Substituted Quinoline Derivatives

Abstract

As a result of research, the present inventors have found that a substituted quinoline derivative has an acetylcholine receptor aggregation-inducing activity and can be useful as an active ingredient of a pharmaceutical composition for preventing and / or treating neuromuscular diseases. The substituted quinoline derivative of the present invention can be used as a preventive agent and / or a therapeutic agent for neuromuscular diseases.

Description

[Technical field]

[0001] The present invention relates to a substituted quinoline derivative which has an acetylcholine receptor aggregation-inducing activity and is expected to be useful as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for the prevention and / or treatment of a neuromuscular disease. [Background technology]

[0002] Neuromuscular junctions (NMJs) are chemical synapses formed between motor nerve axon terminals and skeletal muscles, and are essential for controlling skeletal muscle contraction via the endogenous neurotransmitter acetylcholine. Acetylcholine receptors are highly aggregated in postsynaptic regions formed on skeletal muscle endplates, and such aggregation plays an important role in functional NMJ formation. It is known that the failure or breakdown of the high level of aggregation of acetylcholine receptors is associated with a decline in skeletal muscle contractile function in neuromuscular diseases such as congenital myasthenia caused by mutations or defects in NMJ-related genes and myasthenia gravis caused by autoantibodies against NMJ-constituting proteins (Non-Patent Document 1).

[0003] The acetylcholine receptor expressed in skeletal muscle is a pentameric ligand-gated ion channel formed by the assembly of two α1 subunits and one each of β1, δ, and ε subunits. It has been found that in the acetylcholine receptors of uninnervated muscles such as those of developing fetuses, γ, not ε, forms a pentamer with other subunits. This pentameric acetylcholine receptor highly aggregates to form a postsynapse, and it is known that acetylcholine receptors exist in the postsynaptic region at a density approximately 1000 times higher than in the surrounding area (Non-Patent Document 2).

[0004] It has been reported that activation of the receptor tyrosine kinase MuSK on the skeletal muscle side by the glycoprotein Agrin secreted from the motor nerve axon terminal via the low density lipoprotein receptor-related protein 4 (Lrp4) on the skeletal muscle side is essential for the high degree of aggregation and maintenance of acetylcholine receptors. (Non-Patent Document 3). It is believed that when MuSK is activated, the Agrin dimer forms a tetramer with the Lrp4 dimer, bringing MuSK bound to Lrp4 into close proximity with another MuSK in the same state, causing autophosphorylation of the tyrosine kinase domain of MuSK on the cytoplasmic side. Activation of MuSK leads to changes in the localization and function of various proteins, including Rapsyn, which acts as a scaffold protein, leading to the aggregation of acetylcholine receptors. It has also been reported that DOK7, which has been identified as one of the causative genes of congenital myasthenia, promotes phosphorylation of MuSK from within the cell before motor nerve innervation during ontogeny, and induces muscle-autonomous aggregation of acetylcholine receptors (Non-Patent Document 4). Thus, although various aspects of the mechanisms of NMJ formation and maintenance have been elucidated in recent years, many details remain unclear.

[0005] In research into the treatment of diseases targeting the NMJ, artificial induction of high-grade aggregation of acetylcholine receptors has been investigated, and improvements in pathology have been reported in several disease model animals (Non-Patent Document 5). It has been reported that this has therapeutic effects in neuromuscular disease models such as congenital myasthenia and myasthenia gravis, as well as neurodegenerative disease models such as amyotrophic lateral sclerosis and myelogenous muscular atrophy, and even in sarcopenia models characterized by age-related reduction in skeletal muscle mass (Non-Patent Document 6), indicating that induction of acetylcholine receptor aggregation can provide treatment for various diseases that are accompanied by reduced NMJ function and reduced skeletal muscle contractile function.

[0006] Reported techniques aimed at inducing acetylcholine receptor aggregation include a method in which the DOK7 gene is introduced using an adeno-associated virus to induce activation of MuSK from within the cell (Non-Patent Document 7, Non-Patent Document 8, and Non-Patent Document 9), a method in which dimerization of MuSK is induced from outside the cell using an antibody (Patent Document 1, Non-Patent Document 10, and Non-Patent Document 11), and a technique for gene-modifying Agrin to reduce its molecular weight (Patent Document 2, Non-Patent Document 12, Non-Patent Document 13, and Non-Patent Document 14).

[0007] Non-Patent Document 15 reports that salbutamol, shown in the following formula, has an action of inducing aggregation of acetylcholine receptors.

[0008] [ka]

[0009] Non-Patent Document 16 discloses that the combination of a compound represented by the following formula with Agrin enhances the aggregation-inducing activity of acetylcholine receptors.

[0010] [ka] [Prior art documents] [Patent documents]

[0011] [Patent Document 1] International Publication No. 2013 / 074636 [Patent Document 2] International Publication No. 2011 / 026615 [Non-patent literature]

[0012] [Non-Patent Document 1] Annu. Rev. Physiol., 80, 159-188 (2018) [Non-Patent Document 2] J. Cell Biol., 69, 144-158 (1976) [Non-licensed document 3] Expert Opin. Ther. Targets, 21:10, 949-958 (2017)

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed Document 8

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-licensed Document 14

Non-licensed Document 15

Non-licensed Document 16

[0013] The present invention provides a pharmaceutical composition, in particular a compound which has an acetylcholine receptor aggregation-inducing activity and is expected to be useful as an active ingredient in a pharmaceutical composition for the prevention and / or treatment of neuromuscular diseases. [Means for solving the problem]

[0014] The present inventors have discovered that substituted quinoline derivatives have an acetylcholine receptor aggregation-inducing activity and can be useful as active ingredients in pharmaceutical compositions for the prevention and / or treatment of neuromuscular diseases, and have completed the present invention.

[0015] The present invention relates to a compound of formula (I) or a salt thereof, and to pharmaceutical compositions comprising a compound of formula (I) or a salt thereof and one or more excipients.

[0016] [ka]

[0017] During the ceremony, R 1a and R 1b are the same or different and each represents H, optionally substituted C 1-6 Alkyl, halogen, hydroxy, or -O-(optionally substituted C 1-6 alkyl), and R 1a and R 1b are attached to the same carbon atom, R 1a and R 1b are bonded together to form R 1a and R 1b C together with the carbon atom to which it is attached 3-8 may form a cycloalkyl, R 2is H, optionally substituted C 1-6 Alkyl, halogen, cyano, or -O-(optionally substituted C 1-6 alkyl), R 3 is H or a halogen, R 4 is H, methyl, or halogen; R 5 is methyl, ethyl, or fluoromethyl; X is N or CR X and Y is N or CR Y and R X is H or a halogen, R Y is H or a halogen, L is bond, C 1-6 Alkylene, -O-(C 1-6 alkylene), C 2-6 Alkenylene, C 3-8 Cycloalkylene or C 4-8 is cycloalkenylene, Z is -COOH or -CONR Z1 R Z2 or L and Z together represent optionally substituted C 1-6 Alkyl, -O-(optionally substituted C 1-6 alkyl), or a 3-8 membered optionally substituted heterocyclo ring containing 1 to 2 nitrogen atoms, R Z1 may be substituted C 1-6 alkyl, an optionally substituted 3-8 membered heterocyclo ring containing 1-2 nitrogen atoms, or -SO2-R Z3 and R Z3 C 1-6 Alkyl or C 3-8 is cycloalkyl, R Z2 is H or C 1-6 is alkyl, or R Z1 and R Z2 are bonded together to form R Z1 and RZ2 may form, together with the nitrogen atom to which it is bonded, a 3- to 8-membered optionally substituted heterocyclo ring containing 1 to 2 nitrogen atoms, n is 0 or 1.

[0018] The present invention also relates to a compound of formula (I) or a salt thereof, and to pharmaceutical compositions comprising a compound of formula (I) or a salt thereof and one or more excipients.

[0019] [ka]

[0020] During the ceremony, R 1a and R 1b are the same or different and each represents H, optionally substituted C 1-6 Alkyl, halogen, hydroxy, or -O-(optionally substituted C 1-6 alkyl), and R 1a and R 1b are attached to the same carbon atom, R 1a and R 1b are bonded together to form R 1a and R 1b C together with the carbon atom to which it is attached 3-8 may form a cycloalkyl, R 2 is H, optionally substituted C 1-6 Alkyl, halogen, cyano, or -O-(optionally substituted C 1-6 alkyl), R 3 is H or a halogen, R 4 is H, methyl, or halogen; R 5 is methyl, ethyl, or fluoromethyl; X is N or CR X and Y is N or CR Y However, X and Y are CR at the same time. X and CR Y It will not be, RX is H or a halogen, R Y is H or a halogen, L is bond, C 1-6 Alkylene, -O-(C 1-6 alkylene), C 2-6 Alkenylene, C 3-8 Cycloalkylene or C 4-8 is cycloalkenylene, Z is -COOH or -CONR Z1 R Z2 or L and Z together represent optionally substituted C 1-6 Alkyl, -O-(optionally substituted C 1-6 alkyl), or a 3-8 membered optionally substituted heterocyclo ring containing 1 to 2 nitrogen atoms, R Z1 may be substituted C 1-6 alkyl, an optionally substituted 3-8 membered heterocyclo ring containing 1-2 nitrogen atoms, or -SO2-R Z3 and R Z3 C 1-6 Alkyl or C 3-8 is cycloalkyl, R Z2 is H or C 1-6 is alkyl, or R Z1 and R Z2 are bonded together to form R Z1 and R Z2 may form, together with the nitrogen atom to which it is bonded, a 3- to 8-membered optionally substituted heterocyclo ring containing 1 or 2 nitrogen atoms, n is 0 or 1. Unless otherwise specified in this specification, when a symbol in a chemical formula is used in other chemical formulas, the same symbol has the same meaning.

[0021] The present invention further relates to a pharmaceutical composition for preventing and / or treating a neuromuscular disease, comprising a compound of formula (I) or a salt thereof and a pharma- ceutical acceptable excipient. The pharmaceutical composition comprises an agent for preventing and / or treating a neuromuscular disease, comprising a compound of formula (I) or a salt thereof.

[0022] The present invention relates to a compound of formula (I) or a salt thereof which is an acetylcholine receptor aggregation inducer, a compound of formula (I) or a salt thereof for use as an acetylcholine receptor aggregation inducer, an acetylcholine receptor aggregation inducer comprising the compound of formula (I) or a salt thereof, use of the compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the prevention and / or treatment of neuromuscular diseases, a compound of formula (I) or a salt thereof for the prevention and / or treatment of neuromuscular diseases, a compound of formula (I) or a salt thereof for use in the prevention and / or treatment of neuromuscular diseases, and a method for the prevention and / or treatment of neuromuscular diseases which comprises administering an effective amount of a compound of formula (I) or a salt thereof to a subject.

[0023] The term "subject" refers to a human or animal, and in certain embodiments, refers to a human. Effect of the Invention

[0024] The compound of formula (I) or a salt thereof has an acetylcholine receptor aggregation-inducing activity and can be used as an agent for the prevention and / or treatment of neuromuscular diseases. [Brief description of the drawings]

[0025] [Figure 1] 1 shows the results of evaluating the effect of the compound of Example 2 in suppressing a decrease in grip strength in an animal model of MuSK-type myasthenia gravis. The vertical axis shows the muscle strength (kg) of the limbs of the mouse measured by a grip strength measuring device, and shows the mean value ± standard error.

[0026] [Diagram 2] 2 shows the results of evaluating the effect of the compounds of Example 18 and Example 19 on suppressing a decrease in grip strength in an animal model of MuSK-type myasthenia gravis. The vertical axis shows the muscle strength (kg) of the limbs of the mouse measured by a grip strength measuring device, and shows the average value ± standard error. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] The present invention will be described in detail below. As used herein, the following terms have the meanings indicated below unless otherwise specified. The definitions below are intended to clarify, but not limit, the terms defined. If a term is not specifically defined as used herein, it is used with the meaning generally accepted by those of ordinary skill in the art.

[0028] In the present invention, "alkyl" refers to linear or branched alkyl. 1-6 The term "alkyl" refers to a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms (hereinafter, the number of carbon atoms will be described in the same manner), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl. 1-6 In one embodiment, "alkyl" is C 1-3 In another embodiment it is alkyl, in another embodiment it is methyl, ethyl or isopropyl, in another embodiment it is methyl or ethyl, and in yet another embodiment it is methyl.

[0029] "C 1-3 "Alkyl" is, for example, methyl, ethyl, n-propyl or isopropyl. 1-3 "Alkyl" in one embodiment is methyl or ethyl, and in another embodiment is methyl.

[0030] "Alkylene" is a divalent group obtained by removing a hydrogen atom from the above "alkyl". 1-6 "Alkylene" is, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethylethylene, or 1,1,2,2-tetramethylethylene. 1-6"Alkylene" in one embodiment is methylene, ethylene or propylene, in another embodiment is methylene, and in yet another embodiment is ethylene.

[0031] "Cycloalkyl" refers to a saturated hydrocarbon ring group which may be bridged or spirocyclized. 3-8 "Cycloalkyl" is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. 3-8 "Cycloalkyl" in one embodiment is cyclopropyl.

[0032] "Cycloalkylene" is a divalent group obtained by removing a hydrogen atom from the above "cycloalkyl". 3-8 Cycloalkylene" is, for example, cyclopropanediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, cycloheptanediyl, or cyclooctanediyl. 3-8 "Cycloalkylene" in one embodiment is cyclohexanediyl.

[0033] "Alkenyl" means a straight or branched alkyl group having one double bond in the "alkyl". 2-6 Alkenyl" is, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, or 5-hexenyl. 2-6 "Alkenyl" in one embodiment is ethenyl.

[0034] "Alkenylene" is a divalent group obtained by removing a hydrogen atom from the above "alkenyl". 2-6Alkenylene" is, for example, ethenylene, 1-propenylene, 2-propenylene, 2-methyl-1-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 3-methyl-2-butenylene, 1-pentenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene, 4-methyl-3-pentenylene, 1-hexenylene, 3-hexenylene, or 5-hexenylene. 2-6 "Alkenylene" in one embodiment is ethenylene.

[0035] A "cycloalkenyl" is an unsaturated hydrocarbon ring group having one double bond in the ring. 4-8 "Cycloalkenyl" is, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl.

[0036] "Cycloalkenylene" is a divalent group obtained by removing a hydrogen atom from the above "cycloalkenyl". 4-8 Cycloalkenylene" is, for example, cyclobutenediyl, cyclopentenediyl, cyclohexenediyl, cycloheptenediyl, or cyclooctenediyl. 4-8 "Cycloalkenylene" in one embodiment is cyclohexenediyl.

[0037] The term "heterocyclo group" refers to a C 1-6A 3-8 membered heterocyclo ring group having 1 to 4 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms as ring constituent atoms which may be bridged with an alkylene, and which may further form a 3-6 membered spiro ring having a nitrogen atom as a ring constituent atom, and which may have an oxidized sulfur atom as a ring constituent atom which may have a double bond in the ring, and specific examples thereof include azepanyl, diazepanyl, oxazepanyl, thiazepanyl, aziridinyl, azetidine. Examples of the alkyl group include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrazolidinyl, piperazinyl, azepanyl, azocanyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, morpholinyl, tetrahydrothiopyranyl, oxathiolanyl, oxiranyl, oxetanyl, dioxolanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, 1,4-dioxanyl, and 2,6-diazaspiro[3.3]heptanyl.

