Bicyclic derivatives for treating internal parasites

Abstract

The present invention provides compounds of formula (I), which are useful in the control of endoparasites in warm-blooded animals, such as heartworm. [Formula 1] TIFF2022535110000076.tif34133

Description

Technical Field

[0001] Cross-reference to related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 858,465, filed on June 7, 2019, and U.S. Provisional Patent Application No. 62 / 947,852, filed on December 13, 2019, the entire contents of each of which are hereby incorporated by reference in their entirety.

[0002] The present invention relates to pharmaceutical chemistry, pharmacology, and veterinary and human medicine. More particularly, the present invention relates to compounds of formula (I) and their use in the control of internal parasites (e.g., Dirofilaria immitis) in warm-blooded animals.

Background Art

[0003] Dirofilaria immitis is a parasitic roundworm that spreads from host to host by being bitten by mosquitoes. Its life cycle begins when a female mosquito takes a blood meal from an infected host. The mosquito ingests immature Dirofilaria immitis, which then molts to the infective larval stage and migrates to the mouthparts of the mosquito. The mosquito then takes a blood meal on the body surface of a susceptible host, such as a dog or cat, and deposits the infective larvae. The larvae then molt inside the new host to the next larval stage and then migrate through the body and ultimately reach the blood vessels. As the larvae migrate through the tissues, they molt to become juvenile adults. The juvenile adults ultimately migrate to the blood vessels of the lungs, where they mature into sexually active adults. The adult Dirofilaria immitis then reproduce and release immature Dirofilaria immitis, completing the cycle. Dirofilaria immitis infection can cause serious illness in the host.

[0004] Adult canine filariasis can be treated with arsenic-based compounds; the treatment is time-consuming, cumbersome, and often only partially successful. Therefore, treatment has focused on the control of canine filariasis. Control of canine filariasis is currently only carried out by administering drugs regularly throughout the year. Typical treatments include macrocyclic lactones such as ivermectin, moxidectin, and milbemycin oxime. Unfortunately, the development of resistance of canine filaria to macrocyclic lactones has been observed. Therefore, new compounds are needed to effectively control canine filariasis by prevention or by directly killing canine filaria. Specific treatments for internal parasites are described in WO2017 / 178416, WO2018 / 087036, WO2018 / 197401, WO2019 / 025341, and WO2019 / 002132.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Summary of the Invention

Means for Solving the Problems

[0006] The present invention provides a compound represented by formula (I) for effectively treating and / or controlling internal parasites (e.g., canine filaria) in warm-blooded animals.

[0007] In one embodiment, the present invention relates to formula (I):

Chemical formula

[0008] 〔wherein, n is 0 or 1; X1 is selected from the group consisting of N and CR1; X2 is selected from the group consisting of N and CR2; X3 is selected from the group consisting of N and CR3; X4 is selected from the group consisting of N and CR4; X5 is selected from the group consisting of N and CR5; X6 is selected from the group consisting of N and CR6; G is

Chemical formula

[0009] selected from the group consisting of; M is selected from the group consisting of N-R 13 , O, and S; Y1 is selected from the group consisting of CR8R9, O, S, and NR 10 ; Y2 is selected from the group consisting of CR8R9, O, S, and NR 10 ; wherein at least one of the groups Y1 or Y2 is CR8R9; Z1 is selected from the group consisting of N, O, S, and CR 11 ; Z2 is selected from the group consisting of nil, N, and CR 11 ; Z3 is selected from the group consisting of nil, N, and CR 11 ; Z4 is selected from the group consisting of N, O, S, and CR 11 ; wherein 2 or less of Z1, Z2, Z3, and Z4 are N, and wherein only one of Z1 and Z4 is O or S, Z2 is nil only when Z1 is O or S, and Z3 is nil only when Z4 is O or S; R1 is selected from the group consisting of hydrogen, halogen, hydroxyl, -SH, -SC1-C4 alkyl, -S(O)(C1-C4 alkyl), -S(O)2(C1-C4 alkyl), cyano, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4-alkoxy, -B(OR 15 )(OR 16 ), where R 15 is each time selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl, R 16 is each time selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl, or R 15 and R 16 together with the oxygen atom to which they are attached form a 5- to 7-membered ring (where the ring may be substituted with 1 to 4 C1-C4 alkyl; -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2); R2 is selected from the group consisting of hydrogen, halogen, hydroxyl, -SH, -SC1-C4 alkyl, -S(O)(C1-C4 alkyl), -S(O)2(C1-C4 alkyl), cyano, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4-alkoxy, -B(OR 15 )(OR 16 ), where R 15 is each time selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl, R 16 is each time selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl, or R 15 and R 16 together with the oxygen atom to which they are attached form a 5- to 7-membered ring (where the ring may be substituted with 1 to 4 C1-C4 alkyl; -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2); R3 is selected from the group consisting of hydrogen, halogen, hydroxyl, -SH, -SC1-C4 alkyl, -S(O)(C1-C4 alkyl), -S(O)2(C1-C4 alkyl), cyano, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4-alkoxy, -B(OR 15 )(OR16 ) selected from the group consisting of, wherein R 15 is, each time, selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl, R 16 is, each time, selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl, or R 15 and R 16 together with the oxygen atom to which they are attached form a 5- to 7-membered ring (wherein the ring may be substituted with 1 to 4 C1-C4 alkyl; -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2); R4 is halogen, cyano, -CHO, hydroxyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkyl substituted with C1-C4 alkoxy, benzyl optionally substituted with 1 to 5 halogen atoms, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NH(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6-cycloalkyl), -N(C1-C4 alkyl)(4- to 7-membered heterocycloalkyl), -NH(4- to 7-membered heterocycloalkyl), -N(C1-C4 alkyl)(C1-C4 alkoxy), -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -C(O)N(C1-C4 alkyl)(4- to 7-membered heterocycloalkyl), -NHSO2(C1-C4 alkyl), -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -B(OR 15 )(OR 16 ) selected from the group consisting of, wherein R 15 is, each time, selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl, R 16 is, each time, selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl, or R 15 and R 16forms, together with the oxygen atoms to which they are attached, a 5- to 7-membered ring (wherein the ring may be substituted with 1 to 4 C1-C4 alkyl); a 6- to 10-membered aryl; a monocyclic heteroaromatic ring [wherein the monocyclic heteroaromatic ring is selected from the group consisting of a 4- to 7-membered heterocycloalkyl, a 5-membered heteroaryl having at least 1 nitrogen atom (wherein the 5-membered heteroaryl ring is attached to the remainder of the molecule via its nitrogen atom), and a 6-membered heteroaryl having at least 1 nitrogen atom]; wherein the aryl ring, heterocycloalkyl ring, and heteroaryl ring in R4 are each independently substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NH(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6-cycloalkyl), -NHSO2(C1-C4 alkyl), -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -S(O)C1-C4-halogenoalkyl, and -SO2C1-C4 halogenoalkyl;Here, the C3-C6 cycloalkyl ring and heterocycloalkyl ring in R4 may be substituted with a spiro group, and in that case, the spiro group is a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, S, or O. Here, the spiro group may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NH(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6-cycloalkyl), -NHSO2(C1-C4 alkyl), -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -S(O)C1-C4-halogenoalkyl, and -SO2C1-C4 halogenoalkyl; and here, each C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 alkoxy in R4 may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, cyano, carboxy, carbamoyl, C1-C4 alkoxycarbonyl, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, and C1-C4 alkoxy; R5 is selected from the group consisting of hydrogen, halogen, hydroxyl, -SH, -SC1-C4 alkyl, -S(O)(C1-C4 alkyl), -S(O)2(C1-C4 alkyl), cyano, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4-alkoxy, -B(OR 15 )(OR 16 ), where R 15 is each time selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, R 16 is each time selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, or R 15 and R 16together with the oxygen atom to which they are attached form a 5- to 7-membered ring (wherein the ring may be substituted with 1 to 4 C1-C4 alkyl; -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2); R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, -SH, -SC1-C4 alkyl, -S(O)(C1-C4 alkyl), -S(O)2(C1-C4 alkyl), cyano, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4-alkoxy, -B(OR 15 )(OR 16 ), wherein R 15 is each independently selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl, R 16 is each independently selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl, or R 15 and R 16 together with the oxygen atom to which they are attached form a 5- to 7-membered ring (wherein the ring may be substituted with 1 to 4 C1-C4 alkyl; -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2); R7 is selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl (wherein these may be substituted with 1 to 5 halogen atoms, -C(H)O, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 halogenoalkyl and C1-C4-alkoxy); R8 is each independently selected from the group consisting of hydrogen, fluoro and C1-C4 alkyl; R9 is each independently selected from the group consisting of hydrogen, fluoro and C1-C4 alkyl; R 10 is selected from the group consisting of hydrogen and C1-C4 alkyl; R 11 is each independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4-alkoxy, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2; and, Q is (i) an aryl having 6 to 10 members [wherein the aryl having 6 to 10 members may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NH(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6-cycloalkyl), -NHSO2(C1-C4 alkyl), -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -S(O)C1-C4-halogenoalkyl and -SO2C1-C4 halogenoalkyl, and wherein the aryl having 6 to 10 members may be condensed with a 4- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group consisting of O, S and N, and wherein the carbon of the heterocycloalkyl may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2, and wherein any N in the heterocycloalkyl is substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl if possible according to its valence]; (ii) a 5- to 10-membered heteroaryl having one, two or three heteroatoms independently selected from the group consisting of O, S and N, wherein the carbon atoms of the 5- to 10-membered heteroaryl may be substituted with one, two, three, four or five substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, benzyloxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -S(O)C1-C4-halogenoalkyl and -SO2C1-C4 halogenoalkyl, and any N in the heteroaryl may be substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl, if possible according to its valence; (iii) a 4- to 7-membered heterocycloalkyl having one, two or three heteroatoms independently selected from the group consisting of O, S and N, wherein the heterocycloalkyl may be benzofused, and the carbon atoms of the 4- to 7-membered heterocycloalkyl or the optionally benzofused 4- to 7-membered heterocycloalkyl may be substituted with one, two, three or four substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2, and any N in the heterocycloalkyl may be substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl; (iv) aryloxy having 6 to 10 members [wherein the aryloxy having 6 to 10 members may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NH(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6-cycloalkyl), -NHSO2(C1-C4 alkyl), -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -S(O)C1-C4-halogenoalkyl and -SO2C1-C4 halogenoalkyl]; (v) arylthio-oxy having 6 to 10 members [wherein the arylthio-oxy having 6 to 10 members may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NH(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6-cycloalkyl), -NHSO2(C1-C4 alkyl), -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -S(O)C1-C4-halogenoalkyl and -SO2C1-C4 halogenoalkyl]; and, (vi) 5- to 10-membered heteroaryloxy [wherein the 5- to 10-membered heteroaryloxy may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NH(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6-cycloalkyl), -NHSO2(C1-C4 alkyl), -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -S(O)C1-C4-halogenoalkyl and -SO2C1-C4 halogenoalkyl]; selected from the group consisting of; R 13 is selected from the group consisting of hydroxy, C1-C4 alkoxy and -NH2; and, R 14 is, each time independently selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2) To provide a compound represented by or a salt thereof.

[0010] In one embodiment, the present invention further provides a composition comprising a compound represented by formula (I) or a salt thereof and an acceptable excipient, wherein the composition may further comprise at least one additional active compound.

[0011] In one embodiment, the present invention further provides a method for treating a parasite, the method comprising administering to a subject in need of such treatment an effective amount of a compound represented by formula (I) or a salt thereof, wherein the method may further comprise, optionally, an effective amount of at least one additional active compound.

[0012] In one embodiment, the present invention further provides a method for controlling parasites, wherein the method comprises administering to a subject in need of such control an effective amount of a compound represented by formula (I) or a salt thereof, and wherein the method optionally further comprises an effective amount of at least one additional active compound.

[0013] In one embodiment, the present invention further provides a method for treating or controlling parasites, wherein the method comprises contacting the environment of a subject with an effective amount of a compound represented by formula (I) or a salt thereof, and wherein the method optionally further comprises an effective amount of at least one additional active compound.

[0014] Accordingly, the present invention also provides the use of the compounds of the present invention as medicaments, which includes use for manufacturing medicaments. In one embodiment, the present invention provides the manufacture of a medicament comprising a compound represented by formula (I) or a salt thereof for treating parasites. In one embodiment, the present invention provides the manufacture of a medicament comprising a compound represented by formula (I) or a salt thereof for controlling parasites.

[0015] The present invention further provides a process for manufacturing the compounds of the present invention and their intermediates.

Embodiments for Carrying out the Invention

[0016] The term "C1-C4 alkyl" refers to a straight-chain or branched-chain alkyl chain having 1 to 4 carbon atoms, and includes methyl, ethyl, propyl, isopropyl, butyl, and the like.

[0017] The term "C1-C4 haloalkyl" refers to a straight-chain or branched-chain alkyl chain having 1 to 4 carbon atoms and 1 to 5 halogens, and includes fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and the like.

[0018] The term "C2-C4 alkenyl" refers to a straight-chain or branched alkenyl chain having 2 to 4 carbon atoms and one carbon-carbon double bond, and includes ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, and the like.

[0019] The term "C2-C4 alkynyl" refers to a straight-chain or branched alkynyl chain having 2 to 4 carbon atoms and one carbon-carbon triple bond, and includes acetylene, propargyl, and the like.

[0020] The term "C1-C4 alkoxy" refers to C1-C4 alkyl bonded via an oxygen atom, and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.

[0021] The term "C3-C6 cycloalkyl" refers to an alkyl ring having 3 to 6 carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0022] The terms "halogen" and "halogeno" refer to a chloro atom, a fluoro atom, a bromo atom, or an iodo atom.

[0023] The term "C6-membered or C 10 membered aryl" refers to phenyl or naphthyl.

[0024] The term "C6-membered or C 10 membered aryloxy" refers to phenyl or naphthyl bonded via an oxygen atom, and includes phenoxy and naphthyloxy.

[0025] The term "C6-membered or C 10 membered arylthio-oxy" refers to phenyl or naphthyl bonded via a sulfur atom, and includes phenylthio-oxy and naphthylthio-oxy. Further, the term "C6-membered or C 10It is understood that the term "arylthio-oxy of the member" also includes those in which the sulfur is -SO2- and -S(O)-.

[0026] The term "4- to 7-membered heterocycloalkyl" refers to a 4- to 7-membered monocyclic saturated or partially (but not completely) unsaturated ring having one or more heteroatoms (preferably 1, 2, or 3 heteroatoms) selected from the group consisting of nitrogen, oxygen, and sulfur, and the ring may optionally contain a carbonyl to form a lactam or lactone. It is understood that when sulfur is included, the sulfur can be either -S-, -SO-, or -SO2-. For example, but not limited to, the term includes azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuryl, hexahydropyrimidinyl, tetrahydropyrimidinyl, dihydroimidazolyl, and the like.

[0027] The term "5-membered heteroaryl" refers to a 5-membered monocyclic fully unsaturated ring having 1 to 4 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. For example, but not limited to, the term includes furyl, thienyl, pyrrolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and the like. It is understood that 5-membered heteroaryl can be attached as a substituent via a ring carbon atom or a ring nitrogen atom (such a bonding mode being available, for example, for pyrrolyl, imidazolyl, pyrazolyl, triazolyl, etc.).

[0028] The term "6-membered heteroaryl" refers to a 6-membered monocyclic fully unsaturated ring having 1 to 5 carbon atoms and one or more (typically 1 to 4) heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. For example, without limitation, the term includes pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, etc. It is understood that the 6-membered heteroaryl can be attached as a substituent via a ring carbon atom or a ring nitrogen atom (when such a bonding mode is available).

[0029] The term "5- to 10-membered heteroaryl" refers to a 5- to 10-membered monocyclic or polycyclic fully unsaturated ring or ring system having one or more heteroatoms (preferably 1, 2, or 3 heteroatoms) selected from the group consisting of 1 to 9 carbon atoms and nitrogen, oxygen, and sulfur. For example, without limitation, the term includes furyl, thienyl, pyrrolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, azepinyl, diazepinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, benzimidazolyl, benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl, benzopyrazinyl, benzopyrazolyl, quinazolinyl, thienopyridyl, quinolinyl, isoquinolinyl, benzothiazolyl, etc. It is understood that a 5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group of O, S, and N can be attached as a substituent via a ring carbon atom or a ring nitrogen atom (when such a bonding mode is available).

[0030] The term "5- to 10-membered heteroaryloxy" refers to a 5- to 10-membered heteroaryl attached via an oxygen atom, where the 5- to 10-membered heteroaryl has one or more heteroatoms (preferably 1, 2, or 3 heteroatoms) selected from the group of O, S, and N, and includes imidazoloxy, pyrazoloxy, pyridyloxy, pyrimidyloxy, quinolyloxy, etc.

[0031] The term "oxo" refers to an oxygen atom that is doubly bonded to the carbon to which it is attached, forming the carbonyl of a ketone or an aldehyde. For example, a pyridone radical is intended as an oxo-substituted 6-membered heteroaryl.

[0032] The term "carboxyl" refers to the following group:

Chem.

[0033] is shown.

[0034] The term "carbamoyl" refers to the following group:

Chem.

[0035] is shown.

[0036] The term "C1-C4 alkoxycarbonyl" refers to the following group:

Chem.

[0037] 〔wherein, R is C1-C4 alkyl〕 is shown.

[0038] The term "nil" as used herein with respect to a group, substituent or moiety, etc. indicates that the group, substituent or moiety is absent. When a group, substituent or moiety is normally attached to two or more other groups, substituents or moieties, the others are attached together in place of the group, substituent or moiety, and this is nil. For example, in the case of a compound having the structure A-B-C (where B is nil), A is directly attached to C, and the compound is A-C. As another example, in the case of a compound having the structure A-B-C (where C is nil), the compound is A-B.

[0039] The term "salt" refers to salts of organic acids and organic bases, or salts of inorganic acids and inorganic bases, which are veterinarily or pharmaceutically acceptable. Such salts are well known in the art and include the salts described in "Journal of Pharmaceutical Science, 66, 2-19(1977)". An example thereof is hydrochloride.

[0040] The term "substituted", when used in "optionally substituted", refers to a hydrogen radical that has been replaced by a non-hydrogen radical (substituent) at one or more hydrogen radicals of a group. It is understood that the substituents may be the same or different for each substitution position. The combinations of groups and substituents contemplated by the present invention are stable or chemically feasible. In the case of the compounds described herein, the groups and substituents can be selected according to the valence of the atoms and the substituents, so that the selection and substitution result in a stable compound (e.g., a stable compound that does not spontaneously undergo transformation (e.g., transformation by rearrangement, cyclization, elimination, etc.)).

[0041] When a cycloalkyl ring or a heterocycloalkyl ring is substituted with a spiro group, it is understood that the spiro group can be attached at any position of the cycloalkyl or heterocycloalkyl to form an additional ring so that, if possible according to its valence, the spiro group is attached to the cycloalkyl ring or heterocycloalkyl ring via a common atom. Examples of such spiro-substituted rings include 2-oxa-6-azaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, 2-azaspiro[3.4]octane, 6-oxa-2-azaspiro[3.4]octane, and the like.

