Bicyclic derivatives for treating internal parasites

Abstract

The present invention provides compounds of formula (I): which are useful for controlling endoparasites, such as heartworms, in warm-blooded animals.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 858,465, filed on June 7, 2019, and U.S. Provisional Application No. 62 / 947,852, filed on December 13, 2019, the contents of each of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to medicinal 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 endoparasites such as heartworms in warm-blooded animals. Background Art

[0004] Heartworm (Dirofilaria immitis) is a parasitic roundworm that is transmitted between hosts through mosquito bites. The life cycle begins when a female mosquito obtains a blood meal from an infected host. The mosquito ingests immature heartworms, which then molt to the infective larval stage and travel to the mosquito's mouth. The mosquito then feeds on a susceptible host such as a dog or cat, injecting the infective larvae. The larvae then molt to the next larval stage in the new host, and then migrate in the body, eventually entering the blood vessels. As the larvae migrate within the tissues, they molt into young adults. The young adults eventually move into the blood vessels of the lungs, where they mature into sexually active adults. The adult heartworms then reproduce and release the immature heartworms, completing the cycle. Heartworm infection can cause serious illness to the host.

[0005] Adult heartworm infections can be treated with arsenic-based compounds; such treatments are time-consuming, cumbersome, and often only partially successful. Treatments therefore focus on controlling heartworm infections. Heartworm control is currently only done through regular dosing throughout the year. Typical treatments include macrolides such as ivermectin, moxidectin, and milbemycin oxime. Unfortunately, Dirofilaria immitis has been observed to develop resistance to macrolides. Therefore, new compounds that effectively control heartworm infections, either by prevention or by directly killing heartworms, are needed. Certain treatments for internal parasites are described in WO 2017 / 178416, WO 2018 / 087036, WO 2018 / 197401, WO 2019 / 025341, and WO 2019 / 002132. Summary of the invention

[0006] The present invention provides compounds of formula (I) that are effective in treating and / or controlling endoparasites (eg, heartworms) in warm-blooded animals.

[0007] In one embodiment, the present invention provides a compound of formula (I):

[0008]

[0009] in

[0010] n is 0 or 1;

[0011] X1 is selected from N and CR1;

[0012] X2 is selected from N and CR2;

[0013] X3 is selected from N and CR3;

[0014] X4 is selected from N and CR4;

[0015] X5 is selected from N and CR5;

[0016] X6 is selected from N and CR6;

[0017] G is selected from

[0018]

[0019] M is selected from NR 13 , O and S;

[0020] Y1 is selected from CR8R9, O, S and NR 10 ;

[0021] Y2 is selected from CR8R9, O, S and NR 10 ;

[0022] wherein at least one of the groups Y1 or Y2 is CR8R9;

[0023] Z1 is selected from N, O, S and CR 11 ;

[0024] Z2 is selected from None, N and CR 11 ;

[0025] Z3 is selected from None, N and CR 11 ;

[0026] Z4 is selected from N, O, S and CR 11 ;

[0027] wherein no more than 2 of Z1, Z2, Z3 and Z4 are N and wherein only one of Z1 and Z4 is O or S, Z2 is absent only when Z1 is O or S, and Z3 is absent only when Z4 is O or S;

[0028] R1 is selected from the group consisting of: hydrogen; halogen; hydroxy; -SH; -SC1-C4 alkyl; -S(O)(C1-C4 alkyl); -S(O)2(C1-C4 alkyl); cyano; C1-C4 alkyl; C1-C4 haloalkyl; C1-C4-alkoxy; -B(OR 15 )(OR 16 ), where R 15 is selected from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl at each use, R 16 is selected from hydrogen, C1-C4 alkyl and C3-C6 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, which is optionally substituted with 1 to 4 C1-C4 alkyl groups; -NH2; -NH(C1-C4 alkyl); and -N(C1-C4 alkyl)2;

[0029] R2 is selected from: hydrogen; halogen; hydroxy; -SH; -SC1-C4 alkyl; -S(O)(C1-C4 alkyl); -S(O)2(C1-C4 alkyl); cyano; C1-C4 alkyl; C1-C4 haloalkyl; C1-C4-alkoxy; -B(OR 15 )(OR 16 ), where R 15 is selected from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl at each use, R 16 is selected from hydrogen, C1-C4 alkyl and C3-C6 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, which is optionally substituted with 1 to 4 C1-C4 alkyl groups; -NH2; -NH(C1-C4 alkyl); and -N(C1-C4 alkyl)2;

[0030] R3 is selected from the group consisting of: hydrogen; halogen; hydroxy; -SH; -SC1-C4 alkyl; -S(O)(C1-C4 alkyl); -S(O)2(C1-C4 alkyl); cyano; C1-C4 alkyl; C1-C4 haloalkyl; C1-C4-alkoxy; -B(OR 15 )(OR 16 ), where R 15 is selected from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl at each use, R 16 is selected from hydrogen, C1-C4 alkyl and C3-C6 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, which is optionally substituted with 1 to 4 C1-C4 alkyl groups; -NH2; -NH(C1-C4 alkyl); and -N(C1-C4 alkyl)2;

[0031] R4 is selected from the group consisting of: halogen; cyano; -CHO; hydroxy; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C3-C6 cycloalkyl; C1-C4 haloalkyl; -C1-C4-alkoxy-substituted -C1-C4 alkyl; benzyl optionally substituted by 1 to 5 halogen atoms; C1-C4 alkoxy; -NH2; -NH(C1-C4 alkyl); -N(C1-C4 alkyl)2;

[0032] -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);

[0033] -NHSO2(C1-C4 alkyl); -SC1-C4 alkyl; -S(O)C1-C4 alkyl; -SO2C1-C4 alkyl;

[0034] -B(OR 15 )(OR 16 ), where R 15 is selected from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl at each use, R 16 is selected from 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 which is optionally substituted with 1 to 4 C1-C4 alkyl groups; a 6- or 10-membered aryl group; a monocyclic heterocyclic ring selected from 4- to 7-membered heterocycloalkyl, a 5-membered heteroaryl having at least one nitrogen atom through which the 5-membered heteroaryl ring is attached to the rest of the molecule, and a 6-membered heteroaryl having at least one nitrogen atom; each of the aryl, heterocycloalkyl and heteroaryl rings in R4 is optionally substituted with 1, 2 or 3 groups independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, 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-haloalkyl and -SO2C1-C4 haloalkyl substituents; wherein the C3-C6 cycloalkyl and heterocycloalkyl rings in R4 are optionally substituted by spiro groups, wherein the spiro groups are 3- to 6-membered cycloalkyl or contain 1, 2 or 3 heteroatoms independently selected from N, S or O, wherein the spirocyclic group is optionally substituted by 1, 2 or 3 independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, 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-haloalkyl and -SO2C1-C4 haloalkyl substituents substituted; and wherein each C1-C4 alkyl, C3-C6 cycloalkyl and C1-C4 alkoxy in R4 may be optionally substituted with 1, 2 or 3 substituents independently selected from halogen, hydroxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, cyano, carboxyl, carbamoyl, C1-C4 alkoxycarbonyl, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2 and C1-C4 alkoxy;

[0035] R5 is selected from the group consisting of: hydrogen; halogen; hydroxy; -SH; -SC1-C4 alkyl; -S(O)(C1-C4 alkyl); -S(O)2(C1-C4 alkyl); cyano; C1-C4 alkyl; C1-C4 haloalkyl; C1-C4-alkoxy; -B(OR 15 )(OR 16 ), where R15 is selected from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl at each use, R 16 is selected from hydrogen, C1-C4 alkyl and C3-C6 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, which is optionally substituted with 1 to 4 C1-C4 alkyl groups; -NH2; -NH(C1-C4 alkyl); and -N(C1-C4 alkyl)2;

[0036] R6 is selected from the group consisting of: hydrogen; halogen; hydroxy; -SH; -SC1-C4 alkyl; -S(O)(C1-C4 alkyl); -S(O)2(C1-C4 alkyl); cyano; C1-C4 alkyl; C1-C4 haloalkyl; C1-C4-alkoxy; -B(OR 15 )(OR 16 ), where R 15 is selected from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl at each use, R 16 is selected from hydrogen, C1-C4 alkyl and C3-C6 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, which is optionally substituted with 1 to 4 C1-C4 alkyl groups; -NH2; -NH(C1-C4 alkyl); and -N(C1-C4 alkyl)2;

[0037] R7 is selected from: hydrogen; C1-C4 alkyl; and C3-C6 cycloalkyl optionally substituted by 1 to 5 halogen atoms; -C(H)O; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 haloalkyl; and C1-C4-alkoxy;

[0038] R8 is independently selected at each selection from hydrogen, fluorine and C1-C4 alkyl;

[0039] R9 is independently selected at each selection from hydrogen, fluorine and C1-C4 alkyl;

[0040] R 10 is selected from hydrogen and C1-C4 alkyl;

[0041] R 11 is independently selected at each selection from hydrogen, halogen, hydroxy, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4-alkoxy, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2; and Q is selected from

[0042] (i) a 6- or 10-membered aryl group, which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from halogen, cyano, nitro, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, 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-haloalkyl and -SO2C1 -C4 haloalkyl, wherein the 6- or 10-membered aryl is optionally fused with a 4- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from O, S and N and wherein the carbons of the heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, 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 hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl where valence permits;

[0043] (ii) a 5- to 10-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from O, S and N, wherein the carbons of the 5- to 10-membered heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, cyano, nitro, hydroxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, 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-haloalkyl and -SO2C1-C4 haloalkyl, and any N in the heteroaryl is optionally substituted with a substituent selected from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl where valence permits;

[0044] (iii) a 4- to 7-membered heterocycloalkyl having 1, 2 or 3 heteroatoms independently selected from O, S and N, wherein the heterocycloalkyl is optionally benzo-fused, wherein the carbons of the 4- to 7-membered heterocycloalkyl or optionally benzo-fused 4- to 7-membered heterocycloalkyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2 and any N in the heterocycloalkyl is optionally substituted with a substituent selected from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl;

[0045] (iv) a 6- or 10-membered aryloxy group optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, 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-haloalkyl and -SO2C1-C4 haloalkyl;

[0046] (v) a 6- or 10-membered arylthiooxy group optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, 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-haloalkyl and -SO2C1-C4 haloalkyl; and

[0047] (vi) a 5- to 10-membered heteroaryloxy group optionally 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 haloalkyl, 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-haloalkyl and -SO2C1-C4 haloalkyl;

[0048] R 13 is selected from hydroxy, C1-C4 alkoxy and -NH2; and

[0049] R 14 is independently selected at each selection from hydrogen, halogen, cyano, nitro, hydroxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2;

[0050] or a salt thereof.

