 5.9 Hz, 1H), 8.07 (d, J = 2.9 Hz, 1H), 7.78 (dd, J = 8.7, 2.5 Hz, 1H), 7.65–7.60 (m, 2H), 7.51 (td, J = 8.5, 2.6 Hz, 1H), 7.48–7.41 (m, 2H), 7.39–7.30 (m, 1H), 7.11 (dt, J = 15.1, 4.4 Hz, 1H), 6.80 (dt, J = 15.1, 1.9 Hz, 1H), 4.28 (ddd, J = 6.2, 4.4, 1.9 Hz, 2H).

[0882] Example 129: N-[(2E)-3-(2-Chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydro Pyridine-3-carboxamide

[0883] Purity: 93% (254 nm); Rt = 2.36 min, m / z = 429.1 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 10.03 (s, 1H), 8.61 (d, J = 2.8 Hz, 1H), 8.10–8.05 (m, 2H), 7.78–7.69 (m, 2H), 7.66–7.59 (m, 3H), 7.50–7.41 (m, 2H), 7.40–7.31 (m, 1H), 7.11 (dt, J = 15.1, 4.4 Hz, 1H), 6.82 (dt, J = 15.0, 1.8 Hz, 1H), 4.34–4.21 (m, 2H).

[0884] Example 130: N-[(2E)-3-(4-chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydro Pyridine-3-carboxamide

[0885] Purity: 97.2% (254 nm); Rt = 2.55 min, m / z = 427.01 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 10.03 (t, J = 6.0 Hz, 1H), 8.59 (d, J = 2.9 Hz, 1H), 8.07 (d, J = 2.9 Hz, 1H), 7.93–7.85 (m, 2H), 7.76–7.69 (m, 2H), 7.65–7.59 (m, 2H), 7.45 (t, J = 7.7 Hz, 2H), 7.39–7.31 (m, 1H), 7.01 (dt, J = 15.1, 4.3 Hz, 1H), 6.78 (dt, J = 15.1, 1.9 Hz, 1H), 4.23 (ddd, J = 6.2, 4.4, 1.9 Hz, 2H).

[0886] Example 131: N-[(2E)-3-[(4-chlorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxy 1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0887] Purity: 93.2% (254 nm); RT = 4.96 min, m / z = 406.17 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 10.00 (t, J = 6.0 Hz, 1H), 8.04 (s, 1H), 7.91–7.82 (m, 2H), 7.71–7.58 (m, 2H), 6.81 (dt, J = 15.0, 4.6 Hz, 1H), 6.50 (dt, J = 14.8, 1.8 Hz, 1H), 4.73 (s, 1H), 4.18–4.06 (m, 2H), 2.58 (t, J = 5.9 Hz, 2H), 1.74–1.64 (m, 4H).

[0888] Example 132: N-[(2E)-3-[(2-fluorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxy 1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0889] Purity: 92.2% (254 nm); RT = 3.54 min, m / z = 390.21 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 10.04 (t, J = 6.0 Hz, 1H), 8.05 (s, 1H), 7.88 (td, J = 7.8, 1.9 Hz, 1H), 7.74–7.64 (m, 1H), 7.44–7.34 (m, 2H), 6.96–6.85 (m, 1H), 6.58 (d, J = 14.9 Hz, 1H), 5.03 (s, 1H), 4.23–4.15 (m, 2H), 2.59 (t, J = 6.0 Hz, 2H), 1.74–1.64 (m, 4H).

[0890] Example 133: N-[(2E)-3-[(3-chloro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0891] Purity: 93.4% (254 nm); RT = 2.06 min, m / z = 436.0 [M+1]; 1 H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.99 (t, J = 5.9 Hz, 1H), 8.04 (s, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.79 (dd, J = 8.7, 2.3 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.77 (dt, J = 14.9, 4.6 Hz, 1H), 6.50 (dt, J = 14.9, 1.8 Hz, 1H), 4.63 (s, 1H), 4.18–4.08 (m, 2H), 3.94 (s, 3H), 2.58 (t, J = 5.9 Hz, 2H), 1.77–1.61 (m, 4H).

[0892] Example 134: N-[(2E)-3-[(3-chlorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxy 1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0893] Purity: 91.7% (254 nm); RT = 2.09 min, m / z = 406.06 [M+1]; 1 H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 10.00 (t, J = 6.0 Hz, 1H), 8.04 (s, 1H), 7.86 (t, J = 1.9 Hz, 1H), 7.81 (dt, J = 7.8, 1.4 Hz, 1H), 7.72 (ddd, J = 8.0, 2.1, 1.1 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 6.85 (dt, J = 15.1, 4.6 Hz, 1H), 6.54 (d, J = 15.0 Hz, 1H), 4.81 (s, 1H), 4.15 (t, J = 5.6 Hz, 2H), 2.59 (d, J = 5.6 Hz, 2H), 1.77–1.62 (m, 4H).

[0894] Example 135: N-[(2E)-3-[(2,4-difluorophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]- 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0895] Purity: 93.1% (254 nm); RT = 2.43 min, m / z = 408.09 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 10.04 (t, J = 6.0 Hz, 1H), 8.05 (s, 1H), 7.93 (td, J = 8.7, 6.4 Hz, 1H), 7.49 (ddd, J = 10.4, 9.2, 2.5 Hz, 1H), 7.30 (td, J = 8.7, 2.3 Hz, 1H), 6.95–6.86 (m, 1H), 6.56 (d, J = 15.0 Hz, 1H), 5.11 (s, 1H), 4.24–4.13 (m, 2H), 2.59 (t, J = 6.0 Hz, 2H), 1.69 (q, J = 8.2 Hz, 4H).

[0896] Example 136: N-[(2E)-3-[(4-cyanophenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2- Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0897] Purity: 97.0% (254 nm); RT = 2.27 min, m / z = 397.08 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 10.01 (t, J = 5.9 Hz, 1H), 8.09–7.99 (m, 4H), 6.88 (dt, J = 14.9, 4.6 Hz, 1H), 6.59–6.50 (m, 1H), 4.93 (s, 1H), 4.16 (t, J = 5.2 Hz, 2H), 2.58 (t, J = 6.0 Hz, 2H), 1.76–1.62 (m, 4H).

[0898] Example 137: N-[(2E)-3-[imino(4-methoxy-3-methylphenyl)oxy-λ 6 -thio]prop-2-ene-1- 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0899] Purity: 95.7% (254 nm); RT = 1.89 min, m / z = 416.22 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.98 (t, J = 5.9 Hz, 1H), 8.04 (s, 1H), 7.68 (dd, J = 8.6, 2.5 Hz, 1H), 7.61 (dd, J = 2.4, 1.0 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H), 6.70 (dt, J = 15.0, 4.7 Hz, 1H), 6.43 (dt, J = 14.8, 1.8 Hz, 1H), 4.35 (s, 1H), 4.11 (t, J = 5.1 Hz, 2H), 3.86 (s, 3H), 2.58 (t, J = 6.0 Hz, 2H), 2.19 (s, 3H), 1.69 (q, J = 8.2 Hz, 4H).

[0900] Example 138: N-[(2E)-3-[Imino(oxo)[4-(propan-2-yloxy)phenyl]-λ 6 -thio]prop-2-ene- 1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0901] Purity: 91.9% (254 nm); RT = 2.12 min, m / z = 430.23 [M+1]; 1 H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 10.01 (s, 1H), 8.04 (s, 1H), 7.79–7.69 (m, 2H), 7.10–7.02 (m, 2H), 6.71 (dt, J = 15.0, 4.6 Hz, 1H), 6.49–6.40 (m, 1H), 4.72 (p, J = 6.0 Hz, 1H), 4.39 (s, 1H), 4.12 (t, J = 5.2 Hz, 2H), 2.57 (d, J = 6.3 Hz, 2H), 1.67 (dd, J = 15.1, 6.5 Hz, 4H), 1.29 (d, J = 6.0 Hz, 6H).

[0902] Example 139: N-[(2E)-3-[imino(4-methoxy-2-methylphenyl)oxy-λ 6 -thio]prop-2-ene-1- 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0903] Purity: 92.5% (254 nm); RT = 1.84 min, m / z = 416.2 [M+1]; 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 10.02 (t, J = 5.9 Hz, 1H), 8.04 (s, 1H), 7.91 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.74 (dt, J = 15.0, 4.8 Hz, 1H), 6.44–6.37 (m, 1H), 4.46 (s, 1H), 4.15 (t, J = 5.2 Hz, 2H), 3.81 (s, 3H), 2.58 (s, 2H), 1.69 (q, J = 7.6 Hz, 4H).