[0042] The term "stable" refers to a compound that does not substantially change when subjected to the conditions that enable their manufacture. In non-limiting examples, a stable compound or a chemically feasible compound is one that does not substantially change when maintained at a temperature of 40 °C or less for about one week in the absence of moisture or other chemically reactive conditions.

[0043] When terms defined herein refer to a number of carbon atoms, it is understood that the recited number refers to the recited group and does not include carbon atoms that may be present within substituents in that group, or carbon atoms that may be present as part of a fused ring, including benzo-fused rings.

[0044] One of ordinary skill in the art will understand that some of the compounds of the present invention exist as isomers. All stereoisomers (which include geometric isomers, enantiomers, and diastereomers) in any ratio of the compounds of the present invention are intended to be within the scope of the present invention.

[0045] One of ordinary skill in the art will further understand that some of the compounds of the present invention exist as tautomers. All tautomeric forms of the compounds of the present invention are intended to be within the scope of the present invention.

[0046] The compounds of the present invention further include all isotopic variants in which at least one atom having a major atomic mass is replaced by an atom having the same atomic number but a different atomic mass from the major atomic mass. The use of isotopic variants (e.g., deuterium, 2 H) can improve metabolic stability. Further, certain isotopic variants of the compounds of the present invention can incorporate radioactive isotopes (e.g., tritium, 3 H, or 14 C), which can be useful in tissue distribution studies of drugs and / or substrates. Isotopes that emit positrons (e.g., 11 C, 18 F, 15 O and 13Replacement by (N) may be useful in positron emission tomography (PET) studies.

[0047] The terms "compounds of the invention", "a compound of the invention", "compounds of the present invention", etc. include embodiments of formula (I) and other more specific embodiments included in formula (I) described herein and the exemplary compounds described herein and the respective salts of these embodiments.

[0048] A compound represented by formula (I) having G as defined is of the formula:

Chemical formula

[0049] represented by

[0050] Further embodiments of the compounds of the present invention are described below.

[0051] (a) One embodiment relates to a compound represented by formula (Ia).

[0052] (b) One embodiment relates to a compound represented by formula (Ib).

[0053] (1) One embodiment relates to a compound represented by formula (Ic).

[0054] (2) One embodiment relates to compounds of formula (I), embodiment (a), embodiment (b) and (1) [wherein at least one of X1, X2, X3 and X5 is N].

[0055] (c) One embodiment relates to a compound represented by formula (I), formula (Ia), formula (Ib) or formula (Ic) [wherein, X1 is CR1; X2 is CR2; X3 is CR3; X4 is CR4; X5 is CR5; and X6 is N] or a salt thereof.

[0056] (d) One embodiment relates to a compound represented by formula (I), formula (Ia), formula (Ib) or formula (Ic) [wherein, X1 is CR1; X2 is CR2; X3 is CR3; X4 is CR4; X5 is N; and X6 is N] or a salt thereof.

[0057] (e) One embodiment relates to a compound represented by formula (I), formula (Ia) or formula (Ib) [wherein, X1 is CR1; X2 is CR2; X3 is CR3; X4 is CR4; X5 is N; and X6 is CR6] or a salt thereof.

[0058] (f) One embodiment relates to a compound represented by formula (I), formula (Ia), formula (Ib) or formula (Ic) [wherein, X1 is CR1; X2 is CR2; X3 is CR3; X4 is N; X5 is N; and X6 is N] or a salt thereof.

[0059] (g) One embodiment relates to formula (I) and the compounds of embodiments (a), (b), (1), (2), (c), (d), (e) and (f) [wherein, Q is an aryl having 6 to 10 members which may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NH(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6-cycloalkyl), -NHSO2(C1-C4 alkyl), -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -S(O)C1-C4-halogenoalkyl and -SO2C1-C4 halogenoalkyl] or a salt thereof.

[0060] (h) One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e) and (f) [wherein Q is halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NH(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6-cycloalkyl), -NHSO2(C1-C4 alkyl), -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -S(O)C1-C4-halogenoalkyl and -SO2C1-C4 halogenoalkyl, and is a 6-membered aryl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: and wherein the 6-membered aryl is fused to a 4- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group consisting of O, S and N; and wherein the carbon of the heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2; and any N within the heterocycloalkyl is substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl], or a salt thereof.

[0061] (i) One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e) and (f) [wherein Q is a 5- to 10-membered heteroaryl having one or two heteroatoms selected from the group of O, S and N, wherein the carbon of the heteroaryl is halogen, cyano, nitro, -OH, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2, independently selected from the group consisting of 1, 2 or 3 substituents, and any N within the heteroaryl may be substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl] or a salt thereof.

[0062] (j) One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e) and (f) [wherein Q is a 4- to 7-membered heterocycloalkyl having one or two heteroatoms selected from the group of O, S, N, wherein the heterocycloalkyl may be benzo-fused, wherein the carbon of the heterocycloalkyl or optionally benzo-fused heterocycloalkyl is halogen, cyano, nitro, hydroxyl, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2, independently selected from the group consisting of 1, 2, 3 or 4 substituents, and any N within the heterocycloalkyl may be substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl] or a salt thereof.

[0063] (k) One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e) and (f) [wherein Q is halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NH(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6-cycloalkyl), -NHSO2(C1-C4 alkyl), -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -S(O)C1-C4-halogenoalkyl and -SO2C1-C4 halogenoalkyl, and is a 6- to 10-membered aryloxy optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of] or a salt thereof.

[0064] (l) One embodiment relates to a compound of formula (I) and embodiments (1), (2), (a), (b), (c), (d), (e) and (f) [wherein Q is halogen, cyano, nitro, hydroxyl, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NH(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6-cycloalkyl), -NHSO2(C1-C4 alkyl), -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -S(O)C1-C4-halogenoalkyl and -SO2C1-C4 halogenoalkyl, and is a 5- to 10-membered heteroaryloxy optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of] or a salt thereof.

[0065] (m) One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e)(f), (g), (h), (i), (j), (k) and (l) [wherein n is 1] or a salt thereof.

[0066] (n) One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l) and (m) [wherein Y1 is CR8R9 and Y2 is O] or a salt thereof.

[0067] (o) One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m) and (n) [wherein R4 is selected from the group consisting of C1-C4 alkyl, C3-C6 cycloalkyl, -N(C1-C4 alkyl)2 and 4-7 membered heterocycloalkyl] or a salt thereof.

[0068] (p) One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (1), (2), (g), (h), (i), (j), (k), (l), (m) and (n) [wherein R4 is -N(C1-C4 alkyl)2] or a salt thereof.

[0069] (q) One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o) and (p) [wherein M is O] or a salt thereof.

[0070] (r) One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o) and (p) [wherein M is NR 13 and] of a compound or a salt thereof.

[0071] (s) One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o) and (p) [wherein M is S] or a salt thereof.

[0072] (t) One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o), (p), (q), (r) and (s) [wherein, Z1 is CR 11 wherein Z2 is CR 11 wherein Z3 is nil, and Z4 is S] or a salt thereof.

[0073] (u) Another embodiment relates to each salt of the exemplified compounds.

[0074] Another embodiment provides a compound of the formula:

Chemical formula

[0075] [wherein, X1, X2, X3, X4, X5, X6, R1, R4, R5, R7 and Q are as defined in the "Summary of the Invention"] or a salt of any of the above compounds.

[0076] In another embodiment regarding formula (Ia-1) to formula (Ia-8a) [that is, formula (Ia-1), formula (Ia-2), formula (Ia-3), formula (Ia-4), formula (Ia-5), formula (Ia-6), formula (Ia-7), formula (Ia-8), formula (Ia-1a), formula (Ia-2a), formula (Ia-3a), formula (Ia-4a), formula (Ia-5a), formula (Ia-6a), formula (Ia-7a) and formula (Ia-8a)], when R1 is present [that is, when specifically shown in the formula], it is selected from hydrogen, halogen and cyano. In another embodiment regarding formula (Ia-1) to formula (Ia-8a), when R1 is present, it is selected from hydrogen, fluoro and cyano. In another embodiment regarding formula (Ia-1) to formula (Ia-8a), when R1 is present, it is hydrogen or fluoro. In another embodiment regarding formula (Ia-1) to formula (Ia-8a), when R1 is present, it is hydrogen. In another embodiment regarding formula (Ia-1) to formula (Ia-8a), when R1 is present, it is fluoro.

[0077] In another embodiment regarding formula (Ia-1) to formula (Ia-8a), when R4 is present,

Chemical formula

[0078] is selected from.

[0079] In another embodiment regarding formula (Ia-1) to formula (Ia-8a), when R4 is present,

Chemical formula

[0080] is selected from.

[0081] In another embodiment regarding formula (Ia-1) to formula (Ia-8a), when R4 is present,

Chemical formula

[0082] is selected from.

[0083] In another embodiment regarding formulas (Ia-1) to (Ia-8a), when present, R5 is hydrogen, halogen, C1-C4 alkyl or C1-C4 halogenoalkyl. In another embodiment regarding formulas (Ia-1) to (Ia-8a), when present, R5 is hydrogen, C1-C4 alkyl or C1-C4 halogenoalkyl. In another embodiment regarding formulas (Ia-1) to (Ia-8a), when present, R5 is hydrogen, methyl or trifluoromethyl.

[0084] In another embodiment regarding formulas (Ia-1) to (Ia-8a), when present, R7 is hydrogen.

[0085] In another embodiment regarding formulas (Ia-1) to (Ia-8a), Q is selected from 6-membered aryl and 5-membered or 6-membered heteroaryl (wherein the heteroaryl has 1, 2 or 3 heteroatoms independently selected from N, O and S), wherein the aryl and heteroaryl may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, C1-C4 halogenoalkyl and C1-C4 alkoxy. In another embodiment regarding formulas (Ia-1) to (Ia-8a), Q is selected from 6-membered aryl which may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen.

[0086] In another embodiment regarding formulas (Ia-1) to (Ia-8a), Q is

Chemical formula

[0087] is selected from.

[0088] In another embodiment regarding formulas (Ia-1) to (Ia-8a), Q is [Chemical formula] TIFF0007693558000016.tif58150

[0089] is selected from the following.

[0090] In another embodiment regarding formulas (Ia-1) to (Ia-8a), X1, X2, X3, X4, X5, X6, when present, are as defined in the "Summary of the Invention"; R1, when present, is selected from hydrogen, halogen, and cyano; R4, when present, [Chemical formula]

[0091] is selected from the following; R5, when present, is selected from hydrogen, methyl, and trifluoromethyl; R7, when present, is hydrogen; and, Q is [Chemical formula] TIFF0007693558000019.tif140147

[0092] is selected from the following; or a salt thereof.

[0093] In another embodiment regarding formulas (Ia-1) to (Ia-8a), X1, X2, X3, X4, X5, X6, when present, are as defined in the "Summary of the Invention"; R1, when present, is selected from hydrogen, halogen, and cyano; R4, when present, [Chemical formula]

[0094] selected from; R5, when present, is selected from hydrogen; R7, when present, is hydrogen; and, Q is [Chemical formula]

[0095] selected from; or a salt thereof.

[0096] In another embodiment, the compound represented by formula (I) or a salt thereof is of formula (Ia-5) [Chemical formula]

[0097] [wherein R1, R4 and Q are as defined in "Summary of the Invention"] It is represented by. Preferably, R1 is hydrogen, halogen or cyano. More preferably, R1 is hydrogen or fluoro. Preferably, R4 is 4-morpholino or dimethylamino. Preferably, Q is a 6-membered aryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NH(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6-cycloalkyl), -NHSO2(C1-C4 alkyl), -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -S(O)C1-C4-halogenoalkyl and -SO2C1-C4 halogenoalkyl, wherein the 6- to 10-membered aryl may be condensed with a 4- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group of O, S and N, and wherein the carbon of the heterocycloalkyl may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2, and any N in the heterocycloalkyl is substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl if possible according to its valence. Preferably, Q is a 6-membered aryl substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, C1-C4 alkyl, C1-C4 halogenoalkyl and cyano. Preferably, Q is

Chemical formula

[0098] selected from.

[0099] The compounds of the present invention can be prepared by various methods, some of which are described below. All substituents are as previously defined unless otherwise indicated.

[0100] The product of each step can be recovered by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, etc. In this method, it may be necessary to protect certain groups (e.g., hydroxyl group, thiol group, amino group or carboxyl group) in order to minimize unwanted reactions. The selection, use and removal of protecting groups are well known and understood as standard techniques (e.g., "T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Chemistry (John Wiley and Sons, 1991)").

[0101] As used herein: AcOH represents acetic acid; aq represents aqueous, br represents broad, CH3CN represents acetonitrile, CH2Cl2 represents methylene chloride, d represents a doublet, dd represents a doublet of doublets, DIPEA represents N,N-diisopropylethylamine, DMA represents N,N-dimethylacetamide, DMF represents N,N-dimethylformamide, DMSO represents dimethyl sulfoxide, ee represents enantiomeric excess, eq represents equivalent, ES represents electrospray ionization, EtOAc represents EtOAc, EtOH represents EtOH, HATU represents 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, HPLC represents high performance liquid chromatography, iPrOH represents isopropanol, J represents coupling constant, KOAc represents potassium acetate, K2CO3 represents potassium carbonate, LCMS represents liquid chromatography - mass spectrometry, m / z represents mass-to-charge ratio, M represents molarity, m represents a multiplet, MeOH represents mEtOH, min. represents minute, NaHCO3 represents sodium bicarbonate, Na2CO3 represents sodium carbonate, NEt3 represents triethylamine, NMR represents nuclear magnetic resonance, NMP represents N-methylpyrrolidone, PEG represents polyethylene glycol, q represents a quartet, quint represents a quintet, rt represents rt, R t represents retention time, s represents a singlet, sat. represents saturated, T represents temperature, t represents a triplet, td represents a doublet of triplets, THF represents THF, wt represents weight, and δ represents chemical shift.

[0102] Scheme A

Chem.

[0103] Scheme A represents the reaction of a compound represented by formula (1) with a compound represented by formula (2) to produce a compound represented by formula (Ia). The compound represented by formula (1) is such that group A1 is a hydroxyl group or an activating group discussed below, and Q, M, X1, X2, X3, X4, X5, and X6 are those desired in the final compound represented by formula (Ia) or groups that give rise to the desired Q, M, X1, X2, X3, X4, X5, and X6 in the final compound represented by formula (Ia). For example, the compound represented by formula (1) can be a compound in which the indicated group "Q" is a halogen, where the compound is further refined in a subsequent step (not shown) to produce a compound in which Q is defined in formula (Ia). Furthermore, for example, a compound in which M is O can be further refined to a compound in which M is S or a compound in which M is NR 13 and. The preparation of such compounds represented by formula (1) is readily understood in the art. The compound represented by formula (2) is such that R7, n, Y1, Y2, Z1, Z2, Z3, and Z4 are those desired in the final compound represented by formula (Ia) or groups that give rise to the desired R7, Y1, Y2, Z1, Z2, Z3, and Z4 in the final compound represented by formula (Ia). The preparation of such compounds represented by formula (2) is readily understood in the art.

[0104] As described above, Scheme A shows a reaction in which a compound represented by formula (1) is reacted with a compound represented by formula (2) to produce a compound represented by formula (Ia). Typical groups A1 are hydroxyl, or a leaving group such as chloro, bromo or imidazolyl, an activating moiety, a mixed anhydride of another carboxylic acid (e.g., formic acid, acetic acid), or the remaining portion of a symmetrical anhydride formed from two compounds represented by formula (1). For example, standard amide formation conditions can be used, such as those using a coupling agent (which includes those used in peptide coupling), such as 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU), dicyclohexylcarbodiimide (DCC) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide·HCl. Additives such as 4-(dimethylamino)pyridine, 1-hydroxybenzotriazole, etc. can be used to promote the reaction if necessary or desirable. Such reactions are generally carried out using a base (e.g., N-methylmorpholine or NEt3) in a variety of suitable solvents (e.g., CH2Cl2, DMF, NMP, DMA and THF, etc.). Such reactions are well understood in the art.

[0105] It will be understood by those skilled in the art that the compound represented by formula (Ia) can be refined in various ways to produce another compound represented by formula (Ia). Such reactions include hydrolysis, oxidation, reduction, alkylation, arylation (which includes heteroaryl groups), amidation, sulfonation, etc.

[0106] Furthermore, in some optional steps (not shown), the compound represented by formula (Ia) can be converted to a salt by methods well known and understood in the art.

[0107] Scheme B [Chemical formula]

[0108] Scheme B represents the reaction of the compound represented by formula (3) and the compound represented by formula (4) to produce the compound represented by formula (Ib). The compound represented by formula (3) is a compound in which Q, R7, X1, X2, X3, X4, X5 and X6 are those desired in the final compound represented by formula (I) or groups that give rise to the desired Q, R7, X1, X2, X3, X4, X5 and X6 in the final compound represented by formula (Ib). For example, the compound represented by formula (3) can be a compound in which the shown group "Q" is a halogen, where the compound is further refined in a subsequent step (not shown) to produce a compound in which Q is defined in formula (Ib). The preparation of such a compound represented by formula (3) is readily understood in the art. The compound represented by formula (4) is a compound in which the group A2 is a carboxy group or an activating group discussed below, and n, Y1, Y2, Z1, Z2, Z3 and Z4 are those desired in the final compound represented by formula (Ib) or groups that give rise to the desired Y1, Y2, Z1, Z2, Z3 and Z4 in the final compound represented by formula (Ib). The preparation of such a compound represented by formula (4) is readily understood in the art.

[0109] As described above, Scheme B shows a reaction in which a compound represented by formula (3) is reacted with a compound represented by formula (4) to produce a compound represented by formula (Ib). Typical groups A2 are carboxy or acid chlorides or acid bromides, or imidazides, activating moieties, mixed anhydrides of another carboxylic acid (e.g., formic acid, acetic acid), or the remaining portion of a symmetric anhydride formed from two compounds represented by formula (4) [wherein A2 is a carboxy derivative or another activating moiety]. Such reactions are generally carried out using a base (e.g., N-methylmorpholine or triethylamine) in a variety of suitable solvents (e.g., CH2Cl2, DMF, N-methylpyrrolidone (NMP), DMA, and THF, etc.). As is well known, the compound of (Ib) where M is O can be further refined to a compound where M is S or a compound where M is NR 13 and.

[0110] Scheme C

Chemical formula

[0111] Scheme C represents the reaction of a compound represented by formula (5) with a compound represented by formula (6) to produce a compound represented by formula (Ib). The compound represented by formula (5) is the same as the compound represented by formula (3) described in Scheme B. The compound represented by formula (6) is a compound in which the indicated R7 and n, Y1, Y2, Z1, Z2, Z3, and Z4 are those desired in the final compound represented by formula (Ib) or groups that give rise to the indicated R7 and Y1, Y2, Z1, Z2, Z3, and Z4 desired in the final compound represented by formula (Ib). The preparation of such compounds represented by formula (6) is readily understood in the art. The formation of unsymmetrical ureas using phosgene, carbonyldiimidazole, isopropenyl carbamate, and optionally substituted phenoxycarbonyl halides (e.g., p-nitrophenoxycarbonyl chloride, etc.) is well known.

[0112] Such reactions are generally carried out continuously by adding phosgene, carbonyldiimidazole, isopropenyl carbamate, and optionally substituted phenoxycarbonyl halides to either the compound represented by formula (5) or the compound represented by formula (6) in a variety of suitable solvents (e.g., CH2Cl2, DMF, N-methylpyrrolidone (NMP), DMA, and THF, etc.) using a base (e.g., N-methylmorpholine or triethylamine). Then, the other of compound (5) or compound (6) is added.