[0051] In one embodiment, the present invention also provides a composition comprising: a compound of formula (I) or a salt thereof and an acceptable excipient, and the composition optionally further comprises at least one additional active compound.

[0052] In one embodiment, the present invention also provides a method for treating parasites, comprising: administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.

[0053] In one embodiment, the present invention also provides a method of controlling parasites, comprising: administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.

[0054] In one embodiment, the present invention also provides a method of treating or controlling parasites, comprising contacting the environment of a subject with an effective amount of a compound of formula (I) or a salt thereof, optionally further comprising an effective amount of at least one additional active compound.

[0055] Therefore, the present invention provides the use of the compounds of the present invention as a medicament, including for the manufacture of a medicament. In one embodiment, the present invention provides the manufacture of a medicament comprising a compound of formula (I) or a salt thereof for treating parasites. In one embodiment, the present invention provides the manufacture of a medicament comprising a compound of formula (I) or a salt thereof for controlling parasites.

[0056] The present invention also provides processes for preparing the compounds of the present invention and their intermediates. DETAILED DESCRIPTION

[0057] The term "C1-C4 alkyl" refers to a straight or branched alkyl chain having one to four carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl and the like.

[0058] The term "C1-C4 haloalkyl" refers to a straight or branched alkyl chain having one to four carbon atoms and one to five halogens, and includes fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and the like.

[0059] The term "C2-C4 alkenyl" refers to a straight or branched alkenyl chain having two to four carbon atoms and one carbon-carbon double bond, and includes ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, and the like.

[0060] The term "C2-C4 alkynyl" refers to a straight or branched alkynyl chain having two to four carbon atoms and one carbon-carbon triple bond, and includes acetylene, propargyl, and the like.

[0061] The term "C1-C4 alkoxy" refers to a C1-C4 alkyl group linked through an oxygen atom, and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.

[0062] The term "C3-C6 cycloalkyl" refers to an alkyl ring of three to six carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0063] The terms "halogen" and "halo" refer to a chlorine, fluorine, bromine or iodine atom.

[0064] The term "C6- or C 10 "-aryl" means phenyl or naphthyl.

[0065] The term "C6- or C 10 The term "phenyl- or naphthyl-based aryloxy" refers to a phenyl or naphthyl group linked via an oxygen atom, and includes phenoxy and naphthoxy.

[0066] The term "C6- or C 10"-arylthio-oxy" refers to a phenyl or naphthyl group attached through a sulfur atom and includes phenylthiooxy and naphthylthiooxy. It should also be understood that the term "C6- or C 10 The term "-arylsulfoxy" also encompasses those wherein sulfur is -SO2- and -S(O)-.

[0067] 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 selected from nitrogen, oxygen and sulfur, preferably one, two or three heteroatoms selected from nitrogen, oxygen and sulfur, and the ring optionally includes a carbonyl group to form a lactam or lactone. It should be understood that in the case of including sulfur, sulfur can be -S-, -SO- or -SO2-. The term, for example but not limited to, includes azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, dihydroimidazolyl, etc.

[0068] The term "5-membered heteroaryl" refers to a five-membered monocyclic fully unsaturated ring having one to four carbon atoms and one to four heteroatoms selected from nitrogen, oxygen and sulfur. The term includes, for example but not limited to, furyl, thienyl, pyrrolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, etc. It should be understood that the 5-membered heteroaryl can be connected as a substituent through a ring carbon or ring nitrogen atom, where such a connection mode is available, for example, for pyrrolyl, imidazolyl, pyrazolyl, triazolyl, etc.

[0069] The term "6-membered heteroaryl" refers to a six-membered monocyclic fully unsaturated ring having one to five carbon atoms and one or more, typically one to four, heteroatoms selected from nitrogen, oxygen and sulfur. The term includes, for example but not limited to, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, and the like. It should be understood that the 6-membered heteroaryl may be attached as a substituent via a ring carbon or ring nitrogen atom, where such a mode of attachment is available.

[0070] The term "5- to 10-membered heteroaryl" refers to a five- to ten-membered monocyclic or polycyclic fully unsaturated ring or ring system having one to nine carbon atoms and one or more heteroatoms selected from nitrogen, oxygen and sulfur, preferably one, two or three heteroatoms selected from nitrogen, oxygen and sulfur. This term includes, for example but not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, aza Base, diazepine , benzothiophenyl, indolyl, isoindolyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzoxazolyl, benzopyrazinyl, benzopyrazolyl, quinazolinyl, thienopyridinyl, quinolinyl, isoquinolinyl, benzothiazolyl, etc. It is understood that the 5- to 10-membered heteroaryl having 1, 2 or 3 heteroatoms selected from O, S and N may be attached as a substituent via a ring carbon or ring nitrogen atom, where such a mode of attachment is available.

[0071] The term "5- to 10-membered heteroaryloxy" refers to a 5- to 10-membered heteroaryl group having one or more heteroatoms selected from O, S and N, preferably 1, 2 or 3 heteroatoms selected from O, S and N, connected through an oxygen atom, and includes imidazolyloxy, pyrazolyloxy, pyridinyloxy, pyrimidinyloxy, quinolyloxy and the like.

[0072] The term "oxo" refers to an oxygen atom double-bonded to the carbon to which it is attached to form a carbonyl group of a ketone or aldehyde. For example, a pyridone radical is considered to be an oxo-substituted 6-membered heteroaryl group.

[0073] The term "carboxyl" refers to the following group:

[0074]

[0075] The term "carbamoyl" refers to the following radical:

[0076]

[0077] The term "C1-C4 alkoxycarbonyl" refers to the following groups:

[0078]

[0079] Wherein R is a C1-C4 alkyl group.

[0080] As used herein with respect to a group, substituent, moiety, etc., the term "nil" means that the group, substituent, or moiety is not present. If a group, substituent, or moiety is generally bonded to two or more other groups, substituents, or moieties, then the other groups, substituents, or moieties are bonded together, replaced by the group, substituent, or moiety that is nil. For example, for a compound having structure ABC; wherein B is nil, then A is directly bonded to C and the compound is AC. For another example, for a compound having structure ABC; wherein C is nil, then the compound is AB.

[0081] The term "salt" refers to salts of veterinary or pharmaceutically acceptable organic or inorganic acids and bases. Such salts are well known in the art and include those described in Journal of Pharmaceutical Science, 66, 2-19 (1977). An example is hydrochloride.

[0082] The term "substituted", including when used in "optionally substituted", refers to one or more hydrogen radicals of a group being replaced with non-hydrogen radicals (substituents). It should be understood that at each substitution position, the substituents may be the same or different. The combinations of groups and substituents contemplated by the present invention are those that are stable or chemically feasible. For the compounds described herein, the groups and substituents thereof may be selected based on the allowed valence states of the atoms and substituents, such that selection and substitution produce stable compounds, for example, which do not spontaneously transform, such as by rearrangement, cyclization, elimination, etc.

[0083] It should be understood that when cycloalkyl or heterocycloalkyl ring is substituted by spirocyclic group, when valence state allows, spirocyclic group can be connected to any position of cycloalkyl or heterocycloalkyl, thereby forming other ring, so that spirocyclic group is connected to cycloalkyl or heterocycloalkyl ring by shared atom.The example of such spirocyclic substituted ring includes 2-oxa-6-azaspiro [3.3] heptane, 2-azaspiro [3.3] heptane, 2-azaspiro [3.4] octane, 6-oxa-2-azaspiro [3.4] octane etc.

[0084] The term "stable" refers to a compound that is not substantially altered when subjected to conditions that permit its production. In a non-limiting example, a stable compound or chemically feasible compound is one that is not substantially altered when kept at 40° C. or less for about a week in the absence of moisture or other chemically reactive conditions.

[0085] It will be understood that where terms defined herein refer to numbers of carbon atoms, the referenced number relates to the referenced group and does not include any carbon in any optional substituents that may be present thereon or any carbon that may be present as part of a fused ring (including benzo-fused rings).