[0904] Example 140: N-[(2E)-3-[imino(oxo)(4-phenoxyphenyl)-λ 6 -thio]prop-2-en-1-yl]- 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0905] Purity: 92.0% (254 nm); RT = 2.53 min, m / z = 464.08 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 10.01 (t, J = 5.9 Hz, 1H), 8.05 (s, 1H), 7.89–7.79 (m, 2H), 7.54–7.43 (m, 2H), 7.26 (t, J = 7.4 Hz, 1H), 7.19–7.06 (m, 4H), 6.76 (dt, J = 14.9, 4.6 Hz, 1H), 6.54–6.42 (m, 1H), 4.53 (s, 1H), 4.14 (t, J = 5.1 Hz, 2H), 2.64–2.56 (m, 2H), 1.78–1.56 (m, 4H).

[0906] Example 141: N-[(2E)-3-{[4-(dimethylamino)phenyl](imino)oxy-λ 6 -sulfhydryl}prop-2-ene- 1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0907] Purity: 92.9% (254 nm); RT = 1.56 min, m / z = 415.24 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 9.98 (t, J = 6.0 Hz, 1H), 8.04 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.9 Hz, 2H), 6.63 (dt, J = 14.9, 4.8 Hz, 1H), 6.39 (d, J = 14.9 Hz, 1H), 4.29 (s, 1H), 4.10 (t, J = 5.4 Hz, 2H), 2.99 (s, 6H), 2.63–2.53 (m, 4H), 1.77–1.61 (m, 4H).

[0908] Example 142: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 6-methyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0909] Purity: 97.3% (254 nm); RT = 2.91 min, m / z = 434.01 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 9.99 (t, J = 5.9 Hz, 1H), 8.03 (s, 1H), 7.69–7.60 (m, 2H), 7.35 (t, J = 8.4 Hz, 1H), 6.76 (dt, J = 14.9, 4.6 Hz, 1H), 6.52–6.45 (m, 1H), 4.60 (s, 1H), 4.16–4.09 (m, 2H), 3.92 (s, 3H), 2.65–2.60 (m, 2H), 2.16–2.07 (m, 2H), 1.84–1.74 (m, 2H), 1.36–1.29 (m, 1H), 1.00 (d, J = 6.5 Hz, 3H).

[0910] Example 143: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 2-Oxo-1,2-dihydroquinoline-3-carboxamide

[0911] Purity: 92.3% (254 nm); RT = 3.12 min, m / z = 416.04 [M+1]; 1 H NMR (400MHz, DMSO-d6) δ12.49(s,1H),9.95(t,J=6.0Hz,1H),8.83(s,1H),7.95(dd,J=7.9,1.4Hz,1H),7.73–7.57(m,3H ),7.43(d,J=8.3Hz,1H),7.39–7.24(m,2H),6.79(dt,1H),6.60(d,1H),4.61(s,1H),4.19(t,J=4.9Hz,2H),3.92(s,3H).

[0912] Example 144: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 2-Oxo-6-(propan-2-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0913] Purity: 97.5% (254 nm); RT = 2.66 min, m / z = 462.12 [M+1]; 1 H NMR (400MHz, DMSO-d6) δ12.28 (s, 1H), 9.99 (t, J = 5.9Hz, 1H), 8.06 (s, 1H), 7.69–7. 59(m,2H),7.35(t,J=8.4Hz,1H),6.76(dt,J=14.9,4.6Hz,1H),6.48(d,J=15.0Hz, 1H),4.60(s,1H),4.18–4.08(m,2H),3.92(s,3H),2.62–2.53(m,2H),2.30–2.17(m ,1H),1.91–1.83(m,1H),1.61–1.49(m,1H),1.46–1.21(m,3H),0.97–0.89(m,6H).

[0914] Example 145: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 2-Oxo-1H,2H,5H,7H,8H-pyrano[4,3-b]pyridine-3-carboxamide

[0915] Purity: 79.1% (254 nm); RT = 2.03 min, m / z = 422.1 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.95 (t, J = 5.9 Hz, 1H), 8.05 (s, 1H), 7.64 (ddd, J = 10.5, 8.0, 2.4 Hz, 2H), 7.35 (t, J = 8.6 Hz, 1H), 6.76 (dt, J = 15.0, 4.6 Hz, 1H), 6.49 (d, J = 14.9 Hz, 1H), 4.59 (s, 1H), 4.52–4.47 (m, 2H), 4.14 (t, J = 5.6 Hz, 2H), 3.92 (s, 3H), 3.85 (t, J = 5.7 Hz, 2H), 2.67 (t, J = 6.1 Hz, 2H).

[0916] Example 146: N-[(2E)-3-[imino(oxo)(3-phenoxyphenyl)-λ 6 -thio]prop-2-en-1-yl]- 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0917] Purity: 86.5% (254 nm); RT = 2.61 min, m / z = 464.18 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 10.02 (s, 1H), 8.04 (s, 1H), 7.64–7.55 (m, 2H), 7.48–7.36 (m, 3H), 7.29–7.18 (m, 2H), 7.13–7.06 (m, 2H), 6.77 (dt, J = 14.9, 4.7 Hz, 1H), 6.54–6.45 (m, 1H), 4.65 (s, 1H), 4.14 (t, J = 5.3 Hz, 2H), 2.58 (t, J = 5.8 Hz, 2H), 1.77–1.62 (m, 4H).

[0918] Example 147: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 2-Oxo-6-(trifluoromethyl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0919] Purity: 93.1% (254 nm); RT = 2.31 min, m / z = 488.39 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 9.98 (s, 1H), 8.13 (s, 1H), 7.70–7.60 (m, 2H), 7.35 (t, J = 8.5 Hz, 1H), 6.77 (dt, J = 14.9, 4.6 Hz, 1H), 6.48 (d, J = 15.0 Hz, 1H), 4.60 (s, 1H), 4.13 (t, J = 5.5 Hz, 2H), 3.92 (s, 3H), 2.87–2.64 (m, 5H), 2.08 (d, J = 13.0 Hz, 1H), 1.67–1.56 (m, 1H).

[0920] Example 148: 6-tert-butyl-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio] Prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0921] Purity: 95.8% (254 nm); RT = 1.86 min, m / z = 476.27 [M+1]; 1 H NMR(400MHz,DMSO-d6)δ12.28(s,1H),10.00(t,J=5.9Hz,1H),8.07(s,1H), 7.70–7.59(m,2H),7.35(t,J=8.4Hz,1H),6.77(dt,J=15.0,4.6Hz,1H),6.52 –6.45(m,1H),4.60(s,1H),4.12(d,J=5.2Hz,2H),3.92(s,3H),2.63–2.55(m ,2H),2.30–2.20(m,1H),1.99–1.89(m,1H),1.38–1.20(m,3H),0.91(s,9H).

[0922] Example 149: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 2-Oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide

[0923] Purity: 87.9% (254 nm); RT = 2.76 min, m / z = 442.3 [M+1]; 1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),8.57(d,J=3.0Hz,1H),8.46(s,1H),8.09(d,J=2.8Hz,1H),7.72–7.56(m,5H),7.51–7. 40(m,2H),7.40–7.29(m,1H),6.80(dt,J=15.0,4.6Hz,1H),6.62–6.49(m,1H),4.61(s,1H),4.21–4.14(m,2H),3.92(s,3H).

[0924] Example 150: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 2-oxo-1H,2H,5H,6H,7H,8H,9H-cycloheptyl[b]pyridine-3-carboxamide

[0925] Purity: 93.0% (254 nm); RT = 2.1 min, m / z = 434.29 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.05–9.94 (m, 1H), 8.10 (s, 1H), 7.69–7.60 (m, 2H), 7.35 (t, J = 8.5 Hz, 1H), 6.77 (dt, J = 15.0, 4.6 Hz, 1H), 6.53–6.45 (m, 1H), 4.59 (s, 1H), 4.20–4.09 (m, 2H), 3.92 (s, 3H), 2.84–2.74 (m, 2H), 2.66–2.59 (m, 2H), 1.82–1.72 (m, 2H), 1.64–1.46 (m, 4H).