[0113] In Schemes B and C, it will be understood by those skilled in the art that the compound represented by formula (Ib) can be elaborated in various ways to produce another compound represented by formula (Ib). Such reactions include hydrolysis, oxidation, reduction, alkylation, arylation (which includes heteroaryl groups), amidation, sulfonation, etc. As is well known, the compound of (Ib) where M is O can be further elaborated to a compound where M is S or M is NR 13 and is a compound.

[0114] Furthermore, in optional steps (not shown), the compound represented by formula (Ib) can be converted to a salt by methods well known and understood in the art.

[0115] The following examples are intended to be illustrative and non-limiting and represent particular embodiments of the invention.

[0116] Analytical methods A and B were performed using an Agilent 1200 Infinity Series Liquid Chromatography (LC) system consisting of a 1260 HiP degasser (G4225A), a 1260 Binary Pump (G1312B), a 1290 autosampler (G4226A), a 1290 thermostat column compartment (G1316C), and a 1260 Diode Array Detector (G4212B) connected to an Agilent 6150 single quadrupole mass spectrometry (MS) detector. The injection volume was set to 1 μL by default. UV (DAD) acquisition was performed at 40 Hz with a scan range of 190 - 400 nm (5 nm steps). A 1:1 flow split was used before the MS detector. MS was operated in both positive and negative ion modes using an electrospray ionization source (ESI). The nebulizer pressure was set to 50 psi, and the temperature and flow rate of the drying gas were set to 350 °C and 12 L / min, respectively. The capillary voltage used was 4000 V in positive mode and 3500 V in negative mode. The MS acquisition range was set to 100 - 800 m / z (step size 0.2 m / z) in both polarity modes. The fragmentor voltage was set to 70 (ESI+) or 120 (ESI-), the Gain was set to 0.40 (ESI+) or 1.00 (ESI-), and the ion count threshold was set to 4000 (ESI+) or 1000 (ESI-). The overall MS scan cycle time was 0.15 seconds / cycle. Data acquisition was performed using Agilent Chemstation software.

[0117] Method A: The analysis was performed on a Phenomenex Gemini-NX C18 column with a length of 50 mm, an inner diameter of 2.1 mm, and a particle size of 3 μm. The mobile phases used were as follows: A1 = water (containing 0.1% formic acid) / B1 = CH3CN (containing 0.1% formic acid). The analysis was carried out at a temperature of 50 °C and a flow rate of 1.2 mL / min with a gradient elution from 5% to 95% (B1) over 1.5 minutes followed by a hold at 95% (B1) for 0.5 minutes.

[0118] Method B: The analysis was performed on a Waters XBridge C18 column with a length of 50 mm, an inner diameter of 2.1 mm, and a particle size of 3.5 μm. The mobile phase used was as follows: A2 = water (containing 10 mM ammonium bicarbonate; adjusted to pH 9 using ammonium hydroxide) / B2 = CH3CN. The analysis was carried out at a temperature of 50 °C and a flow rate of 1.2 mL / min with a gradient elution from 5% to 95% (B2) over 1.5 minutes followed by a hold at 95% (B2) for 0.5 minute.

[0119] Analytical methods C and D were performed using a Waters Acquity UPLC Liquid Chromatography (LC) system coupled to a Waters SQ Detector 2 single quadrupole mass spectrometry (MS) detector. UV (DAD) acquisition was performed in the scan range of 200 - 400 nm (resolution of 1.2 nm). MS was operated in both positive and negative ion modes using an electrospray ionization source (ESI). Capillary voltage 3.50 (kV), cone voltage 35 (V), and desolvation temperature 550 °C. Desolvation gas flow rate 1000 (L / hour), cone gas flow rate 50 (L / hour). The MS acquisition range was set to 100 - 1500 m / z. The MS scan cycle time was 0.5 second. Data acquisition was performed using Waters Masslynx software.

[0120] Method C: The analysis was performed on an Acquity UPLC BEH C18 column with a length of 50 mm, an inner diameter of 2.1 mm, and a particle size of 1.7 μm. The mobile phase used was as follows: A1 = water (containing 0.1% formic acid) / B1 = CH3CN (containing 0.1% formic acid). The injection volume was 0.1 μL. The analysis was carried out at a temperature of 40 °C and a flow rate of 0.6 mL / min by gradient elution. Information on the method (time (min) and B%): 0 - 5; 0.3 - 5; 2.5 - 95; 3.7 - 95; 4 - 5; 4.6 - 5.

[0121] Method D: The analysis was performed on an Acquity UPLC BEH C18 column with a length of 50 mm, an inner diameter of 2.1 mm, and a particle size of 1.7 μm. The mobile phases used were as follows: A1 = water (containing 10 mM ammonium acetate) / B1 = CH3CN (containing 0.1% formic acid). The injection volume was 0.1 μL. The analysis was carried out by gradient elution at a temperature of 45 °C and a flow rate of 0.5 mL / min. Information on the method (time (min) and A%): 0 - 98; 0.3 - 98; 3.2 - 2; 4.4 - 2; 4.7 - 98.

Example

[0122] Example 1.1 N-[8-(3,5-dichlorophenyl)-4-(dimethylamino)-3-quinolyl]-2,3-dihydro-1,4-benzoxazine-4-carboxamide

Chem.

[0123] A solution of 8-bromoquinolin-4-ol (2 g, 8.82 mmol) dissolved in propionic acid (20 mL, 265 mmol) was stirred, and thereto, nitric acid (1 mL, 16 mmol) was slowly added dropwise over 5 minutes at 100 °C. The reaction mixture was heated to 125 °C and stirred for 45 minutes. Then, the reaction mixture was cooled to room temperature, whereby the product precipitated. The solid was collected by filtration, washed with water (3 × 10 mL), iPrOH (10 mL), isooctane (10 mL), and then dried in a vacuum oven for 1 hour to obtain 8-bromo-3-nitroquinolin-4-ol.

[0124] LCMS (Method B): R t = 0.54 min, m / z = 269 [M+H] + . To a solution of 8-bromo-3-nitroquinolin-4-ol (1.52 g, 5.37 mmol) was added POCl3 (10 mL, 107 mmol). The suspension was heated to reflux and stirred for 2 hours. The reaction mixture was cooled to room temperature and allowed to stand overnight. The reaction mixture was concentrated under reduced pressure (azeotropic with toluene) to give 8-bromo-4-chloro-3-nitroquinoline. This was used directly in the next step without further purification.

[0125] To a solution of 8-bromo-4-chloro-3-nitroquinoline (2.32 g, 5.38 mmol) dissolved in THF (30 mL) was slowly added dimethylamine (2 M in THF, 7 mL, 14 mmol). The reaction was stirred at room temperature for 1.5 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 (50 mL each). Brine (50 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were concentrated under reduced pressure to give 8-bromo-N,N-dimethyl-3-nitroquinolin-4-amine.

[0126] LCMS (Method B): R t = 1.13 min, m / z = 296 [M+H] + . To a solution of 8-bromo-N,N-dimethyl-3-nitroquinolin-4-amine (505 mg, 1.62 mmol) were added (3,5-dichlorophenyl)boronic acid (314 mg, 1.61 mmol), tetrakis(triphenylphosphine)palladium(0) (92 mg, 0.08 mmol), and Na2CO3 (351 mg, 3.28 mmol). The vial was sealed and then evacuated and backfilled with N2 three times. After adding 1,4-dioxane (9 mL), water (3 mL) was added and the reaction was heated at 100 °C for 1 hour in a microwave oven. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 (both 50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 × 25 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography to give 8-(3,5-dichlorophenyl)-N,N-dimethyl-3-nitroquinolin-4-amine.

[0127] LCMS (Method B): R t = 1.57 min, m / z = 362 [M+H] + . A suspension of 8-(3,5-dichlorophenyl)-N,N-dimethyl-3-nitroquinolin-4-amine (401 mg, 1.05 mmol) in THF (5 mL), EtOH (5 mL), and water (2.5 mL) was stirred while iron (184 mg, 3.23 mmol) and NH4Cl (168 mg, 3.13 mmol) were added. The reaction was heated to 75 °C and stirred for 45 minutes. The reaction was cooled to room temperature and then partitioned between saturated aqueous NaHCO3 and EtOAc (both 25 mL). The mixture was filtered through Celite® (washed with EtOAc) and the layers of the filtrate were separated. The aqueous layer was extracted with EtOAc (2 × 25 mL) and the combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography to give 8-(3,5-dichlorophenyl)-N4,N4-dimethylquinoline-3,4-diamine.

[0128] LCMS (Method B): R t= 1.48 min, m / z = 363.2 [M+H] + . A solution of 4-nitrophenyl chloroformate (88 mg, 0.42 mmol) in THF (2 mL) was stirred, and thereto was added dropwise over 3 minutes a solution of 8-(3,5-dichlorophenyl)-N4,N4-dimethyl-quinoline-3,4-diamine (148 mg, 0.42 mmol) in THF (2.5 mL) at 0 °C under a N2 atmosphere. The reaction mixture was stirred at 0 °C for 30 minutes. The solution of the reaction mixture was used directly in the next step.

[0129] To the reaction mixture were added 3,4-dihydro-2H-1,4-benzoxazine (71 mg, 0.51 mmol) and NEt3 (132 μL, 0.94 mmol) in THF (0.5 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between saturated aqueous NaHCO3 and CH2Cl2 (both 20 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The combined organic layers were passed through Celite® and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound.

[0130] LCMS (Method B): R t = 1.62 min, m / z = 493.0 [M+H] + . 1 1H NMR (400 MHz, CDCl3) δ [ppm]: 9.95 (s, 1 H), 9.13 (s, 1 H), 7.91 (quint, J = 4.8 Hz, 1 H), 7.55 (d, J = 2 Hz, 1 H), 7.53 (d, J = 5.2 Hz, 1 H), 7.43 (dd, J = 1.6, 8.4 Hz, 1 H), 7.38 (t, J = 2 Hz, 1 H), 7.17 (m, 1 H), 7.01 (m, 2 H), 4.36 (t, J = 4.4 Hz, 2 H), 4.02 (t, J = 4.8 Hz, 2 H), 2.9 (s, 6 H). Example 2.1 8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide

Chem.

[0131] A mixture of 2-chloro-3-fluoro-pyridine-4-carboxylic acid (10.1 g, 56.3 mmol) and SOCl2 (40 mL, 547 mmol) was heated at 80 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. It was used directly in the next step: After adding toluene (145 mL) and NEt3 (9.8 mL, 70 mmol), ethyl 3-(dimethylamino)-prop-2-enoate (10.2 g, 69.6 mmol) was added. The reaction mixture was heated at 80 °C for 45 min with stirring. The mixture was cooled to room temperature and filtered through Celite® (washed with EtOAc). The filtrate was concentrated under reduced pressure, and the residue was partitioned between EtOAc and aqueous 2 M HCl (150 mL each). The layers were separated, and the aqueous layer was extracted with EtOAc (150 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give ethyl 2-(2-chloro-3-fluoro-pyridine-4-carbonyl)-3-(dimethylamino)-prop-2-enoate.

[0132] LCMS (Method B): R t = 0.86 min, m / z = 301.00 [M+H] + . To a solution of ethyl 2-(2-chloro-3-fluoro-pyridine-4-carbonyl)-3-(dimethylamino)-prop-2-enoate (188 mg, 0.59 mmol) in diethyl ether (2.4 mL) and EtOH (0.6 mL) was added 4-methoxybenzylamine (94 μL, 0.71 mmol). The reaction mixture was stirred at room temperature for 15 min to form a precipitate. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with cyclohexane to give ethyl 2-(2-chloro-3-fluoro-pyridine-4-carbonyl)-3-[(4-methoxyphenyl)methyl-amino]-prop-2-enoate.

[0133] LCMS (Method B): R t = 1.21 min, m / z = 393 [M+H] + . A solution of ethyl 2-(2-chloro-3-fluoro-pyridine-4-carbonyl)-3-[(4-methoxyphenyl)methyl-amino]-prop-2-enoate (214 mg, 518 μmol) in DMF (2.6 mL) was added with K2CO3 (230 mg, 1.66 mmol) at room temperature. The reaction mixture was heated at 40 °C for 2 hours with stirring. After cooling to room temperature, the reaction mixture was poured into ice water (20 mL) to form a fine precipitate. The precipitate was dissolved in EtOAc (20 mL), and the layer was separated. The aqueous layer was extracted with EtOAc (2 × 10 mL), the organic layers were combined, washed with water (20 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain ethyl 8-chloro-1-[(4-methoxyphenyl)methyl]-4-oxo-1,7-naphthyridine-3-carboxylate.

[0134] LCMS (Method B): R t = 1.01 min, m / z = 373 [M+H] + . (3,5-Dichlorophenyl)boronic acid (110 mg, 0.56 mmol) was mixed with 1,1'-bis(diphenylphosphino)ferrocene-Pd(II)·CH2Cl2 complex and Na2CO3 (100 mg, 0.93 mmol). The vial was sealed, then evacuated and backfilled with N2. Then, ethyl 8-chloro-1-[(4-methoxyphenyl)methyl]-4-oxo-1,7-naphthyridine-3-carboxylate (186 mg, 0.47 mmol) in 1,4-dioxane (2.4 mL, 28 mmol) was added, then water (0.8 mL) was added, and the reaction mixture was heated in a microwave oven at 100 °C for 1 hour. The reaction mixture was filtered through Celite® (washed with EtOAc). The filtrate was washed with water (20 mL), dried over anhydrous MgSO4, filtered, concentrated under reduced pressure, and then purified by column chromatography to obtain ethyl 8-(3,5-dichlorophenyl)-1-[(4-methoxyphenyl)methyl]-4-oxo-1,7-naphthyridine-3-carboxylate.

[0135] LCMS (Method B): R t = 1.30 min, m / z = 483 [M+H] + . To a solution of ethyl 8-(3,5-dichlorophenyl)-1-[(4-methoxyphenyl)methyl]-4-oxo-1,7-naphthyridine-3-carboxylate (877 mg, 1.72 mmol) dissolved in CH2Cl2 (9 mL), anisole (1 mL, 1.74 mmol) was added, then TFA (2.5 mL, 33 mmol) was added. The resulting reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. To the crude product was added a mixture of saturated aqueous NaHCO3 and EtOAc (both 25 mL), and the resulting suspension was stirred vigorously for 15 minutes. The precipitate was separated by filtration (washed with water and then with EtOAc) and dried under reduced pressure to obtain ethyl 8-(3,5-dichlorophenyl)-4-hydroxy-1,7-naphthyridine-3-carboxylate.

[0136] LCMS (Method B): R t= 0.9 min, m / z = 363 [M+H] + . A suspension of ethyl 8-(3,5-dichlorophenyl)-4-hydroxy-1,7-naphthyridine-3-carboxylate (61 mg, 0.13 mmol) in CH2Cl2 (2 mL) was stirred, and oxalyl chloride (17 μL, 192 μmol) was added thereto, followed by addition of DMF (1 μL, 13 μmol). The resulting mixture was stirred at room temperature for 45 minutes. The reaction was quenched by adding saturated aqueous NaHCO3 solution (5 mL), and the mixture was partitioned between water and CH2Cl2 (10 mL each). The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain ethyl 4-chloro-8-(3,5-dichlorophenyl)-1,7-naphthyridine-3-carboxylate.

[0137] LCMS (Method B): R t = 1.6 min, m / z = 381 [M+H] + . Ethyl 4-chloro-8-(3,5-dichlorophenyl)-1,7-naphthyridine-3-carboxylate (59 mg, 0.12 mmol) and dimethylamine·HCl (17 mg, 0.2 mmol) in 1,4-dioxane (0.5 mL) were added to a microwave vial. The vial was sealed, DIPEA (73 μL, 0.41 mmol) was added, and the reaction mixture was heated in a microwave oven at 100 °C for 30 minutes. The mixture was diluted with EtOAc (10 mL), washed with saturated aqueous NaHCO3 solution (10 mL) and brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain ethyl 8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxylate.

[0138] LCMS (Method B): R t = 1.5 min, m / z = 390 [M+H] + . A solution of ethyl 8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxylate (556 mg, 1.35 mmol) in THF (14 mL) was stirred while a solution of lithium hydroxide (99 mg, 4.05 mmol) in water (4.5 mL) and MeOH (4.5 mL) was added thereto. The reaction mixture was heated at 40 °C for 2 h and stirred at room temperature overnight. Then the mixture was concentrated under reduced pressure and the residue was taken up in water (25 mL). The aqueous layer was washed with EtOAc (25 mL) and then adjusted to pH 4 by addition of aqueous 2 M HCl, whereby a suspension was formed. The precipitate was separated by filtration and dried in a vacuum oven overnight to afford 8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxylic acid as a solid.

[0139] LCMS (method B): R t = 0.78 min, m / z = 362 [M+H] + . At room temperature and under a N2 atmosphere, sodium nitrite (309 mg, 4.48 mmol) in water (1.6 mL) was added to a solution of 3,4-dihydro-2H-1,4-benzoxazine (504 mg, 3.73 mmol) in EtOH (4 mL). Then the mixture was cooled to 0 °C. To the reaction was added dropwise concentrated HCl (0.39 mL, 4.7 mmol) at 0 °C. Then the reaction was stirred at 0 °C for 15 min.

[0140] A solution of sodium hydroxide (1.43 g, 35.87 mmol) in water (3.7 mL) was added at 0 °C, then sodium bisulfite (2.40 g, 11.75 mmol) was added. The resulting suspension was heated to 90 °C for 2 h and then cooled to room temperature.

[0141] The reactant was diluted with water (30 mL), and then extracted with toluene (30 mL) and EtOAc (15 mL). The combined organic layers were separated and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 2,3-dihydro-1,4-benzoxazin-4-amine as a pale yellow oil (354 mg).

[0142] LCMS (Method B) R t = 0.63 min, m / z = 151 [M+H] + . A suspension of 8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxylic acid (158 mg, 0.41 mmol) in DMF (5 mL) was stirred while NEt3 (0.25 mL, 1.8 mmol) was added thereto, and then 2,3-dihydro-1,4-benzoxazin-4-amine (79 mg, 0.501 mmol) and PyBOP (341 mg, 0.64 mmol) were added. The reaction mixture was stirred at room temperature under nitrogen for 48 h. The reaction mixture was washed with brine (25 mL) and extracted with CH2Cl2 (3 × 15 mL). The combined organic layers were separated and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound.

[0143] LCMS (Method B) R t = 1.35 min, m / z = 494 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.7 (s, 1 H), 8.90 (s, 1 H), 8.67 (d, J = 4.4 Hz, 1 H), 8.1 (m, 2 H), 7.75 (t, J = 2 Hz, 1 H), 7.03 (dd, J = 8, 1.2 Hz, 1 H), 6.85 (td, J = 2, 8 Hz, 1 H), 6.69 - 6.78 (m, 2 H), 4.38 (t, J = 4.4 Hz, 2 H), 3.68 (s, 2 H), 3.13 (s, 6 H). The following compounds were prepared in the same manner by the method of Example 2.1.

Table 1

[0144] Example 3.1 8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxamide

Chem.

