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

Abstract

The present invention relates to 3-(sulfonyl or sulfonimidoyl)prop-2-en-1-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide derivatives having the formula: or a pharmaceutically acceptable salt thereof. The present invention further relates to the compounds according to the invention for use as medicaments and for use in 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. [Chemical 1] JPEG2025521573000023.jpg2955

Description

Technical Field

[0001] The present invention relates to 3-(sulfonyl or sulfonimidoyl)prop-2-en-1-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide derivatives or pharmaceutically acceptable salts thereof. The present invention further relates to the compounds according to the invention for use as pharmaceuticals and for use in 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] Cell homeostasis depends on adaptation to the environment through a number of signaling cascades that convert external and internal cues and stresses into appropriate responses. Signaling is most commonly amplified through rapid and specific post-translational modifications (PTMs) of signaling proteins, leading to adaptive changes at the transcriptional and translational levels. Failure to adapt can cause cell damage and cell death, resulting in disease. Methionine 1 (Met1)-linked ubiquitin (also called linear ubiquitin) has emerged over the past decade as a PTM that is crucial for controlling vital signaling cascades and preventing cell death. Thus, dysregulation of Met1-linked ubiquitination is associated with severe pathologies including immune disorders, cancer, and neurodegeneration, highlighting that the balance of just one single subtype of PTM can be essential for preventing and treating diseases that threaten life by maintaining homeostasis. The linear ubiquitin (Ub) chain assembly complex (LUBAC) is the only known mammalian ubiquitin ligase that generates Met1-linked ubiquitin. Thus, 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-associated RH domain-interacting protein (SHARPIN). Among these three proteins, HOIP (RNF31) has significant specificity and assembles only Met1-Ub, while HOIL-1 and SHARPIN have been found to function as cofactors in LUBAC and are important for HOIP activation. LUBAC was first described to regulate signaling in response to activation of tumor necrosis factor (TNF) receptor 1 (TNF-R1), and subsequently has been found to regulate signaling by a wide range of NF-κB-activating immune receptors, including cytokine receptors, Toll-like receptors (TLRs), NOD-like receptors (NLRs), and antigen receptors. Thus, LUBAC can be regarded as one of the core components of the NF-κB-activating signaling pathway.

[0004] Further detailed information regarding the mechanisms and pathways involved in Met1-linked ubiquitin PTM and subsequent control of vital signaling cascades and prevention of cell death is described, for example, by 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 signalling 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-ΚB Activation Pathway.” Frontiers in immunology (2020): 3042).

[0005] Considering the above, by controlling the function of LUBAC, the role and regulation of Met1-linked ubiquitin can be controlled, and thus the onset of diseases such as cancer can be subsequently controlled. It is considered that by providing Met1-linked ubiquitination inhibitors, specifically, 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 is a compound having the formula (I), wherein

Chemical formula

[0006] wherein, n is 1, 2, 3 or 4, A is oxygen or nitrogen, X is carbon or nitrogen, or 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 R 3 and R 4 together with the carbon to which they are attached form (C3-C6)cycloalkyl, R 5 is selected from the group consisting of hydrogen, halo, or (C1-C6)alkyl, R 6 is 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, and the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with 1 to 4 halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C2-C9)heterocycloalkyl, (C3-C6)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, cyano, primary, secondary, or tertiary amino, When X is carbon, R 7 is R 7’ and R 7’’ wherein R 7’ is selected from the group consisting of hydrogen, halo or (C1-C6) alkyl, and 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, and the aryl and heteroaryl groups are optionally substituted with 1 to 3 (C1-C6) alkyl groups, 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, and the aryl and heteroaryl groups are optionally substituted with 1 to 3 (C1-C6) alkyl groups, or R 7 is R 8 M-, -R 8 where -R 8 M- is selected from the group consisting of -C(O)-, R 8 -O-C(O)-, R 8 -NH-C(O)-, or R 8 -S(O)2-, -R 8is 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, and the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and bicycloalkyl groups are optionally substituted with 1 to 4 halo, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) acyl, (C1-C6) aryl, (C6-C10) alkoxy, cyano, oxo or hydroxy, a compound, or a pharmaceutically acceptable salt thereof is provided herein.

[0007] The compounds of the present invention exhibit promising RNF31 inhibitory properties (in a cell-free HTRF-based HOIP inhibition assay) and have thus been found to be promising candidates as Met1-binding ubiquitination inhibitors. It has further been found that the compounds of the present invention downregulate the nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) signaling pathway and / or upregulate tumor necrosis factor α (TNFα)-induced cytotoxicity.

[0008] Considering the compounds of the present invention, R 3 , R 4 and R 5 compounds that are hydrogen have been found to further exhibit RNF31 inhibitory properties of the NF-κB signaling pathway and improved downregulation properties of the NF-κB signaling pathway and / or upregulation properties of TNFα-induced cytotoxicity.

[0009] Similarly, R from the group consisting of (C6-C10) aryl or (C2-C9) heteroaryl 6By selecting, aryl and heteroaryl groups are optionally substituted with 1 to 4 halos, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C2-C9)heterocycloalkyl, (C3-C6)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, cyano, primary, secondary, or tertiary amino, and more promising candidates for Met1-linked ubiquitination inhibition are identified.

[0010] Preferably, when X is carbon, R 7 is R 7’ and R 7’’ where R 7’ is selected from the group consisting of hydrogen, halo or (C1-C6)alkyl, and 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, and the aryl and heteroaryl groups are optionally substituted with 1 to 3 (C1-C6)alkyls. 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, and the aryl and heteroaryl groups are optionally substituted with 1 to 3 (C1-C6)alkyls, or R 7 is R 8 M-, -R 8 where M- is selected from the group consisting of R 8 -O-C(O)-, R 8 -NH-C(O)-, or R 8 -S(O)2-. -R 8is 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, and the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and bicycloalkyl groups are optionally substituted with 1 to 4 halo, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)acyl, (C1-C6)aryl, (C6-C10)alkoxy, cyano, oxo or hydroxy.

[0011] In an embodiment of the present invention, n can be 1, 2 or 3 which results in a compound having improved Met1 binding ubiquitination inhibitory properties. Further, in a preferred embodiment, it is noted that the present invention requires that when X is nitrogen, R 7 is not hydrogen.

[0012] In a particular embodiment of the present invention, the present invention is a compound having formula (II), [Chemical Formula] wherein, n is 1, 2, or 3, A is oxygen or nitrogen, R’ is selected from the group consisting of (C6-C10) aryl or (C2-C9) heteroaryl, and the aryl and heteroaryl groups are optionally substituted with 1 to 4 halos, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C6) cycloalkyl, (C2-C9) heterocycloalkyl, (C3-C6) cycloalkoxy, (C6-C10) aryl, (C6-C10) aryloxy, cyano, primary, secondary, or tertiary amino, a compound, or a pharmaceutically acceptable salt thereof. Preferably, with respect to formula (II), certain active compounds are obtained, (C6-C10) aryl is phenyl, or (C2-C9) heteroaryl is pyridinyl, and it has been found that the phenyl and pyridinyl groups are optionally substituted with 1 to 3 fluorines, chlorines, bromines, or methoxys.

[0013] In a further specific embodiment of the present invention, the present invention is a compound having formula (III), wherein

Chemical formula

[0014] When it is stated that any of the groups in the compounds of the present invention is optionally substituted, this group can be unsubstituted or substituted by one or more substituents. Typically, such a group is unsubstituted or substituted by 1, 2, or 3 substituents, specifically 1 or 2 substituents.

[0015] For medical use, the salts of the compounds of the present invention are pharmaceutically acceptable salts. However, other salts may be useful in the preparation of the compounds for use in the present invention or their pharmaceutically acceptable salts.

[0016] Suitable pharmaceutically acceptable salts of the compounds of the present invention include, for example, acid addition salts that can be formed by mixing a solution of the compounds 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. Further, when the compound used in the present invention bears an acidic moiety, for example, carboxy, its suitable pharmaceutically acceptable salts may include alkali metal salts such as sodium salts or potassium salts, alkaline earth metal salts such as calcium salts or magnesium salts, ammonium salts, and salts formed with suitable organic ligands such as quaternary ammonium salts, and meglumine salts.

[0017] The present invention includes solvates of the compounds of the present invention. Such solvates can be formed with common organic solvents such as hydrocarbon solvents like benzene or toluene, chlorinated solvents like chloroform or dichloromethane, alcohol solvents like methanol, ethanol or isopropanol, ether solvents like diethyl ether or tetrahydrofuran, or ester solvents like ethyl acetate. Alternatively, the solvates of the compounds of formula (I) may be formed with water, in which case they are hydrates.

[0018] The present invention also includes co-crystals of the compounds of the present invention. The term "co-crystal" is used to describe a situation where neutral molecular components are present in a crystalline compound in a specific stoichiometric ratio. The preparation of pharmaceutical co-crystals allows for modification of the crystalline form of the active pharmaceutical ingredient, which in turn can alter its physicochemical properties without impairing its intended biological activity. Typical examples of co-crystal formers that can be present in the co-crystal along with the active pharmaceutical ingredient include L-ascorbic acid, citric acid, glutaric acid, urea, and nicotinamide.

[0019] The present invention further includes prodrugs of the compounds of the present invention. Generally, such prodrugs are functional derivatives of the compounds of the present invention and can be readily converted in vivo to the required compounds of the present invention.

[0020] Suitable alkyl groups that may be present on the compounds of the present invention include linear and branched (C1-C6) alkyl groups, such as (C1-C4) alkyl groups. Typical examples include methyl and ethyl groups, as well as linear or branched propyl, butyl, and pentyl groups. Specific alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl, and 3-methylbutyl. Derived expressions such as “(C1-C6) alkoxy” and “(C1-C6) acyl” should be interpreted accordingly. Further, as used herein, the term “di-(C1-C6) alkyl” is intended to refer to two alkyl groups containing 1 to 6 carbon atoms bonded to the same carbon.

[0021] Suitable alkenyl groups that may be present on the compounds of the present invention include linear and branched (C2-C6) alkenyl groups including vinyl and allyl. Suitable alkynyl groups that may be present in the compounds of the present invention include linear and branched (C2-C6) alkynyl groups including ethynyl, propargyl, and butynyl.

[0022] 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.

[0023] 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 its benzo-fused analogs. Suitable heterocycloalkyl groups include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, dihydrobenzothienyl, pyrrolidinyl, indolinyl, isoindolinyl, 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, thiazepanyl, and azocanyl groups.

[0024] As used herein, the term “(C6-C10) aryl” refers to a monovalent carbocyclic aromatic group derived from a single aromatic ring or multiple fused aromatic rings. Suitable aryl groups include a phenyl group and a naphthyl group, preferably a phenyl group.

[0025] 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 fused rings, wherein one or more carbon atoms are replaced by one or more heteroatoms selected from oxygen, sulfur, and nitrogen. Suitable heteroaryl groups include furyl, benzofuryl group, dibenzofuryl group, thienyl group, benzothienyl group, thieno[2,3-c]pyrazolyl group, thieno[3,4-b][1,4]dioxinyl group, dibenzothienyl group, pyrrolyl group, indolyl group, pyrrolo[2,3-b]pyridinyl group, pyrrolo[3,2-c]pyridinyl group, pyrrolo[3,4-b]pyridinyl group, diazepanyl, pyrazolyl group, pyrazolo[1,5-a]pyridinyl group, pyrazolo[3,4-d]pyrimidinyl group, indazolyl group, 4,5,6,7-tetrahydroindazolyl group, oxazolyl group, benzoxazolyl group, isoxazolyl group, thiazolyl group, benzothiazolyl group, isothiazolyl group, imidazolyl group, benzimidazolyl group, imidazo[2,1-b]thiazolyl group, imidazo[1,2-a]pyridinyl group, imidazo[4,5-b]pyridinyl group, purinyl group, imidazo[1,2-a]pyrimidinyl group, imidazo[1,2-a]pyrazinyl group, oxadiazolyl group, thiadiazolyl group, triazolyl group, [1,2,4]triazolo[1,5-a]-pyrimidinyl, benzotriazolyl group, tetrazolyl group, pyridinyl group, quinolinyl group, isoquinolinyl group, naphthyridinyl group, pyridazinyl group, cinnolinyl group, phthalazinyl group, pyrimidinyl group, quinazolinyl group, pyrazinyl group, quinoxalinyl group, pteridinyl group, triazinyl group, and chromenyl group.

[0026] 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" is intended to refer to two halogens bonded to the same carbon.

[0027] 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.

[0028] 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]hexanyl, bicyclo[1.1.1]pentanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, and bicyclo[2.2.2]octanyl groups. Alternatively, or in addition, instead of a (C5-C9) bicycloalkyl group, a (C4-C9) heterobicycloalkyl group may be present on the compounds of the present invention, and a (C4-C9) heterobicycloalkyl group corresponds to a (C5-C9) bicycloalkyl group in which one or more of the carbon atoms are 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, quinuclidinyl, 2-oxa-5-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.2]nonanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl, and 3,9-diazabicyclo[4.2.1]nonanyl.

[0029] In addition to the above terms, derivatives 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” should be interpreted accordingly. For example, suitable (C6-C10) aryl (C1-C6) alkyl groups include benzyl group, phenylethyl group, phenylpropyl group, and naphthylmethyl group. Suitable (C2-C9) heteroaryl (C1-C6) alkyl groups include pyridylmethyl, pyridazinylmethyl, oxadiazolylmethyl, furanylethyl, oxo-pyridinylethyl and 1H-indazolylmethyl groups. Suitable (C3-C10) cycloalkyl (C1-C6) alkyl groups include cyclopropylmethyl group. Suitable (C1-C6) alkoxy (C1-C6) alkyl groups include methoxyethyl and methoxypropyl groups.

[0030] In addition, it should be further noted that any substituent defined for the present invention may further include additional substituents as such. For example, when a particular group is optionally substituted with (C1-C6) alkoxy, the (C1-C6) alkoxy may be further substituted with, for example, halo, hydroxy, cyano, oxo, primary, secondary, or tertiary amino, etc.

[0031] When the compounds of the present invention have one or more asymmetric centers, they can thus exist as enantiomers. When the compounds for use in the present invention have two or more asymmetric centers, they can further exist as diastereomers. The present invention is to be understood to extend to the use of all such enantiomers and diastereomers, and any proportion of mixtures thereof including racemates. The formula (I) and the formulas shown below are intended to represent all individual stereoisomers and all possible mixtures thereof, unless otherwise specified or indicated. In addition, the compounds of the present invention can exist as tautomers, for example, keto (CH2C=O) <-> enol (CH=CHOH) tautomers, amide (NHC=O) <-> hydroxyimine (N=COH) tautomers, or 2-hydroxypyridine <-> 2-pyridone tautomers. The formula (I) and the formulas shown below are intended to represent all individual tautomers and all possible mixtures thereof, unless otherwise specified or indicated.

[0032] It should be understood that each individual atom present in formula (I), or in the formulas shown below, can actually exist in any form of its naturally occurring isotopes, with the most abundant isotope(s) being preferred. Thus, by way of example, each individual hydrogen atom present in formula (I) or in the formulas shown below can be 1 H, 2 H (deuterium) or 3 H (tritium) atoms, preferably 1 H. Similarly, by way of example, each individual carbon atom present in formula (I), or in the formulas shown below, can be 12 C, 13 C, or 14 C atoms, preferably 12 C.