[0038] Among the "heterocyclo ring groups", the "3- to 8-membered heterocyclo ring group containing 1 or 2 nitrogen atoms" is a 3- to 8-membered heterocyclo ring group having 1 or 2 nitrogen atoms and optionally having a double bond in the ring, and examples thereof include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, azocanyl, tetrahydropyridyl, and 2,6-diazaspiro[3.3]heptanyl. In one embodiment, the "3- to 8-membered heterocyclocyclic group containing 1 to 2 nitrogen atoms" is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyridyl, or 2,6-diazaspiro[3.3]heptanyl, in another embodiment, piperidinyl, piperazinyl, or tetrahydropyridyl, in another embodiment, azetidinyl or pyrrolidinyl, in another embodiment, azetidinyl or 2,6-diazaspiro[3.3]heptanyl, in another embodiment, azetidinyl, and in yet another embodiment, 2,6-diazaspiro[3.3]heptanyl.

[0039] "Halogen" is fluoro, chloro, bromo or iodo, and in one embodiment is fluoro, chloro or bromo, in another embodiment is fluoro or chloro, in another embodiment is fluoro, and in yet another embodiment is chloro.

[0040] In the present invention, "optionally substituted" means unsubstituted or substituted with one or more substituents, and in one embodiment, may be substituted with 1 to 5 substituents, and in another embodiment, may be substituted with 1 to 2 substituents. The substitution may be at any position in the group where a hydrogen atom would normally be present.

[0041] R 1a , R 1b and R 2 "Optionally substituted C" 1-6 In some embodiments, the substituents in "alkyl" are hydroxy or -O-(C 1-6 alkyl), in another embodiment it is hydroxy or methoxy, and in yet another embodiment it is hydroxy.

[0042] L and Z together form "optionally substituted C 1-6 Alkyl" and "-O-(optionally substituted C 1-6 In some embodiments, the substituents of "alkyl" are hydroxy, -NH, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2, in another embodiment -NH2, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2, in another embodiment hydroxy, -NH2, -NH(C 1-6 alkyl), in another embodiment, hydroxy, -NH2 and -NH-methyl, in another embodiment, hydroxy or -NH2, in another embodiment, -NH2 or -NH(C 1-6 alkyl), and in yet another embodiment, -NH2 or -NH-methyl.

[0043] R Z1 "Optionally substituted C" 1-6 In some embodiments, the substituents in "alkyl" are -NH, -NH(C1-6 alkyl), -N(C 1-6 heterocyclocyclic group optionally substituted with -alkyl)2, -COOH, or hydroxy; in another embodiment, -NH2, -NH-methyl, -N(methyl)2, -COOH, hydroxyazetidinyl, or morpholinyl.

[0044] In one embodiment, the substituent of the "optionally substituted 3-8 membered heterocyclocyclic group containing 1 to 2 nitrogen atoms" is C 1-6 alkyl, -NH2, -COOH, or oxo, in another embodiment methyl, -NH2, -COOH, or oxo, in another embodiment C 1-6 alkyl or oxo, in another embodiment methyl or oxo, in another embodiment C 1-6 Alkyl, -NH2 or -COOH, in another embodiment methyl, -NH2 or -COOH, in another embodiment C 1-6 In yet another embodiment, it is alkyl, and in yet another embodiment, it is methyl.

[0045] In the present invention, the term "acetylcholine receptor aggregation inducer" refers to a compound that induces acetylcholine receptor aggregation. In one embodiment, the "acetylcholine receptor aggregation inducer" is a compound that has a Max value of 30% or more at a compound concentration of 30 μM or less in the method of Test Example 1 described in the present specification.

[0046] One or more aspects may be combined with other aspects, even if the combination is not specifically described, i.e. all aspects may be freely combined.

[0047] In the present invention, the "neuromuscular disease" refers to myasthenia gravis, congenital myasthenia, amyotrophic lateral sclerosis, myelogenous muscular atrophy, peripheral neuropathy, or age-related sarcopenia, and in one embodiment refers to myasthenia gravis, congenital myasthenia, amyotrophic lateral sclerosis, or myelogenous muscular atrophy, and in another embodiment refers to myasthenia gravis.

[0048] Some embodiments of the compound of formula (I) or a salt thereof according to the present invention are shown below. (1-1)R 1a and R1b are the same or different and each represents H, optionally substituted C 1-6 Alkyl, halogen, hydroxy, or -O-(optionally substituted C 1-6 alkyl), and R 1a and R 1b When both are attached to the same carbon atom, R 1a and R 1b are bonded together to form R 1a and R 1b C together with the carbon atom to which it is attached 3-8 A compound which may form a cycloalkyl group or a salt thereof. (1-2)R 1a and R 1b are the same or different and each is H, methyl, hydroxymethyl, fluoro, hydroxy or methoxy; R 1a and R 1b are attached to the same carbon atom, R 1a and R 1b are combined together to form R 1a and R 1b A compound or a salt thereof which forms cyclopropyl together with the carbon atom to which it is bonded. (1-3)R 1a and R 1b are the same or different and are H or fluoro, or a salt thereof. (2-1)R 2 is H, optionally substituted C 1-6 Alkyl, halogen, cyano, or -O-(optionally substituted C 1-6 alkyl) or a salt thereof. (2-2)R 2 is H, methyl, hydroxymethyl, methoxymethyl, fluoro, cyano, or methoxy, or a salt thereof. (2-3)R 2 is H or fluoro, or a salt thereof. (2-4)R 2 or a salt thereof, wherein (3-1)R 3 is H or a halogen, or a salt thereof. (3-2)R 3is H or fluoro, or a salt thereof. (3-3)R 3 or a salt thereof, wherein (4-1)R 4 is H, methyl or halogen, or a salt thereof. (4-2)R 4 is H or a halogen, or a salt thereof. (4-3)R 4 is H or fluoro, or a salt thereof. (5-1)R 5 is methyl, ethyl, or fluoromethyl, or a salt thereof. (5-2)R 5 is methyl or a salt thereof. (6-1) X is N or CR X , Y is N or CR Y However, X and Y are CR at the same time. X and CR Y A compound or a salt thereof that does not become (6-2) X is N and Y is CR Y or a salt thereof. (6-3) X is CR X and Y is N, or a salt thereof. (6-4) A compound or a salt thereof, wherein X is N and Y is N. (6-5) X is N or CR X , Y is N or CR Y or a salt thereof. (6-6) X is CR X and Y is CR Y or a salt thereof. (7-1)R X is H or a halogen, or a salt thereof. (7-2)R X is H or fluoro, or a salt thereof. (7-3)R X is H or a salt thereof. (8-1)R Y is H or a halogen, or a salt thereof. (8-2)R Yis H or fluoro, or a salt thereof. (8-3)R Y A compound or a salt thereof, wherein (9-1) L is bond, C 1-6 Alkylene, -O-(C 1-6 alkylene), C 2-6 Alkenylene, C 3-8 Cycloalkylene or C 4-8 is cycloalkenylene, Z is -COOH or -CONR Z1 R Z2 or L and Z together represent optionally substituted C 1-6 Alkyl, -O-(optionally substituted C 1-6 alkyl), or a compound which may form an optionally substituted 3-8 membered heterocyclo ring containing 1 or 2 nitrogen atoms, or a salt thereof. (9-2) L is bond, C 1-6 Alkylene, -O-(C 1-6 alkylene), C 2-6 Alkenylene, C 3-8 Cycloalkylene or C 4-8 is cycloalkenylene, Z is -COOH or -CONR Z1 R Z2 or L and Z together form hydroxy and -NHR LZ C which may be substituted with 1 to 2 substituents selected from the group consisting of 1-6 Alkyl, -O-(hydroxy and -NHR LZ C which may be substituted with 1 to 2 substituents selected from the group consisting of 1-6 alkyl), or C 1-6 may form a 3-8 membered heterocyclo ring containing 1-2 nitrogen atoms which may be substituted with 1-2 substituents selected from the group consisting of alkyl and oxo; and R LZ is H or C 1-6 A compound or a salt thereof, which is alkyl. (9-3) L is a bond, methylene, ethylene, -OCH2-, ethenylene, cyclohexanediyl, or cyclohexenediyl; Z is -COOH or -CONR Z1 R Z2 or L and Z together are optionally substituted with a substituent selected from the group consisting of -NH2 and -NH-methyl. 1-3 C optionally substituted with 1 to 2 substituents selected from the group consisting of alkyl, -O-(hydroxy and -NH 1-3 A compound or a salt thereof which may form a 3-8 membered heterocyclo ring containing 1 to 2 nitrogen atoms which may be substituted by a substituent selected from the group consisting of alkyl, methyl and oxo. (9-4) L is a bond, Z is -COOH or -CONR Z1 R Z2 or a salt thereof. (9-5) L is a bond, A compound or a salt thereof, wherein Z is -COOH. (9-6) L is a bond, Z-CONR Z1 R Z2 or a salt thereof. (10-1)R Z1 may be substituted C 1-6 alkyl, an optionally substituted 3-8 membered heterocyclo ring containing 1-2 nitrogen atoms, or -SO2-R Z3 and R Z3 C 1-6 Alkyl or C 3-8 is cycloalkyl, R Z2 is H or C 1-6 is alkyl, or R Z1 and R Z2 are bonded together to form R Z1 and R Z2 may form an optionally substituted 3- to 8-membered heterocyclo ring containing 1 or 2 nitrogen atoms together with the nitrogen atom to which it is bonded, or a salt thereof. (10-2)RZ1 may be substituted C 1-6 alkyl, an optionally substituted 3-8 membered heterocyclo ring containing 1-2 nitrogen atoms, or -SO2-R Z3 and R Z3 C 3-8 is cycloalkyl, R Z2 is H or C 1-6 is alkyl, or R Z1 and R Z2 are bonded together to form R Z1 and R Z2 may form an optionally substituted 3- to 8-membered heterocyclo ring containing 1 or 2 nitrogen atoms together with the nitrogen atom to which it is bonded, or a salt thereof. (10-3)R Z1 is optionally substituted with 1 to 2 substituents selected from the group consisting of -NH2, -NH-methyl, -N(methyl)2 and morpholinyl; 1-3 a 3-8 membered heterocyclic ring containing 1-2 nitrogen atoms which may be substituted by alkyl or methyl, or -SO2-R Z3 and Or R Z1 is a substituent selected from the group consisting of the following formulas (i), (ii) and (iii):

[0049] [ka]

[0050] R Z3 is cyclopropyl, R Z2 is H or methyl, or R Z1 and R Z2 are bonded together to form R Z1 and R Z2 may form a structure of the following formula (iv) or formula (v) together with the nitrogen atom to which it is bonded:

[0051] [ka]

[0052] R Z4 is H or methyl, or a salt thereof. (10-4)R Z1 and R Z2 are bonded together to form R Z1 and R Z2 A compound or a salt thereof which forms a structure of the following formula (vi) or formula (v) together with the nitrogen atom to which it is bonded:

[0053] [ka]

[0054] (10-5)R Z1 and R Z2 are bonded together to form R Z1 and R Z2 A compound or a salt thereof which forms a structure represented by the following formula (vi) together with the nitrogen atom to which it is bonded:

[0055] [ka]

[0056] (10-6)R Z1 and R Z2 are bonded together to form R Z1 and R Z2 A compound or a salt thereof which forms a structure represented by the following formula (v) together with the nitrogen atom to which it is bonded:

[0057] [ka]

[0058] (11-1) A compound or a salt thereof, wherein n is 0 or 1. (11-2) A compound or a salt thereof, wherein n is 0. (11-3) A compound or a salt thereof, wherein n is 1. (12) A compound or a salt thereof that is a combination of two or more of the embodiments described in the above (1-1) to (11-3) that are not contradictory to each other. For example, the following combinations may be mentioned, but are not limited to these. (12-1) A compound or a salt thereof which is a combination of the above embodiments (1-1), (2-1), (3-1), (4-1), (5-1), (6-5), (7-1), (8-1), (9-1), (10-1), or (11-1). (12-2) A compound or a salt thereof which is a combination of the above embodiments (1-2), (2-2), (3-2), (4-3), (5-2), (6-5), (7-2), (8-2), (9-3), (10-3), or (11-1). (12-3) A compound or a salt thereof which is a combination of the above embodiments (1-1), (2-1), (3-1), (4-1), (5-1), (6-1), (7-1), (8-1), (9-1), (10-1), or (11-1). (12-4) A compound or a salt thereof which is a combination of the above embodiments (1-1), (2-1), (3-1), (4-2), (5-2), (6-1), (7-1), (8-1), (9-2), (10-2), or (11-1). (12-5) A compound or a salt thereof which is a combination of the above embodiments (1-2), (2-2), (3-2), (4-3), (5-2), (6-1), (7-2), (8-2), (9-3), (10-3), or (11-1). (12-6) A compound or a salt thereof which is a combination of the above embodiments (1-3), (2-4), (3-3), (4-3), (5-2), (6-2), (8-3), (9-4), (10-4), or (11-1).

[0059] Specific compounds included in the present invention include the following compounds. 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline-7-carboxylic acid, Sodium 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline-7-carboxylate, {2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinolin-7-yl}(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl))methanone, (3-aminoazetidin-1-yl){2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinolin-7-yl}methanone, 2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-3-fluoro-4-methylquinoline-7-carboxylic acid, 2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinoline-7-carboxylic acid, 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinoline-7-carboxylic acid.

[0060] Specific examples of compounds included in the present invention include the following compounds in one embodiment. 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline-7-carboxylic acid, Sodium 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline-7-carboxylate, {2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinolin-7-yl}(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)methanone, (3-aminoazetidin-1-yl){2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinolin-7-yl}methanone, 2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-3-fluoro-4-methylquinoline-7-carboxylic acid, 2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinoline-7-carboxylic acid, 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinoline-7-carboxylic acid, A compound selected from the group consisting of:

[0061] The compound of formula (I) may have tautomers or geometric isomers depending on the type of substituents. In this specification, the compound of formula (I) or a salt thereof may be described in only one isomeric form, but the present invention also includes other isomers, and also includes isolated isomers or mixtures thereof.

[0062] In addition, the compound of formula (I) or a salt thereof may have an asymmetric center or axial chirality, and may have enantiomers (optical isomers) due to the asymmetric center or axial chirality. The compound of formula (I) or a salt thereof includes both isolated individual enantiomers, such as (R) and (S) forms, and mixtures thereof (including racemic and non-racemic mixtures). In one embodiment, the enantiomer is "stereochemically pure". "Stereochemically pure" means a degree of purity that can be recognized by a person skilled in the art as being substantially stereochemically pure. In another embodiment, the enantiomer is a compound having a stereochemical purity of, for example, 90% ee (enantiomeric excess) or more, 95% ee or more, 98% ee or more, or 99% ee or more.

[0063] Furthermore, the present invention also includes pharma- ceutically acceptable prodrugs of the compounds represented by formula (I). A pharma- ceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and "Drug Development" (Hirokawa Shoten, 1990), Vol. 7, Molecular Design, 163-198.

[0064] The salt of the compound of formula (I) is a pharma- ceutically acceptable salt, and may form an acid addition salt or a salt with a base depending on the type of the substituent.Specific examples include, but are not limited to, acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, acid addition salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid, salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, salts with various amino acids such as acetylleucine and amino acid derivatives, and ammonium salts.

[0065] Furthermore, the present invention also includes various hydrates, solvates and crystal polymorphs of the compound of formula (I) and its salts.

[0066] The present invention also encompasses all compounds of formula (I) or salts thereof that are pharma- ceutically acceptable and labeled with one or more radioactive or non-radioactive isotopes. Examples of suitable isotopes for use in isotopic labeling of the compounds of the present invention include hydrogen ( 2 H and 3 H, etc.), carbon ( 11 C. 13 C, and 14 C, etc.), nitrogen ( 13 N, 15 N, etc.), oxygen ( 15 O. 17 O. 18 O etc.), fluorine ( 18 F, etc.), chlorine ( 36 Cl, etc.), iodine ( 123 I and 125 I, etc.), phosphorus ( 32 P, etc.), sulfur ( 35 Isotopically labeled compounds of the present invention may be used in studies such as drug and / or substrate tissue distribution studies. For example, tritium ( 3 H) and carbon-14 (14 Radioisotopes such as C) may be used for this purpose because of their ease of labeling and convenience of detection.