[0145] Thionyl chloride (15 mL, 205 mmol) was added to 3,4-dichloropyridine-2-carboxylic acid (3.96 g, 20.6 mmol), and the reaction mixture was heated to 80 °C for 1 hour. The reaction was cooled to room temperature and concentrated under reduced pressure to give 3,4-dichloropyridine-2-carbonyl chloride. This was used in the next step without further purification.

[0146] A solution of 3,4-dichloropyridine-2-carbonyl chloride (20.6 mmol, 4.76 g) in toluene (50 mL) was stirred while NEt3 (3.5 mL, 25 mmol) was added, followed by ethyl 3-(dimethylamino)prop-2-enoate (3.6 mL, 25 mmol). The reaction was stirred at room temperature overnight. The reaction was filtered through Celite® (washed with EtOAc). The filtrate was concentrated under reduced pressure, and the residue was partitioned between EtOAc and aqueous 1 M HCl (both 100 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were concentrated under reduced pressure to give ethyl 2-(3,4-dichloropyridine-2-carbonyl)-3-(dimethylamino)prop-2-enoate.

[0147] LCMS (Method B) R t = 0.88 min, m / z = 317.0 [M+H] + . A solution of ethyl 2-(3,4-dichloropyridine-2-carbonyl)-3-(dimethylamino)prop-2-enoate (5.58 g, 12.7 mmol) in diethyl ether (50 mL) and EtOH (12 mL) was stirred, and 4-methoxybenzylamine (1.9 mL, 14 mmol) was added thereto. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain ethyl 2-(3,4-dichloropyridine-2-carbonyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate.

[0148] Ethyl 2-(3,4-dichloropyridine-2-carbonyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate (5.92 g, 9.40 mmol) was dissolved in DMF (24 mL). K2CO3 (4.0 g, 28.9 mmol) was added, and the mixture was stirred at 90 °C for 6 hours. The reaction mixture was cooled to room temperature, quenched by adding water (250 mL), and diluted with CH2Cl2 (100 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The organic layers were combined, filtered through Celite®, then washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The crude material was purified by chromatography (0 - 6% MeOH in CH2Cl2) to obtain ethyl 8-hydroxy-1-[(4-methoxyphenyl)methyl]-4-oxo-1,5-naphthyridine-3-carboxylate.

[0149] Ethyl 8-hydroxy-1-[(4-methoxyphenyl)methyl]-4-oxo-1,5-naphthyridine-3-carboxylate (840 mg, 1.09 mmol) was dissolved in CH2Cl2 (11 mL) and DMF (0.05 mL). Oxalyl chloride (0.48 mL, 5.5 mmol) was added to this mixture, and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled and quenched by adding saturated aqueous NaHCO3 (50 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 25 mL). The combined organic layers were concentrated under reduced pressure to give ethyl 4,8-dichloro-1,5-naphthyridine-3-carboxylate.

[0150] Ethyl 4,8-dichloro-1,5-naphthyridine-3-carboxylate (950 mg, 2.21 mmol) was dissolved in THF (5 mL). Dimethylamine (2 mol / L) in THF (1.1 mL, 2.2 mmol, 2 M) was added dropwise to this solution, and the mixture was stirred at room temperature for 30 minutes. The crude reaction mixture was concentrated, and the residue was purified by column chromatography (20 - 50% EtOAc in cyclohexane) to give ethyl 8-chloro-4-(dimethylamino)-1,5-naphthyridine-3-carboxylate.

[0151] LCMS (Method B) R t = 1.07 min, m / z = 280.0 [M+H] + . Ethyl 8-chloro-4-(dimethylamino)-1,5-naphthyridine-3-carboxylate (315 mg, 0.93 mmol) was dissolved in 1,4-dioxane (3 mL) and water (1 mL). To this mixture, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (40 mg, 0.048 mmol) was added, and (3,5-dichlorophenyl)boronic acid (215 mg, 1.13 mmol) and Na2CO3 (300 mg, 2.83 mmol) were added. The mixture was subjected to microwave irradiation at 100 °C for 1 hour. The crude reaction mixture was concentrated, and the residue was purified by column chromatography (5 - 40% EtOAc in cyclohexane) to give ethyl 8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxylate.

[0152] LCMS (Method B) R t = 1.56 min, m / z = 390.0 [M+H] + . A solution of ethyl 8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxylate (272 mg, 0.65 mmol) in 1,4-dioxane (2 mL) was stirred while lithium hydroxide (32 mg, 1.34 mmol) in water (2 mL) was added thereto. The reaction was heated at 100 °C overnight. Then, the reaction mixture was cooled to room temperature. The reaction mixture was quenched by adding water (50 mL) and EtOAc (50 mL). The pH was adjusted to pH = 4 using 2M HCl. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxylic acid.

[0153] LCMS (Method B) R t = 0.82 min, m / z = 362.0 [M+H] + . A mixture of 2,3-dihydro-1,4-benzoxazin-4-amine (0.115 g, 0.73 mmol) and PyBOP (0.63 g, 1.21 mmol) was placed under a N2 atmosphere and treated with a solution of 8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxylic acid (0.24 g, 0.67 mmol) dissolved in THF (3 mL), and then treated with NEt3 (0.42 mL, 3 mmol). The resulting reaction mixture was stirred at room temperature for 48 h. The reaction mixture was quenched by adding saturated aqueous NaHCO3 (100 mL) and diluted with CH2Cl2 (50 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 × 25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The crude product was purified by column chromatography (10 - 50% in cyclohexane) to give the title compound.

[0154] LCMS (Method B) R t = 1.39 min, m / z = 494.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ [ppm]: 9.62 (s, 1 H), 9.24 (s, 1 H), 8.96 (d, J = 4.4 Hz, 1 H), 7.59 (m, 3 H), 7.47 (t, J = 2 Hz, 1 H), 6.79 - 6.95 (m, 4 H), 4.50 (t, J = 4.4 Hz, 2 H), 3.74 (t, J = 4.8 Hz, 2 H), 3.35 (s, 6 H). The following compounds were prepared in the same manner by the method of Example 3.1.

Table 2

[0155] Example 4.1 5-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-1-(dimethylamino)naphthalene-2-carboxamide

Chem.

[0156] A round-bottom flask containing a mixture of 1-bromo-5-nitro-naphthalene (1.04 g, 4.13 mmol), (3,5-dichlorophenyl)boronic acid (0.7 g, 3.6 mmol), Na2CO3 (0.86 g, 8.10 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (156 mg, 0.20 mmol) was evacuated and refilled with N2 three times. The reaction mixture was treated with 1,4-dioxane (20 mL) and degassed water (6 mL), heated to 80 °C, and stirred for 45 minutes. Then, the mixture was cooled to room temperature, diluted with water (40 mL), and extracted with CH2Cl2 (3 × 30 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography, and the appropriate fractions were combined and concentrated under reduced pressure to obtain 1-(3,5-dichlorophenyl)-5-nitro-naphthalene.

[0157] A mixture of 1-(3,5-dichlorophenyl)-5-nitro-naphthalene (928 mg, 2.77 mmol), NH4Cl (0.47 g, 8.72 mmol), and iron (0.47 g, 8.28 mmol) was placed under a N2 atmosphere and then treated with THF (14 mL), EtOH (14 mL), and water (7 mL). The resulting mixture was heated to 75 °C and stirred for 45 minutes. Then, the mixture was cooled to room temperature and filtered through Celite® (washed with CH2Cl2). The filtrate was concentrated under reduced pressure, treated with saturated aqueous NaHCO3 (50 mL), and extracted with CH2Cl2 (3 × 25 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain 5-(3,5-dichlorophenyl)naphthalen-1-amine.

[0158] LCMS (Method B) R t = 1.49 min, m / z = 288.0 [M+H] + . A solution of 5-(3,5-dichlorophenyl)naphthalen-1-amine (881 mg, 2.60 mmol) dissolved in DMF (10 mL) was placed under a N2 atmosphere, cooled to approximately -5 °C on an ice / salt bath, and treated with N-bromosuccinimide (474 mg, 2.58 mmol). Subsequently, the resulting reaction mixture was treated with saturated aqueous NaHCO3 solution (50 mL), forming a light brown precipitate. The mixture was extracted with CH2Cl2 (3 × 30 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography to obtain 2-bromo-5-(3,5-dichlorophenyl)naphthalen-1-amine.

[0159] LCMS (Method B) R t = 1.64 min, m / z = 365.8 [M+H] + . A suspension of 2-bromo-5-(3,5-dichlorophenyl)naphthalen-1-amine (0.73 g, 1.79 mmol) suspended in formic acid (6 mL, 160 mmol) was placed under a N2 atmosphere and treated with formaldehyde solution (37 wt% in water; 110 mmol, 8 mL). The resulting suspension was heated to 100 °C and stirred for 1 hour. After cooling the reaction mixture to room temperature, it was quenched by carefully adding saturated aqueous NaHCO3 (60 mL). Subsequently, the mixture was extracted with CH2Cl2 (3 × 20 mL), the combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 2-bromo-5-(3,5-dichlorophenyl)-N,N-dimethyl-naphthalen-1-amine.

[0160] LCMS (Method B) R t = 1.93 min, m / z = 393.8 [M+H] + . A solution of 2-bromo-5-(3,5-dichlorophenyl)-N,N-dimethylnaphthalene-1-amine (532 mg, 1.28 mmol) in 1,4-dioxane (10 mL) in a pressure vessel was treated with MeOH (10 mL), NEt3 (0.54 mL, 3.9 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (103 mg, 134 μmol), and then stirred at 100 °C for 16 h under a CO atmosphere (50 psi). The reaction mixture was then cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give methyl 5-(3,5-dichlorophenyl)-1-(dimethylamino)naphthalene-2-carboxylate.

[0161] LCMS (method B) R t = 1.75 min, m / z = 374.0 [M+H] + . A solution of methyl 5-(3,5-dichlorophenyl)-1-(dimethylamino)naphthalene-2-carboxylate (421 mg, 1.01 mmol) in 1,4-dioxane (15 mL), water (5 mL) and lithium hydroxide (512 mg, 20.3 mmol) was stirred at 80 °C for 48 h. After the reaction mixture was cooled to room temperature, it was treated with 2M HCl (17.5 mL - to make the mixture weakly basic). The aqueous layer was extracted with CH2Cl2 (3 × 25 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 5-(3,5-dichlorophenyl)-1-(dimethylamino)naphthalene-2-carboxylic acid.

[0162] LCMS (method B) R t = 1.10 min, m / z = 358.0 [M-H] - . A mixture of 2,3-dihydro-1,4-benzoxazin-4-amine (0.082 g, 519 μmol) and PyBOP (452 mg, 869 μmol) was placed under a N2 atmosphere and treated with a solution of 5-(3,5-dichlorophenyl)-1-(dimethylamino)naphthalene-2-carboxylic acid (192 mg, 426 μmol) dissolved in THF (3 mL), and then treated with NEt3 (0.30 mL, 2.2 mmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (15 mL) and extracted with CH2Cl2 (3 × 15 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound.

[0163] LCMS (Method B) R t = 1.61 min, m / z = 492.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ [ppm]: 10.5 (s, 1 H), 8.36 (d, J = 8.6 Hz, 1 H), 7.75 (t, J = 2 Hz, 1 H), 7.64 - 7.68 (m, 1 H), 7.60 - 7.48 (m, 5 H), 6.98 (dd, J = 8, 1.4 Hz, 1 H), 6.86 - 6.80 (m, 1 H), 6.77 (dd, J = 8, 1.6 Hz, 1 H), 6.73 - 6.67 (m, 1 H), 4.38 (t, J = 4.3 Hz, 2 H), 3.70 - 3.63 (m, 2 H), 2.99 (s, 6 H). Example 5.1 8-(3,5-dichlorophenyl)-N-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-4-(dimethylamino)quinoline-3-carboxamide

Chemical formula

[0164] A solution of 2-bromoaniline (7.96 g, 44.9 mmol) and diethyl 2-(ethoxymethylene)propanedioate (11 mL, 53.8 mmol) was heated to 125 °C for 1 hour.

[0165] LCMS (Method B) R t = 1.28 min, m / z = 342.0 [M+H] + Diphenyl ether (100 mL) was added, and the reaction mixture was heated to 250 °C and stirred for 48 h. The reaction mixture was cooled to room temperature to form a precipitate. Diethyl ether (100 mL) was added, and the precipitate was separated by filtration (washing with diethyl ether) and dried under reduced pressure to obtain ethyl 8-bromo-4-hydroxyquinoline-3-carboxylate.

[0166] LCMS (Method B) R t = 0.69, m / z = 296.0 [M+H] + . A suspension of ethyl 8-bromo-4-hydroxyquinoline-3-carboxylate (2.0 g, 6.42 mmol) in CH2Cl2 (20 mL) was placed under a N2 atmosphere and treated with oxalyl chloride (0.60 mL, 6.8 mmol) and DMF (0.02 mL). The reaction mixture was warmed to 50 °C and stirred for 45 min. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to obtain ethyl 8-bromo-4-chloroquinoline-3-carboxylate.

[0167] LCMS (Method B) R t = 1.28 min, m / z = 314.0 [M+H] + . Dimethylamine (2 M) in THF (13 mL) was added to ethyl 8-bromo-4-chloroquinoline-3-carboxylate (2.13 g, 6.42 mmol) under a N2 atmosphere. The resulting mixture was warmed to 60 °C and stirred for 15 min. After the reaction mixture was concentrated under reduced pressure, it was treated with saturated aqueous NaHCO3 (40 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was subjected to column chromatography (20-60% EtOAc in cyclohexane) to obtain ethyl 8-bromo-4-(dimethylamino)quinoline-3-carboxylate.

[0168] LCMS (Method B) R t = 1.23 min, m / z = 323.0 [M+H] + . Under a nitrogen atmosphere, a reaction mixture of ethyl 8-bromo-4-(dimethylamino)quinoline-3-carboxylate (2.22 g, 6.54 mmol), (3,5-dichlorophenyl)boronic acid (1.26 g, 6.61 mmol), bis(diphenylphosphino)ferrocene-Pd(II)·CH2Cl2 complex (0.27 g, 0.33 mmol), and Na2CO3 (1.43 g, 13.5 mmol) in 1,4-dioxane (20 mL) and water (10 mL) was heated to 80 °C and stirred for 30 minutes. After cooling the reaction mixture to room temperature, it was diluted with water (70 mL) and extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were filtered and concentrated under reduced pressure. The residue was purified by column chromatography (0 - 30% EtOAc in cyclohexane) to obtain ethyl 8-(3,5-dichlorophenyl)-4-(dimethylamino)quinoline-3-carboxylate.

[0169] LCMS (Method B) R t = 1.67 min, m / z = 389.0 [M+H] + . A solution of ethyl 8-(3,5-dichlorophenyl)-4-(dimethylamino)quinoline-3-carboxylate (2.82 g, 6.17 mmol) dissolved in 1,4-dioxane (20 mL) was treated with water (10 mL) and lithium hydroxide (0.44 g, 18.5 mmol). The resulting reaction mixture was heated to 100 °C and stirred overnight. The reaction mixture was cooled to room temperature and then acidified with 2M HCl to pH 2 and extracted with EtOAc (3 × 30 mL). The aqueous phase was basified to pH 6 and extracted with 10% MeOH in CH2Cl2 (3 × 30 mL). The combined organic phases were concentrated under reduced pressure to obtain 8-(3,5-dichlorophenyl)-4-(dimethylamino)quinoline-3-carboxylic acid.

[0170] LCMS (Method B) R t= 0.94 min, m / z = 361.0 [M+H] + . A suspension of 8-(3,5-dichlorophenyl)-4-(dimethylamino)quinoline-3-carboxylic acid (160 mg, 0.35 mmol) in DMF (3.5 mL) was stirred while adding NEt3 (200 μL, 1.42 mmol) thereto, and then 2,3-dihydro-1,4-benzoxazin-4-amine (67 mg, 0.42 mmol) and PyBOP (282 mg, 0.53 mmol) were added. The reaction mixture was stirred overnight at room temperature under a N2 atmosphere. The reaction mixture was diluted with brine and extracted twice with CH2Cl2. The crude product was purified by column chromatography eluting with cyclohexane:EtOAc (0 - 40% EtOAc) to obtain the title compound.

[0171] LCMS (Method B) R t = 1.47 min, m / z = 493.0 [M+H] + . 1 H NMR (400 MHz, DMSO) δ [ppm]: 9.04 (s, 1 H), 8.4 (s, 1 H), 8.20 (dd, J = 1.6 Hz, J = 8.8 Hz, 1 H), 7.69 - 7.71 (m, 1 H), 7.58 - 7.62 (m, 1 H), 7.52 (d, J = 2 Hz, 2 H), 7.4 (t, J = 1.6 Hz, 1 H), 6.79 - 6.97 (m, 4 H), 4.49 (t, J = 4.4 Hz, 2 H), 3.74 (t, J = 4.4 Hz, 2 H), 3.19 (s, 6 H). The following compounds were prepared in the same manner by the method of Example 5.1.

Table 3

[0172] Example 6.1 4-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-morpholino-pyrido[3,2-d]pyrimidine-7-carboxamide [Chem.]

[0173] Ethyl 6-hydroxypyrimidine-4-carboxylate (5.03 g, 28.74 mmol) was suspended in DMF (25 mL), and 1,3-dichloro-5,5-dimethylhydantoin (3.48 g, 17.3 mmol) was added thereto under a N2 atmosphere. The mixture was stirred at room temperature overnight. The reaction mixture was partitioned between water (200 mL) and EtOAc (100 mL), and then extracted with EtOAc (2 × 75 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain ethyl 5-chloro-6-hydroxy-pyrimidine-4-carboxylate.

[0174] LCMS (Method A) R t= 0.54 min, m / z = 203.0 [M+H] + . A suspension of ethyl 5-chloro-6-hydroxy-pyrimidine-4-carboxylate (8.74 g, 28.1 mmol) in CH3CN (100 mL) was added with DIPEA (6.4 mL, 36 mmol) at room temperature under N2 atmosphere, and then phosphorus oxychloride (9.44 g, 31.28 mmol) was added. The resulting mixture was stirred at room temperature. The reaction was diluted with CH2Cl2 (100 mL) and slowly poured into water (100 mL). Then the mixture was extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The oil was purified by column chromatography (0 - 10% EtOAc in cyclohexane) to obtain ethyl 6-bromo-5-chloro-pyrimidine-4-carboxylate.

[0175] LCMS (Method A) R t = 0.98 min, m / z = 265.0 [M+H] + . A solution of ethyl 6-bromo-5-chloro-pyrimidine-4-carboxylate (4.31 g, 14.9 mmol) and (3,5-dichlorophenyl)boronic acid (2.71 g, 14.20 mmol) in 1,4-dioxane (55 mL) was stirred while adding K2CO3 (8.69 g, 62.9 mmol) under N2 atmosphere, and then tetrakis(triphenylphosphine)palladium(0) (732 mg, 0.63 mmol) was added. The reaction was degassed and placed under N2 atmosphere, and then heated at 90 °C for 16 h. The mixture was diluted with EtOAc (50 mL) and passed through Celite®. The combined organic filtrates were concentrated under reduced pressure. The residue was purified by column chromatography (0 - 20% EtOAc in cyclohexane) to obtain ethyl 5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carboxylate.