[0033] In a preferred embodiment of the present invention, the compound having RNF31 activity is N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-6-benzyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide, N-[(2Z)-3-(Benzenesulfonyl)-3-fluoroprop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(Benzenesulfonyl)-3-fluoroprop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2Z)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, tert-Butyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide, N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide, N-[(3E)-4-(Benzenesulfonyl)-2-methylbut-3-en-2-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-{1-[(E)-2-(Benzenesulfonyl)ethenyl]cyclopropyl}-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, 6-Acetyl-N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide, N-[(2E)-3-(Benzenesulfonyl)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-(Benzenesulfonyl)but-3-en-2-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(Benzenesulfonyl)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-Methanesulfonylprop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, 6-[2-(Adamantan-1-yl)acetyl]-N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide, N-[(2E)-3-(Benzenesulfonyl)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-(Benzenesulfonyl)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-(Benzenesulfonyl)prop-2-en-1-yl]-6-cyclopropanecarbonyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide, N-[(2E)-3-(Benzenesulfonyl)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-(Benzenesulfonyl)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-(Benzenesulfonyl)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-(Benzenesulfonyl)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-(Benzenesulfonyl)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-(Benzenesulfonyl)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-Fluorobenzenesulfonyl)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-(propan-2-sulfonyl)prop-2-en-1-yl]-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(3-Fluoro-4-methoxybenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(Benzenesulfonyl)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-(Benzenesulfonyl)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-(Benzenesulfonyl)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-(propan-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-(Benzenesulfonyl)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-(benzenesulfonyl)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-fluorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, N-[(2E)-3-(2-Methylpropan-2-sulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(2-Fluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, tert-Butyl 3-{[(2E)-3-(4-fluorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-6-(3,3-dimethylbutanoyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide, tert-Butyl 3-{[(2E)-3-(3-fluoro-4-methoxybenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, N-[(2E)-3-(Benzenesulfonyl)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-(benzenesulfonyl)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-(Benzenesulfonyl)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-(Benzenesulfonyl)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-(Benzenesulfonyl)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-Chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide, 6-Benzyl-N-[(2E)-3-(4-chlorobenzenesulfonyl)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-Fluorobenzenesulfonyl)but-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(2-Fluorobenzenesulfonyl)but-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, Cyclopropylmethyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, Cyclobutyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, (5-Methyl-1,3,4-oxadiazol-2-yl)methyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, 1,1,1-Trifluoropropan-2-yl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, (2,2-Dimethylcyclopropyl)methyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, (2,2-Difluorocyclopropyl)methyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, Oxetan-3-yl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, 1-Methoxypropan-2-yl 3-{[(2E)-3-(benzenesulfonyl)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-(benzenesulfonyl)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-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, Cyclopropyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-6-(2-phenylcyclopropanecarbonyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide, 2-Oxospiro[3.5]nonan-7-yl 3-{[(2E)-3-(benzenesulfonyl)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-(benzenesulfonyl)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-(benzenesulfonyl)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-(benzenesulfonyl)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-fluorobenzenesulfonyl)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-fluorobenzenesulfonyl)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-fluorobenzenesulfonyl)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-methoxybenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide, N-[(2E)-3-(Benzenesulfonyl)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-Chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide, N-[(2E)-3-(3-Fluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(4-Methoxybenzenesulfonyl)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-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, N-[(2E)-3-(2-Chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, Cyclopentyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, (2,2-Dimethylcyclopropyl)methyl 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-Difluorocyclopropyl)methyl 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, Oxetan-3-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-(4-chlorobenzenesulfonyl)-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, Cyclopropylmethyl 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-(2,4-difluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide, N-[(2E)-3-(benzenesulfonyl)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-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, Cyclohexyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, 1-(2,6-Difluorophenyl)ethyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, 1-Acetylpiperidin-4-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, 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, Cyclopropylmethyl 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-carboxylate, 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-bromobenzenesulfonyl)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-(benzenesulfonyl)prop-2-en-1-yl]-2-oxo-6-(propan-2-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, Cyclopropylmethyl 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide, N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-6,6-dimethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-6,6-difluoro-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N3-[(2E)-3-(4-Chlorobenzenesulfonyl)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-Chlorobenzenesulfonyl)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-chlorobenzenesulfonyl)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)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(Benzenesulfonyl)(1,1- 2 H2)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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(3,4-Dimethylphenyl)(imino)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, Cyclopropylmethyl 3-{[(2E)-3-[(4-fluorophenyl)(imino)oxo-λ 6 -sulfanyl]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)phenyl-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(4-tert-Butylphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(4-Ethoxyphenyl)(imino)oxo-λ 6-Sulfanyl]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)oxo-λ 6 -Sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[Imino(3-methoxyphenyl)oxo-λ 6 -Sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[Imino(oxo)[4-(trifluoromethoxy)phenyl]-λ 6 -Sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(4-chlorophenyl)(imino)oxo-λ 6 -Sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(2-fluorophenyl)(imino)oxo-λ 6 -Sulfanyl]prop-2-λ 6 -1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(3-chloro-4-methoxyphenyl)(imino)oxo-λ 6 -Sulfanyl]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)oxo-λ 6 -Sulfanyl]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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(2,4-difluorophenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(4-cyanophenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[imino(4-methoxy-3-methylphenyl)oxo-λ 6 -sulfanyl]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]-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[imino(4-methoxy-2-methylphenyl)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, Cyclopropylmethyl 3-{[(2E)-3-[imino(oxo)phenyl-λ 6 -sulfanyl]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-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ 6-sulfanyl]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(oxo)phenyl-λ 6 -sulfanyl]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(oxo)phenyl-λ 6 -sulfanyl]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)-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-{[4-(dimethylamino)phenyl](imino)oxo-λ 6 -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)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide, N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-6-(propan-2-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]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)-λ 6 -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)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide, N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, Cyclohexyl 3-{[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6-Sulfanyl]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-(trifluoromethyl)phenyl]-λ 6 -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)oxo-λ 6 -Sulfanyl]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)oxo-λ 6 -Sulfanyl]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)oxo-λ 6 -Sulfanyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[Benzyl(imino)oxo-λ 6 -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)oxo-λ 6 -Sulfanyl]prop-2-en-1-yl]-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide, N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -Sulfanyl]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)oxo-λ 6 -sulfanyl]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]oxo-λ 6 -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)oxo-λ 6 -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]-λ 6 -sulfanyl]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]-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-{imino[4-(methylamino)phenyl]oxo-λ 6 -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)oxo-λ 6 -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]-λ 6-Sulfanyl]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)oxo-λ 6 -Sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(4-Acetamidophenyl)(imino)oxo-λ 6 -Sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(4-Cyclopropoxyphenyl)(imino)oxo-λ 6 -Sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-{[3-(Dimethylamino)phenyl](imino)oxo-λ 6 -Sulfanyl}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(4-Cyclohexylphenyl)(imino)oxo-λ 6 -Sulfanyl]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)oxo-λ 6 -Sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[Imino(oxo)[3-(trifluoromethoxy)phenyl]-λ 6 -Sulfanyl]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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide, selected from the group consisting of

[0034] Specifically, in relation to improved RNF31 activity, promising results were obtained, and the compounds are N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-6-benzyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide, tert-Butyl 3-{[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-6-(3-methoxypropanoyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide, N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-6-(2-methoxyethanesulfonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide, 6-[2-(Adamantan-1-yl)acetyl]-N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide, N-[(2E)-3-(Benzenesulfonyl)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-(Benzenesulfonyl)prop-2-en-1-yl]-6-cyclopropanecarbonyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide, N-[(2E)-3-(Benzenesulfonyl)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-(Benzenesulfonyl)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-(Benzenesulfonyl)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-(Benzenesulfonyl)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-Fluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(3-Fluoro-4-methoxybenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(Benzenesulfonyl)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-(Benzenesulfonyl)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-(Benzenesulfonyl)prop-2-en-1-yl]-6-(2-cyclopropylacetyl)-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-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, 2-Methylpropyl 3-{[(2E)-3-(benzenesulfonyl)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-fluorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, N-[(2E)-3-(2-Fluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, tert-Butyl 3-{[(2E)-3-(4-fluorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-6-(3,3-dimethylbutanoyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide, tert-Butyl 3-{[(2E)-3-(3-fluoro-4-methoxybenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, N-[(2E)-3-(Benzenesulfonyl)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-(benzenesulfonyl)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-(Benzenesulfonyl)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-(Benzenesulfonyl)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-(4-Chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide, 6-Benzyl-N-[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide, Cyclopropylmethyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, Cyclobutyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, (5-Methyl-1,3,4-oxadiazol-2-yl)methyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, 1,1,1-Trifluoropropan-2-yl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, (2,2-Dimethylcyclopropyl)methyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, (2,2-Difluorocyclopropyl)methyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, Oxetan-3-yl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, 1-Methoxypropan-2-yl 3-{[(2E)-3-(benzenesulfonyl)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-(benzenesulfonyl)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-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, Cyclopropyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-6-(2-phenylcyclopropanecarbonyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide, 2-Oxospiro[3.5]nonan-7-yl 3-{[(2E)-3-(benzenesulfonyl)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-(benzenesulfonyl)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-(benzenesulfonyl)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-(benzenesulfonyl)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-fluorobenzenesulfonyl)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-fluorobenzenesulfonyl)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-fluorobenzenesulfonyl)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-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide, N-[(2E)-3-(2-Chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide, N-[(2E)-3-(3-Fluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(4-Methoxybenzenesulfonyl)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-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, N-[(2E)-3-(2-Chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, Cyclopentyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, (2,2-Dimethylcyclopropyl)methyl 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-Difluorocyclopropyl)methyl 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, Oxetan-3-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, Cyclopropylmethyl 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-(2,4-difluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide, N-[(2E)-3-(benzenesulfonyl)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-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, Cyclohexyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, 1-(2,6-difluorophenyl)ethyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, 1-acetylpiperidin-4-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, 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, Cyclopropylmethyl 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-carboxylate, 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-bromobenzenesulfonyl)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-(benzenesulfonyl)prop-2-en-1-yl]-2-oxo-6-(propan-2-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, Cyclopropylmethyl 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide, N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-6,6-dimethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-6,6-difluoro-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N3-[(2E)-3-(4-chlorobenzenesulfonyl)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-chlorobenzenesulfonyl)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-chlorobenzenesulfonyl)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)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(benzenesulfonyl)(1,1- 2 H2)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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(3,4-dimethylphenyl)(imino)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, Cyclopropylmethyl 3-{[(2E)-3-[(4-fluorophenyl)(imino)oxo-λ 6-sulfanyl]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)phenyl-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(4-tert-butylphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(4-ethoxyphenyl)(imino)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[imino(3-methoxyphenyl)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[imino(oxo)[4-(trifluoromethoxy)phenyl]-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(4-chlorophenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(2-fluorophenyl)(imino)oxo-λ 6-sulfanyl]prop-2-yl 6 -1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(3-chloro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(2,4-difluorophenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(4-cyanophenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[imino(4-methoxy-3-methylphenyl)oxo-λ 6 -sulfanyl]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]-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[Imino(4-methoxy-2-methylphenyl)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, Cyclopropylmethyl 3-{[(2E)-3-[Imino(oxo)phenyl-λ 6 -sulfanyl]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-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]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(oxo)phenyl-λ 6 -sulfanyl]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(oxo)phenyl-λ 6 -sulfanyl]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)-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-{[4-(Dimethylamino)phenyl](imino)oxo-λ 6 -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)oxo-λ 6-Sulfanyl]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)oxo-λ 6 -Sulfanyl]prop-2-en-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide, N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -Sulfanyl]prop-2-en-1-yl]-2-oxo-6-(propan-2-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -Sulfanyl]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)oxo-λ 6 -Sulfanyl]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)oxo-λ 6 -Sulfanyl]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)-λ 6 -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)oxo-λ 6-sulfanyl]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)oxo-λ 6 -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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide, N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]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)oxo-λ 6-Sulfanyl]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)oxo-λ 6 -Sulfanyl]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, Cyclohexyl 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -Sulfanyl]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-(trifluoromethyl)phenyl]-λ 6 -Sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-({[1,1'-Biphenyl]-4-yl}(imino)oxo-λ 6 -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)oxo-λ 6 -Sulfanyl]prop-2-en-1-yl]-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide, N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -Sulfanyl]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)oxo-λ 6-Sulfanyl]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]oxo-λ 6 -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)oxo-λ 6 -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]-λ 6 -Sulfanyl]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]-λ 6 -Sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-{Imino[4-(methylamino)phenyl]oxo-λ 6 -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)oxo-λ 6 -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]-λ 6 -Sulfanyl]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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(4-Acetamidophenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(4-Cyclopropoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-{[3-(Dimethylamino)phenyl](imino)oxo-λ 6 -sulfanyl}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(4-Cyclohexylphenyl)(imino)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[Imino(oxo)[3-(trifluoromethoxy)phenyl]-λ 6 -sulfanyl]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)oxo-λ 6-sulfanyl]prop-2-en-1-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide.

[0035] Very promising results related to improved tumor necrosis factor (TNF) and / or nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) activity have been obtained, and the compounds are N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-6-benzyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide, N-[(2E)-3-(4-fluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(3-fluoro-4-methoxybenzenesulfonyl)prop-2-en-1-yl]-2-oxo-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, 2-methylpropyl 3-{[(2E)-3-(benzenesulfonyl)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-fluorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, N-[(2E)-3-(2-fluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, 6-Benzyl-N-[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide, 2-(4-Chlorophenyl)ethyl 3-{[(2E)-3-(benzenesulfonyl)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-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide, Cyclopropylmethyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, Cyclobutyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, 1,1,1-Trifluoropropan-2-yl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, (2,2-Dimethylcyclopropyl)methyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6-sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(2-chloro-4-fluorobenzenesulfonyl)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-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide, N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide, N-[(2E)-3-(3-fluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(4-methoxybenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(2-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, Cyclopentyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, (2,2-dimethylcyclopropyl)methyl 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, Cyclopropylmethyl 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, Cyclohexyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate, 1-(2,6-Difluorophenyl)ethyl 3-{[(2E)-3-(benzenesulfonyl)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-(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, N-[(2E)-3-(4-Bromobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-2-oxo-6-(propan-2-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-6,6-dimethyl-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-(Benzenesulfonyl)(1,1- 2 H2)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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(3,4-Dimethylphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(4-tert-Butylphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(4-Ethoxyphenyl)(imino)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[Imino(3-methoxyphenyl)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[Imino(oxo)[4-(trifluoromethoxy)phenyl]-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(4-chlorophenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(3-chloro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(3-chlorophenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[Imino(4-methoxy-3-methylphenyl)oxo-λ 6 -sulfanyl]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]-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[Imino(4-methoxy-2-methylphenyl)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[Imino(oxo)(4-phenoxyphenyl)-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-{[4-(Dimethylamino)phenyl](imino)oxo-λ 6 -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)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide, N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-6-(propan-2-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[Imino(oxo)(3-phenoxyphenyl)-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, 6-tert-Butyl-N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6-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)oxo-λ 6 -Sulfanyl]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)oxo-λ 6 -Sulfanyl]prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide, 6-Benzyl-N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -Sulfanyl]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)oxo-λ 6 -Sulfanyl]prop-2-en-1-yl]-6-[(4-methoxyphenyl)methyl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide, Cyclohexyl 3-{[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -Sulfanyl]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-(trifluoromethyl)phenyl]-λ 6 -Sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-({[1,1'-Biphenyl]-4-yl}(imino)oxo-λ 6-[(2E)-3-{Imino[4-(morpholin-4-yl)phenyl]oxo-λ 6 -sulfanyl}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]oxo-λ 6 -sulfanyl}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, 6 -[(2E)-3-{Imino[4-(morpholin-4-yl)phenyl]oxo-λ 6 -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)oxo-λ 6 -sulfanyl}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, 6 -[(2E)-3-{[3-Cyano-4-(piperidin-1-yl)phenyl](imino)oxo-λ 6 -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]-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, 6 -[(2E)-3-[Imino(oxo)[4-(piperidin-1-yl)phenyl]-λ 6 -sulfanyl]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]-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, 6 -[(2E)-3-[Imino(oxo)[4-(pyrrolidin-1-yl)phenyl]-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-{Imino[4-(methylamino)phenyl]oxo-λ 6 -sulfanyl}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, 6 -[(2E)-3-{Imino[4-(methylamino)phenyl]oxo-λ 6 -sulfanyl}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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, 6 -[(2E)-3-[Imino(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(4-Cyclopropoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, 6 -[(2E)-3-[(4-Cyclopropoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-{[3-(dimethylamino)phenyl](imino)oxo-λ 6 -sulfanyl}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, N-[(2E)-3-[(4-cyclohexylphenyl)(imino)oxo-λ 6 -sulfanyl]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)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, and N-[(2E)-3-[imino(oxo)[3-(trifluoromethoxy)phenyl]-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide selected from the group consisting of.