[0086] Those skilled in the art will appreciate that certain compounds of the present invention exist as isomers. All stereoisomers of the compounds of the present invention, including geometric isomers, enantiomers and diastereomers in any ratio, are considered to be within the scope of the present invention.

[0087] Those skilled in the art will also appreciate that certain compounds of the present invention exist as tautomers. All tautomeric forms of the compounds of the present invention are considered to be within the scope of the present invention.

[0088] The compounds of the present invention also include all isotopic variations in which at least one atom having the predominant atomic mass is replaced by an atom having the same atomic number but an atomic mass different from the predominant atomic mass. 2 The use of H) may provide greater metabolic stability. In addition, certain isotopic variations of the compounds of the invention may incorporate a radioactive isotope (e.g., tritium 3 H or 14 C), which may be useful in drug and / or substrate tissue distribution studies. 11 C. 18 F. 15 O and 13 N substitution may be useful in positron emission tomography (PET) studies.

[0089] The term "compounds of the invention / a compound of the invention / compounds of the present invention, etc." includes embodiments of formula (I) and other more specific embodiments encompassed by formula (I) described herein and exemplary compounds described herein and salts of each of these embodiments.

[0090] Compounds of formula (I) having G as defined have the following formula:

[0091]

[0092] Further embodiments of the compounds of the present invention are provided below:

[0093] (a) One embodiment relates to compounds of formula (Ia).

[0094] (b) One embodiment relates to compounds of formula (Ib).

[0095] (1) One embodiment relates to a compound of formula (Ic).

[0096] (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.

[0097] (c) One embodiment relates to a compound of formula (I), (la), (lb) or (lc) wherein X1 is CR1; X2 is CR2; X3 is CR3; X4 is CR4; X5 is CR5; and X6 is N; or a salt thereof.

[0098] (d) One embodiment relates to a compound of Formula (I), (Ia), (Ib) or (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.

[0099] (e) One embodiment relates to a compound of formula (I), (la) or (lb) wherein X1 is CR1; X2 is CR2; X3 is CR3; X4 is CR4; X5 is N; and X6 is CR6; or a salt thereof.

[0100] (f) One embodiment relates to a compound of formula (I), (la), (lb) or (lc) wherein X1 is CR1; X2 is CR2; X3 is CR3; X4 is N; X5 is N; and X6 is N; or a salt thereof.

[0101] (g) One embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e) and (f) wherein Q is a 6- or 10-membered aryl group which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, 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-haloalkyl and -SO2C1-C4 haloalkyl; or a salt thereof.

[0102] (h) One embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e) and (f) wherein Q is a 6-membered aryl group which is optionally substituted by 1, 2 or 3 groups independently selected from halogen, cyano, nitro, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, 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, -SO2C C1-C4-haloalkyl, -S(O)C1-C4-haloalkyl and -SO2C1-C4-haloalkyl, wherein the 6-membered aryl is fused with a 4- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from O, S and N and wherein the carbons of the heterocycloalkyl are optionally substituted with 1, 2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, 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 hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl; or a salt thereof.

[0103] (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 1 or 2 heteroatoms selected from O, S and N and wherein the carbons of the heteroaryl are optionally substituted with 1, 2 or 3 substituents independently selected from halogen, cyano, nitro, -OH, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2 and any N in the heteroaryl is optionally substituted with a substituent selected from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl; or a salt thereof.

[0104] (j) One embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e) and (f) wherein Q is a 4- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from O, S and N, wherein the heterocycloalkyl is optionally benzo-fused, wherein the carbons of the heterocycloalkyl or optionally benzo-fused heterocycloalkyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2 and any N in the heterocycloalkyl is optionally substituted with a substituent selected from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl; or a salt thereof.

[0105] (k) One embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e) and (f) wherein Q is a 6- or 10-membered aryloxy group which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, 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-haloalkyl and -SO2C1-C4 haloalkyl; or a salt thereof.

[0106] (1) One embodiment relates to compounds of formula (I) and embodiments (1), (2), (a), (b), (c), (d), (e) and (f), wherein Q is a 5- to 10-membered heteroaryloxy group, which is optionally substituted by 1, 2 or 3 groups independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, 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-haloalkyl and -SO2C1-C4 haloalkyl substituents; or their salts.

[0107] (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 (1), wherein n is 1; or a salt thereof.

[0108] (n) One embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (i), (j), (k), (1) and (m), wherein Y1 is CR8R9 and Y2 is O; or a salt thereof;

[0109] (o) One embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (i), (j), (k), (1), (m) and (n), wherein R4 is selected from C1-C4 alkyl, C3-C6 cycloalkyl, -N(C1-C4 alkyl)2 and 4- to 7-membered heterocycloalkyl; or a salt thereof.

[0110] (p) One embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (1), (2), (g), (h), (i), (j), (k), (1), (m) and (n), wherein R4 is -N(C1-C4 alkyl)2; or a salt thereof.

[0111] (q) One embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (i), (j), (k), (1), (m), (n), (o) and (p), wherein M is O; or a salt thereof.

[0112] (r) One embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (i), (j), (k), (1), (m), (n), (o) and (p), wherein M is NR 13 ; or a salt thereof.

[0113] (s) One embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (i), (j), (k), (1), (m), (n), (o) and (p), wherein M is S; or a salt thereof.

[0114] (t) One embodiment relates to compounds 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 , Z2 is CR 11 , Z3 is none, and Z4 is S; or a salt thereof.

[0115] (u) Another embodiment relates to a salt of each of the exemplified compounds.

[0116] Another embodiment provides a compound of the formula:

[0117]

[0118]

[0119]

[0120] or a salt of any of the foregoing compounds;

[0121] wherein X1, X2, X3, X4, X5, X6, R1, R4, R5, R7 and Q are as defined in the Summary of the Invention.

[0122] In another embodiment of Formulas (Ia-1) to (Ia-8a) [i.e., Formulas (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-1a), (Ia-2a), (Ia-3a), (Ia-4a), (Ia-5a), (Ia-6a), (Ia-7a) and (Ia-8a)], R1, when present [i.e., when explicitly depicted in the formula], is selected from hydrogen, halogen and cyano. In another embodiment of Formulas (Ia-1) to (Ia-8a), R1, when present, is selected from hydrogen, fluorine and cyano. In another embodiment of Formulas (Ia-1) to (Ia-8a), R1, when present, is hydrogen or fluorine. In another embodiment of Formulas (Ia-1) to (Ia-8a), R1, when present, is hydrogen. In another embodiment of Formulae (Ia-1) to (Ia-8a), R1, when present, is fluoro.

[0123] In another embodiment of Formulae (Ia-1) to (Ia-8a), R4, when present, is selected from:

[0124]

[0125] In another embodiment of Formulae (Ia-1) to (Ia-8a), R4, when present, is selected from:

[0126]

[0127] In another embodiment of Formulae (Ia-1) to (Ia-8a), R4, when present, is selected from:

[0128]

[0129] In another embodiment of formula (Ia-1) to (Ia-8a), R5, when present, is hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl. In another embodiment of formula (Ia-1) to (Ia-8a), R5, when present, is hydrogen, C1-C4 alkyl or C1-C4 haloalkyl. In another embodiment of formula (Ia-1) to (Ia-8a), R5, when present, is hydrogen, C1-C4 alkyl or C1-C4 haloalkyl. In another embodiment of formula (Ia-1) to (Ia-8a), R5, when present, is hydrogen, methyl or trifluoromethyl.

[0130] In another embodiment of Formulae (Ia-1) to (Ia-8a), R7, when present, is hydrogen.

[0131] In another embodiment of formula (Ia-1) to (Ia-8a), Q is selected from 6-membered aryl and 5- or 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the aryl or heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, C1-C4 haloalkyl and C1-C4 alkoxy. In another embodiment of formula (Ia-1) to (Ia-8a), Q is selected from 6-membered aryl, wherein the aryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen.

[0132] In another embodiment of Formula (Ia-1) to (Ia-8a), Q is selected from:

[0133]

[0134]

[0135] In another embodiment of Formula (Ia-1) to (Ia-8a), Q is selected from:

[0136]

[0137] In another embodiment of Formula (Ia-1) to (Ia-8a),

[0138] X1, X2, X3, X4, X5, and X6, when present, are as defined in the Summary of the Invention;

[0139] R1, when present, is selected from hydrogen, halogen and cyano;

[0140] R4, when present, is selected from:

[0141]

[0142] R5, when present, is selected from hydrogen, methyl and trifluoromethyl;

[0143] R7, when present, is hydrogen; and

[0144] Q is selected from:

[0145]

[0146]

[0147] or a salt thereof.

[0148] In another embodiment of Formula (Ia-1) to (Ia-8a),

[0149] X1, X2, X3, X4, X5, and X6, when present, are as defined in the Summary of the Invention;

[0150] R1, when present, is selected from hydrogen, halogen and cyano;

[0151] R4, when present, is selected from:

[0152]

[0153] R5, when present, is selected from hydrogen;

[0154] R7, when present, is hydrogen; and

[0155] Q is selected from:

[0156]

[0157] or a salt thereof.