[0176] LCMS (Method B) R t = 1.43 min, m / z = 331.0 [M+H]+ . To a mixture of ethyl 5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carboxylate (2.90 g, 8.75 mmol) in THF (85 mL) and water (30 mL), lithium hydroxide (624 mg, 25.6 mmol) was added at room temperature under a N2 atmosphere. The resulting mixture was heated to 50 °C for 1 h. The reaction was cooled to room temperature and then concentrated under reduced pressure to remove THF. The resulting solution was diluted with water (50 mL) and then acidified to pH = 1 using 2 M HCl to precipitate a solid. The precipitate was filtered off and washed with water (25 mL). The precipitate was then dried under reduced pressure at 50 °C to obtain 5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carboxylic acid.

[0177] LCMS (Method B) R t = 0.72 min, m / z = 303.0 [M+H] + . A suspension of 5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carboxylic acid (2.49 g, 7.82 mmol) in thionyl chloride (30 mL, 411 mmol) was heated to 80 °C under a N2 atmosphere. DMF (0.5 mL, 6 mmol) was added and the reaction was completely dissolved. The reaction was then concentrated under reduced pressure and placed in toluene (20 mL) and azeotroped (3 times) to obtain 5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carbonyl chloride. This was used without further purification.

[0178] A solution of 5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carbonyl chloride (2.65 g, 7.82 mmol) in toluene (20 mL) was added with NEt3 (2 mL, 14 mmol) at room temperature under a N2 atmosphere, and then ethyl 3-(dimethylamino)prop-2-enoate (1.4 mL, 9.7 mmol) was added. The reaction mixture was stirred at room temperature under a N2 atmosphere. The reaction mixture was diluted with EtOAc (125 mL) and filtered through Celite®. The Celite® was washed with EtOAc (125 mL). The combined organic filtrates were concentrated under reduced pressure. The residue was taken up in EtOAc (250 mL) and 2 M HCl (aqueous, 100 mL). The aqueous layer was extracted with EtOAc (125 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain ethyl 2-[5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carbonyl]-3-(dimethylamino)prop-2-enoate.

[0179] LCMS (Method B) R t = 1.24 min, m / z = 428.0 [M+H] + . A solution of ethyl 2-[5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carbonyl]-3-(dimethylamino)prop-2-enoate (3.59 g, 6.29 mmol) in diethyl ether (25 mL) and EtOH (6 mL) was added with 4-methoxybenzylamine (1.20 mL, 9.09 mmol) over 1 h at room temperature under a N2 atmosphere. The reaction mixture was diluted with water (150 mL) and extracted with CH2Cl2 (4 × 75 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain ethyl 2-[5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carbonyl]-3-[(4-methoxyphenyl)methylamino]prop-2-enoate. This material was used without further purification.

[0180] LCMS (Method B) R t = 1.49 min, m / z = 520.0 [M+H]+ . Ethyl 2-[5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carbonyl]-3-[(4-methoxyphenyl)methylamino]prop-2-enoate (4.4 g, 5.66 mmol) was dissolved in DMF (15 mL), and K2CO3 (2.37 g, 17.1 mmol) was added thereto at room temperature under a N2 atmosphere. The resulting mixture was heated to 90 °C for 24 hours. The reaction was cooled to room temperature and then poured into water (300 mL) and extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-5% MeOH in CH2Cl2) to obtain ethyl 4-(3,5-dichlorophenyl)-5-[(4-methoxyphenyl)methyl]-8-oxo-pyrido[3,2-d]pyrimidine-7-carboxylate.

[0181] LCMS (Method B) R t = 1.17 min, m / z = 484.0 [M+H] + . Ethyl 4-(3,5-dichlorophenyl)-5-[(4-methoxyphenyl)methyl]-8-oxo-pyrido[3,2-d]pyrimidine-7-carboxylate (1.89 g, 3.70 mmol) was dissolved in CH2Cl2 (75 mL) and DMF (0.5 mL), and oxalyl chloride (2 mL, 23.1 mmol) was slowly added thereto at room temperature under a N2 atmosphere. The reaction was heated to reflux at 60 °C for 1 hour. The mixture was cooled to room temperature and then quenched by adding saturated aqueous NaHCO3 solution (200 mL) and extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were then concentrated under reduced pressure to obtain ethyl 8-chloro-4-(3,5-dichlorophenyl)pyrido[3,2-d]pyrimidine-7-carboxylate.

[0182] LCMS (Method B) R t = 1.52 min, m / z = 382.0 [M+H] + . A solution of ethyl 8-chloro-4-(3,5-dichlorophenyl)pyrido[3,2-d]pyrimidine-7-carboxylate (502 mg, 0.93 mmol) in THF (10 mL, 123 mmol) was added dropwise with morpholine (0.17 mL, 1.9 mmol) at room temperature under a N2 atmosphere. The reaction mixture was stirred at room temperature for 3 hours. Then the reaction was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with CH2Cl2 (3 × 25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (10 - 25% EtOAc in cyclohexane) to give ethyl 4-(3,5-dichlorophenyl)-8-morpholino-pyrido[3,2-d]pyrimidine-7-carboxylate.

[0183] LCMS (Method B) R t = 1.56 min, m / z = 433.0 [M+H] + . To a mixture of ethyl 4-(3,5-dichlorophenyl)-8-morpholino-pyrido[3,2-d]pyrimidine-7-carboxylate (337.5 mg, 0.717 mmol) in 1,4-dioxane (15 mL) and water (5 mL) was added lithium hydroxide (61.6 mg, 2.52 mmol) at room temperature under a N2 atmosphere. The resulting mixture was heated to 80 °C. The reaction was concentrated under reduced pressure, and the residue was taken up in water (20 mL) and acidified with 2M HCl. The resulting precipitate was filtered off, washed with water (20 mL), and then dried under reduced pressure at 45 °C overnight to give 4-(3,5-dichlorophenyl)-8-morpholino-pyrido[3,2-d]pyrimidine-7-carboxylic acid.

[0184] LCMS (Method B) R t = 0.80 min, m / z = 405.0 [M+H] + . A suspension of 4-(3,5-dichlorophenyl)-8-morpholino-pyrido[3,2-d]pyrimidine-7-carboxylic acid (125.1 mg, 0.31 mmol) in THF (3 mL) was added with NEt3 (0.18 mL, 1.3 mmol), and then PyBOP (259 mg, 0.49 mmol) was added. The reaction mixture was stirred at room temperature under a N2 atmosphere. Then, 2,3-dihydro-1,4-benzoxazin-4-amine (60.5 mg, 0.40 mmol) in THF (1 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 22 h. The mixture was diluted with brine (25 mL) and extracted with CH2Cl2 (3 × 15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (5-40% EtOAc in cyclohexane) to obtain the title compound.

[0185] LCMS (Method B) R t = 1.38 min, m / z = 537.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.75 (s, 1 H), 9.38 (s, 1 H), 8.92 (s, 1 H), 8.31 (d, J = 2 Hz, 2 H), 7.87 (t, J = 2 Hz, 1 H), 7.01 (dd, J = 1.2, 8 Hz, 1 H), 6.85 (td, J = 1.6, 8.4 Hz, 1 H), 6.69 - 6.78 (m, 2 H), 4.38 (t, J = 4.4 Hz, 2 H), 3.86 (t, J = 4 Hz, 4 H), 3.63 - 3.73 (m, 6 H). Example 7.1 8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,6-naphthyridine-3-carboxamide

Chemical Structure

[0186] A solution of 3,4-dihydro-2H-1,4-benzoxazine dissolved in EtOH (8 mL) was stirred while sodium nitrite (612 mg, 8.87 mmol) in water (3.2 mL) was added dropwise thereto at 0 °C. After 5 minutes had elapsed, HCl (0.8 mL) was added dropwise, and the reaction mixture was stirred at 0 °C for 2 hours. To the reaction mixture, NaOH (2.96 g, 74 mmol) in water (7.5 mL) was added dropwise, and then sodium dithionite (4.4 g, 22.2 mmol) was added at 0 °C. The resulting reaction mixture was heated to 90 °C for 4 hours. The reaction mixture was dissolved in EtOAc (20 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dehydrated over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography eluting with 0 - 50% EtOAc in petroleum ether.

[0187] LCMS (Method C) R t = 0.89 min, m / z = 152.36 [M+H] + . A mixture of 3-bromopyridin-4-amine (10.0 g, 57.8 mmol) and diethyl 2-(ethoxymethylene)propanedioate (32.8 mL, 173 mmol) was heated to 120 °C for 16 hours. The reaction mixture was brought to room temperature and concentrated to dryness under reduced pressure, and purified by column chromatography eluting with 0 - 50% EtOAc in petroleum ether to obtain diethyl 2-[[(3-bromo-4-pyridyl)amino]methylene]propanedioate.

[0188] LCMS (Method C) R t = 1.71 min, m / z = 343.19 [M+H]+. A solution of ethyl 2-[[(3-bromo-4-pyridyl)amino]methylene]propanedioate (2.8 g, 8.12 mmol) in diphenyl ether (42 mL) was heated to 250 °C for 30 minutes. The reaction mixture was cooled to room temperature and petroleum ether (50 mL) was added. The resulting solid compound was filtered, washed with petroleum ether (50 mL), and dried under reduced pressure to obtain ethyl 8-bromo-4-hydroxy-1,6-naphthyridine-3-carboxylate.

[0189] LCMS (Method C) R t = 1.16 min, m / z = 297.11 [M+H]+. Ethyl 8-bromo-4-hydroxy-1,6-naphthyridine-3-carboxylate (4.3 g, 14.5 mmol) was added to POCl3 (43 mL), and the mixture was heated to 90 °C for 6 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (3 × 30 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with 0-20% EtOAc in petroleum ether.

[0190] LCMS (Method C) R t = 2.30 min, m / z = 315.09 [M+H]+. A solution of ethyl 8-bromo-4-chloro-1,6-naphthyridine-3-carboxylate (3 g, 9.5 mmol) in THF (60 mL) was stirred, and morpholine (4.1 g, 47.5 mmol) was added thereto at room temperature. The mixture was stirred for 30 minutes. The reaction mixture was concentrated to dryness under reduced pressure. The crude product was purified by column chromatography eluting with 0-50% EtOAc in petroleum ether to obtain ethyl 8-bromo-4-morpholino-1,6-naphthyridine-3-carboxylate.

[0191] LCMS (Method C) R t = 1.65 min, m / z = 366.24 [M+H]+. A solution of ethyl 8-bromo-4-morpholino-1,6-naphthyridine-3-carboxylate (0.8 g, 2.18 mmol) and (3,5-dichlorophenyl)boronic acid (1.04 g, 5.46 mmol) in 1,4-dioxane / water (16 / 4 mL) was stirred, to which Cs2CO3 (2.13 g, 6.55 mmol) was added, then tetrafluoroborate of tri-tert-butylphosphonium (0.127 g, 0.43 mmol) was added, and the mixture was degassed under N2 for 10 minutes. PdCl2(dppf) (0.16 g, 0.21 mmol) was added to the reaction mixture, and the mixture was heated at 90 °C for 16 hours. The reaction mixture was dissolved in EtOAc (30 mL) and washed with water (15 mL) and brine (10 mL). The organic layer was dehydrated with anhydrous Na2SO4 and concentrated to dryness. The crude product was purified by column chromatography eluting with 0 - 50% EtOAc in petroleum ether.

[0192] LCMS (Method C) R t = 2.33 min, m / z = 432.30 [M+H] + . A solution of ethyl 8-(3,5-dichlorophenyl)-4-morpholino-1,6-naphthyridine-3-carboxylate (0.55 g, 1.27 mmol) in EtOH:THF:water (1:1:1, 9 mL) was stirred, to which LiOH.H2O (0.16 g, 3.81 mmol) was added at room temperature, and the mixture was heated at 70 °C for 4 hours. The reaction mixture was cooled to room temperature and then concentrated to remove the solvent. Under cooling conditions (0 °C), the pH was adjusted to 6 - 7 using 0.5 M aqueous HCl, and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were dehydrated with anhydrous Na2SO4 and concentrated to dryness.

[0193] LCMS (Method C) R t = 2.15 min, m / z = 403.9 [M+H] + . A solution of 8-(3,5-dichlorophenyl)-4-morpholino-1,6-naphthyridine-3-carboxylic acid (0.3 g, 0.74 mmol) and 2,3-dihydro-1,4-benzoxazin-4-amine (134 mg, 0.89 mmol) in DMF (5 mL) was stirred, and thereto were added HATU (0.34 g, 0.89 mmol) and DIPEA (0.38 g, 2.2 mmol) at room temperature. The resulting reaction mixture was heated to 60 °C for 16 h. The reaction mixture was quenched by adding water (5 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with 0 - 100% EtOAc in petroleum ether to give the title compound.

[0194] LCMS (Method D) R t = 2.12 min, m / z = 536.24 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.75 (s, 1 H), 9.03 (s, 1 H), 8.84 (s, 1 H), 7.77 (d, J = 2 Hz, 2 H), 7.72 (t, J = 2 Hz, 1 H), 7.03 (m, 1 H), 6.85 (td, J = 2, 7.2 Hz, 1 H), 6.72 - 6.78 (m, 2 H), 4.38 (t, J = 4.4 Hz, 2 H), 3.92 (t, J = 3.6 Hz, 4 H), 3.69 (br s, 2 H), 3.39 (t, J = 4 Hz, 4 H). Example 8.1 N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-methyl-4-morpholino-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide

Chemical Structure

[0195] A solution of 8-bromo-1H-3,1-benzoxazine-2,4-dione (0.8 g, 3.3 mmol) and ethyl 3-oxobutanoate (0.86 g, 6.61 mmol) in DMA (5 mL) was stirred while NaOH (0.132 g, 3.3 mmol) was added thereto. The resulting reaction mixture was stirred at 100 °C for 12 hours. The mixture was quenched by adding water (200 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with n-pentane (30 mL) to obtain ethyl 8-bromo-4-hydroxy-2-methyl-quinoline-3-carboxylate.

[0196] LCMS (Method C) R t = 1.54 min, m / z = 310.22 [M+H] + . A solution of ethyl 8-bromo-4-hydroxy-2-methyl-quinoline-3-carboxylate (0.3 g, 0.96 mmol) in EtOH (5 mL) was stirred while KOH (0.814 g, 14.5 mmol) was added thereto at room temperature, and the mixture was heated to 80 °C for 24 hours. The reaction mixture was brought to room temperature and concentrated. The pH of the residue was adjusted to 1-2 using 2N aqueous HCl, and the precipitated solid was filtered, washed with water (10 mL), and dried to obtain 8-bromo-4-hydroxy-2-methyl-quinoline-3-carboxylic acid.

[0197] LCMS (Method C) R t = 1.46 min, m / z = 280.05 [M-H] - . A mixture of 8-bromo-4-hydroxy-2-methyl-quinoline-3-carboxylic acid (0.2 g, 0.7 mmol) and POCl3 (10 mL) was heated at 90 °C for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain 8-bromo-4-chloro-2-methyl-quinoline-3-carbonyl chloride.

[0198] A solution of 2,3-dihydro-1,4-benzoxazin-4-amine (0.188 g, 1.25 mmol) dissolved in THF (3 mL) was stirred while adding DIPEA (0.342 g, 2.5 mmol) thereto, and the mixture was cooled to 0 - 5 °C. To the reaction mixture, a solution of 8-bromo-4-chloro-2-methyl-quinoline-3-carbonyl chloride (0.2 g, 0.62 mmol) dissolved in 2 mL of THF was added, and the mixture was stirred at room temperature. The reaction mixture was quenched by adding water (100 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by column chromatography to obtain 8-bromo-4-chloro-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-methyl-quinoline-3-carboxamide.

[0199] LCMS (Method C) Rt = 2.12 min, m / z = 432.06 [M+H] + . A solution of 8-bromo-4-chloro-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-methyl-quinoline-3-carboxamide (0.25 g, 0.57 mmol) and morpholine (0.5 g, 5.77 mmol) dissolved in THF (5 mL) was stirred while adding Et3N (0.116 g, 1.15 mmol) thereto. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by adding water (100 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether (30 mL) to obtain 8-bromo-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-methyl-4-morpholino-quinoline-3-carboxamide.

[0200] LCMS (Method C) Rt = 2.25 min, m / z = 483.49 [M+H] + . 8-Bromo-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-methyl-4-morpholinoquinoline-3-carboxamide (0.3 g, 0.62 mmol) and (2,3,5-trifluorophenyl)boronic acid (0.656 g, 3.72 mmol) were dissolved in 1,4-dioxane (12 mL):water (3 mL), and while stirring the solution, Cs2CO3 was added thereto. The reaction mixture was degassed with N2 gas for 10 minutes, and then [(t-Bu)3PH]BF4 (0.036 g, 0.12 mmol) and PdCl2(dppf) (0.045 g, 0.06 mmol) were added, and the mixture was heated at 90 °C for 16 hours. The reaction mixture was quenched by adding water (200 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by column chromatography, eluting with 10% EtOAc in petroleum ether to obtain Example 8.1.

[0201] LCMS (Method C) Rt = 2.29 min, m / z = 535.22 [M+H] + . 1 H NMR (400 MHz, DMSO) δ [ppm]: 10.57 (s, 1 H), 8.31 (d, J = 7.6 Hz, 2 H) 7.79 (d, J = 6.4 Hz, 2 H), 7.69 (t, J = 8.4 Hz, 1 H), 7.59 - 7.61 (m, 1 H), 7.20 - 7.21 (m, 1 H), 6.99 (d, J = 6.8 Hz, 1 H), 6.85 (td, J = 1.6, 6.8 Hz, 1 H), 6.74 - 6.79 (m, 2 H), 4.39 (t, J = 4 Hz, 2 H), 3.87 (t, J = 4 Hz, 4 H), 3.72 (br s, 2 H), 3.32 (br s, 4 H), 2.55 (s, 3 H). Example 8.2 N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-2-(trifluoromethyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide

Chemical Structure

[0202] Step 1: A solution of 7-bromoindoline-2,3-dione (2.5 g, 11.06 mmol) and ethyl 4,4,4-trifluorobut-2-enoate (1.83 g, 11.06 mmol) in DMF (15 mL) was stirred, and Na2CO3 (2.34 g, 22.12 mmol) was added thereto, followed by addition of tert-butyl hydroperoxide (TBHP, 0.99 g, 11.06 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by adding water (20 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by column chromatography eluting with 0-50% EtOAc in petroleum ether to give ethyl 8-bromo-4-hydroxy-2-(trifluoromethyl)quinoline-3-carboxylate.

[0203] LCMS (method C) Rt = 2.29 min, m / z = 364.14 [M+H] + . Step 2: A solution of ethyl 8-bromo-4-hydroxy-2-(trifluoromethyl)quinoline-3-carboxylate (1.75 g, 4.80 mmol) in EtOH (10 mL) was stirred, and KOH (5.39 g, 96.12 mmol) was added thereto at room temperature and heated to 90 °C for 24 hours. The reaction mixture was brought to room temperature and concentrated. The pH of the residue was adjusted to 1-2 using 2N aqueous HCl, and the precipitated solid was filtered, washed with water (10 mL), washed with diethyl ether (20 mL), and dried to give 8-bromo-4-hydroxy-2-(trifluoromethyl)quinoline-3-carboxylic acid.