[0926] Example 151: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- [2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide]

[0927] Purity: 92.7% (254 nm); RT = 1.9 min, m / z = 406.19 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 10.09 (s, 1H), 8.21 (s, 1H), 7.69–7.59 (m, 2H), 7.35 (t, J = 8.4 Hz, 1H), 6.77 (dt, J = 14.9, 4.6 Hz, 1H), 6.49 (dt, J = 15.0, 1.9 Hz, 1H), 4.60 (s, 1H), 4.13 (t, J = 5.4 Hz, 2H), 3.92 (s, 3H), 2.82 (t, J = 7.6 Hz, 2H), 2.71 (t, J = 7.3 Hz, 2H), 2.05 (p, J = 7.6 Hz, 2H).

[0928] Example 152: 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene- 1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid tert-butyl ester

[0929] Purity: 94.9% (254 nm); RT = 2.24 min, m / z = 521.22 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.94 (t, J = 5.9 Hz, 1H), 8.13 (s, 1H), 7.71–7.58 (m, 2H), 7.35 (t, J = 8.4 Hz, 1H), 6.77 (dt, J = 14.9, 4.6 Hz, 1H), 6.54–6.43 (m, 1H), 4.60 (s, 1H), 4.32 (s, 2H), 4.14 (d, J = 4.6 Hz, 2H), 3.92 (s, 3H), 3.57 (t, J = 5.9 Hz, 2H), 2.65 (d, J = 6.0 Hz, 2H), 1.42 (s, 9H).

[0930] Example 153: 6-Benzyl-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]propyl- 2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0931] Purity: 86.9% (254 nm); RT = 2.83 min, m / z = 511.23 [M+1]; 1 H NMR (400MHz, DMSO-d6) δ12.43(s,1H),9.97(t,J=6.0Hz,1H),8.01(s,1H),7.69–7.60(m,2H),7.34(d,J=4.2Hz,5H),7.27(dt,J=8.9,4.2Hz,1H) ,6.76(dt,J=15.1,4.6Hz,1H),6.53–6.45(m,1H),4.60(s,1H),4.12(t, J=5.2Hz,2H),3.92(s,3H),3.66(s,2H),3.39(s,2H),2.71–2.64(m,4H).

[0932] Example 154: N-[(2E)-3-[Imino(oxo)[4-(trifluoromethyl)phenyl]-λ 6 -thio]prop-2-ene-1- 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0933] Purity: 88.0% (254 nm); RT = 2.34 min, m / z = 440.23 [M+1]; 1 H NMR (400MHz, DMSO-d6) δ12.25(s,1H),10.07–9.97(m,1H),8.07(d,J=8.2Hz,2H),8.04(s,1H),7.97(d,J=8.3Hz,2H),6.8 8(dt,J=15.0,4.6Hz,1H),6.55(d,J=15.0Hz,1H),4.89(s,1H),4.21–4.11(m,2H),2.62–2.55(m,2H),1.77–1.63(m,4H).

[0934] Example 155: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 8,8-dimethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0935] Purity: 97.0% (254 nm); RT = 2.36 min, m / z = 448.0 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 10.06–9.88 (m, 1H), 8.03 (s, 1H), 7.69–7.60 (m, 2H), 7.35 (t, J = 8.5 Hz, 1H), 6.77 (dt, J = 15.0, 4.5 Hz, 1H), 6.50 (dd, J = 14.9, 1.8 Hz, 1H), 4.59 (s, 1H), 4.23–4.11 (m, 2H), 3.92 (s, 3H), 1.74–1.55 (m, 4H), 1.30 (s, 6H).

[0936] Example 156: N-[(2E)-3-({[1,1'-biphenyl]-4-yl}(imino)oxy-λ 6 -sulfenyl)prop-2-ene-1- 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0937] Purity: 97.3% (254 nm); RT = 2.49 min, m / z = 448.44 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 10.03 (t, J = 5.3 Hz, 1H), 8.04 (s, 1H), 7.96–7.90 (m, 2H), 7.89–7.83 (m, 2H), 7.77–7.70 (m, 2H), 7.52 (dd, J = 8.3, 6.7 Hz, 2H), 7.48–7.41 (m, 1H), 6.83 (dt, J = 15.0, 4.6 Hz, 1H), 6.57–6.49 (m, 1H), 4.63 (s, 1H), 4.21–4.11 (m, 2H), 2.58 (t, J = 5.8 Hz, 2H), 1.77–1.62 (m, 4H).

[0938] Example 157: N-[(2E)-3-[benzyl(imino)oxy-λ 6 -thio]prop-2-en-1-yl]-2-oxo-1,2, 5,6,7,8-Hexahydroquinoline-3-carboxamide

[0939] Purity: 94.9% (254 nm); RT = 1.82 min, m / z = 386.2 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 10.02 (t, J = 5.9 Hz, 1H), 8.10 (s, 1H), 7.35–7.26 (m, 5H), 6.53 (dt, J = 15.1, 4.6 Hz, 1H), 6.38–6.28 (m, 1H), 4.30 (s, 2H), 4.15–4.08 (m, 2H), 3.86 (s, 1H), 2.64–2.54 (m, 4H), 1.77–1.64 (m, 4H).

[0940] Example 158: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 2-Oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide

[0941] Purity: 88.6% (254 nm); RT = 3.05 min, m / z = 417.3 [M+1]; 1 H NMR (400MHz, DMSO-d6) δ12.86(s,1H),9.95–9.82(m,1H),8.83(s,1H),8.67(dd,J=4.7,1.8Hz,1H),8.40(d,J=7.7Hz,1H),7.70–7.6 0(m,2H),7.35(t,J=8.2Hz,2H),6.80(dt,J=15.0,4.5Hz,1H),6.60(d,J=14.9Hz,1H),4.60(s,1H),4.23–4.16(m,2H),3.92(s,3H).

[0942] Example 159: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 2-Oxo-1,2-dihydro-1,6-naphthyridine-3-carboxamide

[0943] Purity: 94.9% (254 nm); RT = 1.64 min, m / z = 417.14 [M+1]; 1 H NMR (400MHz, DMSO-d6) δ12.68(s,1H),9.74(s,1H),9.11(s,1H),8.89(s,1H),8.57(d,J=5.7Hz,1H),7.70–7.58(m,2H),7.35(t,J=8.5 Hz, 1H), 7.30 (d, J = 5.7Hz, 1H), 6.79 (dt, J = 15.0, 4.5Hz, 1H), 6.60 (d, J = 14.7Hz, 1H), 4.59 (s, 1H), 4.19 (d, J = 4.5Hz, 2H), 3.92 (s, 3H).

[0944] Example 160: N-[(2E)-3-{Imino[4-(morpholin-4-yl)phenyl]oxy-λ 6 -sulfenyl}prop-2-ene-1- 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0945] Purity: 91.4% (254 nm); RT = 2.15 min, m / z = 457.25 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 9.97 (t, J = 6.0 Hz, 1H), 8.03 (s, 1H), 7.63 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 6.65 (dt, J = 14.9, 4.7 Hz, 1H), 6.39 (d, J = 15.0 Hz, 1H), 4.24 (s, 1H), 4.10 (t, J = 5.2 Hz, 2H), 3.72 (t, J = 4.9 Hz, 4H), 3.25 (t, J = 5.0 Hz, 4H), 2.56 (d, J = 6.2 Hz, 2H), 1.68 (s, 4H).

[0946] Example 161: N-[(2E)-3-[Imino(oxo)[4-(piperidin-1-yl)phenyl]-λ 6 -thio]prop-2-ene-1- 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0947] Purity: 91.3% (254 nm); RT = 5.58 min, m / z = 455.24 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 7.90 (s, 1H), 7.64–7.51 (m, 2H), 7.03–6.93 (m, 2H), 6.64 (dt, J = 14.9, 4.6 Hz, 1H), 6.43–6.32 (m, 1H), 4.15 (s, 1H), 4.08 (d, J = 5.9 Hz, 2H), 1.68 (d, J = 12.1 Hz, 4H), 1.57 (d, J = 2.5 Hz, 6H).

[0948] Example 162: N-[(2E)-3-[Imino(oxo)[4-(pyrrolidin-1-yl)phenyl]-λ 6 -thio]prop-2-ene- 1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0949] Purity: 96.4% (254 nm); RT = 2.01 min, m / z = 441.21 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 9.99 (d, J = 6.2 Hz, 1H), 8.02 (s, 1H), 7.63–7.51 (m, 2H), 6.66–6.48 (m, 3H), 6.47–6.30 (m, 1H), 4.08 (q, J = 3.7, 3.0 Hz, 3H), 3.27 (d, J = 6.3 Hz, 4H), 2.56 (d, J = 6.1 Hz, 2H), 2.02–1.89 (m, 4H), 1.77–1.52 (m, 4H).