[0158] In another embodiment, the compound of formula (I) or a salt thereof has formula (Ia-5),

[0159]

[0160] Wherein R1, R4 and Q are as defined in the summary of the invention. Preferably, R1 is hydrogen, halogen or cyano. More preferably, R1 is hydrogen or fluorine. Preferably, R4 is 4-morpholino or dimethylamino. Preferably, Q is a 6-membered aryl group, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, 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-haloalkyl and -SO2C1 -C4 haloalkyl, wherein the 6- or 10-membered aryl is optionally fused with a 4- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from O, S and N and wherein the carbons of the heterocycloalkyl are optionally substituted by 1, 2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxyl, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2 and any N in the heterocycloalkyl is substituted by a substituent selected from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl where valence permits. Preferably, Q is a 6-membered aryl substituted by 1, 2, 3, 4 or 5 substituents independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl and cyano. Preferably, Q is selected from:

[0161]

[0162] The compounds of the present invention can be prepared by a variety of procedures, some of which are described below. Unless otherwise indicated, all substituents are as previously defined.

[0163] The products of each step can be recovered by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, etc. The procedure may require protection of certain groups, such as hydroxyl, thiol, amino or carboxyl groups, to minimize unwanted reactions. The selection, use and removal of protecting groups are well known and considered standard practice, for example, in TW Greene and PGM Wuts, Protective Groups in Organic Chemistry (John Wiley and Sons, 1991).

[0164] As used herein: AcOH refers to acetic acid; aq. refers to aqueous solution, br refers to broad, CH3CN refers to acetonitrile, CH2Cl2 refers to dichloromethane, d refers to doublet, dd refers to double doublet, DIPEA refers to N-diisopropylethylamine, DMA refers to N,N-dimethylacetamide, DMF refers to N,N-dimethylformamide, DMSO refers to dimethyl sulfoxide, ee: refers to enantiomeric excess, eq. refers to equivalent, ES refers to electrospray ionization, EtOAc refers to EtOAc, EtOH refers to EtOH, HATU refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] Pyridinium 3-oxide hexafluorophosphate, HPLC refers to high performance liquid chromatography, iPrOH refers to isopropanol, J refers to coupling constant, KOAc refers to potassium acetate, K2CO3 refers to potassium carbonate, LCMS refers to liquid chromatography-mass spectrometry, m / z: refers to mass-to-charge ratio, M refers to molar concentration, m refers to multiplet, MeOH refers to mEtOH, min. refers to minute, NaHCO3 refers to sodium bicarbonate, Na2CO3 refers to sodium carbonate, NEt3 refers to triethylamine, NMR refers to nuclear magnetic resonance, NMP refers to N-methylpyrrolidone, PEG refers to polyethylene glycol, q refers to quartet, quint refers to quintet, rt refers to rt, R t refers to retention time, s refers to singlet, sat. refers to saturation, T refers to temperature, t refers to triplet, td refers to triplet doublet, THF refers to THF, wt refers to weight, and δ refers to chemical shift.

[0165] Plan A

[0166]

[0167] Scheme A depicts the reaction of a compound of formula (1) with a compound of formula (2) to obtain a compound of formula (Ia). The compound of formula (1) depicted is a compound wherein the group A1 is a hydroxyl group or an activated group as discussed below, and Q, M, X1, X2, X3, X4, X5, and X6 are as desired in the final compound of formula (Ia) or are groups that produce Q, M, X1, X2, X3, X4, X5, and X6 as desired in the final compound of formula (Ia). For example, the compound of formula (1) may be a compound wherein the group "Q" depicted is a halogen, which is further processed in a subsequent step not shown to obtain a compound wherein Q is as defined in formula (Ia). Also for example, a compound wherein M is O may be further processed to a compound wherein M is S or wherein M is NR 13Compounds of formula (1) are prepared as is well understood in the art. Compounds of formula (2) are compounds in which R7, Y1, Y2, Z1, Z2, Z3 and Z4 are desired in the final product of formula (Ia) or are groups that produce R7, Y1, Y2, Z1, Z2, Z3 and Z4 as desired in the final product of formula (Ia). The preparation of compounds of formula (2) is well understood in the art.

[0168] As described above, Scheme A depicts the reaction of a compound of formula (1) with a compound of formula (2) to obtain a compound of formula (Ia). Typical groups A1 are hydroxyl or a leaving group such as chloro, bromo or imidazolyl, an activating moiety, another carboxylic acid such as formic acid, a mixed anhydride of acetic acid, or another moiety representing a symmetrical anhydride formed from two compounds of formula (1). For example, standard amide formation conditions may be used, such as those using coupling agents, including those used in peptide couplings, such as 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methylammonium (HATU), dicyclohexylcarbodiimide (DCC), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl. If necessary or desired, additives such as 4-(dimethylamino)pyridine, 1-hydroxybenzotriazole, etc. may be used to promote the reaction. Such reactions are typically carried out using a base such as N-methylmorpholine or NEt3 in a variety of suitable solvents such as CH2Cl2, DMF, NMP, DMA, THF, etc. Such reactions are well known and understood in the art.

[0169] Those skilled in the art will recognize that compounds of formula (Ia) can be processed in a variety of ways to obtain other compounds of formula (Ia). Such reactions include hydrolysis, oxidation, reduction, alkylation, arylation (including heteroaryl groups), amidation, sulfonation, and the like.

[0170] Additionally, in an optional step not shown, the compound of formula (Ia) can be converted to a salt by methods well known and understood in the art.

[0171] Plan B

[0172]

[0173] Scheme B depicts the reaction of a compound of formula (3) with a compound of formula (4) to obtain a compound of formula (lb). In the depicted compound of formula (3), Q, R7, X1, X2, X3, X4, X5 and X6 are as desired in the final compound of formula (I) or are groups that produce Q, R7, X1, X2, X3, X4, X5 and X6 as desired in the final compound of formula (lb). For example, a compound of formula (3) may be a compound in which the depicted group "Q" is a halogen, which is further processed in a subsequent step not shown to obtain a compound in which Q is as defined in formula (lb). The preparation of such compounds of formula (3) is well understood in the art. The compound of formula (4) is such a compound, wherein the group A2 is a carboxyl group or an activated group as discussed below, and n, Y1, Y2, Z1, Z2, Z3 and Z4 are as desired in the final product of formula (Ib) or are groups that produce Y1, Y2, Z1, Z2, Z3 and Z4 as desired in the final product of formula (Ib). The preparation of such compounds of formula (4) is well understood in the art.

[0174] As described above, Scheme B depicts the reaction of a compound of formula (3) using a compound of formula (4) to give a compound of formula (Ib). Typically, group A2 is a carboxyl group or an acyl chloride or bromide, or an imidazide, an activated moiety, a mixed anhydride of another carboxylic acid such as formic acid, acetic acid, or another moiety representing a symmetrical anhydride formed from two compounds of formula (4) wherein A2 is a carboxyl derivative or another activated moiety. Such reactions are typically carried out using a base such as N-methylmorpholine or triethylamine in a variety of suitable solvents such as CH2Cl2, DMF, N-methylpyrrolidone (NMP), DMA, THF, and the like. It is well known that compounds of (Ib) wherein M is O can be further elaborated to compounds wherein M is S or wherein M is NR 13 of compounds.

[0175] Plan C

[0176]

[0177] Scheme C depicts the reaction of a compound of formula (5) with a compound of formula (6) to obtain a compound of formula (Ib). The compound of formula (5) depicted is the same as the compound of formula (3) described in Scheme B. The compound of formula (6) is a compound wherein R7 and n, Y1, Y2, Z1, Z2, Z3 and Z4 depicted are as desired in the final product of formula (Ib) or are groups that produce R7 and Y1, Y2, Z1, Z2, Z3 and Z4 depicted as desired in the final product of formula (Ib). The preparation of such compounds of formula (6) is well understood in the art. The formation of asymmetric ureas using phosgene, carbonyldiimidazole, isopropenylcarbamate and optionally substituted phenoxycarbonyl halides such as p-nitrophenoxycarbonyl chloride is well known.

[0178] Such a reaction is generally carried out by adding phosgene, carbonyldiimidazole, isopropenylcarbamate and optionally substituted phenoxycarbonyl halide to a compound of formula (5) or a compound of formula (6) in a sequential manner using a base such as N-methylmorpholine or triethylamine in a variety of suitable solvents such as CH2Cl2, DMF, N-methylpyrrolidone (NMP), DMA, THF, etc. Then, the other of compound (5) or compound (6) is added.

[0179] One of ordinary skill in the art will recognize that in Schemes B and C, compounds of formula (Ib) can be processed in a variety of ways to provide other compounds of formula (Ib). Such reactions include hydrolysis, oxidation, reduction, alkylation, arylation (including heteroaryl groups), amidation, sulfonation, etc. It is well known that compounds of (Ib) wherein M is O can be further processed to compounds wherein M is S or wherein M is NR 13 of compounds.

[0180] Additionally, in an optional step not shown, the compound of formula (Ib) can be converted to a salt by methods well known and understood in the art.

[0181] The following examples are intended to be illustrative rather than limiting and represent specific embodiments of the present invention.

[0182] 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 thermostated column compartment (G1316C), and a 1260 diode array detector (G4212B) coupled to an Agilent 6150 single quadrupole mass spectrometer (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 step size). A 1:1 split was used before the MS detector. The 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 drying gas temperature and flow 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 with a step size of 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 total MS scan cycle time was 0.15 s / cycle. Data acquisition was performed using Agilent Chemstation software.

[0183] Method A: The analysis was performed on a Phenomenex Gemini-NX C18 column, 50 mm long, 2.1 mm internal diameter, 3 μm particle size. The mobile phase used was: A1 = water containing 0.1% formic acid / B1 = CH3CN containing 0.1% formic acid. The run was performed at a temperature of 50°C and a flow rate of 1.2 mL / min, with a gradient elution from 5% to 95% (B1) in 1.5 minutes, then held at 95% (B1) for 0.5 minutes.