[0204] LCMS (method C) Rt = 1.79 min, m / z = 335.99 [M+H] + . Step 3:A mixture of 8-bromo-4-hydroxy-2-(trifluoromethyl)quinoline-3-carboxylic acid (1 g, 2.97 mmol) and POCl3 (10 mL) was heated at 90 °C for 2 h. The reaction mixture was brought to room temperature and concentrated under reduced pressure to give 8-bromo-4-chloro-2-(trifluoromethyl)quinoline-3-carbonyl chloride.

[0205] Step 4: A solution of 2,3-dihydro-1,4-benzoxazin-4-amine (0.8 g, 5.36 mmol) in THF (5 mL) was stirred, and DIPEA was added thereto, followed by cooling to 0 - 5 °C. To the reaction mixture, a solution of 8-bromo-4-chloro-2-(trifluoromethyl)quinoline-3-carbonyl chloride (1 g, 2.68 mmol) in 4 mL of THF was added, and the mixture was stirred at room temperature for 16 h. The reaction was quenched by adding water (20 mL), and the mixture was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by column chromatography eluting with 0 - 100% EtOAc in petroleum ether to give 8-bromo-4-chloro-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-(trifluoromethyl)quinoline-3-carboxamide.

[0206] LCMS (Method C) Rt = 2.23 min, m / z = 486.04 [M+H] + . Step 5:A solution of 8-bromo-4-chloro-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-(trifluoromethyl)quinoline-3-carboxamide (0.844 g, 1.73 mmol) in THF (6 mL) was stirred while morpholine (1.5 mL, 17.34 mmol) was added thereto at room temperature, and the mixture was stirred for 16 hours. The reaction mixture was concentrated to dryness. The crude product was purified by column chromatography eluting with 0 - 50% EtOAc in petroleum ether to obtain 8-bromo-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-2-(trifluoromethyl)quinoline-3-carboxamide.

[0207] LCMS (Method C) Rt = 2.18 min, m / z = 537.08 [M+H] + . Step 6: A solution of 8-bromo-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-2-(trifluoromethyl)quinoline-3-carboxamide and (2,3,5-trifluorophenyl)boronic acid (0.687 g, 3.91 mmol) in 1,4-dioxane (15 mL):water (5 mL) was stirred while Cs2CO3 (0.636 g, 1.95 mmol) was added thereto. The reaction mixture was degassed with N2 gas for 10 minutes, then [(t-Bu)3PH]BF4 (0.075 g, 0.26 mmol) and PdCl2(dppf) (0.095, 0.13 mmol) were added. The reaction mixture was heated to 90 °C for 16 hours. The reaction mixture was quenched by adding water (150 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by column chromatography eluting with 0 - 14% EtOAc in petroleum ether to obtain Example 8.2 as a white solid.

[0208] LCMS (Method C) Rt = 2.27 min, m / z = 589.39 [M+H] +. 1H NMR (400 MHz, DMSO) δ [ppm]: 10.62 (s, 1 H), 8.45 (d, J = 8.4 Hz, 2 H), 8.03 (d, J = 7.2 Hz, 2 H), 7.94 (t, J = 8.4 Hz, 1 H), 7.65 - 7.67 (m, 1 H), 7.29 - 7.31 (m, 1 H), 7.03 (d, J = 7.6 Hz, 1 H), 6.83 - 6.87 (mz, 1 H), 6.76 - 6.80 (m, 2 H), 4.39 (t, J = 3.6 Hz, 2 H), 3.87 (br s, 4 H), 3.64 (br s, 2 H), 3.43 (br s, 4 H).

Table 4

[0209] The compounds represented by formula (I) of the present invention are useful for treating and / or controlling endoparasitic nematodes and trematodes, which can cause severe diseases in mammals and poultry, particularly helminths. Typical nematodes for this indication are as follows: Filariidae, Setariidae, Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostonum, Oesophagostonum, Charbertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris, and Parascaris. As the above trematodes, particularly, Fasciolideae, particularly, Fasciola hepatica, etc. can be mentioned.

[0210] Certain parasites of the species of the genera Nematodirus, Cooperia and Oesophagostonum parasitize the intestinal tract of the host animal, other parasites of the species of the genera Haemonchus and Ostertagia parasitize in the stomach, and still other parasites of the species of the genus Dictyocaulus parasitize in the lung tissue. The parasites of this family can be found within internal cell tissues and within organs (such as the heart, blood vessels, lymphatic vessels and subcutaneous tissue). A particularly notable parasite is the dog heartworm, Dirofilaria immitis, of dogs.

[0211] Parasites that can be treated and / or controlled by the compound represented by formula (I) also include the following: cestode parasites (tapeworms), for example, parasites of the family Mesocestoidae, in particular, parasites of the genus Mesocestoides, in particular, Mesocestoides lineatus; the family Dipylidiidae, in particular, Dipylidium caninum, Joyeuxiella spp., in particular, Joyeuxiella pasquali, and Diplopylidium spp., and the family Taeniidae, in particular, Taenia pisformis, Taenia cervi, Taenia ovis, Taeneia hydatigena, Taenia multiceps, Taenia taeniaeformis, Taenia serialis, and Echinococcus spp., most particularly, Taneia hydatigena, Taenia ovis, Taenia multiceps, Taenia serialis; Echinococcus granulosus, and Echinococcus multilocularis.

[0212] Furthermore, the compounds represented by formula (I) are suitable for treating and / or controlling human pathogenic parasites. Among these, typical representatives that appear in the digestive tract are parasites of the following genera: Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Trichuris, and Enterobius. The compounds of the present invention are also effective against the following parasites: Wuchereria, Brugia, Onchocerca, and Loa of the family Dracunculus, as well as parasites of the genera Strongyloides and Trichinella (which, in particular, infect the digestive tract).

[0213] A specific parasite treated and / or controlled by the compounds of the present invention is Dirofilaria immitis. Specific subjects for such treatment are dogs and cats.

[0214] The compounds of the present invention can be administered alone or in the form of a composition. In practice, the compounds of the present invention are usually administered in the form of a composition, i.e., in a state mixed with at least one acceptable excipient. The proportion and nature of any acceptable excipient are determined by the characteristics of the selected compound of the present invention, the selected route of administration, and standard techniques in the fields of veterinary medicine and pharmacy.

[0215] In one embodiment, the present invention provides a composition comprising a compound of the present invention and at least one acceptable excipient.

[0216] In carrying out such treatment and / or control, the compounds of the present invention can be administered in any form and by any route that makes the compound biologically available. The compounds of the present invention can be administered by various routes including the oral route, in particular, by tablets and capsules. The compounds of the present invention can be administered by parenteral routes, more specifically, by inhalation, subcutaneous, intramuscular, intravenous, intra-arterial, transdermal, intranasal, rectal, vaginal, intraocular, topical, sublingual and buccal, intraperitoneal, intraadiposally, intrathecally, and via local delivery (e.g., by catheter or stent). Those skilled in the art can easily select an appropriate dosage form and administration route according to the specific characteristics of the selected compound, the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances. The pharmaceutical compositions of the present invention can be administered to a subject in the form of, for example, tablets, capsules, cachets, papers, troches, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, drenches, solutions, and suspensions.

[0217] The term "acceptable excipient" refers to excipients commonly used in preparing veterinary and pharmaceutical compositions, and must be pure and non-toxic in the amounts used. They are generally solid, semi-solid or liquid substances that can function as a vehicle or medium for the active ingredient as a whole. Some examples of acceptable excipients can be found in "Remington’s Pharmaceutical Sciences and the Handbook of Pharmaceutical Excipients", and such excipients include diluents, vehicles, carriers, ointment bases, binders, disintegrants, lubricants, glidants, sweeteners, flavorants, gel bases, sustained-release matrices, stabilizers, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, and the like.

[0218] In one embodiment, the composition is suitable for oral administration (e.g., tablets or capsules, or liquid formulations, such as solutions or suspensions adapted for oral administration). In one embodiment, the composition is suitable for oral administration (e.g., chewable formulations adapted for oral administration). In yet another embodiment, the composition is a liquid or semi-solid formulation, such as a solution or suspension or paste adapted for parenteral administration.

[0219] Specific compositions for use in a subject for the treatment and / or control of nematodes / helminths include, among others: solutions; emulsions, such as classical emulsions, microemulsions and self-emulsifying compositions (which are water-free organic compositions, preferably oily compositions, that form an emulsion with body fluids when added to the body of the subject); suspensions (drenches); pour-on formulations; food additives; powders; tablets (which include effervescent tablets); boli; capsules (which include microcapsules); and chewable treats. In particular, the form of the composition is a tablet, capsule, food additive or chewable treat.

[0220] The compositions of the present invention are prepared by methods well known in the veterinary and pharmaceutical arts and contain at least one of the compounds of the present invention as an active ingredient. The amount of the compound of the present invention can vary depending on its particular form and, conveniently, can be from 1% by weight to about 50% by weight of the unit dosage form. The pharmaceutical compositions of the present invention are preferably formulated in unit dosage forms and each dosage typically contains from about 0.5 mg to about 100 mg of the compound of the present invention. One or more unit dosage forms can be taken to effect a change in the therapeutic dosage.

[0221] In one embodiment, the present invention further provides a method for treating a parasite, wherein the method comprises administering to a subject in need of such treatment an effective amount of a compound represented by formula (I) or a salt thereof, wherein the method optionally further comprises an effective amount of at least one additional active compound.

[0222] In one embodiment, the present invention further provides a method for controlling a parasite, wherein the method comprises administering to a subject in need of such control an effective amount of a compound represented by formula (I) or a salt thereof, wherein the method optionally further comprises an effective amount of at least one additional active compound.

[0223] In one embodiment, the present invention further provides a method for treating or controlling a parasite, wherein the method comprises contacting the environment of the subject with an effective amount of a compound represented by formula (I) or a salt thereof, wherein the method optionally further comprises an effective amount of at least one additional active compound.

[0224] Accordingly, the present invention also provides the use of the compounds of the present invention as medicaments, which includes use for manufacturing medicaments. In one embodiment, the present invention provides the manufacture of a medicament comprising a compound represented by formula (I) or a salt thereof for treating a parasite. In one embodiment, the present invention provides the manufacture of a medicament comprising a compound or a salt thereof of the present invention for controlling a parasite.

[0225] The terms "treating", "to treat", "treated" or "treatment" include, but are not limited to, suppressing, delaying, halting, reducing, improving, reversing the progression or severity of existing symptoms, or preventing a disorder, condition or disease. For example, adult canine filariasis would be treated by administering a compound of the present invention. Treatment can be therapeutically applied or administered.

[0226] The terms "control", "controlling", or "controlled" include, but are not limited to, reducing, lessening, or improving the risk of a symptom, disorder, condition, or disease, and protecting an animal from a symptom, disorder, condition, or disease. Control may refer to therapeutic administration, prophylactic administration, or preventive administration. It is well understood that infections with larval or immature canine threadworms can be asymptomatic, and that infections with mature parasites can be symptomatic and / or debilitating. Thus, for example, canine threadworm infections would be controlled by acting on the larval or immature parasites to prevent the infection from progressing to an infection with mature parasites.

[0227] Accordingly, the use of the compounds of the present invention in the treatment and / or control of parasites (particularly helminths, particularly endoparasitic nematodes and trematodes) is the use of the compounds of the present invention to act on various forms of parasites throughout their life cycle, regardless of whether the subject exhibits symptoms including morbidity or mortality, and regardless of the stage of attack of the parasites.

[0228] As used herein, "administration to a subject" includes, but is not limited to, dermal administration, subcutaneous administration, intramuscular administration, mucosal administration, submucosal administration, transdermal administration, oral administration, or intranasal administration. Administration can include injection or topical administration.

[0229] The terms "subject" and "patient" include humans, as well as non-human mammals such as dogs, cats, mice, rats, guinea pigs, rabbits, ferrets, cows, horses, sheep, goats, and pigs. It is understood that a more specific subject is a human. Additionally, a more specific subject is a mammalian pet or companion animal such as dogs and cats, and also mice, guinea pigs, ferrets, and rabbits.

[0230] The term "effective amount" refers to an amount that confers a desired benefit on a subject and encompasses administration for both treatment and prophylaxis. This amount varies for each individual subject and depends on numerous factors (e.g., the overall health of the subject and the severity of the underlying cause of the condition being treated, concomitant therapy, and the amount of the compound used to maintain the desired response at a beneficial level).

[0231] The effective amount can be readily determined by a responsible diagnostician as a person skilled in the art by using known techniques and observing the results obtained in similar situations. In determining the effective amount, the dosage, many factors are considered by the responsible diagnostician, and such factors include, but are not limited to, the following: the species of the patient; its size, age, and general health; the specific condition, disorder, infection, or disease involved; the degree or involvement or severity of the condition, disorder, or disease; the response of the individual patient; the specific compound being administered; the method of administration; the bioavailability characteristics of the preparation being administered; the dosing schedule selected; the use of concomitant medications; and other relevant circumstances. The effective amount, the therapeutic dosage of the present invention, is expected to be in the range of 0.5 mg to 100 mg. The specific amount can be determined by a person skilled in the art. These dosages are based on subjects weighing from about 1 kg to about 20 kg, but a diagnostician can determine an appropriate dosage for subjects outside this weight range. The effective amount, the therapeutic dosage of the present invention, is expected to be in the range of 0.1 mg to 10 mg per kg of the subject's body weight. The dosing schedule is expected to be daily, weekly, or monthly administration.

[0232] The compounds of the present invention can be combined with one or more other active compounds or therapies for the treatment of one or more disorders, diseases, or conditions for which it is an indication (which includes the treatment of parasites). The compounds of the present invention can be administered in combination with one or more compounds or therapies for treating parasites and other disorders, simultaneously, sequentially, or separately.

[0233] For example, when used to treat parasites including Dirofilaria immitis, the compounds of the present invention can be combined with macrocyclic lactones (e.g., ivermectin, moxidectin or milbemycin oxime) or imidacloprid. Specific combinations for treating parasites include the compounds of the present invention and ivermectin. Another specific combination for treating parasites includes the compounds of the present invention and milbemycin oxime.

[0234] Accordingly, it is understood that the compositions and methods of the present invention optionally include an effective amount of at least one additional active compound.

[0235] The activity of the compounds as anthelmintics can be determined by various methods including in vitro and in vivo methods.

[0236] Example A Microfilariae of Dirofilaria immitis in dogs Dirofilaria immitis microfilariae are separated by filtration from the blood of infected donor beagles and incubated in a suitable medium. The test compound is diluted in DMSO and added to a 96-well plate containing the parasites. The plate is incubated for the desired time and evaluated for motility using an LCD camera imaging system. The effect of serum is tested by adding up to 20% fetal bovine serum to the assay. The motility inhibition value (%) is generated relative to the mean of the wells with DMSO only.

[0237] In this test, for example, the following compounds from the Preparation Examples showed an EC 50 <0.1 μg / mL: 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 3.1, 3.2, 3.3, 3.4, 4.1, 5.1, 5.2, 5.3, 5.4, 5.6, 5.7, 5.8, 5.10, 5.11, 5.12, 5.13, 5.14, 5.15, 5.16, 5.17, 5.18, 5.19, 5.20, 5.21, 5.22, 5.23, 5.23, 5.24, 6.1, and 7.1.

[0238] Example B1 Gastrointestinal tract of ruminants (Haemonchus contortus larval development assay (Hc LDA)): The eggs of H.c. isolated from the feces of lambs are hatched overnight. The test compound is diluted in DMSO and added to a 96-well plate containing an appropriate medium. The larvae of H.c. are added to each well, and the plate is incubated for the desired time. The motility is evaluated using an LCD camera imaging system. The motility inhibition value (%) is generated by comparing with the average of the wells with DMSO only.

[0239] In this test, for example, the following compounds from the preparation examples showed an EC 50 <1 μg / mL: 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.8, 3.1, 3.2, 3.3, 3.4, 4.1, 5.1, 5.2, 5.3, 5.4, 5.6, 5.7, 5.8, 5.11, 5.12, 5.13, 5.14, 5.15, 5.16, 5.17, 5.18, 5.19, 5.20, 5.21, 5.22, 5.23, 5.23, 5.24, 6.1, and 7.1.

[0240] Example B2 Other nematodes in vitro Caenorhabditis elegans (Ce): The C. elegans development assay (Ce DA) measures the effect of a compound on developing nematodes. The eggs of C. elegans are placed in a 384-well plate together with the treatment formulated in food (E. coli) and DMSO. The plate is incubated at 25 °C for 48 hours to grow the nematodes to the L4 stage. The effect of the compound is measured as a decrease in motility. The efficacy is expressed as the decrease in motility (%) compared to the negative control.

[0241] In this test, for example, the following compounds from the preparation examples showed an EC 90Showed <1 μg / mL: 5.23, 5.35, 5.36, 5.41, 5.45, 5.47, 5.48, 5.49, 5.54, 5.55, 5.56, 5.57, 5.58, 5.59, 5.60, 5.61, 5.62, 5.63.

[0242] Example C Gastrointestinal nematodes The jird (Meriones unguiculatus) is artificially infected with the third-stage larvae of T. colubriformis and H. contortus respectively by gavage. Then, on the 6th day after infection, it is treated orally with the test compound at a dose within the range of 1×3 mg / kg to 1×32 mg / kg (for example, the test compound formulated in DMSO / PEG (2 / 1)). Three days after treatment, the jirds are euthanized and dissected, the H. contortus are recovered from the stomach, and T. colubriformis are recovered from the small intestine. The efficacy is expressed as the percentage reduction in the number of worms compared to the placebo-treated group using Abbott's formula.

[0243] The compounds of Examples 3.3, 5.2, 5.3, 5.4, 5.19, 5.23 and 5.47 were >80% effective against Hc and Tc. The compounds of Examples 3.1, 2.3 and 5.6 were >80% effective against Hc.

[0244] Example D Dirofilaria immitis nematodes Av model: Jirds subcutaneously injected with infectious A. viteae larvae are then treated orally by gavage with the test substance at a dose within the range of 1×3 mg / kg to 5×32 mg / kg (administered once a day for 5 consecutive days) (for example, the test substance formulated in DMSO / PEG (2 / 1)). At necropsy 12 weeks after infection, the efficacy is expressed as the percentage reduction in the number of worms compared to the placebo-treated group using Abbott's formula.

[0245] The compounds of Examples 2.6, 3.4, 5.4, 5.6, 5.7, 5.8, 5.19 and 5.20 were >80% effective against Av.

[0246] Example E L.s. model Mice (BALB / c) were experimentally infected with the third-stage larvae of L. sigmodontis either by subcutaneous injection or exposure to infected mites. Treatment was carried out using the test substance formulated in DMSO / PEG (2 / 1) at a dose in the range of 1 × 3 mg / kg (single dose) to 5 × 32 mg / kg (once daily for 5 consecutive days) by oral gavage or subcutaneous injection. At necropsy 35 - 37 days after infection, the number of worms was counted in the peritoneal and pleural cavities. Efficacy is expressed as the percentage reduction in the number of worms compared to the placebo treatment group using the Abbott's formula. The compounds of Examples 3.3, 5.3, 5.41, 5.47, 5.48 and 5.56 were >80% effective against L.s.