[0036] 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 a drug (chemotherapeutic agent) suitable for use in radiotherapy, targeted therapy, chemotherapy, and / or a drug (immunotherapeutic agent) suitable for use in immunotherapy. Specifically, the use of the compound is combined with such therapies and drugs that cause an increase in the level of tumor necrosis factor (TNF), for example, tumor necrosis factor α (TNFα) as a result of treatment with such chemotherapeutic agents, immunotherapeutic agents, targeted therapy, and / or radiotherapy.

[0037] Examples of radiotherapy that cause an increase in TNF levels such as TNFα 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), Di Maggio, 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).

[0038] Examples of targeted therapies that cause an increase in TNF levels, such as TNFα, 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, Maria Florencia, et al. ("Tumor necrosis factor α blockade: an opportunity to tackle breast cancer." Frontiers in oncology 10 (2020): 584), and Labrie, Marilyn, et al. ("Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer." Nature Reviews Cancer 22.6 (2022): 323-339).

[0039] Examples of chemotherapeutic agents and / or immunotherapeutic agents that cause an increase in TNF levels, such as TNFα, 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, Maria Florencia, et al. (“Tumor necrosis factor α blockade: 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.” OncoTargets 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 therapies in cancer treatment.” Nature reviews cancer 12.4 (2012): 237-251).

[0040] In a third aspect of the present invention, the present invention relates to a compound of the present invention for use in the treatment of cancer. Specifically, the present invention relates to a compound of the present 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. The compounds of the present invention have been found to show promising results in the treatment of ovarian cancer, lung cancer, or hematological malignancies, specifically.

[0041] In a fourth aspect of the present invention, the present invention relates to a method of inhibiting Met1-linked ubiquitination, the method comprising administration of a compound according to the present invention. Such a method may relate to an in vitro method. However, in embodiments of the present invention, the method may also relate to a method of treating a subject such as a human. Accordingly, the present invention relates to a compound of the present invention for inhibiting Met1-linked ubiquitination.

[0042] 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).

[0043] In embodiments of the present invention, the present invention relates to a method for inhibiting Met1-linked ubiquitination, the method comprising administration of a compound according to the present invention, wherein inhibition of Met1-linked ubiquitination includes irreversible or reversible inhibition of the linear ubiquitin (Ub) chain assembly complex (LUBAC) via a covalent bond of the compound. It has been found that the compounds of the present invention inhibit the linear ubiquitin (Ub) chain assembly complex (LUBAC) covalently, specifically inhibiting RNF31 covalently.

[0044] In a fifth aspect, the present invention relates to a composition comprising a compound of the present invention, wherein the composition further comprises at least one carrier.

[0045] 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 a tumor necrosis factor (TNF).

[0046] In this regard, it should be noted that the present invention also relates to a formulation suitable for use as a pharmaceutical composition. Such formulations include, but are not limited to, tablets, powders, capsules, pellets, solutions, suspensions, elixirs, emulsions, gels, creams, patches, or suppositories (including rectal and urethral suppositories).

Examples

[0047] Synthetic route The following reaction scheme shows the preparation of the compounds of the present invention. Unless otherwise indicated, R in the reaction scheme 6 , R 7 , R 8 , X and A are defined as above.

[0048] Scheme 1

Chemical formula

[0049] In Reaction 2 of Scheme 1, the compound of Formula III is oxidized to the corresponding sulfone of Formula IV by treating III with an oxidizing agent such as Oxone® monopersulfate or sodium tungstate and hydrogen peroxide in a mixture of a polar solvent such as water and ethyl acetate or an alcohol solvent such as methanol. The reaction mixture is stirred at room temperature for a period ranging from 8 hours to 72 hours, preferably for 12 hours. R 5When it is not hydrogen, the compound of formula IV is treated with an electrophile, such as Selectfluor® or iodomethane, in the presence of an organic base, such as potassium tert-butoxide, in a polar aprotic solvent, such as tetrahydrofuran. The reaction mixture is stirred at room temperature for a period of 8 hours to 24 hours, preferably 16 hours.

[0050] In reaction 3 of Scheme 1, the compound of formula IV is converted to the compound of formula V by reacting (2-oxoethyl)carbamic acid tert-butyl ester with IV in the presence of an organic base, such as potassium tert-butoxide in a polar aprotic solvent, such as tetrahydrofuran. The reaction mixture is stirred for a period of 1 hour to 24 hours, preferably 1.5 hours.

[0051] In reaction 4 of Scheme 1, removal of the protecting group from the compound of formula V is effected 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 minutes to 3 hours, preferably 1 hour.

[0052] In reaction 5 of Scheme 1, the compound of formula III is oxidized to the corresponding sulfoxide of general structure VI by treating III with an oxidizing agent, such as Oxone® monopersulfate, in a mixture of water and an alcoholic solvent, such as methanol. The reaction is stirred at room temperature for a period of 8 hours to 72 hours, preferably 12 hours.

[0053] In reaction 6 of Scheme 1, the compound of formula VII is converted to the compound of formula VI by treating the sulfoxide with tert-butyl carbamate and iodobenzene diacetate in the presence of rhodium(II) acetate dimer and magnesium oxide in an aprotic solvent, such as dichloromethane. The reaction mixture is stirred at a temperature of 10°C to 70°C, preferably 40°C, for a period of 6 hours to 72 hours, preferably 12 hours.

[0054] In Reaction 7 of Scheme 1, 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 hour to 24 hours, preferably 1.5 hours.

[0055] In Reaction 8 of Scheme 1, removal of the protecting group from the compound of Formula VIII is effected 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 minutes to 3 hours, preferably 1 hour.

[0056] Scheme 2 [Chemical Formula] In Reaction 1 of Scheme 2, 1,3-bis(1,1-dimethylethyl) 2-(2-propyn-1-yl)imidodicarbonate is converted to the corresponding vinyl thioether of Formula IX by treating the alkyne with a thiol in the presence of a rhodium catalyst, preferably tris(triphenylphosphine)rhodium(I) chloride, preferably in DCE. The reaction mixture is stirred at a temperature of -10 °C to about 50 °C, preferably 0 °C, for a period of 12 hours to 80 hours, preferably 24 hours.

[0057] In Reaction 2 of Scheme 2, the compound of Formula IX is oxidized to the corresponding sulfoximine 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 minutes to 3 hours, preferably 30 minutes.

[0058] In Reaction 3 of Scheme 2, the removal of the protecting group from the compound of Formula X is carried out 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 10 minutes to 3 hours, preferably for 30 minutes.

[0059] Scheme 3 [Chemical Formula] In Reaction 1 of Scheme 3, amines of general structures I and II are converted to the corresponding amides of general structure XIII by treating an acid having general structure XI in the presence of an amide coupling agent such as T3P (n-propane phosphonic anhydride) or HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), and an organic base such as triethylamine or diisopropylethylamine in a polar solvent such as N,N-dimethylformamide or acetonitrile. The reaction mixture is stirred for a period of 8 hours to 72 hours, preferably for 16 hours, at room temperature.

[0060] In Reaction 2 of Scheme 3, when X is tert-butyloxycarbonyl (Boc), the removal of the Boc protecting group is carried out 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 for a period of 10 minutes to 4 hours, preferably for 2 hours, at room temperature.

[0061] Scheme 4 [Chemical Formula] In Reaction 1 of Scheme 4, 4-nitrophenyl chloroformate is converted to the corresponding carbonate of Formula XIII by treating chloroformate with an alcohol in the presence of an organic base such as pyridine in an aprotic chlorinated solvent such as dichloromethane. The reaction mixture is stirred for a period of 8 hours to 72 hours, preferably for 12 hours, at room temperature.

[0062] In Reaction 2 of Scheme 4, the compound of formula XIII is converted to the corresponding carbamate of formula XVI by treating XIII with an amine of formula XII (wherein X is nitrogen) in the presence of an inorganic base such as sodium bicarbonate in a mixture of polar aprotic and protic solvents such as water and tetrahydrofuran. The reaction mixture is stirred at room temperature for a period of 1 hour to 12 hours, preferably 2 hours.

[0063] In Reaction 3 of Scheme 4, the compound of formula XIII is converted to the corresponding carbamate of formula structure XIV by treating XIII with 1,2,5,6,7,8 - hexahydro - 2 - oxo - 1,6 - naphthyridine - 3 - carboxylate in the presence of an inorganic base such as sodium bicarbonate in a mixture of polar aprotic and protic solvents such as water and tetrahydrofuran. The reaction mixture is stirred at room temperature for a period of 1 hour to 12 hours, preferably 2 hours.

[0064] In Reaction 4 of Scheme 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 hours to 72 hours, preferably 12 hours.

[0065] In Reaction 5 of Scheme 4, the same procedure as described in Reaction 1 of Scheme 3 is used.

[0066] Scheme 5

Chemical formula

[0067] In Reaction 2 of Scheme 5, the compound of Formula XVII is converted to the corresponding urea of Formula XVIII by treating XVII with an amine of Formula XII (where X is nitrogen) in the presence of an inorganic base such as sodium bicarbonate in a mixture of polar aprotic and protic solvents such as water and tetrahydrofuran. The reaction mixture is stirred at room temperature for a period of 1 hour to 12 hours, preferably 2 hours.

[0068] Scheme 6 [Chemical formula] In Reaction 1 of Scheme 6, the compound of Formula XII where X is nitrogen is converted to the corresponding amide of Formula XIX by treating XII with an acid in the presence of an amide coupling agent such as T3P or HATU and an organic base such as triethylamine or diisopropylethylamine in a polar solvent such as N,N-dimethylformamide or acetonitrile. The reaction mixture is stirred at room temperature for a period of 8 hours to 72 hours, preferably 16 hours.

[0069] In Reaction 2 of Scheme 6, the compound of Formula XII where X is nitrogen is converted to the corresponding sulfonamide of Formula XX by treating XII with an organic sulfonyl chloride in the presence of an organic base such as triethylamine or diisopropylethylamine in a polar solvent such as N,N-dimethylformamide or acetonitrile. The reaction mixture is stirred at room temperature for a period of 8 hours to 72 hours, preferably 16 hours.

[0070] In Reaction 3 of Scheme 6, the compound of Formula XII where X is nitrogen is converted to the corresponding aminoalkyl of Formula XXI by treating XII with an organic bromide or chloride in the presence of an inorganic base such as potassium carbonate in a polar solvent such as N,N-dimethylformamide. The reaction mixture is stirred at room temperature for a period of 2 hours to 24 hours, preferably 4 hours.

[0071] Compound The following examples illustrate the preparation of the compounds of the present invention, but are not limited to their details. NMR data are reported in parts per million (δ), and the deuterium lock signal from the sample solvent (deuterated chloroform unless otherwise specified) is referenced. Commercially available 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.

[0072] Example 1 Preparation of (2E)-3-(4-bromobenzenesulfonyl)prop-2-en-1-amine hydrochloride (Scheme 1) Scheme 1, Reaction 1: Diethyl {[(4-bromophenyl)sulfanyl]methyl}phosphonate Diethyl (tosyloxy)methylphosphonate (3.0 g, 9.1 mmol, 1.0 equiv) and potassium carbonate (3.15 g, 22.8 mmol, 2.5 equiv) were suspended in anhydrous DMF (24.0 mL, 8.0 volumes), then mixed with 4-bromothiophenol (1.91 g, 9.6 mmol, 1.05 equiv) all at once, stirred for 12 h, then stirred by room temperature UPLC, showing complete consumption of the starting material and giving the desired product. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate (20 mL) and distilled water (30 mL) with saturated NaCl solution (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give a pale yellow oil (3.39 g). The oil was dissolved in minimal DCM and purified by flash chromatography eluting with hexane / ethyl acetate (0 - 55%). The product-containing fractions were collected and concentrated under reduced pressure to give the desired product, diethyl {[(4-bromophenyl)sulfanyl]methyl}phosphonate as a colorless oil (3.02 g, Y: 97%). The structure and purity of the product were confirmed by UPLC and 1 1H NMR (CDCl3, 300 MHz). 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).

[0073] Scheme 1, Reaction 2: Diethyl [(4-bromobenzenesulfonyl)methyl]phosphonate {[(4-Bromophenyl)sulfanyl]methyl}phosphonate (0.4 g, 1.18 mmol, 1.0 equiv) was dissolved in anhydrous MeOH (4.0 ml, 10.0 vol), and then a solution of Oxone®, monopersulfate compound (0.91 g, 2.95 mmol, 2.5 equiv) in distilled water (4.0 ml, 10.0 vol) was added, turning the pale yellow solution immediately into a bright white mixture. After stirring for 12 h, UPLC analysis showed complete conversion to the desired product. The mixture was filtered through Celite, washed with MeOH, and concentrated to a low volume under reduced pressure. The reduced filtrate was partitioned between saturated NaCl solution (5 mL), ethyl acetate (20 mL), and water (25 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford the desired product, diethyl [(4-bromobenzenesulfonyl)methyl]phosphonate, as a yellow oil (448 mg, Y: 99%). The product was used in the next step without further purification. The structure and purity of the product were confirmed by UPLC and 1 1H NMR (CDCl3, 300 MHz). UPLC Rt: 1.99, m / z: 373.0 [M+1]; 1 1H 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).

[0074] Scheme 1, Reaction 3: tert-Butyl N-[(2E)-3-(4-bromobenzenesulfonyl)prop-2-en-1-yl]carbamate Potassium tert-butoxide (0.13 g, 1.18 mmol, 1.0 equiv) was suspended in anhydrous THF (9.0 mL) while cooling to 0 °C over 5 min. Diethyl [(4-bromobenzenesulfonyl)methyl]phosphonate (0.45 g, 1.18 mmol, 1.0 equiv) was added dropwise as a solution in anhydrous THF (2.83 mL), immediately forming a yellow solution, which was stirred at 0 °C for 30 min under argon. tert-Butyl N-(2-oxoethyl)carbamate (0.20 g, 1.24 mmol, 1.05 equiv) 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 partitioned 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 layers were extracted with ethyl acetate (3 × 10 mL), and the combined organic layers were 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 - 36%). The fractions containing the washed 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 as a pale yellow oil (211 mg, Y: 47%). The structure and purity of the product as the (E) isomer were confirmed by UPLC and 1 1H NMR (DMSO-d6, 300 MHz). UPLC Rt: 1.87, m / z: 376.0 [M+Na]; Purity (254 nm): 99%; 1 1H NMR (300 MHz, DMSO-d6) δ 7.91 - 7.83 (m, 2H), 7.83 - 7.73 (m, 2H), 7.18 (t, J = 5.2 Hz, 1H), 6.86 (dt, J = 15.1, 4.4 Hz, 1H), 6.68 (d, J = 15.2 Hz, 1H), 3.78 (d, J = 6.0 Hz, 2H), 1.36 (s, 9H).