[0950] Example 163: N-[(2E)-3-[(4-acetylaminophenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0951] Purity: 87.7% (254 nm); RT = 1.98 min, m / z = 429.0 [M+1]; 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 10.33 (s, 1H), 10.03 (s, 1H), 8.02 (s, 1H), 7.80–7.70 (m, 4H), 6.71 (dt, J = 14.9, 4.6 Hz, 1H), 6.44 (d, J = 15.0 Hz, 1H), 4.43 (s, 1H), 4.10 (d, J = 5.7 Hz, 2H), 2.56 (d, J = 6.1 Hz, 2H), 2.07 (s, 3H), 1.75–1.59 (m, 4H).

[0952] Example 164: N-[(2E)-3-[(4-cyclopropyloxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0953] Purity: 99.5% (254 nm); RT = 4.28 min, m / z = 428.19 [M+1]; 1 H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 10.00 (t, J = 5.9 Hz, 1H), 8.04 (s, 1H), 7.82–7.74 (m, 2H), 7.24–7.17 (m, 2H), 6.73 (dt, J = 14.9, 4.6 Hz, 1H), 6.45 (dt, J = 14.9, 1.8 Hz, 1H), 4.42 (s, 1H), 4.12 (t, J = 5.0 Hz, 2H), 3.94 (tt, J = 6.1, 3.0 Hz, 1H), 2.58 (t, J = 5.9 Hz, 2H), 1.69 (q, J = 8.4, 7.9 Hz, 4H), 0.85–0.77 (m, 2H), 0.69 (tt, J = 5.0, 3.2 Hz, 2H).

[0954] Example 165: N-[(2E)-3-{[3-(dimethylamino)phenyl](imino)oxy-λ 6 -sulfhydryl}prop-2-ene- 1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0955] Purity: 58.2% (254 nm); RT = 4.13 min, m / z = 415.22 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 10.03 (t, J = 5.9 Hz, 1H), 8.03 (s, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.19–7.15 (m, 1H), 7.13 (t, J = 2.2 Hz, 1H), 7.08–6.96 (m, 2H), 6.81 (d, J = 14.9 Hz, 1H), 4.21 (d, J = 5.4 Hz, 2H), 2.97 (s, 6H), 2.58 (t, J = 4.5 Hz, 2H), 1.67 (d, J = 12.0 Hz, 4H).

[0956] Example 166: N-[(2E)-3-[(4-cyclohexylphenyl)(imino)oxy-λ 6 -thio]prop-2-en-1-yl]- 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0957] Purity: 99.2% (254 nm); RT = 5.65 min, m / z = 454.22 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 10.01 (t, J = 5.9 Hz, 1H), 8.04 (s, 1H), 7.78–7.73 (m, 2H), 7.45–7.40 (m, 2H), 6.77 (dt, J = 14.9, 4.7 Hz, 1H), 6.47 (dd, J = 14.9, 1.9 Hz, 1H), 4.46 (s, 1H), 4.13 (t, J = 5.0 Hz, 2H), 2.58 (t, J = 6.0 Hz, 3H), 1.84–1.76 (m, 4H), 1.69 (q, J = 10.1, 7.3 Hz, 5H), 1.40 (q, J = 11.5 Hz, 4H), 1.26 (t, J = 12.1 Hz, 1H).

[0958] Example 167: N-[(2E)-3-[(2,3-dihydro-1-benzofuran-5-yl)(imino)oxy-λ 6 -thio]propyl- 2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0959] Purity: 95.6% (254 nm); RT = 2.23 min, m / z = 414.17 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 9.98 (t, J = 5.9 Hz, 1H), 8.03 (s, 1H), 7.68 (d, J = 1.9 Hz, 1H), 7.60 (dd, J = 8.4, 2.1 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.69 (dt, J = 14.9, 4.7 Hz, 1H), 6.42 (dt, J = 14.8, 1.8 Hz, 1H), 4.63 (t, J = 8.8 Hz, 2H), 4.34 (s, 1H), 4.11 (t, J = 5.2 Hz, 2H), 3.23 (t, J = 8.8 Hz, 2H), 2.57 (t, J = 5.9 Hz, 2H), 1.76–1.60 (m, 4H).

[0960] Example 168: N-[(2E)-3-[Imino(oxo)[3-(trifluoromethoxy)phenyl]-λ 6 -thio]prop-2-ene- 1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0961] Purity: 99.1% (254 nm); RT = 4.22 min, m / z = 456.1 [M+1]; 1 1H NMR (400 MHz, acetonitrile-d3) δ 10.10 (s, 1H), 9.96 (s, 1H), 8.10 (s, 1H), 7.89 (ddd, J = 7.9, 1.7, 1.0 Hz, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.64 (t, J = 8.1 Hz, 1H), 7.53 (ddt, J = 8.3, 2.3, 1.1 Hz, 1H), 6.94 (dt, J = 14.9, 4.3 Hz, 1H), 6.48 (dt, J = 14.9, 1.9 Hz, 1H), 4.16 (ddt, J = 6.0, 4.4, 1.7 Hz, 2H), 3.48 (d, J = 24.0 Hz, 1H), 2.60 (t, J = 6.0 Hz, 2H), 2.52 (t, J = 6.0 Hz, 2H), 1.80–1.68 (m, 4H).

[0962] Example 169: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 6-methoxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0963] Purity: 94.3% (254 nm); RT = 2.23 min, m / z = 450.2 [M+1]; 11H NMR (400 MHz, methanol-d4) δ 8.18 (s, 1H), 7.74 (d, 1H), 7.66 (dd, J = 10.6, 2.3 Hz, 1H), 7.29 (t, J = 8.4 Hz, 1H), 6.96 (dt, J = 15.0, 4.5 Hz, 1H), 6.61 (d, J = 15.2 Hz, 1H), 4.25 (d, 2H), 3.97 (s, 3H), 3.75 (t, J = 4.8 Hz, 1H), 3.40 (s, 3H), 2.83 (td, J = 14.0, 12.1, 5.9 Hz, 2H), 2.66 (dd, J = 17.1, 6.2 Hz, 2H), 2.00 (q, J = 6.2 Hz, 2H), 1.39 (d, J = 6.5 Hz, 1H).

[0964] Example 170: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- [2-(2,2,2-trifluoroethyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide]-2-oxo-6-(2,2,2-trifluoroethyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0965] Purity: 93.7% (254 nm); RT = 3.2 min, m / z = 503.08 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.96 (t, J = 5.9 Hz, 1H), 8.04 (s, 1H), 7.72–7.57 (m, 2H), 7.35 (t, J = 8.4 Hz, 1H), 6.77 (dt, J = 14.9, 4.6 Hz, 1H), 6.49 (dt, J = 14.9, 1.9 Hz, 1H), 4.60 (s, 1H), 4.17–4.10 (m, 2H), 3.92 (s, 3H), 3.65 (s, 2H), 3.41–3.34 (m, 2H), 2.93 (t, J = 5.8 Hz, 2H), 2.73–2.65 (m, 2H).

[0966] Example 171: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0967] Purity: 84.1% (254 nm); RT = 2.94 min, m / z = 541.24 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.96 (s, 1H), 8.00 (s, 1H), 7.69–7.59 (m, 2H), 7.35 (t, J = 8.4 Hz, 1H), 7.29–7.19 (m, 2H), 6.94–6.87 (m, 2H), 6.76 (dt, J = 15.0, 4.6 Hz, 1H), 6.53–6.45 (m, 1H), 4.60 (s, 1H), 4.17–4.08 (m, 2H), 3.92 (s, 3H), 3.75 (s, 3H), 3.58 (s, 2H), 3.35 (s, 2H), 2.68–2.60 (m, 4H).

[0968] Example 172: 6-Fluoro-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]propan-2- [1-enyl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0969] Purity: 97.2% (254 nm); RT = 2.25 min, m / z = 438.15 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.95 (t, J = 5.9 Hz, 1H), 8.08 (s, 1H), 7.70–7.59 (m, 2H), 7.35 (t, J = 8.4 Hz, 1H), 6.77 (dt, J = 14.9, 4.6 Hz, 1H), 6.49 (d, J = 15.0 Hz, 1H), 5.10 (dd, J = 48.5, 4.9 Hz, 1H), 4.59 (s, 1H), 4.13 (t, J = 5.3 Hz, 2H), 3.92 (s, 3H), 2.98–2.76 (m, 2H), 2.68 (d, J = 6.4 Hz, 1H), 2.14–1.85 (m, 3H).