[0184] Method B: The analysis was performed on a Waters XBridge C18 column, 50 mm long, 2.1 mm internal diameter, 3.5 μm particle size. The mobile phase used was: A2 = water containing 10 mM ammonium bicarbonate, pH adjusted to 9 with ammonium hydroxide / B2 = CH3CN. The run was performed at a temperature of 50°C and a flow rate of 1.2 mL / min, with a gradient elution from 5% to 95% (B2) in 1.5 minutes, followed by a 0.5 minute hold at 95% (B2).

[0185] 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 spectrometer (MS) detector. UV (DAD) acquisition was performed with a scan range of 200-400 nm (resolution of 1.2 nm). MS was operated using an electrospray ionization source (ESI) in positive and negative ion modes. The capillary voltage was 3.50 (kV), the cone voltage was 35 (V), and the desolvation temperature was 550°C. The desolvation gas flow rate was 1000 (L / Hr) and the cone gas flow rate was 50 (L / Hr). The MS acquisition range was set to 100-1500 m / z. The MS scan cycle time was 0.5 seconds. Data acquisition was performed using Waters Masslynx software.

[0186] Method C: Analysis was performed on an Acquity UPLC BEH C18 column, 50 mm long, 2.1 mm internal diameter, 1.7 μm particle size. The mobile phase used was: A1 = water with 0.1% formic acid / B1 = CH3CN with 0.1% formic acid. The injection volume was 0.1 μL. The run was performed with a gradient elution at a temperature of 40°C and a flow rate of 0.6 mL / min. Method information (time (min) and B%): 0-5; 0.3-5; 2.5-95; 3.7-95; 4-5; 4.6-5.

[0187] Method D: Analysis was performed on an Acquity UPLC BEH C18 column, 50 mm long, 2.1 mm internal diameter, 1.7 μm particle size. The mobile phase used was: A1 = water containing 10 mM ammonium acetate / B1 = CH3CN containing 0.1% formic acid. The injection volume was 0.1 μL. The run was performed with a gradient elution at a temperature of 45°C and a flow rate of 0.5 mL / min. Method information (time (min) and A%): 0-98; 0.3-98; 3.2-2; 4.4-2; 4.7-98.

[0188] Example 1.1

[0189] N-[8-(3,5-dichlorophenyl)-4-(dimethylamino)-3-quinolyl]-2,3-dihydro-1,4-benzoxazine-4-carboxamide

[0190]

[0191] To a stirred solution of 8-bromoquinolin-4-ol (2 g, 8.82 mmol) in propionic acid (20 mL, 265 mmol) at 100 ° C was slowly added nitric acid (1 mL, 16 mmol) over 5 minutes. The reaction was heated to 125 ° C and stirred for 45 minutes. The reaction was then allowed to cool to room temperature, allowing the product to precipitate. The solid was collected by filtration and washed with water (3×10 mL), iPrOH (10 mL), isohexane (10 mL), and then dried in a vacuum oven for 1 hour to give 8-bromo-3-nitro-quinolin-4-ol. LCMS (Method B): R t =0.54min, m / z=269[M+H] + .

[0192] To the solution of 8-bromo-3-nitro-quinoline-4-alcohol (1.52g, 5.37mmol), add POCl (10mL, 107mmol).Suspension is heated to reflux and stirred 2 hours.Reaction mixture is allowed to cool to room temperature, and stand overnight.Vacuum concentration reaction mixture (with toluene azeotrope) obtains 8-bromo-4-chloro-3-nitro-quinoline, which is directly used in the next step without the need for further purification.

[0193] To a solution of 8-bromo-4-chloro-3-nitro-quinoline (2.32 g, 5.38 mmol) in THF (30 mL) was slowly added dimethylamine (2 M in THF, 7 mL, 14 mmol). The reaction was allowed to stir 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 organic layers were combined and concentrated in vacuo to give 8-bromo-N,N-dimethyl-3-nitro-quinoline-4-amine. LCMS (Method B): R t =1.13min, m / z=296[M+H] + .

[0194] To a solution of 8-bromo-N,N-dimethyl-3-nitro-quinolin-4-amine (505 mg, 1.62 mmol) was added (3,5-dichlorophenyl)boric 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, then evacuated and backfilled with N2 three times. 1,4-dioxane (9 mL) was added, followed by water (3 mL), and the reaction was heated to 100 ° C in a microwave for 1 hour. The reaction mixture was distributed between EtOAc and saturated aqueous NaHCO3 (50 mL each). The layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL). The organic layers were combined, concentrated in vacuo, and the residue was purified by column chromatography to give 8-(3,5-dichlorophenyl)-N,N-dimethyl-3-nitro-quinolin-4-amine. LCMS (Method B): R t =1.57min, m / z=362[M+H] + .

[0195] To a stirred suspension of 8-(3,5-dichlorophenyl)-N,N-dimethyl-3-nitro-quinolin-4-amine (401 mg, 1.05 mmol) in THF (5 mL), EtOH (5 mL) and water (2.5 mL) was added iron (184 mg, 3.23 mmol) and NH4Cl (168 mg, 3.13 mmol). The reaction was heated to 75 °C and stirred for 45 minutes. The reaction was allowed to cool to room temperature and then partitioned between saturated aqueous NaHCO3 and EtOAc (25 mL each). The mixture was stirred by Filter (wash with EtOAc) and separate the layers of the filtrate. The aqueous layer was extracted with EtOAc (2×25 mL), and the organic layers were combined and concentrated in vacuo. The residue was purified by column chromatography to give 8-(3,5-dichlorophenyl)-N4,N4-dimethyl-quinoline-3,4-diamine. LCMS (Method B): R t =1.48min, m / z=363.2[M+H] + .

[0196] To a stirred solution of 4-nitrophenyl chloroformate (88 mg, 0.42 mmol) in THF (2 mL) at 0° C. under N 2 atmosphere was added 8-(3,5-dichlorophenyl)-N 4 ,N 4 -dimethyl-quinoline-3,4-diamine (148 mg, 0.42 mmol) in THF (2.5 mL). The reaction was stirred at 0° C. for 30 minutes. The reaction solution was used directly in the next step.

[0197] 3,4-dihydro-2H-1,4-benzoxazine (71 mg, 0.51 mmol) and NEt3 (132 μL, 0.94 mmol) in THF (0.5 mL) were added to the reaction mixture. The reaction was stirred overnight at room temperature. The reaction mixture was partitioned between saturated aqueous NaHCO3 and CH2Cl2 (20 mL each). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic layers were purified by The crude product was purified by column chromatography to give the title compound. LCMS (Method B): R t =1.62min, m / z=493.0[M+H] + . 1 H NMR (400MHz, CDCl3) δ [ppm]: 9.95 (s, 1H), 9.13 (s, 1H), 7.91 (quint, J = 4.8Hz, 1H), 7.55 (d, J = 2Hz, 1H), 7.53 (d, J = 5.2Hz, 1H), 7.4 3(dd,J=1.6,8.4Hz,1H),7.38(t,J=2Hz,1H),7.17(m,1H),7.01(m,2H),4.36(t,J=4.4Hz,2H),4.02(t,J=4.8Hz,2H),2.9(s,6H).

[0198] Example 2.1

[0199] 8-(3,5-Dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide

[0200]

[0201] 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 hours. The reaction was allowed to cool to room temperature and concentrated in vacuo. It was used directly in the next step: toluene (145 mL) and NEt3 (9.8 mL, 70 mmol) were added, followed by 3-(dimethylamino)-prop-2-enoic acid ethyl ester (10.2 g, 69.6 mmol). The reaction was heated at 80°C and stirred for 45 minutes. The mixture was allowed to cool to room temperature and concentrated by The product was filtered (washed with EtOAc). The filtrate was concentrated in vacuo and the residue was partitioned between EtOAc and 2M HCl aqueous solution (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 in vacuo to give ethyl 2-(2-chloro-3-fluoro-pyridine-4-carbonyl)-3-(dimethylamino)-prop-2-enoate. LCMS (Method B): R t =0.86min,m / z=301.00[M+H] + .

[0202] To a solution of 2-(2-chloro-3-fluoro-pyridine-4-carbonyl)-3-(dimethylamino)-prop-2-enoic acid ethyl ester (188 mg, 0.59 mmol) in 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 minutes to form a precipitate. The reaction mixture was concentrated in vacuo to give a residue. The residue was triturated with cyclohexane to give 2-(2-chloro-3-fluoro-pyridine-4-carbonyl)-3-[(4-methoxyphenyl)methyl-amino]-prop-2-enoic acid ethyl ester. LCMS (Method B): R t =1.21min, m / z=393[M+H] + .

[0203] To a solution of 2-(2-chloro-3-fluoro-pyridine-4-carbonyl)-3-[(4-methoxyphenyl)methyl-amino]-prop-2-enoic acid ethyl ester (214 mg, 518 μmol) in DMF (2.6 mL) was added K2CO3 (230 mg, 1.66 mmol) at room temperature. The reaction mixture was heated at 40°C and stirred for 2 hours. 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 layers were separated. The aqueous layer was extracted with EtOAc (2×10 mL), and the combined organic layers were washed with water (20 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give 8-chloro-1-[(4-methoxyphenyl)methyl]-4-oxo-1,7-naphthyridine-3-carboxylic acid ethyl ester. LCMS (Method B): R t =1.01min, m / z=373[M+H] + .