[0075] Scheme 1, Reaction 4: (2E)-3-(4-Bromobenzenesulfonyl)prop-2-en-1-amine hydrochloride Refrigerated 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 minutes. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure to obtain the desired product, (2E)-3-(4-bromobenzenesulfonyl)prop-2-en-1-amine hydrochloride as a white solid (161 mg, Y: 92%), which was carried on to the next reaction without further purification. The structure and purity of the product were confirmed by UPLC and 1 1H NMR (DMSO-d6, 300 MHz). UPLC Rt: 1.41 min, m / z: 276.0 [M+1], Br pattern; Purity (254 nm): 99%; 1 1H NMR (300 MHz, DMSO-d6) δ 8.23 (s, 3H), 7.96 - 7.86 (m, 2H), 7.84 - 7.75 (m, 2H), 7.08 (dt, J = 15.3, 1.6 Hz, 1H), 6.90 (dt, J = 15.3, 5.2 Hz, 1H), 3.72 (d, J = 5.7 Hz, 2H).

[0076] Example 2 [(1E)-3-Aminoprop-1-en-1-yl](4-fluorophenyl)imino-λ 6 -sulfanonedihydrochloride Preparation (Scheme 1) Scheme 1, Reaction 1: Diethyl {[(4-fluorophenyl)sulfanyl]methyl}phosphonate Diethyl (tosyloxy)methylphosphonate (9.86 g, 30 mmol, 1.0 equiv) and potassium carbonate anhydrous (10.4 g, 75 mmol, 2.5 equiv) were suspended in anhydrous DMF (79 mL, 8.0 volumes), then mixed with 4-fluorothiophenol (4.04 g, 31.5 mmol, 1.05 equiv) and stirred at room temperature. UPLC after stirring overnight showed complete consumption of the starting material with formation of the desired product. The reaction mixture was concentrated to a low volume under reduced pressure and partitioned between saturated NaCl solution (10 mL), ethyl acetate (20 mL) and distilled water (70 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (5 × 20 mL). The combined organic layers were 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 - 50%). The product-containing fractions were collected and concentrated under reduced pressure to give the desired product, diethyl {[(4-fluorophenyl)sulfanyl]methyl}phosphonate as a pale yellow oil (8.19 g, Y: 98%). The structure and purity of the product were confirmed by 1 UPLC and 1H NMR (CDCl3, 300 MHz). 1 1H 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).

[0077] Scheme 1, Reaction 5: Diethyl [(4-fluorobenzenesulfinyl)methyl]phosphonate Diethyl {[(4-fluorophenyl)sulfanyl]methyl}phosphonate (8.19 g, 29.4 mmol, 1.0 equiv) was dissolved in anhydrous MeOH (81.9 mL, 10.0 vol), cooled to 0 °C for 20 min, and then a solution of Oxone® monopersulfate compound (9.50 g, 31 mmol, 1.05 equiv) in distilled water (82 mL, 10.0 vol) was added, immediately turning the pale yellow solution into a bright white mixture, which was stirred at 0 °C for 30 min and then allowed to reach room temperature. After stirring overnight, UPLC suggested the complete formation of the desired product along with the consumption of the starting material. The reaction mixture was filtered through celite, washed with MeOH (5 × 20 mL), and concentrated to a low volume under reduced pressure. The concentrated filtrate was partitioned between saturated NaCl solution (20 mL), ethyl acetate (40 mL), and distilled water (80 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (5 × 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the desired product, diethyl [(4-fluorobenzenesulfinyl)methyl]phosphonate, as a pure yellow oil (8.754 g) suitable for the next step. The structure and purity of the product were confirmed by UPLC and 1 1H NMR (CDCl3, 300 MHz). UPLC Rt: 1.53, m / z: 295.00 [M+1]; purity (254 nm): 99%; 1 1H 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).

[0078] Scheme 1, Reaction 6: N-{[(Diethoxyphosphoryl)methyl](4-fluorophenyl)oxo-λ 6 -sulfanylidene}carbamate Diethyl [(4-fluorobenzenesulfinyl)methyl]phosphonate (1.0 g, 3.4 mmol, 1.0 equiv) was added as a solution in anhydrous DCM (20 mL, 0.17 M) to a vial containing rhodium(II) acetate dimer (0.045 g, 0.10 mmol, 0.03 equiv), tert-butyl carbamate (0.80 g, 6.8 mmol, 2.0 equiv) and magnesium oxide (0.55 g, 13.6 mmol, 4.0 equiv). The mixture was degassed with argon for 20 min before addition of iodobenzene diacetate (1.642 g, 5.097 mmol, 1.5 equiv). The vial showed near total consumption of starting material before heating and after stirring at 50 °C by UPLC for 12 h. The reaction mixture was filtered through celite, washed with DCM (6 × 10 mL) and concentrated under reduced pressure to give a yellow oil (3.458 g). The oil was dissolved in minimal DCM and purified by flash chromatography eluting with hexane / ethyl acetate (0 - 65%). The product-containing fractions were collected, concentrated under reduced pressure to give the desired product, tert-butyl N-{[(diethoxyphosphoryl)methyl](4-fluorophenyl)oxo-λ 6 -sulfanylidene}carbamate as a yellow oil (825 mg Y: 59%). The purity and structure of the product were confirmed by UPLC and 1 1H NMR (CDCl3, 300 MHz). UPLC Rt: 1.78, m / z: 432.3 [M+Na]; purity (254 nm): 99%; 1 1H 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).

[0079] Scheme 1, Reaction 7: tert-butyl N-[(2E)-3-({[(tert-butoxy)carbonyl]imino}(4-fluorophenyl)oxo-λ 6 -sulfanyl)prop-2-en-1-yl]carbamate Potassium tert-butoxide (0.14 g, 1.22 mmol, 1.0 equiv) was suspended in anhydrous THF (9.0 ml), and the mixture was cooled at 0 °C for 20 min while degassing with argon. N-{[(Diethoxyphosphoryl)methyl](4-fluorophenyl)oxo-λ 6 -sulfanylidene}carbamate (0.5 g, 1.22 mmol, 1.0 equiv) was added as a solution in anhydrous THF (3.2 ml), and the mixture formed a yellow solution. This was stirred at 0 °C for 30 min, and tert-butyl N-(2-oxoethyl)carbamate (0.20 g, 1.28 mmol, 1.05 equiv) was added as a solution in anhydrous THF (2.44 ml, 0.5 M), and the reaction was stirred under argon until it reached room temperature. After 90 min, the reaction was concentrated to dryness under reduced pressure, then partitioned between ethyl acetate (20 mL) and saturated aqueous NaHCO3 (20 mL). The layers were separated, and the organic layer was washed with saturated NaCl solution (10 mL). The aqueous layer was extracted with ethyl acetate (2 × 10 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give a yellow oil (589 mg). The oil was dissolved in a minimum of DCM and purified by flash chromatography eluting with DCM / ethyl acetate (0 - 12%). The product-containing fractions were collected, concentrated under reduced pressure, and the desired product, tert-butyl N-{[(1E)-3-{[(tert-butoxy)carbonyl]amino}prop-1-en-1-yl](4-fluorophenyl)oxo-λ 6 -sulfanylidene}carbamate was obtained as a yellow oil (225 mg, Y: 44%). The structure and purity of the (E) isomer product were confirmed by UPLC and 1 1H NMR (DMSO-d6, 300 MHz). 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).

[0080] Scheme 1, Reaction 8: [(1E)-3-aminoprop-1-en-1-yl](4-fluorophenyl)imino-λ 6 -sulfanone dihydrochloride Frozen 4N HCl in dioxane, 3.7 - 4.3N (1.36 ml, 5.4 mmol, 10.0 eq) was added to tert-butyl N-[(2E)-3-({[(tert-butoxy)carbonyl]imino}(4-fluorophenyl)oxo-λ 6 -sulfanyl)prop-2-en-1-yl]carbamate (0.23 g, 0.54 mmol, 1.0 eq), and the solution was stirred at room temperature. A white solid formed within the first 10 minutes. After 1 hour, the reaction was concentrated under reduced pressure to give the desired product [(1E)-3-aminoprop-1-en-1-yl](4-fluorophenyl)imino-λ 6 -sulfanone dihydrochloride as a light brown solid (198 mg), which was carried on to the next reaction without further purification. 1 The structure of the product was confirmed by 1H NMR (DMSO-d6, 300 MHz). UPLC Rt: 0.66, m / z = 215.1 [M+1]; Purity (254 nM): 71% (total of 3 peaks); 1 1H NMR (300 MHz, DMSO-d6) δ 8.29 (s, 6H), 8.06 - 7.91 (m, 5H), 7.55 - 7.43 (m, 4H), 6.96 (d, J = 15.1 Hz, 1H), 6.78 (dt, J = 15.1, 5.3 Hz, 1H).

[0081] Example 3 Preparation of (2E)-3-(4-chlorobenzenesulfonyl)-3-fluoroprop-2-en-1-amine hydrochloride (Scheme 1) Scheme 1, Reaction 1: Diethyl {[(4-chlorophenyl)sulfanyl]methyl}phosphonate Anhydrous diethyl (tosyloxy)methylphosphonate (11.2 g, 34.3 mmol, 1.0 equiv) and potassium carbonate (11.8 g, 85.7 mmol, 2.5 equiv) were suspended in anhydrous N,N-dimethylformamide (90.2 ml, 8.0 volume) and stirred for 12 h before being mixed with 4-bromothiophenol (5.6 g, 37.7 mmol, 1.1 equiv) all at once. After stirring at room temperature by UPLC, complete consumption of the starting material was shown and the desired product was obtained. The reaction mixture was concentrated under reduced pressure and partitioned between saturated NaCl solution (50 mL), ethyl acetate (50 mL) and distilled water (750 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (4 × 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give a pale yellow oil (12.896 g). The oil was dissolved in a minimum amount of dichloromethane and purified by flash chromatography eluting with hexane / ethyl acetate (0 - 75%). The product-containing fractions were collected and concentrated under reduced pressure to give the desired product, diethyl {[(4-chlorophenyl)sulfanyl]methyl}phosphonate as a pale yellow oil (9.88 g, Y: 97%). The structure and purity of the product were confirmed by UPLC and 1 1H NMR (CDCl3, 300 MHz). UPLC Rt: 1.84, m / z: 295.1 [M+1] Cl pattern; purity (254 nm): 99%; 1 1H 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).

[0082] Scheme 1, Reaction 2: Diethyl [(4-chlorobenzenesulfonyl)(fluoro)methyl]phosphonate Diethyl {[(4-bromophenyl)sulfanyl]methyl}phosphonate (9.8 g, 33.5 mmol, 1.0 eq) was dissolved in anhydrous methanol (59.3 mL, 6.0 vol), and then a solution of Oxone® monopersulfate compound (22.6 g, 73.7 mmol, 2.2 eq) was added to distilled water (59.3 mL, 6.0 vol), turning the pale yellow solution into a bright white mixture immediately. After stirring for 12 h, UPLC analysis showed complete conversion to the desired product. The mixture was filtered through Celite, washed with MeOH, and concentrated to a low volume under reduced pressure. The reduced filtrate was partitioned between saturated NaCl solution (10 mL), ethyl acetate (30 mL), and water (90 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the desired product, diethyl [(4-chlorobenzenesulfonyl)methyl]phosphonate, as a yellow oil (10.76 g, Y: 98%). The product was used in the next step without further purification. The structure and purity of the product were confirmed by 1 1H NMR (CDCl3, 300 MHz). UPLC Rt: 1.68, m / z: 325.1 [M-1], Cl pattern, purity (254 nm): 98%.

[0083] Potassium tert-butoxide (0.34 g, 3.06 mmol, 1.0 equiv) was added to a dry flask and suspended in anhydrous tetrahydrofuran (25.0 ml) while cooling to 0 °C for 10 min. Diethyl [(4-chlorobenzenesulfonyl)methyl]phosphonate (1.0 g, 3.06 mmol, 1.0 equiv) was added dropwise as a solution in anhydrous tetrahydrofuran (5.6 ml) to form a yellow solution, which was stirred at 0 °C under argon for 30 min. F-TEDA-BF4 (1.14 g, 3.21 mmol, 1.05 equiv) was added dropwise as a solution in anhydrous N,N-dimethylformamide (4.1 ml, 4.1 vol) over 1 min, the reaction was allowed to reach room temperature, and stirred in an argon atmosphere for 16 h. The reaction was quenched with saturated NH4Cl solution (50 mL), stirred for 10 min, concentrated to a small volume under reduced pressure, and partitioned with EtOAc (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 20 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 product-containing fractions were collected and concentrated under reduced pressure to give diethyl [(4-chlorobenzenesulfonyl)(fluoro)methyl]phosphonate as a pale yellow oil (758 mg, Y: 72%). The structure and purity of the product were confirmed by UPLC and 1 1H NMR (CDCl3, 300 MHz). UPLC Rt: 1.79, m / z: 367.0 [M+Na], Cl pattern; purity (254 nm): 98%; 1 1H 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).

[0084] Scheme 1, Reaction 3: tert-Butyl N-[(2E)-3-(benzenesulfonyl)-3-fluoroprop-2-en-1-yl]carbamate Potassium tert-butoxide (0.247 g, 2.2 mmol, 1.0 equiv) was suspended in anhydrous tetrahydrofuran (17.0 ml) and cooled to 0 °C over 5 minutes. As a solution in anhydrous tetrahydrofuran (4.9 ml), [(4-chlorobenzenesulfonyl)(fluoro)methyl]phosphonate (0.758 g, 2.2 mmol, 1.0 equiv) was added dropwise, immediately forming a yellow solution, which was stirred at 0 °C under argon for 30 minutes. As a solution in anhydrous tetrahydrofuran (4.6 ml, 0.5 M), tert-butyl N-(2-oxoethyl)carbamate (0.368 g, 2.31 mmol, 1.05 equiv) was added over 1 minute, and the reaction was stirred under argon and then allowed to reach room temperature. After 90 minutes, the reaction was concentrated under reduced pressure to give a yellow oil, which was partitioned 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 layers were extracted with ethyl acetate (4 × 5 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give a yellow oil. Next, the oil was dissolved in a minimum amount of DCM and purified by flash chromatography eluting with hexane / ethyl acetate (0 - 15%). Fractions containing the E-isomer and Z-isomer were collected separately and concentrated under reduced pressure to give tert-butyl N-[(2E)-3-(4-chlorobenzenesulfonyl)-3-fluoroprop-2-en-1-yl]carbamate as a white solid (170 mg, Y: 22%). By UPLC and 1 H NMR, the geometric shape of the molecule as the (E)-isomer was confirmed in terms of structure and purity using the coupling constant. UPLC Rt: 1.91, m / z: 372.0[M+Na], Cl pattern; purity (254 nm): 94%; 1H NMR (300 MHz, DMSO-d6) δ 7.96 (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).

[0085] Scheme 1, Reaction 4: (2E)-3-(4-chlorobenzenesulfonyl)-3-fluoroprop-2-en-1-amine hydrochloride 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 minutes. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure to obtain the desired product, (2E)-3-(4-chlorobenzenesulfonyl)-3-fluoroprop-2-en-1-amine hydrochloride as a white solid (138 mg, Y: 99%), which was carried on to the next reaction without further purification. The structure and purity of the product were confirmed by UPLC and 1 1H NMR (DMSO-d6, 300 MHz). UPLC Rt: 1.41, m / z: 249.9[M+1], Cl pattern; purity (254 nm): 99%; 1 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 3H), 8.04 - 7.95 (m, 2H), 7.90 - 7.80 (m, 2H), 6.50 (dt, J = 33.0, 6.9 Hz, 1H), 3.70 (s, 2H).