[0970] Example 173: N-[(2E)-3-{[3-cyano-4-(piperidin-1-yl)phenyl](imino)oxy-λ 6 -thio}propyl- 2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0971] Purity: 96.2% (254 nm); RT = 3.07 min, m / z = 480.28 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 9.98 (t, J = 5.8 Hz, 1H), 8.04 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.87 (dd, J = 9.0, 2.3 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 6.77 (dt, J = 14.9, 4.5 Hz, 1H), 6.48 (d, J = 15.0 Hz, 1H), 4.61 (s, 1H), 4.12 (s, 2H), 2.57 (d, J = 6.1 Hz, 2H), 1.67 (s, 5H), 1.60 (s, 2H).

[0972] Example 174: N-[(2E)-3-{Imino[4-(methylamino)phenyl]oxy-λ 6 -sulfenyl}prop-2-ene-1- 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0973] Purity: 88.9% (254 nm); RT = 1.98 min, m / z = 401.21 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 9.97 (t, J = 5.9 Hz, 1H), 8.03 (s, 1H), 7.55–7.46 (m, 2H), 6.64–6.50 (m, 4H), 6.36 (dt, J = 14.8, 1.8 Hz, 1H), 4.12–4.06 (m, 2H), 4.03 (s, 1H), 2.71 (d, J = 4.9 Hz, 3H), 2.57 (t, J = 6.0 Hz, 2H), 1.68 (t, J = 4.3 Hz, 4H).

[0974] Example 175: N-[(2E)-3-{[3-cyano-4-(morpholin-4-yl)phenyl](imino)oxy-λ 6 -thio}propyl- 2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0975] Purity: 97.9% (254 nm); RT = 1.88 min, m / z = 482.18 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 10.05 (s, 1H), 8.05 (d, J = 2.3 Hz, 1H), 8.02 (s, 1H), 7.93 (dd, J = 8.9, 2.4 Hz, 1H), 7.26 (d, J = 8.9 Hz, 1H), 6.79 (dt, J = 14.9, 4.6 Hz, 1H), 6.49 (dt, J = 14.8, 1.8 Hz, 1H), 4.67 (s, 1H), 4.19–4.07 (m, 2H), 3.82–3.69 (m, 4H), 2.62–2.54 (m, 2H), 1.68 (q, J = 7.7 Hz, 4H).

[0976] Example 176: N-[(2E)-3-[Imino(oxo)[4-(2-oxopiperidin-1-yl)phenyl]-λ 6 -thio]propyl- 2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0977] Purity: 93.2% (254 nm); RT = 2.67 min, m / z = 469.37 [M+1]; 1 H NMR (400 MHz, DMSO-d6) δ 10.03 (t, 1H), 8.04 (s, 1H), 7.86–7.81 (m, 2H), 7.52–7.47 (m, 2H), 6.79 (dt, J = 14.9, 4.7 Hz, 1H), 6.53–6.47 (m, 1H), 4.58 (s, 1H), 4.13 (d, J = 6.0 Hz, 2H), 3.66 (t, J = 5.6 Hz, 2H), 2.59 (d, J = 5.9 Hz, 2H), 2.43 (t, J = 6.3 Hz, 2H), 1.90–1.82 (m, 4H), 1.78–1.74 (m, 2H), 1.71–1.64 (m, 4H).

[0978] Example 177: N-[(2E)-3-[imino(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy-λ 6 -thio] Prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide

[0979] Purity: 95.4% (254 nm); RT = 2.22 min, m / z = 441.24 [M+1]; 1 H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 9.97 (t, J = 5.8 Hz, 1H), 8.03 (s, 1H), 7.42 (dd, J = 8.7, 2.4 Hz, 1H), 7.29 (d, J = 2.3 Hz, 1H), 6.65–6.53 (m, 2H), 6.35 (dd, J = 15.0, 1.7 Hz, 1H), 4.13–4.04 (m, 2H), 4.02 (s, 1H), 2.90 (s, 3H), 2.70 (t, J = 6.4 Hz, 2H), 2.57 (d, J = 6.2 Hz, 2H), 1.86 (p, J = 6.2 Hz, 2H), 1.68 (s, 4H).

[0980] Example 178: 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene- 1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid 2,2-difluoroethyl ester

[0981] Purity: 95.1% (254 nm); RT = 1.46 min, m / z = 529.3 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.52 (s, 1H), 9.92 (t, J = 5.9 Hz, 1H), 8.15 (d, J = 8.9 Hz, 1H), 7.69–7.60 (m, 2H), 7.35 (t, J = 8.4 Hz, 1H), 6.77 (dt, J = 14.9, 4.6 Hz, 1H), 6.54–6.46 (m, 1H), 6.43–6.10 (m, 2H), 4.60 (s, 1H), 4.34 (td, J = 15.3, 3.3 Hz, 5H), 4.14 (t, J = 5.4 Hz, 2H), 3.92 (s, 3H), 3.65 (s, 2H), 2.71 (t, J = 5.7 Hz, 2H).

[0982] Example 179: 3-{[(2E)-3-[imino(oxy)phenyl-λ 6 -thio]prop-2-en-1-yl]carbamoyl 2-Oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropyl methyl ester

[0983] Purity: 93.8% (254 nm); RT = 1.9 min, m / z = 471.09 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.94 (t, J = 5.8 Hz, 1H), 8.15 (s, 1H), 7.90–7.83 (m, 2H), 7.68–7.54 (m, 3H), 6.79 (dt, J = 15.0, 4.6 Hz, 1H), 6.50 (dt, J = 14.8, 1.8 Hz, 1H), 4.58 (s, 1H), 4.38 (s, 2H), 4.14 (q, J = 5.0, 4.4 Hz, 2H), 3.89 (d, J = 7.2 Hz, 2H), 3.69–3.56 (m, 2H), 2.69 (d, J = 5.2 Hz, 2H), 1.11 (qq, J = 7.6, 4.8, 3.8 Hz, 1H), 0.56–0.46 (m, 2H), 0.32–0.24 (m, 2H).

[0984] Example 180: 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene- 1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid 2-fluoroethyl ester

[0985] Purity: 95.5% (254 nm); RT = 2.12 min, m / z = 511.13 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.92 (t, J = 6.0 Hz, 1H), 8.15 (s, 1H), 7.68–7.59 (m, 2H), 7.34 (t, J = 8.5 Hz, 1H), 6.76 (dt, J = 14.9, 4.6 Hz, 1H), 6.49 (dt, J = 14.9, 1.8 Hz, 1H), 4.71–4.54 (m, 3H), 4.44–4.35 (m, 0H), 4.35–4.21 (m, 2H), 4.17–4.10 (m, 2H), 3.95–3.89 (m, 3H), 3.68–3.58 (m, 2H), 2.74–2.63 (m, 2H).

[0986] Example 181: 3-{[(2E)-3-[imino(oxy)phenyl-λ 6 -thio]prop-2-en-1-yl]carbamoyl 2-Fluoroethyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate

[0987] Purity: 91.2% (254 nm); RT = 3.26 min, m / z = 463.05 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.94 (t, J = 6.0 Hz, 1H), 8.16 (s, 1H), 7.89–7.83 (m, 2H), 7.69–7.55 (m, 3H), 6.79 (dt, J = 14.9, 4.6 Hz, 1H), 6.50 (dt, J = 14.9, 1.8 Hz, 1H), 4.73–4.54 (m, 3H), 4.38 (s, 2H), 4.29 (ddd, J = 30.3, 4.6, 3.2 Hz, 2H), 4.14 (d, J = 5.6 Hz, 2H), 3.64 (s, 2H), 2.70 (t, J = 5.7 Hz, 2H).

[0988] Example 182: 3-{[(2E)-3-[imino(oxy)phenyl-λ 6 -thio]prop-2-en-1-yl]carbamoyl 2,2-Difluoroethyl 2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate

[0989] Purity: 93.4% (254 nm); RT = 1.72 min, m / z = 480.84 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.93 (t, J = 6.0 Hz, 1H), 8.16 (s, 1H), 7.91–7.82 (m, 2H), 7.68–7.54 (m, 3H), 6.79 (dt, J = 15.0, 4.6 Hz, 1H), 6.50 (dt, J = 14.8, 1.9 Hz, 1H), 6.43–6.11 (m, 2H), 4.58 (s, 1H), 4.47–4.28 (m, 4H), 4.14 (t, J = 5.3 Hz, 2H), 3.65 (s, 2H), 2.70 (t, J = 6.0 Hz, 2H).