[0204] (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, 8-chloro-1-[(4-methoxyphenyl)methyl]-4-oxo-1,7-naphthyridine-3-carboxylic acid ethyl ester (186 mg, 0.47 mmol) in 1,4-dioxane (2.4 mL, 28 mmol) was added, followed by water (0.8 mL), and the reaction mixture was heated in a microwave at 100 ° C for 1 hour. By The reaction mixture was filtered (washed with EtOAc). The filtrate was washed with water (20 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo, then purified by column chromatography to give ethyl 8-(3,5-dichlorophenyl)-1-[(4-methoxyphenyl)methyl]-4-oxo-1,7-naphthyridine-3-carboxylate. LCMS (Method B): R t =1.30min, m / z=483[M+H] + .

[0205] To a solution of 8-(3,5-dichlorophenyl)-1-[(4-methoxyphenyl)methyl]-4-oxo-1,7-naphthyridine-3-carboxylic acid ethyl ester (877 mg, 1.72 mmol) in CH2Cl2 (9 mL) was added anisole (1 mL, 1.74 mmol) and then TFA (2.5 mL, 33 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. A mixture of saturated NaHCO3 aqueous solution and EtOAc (25 mL each) was added to the crude product 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 in a vacuum oven to give 8-(3,5-dichlorophenyl)-4-hydroxy-1,7-naphthyridine-3-carboxylic acid ethyl ester. LCMS (Method B): R t =0.9min, m / z=363[M+H] + .

[0206] To a stirred suspension of ethyl 8-(3,5-dichlorophenyl)-4-hydroxy-1,7-naphthyridine-3-carboxylate (61 mg, 0.13 mmol) in CH2Cl2 (2 mL) was added oxalyl chloride (17 μL, 192 μmol) followed by DMF (1 μL, 13 μmol) and the resulting mixture was stirred at room temperature for 45 minutes. The reaction was quenched by the addition of 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 in vacuo to give ethyl 4-chloro-8-(3,5-dichlorophenyl)-1,7-naphthyridine-3-carboxylate. LCMS (Method B): R t =1.6min, m / z=381[M+H] + .

[0207] To a microwave vial was added 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). The vial was sealed, DIPEA (73 μL, 0.41 mmol) was added and the reaction mixture was heated in a microwave 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 in vacuo to give ethyl 8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxylate. LCMS (Method B): R t =1.5min, m / z=390[M+H] + .

[0208] To a stirred solution of ethyl 8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxylate (556 mg, 1.35 mmol) in THF (14 mL) was added a solution of lithium hydroxide (99 mg, 4.05 mmol) in water (4.5 mL) and MeOH (4.5 mL). The reaction mixture was heated at 40 ° C for 2 hours and stirred overnight at room temperature. Then, the mixture was concentrated in vacuo, and the residue was absorbed in water (25 mL). The aqueous layer was washed with EtOAc (25 mL), and then the pH was adjusted to 4 by adding 2M HCl aqueous solution to form a suspension. The precipitate was separated by filtration and dried in a vacuum oven overnight to obtain 8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxylic acid as a solid. LCMS (Method B): R t =0.78min, m / z=362[M+H]+ .

[0209] To a solution of 3,4-dihydro-2H-1,4-benzoxazine (504 mg, 3.73 mmol) in EtOH (4 mL) was added sodium nitrite (309 mg, 4.48 mmol) in water (1.6 mL) at room temperature under N2 atmosphere. The mixture was then cooled to 0°C. Concentrated HCl (0.39 mL, 4.7 mmol) was added dropwise to the reaction at 0°C. The reaction was then stirred at 0°C for 15 minutes.

[0210] A solution of sodium hydroxide (1.43 g, 35.87 mmol) in water (3.7 mL) was added at 0° C. followed by sodium dithionite (2.40 g, 11.75 mmol). The resulting suspension was heated to 90° C. for 2 hours and then cooled to room temperature.

[0211] The reaction 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 in vacuo. The residue was purified by column chromatography to give 2,3-dihydro-1,4-benzoxazine-4-amine (354 mg) as a light yellow oil. LCMS (Method B) R t =0.63min, m / z=151[M+H] + .

[0212] To a stirred suspension of 8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxylic acid (158 mg, 0.41 mmol) in DMF (5 mL) was added NEt3 (0.25 mL, 1.8 mmol) followed by 2,3-dihydro-1,4-benzoxazin-4-amine (79 mg, 0.501 mmol) and PyBOP (341 mg, 0.64 mmol). The reaction was allowed to stir at room temperature under N2 atmosphere for 48 hours. The reaction was diluted with brine (25 mL) and extracted with CH2Cl2 (3×15 mL). The combined organic layers were separated and concentrated in vacuo. The residue was purified by column chromatography to give the title compound. LCMS (Method B) R t =1.35min, m / z=494[M+H] + . 1H NMR (400MHz, DMSO-d6) δ [ppm]: 10.7 (s, 1H), 8.90 (s, 1H), 8.67 (d, J = 4.4Hz, 1H), 8.1 (m, 2H), 7.75 (t, J = 2Hz, 1H), 7. 03(dd,J=8,1.2Hz,1H),6.85(td,J=2,8Hz,1H),6.69-6.78(m,2H),4.38(t,J=4.4Hz,2H),3.68(s,2H),3.13(s,6H).

[0213] The following compounds were prepared similarly to the method of Example 2.1:

[0214]

[0215]

[0216]

[0217] Example 3.1

[0218] 8-(3,5-Dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxamide

[0219]

[0220] To 3,4-dichloropyridine-2-carboxylic acid (3.96 g, 20.6 mmol) was added thionyl chloride (15 mL, 205 mmol) and the reaction mixture was heated to 80° C. for 1 hour. The reaction was allowed to cool to room temperature and concentrated in vacuo to give 3,4-dichloropyridine-2-carbonyl chloride which was used in the next step without further purification.

[0221] To a stirred solution of 3,4-dichloropyridine-2-carbonyl chloride (20.6 mmol, 4.76 g) in toluene (50 mL) was added NEt3 (3.5 mL, 25 mmol) 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 (washed with EtOAc). The filtrate was concentrated in vacuo and the residue was partitioned between EtOAc and 1M aqueous HCl (100 mL each). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were concentrated in vacuo to give ethyl 2-(3,4-dichloropyridine-2-carbonyl)-3-(dimethylamino)prop-2-enoate. LCMS (Method B) R t =0.88min, m / z=317.0[M+H]+ .

[0222] To a stirred solution of ethyl 2-(3,4-dichloropyridine-2-carbonyl)-3-(dimethylamino)prop-2-enoate (5.58 g, 12.7 mmol) in ether (50 mL) and EtOH (12 mL) was added 4-methoxybenzylamine (1.9 mL, 14 mmol). The reaction was allowed to stir 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 combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give ethyl 2-(3,4-dichloropyridine-2-carbonyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate.

[0223] 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 the addition of 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 combined organic layers were purified by Filtered, then washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and reduced to dryness in vacuo. The crude material was purified by chromatography (0-6% MeOH / CH2Cl2) to give ethyl 8-hydroxy-1-[(4-methoxyphenyl)methyl]-4-oxo-1,5-naphthyridine-3-carboxylate.

[0224] 8-Hydroxy-1-[(4-methoxyphenyl)methyl]-4-oxo-1,5-naphthyridine-3-carboxylic acid ethyl ester (840mg, 1.09mmol) was dissolved in CH2Cl2 (11mL) and DMF (0.05mL). Oxalyl chloride (0.48mL, 5.5mmol) was added to the mixture and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled and quenched by the addition of saturated aqueous NaHCO3 solution (50mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×25mL). The combined organic layers were reduced in vacuo to give 4,8-dichloro-1,5-naphthyridine-3-carboxylic acid ethyl ester.

[0225] 4,8-dichloro-1,5-naphthyridine-3-carboxylic acid ethyl ester (950mg, 2.21mmol) was dissolved in THF (5mL). Dimethylamine (2mol / L) in THF (1.1mL, 2.2mmol, 2M) was added dropwise to the 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 / cyclohexane) to give 8-chloro-4-(dimethylamino)-1,5-naphthyridine-3-carboxylic acid ethyl ester. LCMS (Method B) R t =1.07min, m / z=280.0[M+H] + .

[0226] 8-Chloro-4-(dimethylamino)-1,5-naphthyridine-3-carboxylic acid ethyl ester (315mg, 0.93mmol) was dissolved in 1,4-dioxane (3mL) and water (1mL). To the mixture was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (40mg, 0.048mmol), followed by (3,5-dichlorophenyl)boric acid (215mg, 1.13mmol) and Na2CO3 (300mg, 2.83mmol). 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 / cyclohexane) to give 8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxylic acid ethyl ester. LCMS (Method B) R t =1.56min, m / z=390.0[M+H] + .

[0227] To a stirred 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 added lithium hydroxide (32 mg, 1.34 mmol) in water (2 mL). The reaction was heated to 100°C overnight. Then, the reaction mixture was cooled to room temperature. The reaction mixture was quenched by the addition of water (50 mL) and EtOAc (50 mL). The pH was adjusted to pH = 4 with 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 reduced in vacuo to give 8-(3,5-dichlorophenyl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxylic acid. LCMS (Method B) R t =0.82min, m / z=362.0[M+H] + .