[0086] Example 4 [(1E)-3-aminoprop-1-en-1-yl](imino)[4-(trifluoromethoxy)phenyl]-λ 6 -sulfanone dihydrochloride preparation (Scheme 2) Scheme 2, Reaction 1: tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2E)-3-{[4-(trifluoromethoxy)phenyl]sulfanyl}prop-2-en-1-yl]carbamate 1,3-bis(1,1-dimethylethyl) 2-(2-propyn-1-yl) imidodicarbonate (0.3 g, 1.12 mmol, 1.0 equiv), tris(triphenylphosphine) rhodium(I) chloride (0.03 g, 0.033 mmol, 0.03 equiv) and 1,2-dichloroethane (4.0 ml) were degassed with argon for 30 minutes and cooled to 0 °C. Next, 4-(trifluoromethoxy)thiophenol (0.24 g, 1.23 mmol, 1.1 equiv) was added dropwise over 10 minutes as a solution in 1,2-dichloroethane (1.6 ml), forming a dark brown solution. The reaction was stirred overnight at room temperature under argon and then concentrated under reduced pressure to a dark brown oil. UPLC of the crude material showed formation of the desired product. The oil was dissolved in minimal DCM and purified by flash chromatography eluting with hexane / ethyl acetate (0 - 90%). The product-containing fractions were collected and concentrated under reduced pressure to give a pale yellow oil (428 mg). UPLC and 1 1H NMR (CDCl3, 300 MHz) confirmed the formation of the desired product, tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2E)-3-{[4-(trifluoromethoxy)phenyl]sulfanyl}prop-2-en-1-yl]carbamate, as an approximately 93:7 mixture with a neighboring alkene byproduct formed by addition of thiophenol on the other side of the triple bond. The mixture was used in the next step without further purification. 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).

[0087] Scheme 2, Reaction 2: tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2E)-3-[imino(oxo)[4-(trifluoromethoxy)phenyl]-λ 6-sulfanyl]prop-2-en-1-yl]carbamate tert-Butyl N-[(tert-butoxy)carbonyl]-N-[(2E)-3-{[4-(trifluoromethoxy)phenyl]-sulfanyl}prop-2-en-1-yl]-carbamate (0.43 g, 0.89 mmol, 1.0 eq) was dissolved in MeOH (17.1 ml, 40 vol), cooled to 0 °C for 10 minutes, and then carbamate ammonium (0.28 g, 3.5 mmol, 4.0 eq) was added. The mixture was stirred at 0 °C for 30 minutes, and iodobenzene diacetate (0.71 g, 2.2 mmol, 2.5 eq) was added in three portions at 10-minute intervals. After the addition of the final portion, the mixture was allowed to reach room temperature. After 30 minutes, UPLC showed complete consumption of the starting material. The reaction mixture was concentrated to a low volume under reduced pressure, then dissolved in minimal MeOH, adsorbed onto celite, and purified by flash chromatography eluting with hexane / ethyl acetate (0 - 60%). The product-containing fractions were collected, concentrated under reduced pressure, and the desired product, tert-butyl N-[(tert-butoxy)carbonyl]-N-[(2E)-3-[imino(oxo)[4-(trifluoromethoxy)phenyl]-λ 6 -sulfanyl]prop-2-en-1-yl]carbamate was obtained as a white solid (336 mg, Y: 77%). The structure and purity of the product were confirmed by UPLC and 1 1H NMR (CDCl3, 300 MHz). UPLC Rt: 1.98, m / z: 481.00 [M+1]; purity (NMR): 99%; 1 1H 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).

[0088] Scheme 2, Reaction 3: [(1E)-3-aminoprop-1-en-1-yl](imino)[4-(trifluoromethoxy)phenyl]-λ 6 -sulfanone dihydrochloride Frozen 4N HCl (1.7 mL, 6.9 mmol, 10.0 eq) in dioxane was added to N-[(tert-butoxy)carbonyl]-N-[(2E)-3-[imino(oxo)[4-(trifluoromethoxy)phenyl]-λ 6 -sulfanyl]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 minutes. After 30 minutes, 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 6 -sulfanone dihydrochloride as a white solid (258 mg, Y: 85%), which was carried on to the next reaction without further purification. The structure and purity of the product were confirmed by UPLC and 1 1H NMR (DMSO-d6, 300 MHz). UPLC Rt: 1.39, m / z: 281.00 [M+1]; purity (254): 75%; 1 1H NMR (300 MHz, DMSO-d6) δ 8.43-8.22 (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, 5.3 Hz, 1H), 3.76-3.63 (m, 2H).

[0089] Example 5 Preparation of N-[(2E)-3-(4-bromobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide (Scheme 3) 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 acetonitrile solution (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 minutes. (2E)-3-(4-Bromobenzenesulfonyl)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 hours. The reaction mixture was partitioned between water and DCM, the organic layer was recovered, 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 5% DCM / MeOH 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. LCMS Rt = 3.34 min, m / z = 451 / 453 [M+1], purity: 98.31% (254 nm); 1H NMR (300 MHz, DMSO-d6) δ 12.26 (s, 1H), 10.01 (t, J = 5.9 Hz, 1H), 8.03 (s, 1H), 7.91 - 7.83 (m, 2H), 7.83 - 7.75 (m, 2H), 6.97 (dt, J = 15.1, 4.3 Hz, 1H), 6.68 (dt, J = 15.1, 1.8 Hz, 1H), 4.23 - 4.13 (m, 2H), 2.58 (s, 2H), 1.68 (d, J = 5.6 Hz, 4H).

[0090] Example 6 N-[(2E)-3-[(4-Fluorophenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Preparation (Scheme 3) 2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid (0.023 g, 0.12 mmol, 1.0 equiv) and HATU (0.059 g, 0.16 mmol, 1.0 equiv) were dissolved in anhydrous DMF (0.5 mL). N,N-Diisopropylethylamine (0.11 ml, 0.62 mmol, 4.0 equiv) was added, and the yellow mixture was stirred for 10 minutes. [(1E)-3-Aminoprop-1-en-1-yl](4-fluorophenyl)imino-λ 6 -sulfanone dihydrochloride (0.042 g, 0.14 mmol, 0.9 equiv) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water and DCM, the organic layer was recovered, washed with saturated NaHCO3 solution, saturated NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC eluting with ethyl acetate / 10% MeOH to give N-[(2E)-3-[(4-fluorophenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide (0.012 g, 0.028 mmol, 18%) as an off-white solid. LCMS Rt = 1.85 m / z = 390.10 [M+1] 388.09 [M-1], purity: 92.5% (254 nm); 1 H NMR (300 MHz, DMSO-d6) δ 12.28 (s, 1H), 10.02 (t, J = 5.9 Hz, 1H), 8.03 (s, 1H), 7.98 - 7.85 (m, 2H), 7.48 - 7.36 (m, 2H), 6.79 (dt, J = 14.9, 4.6 Hz, 1H), 6.57 - 6.43 (m, 1H), 4.67 (s, 1H), 4.21 - 4.07 (m, 2H), 2.59 (d, J = 5.6 Hz, 2H), 1.70 (p, J = 7.3, 6.8 Hz, 4H).

[0091] The title compounds of Examples 7 - 65, 126 - 177, and 186 were prepared by a method similar to the method described in Example 5 or 6.

[0092] Example 7 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide LCMS Rt = 2.27 min, m / z = 372.98 [M+1], purity: 98% (254 nm); 1 H NMR (400 MHz, DMSO-d6) 12.26 (s, 1H), 10.02 (t, J = 6.0 Hz, 1H), 8.03 (s, 1H), 7.90 - 7.82 (m, 2H), 7.78 - 7.70 (m, 1H), 7.69 - 7.60 (m, 2H), 6.95 (dt, J = 15.2, 4.5 Hz, 1H), 6.66 (dt, J = 15.0, 1.8 Hz, 1H), 4.18 (ddd, J = 6.3, 4.5, 2.0 Hz, 2H), 2.58 (t, J = 5.9 Hz, 2H), 1.69 (q, J = 8.2 Hz, 4H).

[0093] Example 8 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-6-benzyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide RT = 2.29 min, m / z = 463.90 [M+1], purity: 95% (254 nm); 1 H NMR (300 MHz, DMSO-d6) d 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).

[0094] Example 9 N-[(2Z)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0095] Example 10 tert-Butyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 96.8% (254 nm); RT = 3.15 min, m / z = 473.69 [M+1], 471.72 [M-1]; 1 H NMR (400 MHz, DMSO-d6) 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).

[0096] 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 Purity: 97.9% (254 nm); RT = 2.23 m / z = 408.09 [M+1] 406.04 [M-1]; 11H 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).

[0097] Example 12 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide Purity: 94.6%; RT = 2.56 min, m / z = 395.18 [M+1], 392.97 [M-1], 1 1H NMR (300 MHz, DMSO-d6) 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).

[0098] Example 13 6-Acetyl-N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide Purity: 98.3%; Rt = 2.17 min, m / z = 416.17 [M+1], 414.14 [M-1]; 11H NMR (300 MHz, DMSO-d6) δ 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).

[0099] Example 14 N-[(3E)-4-(Benzenesulfonyl)but-3-en-2-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0100] Example 15 N-[(2E)-3-Methanesulfonylprop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0101] Example 16 N-[(2E)-3-(4-Fluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0102] Example 17 N-[(2E)-3-(Cyclopentanesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 98.6%; RT = 1.52 min, m / z = 365.21 [M+1], 363.18 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 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).

[0103] Example 18 2-Oxo-N-[(2E)-3-(propan-2-sulfonyl)prop-2-en-1-yl]-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 97.0%; RT = 1.76 min, m / z = 339.23 [M+1], 337.16 [M-1]; 1 1H 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).

[0104] Example 19 N-[(2E)-3-(3-Fluoro-4-methoxybenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 99.8%; RT = 1.97 min, m / z = 421.33 [M+1], 419.12 [M-1]; 11H 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).

[0105] Example 20 2 - Oxo - N - [(2Z) - 3 - (propan - 2 - sulfonyl)prop - 2 - en - 1 - yl] - 1,2,5,6,7,8 - hexahydroquinoline - 3 - carboxamide 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).

[0106] Example 21 N - [(2E) - 3 - (4 - chlorobenzenesulfonyl)prop - 2 - en - 1 - yl] - 2 - oxo - 1,2,5,6,7,8 - hexahydroquinoline - 3 - carboxamide Purity: 97.0%; RT = 5.25 min, m / z = 407.17 [M+1], 405.15 [M - 1]; 1 1H 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).

[0107] Example 22 tert-Butyl 3-{[(2E)-3-(2-fluorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate 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).

[0108] Example 23 N-[(2E)-3-(2-methylpropan-2-sulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0109] Example 24 N-[(2E)-3-(2-fluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 91.6%; RT = 2.07 m / z = 391.20 [M+1] 389.10 [M-1]; 1 H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 10.05 (t, J = 5.9 Hz, 1H), 8.04 (s, 1H), 7.88 (td, J = 7.6, 1.8 Hz, 1H), 7.84 - 7.76 (m, 1H), 7.55 - 7.40 (m, 2H), 7.05 (ddd, J = 15.1, 5.1, 3.9 Hz, 1H), 6.76 - 6.63 (m, 1H), 4.22 (ddd, J = 6.3, 4.5, 2.0 Hz, 2H), 2.58 (t, J = 6.0 Hz, 2H), 1.76 - 1.59 (m, 4H).

[0110] Example 25 tert-Butyl 3-{[(2E)-3-(4-fluorobenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 95.0%; RT = 1.66 m / z = 492.42 [M+1] 490.18 [M-1]; 1 H NMR (400 MHz, 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, 4.3 Hz, 1H), 6.68 (dt, J = 15.1, 1.9 Hz, 1H), 4.31 (s, 2H), 4.18 (ddd, J = 6.4, 4.5, 1.9 Hz, 2H), 3.56 (t, J = 5.8 Hz, 2H), 2.65 (t, J = 6.1 Hz, 2H), 1.42 (s, 9H).

[0111] Example 26 tert-Butyl 3-{[(2E)-3-(3-fluoro-4-methoxybenzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 97.9%; RT = 2.72 min, 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).

[0112] Example 27 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 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).

[0113] Example 28 N-[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide Purity: 96.2%; RT = 3.30 min, m / z = 403.12 [M+1], 400.92 [M-1]; 11H 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).

[0114] Example 29 6-Benzyl-N-[(2E)-3-(4-chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide Purity: 82.9%; RT = 2.04 min, m / z = 497.84 [M+1], 495.97 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 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).

[0115] Example 30 N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 97.7%; RT = 2.18 min, m / z = 420.11 [M+1], 418.09 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.26 (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).

[0116] Example 31 N-[(2E)-3-(2,4-Difluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 92.6%; RT = 2.46 min, m / z = 407.27 [M - 1]; 1 1H 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).

[0117] Example 32 N-[(2E)-3-(2,4-Dichlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 97.1%; RT = 2.88 min, m / z = 443.00 [M + 1]; 11H 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).

[0118] Example 33 N-[(2E)-3-(2-chloro-4-fluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0119] Example 34 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 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).

[0120] Example 35 N-[(2E)-3-(4-Fluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide 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).

[0121] Example 36 N-[(2E)-3-(4-Chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide Purity: 92.0%; RT = 2.45 min, m / z = 421.15 [M+1] 419.21 [M-1];1 1H 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).

[0122] Example 37 N-[(2E)-3-(3-Fluoro-4-methoxybenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide 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).

[0123] Example 38 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide 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).

[0124] Example 39 N-[(2E)-3-(3-Fluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0125] Example 40 N-[(2E)-3-(4-Methoxybenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 98.5% (254 nm); RT = 2.37 min, m / z = 403.16 [M+1], 400.89 [M-1]; 11H 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).

[0126] Example 41 N-[(2E)-3-(2-Chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 96.3% (254 nm); RT = 2.01 min, m / z = 407.10 [M+1], 405.38 [M-1]; 1 1H 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).

[0127] 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 Purity: 82.2% (254 nm); RT = 2.26 min, m / z = 395.11 [M+1] 393.30 [M-1]; 11H 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).

[0128] Example 43 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide Purity: 92.0% (254 nm); Rt = 2.06 min, m / z = 359.14 [M+1], 357.26 [M-1]; 1 1H 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).

[0129] Example 44 2-Oxo-N-[(2E)-3-(thiophene-2-sulfonyl)prop-2-en-1-yl]-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 96.3% (254 nm); RT = 2.59 m / z = 379.09 [M+1] 393.30 [M-1]; 11H 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).

[0130] Example 45 N-[(2E)-3-(3,4-Dimethoxybenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 98.5% (254 nm); Rt = 2.20 min, m / z = 433.14 [M+1], 431.36 [M-1]; 1 1H 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).

[0131] Example 46 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-6-(propan-2-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 95.0% (254 nm); Rt = 2.70 min, m / z = 415.12 [M+1], 413.12 [M-1]; 11H 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).

[0132] Example 47 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide Purity: 89.7% (254 nm); Rt = 2.01 min, m / z = 370.10 [M+1], 368.11 [M-1]; 1 1H 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).

[0133] Example 48 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-6,6-dimethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 99.9% (254 nm); Rt = 2.74 min, m / z = 401.16 [M+1], 398.85 [M-1]; 11H 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).

[0134] Example 49 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-6,6-difluoro-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 99.9% (254 nm); Rt = 2.32 min, m / z = 409.13 [M+1], 407.15 [M-1]; 1 1H 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).

[0135] Example 50 N-[(2E)-3-(4-tert-Butylbenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 99.8% (254 nm); Rt = 2.34 min, m / z = 429.18 [M+1] 427.41 [M-1]; 11H 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).