[0067] Substitution of heavier isotopes, e.g., deuterium for hydrogen ( 2 Substitution with positron-emitting isotopes (H) may be therapeutically advantageous (e.g., increased in vivo half-life, reduced dosage, reduced drug interactions) due to increased metabolic stability. 11 C. 18 F, 15 O. 13 Substitution with 1,2-diaminophenyl 2,4-diaminophenyl 1,4-diaminophenyl 1,5-diaminophenyl 1,6-diaminophenyl 1,7-diaminophenyl 1,8-diaminophenyl 1,9 ...

[0068] (Preparation method) The compound of formula (I) and its salts can be produced by applying various known synthesis methods based on the characteristics of its basic structure and the type of substituent. Depending on the type of substituent or functional group, it may be effective to replace the functional group with an appropriate protecting group (a group that can be easily converted to the functional group) at the stage from the starting material to the intermediate. Examples of such protecting groups include those described in "Greene's Protective Groups in Organic Synthesis (4th Edition, 2006)" by PGM Wuts and TW Greene, and may be appropriately selected and used according to the method described in this specification, but are not limited to these. In such a method, a protecting group is introduced, a reaction is performed, and then the protecting group is removed as necessary to obtain the desired compound.

[0069] Also, prodrugs of the compound of formula (I) can be prepared by introducing a specific group at the stage leading from the starting material to the intermediate, similar to the above-mentioned protecting group, or by carrying out a chemical reaction using the compound of formula (I). This reaction can be carried out by a method well known to those skilled in the art, such as ordinary esterification, amidation, dehydration, etc.

[0070] Representative methods for producing the compound of formula (I) are described below. Each preparation method can be performed by referring to the literature cited in this specification. The preparation method of the present invention is not limited to the examples shown below.

[0071] The following abbreviations may be used herein: HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, DMF: N,N-dimethylformamide, THF: tetrahydrofuran, WSC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, COMU: N-[({[(1Z))-1-cyano-2-ethoxy-2-oxoethylidene]amino}oxy)(morpholin-4-yl)methylene]-N-methylmethanaminium hexafluorophosphate, DCC: N,N'-dicyclohexylcarbodiimide, CDI: 1,1'-carbonyldiimidazole, Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, Ruphos: 2-Dicyclohexylphosphino-2',6'-diisopropoxydephenyl, Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl.

[0072] (Preparation method 1) This preparation method is a method for producing a compound of formula (Ib) in which Z is -COOH, or a salt thereof, that is, a compound of formula (Ic), among compounds of formula (I).

[0073] [ka]

[0074] (Wherein, R is C 1-6 represents alkyl, M + represents a metal ion, and is not particularly limited, Na + Or K + (The same applies below.)

[0075] (First step) In this step, a compound of formula (Ia) is subjected to hydrolysis reaction conditions and neutralized to give a compound of formula (Ib). This reaction is carried out by using the compound of formula (Ia) and an excess amount of a basic aqueous solution, stirring in a solvent inert to the reaction at room temperature to reflux conditions for about 1 hour to about 1 day. Thereafter, neutralization treatment is carried out with an acidic aqueous solution. The basic aqueous solution used here is not particularly limited, but examples thereof include an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, and an aqueous lithium hydroxide solution. The solvent is not particularly limited, but examples thereof include alcohols such as methanol, ethanol, and n-propanol, ether solvents such as THF, diethyl ether, and 1,4-dioxane, and mixtures thereof. The acidic aqueous solution used here is not particularly limited, but examples thereof include an aqueous hydrochloric acid solution.

[0076] (Second process) In this step, a compound of formula (Ib) is subjected to salification conditions to obtain a compound of formula (Ic). This reaction is carried out by using the compound of formula (Ib) and an excess amount of a basic aqueous solution, stirring in a solvent inert to the reaction at 0° C. to room temperature for about 1 hour to about 1 day. The basic aqueous solution used here is not particularly limited, but examples thereof include an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, etc. The solvent is not particularly limited, but examples thereof include ether solvents such as THF, diethyl ether, and 1,4-dioxane, alcohols such as methanol, ethanol, and n-propanol, toluene, and mixtures thereof, etc.

[0077] (Preparation method 2) The preparation method includes the step of preparing a compound of formula (I) in which Z is -CONR Z1 R Z2 A method for preparing a compound of formula (Id)

[0078] [ka]

[0079] In this preparation method, a compound of formula (Id) is obtained by subjecting a compound of formula (Ib) and a compound of formula (IIa) to condensation reaction conditions.

[0080] This reaction is carried out by using the compound of formula (Ib) obtained in Preparation Method 1 and the compound of formula (IIa) in an equivalent amount or an excess amount of either one, adding a condensing agent and a base, and stirring in a solvent inert to the reaction at room temperature for about 1 hour to about 1 day. The condensing agent used here is not particularly limited, but examples thereof include HATU, WSC or its hydrochloride, DCC, CDI, COMU, etc. The base is not particularly limited, but examples thereof include organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine, etc., and inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, etc. The solvent is not particularly limited, but examples thereof include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, etc., ether solvents such as THF, diethyl ether, 1,4-dioxane, etc., alcohols such as methanol, ethanol, n-propanol, etc., DMF, and mixtures thereof, etc. When the compound obtained by the condensation reaction has a protecting group, the compound obtained by the condensation reaction can be subjected to deprotection reaction conditions following the condensation reaction to obtain a compound of formula (Id).

[0081] (Preparation method 3) In this preparation method, in the compound of formula (I), L and Z together form -O-(optionally substituted C 1-6 This is a method for preparing a compound of formula (If) by forming a 2-alkyl group.

[0082] [ka]

[0083] (wherein R′ is optionally substituted C 1-6 represents an alkyl group, and W represents a halogen atom. The same applies below.)

[0084] In this preparation method, a compound of formula (Ie) is subjected to alkylation reaction conditions to give a compound of formula (If). This reaction is carried out by using an equivalent amount of a compound of formula (Ie) and a compound of formula (IIb) or an excess amount of one of them, adding a base to the mixture, and stirring in a solvent inert to the reaction at room temperature to about 100°C, preferably about 60°C to about 100°C, under reflux for about 1 hour to about 1 day. The base used here is not particularly limited, but examples thereof include inorganic bases such as potassium carbonate, sodium carbonate, and cesium carbonate. The solvent is not particularly limited, but examples thereof include ether solvents such as THF and 1,4-dioxane, toluene, and DMF. When the compound obtained by the alkylation reaction has a protecting group, the compound of formula (If) can be obtained by subjecting the obtained compound to deprotection reaction conditions after the alkylation reaction.

[0085] (Preparation method 4) The preparation method includes preparing a compound of formula (I) in which L is a bond and Z is -NR Z1 R Z2 The present invention relates to a method for producing a compound of formula (Ih),

[0086] [ka]

[0087] (In the formula, W represents a halogen. The same applies below.)

[0088] In this preparation method, a compound of formula (Ig) is subjected to carbon-nitrogen bond forming reaction conditions to give a compound of formula (Ih). This reaction is carried out by using an equivalent amount of a compound of formula (Ig) and a compound of formula (IIa) or an excess amount of either one, adding a metal catalyst, a ligand, and a base to this mixture, and stirring in a solvent inert to the reaction at reflux at about 80° C. to about 100° C. for about 1 hour to about 1 day. The metal catalyst used here is not particularly limited, but examples thereof include palladium acetate, tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct. The ligand is not particularly limited, but examples thereof include Xantphos, Ruphos, Xphos, BINAP, etc. The base is not particularly limited, but examples thereof include inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, and sodium tert-butoxide, and organic bases such as triethylamine and N,N-diisopropylethylamine. The solvent is not particularly limited, but examples thereof include 1,4-dioxane, toluene, DMF, and mixtures thereof. This reaction may also be carried out under microwave irradiation. When the compound obtained by the carbon-nitrogen bond forming reaction has a protecting group, the compound of formula (Ih) can be obtained by subjecting the compound obtained by the carbon-nitrogen bond forming reaction to deprotection reaction conditions following the carbon-nitrogen bond forming reaction.

[0089] (Raw material synthesis 1) This preparation method is a method for producing a compound of formula (In), which is a representative compound of formula (Ia) that is the starting material of preparation method 1, and in which L is a bond.

[0090] [ka]

[0091] (In the formula, LG represents a boronic acid residue, a boronic acid ester residue, or a potassium trifluoroborate residue. V represents a halogen or a trifluoromethanesulfonic acid residue. U represents a halogen or a hydroxyl. The same applies below.)

[0092] (First step-1) In this step, a compound of formula (Ik) is obtained by subjecting a compound of formula (Ii) and a compound of formula (Ij) to carbon-carbon bond forming reaction conditions. This reaction is carried out by using an equivalent amount of a compound of formula (Ii) and a compound of formula (Ij) or an excess amount of either one, adding a metal catalyst and a base to the mixture, and stirring in a solvent inert to the reaction at room temperature to about 100°C, preferably about 80°C to about 100°C, under reflux for about 1 hour to about 1 day. The metal catalyst used here is not particularly limited, but examples thereof include tetrakis(triphenylphosphine)palladium(0), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, etc. The base is not particularly limited, but examples thereof include inorganic bases such as potassium carbonate, cesium carbonate, potassium phosphate, etc., and organic bases such as triethylamine, N,N'-diisopropylethylamine, etc. The solvent is not particularly limited, and examples thereof include 1,4-dioxane, ethers such as THF, alcohols such as ethanol and methanol, toluene, DMF, water, and mixtures thereof, etc. This reaction may be carried out under microwave irradiation. (First step-2) When U is a hydroxyl group, the compound of formula (Ik) can be obtained by subjecting the compound to the following triflation reaction conditions after the carbon-carbon bond forming reaction. This reaction is carried out by adding an equivalent or more of a triflation reagent and a base to the compound obtained by the carbon-carbon bond forming reaction, and stirring in a solvent inert to the reaction at 0° C. to room temperature for about 30 minutes to about 2 hours. The triflation reagent used here is not particularly limited, but examples thereof include trifluoromethanesulfonic anhydride, N-phenylbis(trifluoromethanesulfonimide), etc. The base is not particularly limited, but examples thereof include organic bases such as 2,6-lutidine, triethylamine, N,N-diisopropylethylamine, etc. The solvent is not particularly limited, but examples thereof include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, etc., ether solvents such as THF, diethyl ether, 1,4-dioxane, etc., toluene, etc.

[0093] (Second process) In this step, a compound of formula (It) is obtained by subjecting a compound of formula (Ik) to carbon monoxide insertion reaction conditions. This reaction is carried out by using a compound of formula (Ik), a metal catalyst, a ligand, a base, and an alcohol, blowing carbon monoxide gas into the mixture, and stirring in a solvent inert to the reaction under a carbon monoxide atmosphere at about 90° C. to reflux for about 2 to about 6 hours. The metal catalyst used here is not particularly limited, but examples thereof include palladium (II) acetate, tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane adduct, etc. The ligand is not particularly limited, but examples thereof include 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate), 1,1'-bis(diphenylphosphino)ferrocene, etc. Examples of the base include, but are not limited to, inorganic bases such as potassium carbonate, sodium carbonate, and cesium carbonate, and organic bases such as triethylamine, N,N-diisopropylethylamine, and pyridine. Examples of the alcohol include, but are not limited to, methanol, ethanol, etc. Examples of the solvent include, but are not limited to, DMF, dimethyl sulfoxide, toluene, etc.

[0094] (Third step) In this step, a compound of formula (Im) is obtained by subjecting a compound of formula (It) to chlorination reaction conditions. This reaction is carried out by using the compound of formula (It) and an excess amount of a chlorinating reagent in a solvent inert to the reaction, and stirring at about 0° C. to room temperature, preferably at room temperature, for about 1 to 3 hours. The chlorinating reagent used here is not particularly limited, but examples thereof include N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, sulfuryl chloride, etc. The solvent is not particularly limited, but examples thereof include acetic acid, water, acetone, acetonitrile, and mixtures thereof.

[0095] (Fourth step) In this step, a compound of formula (In) is obtained by subjecting a compound of formula (Im) and a compound of formula (IIc) to sulfonamidation reaction conditions. This reaction is carried out by using an equivalent amount of the compound of formula (Im) and a compound of formula (IIc) or an excess amount of either one, in a solvent inert to the reaction in the presence of a base, and stirring at about 0° C. to room temperature, preferably at room temperature, for about 1 hour to about 3 hours. The base used here is not particularly limited, but includes organic bases such as triethylamine and N,N-diisopropylethylamine, and inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, and sodium hydroxide. The solvent is not particularly limited, but includes halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, ether solvents such as THF, diethyl ether, and 1,4-dioxane, alcohol solvents such as methanol, ethanol, and isopropanol, water, acetonitrile, toluene, and mixtures thereof.

[0096] (Raw material synthesis 2) This preparation method is for preparing a representative compound of formula (Ij) used in Raw Material Synthesis 1, R 4 This is a process for preparing a compound of formula (Is) where is fluoro, V is trifluoromethanesulfonic acid, and X is N.

[0097] [ka]

[0098] (In the formula, T represents halogen, and TfO represents trifluoromethanesulfonate. The same applies below.)

[0099] (First step) In this step, a compound of formula (Ip) is obtained by subjecting a compound of formula (Io) to chlorination reaction conditions. This reaction is carried out by using the compound of formula (Io) and an equivalent or excess amount of a chlorinating reagent in a solvent inert to the reaction, and stirring at about 0° C. to room temperature, preferably at room temperature, for about 12 hours to about 1 day. The chlorinating reagent used here is not particularly limited, but examples thereof include oxalyl chloride, thionyl chloride, etc. The solvent is not particularly limited, but examples thereof include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, etc., ether solvents such as THF, diethyl ether, 1,4-dioxane, etc., toluene, DMF, etc.

[0100] (Second process) This step is a step of obtaining a compound of formula (Iq) by subjecting a compound of formula (Ip) and a compound of formula (IId) to acylation reaction conditions. This reaction is carried out by using an equivalent amount of the compound of formula (Ip) and a compound of formula (IId) or an excess amount of either one, adding a base thereto, and stirring in a solvent inert to the reaction at about 0° C. to room temperature, preferably at room temperature, for about 30 minutes to about 1 hour. The base used here is not particularly limited, but includes organic bases such as pyridine, triethylamine, and N,N-diisopropylethylamine, and inorganic bases such as potassium carbonate, sodium carbonate, and cesium carbonate. The solvent is not particularly limited, but includes halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, ether solvents such as THF, diethyl ether, and 1,4-dioxane, toluene, DMF, and the like.

[0101] (Third step) In this step, a compound of formula (Ir) is obtained by subjecting a compound of formula (Iq) to cyclization reaction conditions. This reaction is carried out by stirring the compound of formula (Iq) together with a base in a solvent inert to the reaction at a temperature of about 0° C. to room temperature, preferably at room temperature, for about 1 hour to about 3 hours. The base used here is not particularly limited, but examples thereof include inorganic bases such as sodium hydride and potassium t-butoxide. The solvent is not particularly limited, but examples thereof include ether solvents such as THF, diethyl ether, and 1,4-dioxane, toluene, etc.

[0102] (Fourth step) In this step, a compound of formula (Is) is obtained by subjecting a compound of formula (Ir) to triflation reaction conditions. This reaction is carried out by stirring the compound of formula (Ir) together with a triflation reagent and a base in a solvent inert to the reaction at about 0° C. to room temperature, preferably at room temperature, for about 30 minutes to about 2 hours. The triflation reagent used here is not particularly limited, but examples thereof include trifluoromethanesulfonic anhydride, N-phenylbis(trifluoromethanesulfonimide), and the like. The base is not particularly limited, but examples thereof include organic bases such as 2,6-lutidine, triethylamine, and N,N-diisopropylethylamine. The solvent is not particularly limited, but examples thereof include halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, ether solvents such as THF, diethyl ether, and 1,4-dioxane, and toluene.