[0990] Example 183: 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene- 4,4-difluorocyclohexyl]-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate

[0991] Purity: 94.7% (254 nm); RT = 2.35 min, m / z = 583.32 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.95 (t, J = 6.3 Hz, 1H), 8.19 (s, 1H), 7.72–7.56 (m, 2H), 7.35 (t, J = 8.4 Hz, 1H), 6.77 (dt, J = 15.0, 4.6 Hz, 1H), 6.49 (d, J = 15.0 Hz, 1H), 4.85–4.80 (m, 1H), 4.60 (s, 1H), 4.49–4.29 (m, 2H), 4.16–4.12 (m, 2H), 3.92 (s, 3H), 3.65–3.61 (m, 2H), 2.73–2.67 (m, 2H), 2.00–1.96 (m, 4H), 1.83–1.77 (m, 4H).

[0992] Example 184: 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene- 1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclohexyl ester

[0993] Purity: 95.5% (254 nm); RT = 2.47 min, m / z = 547.2 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.95 (t, J = 5.9 Hz, 1H), 8.15 (s, 1H), 7.69–7.59 (m, 2H), 7.35 (t, J = 8.4 Hz, 1H), 6.77 (dt, J = 14.9, 4.6 Hz, 1H), 6.49 (dt, J = 14.9, 1.9 Hz, 1H), 4.62–4.58 (m, 2H), 4.37 (s, 2H), 4.14 (t, J = 5.4 Hz, 2H), 3.92 (s, 3H), 3.64–3.59 (m, 2H), 2.70–2.64 (m, 2H), 1.79–1.75 (m, 2H), 1.72–1.63 (m, 2H), 1.48–1.29 (m, 6H).

[0994] Example 185: 6-(Cyclopropylmethyl)-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 - [thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide

[0995] Purity: 88.9% (254 nm); RT = 1.81 min, m / z = 475.22 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 10.00 (s, 1H), 8.05 (s, 1H), 7.70–7.59 (m, 2H), 7.40–7.31 (m, 1H), 6.77 (dt, J = 14.9, 4.5 Hz, 1H), 6.50 (d, J = 15.1 Hz, 1H), 4.60 (s, 1H), 4.18–4.08 (m, 2H), 3.92 (s, 3H), 3.48–3.40 (m, 2H), 2.75–2.69 (m, 2H), 2.53 (s, 2H), 2.36 (s, 2H), 0.92–0.86 (m, 1H), 0.54–0.45 (m, 2H), 0.16–0.08 (m, 2H).

[0996] Example 186: N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ 6 -thio]prop-2-ene-1- 2-Oxo-1,2-dihydropyridine-3-carboxamide

[0997] Purity: 84.3% (254 nm); RT = 1.93 min, m / z = 366.1 [M+1]; 1H NMR (400MHz, DMSO-d6) δ12.54(d,J=6.1Hz,1H),9.94(t,J=5.9Hz,1H),8.35–8.28(m,1H),7.73(tt,J=7.1,3.5Hz,1H),7.70–7 .61(m,2H),7.35(t,J=8.6Hz,1H),6.78(dt,J=14.9,4.6Hz,1H),6.57–6.44(m,2H),4.15(dt,J=6.0,3.0Hz,2H),3.92(s,3H).

[0998] Bioassay

[0999] Cell-free HTRF-based HOIP inhibition assay

[1000] Similar to the assay described in Katsuya et al. (SLASDiscov 2018), a cell-free homogenous time-resolved fluorescence (HTRF) HOIP inhibition assay was performed to assess the inhibition of HOIP activity by compounds. The assay was performed as follows:

[1001] a) Synthetic recombinant fragment of human E3 ubiquitin protein ligase RNF31 (HOIP) expressed in E. coli system with >90% purity (protein prepared as 1 mg / mL stock in standard preparation);

[1002] b) incubating compounds in a typical concentration range of 100-0.005 μM with a mixture of HOIP and ubiquitin activating enzyme E1 at 25°C, with a final DMSO concentration of 1%, for 1 h at 25°C;

[1003] c) then adding a ubiquitination solution containing E2 and substrate (the reaction was carried out at 25°C for 2.5h); and

[1004] d) HTRF detection was performed using a PHERAstar FSX (BMG Labtech) plate reader (excitation at 337 nm, dual emission at 665 and 620 nm).

[1005] Cell-based dual-luciferase NF-κB reporter assay

[1006] The dual-luciferase reporter assay was designed to search for HOIP inhibitors that affect the NF-κB signaling pathway. The assay was performed in HEK293 cells transfected with plasmids encoding Firefly and NanoLuc luciferase. The NanoLuc luciferase plasmid contains the NF-κB response element that determines its expression. The assay was run following the standard dual-luciferase protocol. The assay consists of several steps:

[1007] - Compounds were dispensed in a concentration range of 100-0.005 μM with a final DMSO concentration of 1% of the final volume (25 μL);

[1008] -30 min later, cells were stimulated with 2.5 ng / mL TNF; and

[1009] After -6 h, Firefly and NanoLuc luciferase activities were determined according to the procedure described by the manufacturer of the Nano-Glo Dual-Luciferase Reporter Assay System.

[1010] TNF-α-induced cytotoxicity assay

[1011] A viability assay using the bladder cancer RT4 cell line was used to identify the potential inhibitory effect of the tested compounds on HOIP activity. Viability was determined by the CellTiter-Glo Luminescent Cell Viability Assay (G7571, Promega), which measures the ability to produce a luminescent signal proportional to the amount of ATP present in viable cells. The assay consists of several steps:

[1012] a) routinely subculturing cells twice a week using a standard complete growth medium composition;

[1013] b) Cells for the assay were prepared by preparing a cell suspension at a density of 0.05 mln cells / mL and dispensing into plates (ViewPlate-384, PerkinElmer) to give 1000 cells / well;

[1014] c) stimulating the cells with 1.25 ng / mL TNFα and the compound and incubating at 37° C. in an atmosphere of 5% CO 2 for 72 h; and

[1015] d) Based on the method described by the manufacturer, use The cytotoxicity was measured by luminescent cell viability assay.

[1016] Results Bioassay

[1017] Compounds of the invention (Examples 5-186) were tested in one or more of the biological assays listed above. Table 1 below includes all IC50 values ​​for biochemical (HTRF) and cellular (TNF, NFkB) activities of the tested compounds.

[1018] Table 1. IC50 values ​​for biochemical and cellular activities

[1019]

[1020]

[1021]

[1022]

[1023]

[1024] BRIEF DESCRIPTION OF THE DRAWINGS

[1025] Figure 1 The percentage inhibition of RNF31 activity in the HTRF assay is shown, wherein the activity of compounds A and B (selected from compounds of the present invention) is shown. The compounds were found to show improved activity compared to compounds known in the art with the same mechanism of action.

[1026] Figure 2 The percent inhibition of NF-κB activity in the luciferase assay is shown, wherein the activity of compounds A and B (selected from compounds of the present invention) is shown. The compounds were found to show improved activity compared to compounds known in the art with the same mechanism of action.

[1027] Figure 3A Shown is the cell viability of RT4 (bladder cancer) after titration with TNF cytokine, while Figure 3B Shown are the cell viability of RT4 after titration of Compound A with or without a fixed concentration of TNF (1.25 ng / ml).

[1028] Figure 4A -J shows the cell viability of various cell lines treated with a fixed concentration of Compound A in the presence of titrated TNF in a TNF cytotoxicity assay. The cell lines used included bladder cancer ( Figure 4A ), skin melanoma ( Figure 4B ), colorectal adenocarcinoma ( Figure 4C ), pancreatic ductal adenocarcinoma ( Figure 4D ), ovarian serous adenocarcinoma ( Figure 4E ), triple-negative breast cancer ( Figure 4F ), lung adenocarcinoma ( Figure 4G )、Osteosarcoma( Figure 4H ), acute monocytic leukemia ( Fig. 4I ) and glioblastoma ( Figure 4J ).

[1029] Figure 5A Shown is the GI50 cell line exposed to titrated levels of TNF for 72 hours in a TNF cytotoxicity assay. Figure 5B Shown is the GI50 cell line treated with a fixed concentration of Compound A for 72 hours in the presence of titrated TNF in a TNF cytotoxicity assay.

[1030] Fig. 6A -D shows the monotherapy effect of Compound A. Mantle cell lymphoma ( Fig. 6A ), lung adenocarcinoma ( Figure 6B ), ovarian serous adenocarcinoma ( Figure 6C ) and diffuse large B-cell lymphoma ( Fig.6D ) of cell viability.