[0228] A mixture of 2,3-dihydro-1,4-benzoxazine-4-amine (0.115 g, 0.73 mmol) and PyBOP (0.63 g, 1.21 mmol) was placed under 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) in THF (3 mL), followed by NEt3 (0.42 mL, 3 mmol). The resulting reaction mixture was allowed to stir at room temperature for more than 48 hours. The reaction mixture was quenched by the addition of saturated aqueous NaHCO3 solution (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 reduced in vacuo. The crude product was purified by column chromatography (10-50% EtOAc / cyclohexane) to give the title compound. LCMS (Method B) R t =1.39min, m / z=494.0[M+H] + . 1 H NMR (400MHz, CDCl3) δ [ppm]: 9.62 (s, 1H), 9.24 (s, 1H), 8.96 (d, J = 4.4Hz, 1H), 7.59 (m, 3H), 7.4 7(t,J=2Hz,1H),6.79-6.95(m,4H),4.50(t,J=4.4Hz,2H),3.74(t,J=4.8Hz,2H),3.35(s,6H).

[0229] The following compounds were prepared similarly to the method of Example 3.1:

[0230]

[0231]

[0232] Example 4.1

[0233] 5-(3,5-Dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-1-(dimethylamino)naphthalene-2-carboxamide

[0234]

[0235] 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 backfilled 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. The mixture was then allowed to cool to room temperature before being diluted with water (40 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography and the appropriate fractions were combined and concentrated in vacuo to give 1-(3,5-dichlorophenyl)-5-nitro-naphthalene.

[0236] 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 allowed to stir for 45 minutes. The mixture was then allowed to cool to room temperature and then filtered through Filter (wash with CH2Cl2). The filtrate was concentrated in vacuo, 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 in vacuo to give 5-(3,5-dichlorophenyl)naphthalen-1-amine. LCMS (Method B) R t =1.49min, m / z=288.0[M+H] + .

[0237] A solution of 5-(3,5-dichlorophenyl)naphthalene-1-amine (881 mg, 2.60 mmol) in DMF (10 mL) was placed under a N2 atmosphere, cooled to approximately -5°C in an ice / salt bath and treated with N-bromosuccinimide (474 ​​mg, 2.58 mmol). The resulting reaction mixture was then treated with saturated aqueous NaHCO3 (50 mL) to form a light brown precipitate. The mixture was extracted with CH2Cl2 (3×30 mL), and the combined organic layers were concentrated in vacuo. The residue was purified by column chromatography to give 2-bromo-5-(3,5-dichlorophenyl)naphthalene-1-amine. LCMS (Method B) R t =1.64min, m / z=365.8[M+H] + .

[0238] A suspension of 2-bromo-5-(3,5-dichlorophenyl)naphthalene-1-amine (0.73 g, 1.79 mmol) 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 warmed to 100°C and allowed to stir for 1 hour. The reaction mixture was allowed to cool to room temperature and then quenched by the careful addition of saturated aqueous NaHCO3 solution (60 mL). The mixture was then extracted with CH2Cl2 (3×20 mL), and the combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give 2-bromo-5-(3,5-dichlorophenyl)-N,N-dimethyl-naphthalene-1-amine. LCMS (Method B) R t =1.93min, m / z=393.8[M+H] + .

[0239] A solution of 2-bromo-5-(3,5-dichlorophenyl)-N,N-dimethyl-naphthalen-1-amine (532 mg, 1.28 mmol) in 1,4-dioxane (10 mL) 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) in a pressure vessel and then stirred at 100°C under a CO atmosphere (50 psi) for 16 hours. The reaction mixture was then allowed to cool to room temperature, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give methyl 5-(3,5-dichlorophenyl)-1-(dimethylamino)naphthalene-2-carboxylate. LCMS (Method B) R t =1.75min, m / z=374.0[M+H] + .

[0240] 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 hours. The reaction mixture was allowed to cool to room temperature and then treated with 2M HCl (17.5 mL - to make the mixture slightly basic). The aqueous layer was extracted with CH2Cl2 (3×25 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give 5-(3,5-dichlorophenyl)-1-(dimethylamino)naphthalene-2-carboxylic acid. LCMS (Method B) R t =1.10min, m / z=358.0[MH] - .

[0241] 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 N2 atmosphere and treated with a solution of 5-(3,5-dichlorophenyl)-1-(dimethylamino)naphthalene-2-carboxylic acid (192 mg, 426 μmol) in THF (3 mL), followed by NEt3 (0.30 mL, 2.2 mmol). The resulting reaction mixture was allowed to stir overnight at room temperature. 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 in vacuo. The crude product was purified by column chromatography to give the title compound. LCMS (Method B) R t =1.61min, m / z=492.2[M+H] + . 1 H NMR (400MHz, DMSO) [ppm]: 10.5 (s, 1H), 8.36 (d, J = 8.6Hz, 1H), 7.75 (t, J = 2Hz, 1H), 7.64-7.68 (m, 1H), 7.60-7.48 (m, 5H), 6.98 (dd, J = 8,1.4Hz,1H),6.86-6.80(m,1H),6.77(dd,J=8,1.6Hz,1H),6.73-6.67(m,1H),4.38(t,J=4.3Hz,2H),3.70-3.63(m,2H),2.99(s,6H).

[0242] Example 5.1

[0243] 8-(3,5-Dichlorophenyl)-N-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-4-(dimethylamino)quinoline-3-carboxamide

[0244]

[0245] A solution of 2-bromoaniline (7.96 g, 44.9 mmol) and diethyl 2-(ethoxymethylene)malonate (11 mL, 53.8 mmol) was heated to 125°C for 1 hour. LCMS (Method B) R t =1.28min, m / z=342.0

[0246] [M+H] + . Add diphenyl ether (100 mL) and heat the reaction to 250 °C and stir for 48 hours. Allow the reaction to cool to room temperature and a precipitate will form. Add diethyl ether (100 mL) and isolate the precipitate by filtration (wash with diethyl ether).

[0247] And vacuum dried to obtain 8-bromo-4-hydroxy-quinoline-3-carboxylic acid ethyl ester. LCMS (Method B) R t =0.69, m / z=296.0[M+H] + .

[0248] A suspension of 8-bromo-4-hydroxy-quinoline-3-carboxylic acid ethyl ester (2.0 g, 6.42 mmol) in CH2Cl2 (20 mL) was placed under 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 allowed to stir for 45 minutes. The reaction mixture was allowed to cool to room temperature and then concentrated in vacuo to give 8-bromo-4-chloro-quinoline-3-carboxylic acid ethyl ester. LCMS (Method B) R t =1.28min, m / z=314.0[M+H] + .

[0249] To 8-bromo-4-chloro-quinoline-3-carboxylic acid ethyl ester (2.13 g, 6.42 mmol) was added dimethylamine (2 M) in THF (13 mL) under N2 atmosphere. The resulting mixture was warmed to 60°C and allowed to stir for 15 minutes. The reaction mixture was concentrated in vacuo, then treated with saturated aqueous NaHCO3 (40 mL) and washed with EtOAc (3 x 10% by volume).

[0250] 30mL) extraction. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The residue was subjected to column chromatography (20-60% EtOAc / cyclohexane) to give ethyl 8-bromo-4-(dimethylamino)quinoline-3-carboxylate. LCMS (Method B) R t =1.23min, m / z=323.0[M+H] + .

[0251] Under N2 atmosphere, a reaction mixture of 8-bromo-4-(dimethylamino)quinoline-3-carboxylic acid ethyl ester (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. The reaction mixture was allowed to cool to room temperature, then diluted with water (70 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic layers were filtered and concentrated in vacuo. The residue was purified by column chromatography (0-30% EtOAc / cyclohexane) to give 8-(3,5-dichlorophenyl)-4-(dimethylamino)quinoline-3-carboxylic acid ethyl ester. LCMS (Method B) Rt =1.67min, m / z=389.0[M+H] + .

[0252] A solution of ethyl 8-(3,5-dichlorophenyl)-4-(dimethylamino)quinoline-3-carboxylate (2.82 g, 6.17 mmol) 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 warmed to 100 °C and stirred overnight. The reaction mixture was allowed to cool to room temperature, then acidified to pH 2 with 2M HCl and extracted with EtOAc (3×30 mL). The aqueous phase was basified to pH 6 and extracted with 10% MeOH / CH2Cl2 (3×30 mL). The organic phases were combined and concentrated in vacuo to give 8-(3,5-dichlorophenyl)-4-(dimethylamino)quinoline-3-carboxylic acid. LCMS (Method B) R t =0.94min, m / z=361.0

[0253] [M+H] + .

[0254] To a stirred suspension of 8-(3,5-dichlorophenyl)-4-(dimethylamino)quinoline-3-carboxylic acid (160 mg, 0.35 mmol) in DMF (3.5 mL) was added NEt3 (200 μL, 1.42 mmol) followed by 2,3-dihydro-1,4-benzoxazin-4-amine (67 mg, 0.42 mmol) and PyBOP (282 mg, 0.53 mmol). The reaction was allowed to stir overnight at room temperature under N2 atmosphere. The reaction 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 give the title compound. LCMS (Method B) R t =1.47min, m / z=493.0[M+H] + . 1 HNMR(400MHz, DMSO)[ppm]:9.04(s,1H),8.4(s,1H),8.20(dd,J=1.6Hz,J=8.8Hz,1H),7.69-7.71(m,1H),7.58-7.62(m,1H ), 7.52 (d, J = 2Hz, 2H), 7.4 (t, J = 1.6Hz, 1H), 6.79-6.97 (m, 4H), 4.49 (t, J = 4.4Hz, 2H), 3.74 (t, J = 4.4Hz, 2H), 3.19 (s, 6H).