[0103] (Raw material synthesis 3) This preparation method is another method for producing a compound of formula (In), which is a representative compound of formula (Ia) used as a starting material in preparation method 1, and in which L is a bond.

[0104] [ka]

[0105] (Wherein, R is C 1-6 (Alkyl. The same applies below.)

[0106] (First step) From the compounds of the formula (Iu) and (Ij), the compound of the formula (In) can be obtained by the same reaction conditions as in the first step-1 of the raw material synthesis 1.

[0107] (Raw material synthesis 4) This preparation method is a method for producing a compound of formula (Ix) in which LG is a boronic acid ester, which is a representative compound of formula (Iu) used as a raw material in Raw Material Synthesis 3.

[0108] [ka]

[0109] (First step) In this step, the compound of formula (Iw) is obtained by subjecting the compound of formula (Iv) and the corresponding amine (IIc) to sulfonamidation reaction conditions. The compound of formula (Iw) can be obtained from the compound of formula (Iv) under the same reaction conditions as in the fourth step of the raw material synthesis 1.

[0110] (Second process) In this step, a compound of formula (Ix) is obtained by subjecting a compound of formula (Iw) and a compound of formula (IIe) to carbon-boron bond forming reaction conditions. This reaction is carried out by using an equivalent amount of a compound of formula (Iw) and a compound of formula (IIe) or an excess amount of either one, adding a metal catalyst and a base to the mixture, and stirring in a solvent inert to the reaction at about 60°C to about 100°C, preferably about 80°C to about 100°C, under reflux conditions for about 1 hour to about 1 day. The metal catalyst used here is not particularly limited, but examples thereof include [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct. The base is not particularly limited, but examples thereof include inorganic bases such as potassium acetate, potassium carbonate, cesium carbonate, and potassium phosphate. The solvent is not particularly limited, but examples thereof include ethers such as 1,4-dioxane and THF, water, and mixtures thereof. This reaction may also be carried out under microwave irradiation.

[0111] The compound of formula (I) is isolated and purified as a free compound, a salt thereof, a hydrate of the free compound or a salt thereof, a solvate of the free compound or a salt thereof, or a crystalline polymorph of the free compound or a salt thereof. The salt of the compound of formula (I) can also be produced by subjecting it to a conventional salification reaction. Isolation and purification are carried out by applying conventional chemical operations such as extraction, fractional crystallization, and various fractional chromatography. Various isomers can be produced by selecting appropriate starting compounds or by separating isomers by utilizing the difference in physicochemical properties. For example, optical isomers can be obtained by a general optical resolution method of a racemate (e.g., fractional crystallization leading to a diastereomeric salt with an optically active base or acid, chromatography using a chiral column, etc.), or can be produced from an appropriate optically active starting compound.

[0112] The pharmacological activity of the compounds of formula (I) can be confirmed by the following tests or modifications thereof known to those skilled in the art.

[0113] In the following test examples of this specification, the following abbreviations may be used. ATCC: American Type Culture Collection, DAPI: 4',6-diamidino-2-phenylindole, DMEM: Dulbecco's modified Eagle's medium, PBS: phosphate buffer, PFA: paraformaldehyde, FBS: fetal bovine serum

[0114] Test Example 1: Evaluation of acetylcholine receptor aggregation-inducing activity in mouse myoblast C2C12 cells The acetylcholine receptor aggregation-inducing effect of the test compound was evaluated by imaging and quantifying the acetylcholine receptor aggregation area induced by differentiation of myoblasts into myotubes using fluorescently labeled Bungarotoxin and measuring the change in area. The following test method was optimized with reference to various reports such as FEBS let., 586, 3111-3116 (2012). The induction effect of the test compound can be determined by obtaining a concentration-response curve in which the logarithmic concentration of the test compound is plotted on the horizontal axis and the area ratio of the acetylcholine receptor aggregation area is plotted on the vertical axis.

[0115] (Test Method) A concentration-response curve was prepared using the acetylcholine receptor aggregation-inducing activity of the test compound in mouse C2C12 cells as an index. C2C12 cells (ATCC number: CRL-1772) were seeded at approximately 5000 cells / well on a 384-well plate (354667; Corning) coated with type I collagen and incubated overnight at 37°C in DMEM + 20% FBS + 1% penicillin / streptomycin medium. The next day, the medium was removed and replaced with differentiation medium containing DMEM + 2% FBS + 1% penicillin / streptomycin, and incubated at 37°C for 4 days. Test compounds were dissolved in DMSO and added to differentiation medium containing 0.1 ng / mL Agrin (550-AG-100; R&D Systems) to a final concentration of 0.0015-30 μM (3-fold serial dilution) or 0.00017-3.3 μM (3-fold serial dilution). The final concentration of DMSO was 0.3%. After 4 days of incubation, the differentiation medium was replaced with a differentiation medium containing a test compound and 0.1 ng / mL Agrin, or 0.1 ng / mL Agrin or 10 ng / mL Agrin alone, and incubated overnight at 37°C. The next day, 10 μl of DMEM containing Bungarotoxin-Alexa488 (B13422; Life Technologies) was added to the differentiation medium containing the test compound and Agrin or Agrin alone so that the final concentration of Bungarotoxin-Alexa488 was 1 μg / mL, and incubated at 37°C for 1 hour to label the acetylcholine receptor. After removing all the medium, 4% PFA was added to each well, incubated at room temperature for 10 minutes, then washed with PBS and incubated in PBS containing 5% goat serum and 0.3% Triton X-100 at room temperature for 30 minutes. After removing the PBS solution, PBS-Tween20 (28352; Thermo Fisher Scientific) containing Anti-Myosin Heavy Chain eFluor® 660 (50-6503-82; eBioscience) and DAPI (340-07971; Dojindo) was added to each well and incubated at room temperature for 1 h to label myotubes and nuclei. After washing three times with PBS-Tween20, the fluorescence was imaged using an IN Cell Analyzer 6000 (GE Healthcare).The control groups did not contain the test compound, but (1) Agrin at a final concentration of 0.1 ng / mL, and (2) Agrin at a final concentration of 10 ng / mL were added. The response of control group (1) was set to 0%, and the response of control group (2) was set to 100%. In the quantification, only the signal of the acetylcholine receptor present on the myotube was used to eliminate nonspecific fluorescence.

[0116] (Evaluation of activity) To quantitatively evaluate the acetylcholine receptor aggregation-inducing activity of a test compound, EC 50 and Max values ​​were used. EC 50 The EC value is the test compound concentration that shows 50% of the area of ​​the acetylcholine receptor aggregation region in the concentration-response curve compared with the area of ​​the 10 ng / mLAgrin aggregation region (defined as 100%). 50 was calculated by nonlinear regression analysis from the concentration-response curve using the area of ​​the aggregation region of the test compound as an index. The maximum value is the maximum response value. The Max value is expressed as a percentage of the maximum response of the test compound in the area of ​​the acetylcholine receptor aggregation region compared to 10 ng / mL Agrin (set as 100%).

[0117] Results of the Example Compounds of the Present Invention (EC 50 and Max values) are shown in Tables 1 and 2 below. In Tables 1 and 2, Ex indicates the Example number described below. EC of Examples 12, 15, 16, 52, 53, 56, 57, 60, 61, 63, and 64 50 was calculated using the molecular weight as the monohydrochloride salt. EC of Examples 10, 13, 17, 58, 59, and 62 50 The molecular weight was calculated as the dihydrochloride salt. EC of other Ex numbers 50 was calculated using the molecular weight of the free compound.

[0118] [Table 1]

[0119] [Table 2]

[0120] As shown in Tables 1 and 2, concentration-response curves were obtained for some example compounds of the present invention using the area of ​​the aggregation region as an index. From the above, it was revealed that the compound of formula (I) has an acetylcholine receptor aggregation-inducing effect.

[0121] Test Example 2: Inhibitory effect on muscle weakness in an animal model of MuSK-type myasthenia gravis In an animal model of MuSK-type myasthenia gravis in which the production of autoantibodies against endogenous MuSK was induced by immunization with human recombinant MuSK protein, the decrease in grip strength was evaluated as an indicator of pathological condition. The inhibitory effect of the administration of a test compound on the decrease in grip strength was judged to be a therapeutic effect of the test compound. (Experimental Equipment) A grip strength measuring device (GPM-100B; Melquest) was used to measure the grip strength of the limbs. (Test Method) Repeated daily oral administration of the test compound to the MuSK-type myasthenia gravis animal model was carried out as follows. Human MuSK recombinant protein (9810-MK; R&D Systems) (7.5 μg) prepared with Freund's Complete Adjuvant (263810; Becton, Dickinson and Company) was administered intradermally to the tail of 8-week-old female DBA / 2 mice (Charles River Japan). Two weeks later, 7.5 μg of human MuSK recombinant protein prepared with Freund's Incomplete Adjuvant (263910; Becton, Dickinson and Company) was administered intradermally to the tail to generate myasthenia gravis mice. One week later, the antibody titer against human MuSK in the serum and the grip strength in a grip strength test were measured, and the mice were divided into groups of 6 individuals each based on the antibody titer and subjected to a test compound administration test. The test compound was orally administered to the mice in the treatment group (3, 10, and 30 mg / kg, suspended in 0.5% methylcellulose twice a day), and the vehicle (0.5% methylcellulose) was used instead of the test compound in the control group. As the normal group, mice of the same age, sex, and strain that had not been immunized with human recombinant MuSK protein were used. Grip strength tests were performed after dosing on the morning of the 5th day. (Data Analysis) The significance test between the normal group and the control group was performed using the Student-t test (*p<0.05). Furthermore, the test between the control group and the test compound group was performed using the Dunnett multiple comparison test (#p<0.05). In all tests, a significance level of less than 5% was considered significant. As shown in FIG. 1, the compound of Example 2 was found to have an inhibitory effect on the decrease in grip strength at doses of 10 mg / kg and 30 mg / kg.

[0122] Test Example 3: Inhibitory effect on muscle weakness in an animal model of MuSK-type myasthenia gravis In an animal model of MuSK-type myasthenia gravis in which the production of autoantibodies against endogenous MuSK was induced by immunization with human recombinant MuSK protein, the decrease in grip strength was evaluated as an indicator of pathological condition. The inhibitory effect of the administration of a test compound on the decrease in grip strength was judged to be a therapeutic effect of the test compound. (Experimental Equipment) A grip strength measuring device (GPM-100B; Melquest) was used to measure the grip strength of the limbs. (Test Method) Daily oral administration of the test compound to the MuSK-type myasthenia gravis animal model was carried out as follows. Human MuSK recombinant protein (9810-MK; R&D Systems) (7.5 μg) prepared with Freund's Complete Adjuvant (263810; Becton, Dickinson and Company) was administered intradermally to the tail of 8-week-old female DBA / 2 mice (Charles River Japan). Two weeks later, 7.5 μg of human MuSK recombinant protein prepared with Freund's Incomplete Adjuvant (263910; Becton, Dickinson and Company) was administered intradermally to the tail to generate myasthenia gravis mice. One week later, serum antibody titers against human MuSK and grip strength in a grip strength test were measured, and the mice were divided into groups of 6 individuals each and subjected to a test compound administration test. The mice in the treatment group were orally administered the test compound (3 and 10 mg / kg, suspended in 0.5% methylcellulose, twice a day), and the mice in the control group were administered vehicle (0.5% methylcellulose) instead of the test compound. As the normal group, mice of the same age, sex, and strain that had not been immunized with human recombinant MuSK protein were used. Grip strength tests were performed after dosing on the morning of the fourth day. (Data Analysis) The significance test between the normal group and the control group was performed using the Student-t test (*p<0.05). Furthermore, the test between the control group and the test compound group was performed using the Dunnett multiple comparison test (#p<0.05). In all tests, a significance level of less than 5% was considered significant. As shown in FIG. 2, the compound of Example 18 was found to have an inhibitory effect on grip strength decline at doses of 3 mg / kg and 10 mg / kg, and the compound of Example 19 was found to have an inhibitory effect on grip strength decline at doses of 10 mg / kg.

[0123] From the above, it is expected that the compound of formula (I) or a salt thereof can be used for the prevention and / or treatment of neuromuscular diseases.

[0124] Pharmaceutical compositions containing one or more of the compounds of formula (I) or salts thereof as active ingredients can be prepared by known methods using excipients commonly used in the art, i.e., pharmaceutical excipients, pharmaceutical carriers, etc. The administration may be in any form, such as oral administration using tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration using injections such as intra-articular, intravenous, and intramuscular injections, suppositories, eye drops, eye ointments, transdermal liquids, ointments, transdermal patches, transmucosal liquids, transmucosal patches, inhalants, etc.

[0125] As solid compositions for oral administration, tablets, powders, granules, etc. are particularly used. In such solid compositions, one or more active ingredients are mixed with at least one inactive excipient. The composition may contain inactive additives such as lubricants, disintegrants, stabilizers, solubilizers, etc. in a conventional manner. Tablets, powders, granules, or pills may be coated with wax, sugar coating, or a film of a gastric or enteric material, if necessary. Liquid compositions for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and contain commonly used inert diluents such as purified water or ethanol, etc. In addition to the inert diluents, the liquid compositions may contain auxiliary agents such as solubilizing agents, wetting agents, suspending agents, sweeteners, flavoring agents, aromatic agents, and preservatives.

[0126] Injectables for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Aqueous solvents include, but are not limited to, distilled water for injection, physiological saline, and the like. Non-aqueous solvents include, but are not limited to, alcohols such as ethanol. Such compositions may further contain isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizers. These are sterilized, for example, by filtration through a bacteria-retaining filter, by blending with a bactericide, or by irradiation. In addition, sterile solid compositions that are dissolved or suspended in sterile water or a sterile injectable solvent before use are also contemplated herein.

[0127] Examples of topical preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, and eye ointments, including commonly used ointment bases, lotion bases, aqueous or non-aqueous liquids, suspensions, emulsions, and the like.

[0128] Transmucosal agents such as inhalants and nasal agents may be in solid, liquid or semi-solid form and may be produced according to known methods. For example, known excipients, pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, etc. may be appropriately added.

[0129] In the case of oral administration, the daily dose is usually about 0.001 to 100 mg / kg body weight, preferably about 0.1 to about 30 mg / kg body weight, more preferably about 0.1 to about 10 mg / kg body weight, administered once to four times a day. In the case of intravenous administration, the appropriate daily dose is about 0.0001 to 10 mg / kg body weight, administered once or in multiple divided doses a day.

[0130] Although it varies depending on the route of administration, dosage form, administration site, and types of excipients and additives, the pharmaceutical composition of the present invention contains one or more compounds of formula (I) or salts thereof as active ingredients in an amount of 0.01 to 100% by weight, and in one embodiment, 0.01 to 50% by weight.

[0131] The compound of formula (I) can be used in combination with various drugs for the treatment and / or prevention of diseases for which the compound of formula (I) is effective. The combination may be administered simultaneously or separately, consecutively, or at a desired time interval. The preparations administered simultaneously may be formulated as a combined preparation or separately. EXAMPLES

[0132] The method for producing the compound of formula (I) is described in more detail below based on the examples. The present invention is not limited to the compounds described in the following examples. In addition, the preparation method of the raw materials is shown as a preparation example. In addition, the preparation method of the compound of formula (I) is not limited to the preparation method of the specific example shown below, and the compound of formula (I) can also be produced by combining these preparation methods and / or methods obvious to those skilled in the art.