Claims

1. Formula (I): 【Chemical Formula 1】 [wherein, n is 0 or 1; X １ is selected from the group consisting of N and CR １ ; X ２ is selected from the group consisting of N and CR ２ ; X ３ is selected from the group consisting of N and CR ３ ; X ４ is selected from the group consisting of N and CR ４ ; X ５ is selected from the group consisting of N and CR ５ ; X ６ is selected from the group consisting of N and CR ６ ; G is 【Chemical Formula 2】 selected from the group consisting of; M is selected from the group consisting of O and S; Y １ is selected from the group consisting of CR ８ R ９ O and S; Y ２ is selected from the group consisting of CR ８ R ９ O and S; where at least one of the groups Y １ or Y ２ is CR ８ R ９ ; Z １ is selected from the group consisting of N, O, S and CR １１ ; Z ２ is selected from the group consisting of N and CR １１ ; Z ３ is selected from the group consisting of N and CR １１ ; Z ４ is N, O, S and CR １１ selected from the group consisting of: Here, Z １ , Z ２ , Z ３ and Z ４ At most two of Z are N; and １ and Z ４ is O or S; R １ is hydrogen, halogen, hydroxyl, -SH, -SC １ -C ４ Alkyl, -S(O ) (C １ -C ４ alkyl), -S(O) ２ (C １ -C ４ Alkyl), cyano, C １ -C ４ Alkyl, C １ -C ４ Halogenoalkyl, C １ -C ４ -alkoxy, -B(OR １５ ) ( OR １６ ) wherein R １５ is hydrogen, C １ -C ４ a Rukill and C ３ -C ６ cycloalkyl; R １６ Each time, water Basic, C １ -C ４ Alkyl and C ３ -C ６ cycloalkyl; or R １５ and R １６ Together with the oxygen atom to which they are attached, they form a 5- to 7-membered ring (here and the ring is 1 to 4 C １ -C ４ Alkyl; -NH ２ 、 -NH(C １ -C ４ alkyl) and and -N(C １ -C ４ alkyl) ２ may be substituted to form; R ２ is hydrogen, halogen, hydroxyl, -SH, -SC １ -C ４ alkyl, -S(O )(C １ -C ４ alkyl), -S(O)( ２ (C １ -C ４ alkyl), cyano, C １ -C ４ alkyl, C １ -C ４ haloalkyl, C １ -C ４ -alkoxy, -B(OR １５ )( OR １６ ), selected from the group consisting of, where R １５ is, each time, hydrogen, C １ -C ４ a lkyl and C ３ -C ６ cycloalkyl, selected from the group consisting of, R １６ is, each time, water element, C １ -C ４ alkyl and C ３ -C ６ cycloalkyl, selected from the group consisting of, or R １５ and R １６ together with the oxygen atom to which they are attached form a 5- to 7-membered ring (here where the ring is 1 to 4 C １ -C ４ alkyl; -NH ２ , -NH(C １ -C ４ alkyl) and and -N(C １ -C ４alkyl) ２ which may be substituted with); R ３ is hydrogen, halogen, hydroxyl, -SH, -SC １ -C ４ alkyl, -S(O )(C １ -C ４ alkyl), -S(O)( ２ )(C １ -C ４ alkyl), cyano, C １ -C ４ alkyl, C １ -C ４ haloalkyl, C １ -C ４ -alkoxy, -B(OR １５ )( OR １６ ), and is selected from the group consisting of, where R １５ is, each time, hydrogen, C １ -C ４ a lkyl and C ３ -C ６ cycloalkyl, and is selected from the group consisting of, or １６ R is hydrogen, C １ -C ４ alkyl and C ３ -C ６ cycloalkyl, and is selected from the group consisting of, or R １５ and R １６ together with the oxygen atom to which they are attached form a 5- to 7-membered ring (where the ring may have 1 to 4 C １ -C ４ alkyl; -NH ２ , -NH(C １ -C ４ alkyl) and -N(C １ -C ４ alkyl) ２ which may be substituted with); R ４ is halogen, cyano, -CHO, hydroxyl, C １ -C ４ alkyl, C ２ -C ４ alkenyl, C ２ -C ４ alkynyl, C ３ -C ６ cycloalkyl, C １ -C ４ halogeno alkyl, C １ -C ４ -C substituted with -alkoxy １ -C ４ alkyl, 1 to 5 benzyl optionally substituted with halogen atoms, C １ -C ４ alkoxy, -NH ２ , -N H(C １ -C ４ alkyl), -N(C １ -C ４ alkyl) ２ , -NH(C ３ -C ６ cyclo alkyl), -N(C １ -C ４ alkyl)(C ３ -C ６ -cycloalkyl), -N(C １ -C ４ alkyl)(4- to 7-membered heterocycloalkyl), -NH(4- to 7-membered heterocyclo alkyl), -N(C １ -C ４ alkyl)(C １ -C ４ alkoxy), -C(O)NH (C １ -C ４ alkyl), -C(O)N(C １ -C ４ alkyl) ２ , -C(O)N(C １ -C ４ alkyl)(4- to 7-membered heterocycloalkyl), -NHSO ２ (C １ -C ４ Alk yl), -SC １ -C ４ alkyl, -S(O)C １ -C ４ alkyl, -SO ２ C １ -C ４ alkyl, -B(OR １５ )(OR １６ ), selected from the group consisting of, wherein R １５ is each time, hydrogen, C １ -C ４ alkyl and C ３ -C ６ selected from the group consisting of cycloalkyl, R １６ is each time, hydrogen, C １ -C ４ alkyl and C ３ -C ６ cycloalkyl, or R selected from the group consisting of, or R １５ and R １６ together with the oxygen atom to which they are attached form a 5- to 7-membered ring (wherein the ring may be substituted with 1 to 4 C １ -C ４ alkyl); a 6- to 10-membered aryl; a monocyclic heterocycle [wherein the monocyclic heterocycle is selected from the group consisting of a 4 to 7-membered heterocycloalkyl, a 5-membered heteroaryl having at least one nitrogen atom (wherein the 5-membered heteroaryl ring is attached to the remainder of the molecule through its nitrogen atom ), and a 6-membered heteroaryl having at least one nitrogen atom]]; wherein the aryl ring, heterocycloalkyl ring and hetero aryl ring in R are each independently halogen, cyano, nitro, hydroxy, oxo, C selected from the group consisting of]; wherein the aryl ring, heterocycloalkyl ring and hetero ４ aryl ring in R are each independently halogen, cyano, nitro, hydroxy, oxo, C １ -C ４ ​Alkyl, C ３ -C ６ Cycloalkyl, C １ -C ４ Haloalkyl, C １ -C ４ Al Oxy, -NH ２ , -NH(C １ -C ４ Alkyl), -N(C １ -C ４ Alkyl) ２ , - NH(C ３ -C ６ Cycloalkyl), -N(C １ -C ４ Alkyl)(C ３ -C ６ -Cyclo Alkyl), -NHSO ２ (C １ -C ４ Alkyl), -SC １ -C ４ Alkyl, -S(O )C １ -C ４ Alkyl, -SO ２ C １ -C ４ Alkyl, -S(O)C １ -C ４ -Halo Alkyl and -SO ２ C １ -C ４ Haloalkyl may be independently selected from the group consisting of 1 , 2 or 3 substituents; wherein, R ４ in the C ３ -C ６ Cyclo Alkyl ring and heterocycloalkyl ring may be substituted with a spiro group, in which case, the spiro group is a 3- to 6-membered cycloalkyl or contains 1, 2 or 3 heteroatoms independently selected from N, S or O selected 4- to 6-membered heterocyclo It is a spiro group, where the spiro group is halogen, cyano, nitro, hydroxy, oxo , C １ -C ４ alkyl, C ３ -C ６ cycloalkyl, C １ -C ４ haloalkyl, C １ -C ４ alkoxy, -NH ２ , -NH(C １ -C ４ alkyl), -N(C １ -C ４ alkyl ) ２ , -NH(C ３ -C ６ cycloalkyl), -N(C １ -C ４ alkyl)(C ３ -C ６ -cycloalkyl), -NHSO ２ (C １ -C ４ alkyl), -SC １ -C ４ alkyl , -S(O)C １ -C ４ alkyl, -SO ２ C １ -C ４ alkyl, -S(O)C １ -C ４ -haloalkyl and -SO ２ C １ -C ４ haloalkyl and may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of; and, where R may be substituted; and, where each C ４ in each C １ -C ４ alkyl, C ３ -C ６ cycloalkyl and C １ -C ４ alkoxy is halogen -NH, hydroxy, -NH ２ , -NH(C １ -C ４ alkyl), -N(C １ -C ４ alkyl ) ２ , cyano, carboxy, carbamoyl, C １ -C ４ alkoxycarbonyl, -C(O )(NH(C １ -C ４ alkyl), -C(O)N(C １ -C ４ alkyl) ２ and C １ -C ４ optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkoxy ; R ５ is hydrogen, halogen, hydroxyl, -SH, -SC １ -C ４ alkyl, -S(O )(C １ -C ４ alkyl), -S(O) ２ (C １ -C ４ alkyl), cyano, C １ -C ４ alkyl, C １ -C ４ haloalkyl, C １ -C ４ -alkoxy, -B(OR １５ )( OR １６ ), where R １５ is each time hydrogen, C １ -C ４ a lkyl and C ３ -C ６ cycloalkyl, and R １６ is each time hydrogen ), C １ -C ４ alkyl and C ３ -C ６ selected from the group consisting of cycloalkyl, or R １５ and R １６ together with the oxygen atom to which they are attached form a 5- to 7-membered ring (where the ring contains 1 to 4 C １ -C ４ alkyl; -NH ２ , -NH(C １ -C ４ alkyl) and and -N(C １ -C ４ alkyl) ２ and may be substituted); R ６ is hydrogen, halogen, hydroxyl, -SH, -SC １ -C ４ alkyl, -S(O )(C １ -C ４ alkyl), -S(O)( ２ (C １ -C ４ alkyl), cyano, C １ -C ４ alkyl, C １ -C ４ haloalkyl, C １ -C ４ -alkoxy, -B(OR １５ )( OR １６ ) selected from the group consisting of, where R １５ is each time hydrogen, C １ -C ４ alkyl and C alkyl selected from the group consisting of cycloalkyl and C ３ -C ６ alkyl selected from the group consisting of cycloalkyl, R １６ is each time hydrogen alkyl, C １ -C ４ alkyl selected from the group consisting of cycloalkyl and C ３ -C ６ alkyl selected from the group consisting of cycloalkyl, or R １５ and R １６together with the oxygen atoms to which they are attached form a 5- to 7-membered ring (wherein the ring is optionally substituted with 1 to 4 C １ -C ４ alkyl; -NH ２ , -NH(C １ -C ４ alkyl) and and -N(C １ -C ４ alkyl) ２ ); R ７ is hydrogen, C １ -C ４ alkyl and C ３ -C ６ cycloalkyl (wherein these may be substituted with 1 to 5 halogen atoms, -C(H)O, C ２ -C ４ alkenyl, C ２ -C ４ alkyn yl, C １ -C ４ halogenoalkyl and C １ -C ４ -alkoxy); is selected from the group consisting of; R ８ is each independently selected from the group consisting of hydrogen, fluoro and C １ -C ４ alkyl; is selected; R ９ is each independently selected from the group consisting of hydrogen, fluoro and C １ -C ４ alkyl; is selected; R １１ is each independently hydrogen, halogen, hydroxyl, cyano, C １ -C ４ al kyl, C １ -C ４ halogenoalkyl, C １ -C ４ -alkoxy, C ３ -C ６ cycloal kill, -NH ２ , -NH(C １ -C ４ alkyl) and -N(C １ -C ４ alkyl) ２ selected independently from the group consisting of ; Q is (i) a 6- or 10-membered aryl [wherein the 6- or 10-membered aryl is halogen, thi ano, nitro, hydroxyl, C １ -C ４ alkyl, C １ -C ４ halogenoalkyl, C １ -C ４ alkoxy, C ３ -C ６ cycloalkyl, -NH ２ , -NH(C １ -C ４ alkyl ), -N(C １ -C ４ alkyl) ２ , -NH(C ３ -C ６ cycloalkyl), -N(C １ -C ４ alkyl)(C ３ -C ６ -cycloalkyl), -NHSO ２ (C １ -C ４ alkyl ), -SC １ -C ４ alkyl, -S(O)C １ -C ４ alkyl, -SO ２ C １ -C ４ aryl, -S(O)C alkyl, -S(O)C １ -C ４ -halogenoalkyl and -SO ２ C １ -C ４ halogenoalkyl Optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of wherein the 6- or 10-membered aryl may be fused with a 4- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group consisting of O, S and N, and wherein the carbon of the heterocycloalkyl is halogen, cyano, nitro, hydroxy xyl, oxo, C １ -C ４ alkyl, C ３ -C ６ cycloalkyl, C １ -C ４ halogeno alkyl, C １ -C ４ alkoxy, -NH ２ , -NH(C １ -C ４ alkyl) and -N( C １ -C ４ alkyl) ２ Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of and any N in the heterocycloalkyl is, if possible according to its valence, hydrogen, C -C １ alkyl and C ４ -C ３ cycloalkyl selected from the group consisting of ６ substituted with a substituent selected from the group consisting of ; (ii) 5- to 10-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S and N [wherein the carbon of the 5- to 10-membered heteroaryl is halogen, cyano, nitro, hydroxyl, C -C alkyl, C １ -C ４ cyclo ３ alkyl, C ６ -C alkyl, C １ -C ４ halogenoalkyl, C １ -C ４ Alkoxy, benzyloxy, -N H ２ , -NH(C １ -C ４ alkyl), -N(C １ -C ４ alkyl) ２ , -SC １ -C ４ alkyl, -S(O)C １ -C ４ alkyl, -SO ２ C １ -C ４ alkyl, -S(O)C １ -C ４ -halogenoalkyl and -SO ２ C １ -C ４ halogenoalkyl may be independently substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of, and any N in the heteroaryl may also be substituted with a substituent selected from the group consisting of hydrogen, C alkyl and C １ -C ４ alkyl and C ３ -C ６ cycloalkyl) ; (iii) a 4- to 7-membered heterocycloalkyl having 1, 2 or 3 heteroatoms independently selected from the group consisting of O, S, N [wherein the heterocycloalkyl may be benzocondensed, and the carbon of the 4- to 7-membered heterocycloalkyl or the 4- to 7-membered heterocycloalkyl which may be benzocondensed may be halogen, cyano, nitro, hydroxyl, oxo, C alkyl, C alkyl, C １ -C ４ alkyl, C ３ -C ６ cycloalkyl, C １ -C ４ halo alkyl, C １ -C ４ alkoxy, -NH ２ , -NH(C １ -C ４ alkyl) and -N (C １ -C ４ alkyl) ２ 1, 2, 3 or 4 substituents independently selected from the group consisting of and any N in the heterocycloalkyl may be hydrogen, C １ -C ４ alkyl and C ３ -C ６ substituted with a substituent selected from the group consisting of cycloalkyl ; (iv) 6- or 10-membered aryloxy [wherein the 6- or 10-membered aryloxy is , halogen, cyano, nitro, hydroxyl, C １ -C ４ alkyl, C ３ -C ６ cyclo alkyl, C １ -C ４ halogenoalkyl, C １ -C ４ alkoxy, -NH ２ , -NH(C １ -C ４ alkyl), -N(C １ -C ４ alkyl) ２ , -NH(C ３ -C ６ cycloalkyl ), -N(C １ -C ４ alkyl)(C ３ -C ６ -cycloalkyl), -NHSO ２ (C １ -C ４ alkyl), -SC １ -C ４ alkyl, -S(O)C １ -C ４Alkyl, -SO ２ C １ -C ４ Alkyl, -S(O)C １ -C ４ -Halogenoalkyl and -SO ２ C １ -C ４ optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of haloalkylene]; (v) 6- or 10-membered arylthio-oxy [wherein the 6- or 10-membered arylthio -oxy is halogen, cyano, nitro, hydroxyl, C １ -C ４ alkyl, C ３ -C ６ cycloalkyl, C １ -C ４ haloalkyl, C １ -C ４ alkoxy, -NH ２ , - NH(C １ -C ４ alkyl), -N(C １ -C ４ alkyl) ２ , -NH(C ３ -C ６ cycl oalkyl), -N(C １ -C ４ alkyl)(C ３ -C ６ -cycloalkyl), -NHSO O ２ (C １ -C ４ alkyl), -SC １ -C ４ alkyl, -S(O)C １ -C ４ alkyl , -SO ２ C １ -C ４ alkyl, -S(O)C １ -C ４ -halogenoalkyl and -SO ２ C １ -C ４ selected independently from the group consisting of halogenoalkyl, and may be substituted with 1, 2 or 3 substituents; and, ] (vi) 5- to 10-membered heteroaryloxy [wherein, the 5- to 10-membered heteroaryl oxy is halogen, cyano, nitro, hydroxyl, oxo, C １ -C ４ alkyl, C ３ -C ６ cycloalkyl, C １ -C ４ halogenoalkyl, C １ -C ４ alkoxy, -NH ２ , -NH(C １ -C ４ alkyl), -N(C １ -C ４ alkyl) ２ , -NH(C ３ -C ６ cycloalkyl), -N(C １ -C ４ alkyl)(C ３ -C ６ -cycloalkyl), - NHSO ２ (C １ -C ４ alkyl), -SC １ -C ４ alkyl, -S(O)C １ -C ４ a alkyl, -SO ２ C １ -C ４ alkyl, -S(O)C １ -C ４ -halogenoalkyl and - SO ２ C １ -C ４ halogenoalkyl, and may be substituted with 1, 2 or 3 substituents selected independently from the group consisting of; ] selected from the group consisting of; R １３ is hydroxy, C １ -C ４ alkoxy and -NH ２ selected from the group consisting of; and, R １４ is, each time, hydrogen, halogen, cyano, nitro, hydroxyl, C １ -C ４ a lkyl, C ３ -C ６ cycloalkyl, C １ -C ４ halogenoalkyl, C １ -C ４ alkox y, C １ -C ４ halogenoalkoxy, -NH ２ , -NH(C １ -C ４ lkyl) and -N (C １ -C ４ lkyl) ２ independently selected from the group consisting of] a compound represented by or a salt thereof.

2. X １ is CR １ ; X ２ is CR ２ ; X ３ is CR ３ ; X ４ is CR ４ ; X ５ is CR ５ ; and X ６ is N, the compound or a salt thereof according to Claim 1.

3. X １ is CR １ ; X ２ is CR ２ ; X ３ is CR ３ ; X ４ is CR ４and ; X ５ is N; and X ６ is N, the compound according to claim 1 or a salt thereof.

4. X １ is CR １ ; X ２ is CR ２ ; X ３ is CR ３ ; X ４ is CR ４ ; and ; X ５ is N; and X ６ is CR ６ ; the compound according to claim 1 or a salt thereof.

5. Q is halogen, cyano, nitro, hydroxy, C １ -C ４ alkyl, C １ -C ４ halo genoalkyl, C １ -C ４ alkoxy, C ３ -C ６ cycloalkyl, -NH ２ , -NH( C １ -C ４ alkyl), -N(C １ -C ４ alkyl) ２ , -NH(C ３ -C ６ cycloal kyl), -N(C １ -C ４ alkyl)(C ３ -C ６ -cycloalkyl), -NHSO ２ ( C １ -C ４ alkyl), -SC １ -C ４ alkyl, -S(O)C １ -C ４ alkyl, -S O ２ C １ -C ４ Alkyl, -S(O)C １ -C ４ -Haloalkyl and -SO ２ C １ -[[]]END]] C ４ Substituted with 1, 2 or 3 substituents independently selected from the group consisting of haloalkyl A 6- or 10-membered aryl which may be substituted, according to any one of claims 1 to 4 Compound or a salt thereof.