[0136] Example 51 N-[(2E)-3-(3,4-Dimethylbenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0137] Example 52 N-[(2E)-3-[(3,4-Dimethoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 92.2% (254 nm); RT = 6.51 min, m / z = 432.15 [M+1] 430.19 [M-1]; 11H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.99 (t, J = 5.9 Hz, 1H), 8.04 (s, 1H), 7.43 (dd, J = 8.5, 2.2 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.72 (dt, J = 14.9, 4.7 Hz, 1H), 6.48 (dt, J = 14.9, 1.8 Hz, 1H), 4.41 (s, 1H), 4.12 (t, J = 5.3 Hz, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 2.58 (t, J = 5.9 Hz, 2H), 1.76 - 1.61 (m, 4H).

[0138] Example 53 N-[(2E)-3-(Benzenesulfonyl)(1,1- 2 H2)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 97.6% (254 nm); Rt = 2.27 min, m / z = 375.20 [M+1], 372.96 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.26 (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 = 15.1 Hz, 1H), 6.67 (d, J = 15.1 Hz, 1H), 2.58 (t, J = 6.0 Hz, 2H), 1.77 - 1.59 (m, 4H).

[0139] Example 54 N-[(2E)-3-[4-(Dimethylamino)benzenesulfonyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0140] Example 55 N-[(2E)-3-(4-Cyclopropylbenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0141] Example 56 N-[(2E)-3-(4-Cyanobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0142] Example 57 N-[(2E)-3-[Imino(4-methoxyphenyl)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 90.6% (254 nm); RT = 2.58 min, m / z = 402.20 [M+1]; 1 H 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).

[0143] Example 58 N-[(2E)-3-[(3,4-Dimethylphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 93.8% (254 nm); RT = 2.58 min, m / z = 400.30 [M+1]; 1 H 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).

[0144] Example 59 6,6-Difluoro-N-[(2E)-3-[(4-fluorophenyl)(imino)oxo-λ 6N-[(2E)-3-[Imino(oxo)phenyl-λ Purity: 97.3% (254 nm); RT = 1.88 min, m / z = 426.20 [M+1], 424.15 [M-1]; 1 H 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).

[0145] Example 60 N-[(2E)-3-[Imino(oxo)phenyl-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0146] Example 61 N-[(2E)-3-[(4-tert-butylphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 84.1% (254 nm); RT = 2.25 min, m / z = 427.97 [M+1] 426.28 [M-1]; 1 1H 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).

[0147] Example 62 N-[(2E)-3-[(4-Ethoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 92.3% (254 nm): RT = 1.93 min, m / z = 416.18 [M+1] 414.23 [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), 7.79 - 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).

[0148] Example 63 N-[(2E)-3-[Imino(4-methoxy-3,5-dimethylphenyl)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0149] Example 64 N-[(2E)-3-[Imino(3-methoxyphenyl)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0150] Example 65 N-[(2E)-3-[Imino(oxo)[4-(trifluoromethoxy)phenyl]-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 92.3% (254 nm); Rt = 2.90 min, m / z = 456.15 [M+1], 454.17 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.27 (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 = 15.0, 4.6 Hz, 1H), 6.54 (dt, J = 14.9, 1.8 Hz, 1H), 4.77 (s, 1H), 4.15 (t, J = 5.4 Hz, 2H), 2.58 (t, J = 5.9 Hz, 2H), 1.77 - 1.62 (m, 4H).

[0151] Example 66 Preparation of N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide hydrochloride (Scheme 3) tert-Butyl 3-{[(2E)-3-(benzenesulfonyl)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 equiv) was suspended in dioxane (5 mL, 0.5 M) and cooled to 0 °C. HCl 4.0 M in dioxane (6.0 ml, 24 mmol, 10 equiv) was added to the reaction mixture and stirred for 2 h. The solution was concentrated to dryness, the residue was triturated with diethyl ether and dried to give N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide hydrochloride (980 mg Y: 98%). UPLC Rt = 1.20 min, m / z = 374.2 [M+1], Purity: 95% (NMR); 11H NMR (300 MHz, DMSO-d6) δ 12.67 (s, 1H), 9.87 (t, J = 5.9 Hz, 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, 6.6 Hz, 2H), 6.95 (dt, J = 15.1, 4.4 Hz, 1H), 6.74 - 6.61 (m, 1H), 4.19 (ddd, J = 6.2, 4.4, 1.9 Hz, 2H), 4.06 (d, J = 4.6 Hz, 2H), 3.42 - 3.27 (m, 2H), 2.89 (t, J = 6.2 Hz, 2H).

[0152] Example 67 Preparation of oxetan-3-yl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate (Scheme 4) Scheme 4, Reaction 1: 4-Nitrophenyl oxetan-3-yl carbonate 4-Nitrophenyl chloroformate (0.30 g, 1.48 mmol, 1.1 eq) was added portionwise at 0 °C to a solution of oxetan-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). 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 aqueous NaHCO3, dried over MgSO4, filtered, and then concentrated under reduced pressure to give 4-nitrophenyl oxetan-3-yl carbonate (0.281 g, Y: 74%) as a slightly yellow oil, which was used in the next step without further purification. 1 The structure of the product was confirmed by 1H NMR (DMSO-d6, 400 MHz). 1 1H NMR (400 MHz, DMSO-d6) δ 8.37 - 8.29 (m, 2H), 7.64 - 7.55 (m, 2H), 5.53 (tt, J = 6.2, 4.7 Hz, 1H), 4.85 (ddd, J = 7.5, 6.2, 1.1 Hz, 2H), 4.67 (ddd, J = 7.8, 4.7, 1.1 Hz, 2H).

[0153] Scheme 4, Reaction 2: Oxetan-3-yl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide (0.050 g, 0.12 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (1 mL). Next, a solution of 4-nitrophenyl oxetan-3-yl carbonate (0.036 g, 0.128 mmol, 1.1 equiv) in aqueous NaHCO3 (0.020 g, 0.23 mmol, 2.0 equiv, 1 mL) and tetrahydrofuran (0.5 mL) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and dissolved in DCM. The organic layer was washed with saturated aqueous NaHCO3 until the yellow color disappeared. The organic layer was collected, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC eluting with 10% DCM / MeOH to give (2,2-difluorocyclopropyl)methyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate as a white solid (21 mg Y: 37%). Rt: 2.38 min, m / z = 474.3 [M+1], purity: 97.79% (254 nm); 11H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.95 (t, J = 5.9 Hz, 1H), 8.15 (s, 1H), 7.90 - 7.82 (m, 2H), 7.77 - 7.69 (m, 1H), 7.64 (dd, J = 8.3, 6.8 Hz, 2H), 6.95 (dt, J = 15.2, 4.4 Hz, 1H), 6.66 (dt, J = 15.1, 1.9 Hz, 1H), 5.31 (p, J = 5.6 Hz, 1H), 4.77 (dd, J = 7.5, 6.3 Hz, 2H), 4.52 (dd, J = 7.6, 5.1 Hz, 2H), 4.49 - 4.41 (m, 1H), 4.40 - 4.29 (m, 1H), 4.18 (td, J = 5.1, 4.2, 2.0 Hz, 2H), 3.78 - 3.54 (m, 2H), 2.77 - 2.68 (m, 2H).

[0154] Example 68 Cyclopropylmethyl 3-{[(2E)-3-[(4-fluorophenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Preparation (Scheme 4) Scheme 4, Reaction 1: Cyclopropylmethyl 4-nitrophenyl carbonate 4-Nitrophenyl chloroformate (1.0 g, 5.0 mmol, 1.0 equiv) was added portionwise at 0 °C to a solution of cyclopropylmethanol (0.32 g, 4.5 mmol, 0.9 equiv) and pyridine (0.6 ml, 7.4 mmol, 1.5 equiv) in DCM (12.4 ml, 0.4 M). 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 aqueous NaHCO3, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to give cyclopropylmethyl 4-nitrophenyl carbonate (0.998 g, Y: 75%) as a slightly yellow oil, which was used in the next step without further purification. 1 The structure and purity of the product were confirmed by 1H NMR (DMSO-d6, 300 MHz). 11H NMR (300 MHz, DMSO-d6) δ 8.37 - 8.27 (m, 2H), 7.64 - 7.50 (m, 2H), 4.10 (d, J = 7.5 Hz, 2H), 1.21 (pt, J = 7.7, 4.7 Hz, 1H), 0.68 - 0.52 (m, 2H), 0.37 (qd, J = 4.6, 2.0 Hz, 2H).

[0155] Scheme 4, Reaction 3: 6-Cyclopropylmethyl 3-ethyl 2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3,6-dicarboxylate 1,2,5,6,7,8-Hexahydro-2-oxo-1,6-naphthyridine-3-carboxylate (0.67 g, 2.6 mmol, 1.0 equiv) was dissolved in THF (11 mL). Next, a solution of cyclopropylmethyl 4-nitrophenyl carbonate (0.70 g, 2.6 mmol, 1.0 equiv) in aqueous NaHCO3 (0.433 g, 5.157 mmol, 2.0 equiv) and THF (2 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and dissolved in DCM. The organic layer was washed with saturated aqueous NaHCO3 until the yellow color disappeared. The organic layer was collected, dried over MgSO4, filtered, and concentrated under reduced pressure to give 6-cyclopropylmethyl 3-ethyl 2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3,6-dicarboxylate (0.625 g, Y: 72%) as a yellow solid. 1 The structure of the product was confirmed by 1H NMR (DMSO-d6, 300 MHz). Purity: 90%( 1 1H-NMR); 1 1H NMR (300 MHz, DMSO-d6) δ 12.01 (s, 1H), 7.93 (s, 1H), 4.32 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.88 (d, J = 7.1 Hz, 2H), 3.61 (t, J = 5.8 Hz, 2H), 2.63 (t, J = 5.9 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.11 (pt, J = 7.2, 4.7 Hz, 1H), 0.58 - 0.43 (m, 2H), 0.33 - 0.21 (m, 2H).

[0156] Scheme 4, Reaction 4: 6-[(Cyclopropylmethoxy)carbonyl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxylic acid 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. Then, 1.0 M aqueous LiOH solution (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 to about pH 3, the resulting precipitate was filtered, washed with water, and dried under reduced pressure to obtain 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 The structure of the product was confirmed by 1H NMR (DMSO-d6, 300 MHz). UPLC: Rt: 1.15 min, m / z: 293.8 [M+1]; Purity (254): 90%; 1 1H NMR (300 MHz, DMSO-d6) δ 14.80 (s, 1H), 13.28 (s, 1H), 8.29 (s, 1H), 4.44 (s, 2H), 3.89 (d, J = 7.1 Hz, 2H), 3.66 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 5.9 Hz, 2H), 1.20 - 1.03 (m, 1H), 0.58 - 0.43 (m, 2H), 0.37 - 0.21 (m, 2H).

[0157] Scheme 4, Reaction 5: Cyclopropylmethyl 3-{[(2E)-3-[(4-fluorophenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate 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). Then, N,N-diisopropylethylamine (0.085 ml, 0.49 mmol, 4.0 eq) was added and the yellow mixture was stirred for 10 minutes. [(1E)-3-Aminoprop-1-en-1-yl](4-fluorophenyl)imino-λ 6 -sulfanone dihydrochloride (0.033 g, 0.11 mmol, 0.9 eq) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water and DCM, the organic layer was recovered, washed with saturated NaHCO3 solution, saturated NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM / MeOH 10% to give cyclopropylmethyl 3-{[(2E)-3-[(4-fluorophenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate (0.005 g, Y: 7%) as a yellow solid. Rt: 2.03 min, m / z = 489.14 [M+1], purity (254): 90.3%; 1 H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 10.07 - 9.95 (m, 1H), 8.14 (s, 1H), 7.96 - 7.88 (m, 2H), 7.46 - 7.37 (m, 2H), 6.80 (dt, J = 15.0, 4.6 Hz, 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 = 7.1 Hz, 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).

[0158] The title compounds of Examples 69 to 98 and 178 to 184 were prepared by a method similar to the method described in Example 67 or 68.

[0159] Example 69 Cyclopropylmethyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 95.6% (254 nm); RT = 1.94 min, m / z = 471.94 [M+1] 470.20 [M-1]; 1 1H 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).

[0160] Example 70 Cyclobutyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 97.9% (254 nm); RT = 1.97 min, m / z = 472.20 [M+1] 469.91 [M-1]; 11H 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).

[0161] Example 71 (5-Methyl-1,3,4-oxadiazol-2-yl)methyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 99.0% (254 nm); RT = 1.81 min, m / z = 514.18 [M+1] 512.21 [M-1]; 1 1H 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).

[0162] Example 72 1,1,1-Trifluoropropan-2-yl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate 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).

[0163] Example 73 (2,2-Dimethylcyclopropyl)methyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 94.5% (254 nm); RT = 2.22 min, m / z = 500.2 [M + 1] 498.40 [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), 7.90 - 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).

[0164] Example 74 (2,2-Difluorocyclopropyl)methyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 99.2% (254 nm); RT = 2.47 min, m / z = 508.41 [M+1] 506.11 [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), 7.91 - 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).

[0165] Example 75 1-Methoxypropan-2-yl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate 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).

[0166] Example 76 2-Fluoroethyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate 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).

[0167] Example 77 2,2-Difluoroethyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 99.7% (254 nm); RT = 2.25 min, m / z = 481.93 [M+1], 480.251 [M-1]; 1 1H 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).

[0168] Example 78 Cyclopropyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 96.3% (254 nm); RT = 2.16 min, m / z = 458.10 [M+1]; 1 H 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).

[0169] Example 79 2-Oxaspiro[3.5]nonan-7-yl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 96.4% (254 nm); RT = 2.19 min, m / z = 542.4 [M+1]; 1 H 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).

[0170] Example 80 2-Methoxyethyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 98.0% (254 nm); RT = 1.91 min, m / z = 476.10 [M+1]; 1 H 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).

[0171] Example 81 (3S)-Oxolan-3-yl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 99.0% (254 nm); RT = 1.89 min, m / z = 488.30 [M+1]; 1 H 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).

[0172] Example 82 (3R)-oxolan-3-yl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 98.9% (254 nm); RT = 1.89 min, m / z = 488.30 [M+1]; 1 H 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).

[0173] Example 83 2-(2-oxopiperidin-1-yl)ethyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate 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).

[0174] Example 84 Cyclopentyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate 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).

[0175] Example 85 (2,2-Dimethylcyclopropyl)methyl 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 Purity: 94.3% (254 nm); RT = 2.89 min m / z = 534.16 [M+1], 532.15 [M-1]; 1 H 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).

[0176] Example 86 (2,2-Difluorocyclopropyl)methyl 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 Purity: 97.4% (254 nm); RT = 2.41 m / z = 542.34 [M+1] 540.06 [M-1]; 1 H 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).

[0177] Example 87 Oxetan-3-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 Purity: 97.5% (254 nm); RT = 1.66 min, m / z = 508.12 [M+1] 506.27 [M-1]; 1 1H 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).

[0178] Example 88 Cyclopropylmethyl 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 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).

[0179] Example 89 2-(Furan-2-yl)ethyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 95.3% (254 nm); RT = 2.55 min, m / z = 512.16 [M+1], 509.89 [M-1]; 1 1H 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).

[0180] Example 90 Cyclohexyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 99.8% (254 nm); RT = 2.89 min, m / z = 500.20 [M+1], 498.33 [M-1]; 11H 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).

[0181] Example 91 1-(2,6-Difluorophenyl)ethyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 98.5% (254 nm); RT = 2.976 min, m / z = 558.13 [M+1] 556.14 [M-1]; 1 1H 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).

[0182] Example 92 1-acetylpiperidin-4-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 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).

[0183] Example 93 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 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).

[0184] Example 94 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 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).