[0133] In the following examples, preparation examples and tables, the following abbreviations may be used. PEx: Preparation Example No., Ex: Example No., PSyn: Preparation Example No. produced by the same method, Syn: Example No. produced by the same method, Str: Chemical structure, DAT: Physical chemical data, ESI+: m / z value in mass spectrometry (ionization method ESI, [M+H]+ unless otherwise specified), APCI / ESI+: APCI / ESI-MS (atmospheric pressure chemical ionization method APCI, APCI / ESI means simultaneous measurement of APCI and ESI. [M+H]+ unless otherwise specified), API-ES+: API-ES MS (atmospheric pressure ionization electrospray method, [M+H]+ unless otherwise specified), J: coupling constant, s: singlet, d: doublet, dd: double doublet, t: triplet, br: broad line (e.g. brs), m: multiplet, rac: racemic mixture.

[0134] For convenience, the concentration (mol / L) is expressed as M. For example, 1M sodium hydroxide solution means 1 mol / L sodium hydroxide solution.

[0135] Preparation Example 1 2-Bromo-1,3-difluoro-5-iodobenzene (15 g) was dissolved in 1,4-dioxane (150 mL), and then phenylmethanethiol (5.7 mL), tris(dibenzylideneacetone)dipalladium(0) (2.2 g), Xantphos (2.7 g) and N,N-diisopropylethylamine (16 mL) were added to the mixture, and the mixture was stirred at 90° C. overnight under an argon atmosphere. After cooling to room temperature, hydrogen chloride (4M ethyl acetate solution, 24 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a residue. Chloroform and basic silica gel were added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered through Celite and washed with chloroform. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 5-(benzylsulfanyl)-2-bromo-1,3-difluorobenzene (13 g) as an oil.

[0136] Preparation Example 2 Tetrakis(triphenylphosphine)palladium(0) (130 mg) was added to a mixture of methyl 3-fluoro-4-methyl-2-[(trifluoromethanesulfonyl)oxy]quinoline-7-carboxylate (410 mg), [4-(benzylsulfanyl)-2,6-difluorophenyl]boronic acid (380 mg), triethylamine (0.47 mL) and 1,4-dioxane (9 mL), and the mixture was stirred at 100° C. for 24 hours under an argon atmosphere. The mixture was allowed to cool to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give methyl 2-[4-(benzylsulfanyl)-2,6-difluorophenyl]-3-fluoro-4-methylquinoline-7-carboxylate (260 mg) as a solid.

[0137] Preparation Example 3 Tetrakis(triphenylphosphine)palladium(0) (51 mg) was added to a mixture of 7-bromo-2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinoline (350 mg), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (330 mg), sodium carbonate (110 mg), 1,4-dioxane (8 mL), and water (2 mL), and the mixture was stirred at 100° C. for 24 hours under an argon atmosphere. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a crude product. Diisopropyl ether (9 mL) was added to the crude tert-butyl 4-(2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinolin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (440 mg), and the mixture was stirred at room temperature for 0.5 hours. The solid was then filtered and dried under reduced pressure to give tert-butyl 4-(2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinolin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (380 mg) as a solid.

[0138] Preparation Example 4 To a mixture of (3S)-1-(4-bromo-3,5-difluorobenzene-1-sulfonyl)-3-fluoropyrrolidine (50 mg), 1,4-dioxane (6 mL), and water (0.8 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (12 mg), tert-butyl {2-[8-fluoro-5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-carboxamido]ethyl}(methyl)carbamate (60 mg), and potassium carbonate (50 mg) were added, and the mixture was stirred at 100°C for 12 hours under an argon atmosphere. After the mixture was allowed to cool to room temperature, water and chloroform were added for extraction, and the organic layer was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl [2-(7-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-8-fluoro-5-methylquinoline-2-carboxamido)ethyl](methyl)carbamate (11 mg) as an oil.

[0139] Preparation Example 5 A mixture of 1-(4-bromo-3-fluorobenzene-1-sulfonyl)-4-fluoropiperidine (800 mg), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (720 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (86 mg), potassium acetate (280 mg), and 1,4-dioxane (8 mL) was stirred under an argon atmosphere at 100° C. for 1 hour. The mixture was allowed to cool to room temperature and filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 4-fluoro-1-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1-sulfonyl]piperidine (810 mg) as a solid.

[0140] Preparation Example 6 To a mixture of tert-butyl 4-(7-bromo-5-methylquinolin-2-yl)piperazine-1-carboxylate (30 mg) and 1,4-dioxane (2 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (20 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (8.0 mg) and potassium acetate (22 mg) were added, and the mixture was stirred overnight at 100°C under an argon atmosphere. The mixture was allowed to cool to room temperature, and then water and ethyl acetate were added, and the mixture was filtered through Celite. Water was added to the filtrate, and it was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl 4-[5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-yl]piperazine-1-carboxylate (18 mg) as an oil.

[0141] Preparation Example 7 5-(Benzylsulfanyl)-2-bromo-1,3-difluorobenzene (8.4 g) was dissolved in 1,4-dioxane (50 mL), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (16 g), [1,1'-bis(diphenyl)phosphino)ferrocene]dichloropalladium(II) (3.9 g), and potassium acetate (6.3 g) were added thereto, and the mixture was stirred at 100°C for 8 hours under an argon atmosphere. After the mixture was cooled to room temperature, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (4.1 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.0 g) and potassium acetate (1.6 g) were added and stirred at 100°C for 16 hours under an argon atmosphere. After the mixture was cooled to room temperature, 2-chloro-4-methylquinolin-7-ol (10 g), tetrakis(triphenylphosphine)palladium(0) (1.5 g), potassium carbonate (5.5 g) and water (9 mL) were added and stirred at 100°C for 24 hours under an argon atmosphere. After the mixture was cooled to room temperature, chloroform and water were added and extracted, and the organic layer was dried over anhydrous sodium sulfate. Insoluble matter was filtered off, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol, chloroform / ethyl acetate, hexane / ethyl acetate: all using neutral silica gel) to give 2-[4-(benzylsulfanyl)-2,6-difluorophenyl]-4-methylquinolin-7-ol (2.4 g) as a solid and 2-[4-(benzylsulfanyl)-2,6-difluorophenyl]-4-methylquinolin-7-ol (9.7 g) as an oil.

[0142] Preparation Example 8 To a mixture of methyl 3-fluoro-4-methyl-2-oxo-1,2-dihydroquinoline-7-carboxylate (440 mg), 2,6-lutidine (0.44 mL), and dichloromethane (9 mL), trifluoromethanesulfonic anhydride (0.48 mL) was added under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the mixture under ice cooling. The mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. Insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain methyl 3-fluoro-4-methyl-2-[(trifluoromethanesulfonyl)oxy]quinoline-7-carboxylate (410 mg) as a solid.

[0143] Preparation Example 9 2-[4-(benzylsulfanyl)-2,6-difluorophenyl]-4-methylquinolin-7-ol (2.4 g) was dissolved in dichloromethane (50 mL), and then N,N-diisopropylethylamine (2.1 mL) and trifluoromethanesulfonic anhydride (1.5 mL) were added to the mixture under ice cooling, and the mixture was stirred at room temperature for 16 hours. The mixture was extracted with chloroform and water, and the organic layer was dried over anhydrous sodium sulfate. Insoluble matter was filtered off, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-[4-(benzylsulfanyl)-2,6-difluorophenyl]-4-methylquinolin-7-yl trifluoromethanesulfonate (1.8 g) as a solid.

[0144] Preparation Example 10 2-[4-(benzylsulfanyl)-2,6-difluorophenyl]-4-methylquinolin-7-yl trifluoromethanesulfonate (1.8 g) was dissolved in DMF (18 mL) and methanol (9 mL), and then palladium(II) acetate (77 mg), 1,1'-bis(diphenylphosphino)ferrocene (190 mg), and triethylamine (0.96 mL) were added to the mixture. Carbon monoxide was bubbled into the mixture for 5 minutes, and then the mixture was stirred at 90°C for 3 hours under a carbon monoxide atmosphere. After the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred for 10 minutes. Then, insoluble matter was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline:water=1:1 and dried over anhydrous sodium sulfate. The insoluble matter was filtered off, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate, chloroform: both using neutral silica gel) to give methyl 2-[4-(benzylsulfanyl)-2,6-difluorophenyl]-4-methylquinoline-7-carboxylate (440 mg) as an oil.

[0145] Preparation Example 11 To a mixture of 3-bromo-2-fluoro-5-methylaniline (700 mg) and dichloromethane (10 mL), pyridine (0.54 mL) and (2E)-3-ethoxyprop-2-enoyl chloride (0.61 mL) were added under ice cooling, and the mixture was stirred at room temperature under an argon atmosphere overnight. 1M hydrochloric acid and water were added to the mixture, the mixture was extracted with chloroform, the organic layer was washed with saturated saline, and then dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (2E)-N-(3-bromo-2-fluoro-5-methylphenyl)-3-ethoxyprop-2-enamide (700 mg) as a solid.

[0146] Preparation Example 12 To a mixture of 4-bromo-3,5-difluorobenzene-1-sulfonyl chloride (11 g), N,N-diisopropylethylamine (15 mL) and dichloromethane (110 mL), 4-fluoropiperidine monohydrochloride (5.1 g) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated, and the resulting residue was extracted with chloroform and water, and the organic layer was dried over anhydrous magnesium sulfate and concentrated. The resulting residue was dissolved in ethyl acetate and chloroform, and silica gel was added to the solution. Insoluble matter was removed by filtration through Celite, and the insoluble matter was washed with ethyl acetate. The combined filtrate was concentrated, and ethyl acetate (25 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 0.5 hours. The resulting solid was collected by filtration and dried to obtain 1-(4-bromo-3,5-difluorobenzene-1-sulfonyl)-4-fluoropiperidine (10 g) as a solid.

[0147] Preparation Example 13 Methyl 2-[4-(benzylsulfanyl)-2,6-difluorophenyl]-3-fluoro-4-methylquinoline-7-carboxylate (510 mg) was suspended in acetic acid (8 mL) and water (2 mL), and then N-chlorosuccinimide (0.62 g) was added under ice cooling, and the mixture was stirred at room temperature for 55 minutes. Ice was added to the mixture at room temperature, and the mixture was stirred until the ice melted, and then the solid was collected by filtration. This solid was dissolved in chloroform and extracted, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Dichloromethane (7.5 mL) and triethylamine (0.47 mL) were added to the obtained residue, and (3S)-3-fluoropyrrolidine monohydrochloride (0.15 g) was added to the mixture, and the mixture was stirred at room temperature for 40 minutes. Water was added to the mixture, and the mixture was separated into two layers, the aqueous layer and the organic layer, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, chloroform / methanol: both using neutral silica gel) to obtain methyl 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinoline-7-carboxylate (340 mg) as a solid.

[0148] Preparation Example 14 1-(4-bromo-3,5-difluorobenzene-1-sulfonyl)-4-fluoropiperidine (11 g) was dissolved in dehydrated THF (100 mL), and then n-butyllithium (1.6M n-hexane solution, 20 mL) was added to the mixture under argon atmosphere and cooled with dry ice / acetone, and the mixture was stirred at the same temperature for 15 minutes. Zinc chloride (4.2 g) was added to the mixture, and the mixture was stirred at the same temperature for 0.5 hours, then warmed to room temperature and stirred for another 0.5 hours. Methyl 2-chloro-4-methylquinoline-7-carboxylate (6 g) and tetrakis(triphenylphosphine)palladium(0) (3 g) were added to the mixture, and the mixture was stirred at 60° C. for 5 hours under argon atmosphere. After the mixture was cooled to room temperature, 1M hydrochloric acid was added, followed by water and extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give methyl 2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinoline-7-carboxylate (8.4 g) as a solid.

[0149] Preparation Example 15 2-Chloro-4-methylquinoline-7-carboxylic acid (20 g) was dissolved in DMF (100 mL), and potassium carbonate (17 g) and iodomethane (9 mL) were added to the mixture under ice cooling, and the mixture was stirred at room temperature for 0.5 hours. DMF (50 mL) was further added to the mixture, and the mixture was stirred at room temperature for 5 hours. The mixture was ice-cooled, and ice water (200 mL) was added to the mixture, and the solid was collected by filtration, washed with water, and dried under reduced pressure. Acetonitrile (200 mL) was added to the obtained solid, and the mixture was stirred for 0.5 hours. The solid was then collected by filtration and dried under reduced pressure to obtain methyl 2-chloro-4-methylquinoline-7-carboxylate (15 g) as a solid.

[0150] Preparation Example 16 5-(benzylsulfanyl)-2-bromo-1,3-difluorobenzene (13 g) was dissolved in THF (130 mL), and then n-butyllithium (1.6M n-hexane solution, 31 mL) was added to the mixture under argon atmosphere and dry ice / methanol cooling, and the mixture was stirred at the same temperature for 30 minutes. Trimethylborate (6.8 mL) was added to the mixture at the same temperature, and the mixture was warmed to room temperature and stirred for 2 hours. 1M hydrochloric acid (180 mL) was added to the mixture under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. Acetonitrile was added to the obtained residue, and the solid was collected by filtration and dried under reduced pressure to obtain [4-(benzylsulfanyl)-2,6-difluorophenyl]boronic acid (6.5 g) as a solid.

[0151] Preparation Example 17 DMF (0.04 mL) was added to a mixture of (diethoxyphosphoryl)(fluoro)acetic acid (6.5 g), oxalyl chloride (10 mL) and dichloromethane (60 mL) under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure, toluene was added, and the mixture was concentrated under reduced pressure again to obtain a residue. A mixture of the obtained residue and dichloromethane (30 mL) was added dropwise to a mixture of methyl 4-acetyl-3-aminobenzoate (4.1 g), pyridine (4 mL) and dichloromethane (30 mL) under ice cooling. The mixture was then warmed to room temperature and stirred. 1M hydrochloric acid (50 mL) was added to the mixture under ice cooling, and the mixture was extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (50 mL) was added to the obtained residue, and the mixture was triturated, and then the mixture was stirred at room temperature for 1 hour. The solid was collected by filtration and dried under reduced pressure to give methyl 4-acetyl-3-[2-(diethoxyphosphoryl)-2-fluoroacetamido]benzoate (6.6 g) as a solid.

[0152] Preparation Example 18 A mixture of methyl 4-acetyl-3-[2-(diethoxyphosphoryl)-2-fluoroacetamido]benzoate (1.0 g) and THF (20 mL) was added to a mixture of sodium hydride (60% oil, 220 mg) and THF (10 mL) over 3 minutes under argon atmosphere while cooling with water, and then stirred at room temperature for 1.5 hours. A saturated aqueous ammonium chloride solution and water were added to the mixture under ice cooling, and the mixture was concentrated under reduced pressure. THF was added to the obtained residue, and the mixture was stirred for 45 minutes under ice cooling. The solid was collected by filtration and dried under reduced pressure to obtain methyl 3-fluoro-4-methyl-2-oxo-1,2-dihydroquinoline-7-carboxylate (440 mg) as a solid.

[0153] Preparation Example 19 Methyl 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinoline-7-carboxylate (380 mg) was suspended in THF (6 mL), and the mixture was cooled on ice under an argon atmosphere. Diisobutylaluminum hydride (1M toluene solution, 3 mL) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled on ice, and 1M aqueous potassium sodium tartrate solution was added dropwise to the mixture, and ethyl acetate was added, and the mixture was stirred at room temperature for 30 minutes. Potassium sodium tartrate, water, and ethyl acetate were added to the mixture, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinolin-7-yl)methanol (350 mg) as a solid.

[0154] Preparation Example 20 A mixture of 3-(2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinolin-7-yl)propanenitrile (110 mg) and dichloromethane (4 mL) was cooled on ice under an argon atmosphere, and then diisobutylaluminum hydride (1M toluene solution, 350 μL) was added, and the mixture was stirred on ice for 40 minutes. Diisobutylaluminum hydride (1M toluene solution, 250 μL) was added to the mixture on ice, and the mixture was stirred on ice for 30 minutes. A 10% aqueous citric acid solution, water, and ethyl acetate were added to the mixture on ice, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 3-(2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinolin-7-yl)propanal (61 mg) as a solid.