[1031] Fig. 7A Shown is the cell viability of PBMC (healthy peripheral blood mononuclear cells) after titration with Compound A after 72 hours, while Figure 7B Cell viability of PBMCs treated with titrations of TNF for 72 hours with or without a fixed concentration of compound is shown. The results presented in Figure 7 show that even with the addition of TNF, there is an effect on the tumor.

[1032] Fig. 8A Shown is tumor growth over time of EMT6 (triple negative breast cancer) tumor cells transplanted into syngeneic mice. Mice were treated with Compound A daily for 10 days. Figure 8B Shown are the differences in tumor volume at day 15 between mice treated with Compound A and mice treated with vehicle alone.

Claims

1. A compound having formula (I): or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Both are hydrogen or, where: yes in: n is 1, 2, 3, or 4; A is oxygen or nitrogen; X is carbon or nitrogen, or wherein R 7 -X is oxygen; Y is carbon or nitrogen; Z is hydrogen, (C1-C6)alkyl or di-(C1-C6)alkyl; R 3 and R 4 are each independently selected from the group consisting of hydrogen, (C1-C4) alkyl, or wherein R 3 and R 4 Together with the carbon to which they are attached they form a (C3-C6)cycloalkyl group; R 5 Selected from the group consisting of hydrogen, halo or (C1-C6)alkyl; R 6 Selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with one to four halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C2-C9)heterocycloalkyl, (C3-C6)cycloalkyloxy, (C6-C10)aryl, (C6-C10)aryloxy, cyano, primary, secondary or tertiary amino groups; When X is carbon, R 7 YesR 7 ' and R 7 ”, where R 7 ' is selected from the group consisting of: hydrogen, halo or (C1-C6) alkyl, and wherein R 7 " is selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, wherein the aryl and heteroaryl groups are optionally substituted with one to three (C1-C6)alkyl; When X is nitrogen, R 7 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, wherein the aryl and heteroaryl groups are optionally substituted with one to three (C1-C6)alkyl, or wherein R 7 YesR 8 M-, where: -R 8 M-Selected from the group consisting of: R 8 -C(O)-、R 8 -OC(O)-、R 8 -NH-C(O)- or R 8 -S(O)2-; and -R 8 Selected from the group consisting of: (C1-C6)alkyl, (C3-C10)cycloalkyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl, (C4-C9)spiroheterocycloalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C1-C6)alkyl, (C4-C9)bicycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and bicycloalkyl groups are optionally substituted with one to four halo, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)alkoxy, cyano, oxo or hydroxyl.

2. The compound according to claim 1, wherein: R 3 , R 4 and R 5 is hydrogen; and R 6 Selected from the group consisting of (C6-C10)aryl or (C2-C9)heteroaryl, wherein the aryl and heteroaryl groups are optionally substituted with one to four halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C2-C9)heterocycloalkyl, (C3-C6)cycloalkyloxy, (C6-C10)aryl, (C6-C10)aryloxy, cyano, primary amino, secondary amino or tertiary amino.

3. The compound according to claim 1 or 2, wherein: R 3 , R 4 and R 5 is hydrogen; and When X is carbon, R 7 YesR 7 ' and R 7 ”, where R 7 ' is selected from the group consisting of hydrogen, halo or (C1-C6) alkyl, and wherein R 7 " is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, wherein the aryl and heteroaryl groups are optionally substituted with one to three (C1-C6)alkyl; When X is nitrogen, R 7 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl, wherein the aryl and heteroaryl groups are optionally substituted with one to three (C1-C6)alkyl, or wherein R 7 YesR 8 M-, where: -R 8 M-Selected from the group consisting of: R 8 -OC(O)-、R 8 -NH-C(O)- or R 8 -S(O)2-; and -R 8 Selected from the group consisting of: (C1-C6)alkyl, (C3-C10)cycloalkyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl, (C4-C9)spiroheterocycloalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C1-C6)alkyl, (C4-C9)bicycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and bicycloalkyl groups are optionally substituted with one to four halo, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)alkoxy, cyano, oxo or hydroxyl.

4. A compound according to any one of the preceding claims, wherein: n is 1, 2, or 3; 5. A compound according to any one of the preceding claims, wherein when X is nitrogen, R 7 Not hydrogen.

6. A compound having formula (II): or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2, or 3; A is oxygen or nitrogen; and R' is selected from the group consisting of (C6-C10)aryl or (C2-C9)heteroaryl, wherein the aryl and heteroaryl groups are optionally substituted with one to four halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C2-C9)heterocycloalkyl, (C3-C6)cycloalkyloxy, (C6-C10)aryl, (C6-C10)aryloxy, cyano, primary amino, secondary amino or tertiary amino.

7. The compound of claim 6, wherein (C6-C10)aryl is phenyl, or (C2-C9)heteroaryl is pyridinyl, wherein the phenyl and pyridinyl groups are optionally substituted with one to three fluoro, chloro, bromo or methoxy groups.

8. A compound having formula (III): or a pharmaceutically acceptable salt thereof, wherein: A is oxygen or nitrogen; R" is selected from the group consisting of (C6-C10)aryl or (C2-C9)heteroaryl, wherein the aryl and heteroaryl groups are optionally substituted with one to four halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C2-C9)heterocycloalkyl, (C3-C6)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, cyano, primary amino, secondary amino or tertiary amino; M' is carbon or -OC(O)-; and R'' is selected from the group consisting of (C1-C6)alkyl, (C3-C10)cycloalkyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl, (C4-C9)spiroheterocycloalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C1-C6)alkyl, (C4-C9)bicycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and bicycloalkyl groups are optionally substituted with one to four halo, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)alkoxy, cyano, oxo or hydroxyl.