[0185] Example 95 Cyclopropylmethyl 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-carboxylate Purity: 90.5% (254 nm); RT = 2.42 min, m / z = 507.14 [M+1], 505.20 [M-1]; 1 1H 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).

[0186] Example 96 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 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).

[0187] Example 97 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 Purity: 92.1% (254 nm); RT = 2.43 min, m / z = 534.25 [M+1], 532.24 [M-1]; 1 1H 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).

[0188] Example 98 Cyclopropylmethyl 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate 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).

[0189] Example 99 Preparation of 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 (Scheme 5) Scheme 5, Reaction 1: 4-Nitrophenyl N-tert-butylcarbamate 4-Nitrophenyl chloroformate (0.14 g, 0.68 mmol, 1.0 equiv) was added portionwise at 0 °C to a solution of tert-butylamine (0.072 ml, 0.68 mmol, 1.0 equiv) and pyridine (0.083 ml, 1.03 mmol, 1.5 equiv) in DCM (12.4 ml, 0.4 M). 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 aqueous NaHCO3, dried over MgSO4, filtered, and then concentrated under reduced pressure to give 4-nitrophenyl N-tert-butylcarbamate (0.137 g, Y: 70%) as a pale yellow solid, which was used in the next step without further purification. 1 The structure and purity of the product were confirmed by 1H NMR (DMSO-d6, 400 MHz). 1 1H NMR (400 MHz, DMSO-d6) δ 8.30 - 8.22 (m, 2H), 7.88 (s, 1H), 7.42 - 7.33 (m, 2H), 1.31 (s, 9H).

[0190] 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 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), and a solution of 4-nitrophenyl N-tert-butylcarbamate (0.027 g, 0.094 mmol, 1.1 eq) in aqueous NaHCO3 (0.014 g, 0.17 mmol, 2.0 eq) and anhydrous THF (0.86 ml, 0.1 M) was added. The reaction mixture 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 aqueous NaHCO3 until the yellow color disappeared. The organic layer was collected, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC eluting with 10% DCM / MeOH 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. Rt = 2.55 min, m / z = 507.10 [M+1], 505.10 [M-1], purity: 99.6% (254 nm); 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (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, 4.3 Hz, 1H), 6.75 - 6.61 (m, 1H), 5.89 (s, 1H), 4.26 (s, 2H), 4.19 (d, J = 5.0 Hz, 2H), 3.53 (t, J = 5.8 Hz, 2H), 2.62 (t, J = 5.6 Hz, 2H), 1.26 (s, 9H).

[0191] The title compounds of Examples 100 and 101 were prepared by a method similar to the method described in Example 99.

[0192] Example 100 N3-[(2E)-3-(4-Chlorobenzenesulfonyl)prop-2-en-1-yl]-N6-(cyclopropylmethyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3,6-dicarboxamide Purity: 99.6 (254 nm); RT = 3.24 min, m / z = 505.1 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.29 (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, 4.4 Hz, 1H), 6.75 - 6.65 (m, 2H), 4.30 (s, 2H), 4.22 - 4.15 (m, 2H), 3.57 (t, J = 5.8 Hz, 2H), 2.92 (t, J = 6.1 Hz, 2H), 2.63 (t, J = 5.8 Hz, 2H), 0.98 - 0.86 (m, 1H), 0.41 - 0.33 (m, 2H), 0.18 - 0.10 (m, 2H).

[0193] Example 101 N3-[(2E)-3-(4-Chlorobenzenesulfonyl)prop-2-en-1-yl]-N6-cyclopropyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3,6-dicarboxamide Purity: 98.4% (254 nm) RT = 2.11 min, m / z = 491.10 [M+1], 489.23 [M-1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.45 (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, 4.4 Hz, 1H), 6.74 - 6.64 (m, 2H), 4.25 (s, 2H), 4.18 (dq, J = 4.3, 2.1 Hz, 2H), 3.53 (t, J = 5.8 Hz, 2H), 2.61 (t, J = 5.8 Hz, 2H), 0.55 (td, J = 6.9, 4.6 Hz, 2H), 0.42 - 0.32 (m, 2H).

[0194] Example 102 Preparation of N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-6-(3,3-difluorocyclobutanecarbonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide (Scheme 6, Reaction 1) 4,4-Difluorocyclohexanecarboxylic acid (13 mg, 0.08 mmol, 1.1 equiv) was dissolved in DMF (0.8 mL). Then, N,N-diisopropylethylamine (0.051 mL, 0.29 mmol, 4 equiv) and T3P, 50% w / w solution in DMF (0.092 mL, 0.15 mmol, 2 equiv) were added and the solution was shaken for 10 minutes, after which N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide (30 mg, 0.07 mmol, 1 equiv) was added. The reaction mixture was shaken for a further 2 hours and UPLC control showed consumption of the starting material. Next, saturated NaHCO3 solution and DCM were added, the two phases were separated, the organic phase was recovered and concentrated to dryness. The residue was purified by preparative TLC eluting with DCM / MeOH 6%. The desired product was recovered and concentrated to dryness to give N-[(2E)-3-(benzenesulfonyl)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. Rt = 2.24 min, m / z = 492.17 [M+1], 490.16 [M-1], purity: 95% (254 nm); 11H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.96 (s, 1H), 8.17 (d, J = 13.6 Hz, 1H), 7.86 (dd, J = 7.3, 1.7 Hz, 2H), 7.76 - 7.70 (m, 1H), 7.67 - 7.61 (m, 2H), 6.95 (dt, J = 15.3, 4.4 Hz, 1H), 6.66 (dd, J = 15.2, 2.6 Hz, 1H), 4.43 (d, J = 6.2 Hz, 2H), 4.19 (s, 2H), 3.72 (t, J = 5.9 Hz, 1H), 3.62 (t, J = 5.8 Hz, 1H), 2.89 - 2.75 (m, 4H), 2.75 - 2.70 (m, 2H), 2.69 - 2.62 (m, 1H).

[0195] Example 103 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-6-(2-methoxyethanesulfonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide (Scheme 6, Reaction 2) N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide (30 mg, 0.072 mmol, 1 equiv) was dissolved in DMF (0.72 mL), and N,N-diisopropylethylamine (0.038 mL, 0.22 mmol, 3 equiv) and 2-methoxyethane-1-sulfonyl chloride (0.010 mL, 0.087 mmol, 1.2 equiv) were added. The reaction mixture was stirred at room temperature for 2 h. LCMS indicated complete consumption of the starting material. Next, the mixture was poured into water and extracted with DCM. The organic phase was collected, half of its volume was concentrated, and it was passed through a silica NH2 cartridge eluting with MeOH. The filtrate was collected, concentrated under reduced pressure, and purified by preparative TLC eluting with 6% DCM / MeOH to give N-[(2E)-3-(benzenesulfonyl)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. RT = 2.07 min, m / z = 496.10 [M+1], 493.93 [M-1], Purity: 94% (254 nm); 1 H NMR (400 MHz, DMSO-d6) δ 12.52 (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, 4.4 Hz, 1H), 6.67 (dt, J = 15.0, 1.9 Hz, 1H), 4.22 (s, 2H), 4.21 - 4.16 (m, 2H), 3.65 (t, J = 5.9 Hz, 2H), 3.47 (t, J = 5.9 Hz, 2H), 3.41 (t, J = 5.9 Hz, 2H), 3.23 (s, 3H), 2.75 (t, J = 5.9 Hz, 2H).

[0196] Example 104 N-[(2E)-3-(Benzenesulfonyl)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) N-[(2E)-3-(Benzenesulfonyl)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 equiv) was dissolved in DMF (0.24 ml, 0.3 M). Next, Na2CO3 (0.022 g, 0.21 mmol, 3.0 equiv) and 3-(bromomethyl)pyridine (0.021 g, 0.08 mmol, 1.0 equiv) 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 off, collected, then dissolved in a minimal amount of DCM and purified by preparative TLC eluting with 5% DCM / MeOH to give N-[(2E)-3-(benzenesulfonyl)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. Rt = 1.75 min, m / z = 464.96 [M+1], Purity: 97.54% (210 nm); 11H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 10.02 (s, 1H), 8.53 (d, J = 2.2 Hz, 1H), 8.49 (dd, J = 4.8, 1.7 Hz, 1H), 8.01 (s, 1H), 7.86 (t, J = 1.3 Hz, 1H), 7.84 (d, J = 1.6 Hz, 1H), 7.77 - 7.69 (m, 2H), 7.67 - 7.61 (m, 2H), 7.40 - 7.35 (m, 1H), 6.94 (dt, J = 15.1, 4.4 Hz, 1H), 6.65 (dt, J = 15.0, 1.8 Hz, 1H), 4.21 - 4.13 (m, 2H), 3.68 (s, 2H), 3.39 (s, 2H), 2.71 - 2.63 (m, 4H).

[0197] The title compounds of Examples 105 to 125 and 185 were prepared by a method similar to the method described in Examples 102 to 104.

[0198] Example 105 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-6-(3-methoxypropanoyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide Purity: 96.0 (254 nm); RT = 2.26 min, m / z = 460.48 [M+1], 458.16 [M-1]; 1 1H NMR (300 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.95 (t, J = 5.9 Hz, 1H), 8.15 (d, J = 6.7 Hz, 1H), 7.90 - 7.81 (m, 2H), 7.78 - 7.69 (m, 1H), 7.64 (dd, J = 8.2, 6.6 Hz, 2H), 6.95 (dt, J = 15.1, 4.3 Hz, 1H), 6.66 (d, J = 15.6 Hz, 1H), 4.45 (d, J = 25.7 Hz, 2H), 4.18 (s, 2H), 3.69 (t, J = 5.8 Hz, 2H), 3.56 (d, J = 2.7 Hz, 2H), 3.21 (d, J = 6.1 Hz, 3H), 2.77 - 2.58 (m, 4H).

[0199] Example 106 6-[2-(Adamantan-1-yl)acetyl]-N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide Purity: 99.3% (254 nm); RT = 1.50 min, m / z = 550.3 [M+1]; 1 H 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).

[0200] Example 107 N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-2-oxo-6-[(1r,4r)-4-methoxycyclohexanecarbonyl]-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide Purity: 98.7% (254 nm); RT = 1.97 min, m / z = 514.4 [M+1]; 11H 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).

[0201] Example 108 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-6-(4,4-difluorocyclohexanecarbonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide Purity: 94% (254 nm); RT = 1.90 min, m / z = 520.24 [M+1], 518.36 [M-1]; 1 1H 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).

[0202] Example 109 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-6-cyclopropanecarbonyl-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide Purity: 96.0% (254 nm); RT = 1.33 min, m / z = 442.23 [M+1], 440.16 [M-1]; 1 H 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).

[0203] Example 110 N-[(2E)-3-(Benzenesulfonyl)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 Purity: 97.7% (254 nm); RT = 1.99 min, m / z = 496.20 [M+1], 494.20 [M-1]; 1 H 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).

[0204] Example 111 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-6-(1-cyanocyclobutanecarbonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide 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).

[0205] Example 112 N-[(2E)-3-(Benzenesulfonyl)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 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).

[0206] Example 113 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-6-(oxolane-3-carbonyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide 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).

[0207] Example 114 N-[(2E)-3-(Benzenesulfonyl)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 Purity: 99.4% (254 nm); RT = 2.31 min, m / z = 482.21 [M+1]; 1 1H 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).

[0208] Example 115 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-6-(1-methylcyclobutanecarbonyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide 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).

[0209] Example 116 N-[(2E)-3-(benzenesulfonyl)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 Purity: 92.2% (254 nm); RT = 2.61 min, m / z = 525.15 [M+1], 523.22 [M-1]; 1 1H 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).

[0210] Example 117 N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-6-(2-cyclopropylacetyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide Purity: 97.9% (254 nm); RT = 1.99 min, m / z = 456.22 [M+1]; 11H 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).

[0211] Example 118 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-6-(1-phenylpyrrolidine-3-carbonyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide Purity: 95.9% (254 nm); RT = 2.73 min, m / z = 547.20 [M+1]; 1 1H 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).

[0212] Example 119 2-Methylpropyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 96.9% (254 nm); RT = 2.58 min, m / z = 474.2 [M+1], 472.19 [M-1]; 1 H 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).

[0213] Example 120 N-[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]-6-(3,3-dimethylbutanoyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide Purity: 91.9% (254 nm); RT = 2.34 min, m / z = 472.24 [M+1], 470.47 [M-1]; 1 H NMR (300 MHz, DMSO-d6) 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).

[0214] Example 121 N-[(2E)-3-(Benzenesulfonyl)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 Purity: 82.1% (254 nm); RT = 3.42 min, m / z = 518.18 [M+1], 516.17 [M-1]; 1 H NMR (400 MHz, DMSO-d6) 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).

[0215] Example 122 2-(4-Chlorophenyl)ethyl 3-{[(2E)-3-(benzenesulfonyl)prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate 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).

[0216] Example 123 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-6-[(pyridazin-3-yl)methyl]-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide 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).

[0217] Example 124 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-6-(3-methoxy-3-methylbutanoyl)-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide 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).

[0218] Example 125 N-[(2E)-3-(Benzenesulfonyl)prop-2-en-1-yl]-2-oxo-6-(2-phenylcyclopropanecarbonyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide 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).

[0219] Example 126 N-[(2E)-3-(2,4-Dichlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide 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).

[0220] Example 127 N-[(2E)-3-(2,4-Difluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide 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).

[0221] Example 128 N-[(2E)-3-(2-Chloro-4-fluorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide Purity: 95% (254 nm); Rt = 1.94 min, m / z = 447.1 [M+1], 445.08 [M-1]; 1 H 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).

[0222] Example 129 N-[(2E)-3-(2-Chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide Purity: 93% (254 nm); Rt = 2.36 min, m / z = 429.1 [M+1]; 1 H 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).

[0223] Example 130 N-[(2E)-3-(4-Chlorobenzenesulfonyl)prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide 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).

[0224] Example 131 N-[(2E)-3-[(4-chlorophenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0225] Example 132 N-[(2E)-3-[(2-fluorophenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 92.2% (254 nm); RT = 3.54 min, m / z = 390.21 [M+1]; 11H 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).

[0226] Example 133 N-[(2E)-3-[(3-chloro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 93.4% (254 nm); RT = 2.06 min, m / z = 436.0 [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), 7.83 (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).

[0227] Example 134 N-[(2E)-3-[(3-chlorophenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 91.7% (254 nm); RT = 2.09 min, m / z = 406.06 [M+1]; 11H 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).

[0228] Example 135 N-[(2E)-3-[(2,4-Difluorophenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 93.1% (254 nm); RT = 2.43 min, m / z = 408.09 [M+1]; 1 1H 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).

[0229] Example 136 N-[(2E)-3-[(4-Cyanophenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 97.0% (254 nm); RT = 2.27 min, m / z = 397.08 [M+1]; 11H 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).

[0230] Example 137 N-[(2E)-3-[Imino(4-methoxy-3-methylphenyl)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0231] Example 138 N-[(2E)-3-[Imino(oxo)[4-(propan-2-yloxy)phenyl]-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 91.9% (254 nm); RT = 2.12 min, m / z = 430.23 [M+1]; 11H 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).

[0232] Example 139 N-[(2E)-3-[Imino(4-methoxy-2-methylphenyl)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 92.5% (254 nm); RT = 1.84 min, m / z = 416.2 [M+1]; 1 1H 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).

[0233] Example 140 N-[(2E)-3-[Imino(oxo)(4-phenoxyphenyl)-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0234] Example 141 N-[(2E)-3-{[4-(dimethylamino)phenyl](imino)oxo-λ 6 -sulfanyl}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0235] Example 142 N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-6-methyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 97.3% (254 nm); RT = 2.91 min, m / z = 434.01 [M+1]; 11H 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).