[0155] Preparation Example 21 (2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinolin-7-yl)methanol (350 mg) was suspended in dichloromethane (7.5 mL) and 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one (500 mg) was added to the mixture under ice cooling, and the mixture was stirred under ice for 1 hour. After adding saturated aqueous sodium bicarbonate solution to the mixture under ice cooling, the mixture was extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinoline-7-carbaldehyde (330 mg) as a solid.

[0156] Preparation Example 22 A mixture of sodium hydride (60% oil, 63 mg) and THF (3 mL) was cooled on ice under an argon atmosphere, diethyl cyanomethylphosphonate (260 μL) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled on ice, and a mixture of 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinoline-7-carbaldehyde (330 mg) and THF (9 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (2E)-3-(2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinolin-7-yl)prop-2-enenitrile (360 mg) as a solid.

[0157] Preparation Example 23 (2E)-3-(2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinolin-7-yl)prop-2-enenitrile (210 mg) was dissolved in THF (3 mL) and ethanol (3 mL), and then 10% palladium carbon (water content 50%, 49 mg) was added to the mixture under an argon atmosphere. After replacing the argon with hydrogen, the mixture was stirred at room temperature under normal pressure for 3 hours. Celite was added to the mixture, and insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 3-(2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinolin-7-yl)propanenitrile (220 mg) as a solid.

[0158] Preparation Example 24 The reaction was carried out in two batches. To a mixture of 7-bromo-8-fluoro-2-{2-fluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline (150 mg) and tert-butyl 3-oxopiperazine-1-carboxylate (120 mg) in 1,4-dioxane (3 mL), cesium carbonate (200 mg), Xantphos (36 mg) and palladium acetate (10 mg) were added, bubbled with nitrogen for 2 minutes and sealed in a tube. The mixture was heated to 140° C. in a microwave for 35 minutes. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the crude product. The crude product was further purified by preparative thin layer chromatography (petroleum ether / ethyl acetate) to give tert-butyl 4-(8-fluoro-2-{2-fluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinolin-7-yl)-3-oxopiperazine-1-carboxylate (70 mg) as an oil.

[0159] Preparation Example 25 To a mixture of 2-{2-fluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinolin-7-ol (1.0 g) and DMF (10 mL), tert-butyl-N-(2-bromoethyl)carbamate (740 mg) and potassium carbonate (700 mg) were added and stirred at 100° C. for 3 hours. To the mixture, tert-butyl-N-(2-bromoethyl)carbamate (170 mg) was added and stirred at 100° C. for 6 hours. After the mixture was allowed to cool to room temperature, ethyl acetate and water were added for extraction, and the organic layer was dried over anhydrous magnesium sulfate. The insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate, chloroform / methanol: both using neutral silica gel) to give tert-butyl {2-[(2-{2-fluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinolin-7-yl)oxy]ethyl}carbamate (930 mg) as a solid.

[0160] Preparation Example 26 A mixture of {2-bromo-5-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}methanol (0.21 g), 3,4-dihydro-2H-pyran (100 μL), pyridinium p-toluenesulfonate (15 mg) and dichloromethane (3 mL) was stirred at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (3S)-1-(4-bromo-3-{[(oxan-2-yl)oxy]methyl}benzene-1-sulfonyl)-3-fluoropyrrolidine (0.24 g) as a solid.

[0161] Preparation Example 27 To a mixture of methyl 2-(4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]-2-{[(oxan-2-yl)oxy]methyl}phenyl)-4-methylquinoline-7-carboxylate (180 mg), THF (2 mL) and methanol (2 mL), 1M hydrochloric acid (1 mL) was added, and the mixture was stirred overnight. The mixture was extracted with saturated aqueous sodium bicarbonate and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to give methyl 2-{4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]-2-(hydroxymethyl)phenyl}-4-methylquinoline-7-carboxylate (150 mg) as a solid.

[0162] Preparation Example 28 To a mixture of 2-bromo-5-[(3S)-3-fluoropyrrolidine-1-sulfonyl]benzoic acid (440 mg) and THF (10 mL), borane-THF complex (0.91M THF solution, 4 mL) was added under ice cooling, and the mixture was warmed to room temperature and stirred overnight. Water and 1M hydrochloric acid were added to the reaction mixture under ice cooling, and the mixture was stirred and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain {2-bromo-5-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}methanol (270 mg) as a solid.

[0163] Preparation Example 29 A mixture of 7-bromo-2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline (200 mg), 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (0.18 mL), tris(dibenzylideneacetone)dipalladium(0) (38 mg), tri-tert-butylphosphine (0.02 mL), triethylamine (0.12 mL), and DMF (2 mL) was stirred at 120° C. for 0.5 hours under microwave irradiation. After the mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid and saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate: using basic silica gel) to give methyl (2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinolin-7-yl)acetate (65 mg) as an oil.

[0164] Preparation Example 30 7-[4-(benzylsulfanyl)-2,6-difluorophenyl]-5-methyl-1,8-naphthyridine-2-carbonitrile (3.7 g) was suspended in methanol (30 mL), and then sodium methoxide (5M methanol solution, 4.4 mL) was added, and the mixture was stirred at room temperature for 5 hours. 6M hydrochloric acid (8.8 mL) was added to the mixture under ice cooling, and the mixture was stirred at room temperature for 0.5 hours. Saturated aqueous sodium bicarbonate and ethyl acetate were added to the mixture under ice cooling, and the mixture was concentrated under reduced pressure. The resulting residue was extracted with ethyl acetate, and the organic layer was washed with saturated saline, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (10 mL), diethyl ether (5 mL) was added, and the mixture was stirred at room temperature overnight. The resulting solid was collected by filtration and dried under reduced pressure to obtain methyl 7-[4-(benzylsulfanyl)-2,6-difluorophenyl]-5-methyl-1,8-naphthyridine-2-carboxylate (3.6 g) as a solid.

[0165] Preparation Example 31 To a mixture of 2-[4-(benzylsulfanyl)-2,6-difluorophenyl]-7-chloro-4-methyl-1,8-naphthyridine (5.9 g) and DMF (60 mL), zinc cyanide (3.5 g) and tetrakis(triphenylphosphine)palladium(0) (1.7 g) were added, and the mixture was stirred at 120° C. for 1.5 hours under an argon atmosphere. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. To the resulting mixture of residues, basic silica gel (120 mL) and chloroform (120 mL) were added, and the mixture was stirred at room temperature for 0.5 hours. Insoluble matter was filtered off, washed with chloroform, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform) to obtain a crude product. The resulting crude 7-[4-(benzylsulfanyl)-2,6-difluorophenyl]-5-methyl-1,8-naphthyridine-2-carbonitrile (5.8 g) was added with ethyl acetate (35 mL) and the mixture was stirred at room temperature for 4 hours. The solid was collected by filtration and dried under reduced pressure to give 7-[4-(benzylsulfanyl)-2,6-difluorophenyl]-5-methyl-1,8-naphthyridine-2-carbonitrile (3.7 g) as a solid.

[0166] Preparation Example 32 tert-Butyl 3-[6-chloro-2-(2,2-dimethylpropanamido)pyridin-3-yl]-3-hydroxybutanoate (27 g) was dissolved in THF (160 mL), and then 3M hydrochloric acid (160 mL) was added to the mixture, and the mixture was stirred at 90° C. for 2 days. 3M hydrochloric acid (80 mL) was added to the mixture, and the mixture was stirred at 90° C. for 2 hours. After neutralizing the mixture with saturated aqueous sodium bicarbonate and 1M aqueous sodium hydroxide, the mixture was stirred under ice cooling for 0.5 hours. The solid was collected by filtration and dried under reduced pressure. The obtained solid was suspended in acetonitrile and washed. The solid was collected by filtration and dried under reduced pressure to obtain 7-chloro-4-methyl-1,8-naphthyridin-2-ol (11 g) as a solid.

[0167] Preparation Example 33 Under an argon atmosphere, tert-butyl acetate (24 mL) was added dropwise to a mixture of lithium hexamethyldisilazide (1.3M THF solution, 140 mL) and THF (150 mL) while cooling with dry ice / acetone, and the mixture was stirred at the same temperature for 1 hour. A mixture of N-(3-acetyl-6-chloropyridin-2-yl)-2,2-dimethylpropanamide (21 g) and THF (50 mL) was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hour. Water was added to the mixture under ice cooling, and the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl 3-[6-chloro-2-(2,2-dimethylpropanamide)pyridin-3-yl]-3-hydroxybutanoate (27 g) as a solid.

[0168] Preparation Example 34 N-(6-chloropyridin-2-yl)-2,2-dimethylpropanamide (13 g) was dissolved in THF (100 mL), and n-butyllithium (1.6M n-hexane solution, 100 mL) was added dropwise to the solution at -50°C under an argon atmosphere, and the mixture was stirred for 2 hours under ice-salt water cooling. A mixture of N-methoxy-N-methylacetamide (13 mL) and THF (20 mL) was added dropwise to the mixture at -40°C, and the mixture was stirred at the same temperature for 1.5 hours. After adding a saturated aqueous ammonium chloride solution to the mixture, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain N-(3-acetyl-6-chloropyridin-2-yl)-2,2-dimethylpropanamide (12 g) as a solid.

[0169] Preparation Example 35 A mixture of 7-chloro-2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methyl-1,8-naphthyridine (150 mg), tris(dibenzylideneacetone)dipalladium(0) (32 mg), 5-(di-tert-butylphosphanyl)-1',3',5'-triphenyl-1'H-1,4'-bipyrazole (35 mg), and toluene (3 mL) was stirred at 90° C. for 5 minutes under an argon atmosphere. To this mixture, tert-butyl-2-hydroxyacetic acid (140 μL) and cesium carbonate (340 mg) were added, and the mixture was stirred at 90° C. for 3 hours under an argon atmosphere. After the mixture was allowed to cool to room temperature, ethyl acetate and water were added to it for extraction, and the organic layer was dried over anhydrous magnesium sulfate. The insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate: neutral silica gel used, hexane / ethyl acetate: basic silica gel used) to give tert-butyl [(7-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-5-methyl-1,8-naphthyridin-2-yl)oxy]acetic acid (120 mg) as a solid.

[0170] Preparation Example 36 A mixture of 7-chloro-2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methyl-1,8-naphthyridine (200 mg), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (290 mg), SPhos Pd G4 (18 mg, CAS number: 1599466-87-1, Sigma-Aldrich), cesium fluoride (210 mg), and 1,4-dioxane (3 mL) was stirred under microwave irradiation at 100° C. for 3 hours. Ethyl acetate and water were added to the mixture, followed by extraction, and the organic layer was dried over anhydrous magnesium sulfate. The insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate: neutral silica gel used, hexane / ethyl acetate: basic silica gel used) to give tert-butyl 4-(7-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-5-methyl-1,8-naphthyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (170 mg) as an oil.

[0171] Preparation Example 37 7-Bromo-2-chloro-5-methylquinoline (100 mg) was dissolved in toluene (4 mL), then tert-butyl piperazine-1-carboxylate (150 mg) was added, and the mixture was stirred under microwave irradiation at 140° C. for 2 hours. tert-Butyl piperazine-1-carboxylate (150 mg) was added to the mixture, and the mixture was stirred under microwave irradiation at 140° C. for 2 hours. The mixture was allowed to cool to room temperature and purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl 4-(7-bromo-5-methylquinolin-2-yl)piperazine-1-carboxylate (31 mg) as an oil.

[0172] Preparation Example 38 7-Bromo-2-iodo-5-methylquinoline (100 mg) was dissolved in 1,4-dioxane (3 mL), and then copper(I) cyanide (35 mg), tris(dibenzylideneacetone)dipalladium(0) (15 mg) and 1,1'-bis(diphenylphosphino)ferrocene (9 mg) were added to the mixture, which was then stirred for 4 hours at 120°C under microwave irradiation. The mixture was allowed to cool to room temperature, and then purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 7-bromo-5-methylquinoline-2-carbonitrile (33 mg) as a solid.

[0173] Preparation Example 39 To a mixture of 7-bromo-8-fluoro-5-methylquinolin-2(1H)-one (300 mg) and phosphoryl chloride (1.3 mL), N,N-diethylaniline (0.1 mL) was added at room temperature, and the mixture was stirred at 100° C. overnight under an argon atmosphere. After cooling to room temperature, the mixture was poured into ice water, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was extracted with chloroform, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 7-bromo-2-chloro-8-fluoro-5-methylquinoline (300 mg) as a solid.

[0174] Preparation Example 40 Sodium iodide (1.6 g) and acetyl chloride (0.23 mL) were added to a mixture of 7-bromo-2-chloro-8-fluoro-5-methylquinoline (290 mg) and acetonitrile (7 mL) at room temperature, and the mixture was stirred at 80°C under an argon atmosphere for 6 hours. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the resulting residue, the mixture was extracted with chloroform, and the organic layer was washed with an aqueous solution of sodium thiosulfate, water, and saturated saline, and then dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain 7-bromo-8-fluoro-2-iodo-5-methylquinoline (400 mg) as a solid.

[0175] Preparation Example 41 Methyl 2-[4-(benzylsulfanyl)-2,6-difluorophenyl]-4-methylquinoline-7-carboxylate (440 mg) was dissolved in acetic acid (7 mL) and water (1.8 mL), and then N-chlorosuccinimide (810 mg) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. Cold water was added to the mixture under ice cooling, and the solid was collected by filtration. This solid was dissolved in chloroform, and then cold water was added for extraction, and the organic layer was dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated. The obtained residue (200 mg) was dissolved in dichloromethane (2 mL), (3S)-3-fluoropyrrolidine monohydrochloride (91 mg) and N,N-diisopropylethylamine (0.17 mL) were added, and the mixture was stirred at room temperature for 0.5 hours. Dichloromethane and water were added to the mixture, and the mixture was stirred at room temperature for 5 minutes and extracted. The organic layer was dried over anhydrous sodium sulfate. The insoluble matter was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give methyl 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline-7-carboxylate (90 mg) as a solid.

[0176] Preparation Example 42 Methyl 2-[4-(benzylsulfanyl)-2,6-difluorophenyl]-3-fluoro-4-methylquinoline-7-carboxylate (500 mg) was suspended in acetic acid (8 mL) and water (2 mL). N-chlorosuccinimide (590 mg) was added to this mixture under ice cooling, and the mixture was stirred at room temperature for 1 hour. Ice was added to the mixture at room temperature, and the mixture was stirred until the ice melted, and the solid was collected by filtration. This solid was dissolved in chloroform and extracted, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Dichloromethane (12 mL) and triethylamine (0.46 mL) were added to the obtained residue, and then 4-fluoropiperidine monohydrochloride (170 mg) was added to it, and the mixture was stirred at room temperature for 15 minutes. Chloroform and water were added to the mixture for extraction, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain methyl 2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-3-fluoro-4-methylquinoline-7-carboxylate (380 mg) as a solid.

[0177] Preparation Example 110 Methyl 2-{4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]-2-(hydroxymethyl)phenyl}-4-methylquinoline-7-carboxylate (90 mg) was dissolved in DMF (2 mL), and then sodium hydride (60% oil, 16 mg) and iodomethane (30 μL) were added thereto under ice cooling, and the mixture was stirred at room temperature for 4 hours. Water was added to the mixture, and then ethyl acetate was added thereto for extraction, and the organic layer was dried over anhydrous magnesium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain methyl 2-{4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]-2-(methoxymethyl)phenyl}-4-methylquinoline-7-carboxylate (110 mg) as a solid.

[0178] Preparation Example 120 A mixture of (2E)-N-(3-bromo-2-fluoro-5-methylphenyl)-3-ethoxyprop-2-enamide (700 mg) and concentrated sulfuric acid (6 mL) was stirred overnight at room temperature under argon atmosphere. The mixture was poured onto ice and the mixture was stirred at room temperature for 1 hour. The solid was collected by filtration, washed with water, and dried under reduced pressure. The resulting solid was suspended in ethyl acetate. The solid was collected by filtration, washed with ethyl acetate, and dried to give 7-bromo-8-fluoro-5-methylquinolin-2(1H)-one (550 mg) as a solid.