6. Q is halogen, cyano, nitro, hydroxy, C １ -C ４ Alkyl, C １ -C ４ Halo Genoaalkyl, C １ -C ４ Alkoxy, C ３ -C ６ Cycloalkyl, -NH ２ , -NH( C １ -C ４ Alkyl), -N(C １ -C ４ Alkyl) ２ , -NH(C ３ -C ６ Cycloal Kil), -N(C １ -C ４ Alkyl)(C ３ -C ６ -Cycloalkyl), -NHSO ２ ( C １ -C ４ Alkyl), -SC １ -C ４ Alkyl, -S(O)C １ -C ４ Alkyl, -S O ２ C １ -C ４ Alkyl, -S(O)C １ -C ４ -Haloalkyl and -SO ２ C １ -[[]]END]] C ４ substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogenoalkyl; and optionally 6-membered aryl, wherein the 6-membered aryl is selected from the group of O, S and N. and a 4- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected therefrom. and wherein the carbon of the heterocycloalkyl is selected from the group consisting of halogen, cyano, nitro, , Hydroxy, Oxo, C １ -C ４ Alkyl, C ３ -C ６ Cycloalkyl, C １ -C ４ Halogenoalkyl, C １ -C ４ Alkoxy, -NH ２ , -NH(C １ -C ４ Alkyl) and Bi-N(C １ -C ４ Alkyl) ２ one, two or three substitutions independently selected from the group consisting of group, and any N in the heterocycloalkyl is hydrogen, C １ -C ４ Alkyl and C ３ -C ６ substituted with a substituent selected from the group consisting of cycloalkyl The compound or salt thereof according to any one of claims 1 to 4,

7. Q is 5 to 10 having 1 or 2 heteroatoms selected from the group consisting of O, S and N. and n-membered heteroaryl, wherein the carbon of the heteroaryl is selected from the group consisting of halogen, cyano, nitro, and nitro. Toro, -OH, C １ -C ４ Alkyl, C ３ -C ６ Cycloalkyl, C １ -C ４ Halogenor Lukir, C １ -C ４ Alkoxy, -NH ２ ,, -NH(C １ -C ４ Alkyl) and -N(C １ -C ４ Alkyl) ２ Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of And any N in the heteroaryl may be hydrogen, C １ -C ４ Alkyl And C ３ -C ６ Optionally substituted with a substituent selected from the group consisting of cycloalkyl The compound according to any one of claims 1 to 4 or a salt thereof.

8. Q is a 4- to 7-membered Heterocycloalkyl having 1 or 2 heteroatoms selected from the group consisting of O, S, and N, wherein the heterocycloalkyl may be benzo-fused And where the heterocycloalkyl or optionally benzo-fused heterocyclo The carbon of the roalkyl is halogen, cyano, nitro, hydroxy, oxo, C １ -C ４ Al Kil, C ３ -C ６ Cycloalkyl, C １ -C ４ Halogenoalkyl, C １ -C ４ Alkoxy ,, -NH ２ ,, -NH(C １ -C ４ Alkyl) and -N(C １ -C ４ Alkyl) ２ Consisting of Optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of And any N in the heterocycloalkyl is hydrogen, C １ -C ４ alkyl and C ３ -C ６ cyclo optionally substituted with a substituent selected from the group consisting of lower alkyl, the compound or a salt thereof according to any one of claims 1 to 4. Claim 9 wherein n is 1, the compound or a salt thereof according to any one of claims 1 to 8. Claim 10 Y １ is CR ８ R ９ and Y ２ is O, the compound or a salt thereof according to any one of claims 1 to 9. Claim 11 R ４ is C １ -C ４ alkyl, C ３ -C ６ cycloalkyl, -N(C １ -C ４ alkyl ) ２ and selected from the group consisting of 4- to 7-membered heterocycloalkyl, the compound or a salt thereof according to any one of claims 1 to 10. Claim 12 G is Formula 3 and M is O, the compound or a salt thereof according to any one of claims 1 to 11. Claim 13 G is Formula 4 and M is O, the compound or a salt thereof according to any one of claims 1 to 11. Claim 14 Formula (Ia-5) Formula 5 wherein R １, R ４ and Q are as defined in claim 1. A compound represented by formula (I) according to claim 1 or a salt thereof, represented by

15. R １ being hydrogen, halogen or cyano, a compound represented by formula (Ia-5) according to claim 14 or a salt thereof.

16. R １ being hydrogen or fluoro, a compound represented by formula (Ia-5) according to claim 14 or claim 15 or a salt thereof.

17. R ４ being 4-morpholino or dimethylamino, a compound represented by formula (Ia-5) according to any one of claims 14 to 16 or a salt thereof.

18. Q is halogen, cyano, nitro, hydroxyl, C １ -C ４ alkyl, C １ -C ４ hal ogenoalkyl, C １ -C ４ alkoxy, C ３ -C ６ cycloalkyl, -NH ２ , -NH (C １ -C ４ alkyl), -N(C １ -C ４ alkyl) ２ , -NH(C ３ -C ６ cycloa lkyl), -N(C １ -C ４ alkyl)(C ３ -C ６ -cycloalkyl), -NHSO ２ (C １ -C ４ alkyl), -SC １ -C ４ Alkyl, -S(O)C １ -C ４ Alkyl, - SO ２ C １ -C ４ Alkyl, -S(O)C １ -C ４ -Haloalkyl and -SO ２ C １ -C ４ Selected independently from the group consisting of 1, 2, 3, 4 or 5 substituents of haloalkyl, which may be substituted with A 6-membered aryl which may be substituted with a substituent, wherein the 6- or 10-membered aryl is A 4- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group of O, S and N May be condensed with a heterocycloalkyl, and wherein the carbon of the heterocycloalkyl Is halogen, cyano, nitro, hydroxyl, oxo, C １ -C ４ Alkyl, C ３ - C ６ Cycloalkyl, C １ -C ４ Haloalkyl, C １ -C ４ Alkoxy, -NH ２ , -NH(C １ -C ４ Alkyl) and -N(C １ -C ４ Alkyl) ２ Selected independently from the group of May be substituted with 1, 2 or 3 substituents, and any N within the heterocycloalkyl If possible according to its valence, is hydrogen, C １ -C ４ Alkyl and C ３ - C ６ Cycloalkyl, which is substituted with a substituent selected from the group consisting of, Claims 14 to 1 The compound represented by formula (Ia-5) according to any one of 7 or a salt thereof.

19. Q is 【Chemical Formula 6】 selected from, the compound represented by formula (Ia-5) according to any one of claims 14 to 18 or a salt thereof.

20. N-[8-(3,5-dichlorophenyl)-4-(dimethylamino)-3-quinolyl] -2,3-dihydro-1,4-benzoxazine-4-carboxamide; (Example 1.1 ） 8-(3,5-Dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide; (Example 2.1) 8-(3,5-Dichlorophenyl)-N-(3,4-dihydro-2H-quinolin-1-yl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide; (Example 2.2) 8-(3,5-Dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,7-naphthyridine-3-carboxamide; (Example 2.3) 8-(3,5-Dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxamide; (Example 3.1) 5-(3,5-Dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-1-(dimethylamino)naphthalene-2-carboxamide; (Example 4.1), and 8-(3,5-Dichlorophenyl)-N-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-4-(dimethylamino)quinoline-3-carboxamide; (Example 5.1) The compound according to claim 1 or a salt of any of the above compounds, selected from the group consisting of (Example 2.6) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(2,3-dichlorophenyl)-1,7-naphthyridine-3-carboxamide; (Example 2.7) 8-(3,5-Dichloro-4-fluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,7-naphthyridine-3-carboxamide; (Example 2.8) 8-(5-Chloro-3-pyridyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,7-naphthyridine-3-carboxamide; (Example 2.9) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-thiomorpholino-8-(2,3,5-trifluorophenyl)-1,7-naphthyridine-3-carboxamide; (Example 2.10) (Example 2.11) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-morpholino- ​ ​ ​ ​

21. N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino- 8-(2,3,5-Trifluorophenyl)-1,7-naphthyridine-3-carboxamide ; (Example 2.4) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-[methoxy( methyl)amino]-8-(2,3,5-trifluorophenyl)-1,7-naphthyridine -3-carboxamide; (Example 2.5) 8-[3-Chloro-5-(trifluoromethyl)phenyl]-N-(2,3-dihydro -1,4-benzoxazin-4-yl)-4-morpholino-1,7-naphthyridine-3 -carboxamide; ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-(1,1-di oxo-1,4-thiazinan-4-yl)-8-(2,3,5-trifluorophenyl) -1,7-naphthyridine-3-carboxamide; ​ ​ 8-(3,4,5-Trifluorophenyl)-1,7-naphthyridine-3-carboxamide ; (Example 2.12) 8-(2,3-Dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxamide ; (Example 3.2) 8-(3,5-Dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,5-naphthyridine-3-carboxamide; (Example 3.3) (Example 3.4) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(2,3,5-trifluorophenyl)-1,5-naphthyridine-3-carboxamide; (Example 3.4) 8-(2,3-Dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; (Example 5.2) 8-(3,5-Dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; (Example 5.3) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4 -morpholino-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; (Example 5.4) 8-(5-Chloro-3-pyridyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; (Example 5.5) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; (Example 5 8-(3,5-Dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-carboxamide; (Example 5.7) 8-(3,5-Difluorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-carboxamide; (Example 5.8) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-pyrimidin-5-yl-quinoline-3-carboxamide; (Example 5.9) ​ ​ ．６） ​ ​ （ ​ ​ ​ ​ ​ ​ ​ N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-thiomorpholino -8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; (Example 5.10) 8-[2-Chloro-6-(trifluoromethyl)-4-pyridyl]-N-(2,3-di hydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-car boxamide; (Example 5.11) 8-(2,6-Dichloro-4-pyridyl)-N-(2,3-dihydro-1,4-benz oxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; (Example 5 ．１２） 8-(3,5-Dichloro-2-fluoro-phenyl)-N-(2,3-dihydro-1, 4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; (Example 5.13) 8-(5-Chloro-2-fluoro-3-pyridyl)-N-(2,3-dihydro-1,4 -benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; （ Example 5.14) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-(1,1-di oxo-1,4-thiazinan-4-yl)-8-(2,3,5-trifluorophenyl) quinoline-3-carboxamide; (Example 5.15) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-morpholino- 8-(2,4,5-trifluorophenyl)quinoline-3-carboxamide; (Example 5 ．１６） 8-(6-Chloropyrazin-2-yl)-N-(2,3-dihydro-1,4-benzoxa zin-4-yl)-4-morpholino-quinoline-3-carboxamide; (Example 5. １７） 8-(4,5-Dichloro-3-pyridyl)-N-(2,3-dihydro-1,4-benz oxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; (Example 5 ．１８） 8-(5-Chloro-2,3-difluoro-phenyl)-N-(2,3-dihydro-1, 4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; (Example 5.19) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-morpholino- 8-(2,3,4,5-tetrafluorophenyl)quinoline-3-carboxamide; (Ex ample 5.20) 8-(4-Chloro-5-fluoro-3-pyridyl)-N-(2,3-dihydro-1,4 -benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; （ Example 5.21) 8-[4-Chloro-6-(trifluoromethyl)-2-pyridyl]-N-(2,3-di Hydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-car boxamide; (Example 5.22) 8-(3,5-Dichloro-2,4-difluoro-phenyl)-N-(2,3-dihydro -1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carbox amide; (Example 5.23) N-Indolin-1-yl-4-morpholino-8-(2,3,5-trifluoropheny l)quinoline-3-carboxamide; (Example 5.24) 8-(4,6-Dichloro-2-pyridyl)-N-(2,3-dihydro-1,4-benz oxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; (Example 5 ．２５） N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-8-(6-fluoro piperazin-2-yl)-4-morpholino-quinoline-3-carboxamide; (Example 5 .) 8-[2-Chloro-6-(trifluoromethyl)pyrimidin-4-yl]-N-(2, 3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3 -carboxamide; (Example 5.27) 8-(6-Chloro-5-fluoro-2-pyridyl)-N-(2,3-dihydro-1,4 -benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; （ (Example 5.28) 8-(6-Chloro-3-fluoro-2-pyridyl)-N-(2,3-dihydro-1,4 -benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; （ (Example 5.29) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-8-(6-ethoxy pyrazin-2-yl)-4-morpholino-quinoline-3-carboxamide; (Example 5 ．３０） 4-(Azetidin-1-yl)-N-(2,3-dihydro-1,4-benzoxazin -4-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxami de; (Example 5.31) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-pyrrolidin -1-yl-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; (Example 5.32) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-[2-methoxy ethyl(methyl)amino]-8-(2,3,5-trifluorophenyl)quinoline-3 -carboxamide; (Example 5.33) 4-[Bis(2-methoxyethyl)amino]-N-(2,3-dihydro-1,4-ben zoxazin-4-yl)-8-(2,3,5-trifluorophenyl)quinoline-3- carboxamide; (Example 5.34) 7-Cyano-8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4- benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; (Example Example 5.35 4-Cyclopropyl-N-(2,3-dihydro-1,4-benzoxazin-4-yl )-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; (Example 5.36 N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(3-fluoro azetidin-1-yl)-8-(2,3,5-trifluorophenyl)quinoline-3- carboxamide; (Example 5.37 N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(3-hydroxy azetidin-1-yl)-8-(2,3,5-trifluorophenyl)quinoline-3 -carboxamide; (Example 5.38 N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-oxazolidin -3-yl-8-(2,3,5-trifluorophenyl)quinoline-3-carboxami do; (Example 5.39 N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-(2-oxa -6-azaspiro[3.3]heptan-6-yl)-8-(2,3,5-trifluorop enyl)quinoline-3-carboxamide; (Example 5.40) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4 -morpholino-8-(3,4,5-trifluorophenyl)quinoline-3-carboxami de; (Example 5.41 4-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxa dine-4-yl)-8-morpholino-pyrido[3,2-d]pyrimidine-7-carboxa mide; (Example 6.1), and, 8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxa dine-4-yl)-4-morpholino-1,6-naphthyridine-3-carboxamide; (Example 7.1 A compound selected from the group consisting of, or a salt of any of the foregoing compounds.

22. N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-isoxazol yl-8-(2,3,5-trifluorophenyl)quinoline-3-carbox amide; (Example 5.42) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-morpholino- 8-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]quinoline-3- carboxamide; (Example 5.43 8-(2,6-dichloropyrimidin-4-yl)-N-(2,3-dihydro-1,4- benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; (Example 5.44 N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-tetrahydro pyran-4-yl-8-(2,3,5-trifluorophenyl)quinoline-3-carboxy samide; (Example 5.45 4-[acetyl(methyl)amino]-N-(2,3-dihydro-1,4-benzoxa dine-4-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxy samide; (Example 5.46 8-(3,5-dichloro-2-fluoro-phenyl)-N-(2,3-dihydro-1, 4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-ca ruboxamide; (Example 5.47 8-(3,5-Dichloro-2,4-difluoro-phenyl)-N-(2,3-dihydro -1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline- 3-carboxamide; (Example 5.48) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-morpholino- 8-(2,3,6-trifluoro-4-pyridyl)quinoline-3-carboxamide; (Ex ample 5.49) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-8-(4-fluoro -2,6-dimethyl-phenyl)-4-morpholino-quinoline-3-carboxamide; (Example 5.50) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-8-[4-ethyl sulfanyl-6-(trifluoromethyl)pyrimidin-2-yl]-4-morpholino- quinoline-3-carboxamide; (Example 5.51) 8-[4-Benzyloxy-6-(trifluoromethyl)pyrimidin-2-yl]-N -(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quino line-3-carboxamide; (Example 5.52) [3-(2,3-Dihydro-1,4-benzoxazin-4-ylcarbamoyl)-8 -(2,3,5-trifluorophenyl)-4-quinolyl]boronic acid; (Example 5.53 ） 8-(3,5-Dichloro-2,4-difluoro-phenyl)-7-fluoro-N-indol in-1-yl-4-morpholino-quinoline-3-carboxamide; (Example 5.54 ） N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-(1-methoxy ethyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide ; (Example 5.55) 8-(3,5-Dichloro-2,4-difluoro-phenyl)-N-(2,3-dihydro -1,4-benzoxazin-4-yl)-4-(dimethylamino)-7-fluoro-q uinoline-3-carboxamide; (Example 5.56) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-morpholino- 8-(2,3,5,6-tetrafluorophenyl)quinoline-3-carboxamide; (Ex ample 5.57) 4-Cyclopropyl-8-(3,5-dichloro-2,4-difluoro-phenyl)-N -(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-quinoli ne-3-carboxamide; (Example 5.58) 8-[3,5-Bis(trifluoromethyl)phenyl]-N-(2,3-dihydro-1 ,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3- carboxamide; (Example 5.59) 8-(5-Chloro-2,3-difluoro-phenyl)-N-(2,3-dihydro-1, 4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-ca rboxamide; (Example 5.60) 8-[3-Chloro-5-(trifluoromethyl)phenyl]-N-(2,3-dihydro -1,4-Benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline- 3-carboxamide; (Example 5.61) 8-(3,5-Dichloro-2,4-difluoro-phenyl)-N-(2,3-dihydro -1,4-Benzoxazin-4-yl)-7-fluoro-4-[methoxy(methyl)ami no]quinoline-3-carboxamide; (Example 5.62) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-morpholino- 8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide; (Example ５．６３） 8-[3,5-Dichloro-4-(trifluoromethyl)phenyl]-N-(2,3-di hydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-car boxamide; (Example 5.64) 8-(3-Chloro-2,5,6-trifluoro-phenyl)-N-(2,3-dihydro -1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline- 3-carboxamide; (Example 5.65) 8-(3-Chloro-5-cyano-phenyl)-N-(2,3-dihydro-1,4-ben zoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; (Example ５．６６） 8-(3-Cyano-2,5-difluoro-phenyl)-N-(2,3-dihydro-1, 4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; (Example 5.67) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-(2,2,2 -Trifluoro-1-methyl-ethyl)-8-(2,3,5-trifluorophenyl)qui noline-3-carboxamide; (Example 5.68) N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-2-methyl-4- morpholino-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide ; (Example 8.1), and, N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-morpholino- 2-(trifluoromethyl)-8-(2,3,5-trifluorophenyl)quinoline-3 -carboxamide; (Example 8.2) A compound or a salt of any of the above compounds selected from the group consisting of. Claim 23 A composition comprising the compound or a salt thereof according to any one of claims 1 to 22 and at least one acceptable carrier. Claim 24 Use of the compound or a salt thereof according to any one of claims 1 to 22 as a therapeutic agent for non-human warm-blooded animals. Claim 25 For treating internal parasites, the compound or a salt thereof according to any one of claims 1 to 22 Use in the manufacture of a medicament for the eyes. Claim 26 Use in the manufacture of a medicament for treating canine filarial worms of the compound or a salt thereof according to any one of claims 1 to 22. Use in the manufacture of a medicament for the eyes. Claim 27 Use in the manufacture of a medicament for controlling canine filarial worms of the compound or a salt thereof according to any one of claims 1 to 22. Use in the manufacture of a medicament for the eyes.

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