[0236] Example 143 N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2-dihydroquinoline-3-carboxamide Purity: 92.3% (254 nm); RT = 3.12 min, m / z = 416.04 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 9.95 (t, J = 6.0 Hz, 1H), 8.83 (s, 1H), 7.95 (dd, J = 7.9, 1.4 Hz, 1H), 7.73 - 7.57 (m, 3H), 7.43 (d, J = 8.3 Hz, 1H), 7.39 - 7.24 (m, 2H), 6.79 (dt, 1H), 6.60 (d, 1H), 4.61 (s, 1H), 4.19 (t, J = 4.9 Hz, 2H), 3.92 (s, 3H).

[0237] Example 144 N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-6-(propan-2-yl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, Purity: 97.5% (254 nm); RT = 2.66 min, m / z = 462.12 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 9.99 (t, J = 5.9 Hz, 1H), 8.06 (s, 1H), 7.69 - 7.59 (m, 2H), 7.35 (t, J = 8.4 Hz, 1H), 6.76 (dt, J = 14.9, 4.6 Hz, 1H), 6.48 (d, J = 15.0 Hz, 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).

[0238] Example 145 N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1H,2H,5H,7H,8H-pyrano[4,3-b]pyridine-3-carboxamide Purity: 79.1% (254 nm); RT = 2.03 min, m / z = 422.1 [M+1]; 1 1H 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).

[0239] Example 146 N-[(2E)-3-[Imino(oxo)(3-phenoxyphenyl)-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0240] Example 147 N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-6-(trifluoromethyl)-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0241] Example 148 6-tert-Butyl-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 95.8% (254 nm); RT = 1.86 min, m / z = 476.27 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 10.00 (t, J = 5.9 Hz, 1H), 8.07 (s, 1H), 7.70 - 7.59 (m, 2H), 7.35 (t, J = 8.4 Hz, 1H), 6.77 (dt, J = 15.0, 4.6 Hz, 1H), 6.52 - 6.45 (m, 1H), 4.60 (s, 1H), 4.12 (d, J = 5.2 Hz, 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).

[0242] Example 149 N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxamide Purity: 87.9% (254 nm); RT = 2.76 min, m / z = 442.3 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.57 (d, J = 3.0 Hz, 1H), 8.46 (s, 1H), 8.09 (d, J = 2.8 Hz, 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, 4.6 Hz, 1H), 6.62 - 6.49 (m, 1H), 4.61 (s, 1H), 4.21 - 4.14 (m, 2H), 3.92 (s, 3H).

[0243] Example 150 N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H,8H,9H-cyclohepta[b]pyridine-3-carboxamide 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).

[0244] Example 151 N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1H,2H,5H,6H,7H-cyclopenta[b]pyridine-3-carboxamide 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).

[0245] Example 152 tert-Butyl 3-{[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 94.9% (254 nm); RT = 2.24 min, m / z = 521.22 [M+1]; 11H 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).

[0246] Example 153 6-Benzyl-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide Purity: 86.9% (254 nm); RT = 2.83 min, m / z = 511.23 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.97 (t, J = 6.0 Hz, 1H), 8.01 (s, 1H), 7.69 - 7.60 (m, 2H), 7.34 (d, J = 4.2 Hz, 5H), 7.27 (dt, J = 8.9, 4.2 Hz, 1H), 6.76 (dt, J = 15.1, 4.6 Hz, 1H), 6.53 - 6.45 (m, 1H), 4.60 (s, 1H), 4.12 (t, J = 5.2 Hz, 2H), 3.92 (s, 3H), 3.66 (s, 2H), 3.39 (s, 2H), 2.71 - 2.64 (m, 4H).

[0247] Example 154 N-[(2E)-3-[imino(oxo)[4-(trifluoromethyl)phenyl]-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 88.0% (254 nm); RT = 2.34 min, m / z = 440.23 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 10.07 - 9.97 (m, 1H), 8.07 (d, J = 8.2 Hz, 2H), 8.04 (s, 1H), 7.97 (d, J = 8.3 Hz, 2H), 6.88 (dt, J = 15.0, 4.6 Hz, 1H), 6.55 (d, J = 15.0 Hz, 1H), 4.89 (s, 1H), 4.21 - 4.11 (m, 2H), 2.62 - 2.55 (m, 2H), 1.77 - 1.63 (m, 4H).

[0248] Example 155 N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-8,8-dimethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 97.0% (254 nm); RT = 2.36 min, m / z = 448.0 [M+1]; 1 1H 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).

[0249] Example 156 N-[(2E)-3-({[1,1'-Biphenyl]-4-yl}(imino)oxo-λ 6 -sulfanyl)prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 97.3% (254 nm); RT = 2.49 min, m / z = 448.44 [M+1]; 11H 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).

[0250] Example 157 N-[(2E)-3-[benzyl(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0251] Example 158 N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide Purity: 88.6% (254 nm); RT = 3.05 min, m / z = 417.3 [M+1]; 11H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 9.95 - 9.82 (m, 1H), 8.83 (s, 1H), 8.67 (dd, J = 4.7, 1.8 Hz, 1H), 8.40 (d, J = 7.7 Hz, 1H), 7.70 - 7.60 (m, 2H), 7.35 (t, J = 8.2 Hz, 2H), 6.80 (dt, J = 15.0, 4.5 Hz, 1H), 6.60 (d, J = 14.9 Hz, 1H), 4.60 (s, 1H), 4.23 - 4.16 (m, 2H), 3.92 (s, 3H).

[0252] Example 159 N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxamide Purity: 94.9% (254 nm); RT = 1.64 min, m / z = 417.14 [M+1]; 1 1H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 9.74 (s, 1H), 9.11 (s, 1H), 8.89 (s, 1H), 8.57 (d, J = 5.7 Hz, 1H), 7.70 - 7.58 (m, 2H), 7.35 (t, J = 8.5 Hz, 1H), 7.30 (d, J = 5.7 Hz, 1H), 6.79 (dt, J = 15.0, 4.5 Hz, 1H), 6.60 (d, J = 14.7 Hz, 1H), 4.59 (s, 1H), 4.19 (d, J = 4.5 Hz, 2H), 3.92 (s, 3H).

[0253] Example 160 N-[(2E)-3-{imino[4-(morpholin-4-yl)phenyl]oxo-λ 6 -sulfanyl}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, 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).

[0254] Example 161 N-[(2E)-3-[Imino(oxo)[4-(piperidin-1-yl)phenyl]-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0255] Example 162 N-[(2E)-3-[Imino(oxo)[4-(pyrrolidin-1-yl)phenyl]-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 96.4% (254 nm); RT = 2.01 min, m / z = 441.21 [M+1]; 11H 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).

[0256] Example 163 N-[(2E)-3-[(4-Acetamidophenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 87.7% (254 nm); RT = 1.98 min, m / z = 429.0 [M+1]; 1 1H 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).

[0257] Example 164 N-[(2E)-3-[(4-Cyclopropoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 99.5% (254 nm); RT = 4.28 min, m / z = 428.19 [M+1]; 11H 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).

[0258] Example 165 N-[(2E)-3-{[3-(Dimethylamino)phenyl](imino)oxo-λ 6 -sulfanyl}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 58.2% (254 nm); RT = 4.13 min, m / z = 415.22 [M+1]; 1 1H 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).

[0259] Example 166 N-[(2E)-3-[(4-Cyclohexylphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 99.2% (254 nm); RT = 5.65 min, m / z = 454.22 [M+1]; 11H 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).

[0260] Example 167 N-[(2E)-3-[(2,3-Dihydro-1-benzofuran-5-yl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 95.6% (254 nm); RT = 2.23 min, m / z = 414.17 [M+1]; 1 1H 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).

[0261] Example 168 N-[(2E)-3-[Imino(oxo)[3-(trifluoromethoxy)phenyl]-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0262] Example 169 N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-6-methoxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 94.3% (254 nm); RT = 2.23 min, m / z = 450.2 [M+1]; 1 1H 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).

[0263] Example 170 N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6-Sulfanyl]prop-2-en-1-yl]-2-oxo-6-(2,2,2-trifluoroethyl)-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide Purity: 93.7% (254 nm); RT = 3.2 min, m / z = 503.08 [M+1]; 1 H 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).

[0264] Example 171 N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -Sulfanyl]prop-2-en-1-yl]-6-[(4-methoxyphenyl)methyl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide Purity: 84.1% (254 nm); RT = 2.94 min, m / z = 541.24 [M+1]; 1 H 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).

[0265] Example 172 6-Fluoro-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 97.2% (254 nm); RT = 2.25 min, m / z = 438.15 [M+1]; 1 H 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).

[0266] Example 173 N-[(2E)-3-{[3-cyano-4-(piperidin-1-yl)phenyl](imino)oxo-λ 6 -sulfanyl}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 96.2% (254 nm); RT = 3.07 min, m / z = 480.28 [M+1]; 1 H 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).

[0267] Example 174 N-[(2E)-3-{imino[4-(methylamino)phenyl]oxo-λ 6 -sulfanyl}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide, Purity: 88.9% (254 nm); RT = 1.98 min, m / z = 401.21 [M+1]; 1 H 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).

[0268] Example 175 N-[(2E)-3-{[3-cyano-4-(morpholin-4-yl)phenyl](imino)oxo-λ 6 -sulfanyl}prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide Purity: 97.9% (254 nm); RT = 1.88 min, m / z = 482.18 [M+1]; 1 H 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).

[0269] Example 176 N-[(2E)-3-[imino(oxo)[4-(2-oxopiperidin-1-yl)phenyl]-λ 6-Sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0270] Example 177 N-[(2E)-3-[Imino(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)oxo-λ 6 -Sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 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).

[0271] Example 178 2,2-Difluoroethyl 3-{[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ6 -sulfanyl]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 95.1% (254 nm); RT = 1.46 min, m / z = 529.3 [M+1]; 1 H 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).

[0272] Example 179 Cyclopropylmethyl 3-{[(2E)-3-[imino(oxo)phenyl-λ 6 -sulfanyl]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 93.8% (254 nm); RT = 1.9 min, m / z = 471.09 [M+1]; 1 H 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).

[0273] Example 180 2-Fluoroethyl 3-{[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 95.5% (254 nm); RT = 2.12 min, m / z = 511.13 [M+1]; 1 1H 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).

[0274] Example 181 2-Fluoroethyl 3-{[(2E)-3-[imino(oxo)phenyl-λ 6 -sulfanyl]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate 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).

[0275] Example 182 2,2-difluoroethyl 3-{[(2E)-3-[imino(oxo)phenyl-λ 6 -sulfanyl]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 93.4% (254 nm); RT = 1.72 min, m / z = 480.84 [M+1]; 1 H 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).

[0276] Example 183 4,4-difluorocyclohexyl 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 94.7% (254 nm); RT = 2.35 min, m / z = 583.32 [M+1]; 11H 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).

[0277] Example 184 Cyclohexyl 3-{[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -sulfanyl]prop-2-en-1-yl]carbamoyl}-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-6-carboxylate Purity: 95.5% (254 nm); RT = 2.47 min, m / z = 547.2 [M+1]; 1 1H 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).

[0278] Example 185 6-(Cyclopropylmethyl)-N-[(2E)-3-[(3-fluoro-4-methoxyphenyl)(imino)oxo-λ 6-Sulfanyl]prop-2-en-1-yl]-2-oxo-1,2,5,6,7,8-hexahydro-1,6-naphthyridine-3-carboxamide Purity: 88.9% (254 nm); RT = 1.81 min, m / z = 475.22 [M+1]; 1 H 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).

[0279] Example 186 N-[(2E)-3-[(3-Fluoro-4-methoxyphenyl)(imino)oxo-λ 6 -Sulfanyl]prop-2-en-1-yl]-2-oxo-1,2-dihydropyridine-3-carboxamide Purity: 84.3% (254 nm); RT = 1.93 min, m / z = 366.1 [M+1]; 1 H NMR (400 MHz, DMSO-d6) δ 12.54 (d, J = 6.1 Hz, 1H), 9.94 (t, J = 5.9 Hz, 1H), 8.35 - 8.28 (m, 1H), 7.73 (tt, J = 7.1, 3.5 Hz, 1H), 7.70 - 7.61 (m, 2H), 7.35 (t, J = 8.6 Hz, 1H), 6.78 (dt, J = 14.9, 4.6 Hz, 1H), 6.57 - 6.44 (m, 2H), 4.15 (dt, J = 6.0, 3.0 Hz, 2H), 3.92 (s, 3H).

[0280] Biological assay Cell-free HTRF-based HOIP inhibition assay A cell-free homogeneous time-resolved fluorescence (HTRF) HOIP inhibition assay was performed to evaluate the inhibition of HOIP activity by compounds similar to the assay described by Katsuya et al (SLAS Discov 2018). This assay was performed in the following steps: a) Synthesis of a recombinant fragment of human E3 ubiquitin-protein ligase RNF31 (HOIP) expressed with >90% purity in an E. coli system (the protein was prepared as a 1 mg / mL stock in a standard formulation), b) Typical concentration range: Incubation of the compound at 100 - 0.005 μM at 25 °C for 1 hour with a final DMSO concentration of 1% in a mixture of HOIP and ubiquitin-activating enzyme E1, c) Subsequently, addition of a ubiquitination solution containing E2 and substrate (the reaction proceeds for 2.5 hours at 25 °C), and d) HTRF detection was performed using a PHERAstar FSX (BMG Labtech) plate reader (excitation at 337 nm, dual emission at 665 and 620 nm).

[0281] Cell-based dual luciferase NF-κB reporter assay The dual luciferase reporter assay was designed to find inhibitors of HOIP that affect the NF-κB signaling pathway. The assay was performed in HEK293 cells transfected with plasmids encoding Firefly and NanoLuc luciferases. The NanoLuc luciferase plasmid contains an NF-κB response element that determines its expression. The assay was performed according to a standard dual luciferase protocol. The assay consisted of several steps: - The compound was dispensed in the following concentration range: 100 - 0.005 μM with a final DMSO concentration of 1% (25 μL) of the final volume, - Cells were stimulated with 2.5 ng / mL TNF after 30 minutes, and - After 6 hours, the firefly and NanoLuc luciferase activities were determined according to the procedure described by the manufacturer of the Nano-Glo Dual-Luciferase Reporter Assay System.

[0282] TNF-α-induced cytotoxicity assay Using a survival assay with the bladder cancer RT4 cell line, the potential inhibitory effect of the test compound on HOIP activity was identified. The survival rate was determined by the CellTiter-Glo luminescent cell viability assay (G7571, Promega), which measures the ability to generate a luminescence signal proportional to the amount of ATP present in live cells. The assay consists of several steps: a) Cells were subcultured twice a week regularly using a standard complete growth medium composition, b) Cells were prepared for the assay by creating a cell suspension at a density of 0.05 mln cells / mL and dispensing it into plates (ViewPlate-384, PerkinElmer) to obtain 1000 cells / well, c) Cells were stimulated with 1.25 ng / mL of TNFα and the compound and incubated at 37 °C for 72 hours in an atmosphere with 5% CO2, and Cytotoxicity for detection was measured by the CellTiter-Glo® luminescent cell viability assay based on the method described by the manufacturer.

[0283] Results Biological assays The compounds of the present invention (Examples 5 to 186) were tested in one or more of the above biological assays. Table 1 below includes all IC50 values of the biochemical (HTRF) and cellular (TNF, NFkB) activities of the tested compounds.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Brief Description of the Drawings

[0284]

Figure 1

Figure 2

Figure 3A

Figures 4A-4J

Figure 5A

Figures 6A-6D

Figure 7A

Figure 8A

Figure 8B

Images