[0179] Preparation Example 123 To a mixture of diethyl (2,2-diethoxyethyl)propanedioate (0.47 g) and THF (5 mL) was added sodium hydride (60% oil, 82 mg) under ice-cooling in an argon atmosphere, and the mixture was stirred at room temperature for 1 hour. A solution of 1-bromo-3-(bromomethyl)-5-methoxybenzene (0.50 g) in THF (3 mL) was added, and the mixture was stirred at room temperature for 4 hours. Methanol (3 mL) and 3M aqueous potassium hydroxide solution (3 mL) were added, and the mixture was stirred at 120° C. for 1 hour under microwave irradiation. The mixture was concentrated under reduced pressure. DMF (3 mL) and iodomethane (0.3 mL) were added to the resulting residue, and the mixture was stirred at room temperature overnight. 1M hydrochloric acid (9 mL) was added to the mixture under ice-cooling, and the mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline, and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain methyl 2-[(3-bromo-5-methoxyphenyl)methyl]-4,4-diethoxybutanoate (0.48 g) as an oil.

[0180] Preparation Example 124 A solution of methyl 2-[(3-bromo-5-methoxyphenyl)methyl]-4,4-diethoxybutanoate (0.39 g) in methanol (3.9 mL) was added to a mixture of 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (0.27 g) and 80% sulfuric acid (3.9 mL) under ice cooling, and the mixture was stirred at room temperature for 0.5 hours. Water was added to the mixture under ice cooling, and the solid was collected by filtration. The solid was dissolved in ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain methyl 5-bromo-7-methoxynaphthalene-2-carboxylate (0.12 g) as a solid.

[0181] Preparation Example 125 A mixture of methyl 5-bromo-7-methoxynaphthalene-2-carboxylate (0.12 g), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (180 μL), SPhos Pd G4 (31 mg, CAS number: 1599466-87-1, Sigma-Aldrich), cesium carbonate (0.38 g), 1,4-dioxane (4 mL) and water (0.4 mL) was stirred at 100° C. for 0.5 hours under microwave irradiation. Ethyl acetate was added, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain methyl 7-methoxy-5-methylnaphthalene-2-carboxylate (80 mg) as a solid.

[0182] Preparation Example 126 To a mixture of methyl 7-methoxy-5-methylnaphthalene-2-carboxylate (43 mg) and dichloromethane (1.3 mL), tribromoborane (1M dichloromethane solution, 0.51 mL) was added under ice-cooling in an argon atmosphere, and the mixture was stirred at room temperature for 0.5 hours. Methanol was added to the mixture under ice-cooling, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain methyl 7-hydroxy-5-methylnaphthalene-2-carboxylate (27 mg) as a solid.

[0183] Preparation Example 127 A mixture of 5-methyl-7-[(trifluoromethanesulfonyl)oxy]naphthalene-2-methyl ester (35 mg), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (35 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (17 mg), potassium acetate (30 mg) and 1,4-dioxane (1 mL) was stirred for 3 hours under an argon atmosphere at 100° C. After the mixture was cooled to room temperature, (3S)-1-(4-bromo-3,5-difluorobenzene-1-sulfonyl)-3-fluoropyrrolidine (56 mg), potassium carbonate (40 mg) and water (0.2 mL) were added and stirred overnight under an argon atmosphere at 100° C. After the mixture was cooled to room temperature, chloroform was added to the mixture, filtered through Celite, and washed with chloroform. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give methyl 7-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-5-methylnaphthalene-2-carboxylate (34 mg) as a solid.

[0184] Example 1 Methyl 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline-7-carboxylate (90 mg) was dissolved in THF (1 mL) and ethanol (1 mL), and then 1M aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. 1M hydrochloric acid (1 mL) was added to the mixture, and then chloroform and saturated saline were added thereto for extraction, and the organic layer was dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, the filtrate was concentrated, and then diethyl ether (2 mL) was added to the residue. The obtained solid was collected by filtration and dried under reduced pressure to obtain 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline-7-carboxylic acid (80 mg) as a solid.

[0185] Example 2 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline-7-carboxylic acid (3.0 g) was dissolved in THF (61 mL), and then 1M aqueous sodium hydroxide solution (6.8 mL) was added to the mixture and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and ethanol was added to the mixture and concentrated again. Ethanol (30 mL) was added to the mixture and the mixture was stirred under ice cooling. The solid was collected by filtration and dried under reduced pressure to obtain sodium 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline-7-carboxylate (2.7 g) as a solid.

[0186] Example 3 A mixture of 2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinoline-7-carboxylic acid (290 mg), 2-methyl-2,6-diazaspiro[3.3]heptane dihydrochloride (72 mg), N,N-diisopropylethylamine (0.3 mL), HATU (150 mg) and dichloromethane (3 mL) was stirred at room temperature overnight. The mixture was purified by silica gel column chromatography (hexane / ethyl acetate: basic silica gel, chloroform / methanol: neutral silica gel) to obtain {2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinolin-7-yl}(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)methanone (170 mg) as a solid.

[0187] Example 4 A mixture of 2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinoline-7-carboxylic acid (200 mg), tert-butyl (azetidin-3-yl)carbamate monohydrochloride (140 mg), N,N-diisopropylethylamine (0.35 mL), HATU (340 mg) and dichloromethane (6 mL) was stirred at room temperature overnight. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate). The obtained product was dissolved in dichloromethane (6 mL), and then trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and then a saturated aqueous solution of sodium bicarbonate and water were added, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give (3-aminoazetidin-1-yl){2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinolin-7-yl}methanone (160 mg) as a solid.

[0188] Example 5 Methyl 2-[2-fluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinoline-7-carboxylate (400 mg) was suspended in methanol (4 mL) and THF (4 mL), and 1M aqueous sodium hydroxide solution (1.7 mL) was added at room temperature, and the mixture was stirred at 75° C. for 1 hour. After the reaction mixture was allowed to cool to room temperature, 1M hydrochloric acid was added to the mixture, the reaction mixture was concentrated under reduced pressure, and extracted with water and chloroform. The organic layer was concentrated under reduced pressure to obtain 2-[2-fluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinoline-7-carboxylic acid (370 mg) as a solid.

[0189] Example 6 tert-Butyl [(7-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-5-methyl-1,8-naphthyridin-2-yl)oxy]acetate (120 mg) was dissolved in methanol (1 mL), and then hydrogen chloride (4M 1,4-dioxane solution, 1 mL) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the resulting residue was dissolved in methanol (1 mL), and 1M aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was neutralized by adding 1M hydrochloric acid, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to give [(7-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-5-methyl-1,8-naphthyridin-2-yl)oxy]acetic acid (85 mg) as a solid.

[0190] Example 7 The reaction was carried out in two batches. Palladium acetate (13 mg) was added to a mixture of 7-bromo-8-fluoro-2-{2-fluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline (280 mg), potassium carbonate (160 mg) and dicyclohexyl(3-dicyclohexylphosphaniumylpropyl)phosphonium; ditetrafluoroborate (69 mg) in DMF (5.5 mL). The mixture was degassed and purged with CO three times, then stirred at 115° C. under CO atmosphere for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by Biotage flash reverse-phase C-18 column chromatography (methanol / water, 0.1% acetic acid condition) to give 8-fluoro-2-{2-fluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline-7-carboxylic acid (70 mg) as a solid.

[0191] Example 8 7-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-5-methylquinoline-2-carbonitrile (20 mg) was suspended in methanol (1 mL), and then sodium methoxide (28% methanol solution, 0.03 mL) was added, and the mixture was stirred at room temperature for 3 hours. Sodium methoxide (28% methanol solution, 0.02 mL) was further added to the mixture, and the mixture was stirred at room temperature overnight. 1M hydrochloric acid (0.11 mL) was added to the mixture under ice cooling, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to the mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate). The obtained residue was dissolved in THF (0.3 mL) and methanol (0.3 mL), water (0.3 mL) and lithium hydroxide (3 mg) were added, and the mixture was stirred at room temperature for 4 hours. The mixture was added with 1M aqueous sodium hydroxide solution (0.1 mL) and stirred at room temperature for 3 hours, then at 50° C. overnight. The mixture was neutralized with 1M hydrochloric acid and extracted with chloroform / 2-propanol. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate and hexane were added to the resulting residue, and the solid was collected by filtration and dried under reduced pressure to give 7-{2-fluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]-6-methoxyphenyl}-5-methylquinoline-2-carboxylic acid (4.4 mg) as a solid.

[0192] Example 9 2-{2-fluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline-7-carboxylic acid (30 mg) and cyclopropanesulfonamide (17 mg) were suspended in dichloromethane (3 mL), 4-dimethylaminopyridine (10 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21 mg) were added, and the mixture was stirred at room temperature for 3 hours. The mixture was extracted with chloroform and water, and the organic layer was dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol) to obtain N-(cyclopropanesulfonyl)-2-{2-fluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline-7-carboxamide (32 mg) as a solid.

[0193] Example 10 A mixture of 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline-7-carboxylic acid (50 mg), N-(tert-butoxycarbonyl)-N-methyl-1,2-ethylenediamine (40 mg), N,N-diisopropylethylamine (0.06 mL), HATU (64 mg), and dichloromethane (1 mL) was stirred at room temperature for 1 hour. The mixture was purified by silica gel column chromatography (hexane / ethyl acetate), and the resulting product (72 mg) was dissolved in ethyl acetate (1 mL), hydrogen chloride (4M ethyl acetate solution, 1 mL) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, then ethyl acetate was added, and the mixture was triturated. The solid was collected by filtration and dried under reduced pressure to give 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methyl-N-[2-(methylamino)ethyl]quinoline-7-carboxamide hydrochloride (55 mg) as a solid.

[0194] Example 11 To a mixture of 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinoline-7-carboxylic acid (60 mg), ethyl 3-methylazetidine-3-carboxylate hydrochloride (31 mg) and dichloromethane (2 mL), N,N-diisopropylethylamine (67 mg) and HATU (98 mg) were added, and the mixture was stirred at room temperature for 12 hours. DMF (1 mL) and N,N-diisopropylethylamine (10 drops) were added to the mixture, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in THF (1.5 mL) and methanol (1.5 mL), 1M aqueous solution of sodium hydroxide (0.75 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. 1M hydrochloric acid (2 mL) was added to the mixture, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (water / acetonitrile: using ODS silica gel) to obtain a crude product. Crude 1-(2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinoline-7-carbonyl)-3-methylazetidine-3-carboxylic acid (55 mg) was added to diisopropyl ether (2 mL) and hexane (3 mL), and the solid was collected by filtration, washed with hexane, and dried under reduced pressure to obtain 1-(2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinoline-7-carbonyl)-3-methylazetidine-3-carboxylic acid (36 mg) as a solid.

[0195] Example 12 To a mixture of 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline-7-carboxylic acid (60 mg), methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoic acid monohydrochloride (69 mg) and dichloromethane (2 mL), N,N-diisopropylethylamine (140 μL) and HATU (100 mg) were added and stirred at room temperature for 17 hours. A saturated aqueous solution of sodium bicarbonate and water were added to the mixture, the mixture was extracted with chloroform, and the organic layer was concentrated under reduced pressure. The resulting residue was dissolved in THF (1.5 mL) and methanol (1.5 mL), 1M aqueous solution of sodium hydroxide (0.75 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. 1M hydrochloric acid (2 mL) was added to the mixture, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (water / acetonitrile:ODS silica gel used). The obtained product (38 mg) was dissolved in THF (2 mL), hydrogen chloride (4M 1,4-dioxane solution, 8 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (water / acetonitrile: using ODS silica gel) to obtain a crude product. The obtained crude (2S)-3-amino-2-(2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline-7-carboxamide)propanoic acid hydrochloride (30 mg) was added to diisopropyl ether (3 mL), and the solid was filtered and dried under reduced pressure to obtain (2S)-3-amino-2-(2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline-7-carboxamide)propanoic acid hydrochloride (26 mg) as a solid.

[0196] Example 13 tert-Butyl {2-[(2-{2-fluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinolin-7-yl)oxy]ethyl}carbamate (5.7 g) was dissolved in chloroform (40 mL) and methanol (20 mL), then hydrogen chloride (4M 1,4-dioxane solution, 20 mL) was added, and the mixture was stirred at room temperature for 5 hours. After concentrating the reaction mixture under reduced pressure, ethyl acetate was added to the residue, and the solid was collected by filtration and dried under reduced pressure to obtain 2-[(2-{2-fluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinolin-7-yl)oxy]ethan-1-amine hydrochloride (5.0 g) as a solid.

[0197] Example 14 To a mixture of tert-butyl 6-{2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinoline-7-carbonyl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (150 mg) and dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added and stirred at room temperature for 0.5 hours. The mixture was concentrated, and then chloroform and 1M aqueous sodium hydroxide solution were added. The aqueous layer was extracted with chloroform, and the organic layer was concentrated. Dichloromethane and hexane were added to the obtained residue, and the solid was collected by filtration and washed with hexane to obtain (2,6-diazaspiro[3.3]heptane-2-yl){2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinolin-7-yl}methanone (68 mg) as a solid.

[0198] Example 15 To a mixture of tert-butyl [2-(7-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-8-fluoro-5-methylquinoline-2-carboxamido)ethyl](methyl)carbamate (11 mg) and dichloromethane (1 mL), trifluoroacetic acid (0.05 mL) was added, and the mixture was stirred at room temperature under an argon atmosphere for 2 hours. The mixture was purified by silica gel column chromatography (chloroform / methanol: basic silica gel used) and concentrated. Ethyl acetate (0.5 mL) was added to the obtained residue, followed by hydrogen chloride (4M ethyl acetate solution, 0.01 mL), and the mixture was concentrated under reduced pressure. 2-Propanol and toluene were added to the obtained residue, and the mixture was triturated and concentrated under reduced pressure. The resulting residue was triturated with dichloromethane and hexane, concentrated in vacuo, and then dried under reduced pressure to give 7-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-8-fluoro-5-methyl-N-[2-(methylamino)ethyl]quinoline-2-carboxamide hydrochloride (6.6 mg) as a solid.

[0199] Example 16 A mixture of 3-(2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinolin-7-yl)propanal (60 mg), methylamine (2M THF solution, 0.62 mL) and dichloromethane (1.5 mL) was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (50 mg) was added to the mixture under ice cooling, and the mixture was warmed to room temperature over 2 hours and stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol: using basic silica gel) to obtain a crude product. Hydrogen chloride (4M ethyl acetate solution, 0.038 mL) was added to the mixture of the obtained crude 3-(2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinolin-7-yl)-N-methylpropan-1-amine (38 mg) and ethyl acetate (3 mL), and the mixture was stirred at room temperature for 15 minutes. The solid was collected by filtration and dried under reduced pressure to obtain 3-(2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinolin-7-yl)-N-methylpropan-1-amine hydrochloride (34 mg) as a solid.

[0200] Example 17 A mixture of 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methyl-7-(piperidin-4-yl)-1,8-naphthyridine hydrochloride (35 mg), formaldehyde (36% aqueous solution, 0.05 mL), sodium triacetoxyborohydride (26 mg), acetic acid (0.01 mL), dichloromethane (2 mL) and methanol (0.2 mL) was stirred at room temperature for 30 minutes. The mixture was extracted with a saturated aqueous solution of sodium bicarbonate and chloroform, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform: basic silica gel used). The resulting solid was dissolved in methanol (1 mL), hydrogen chloride (4 M in 1,4-dioxane, 0.2 mL) was added, and the mixture was concentrated under reduced pressure to give 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methyl-7-(1-methylpiperidin-4-yl)-1,8-naphthyridine hydrochloride (30 mg) as a solid.