9. A compound according to any one of the preceding claims, wherein: A is nitrogen.

10. The compound according to any one of the preceding claims, wherein the compound is selected from the group consisting of: N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-benzyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2Z)-3-(phenylsulfonyl)-3-fluoroprop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)-3-fluoroprop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2Z)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; tert-Butyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide; N-[(3E)-4-(phenylsulfonyl)-2-methylbut-3-en-2-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-{1-[(E)-2-(phenylsulfonyl)vinyl]cyclopropyl}-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; 6-Acetyl-N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(3-methoxypropanoyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(3E)-4-(phenylsulfonyl)but-3-en-2-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(2-methoxyethanesulfonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-methylsulfonylprop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; 6-[2-(adamantan-1-yl)acetyl]-N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-[(1r,4r)-4-methoxycyclohexanecarbonyl]-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(4,4-difluorocyclohexanecarbonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-cyclopropanecarbonyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-{bicyclo[2.2.1]heptane-1-carbonyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(3,3-difluorocyclobutanecarbonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(1-cyanocyclobutanecarbonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(2-phenyl-2H-1,2,3-triazole-4-carbonyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(oxolane-3-carbonyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-{3-methylbicyclo[1.1.1]pentane-1-carbonyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-(4-Fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(Cyclopentanesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; 2-Oxo-N-[(2E)-3-(propane-2-sulfonyl)prop-2-en-1-yl]-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(3-Fluoro-4-methoxyphenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(1-methylcyclobutanecarbonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(4-cyclopropyl-1,3-thiazole-2-carbonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(2-cyclopropylacetyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; 2-Oxo-N-[(2Z)-3-(propane-2-sulfonyl)prop-2-en-1-yl]-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(1-phenylpyrrolidine-3-carbonyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; 2-Methylpropyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; tert-Butyl 3-{[(2E)-3-(2-fluorophenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; N-[(2E)-3-(2-methylpropane-2-sulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(2-Fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; tert-Butyl 3-{[(2E)-3-(4-fluorophenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(3,3-dimethylbutyryl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; tert-Butyl 3-{[(2E)-3-(3-fluoro-4-methoxyphenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-[(1-methyl-1H-indazol-4-yl)methyl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; 2-(4-chlorophenyl)ethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; tert-Butyl 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-[(pyridin-3-yl)methyl]-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-[(pyridazin-3-yl)methyl]-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6-(3-methoxy-3-methylbutanoyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-(4-Chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide; 6-Benzyl-N-[(2E)-3-(4-chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide; N-[(2Z)-3-(2-Fluorophenylsulfonyl)but-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(2-Fluorophenylsulfonyl)but-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester; 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclobutyl ester; 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid (5-methyl-1,3,4-oxadiazol-2-yl)methyl ester; 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid 1,1,1-trifluoropropan-2-yl ester; 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid (2,2-dimethylcyclopropyl)methyl ester; 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid (2,2-difluorocyclopropyl)methyl ester; 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid oxetan-3-yl ester; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; 1-methoxypropan-2-yl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; 2-Fluoroethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; 2,2-difluoroethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropyl ester; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(2-phenylcyclopropanecarbonyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; 2-oxaspiro[3.5]nonan-7-yl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; 2-Methoxyethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; N-[(2E)-3-(2,4-difluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(2,4-dichlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; (3S)-Oxolan-3-yl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; (3R)-oxolan-3-yl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; N-[(2E)-3-(2-chloro-4-fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(2,4-difluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide; N-[(2E)-3-(2,4-dichlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide; N-[(2E)-3-(2-chloro-4-fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide; N-[(2E)-3-(2,4-difluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide; N-[(2E)-3-(4-fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide; N-[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide; N-[(2Z)-3-(4-chlorobenzenesulfonyl)but-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(4-chlorobenzenesulfonyl)but-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(3-fluoro-4-methoxyphenylsulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide; N-[(2Z)-3-(4-chlorobenzenesulfonyl)but-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide; N-[(2E)-3-(4-chlorobenzenesulfonyl)but-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide; N-[(2E)-3-(2-Chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide; N-[(2E)-3-(3-Fluorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(4-methoxyphenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; 2-(2-oxopiperidin-1-yl)ethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; N-[(2E)-3-(2-Chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopentyl ester; 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid (2,2-dimethylcyclopropyl)methyl ester; 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid (2,2-difluorocyclopropyl)methyl ester; 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid oxetan-3-yl ester; N-[(2E)-3-(4-Chlorophenylsulfonyl)-3-fluoroprop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2Z)-3-(4-chlorobenzenesulfonyl)-3-fluoroprop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester; N-[(2E)-3-(2,4-difluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide; 2-(Furan-2-yl)ethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclohexyl ester; 1-(2,6-difluorophenyl)ethyl 3-{[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid 1-acetylpiperidin-4-yl ester; 2-Fluoroethyl 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; 1-methoxypropan-2-yl 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; N-[(2E)-3-[(5-chloropyridin-2-yl)sulfonyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; 2-Oxo-N-[(2E)-3-(thiophene-2-sulfonyl)prop-2-en-1-yl]-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; 3-{[(2E)-3-[(5-chloropyridin-2-yl)sulfonyl]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester; 2,2-difluoroethyl 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; 2,2,2-trifluoroethyl 3-{[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; N-[(2E)-3-(4-bromophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(3,4-dimethoxybenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-6-(prop-2-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6,6-dimethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)prop-2-en-1-yl]-6,6-difluoro-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N3-[(2E)-3-(4-chlorophenylsulfonyl)prop-2-en-1-yl]-N6-(cyclopropylmethyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3,6-dicarboxamide; N3-[(2E)-3-(4-chlorophenylsulfonyl)prop-2-en-1-yl]-N6-cyclopropyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3,6-dicarboxamide; N6-tert-butyl-N3-[(2E)-3-(4-chlorophenylsulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3,6-dicarboxamide; N-[(2E)-3-[(4-fluorophenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(4-tert-Butylbenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(3,4-dimethylbenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3,4-dimethoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(phenylsulfonyl)(1,1-2H2)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[4-(Dimethylamino)benzenesulfonyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(4-cyclopropylbenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-(4-cyanobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[Imino(4-methoxyphenyl)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3,4-dimethylphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; 6,6-difluoro-N-[(2E)-3-[(4-fluorophenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; 3-{[(2E)-3-[(4-fluorophenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester; N-[(2E)-3-[Imino(oxy)phenyl-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(4-tert-butylphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(4-ethoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[Imino(4-methoxy-3,5-dimethylphenyl)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[Imino(3-methoxyphenyl)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[Imino(oxo)[4-(trifluoromethoxy)phenyl]-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(4-chlorophenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(2-fluorophenyl)(imino)oxy-λ6-thio]propan-2-λ6-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3-chloro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; 2,2-difluoroethyl 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; N-[(2E)-3-[(3-chlorophenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(2,4-difluorophenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(4-cyanophenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[Imino(4-methoxy-3-methylphenyl)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[Imino(oxo)[4-(propan-2-yloxy)phenyl]-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[Imino(4-methoxy-2-methylphenyl)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; 3-{[(2E)-3-[Imino(oxy)phenyl-λ6-thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclopropylmethyl ester; 2-Fluoroethyl 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; 2-Fluoroethyl 3-{[(2E)-3-[Imino(oxy)phenyl-λ6-thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; 2,2-difluoroethyl 3-{[(2E)-3-[imino(oxy)phenyl-λ6-thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; N-[(2E)-3-[Imino(oxo)(4-phenoxyphenyl)-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-{[4-(dimethylamino)phenyl](imino)oxy-λ6-sulfanyl}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-6-methyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-6-(prop-2-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-6-methoxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-6-(2,2,2-trifluoroethyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1H,2H,5H,7H,8H-pyrano[4,3-b]pyridine-3-carboxamide; N-[(2E)-3-[Imino(oxo)(3-phenoxyphenyl)-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-6-(trifluoromethyl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; 6-tert-butyl-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide; tert-Butyl 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; 6-Benzyl-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-6-[(4-methoxyphenyl)methyl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; 4,4-difluorocyclohexyl 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate; 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylic acid cyclohexyl ester; N-[(2E)-3-[Imino(oxo)[4-(trifluoromethyl)phenyl]-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-8,8-dimethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; 6-(Cyclopropylmethyl)-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide; N-[(2E)-3-({[1,1'-biphenyl]-4-yl}(imino)oxy-λ6-thio)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[benzyl(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide; N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxamide; 6-Fluoro-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-{Imino[4-(morpholin-4-yl)phenyl]oxy-λ6-sulfanyl}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-{[3-cyano-4-(piperidin-1-yl)phenyl](imino)oxy-λ6-sulfanyl}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[Imino(oxo)[4-(piperidin-1-yl)phenyl]-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[Imino(oxo)[4-(pyrrolidin-1-yl)phenyl]-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-{Imino[4-(methylamino)phenyl]oxy-λ6-sulfanyl}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-{[3-cyano-4-(morpholin-4-yl)phenyl](imino)oxy-λ6-sulfanyl}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[Imino(oxo)[4-(2-oxopiperidin-1-yl)phenyl]-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[Imino(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(4-acetylaminophenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(4-cyclopropyloxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-{[3-(dimethylamino)phenyl](imino)oxy-λ6-sulfanyl}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(4-cyclohexylphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[(2,3-dihydro-1-benzofuran-5-yl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; N-[(2E)-3-[Imino(oxo)[3-(trifluoromethoxy)phenyl]-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide; and N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxy-λ6-thio]prop-2-en-1-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide.

11. A compound according to any one of the preceding claims for use as a medicament.

12. The compound for use as a medicament according to claim 11, wherein the use of the compound is combined with radiotherapy, an agent suitable for chemotherapy and / or an agent suitable for immunotherapy, in particular wherein the use of the compound is combined with a chemotherapeutic agent, an immunotherapeutic agent, a targeted therapy and / or a radiotherapy that increases the level of tumor necrosis factor (TNF).

13. A compound according to any one of claims 1 to 10 for use in the treatment of cancer.

14. A compound according to any one of claims 1 to 10 for use in the treatment of melanoma, bladder cancer, colon cancer, pancreatic cancer, ovarian cancer, breast cancer, bone cancer, lung cancer or a hematological malignancy.

15. A compound according to any one of claims 1 to 10 for use in the treatment of ovarian cancer, lung cancer or a haematological malignancy.

16. A method for inhibiting Met1-linked ubiquitination, wherein the method comprises administering a compound according to any one of claims 1 to 10.

17. The method according to claim 16, wherein the inhibition of the Met1-linked ubiquitination comprises inhibition of the linear ubiquitin (Ub) chain assembly complex (LUBAC), preferably inhibition of RNF31 (HOIP).

18. The method according to claim 16 or 17, wherein the inhibition of the Met1-linked ubiquitination comprises irreversible or reversible inhibition of the linear ubiquitin (Ub) chain assembly complex (LUBAC), preferably irreversible inhibition of RNF31 (HOIP) by covalent binding of the compound.

19. A composition comprising a compound according to any one of claims 1 to 10, wherein the composition further comprises at least one carrier.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10.

21. The pharmaceutical composition of claim 20, wherein the composition further comprises at least one pharmaceutically acceptable carrier.

22. The pharmaceutical composition according to claim 20 or 21, wherein the composition further comprises tumor necrosis factor (TNF).

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