[0201] Example 18 To a mixture of methyl 2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-3-fluoro-4-methylquinoline-7-carboxylate (0.38 g) and THF (4 mL), 1M aqueous sodium hydroxide solution (2.5 mL) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and 1M hydrochloric acid (2.5 mL) was added to the residue under ice cooling, and the mixture was stirred at room temperature for 0.5 hours. The solid was collected by filtration and dried under reduced pressure to obtain 2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-3-fluoro-4-methylquinoline-7-carboxylic acid (0.33 g) as a solid.

[0202] Example 19 Methyl 2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinoline-7-carboxylate (8.4 g) was suspended in THF (150 mL), 1M aqueous sodium oxide (50 mL) was added, and the mixture was stirred at room temperature overnight. The mixture was ice-cooled, neutralized by adding 1M hydrochloric acid, and the mixture was concentrated under reduced pressure to remove most of the THF and stirred overnight. The solid was collected by filtration, washed with water, and the resulting solid was washed with chloroform. The solid was collected by filtration and dried under reduced pressure to give 2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinoline-7-carboxylic acid (4.8 g) as a solid. The filtrate was further concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to obtain 2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinoline-7-carboxylic acid (0.7 g) as a solid. The obtained 2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinoline-7-carboxylic acid solids (4.8 g and 0.7 g) were mixed, and chloroform, methanol, and acetone were added to dissolve the solids, and then activated carbon was added thereto, and the mixture was stirred for 15 minutes, and then filtered through Celite. The filtrate was concentrated under reduced pressure, and acetone (160 mL) was added to the obtained solids, and the mixture was stirred, and then water (18 mL) was added and the mixture was stirred at 65° C. for 2 hours. The mixture was allowed to cool to room temperature, and then water (140 mL) was added over 30 minutes, and the mixture was stirred at room temperature for 30 minutes, and further stirred under ice-cooling for 1 hour. The resulting solid was collected by filtration, washed with ice-cold acetone and water (1:1), and dried under reduced pressure to give 2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinoline-7-carboxylic acid (4.8 g) as a solid.

[0203] Example 20 Methyl 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinoline-7-carboxylate (200 mg) was suspended in THF (3 mL) and ethanol (3 mL), 1M aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 1 hour. 1M hydrochloric acid (2 mL) was added to the reaction mixture, and water (20 mL) was added, and the mixture was stirred for 5 minutes under ice cooling. The solid was collected by filtration and dried under reduced pressure to obtain 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinoline-7-carboxylic acid (170 mg) as a solid.

[0204] The compounds in the Preparations and Examples shown in the following tables were prepared in the same manner as in the Preparations and Examples above. In Tables 3 to 28 and 35 to 51, "y HCl" means that the compound is in the free form or monohydrochloride, and "m HCl" means that the compound is in the free form, monohydrochloride, or dihydrochloride. In Tables 3 to 28 and 35 to 51, the compounds marked with "*" are racemic mixtures.

[0205] [Table 3]

[0206] [Table 4]

[0207] [Table 5]

[0208] [Table 6]

[0209] [Table 7]

[0210]

Table 8

[0211]

Table 9

[0212]

Table 10

[0213]

Table 11

[0214]

Table 12

[0215]

Table 13

[0216]

Table 14

[0217]

Table 15

[0218]

Table 16

[0219]

Table 17

[0220]

Table 18

[0221]

Table 19

[0222]

Table 20

[0223]

Table 21

[0224]

Table 22

[0225]

Table 23

[0226]

Table 24

[0227]

Table 25

[0228]

Table 26

[0229]

Table 27

[0230]

Table 28

[0231]

Table 29

[0232]

Table 30

[0233]

Table 31

[0234]

Table 32

[0235]

Table 33

[0236]

Table 34

[0237]

Table 35

[0238]

Table 36

[0239]

Table 37

[0240]

Table 38

[0241]

Table 39

[0242]

Table 40

[0243]

Table 41

[0244]

Table 42

[0245]

Table 43

[0246]

Table 44

[0247]

Table 45

[0248]

Table 46

[0249]

Table 47

[0250]

Table 48

[0251]

Table 49

[0252] [Table 50]

[0253] [Table 51]

[0254] [Table 52]

[0255] [Table 53]

[0256] [Table 54]

[0257] [Table 55]

[0258] In addition to the present invention, the following compound S1 can be produced using the above-mentioned production method, the method described in the Examples, the method for synthesizing sulfonimide compounds (Organic. Letters, 22: pp2702-2706 (2020)), a method obvious to a person skilled in the art, or a modified method thereof. It is expected that the compound S1 has an acetylcholine receptor aggregation-inducing effect and can be used for the prevention and / or treatment of neuromuscular diseases.

[0259] [ka]

[0260] Although the present invention has been described in detail with reference to specific embodiments thereof, it is apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present invention. All references cited herein are incorporated in their entirety. This application is based on International Application No. PCT / CN2021 / 141500, filed on December 27, 2021, the entire contents of which are incorporated herein by reference. [Industrial Applicability]

[0261] The compound of formula (I) or a salt thereof has an acetylcholine receptor aggregation-inducing activity and is expected to be usable as an agent for the prevention and / or treatment of neuromuscular diseases.

Claims

1. A compound of formula (I) or a salt thereof: 【Chemical 1】 During the ceremony, R 1a and R 1b are the same or different and each represent H, optionally substituted C 1-6 Alkyl, halogen, hydroxy, or -O-(optionally substituted C 1-6 alkyl), and R 1a and R 1b are attached to the same carbon atom, R 1a and R 1b are bonded to each other, R 1a and R 1b C along with the carbon atom to which it is attached 3-8 may form a cycloalkyl, R 2 H, optionally substituted C 1-6 alkyl, halogen, cyano, or -O-(optionally substituted C 1-6 alkyl), R 3 is H or a halogen, R 4 is H, methyl, or halogen; R 5 is methyl, ethyl, or fluoromethyl; X is N or CR X and Y is N or CR Y and R X is H or a halogen, R Y is H or a halogen, L is bond, C 1-6 Alkylene, -O-(C 1-6 alkylene), C 2-6 Alkenylene, C 3-8 Cycloalkylene, or C 4-8 is cycloalkenylene, Z is -COOH or -CONR Z1 R Z2 or L and Z together represent optionally substituted C 1-6 Alkyl, -O-(optionally substituted C 1-6 alkyl), or a 3-8 membered optionally substituted heterocyclo ring containing 1 or 2 nitrogen atoms, R Z1 may be substituted C 1-6 alkyl, an optionally substituted 3- to 8-membered heterocyclo ring containing 1 to 2 nitrogen atoms, or -SO 2 -R Z3 and R Z3 C 1-6 Alkyl or C 3-8 is cycloalkyl, R Z2 is H or C 1-6 is alkyl, or R Z1 and R Z2 are bonded to each other, R Z1 and R Z2 may form, together with the nitrogen atom to which it is bonded, an optionally substituted 3- to 8-membered heterocyclo ring containing 1 or 2 nitrogen atoms, n is 0 or 1.

2. The compound according to claim 1 or a salt thereof, R 1a and R 1b are the same or different and are H, methyl, hydroxymethyl, fluoro, hydroxy, or methoxy; R 1a and R 1b are attached to the same carbon atom, R 1a and R 1b Together, R 1a and R 1b together with the carbon atom to which is attached may form a cyclopropyl; R 2 is H, methyl, hydroxymethyl, methoxymethyl, fluoro, cyano, or methoxy; R 3 is H or fluoro, R 4 is H or fluoro, R 5 is methyl, X is N or CR X and Y is N or CR Y and R X is H or fluoro, R Y is H or fluoro, L is a bond, methylene, ethylene, -OCH 2 -, ethenylene, cyclohexanediyl, or cyclohexenediyl; Z is -COOH or -CONR Z1 R Z2 , or L and Z together form -NH 2 and -NH-methyl, 1-3 Alkyl, -O-(hydroxy and -NH 2 C optionally substituted with 1 to 2 substituents selected from the group consisting of 1-3 and optionally forming a 3- to 8-membered heterocyclic ring containing 1 to 2 nitrogen atoms optionally substituted with a substituent selected from the group consisting of alkyl, methyl, and oxo; R Z1 But -NH 2 , -NH-methyl, -N(methyl) 2 C optionally substituted by 1 to 2 substituents selected from the group consisting of morpholinyl 1-3 a 3- to 8-membered heterocyclic ring containing 1 to 2 nitrogen atoms optionally substituted with alkyl or methyl, or -SO 2 -R Z3 and Or R Z1 is a substituent selected from the group consisting of the following formulas (i), (ii), and (iii): 【Chemistry 2】 R Z3 is cyclopropyl, R Z2 is H or methyl, or R Z1 and R Z2 are bonded to each other, R Z1 and R Z2 may form a structure of the following formula (iv) or formula (v) together with the nitrogen atom to which it is bonded: 【Chemistry 3】 R Z4 is H or methyl.

3. A compound of formula (I) or a salt thereof, 【Chemistry 4】 During the ceremony, R 1a and R 1b are the same or different and each represent H, optionally substituted C 1-6 Alkyl, halogen, hydroxy, or -O-(optionally substituted C 1-6 alkyl), and R 1a and R 1b are attached to the same carbon atom, R 1a and R 1b are bonded to each other, R 1a and R 1b C along with the carbon atom to which it is attached 3-8 may form a cycloalkyl, R 2 H, optionally substituted C 1-6 alkyl, halogen, cyano, or -O-(optionally substituted C 1-6 alkyl), R 3 is H or a halogen, R 4 is H, methyl, or halogen; R 5 is methyl, ethyl, or fluoromethyl; X is N or CR X and Y is N or CR Y However, X and Y are CR at the same time. X and CR Y It will not be, R X is H or a halogen, R Y is H or a halogen, L is bond, C 1-6 Alkylene, -O-(C 1-6 alkylene), C 2-6 Alkenylene, C 3-8 Cycloalkylene, or C 4-8 is cycloalkenylene, Z is -COOH or -CONR Z1 R Z2 or L and Z together represent optionally substituted C 1-6 Alkyl, -O-(optionally substituted C 1-6 alkyl), or a 3-8 membered optionally substituted heterocyclo ring containing 1 or 2 nitrogen atoms, R Z1 may be substituted C 1-6 alkyl, an optionally substituted 3- to 8-membered heterocyclo ring containing 1 to 2 nitrogen atoms, or -SO 2 -R Z3 and R Z3 C 1-6 Alkyl or C 3-8 is cycloalkyl, R Z2 is H or C 1-6 is alkyl, or R Z1 and R Z2 are bonded to each other, R Z1 and R Z2 may form, together with the nitrogen atom to which it is bonded, an optionally substituted 3- to 8-membered heterocyclo ring containing 1 or 2 nitrogen atoms, n is 0 or 1.

4. The compound or salt thereof according to claim 3, R 4 is H or a halogen, R 5 is methyl, L is bond, C 1-6 Alkylene, -O-(C 1-6 alkylene), C 2-6 Alkenylene, C 3-8 Cycloalkylene, or C 4-8 is cycloalkenylene, Z is -COOH or -CONR Z1 R Z2 or L and Z together form hydroxy and -NHR LZ C optionally substituted with 1 to 2 substituents selected from the group consisting of 1-6 Alkyl, -O-(hydroxy and -NHR LZ C optionally substituted with 1 to 2 substituents selected from the group consisting of 1-6 alkyl), or C 1-6 may form a 3-8 membered heterocyclocyclic group containing 1 to 2 nitrogen atoms optionally substituted with 1 to 2 substituents selected from the group consisting of alkyl and oxo; R LZ is H or C 1-6 is alkyl, R Z1 optionally substituted C 1-6 alkyl, an optionally substituted 3- to 8-membered heterocyclo ring containing 1 to 2 nitrogen atoms, or -SO 2 -R Z3 and R Z3 C 3-8 is cycloalkyl, R Z2 is H or C 1-6 is alkyl, or R Z1 and R Z2 are bonded to each other, R Z1 and R Z2 may be joined together with the nitrogen atom to which it is attached to form an optionally substituted 3- to 8-membered heterocyclo ring containing 1 to 2 nitrogen atoms.

5. The compound or salt thereof according to claim 4, R 1a and R 1b are the same or different and are H, methyl, hydroxymethyl, fluoro, hydroxy, or methoxy; R 1a and R 1b are attached to the same carbon atom, R 1a and R 1b are bonded to each other, R 1a and R 1b together with the carbon atom to which is attached may form a cyclopropyl; R 2 is H, methyl, hydroxymethyl, methoxymethyl, fluoro, cyano, or methoxy; R 3 is H or fluoro, R 4 is H or fluoro, R X is H or fluoro, R Y is H or fluoro, L is a bond, methylene, ethylene, -OCH 2 -, ethenylene, cyclohexanediyl, or cyclohexenediyl; Z is -COOH or -CONR Z1 R Z2 or L and Z together form -NH 2 C optionally substituted with a substituent selected from the group consisting of -NH-methyl 1-3 Alkyl, -O-(hydroxy and -NH 2 C optionally substituted with 1 to 2 substituents selected from the group consisting of 1-3 a 3- to 8-membered heterocyclic ring containing 1 to 2 nitrogen atoms optionally substituted with a substituent selected from the group consisting of alkyl, methyl, and oxo; R Z1 But -NH 2 , -NH-methyl, -N(methyl) 2 C optionally substituted by 1 to 2 substituents selected from the group consisting of morpholinyl 1-3 a 3- to 8-membered heterocyclic ring containing 1 to 2 nitrogen atoms optionally substituted with alkyl or methyl, or -SO 2 -R Z3 and Or R Z1 is a substituent selected from the group consisting of the following formulas (i), (ii), and (iii): 【Chemistry 5】 R Z3 is cyclopropyl, R Z2 is H or methyl, or R Z1 and R Z2 are bonded to each other, R Z1 and R Z2 may form a structure of the following formula (iv) or formula (v) together with the nitrogen atom to which it is bonded: 【Chemistry 6】 R Z4 is H or methyl.

6. 6. The compound or salt thereof according to claim 5, wherein R 1a and R 1b are the same or different and are each H or fluoro, R 2 is fluoro, R 3 is fluoro, X is N and Y is CR Y and R Y But H, L is a bond, Z is -COOH or -CONR Z1 R Z2 can be, R Z1 and R Z2 are bonded to each other, R Z1 and R Z2 together with the nitrogen atom to which it is bonded, form a structure of the following formula (vi) or formula (v). 【Chemistry 7】

7. 2. The compound or salt thereof according to claim 1, wherein the compound is selected from the group consisting of the following compounds: 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline-7-carboxylic acid, sodium 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-4-methylquinoline-7-carboxylate, {2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinolin-7-yl}(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl))methanone, (3-aminoazetidin-1-yl){2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinolin-7-yl}methanone, 2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-3-fluoro-4-methylquinoline-7-carboxylic acid, 2-[2,6-difluoro-4-(4-fluoropiperidine-1-sulfonyl)phenyl]-4-methylquinoline-7-carboxylic acid, and 2-{2,6-difluoro-4-[(3S)-3-fluoropyrrolidine-1-sulfonyl]phenyl}-3-fluoro-4-methylquinoline-7-carboxylic acid.

8. A pharmaceutical composition comprising the compound of claim 1 or a salt thereof and a pharmaceutically acceptable excipient.

9. The pharmaceutical composition according to claim 8, which is a pharmaceutical composition for the prevention and / or treatment of a neuromuscular disease.

10. Use of the compound or salt thereof according to claim 1 for the manufacture of a pharmaceutical composition for the prevention and / or treatment of a neuromuscular disease.

11. Use of the compound or salt thereof according to claim 1 for the prevention and / or treatment of a neuromuscular disease.

12. 10. The compound or salt thereof according to claim 1 for use in the prevention and / or treatment of a neuromuscular disease.

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