[0255] The following compounds were prepared similarly to the method of Example 5.1:

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273] Example 6.1

[0274] 4-(3,5-Dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-morpholino-pyrido[3,2-d]pyrimidine-7-carboxamide

[0275]

[0276] To a suspension of ethyl 6-hydroxypyrimidine-4-carboxylate (5.03 g, 28.74 mmol) in DMF (25 mL) was added 1,3-dichloro-5,5-dimethylhydantoin (3.48 g, 17.3 mmol) under N2 atmosphere. The mixture was stirred at room temperature overnight. The reaction 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 in vacuo to give ethyl 5-chloro-6-hydroxy-pyrimidine-4-carboxylate. LCMS (Method A) R t =0.54min, m / z=203.0[M+H] + .

[0277] To a suspension of 5-chloro-6-hydroxy-pyrimidine-4-carboxylic acid ethyl ester (8.74 g, 28.1 mmol) in CH3CN (100 mL) was added DIPEA (6.4 mL, 36 mmol) and then phosphorus oxybromide (9.44 g, 31.28 mmol) at room temperature under N2 atmosphere. The resulting mixture was stirred at room temperature. The reaction was diluted with CH2Cl2 (100 mL) and slowly poured into water (100 mL). The mixture was then extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The oil was purified by column chromatography (0-10% EtOAc / cyclohexane) to give 6-bromo-5-chloro-pyrimidine-4-carboxylic acid ethyl ester. LCMS (Method A) R t =0.98min, m / z=265.0[M+H] + .

[0278] To a stirred solution of 6-bromo-5-chloro-pyrimidine-4-carboxylic acid ethyl ester (4.31 g, 14.9 mmol) and (3,5-dichlorophenyl)boronic acid (2.71 g, 14.20 mmol) in 1,4-dioxane (55 mL) under N2 was added K2CO3 (8.69 g, 62.9 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (732 mg, 0.63 mmol). The reaction was degassed and placed under N2 and then heated to 90°C over 16 hours. The mixture was diluted with EtOAc (50 mL) and filtered through The combined organic filtrates were concentrated in vacuo. The residue was purified by column chromatography (0-20% EtOAc / cyclohexane) to give ethyl 5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carboxylate. LCMS (Method B) R t =1.43min, m / z=331.0[M+H] + .

[0279] 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) was added lithium hydroxide (624 mg, 25.6 mmol) at room temperature under N2 atmosphere. The resulting mixture was heated to 50 ° C for 1 hour. 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 with 2M HCl until pH = 1, causing solid precipitation. The precipitate was filtered off and washed with water (25 mL). The precipitate was then dried in vacuo at 50 ° C to give 5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carboxylic acid. LCMS (Method B) R t =0.72min, m / z=303.0[M+H] + .

[0280] 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 N2 atmosphere. DMF (0.5 mL, 6 mmol) was added and the reactants dissolved completely. The reactants were then concentrated in vacuo, taken up in toluene (20 mL) and azeotroped (3 times) to give 5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carbonyl chloride, which was used without further purification.

[0281] To 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 NEt (2 mL, 14 mmol) followed by ethyl 3-(dimethylamino)prop-2-enoate (1.4 mL, 9.7 mmol) at room temperature under N2 atmosphere. The reaction was stirred at room temperature under N2 atmosphere. The reaction was diluted with EtOAc (125 mL) and filtered. Filter. Rinse with EtOAc (125 mL) The combined organic filtrate was concentrated in vacuo. The residue was taken up in EtOAc (250 mL) and 2M HCl (aqueous solution, 100 mL). The aqueous layer was extracted with EtOAc (125 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give ethyl 2-[5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carbonyl]-3-(dimethylamino)prop-2-enoate. LCMS (Method B) R t =1.24min, m / z=428.0[M+H] + .

[0282] To 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 4-methoxybenzylamine (1.20 mL, 9.09 mmol) over 1 hour at room temperature under N2 atmosphere. The reaction 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 in vacuo to give ethyl 2-[5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carbonyl]-3-[(4-methoxyphenyl)methylamino]prop-2-enoate. The material was taken on without any further purification. LCMS (Method B) R t =1.49min, m / z=520.0[M+H] + .

[0283] To a solution of ethyl 2-[5-chloro-6-(3,5-dichlorophenyl)pyrimidine-4-carbonyl]-3-[(4-methoxyphenyl)methylamino]prop-2-enoate (4.4 g, 5.66 mmol) in DMF (15 mL) was added K2CO3 (2.37 g, 17.1 mmol) at room temperature under N2 atmosphere. The resulting mixture was heated to 90°C for 24 hours. The reaction was cooled to room temperature, 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 in vacuo. The residue was purified by column chromatography (0-5% MeOH / CH2Cl2) to give ethyl 4-(3,5-dichlorophenyl)-5-[(4-methoxyphenyl)methyl]-8-oxo-pyrido[3,2-d]pyrimidine-7-carboxylate. LCMS (Method B) R t =1.17min, m / z=484.0[M+H] + .

[0284] To a solution of 4-(3,5-dichlorophenyl)-5-[(4-methoxyphenyl)methyl]-8-oxo-pyrido[3,2-d]pyrimidine-7-carboxylic acid ethyl ester (1.89 g, 3.70 mmol) in CH2Cl2 (75 mL) and DMF (0.5 mL) was slowly added oxalyl chloride (2 mL, 23.1 mmol) at room temperature under 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 the addition of saturated aqueous NaHCO3 solution (200 mL) and extracted with CH2Cl2 (3×100 mL). The combined organic layers were combined and then concentrated in vacuo to give 8-chloro-4-(3,5-dichlorophenyl)pyrido[3,2-d]pyrimidine-7-carboxylic acid ethyl ester. LCMS (Method B) R t =1.52min, m / z=382.0[M+H] + .

[0285] To a solution of 8-chloro-4-(3,5-dichlorophenyl)pyrido[3,2-d]pyrimidine-7-carboxylic acid ethyl ester (502mg, 0.93mmol) in THF (10mL, 123mmol) was added morpholine (0.17mL, 1.9mmol) dropwise at room temperature under N2 atmosphere. The reaction was stirred at room temperature for 3 hours. The reaction was then quenched with saturated NaHCO3 aqueous solution (50mL) and extracted with CH2Cl2 (3×25mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (10-25% EtOAc / cyclohexane) to give 4-(3,5-dichlorophenyl)-8-morpholino-pyrido[3,2-d]pyrimidine-7-carboxylic acid ethyl ester. LCMS (Method B) R t =1.56min, m / z=433.0[M+H] + .

[0286] 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 N2 atmosphere. The resulting mixture was heated to 80 °C. The reaction was concentrated in vacuo, and the residue was taken up in water (20 mL) and acidified with 2M HCl. The resulting precipitate was filtered off and washed with water (20 mL), then dried in vacuo at 45 °C overnight to give 4-(3,5-dichlorophenyl)-8-morpholino-pyrido[3,2-d]pyrimidine-7-carboxylic acid. LCMS (Method B) R t =0.80min, m / z=405.0[M+H] + .

[0287] To 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 NEt3 (0.18 mL, 1.3 mmol) followed by PyBOP (259 mg, 0.49 mmol). The reaction was stirred at room temperature under an atmosphere of N2. 2,3-dihydro-1,4-benzoxazine-4-amine (60.5 mg, 0.40 mmol) in THF (1 mL) was then added to the reaction. The mixture was stirred at room temperature for 22 hours. 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 in vacuo. The residue was purified by column chromatography (5-40% EtOAc / cyclohexane) to give the title compound. LCMS (Method B) R t =1.38min, m / z=537.0[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ [ppm]: 10.75 (s, 1H), 9.38 (s, 1H), 8.92 (s, 1H), 8.31 (d, J = 2Hz, 2H), 7.87 (t, J = 2Hz, 1H), 7.01 (dd, J = 1.2,8Hz,1H),6.85(td,J=1.6,8.4Hz,1H),6.69-6.78(m,2H),4.38(t,J=4.4Hz,2H),3.86(t,J=4Hz,4H),3.63-3.73(m,6H).

[0288] Example 7.1

[0289] 8-(3,5-Dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,6-naphthyridine-3-carboxamide

[0290]

[0291] To a stirred solution of 3,4-dihydro-2H-1,4-benzoxazine in EtOH (8 mL) was added sodium nitrite (612 mg, 8.87 mmol) in water (3.2 mL) dropwise at 0°C. After 5 minutes, HCl (0.8 mL) was added dropwise and the reaction mixture was stirred at 0°C for 2 hours. NaOH (2.96 g, 74 mmol) in water (7.5 mL) was added dropwise to the reaction mixture at 0°C, followed by sodium dithionite (4.4 g, 22.2 mmol). The resulting reaction mixture was heated to 90°C for 4 hours. The reaction mixture was dissolved in EtOAc (20 mL), washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude compound was purified by column chromatography, eluting with 0-50% EtOAc / petroleum ether. LCMS (Method C) R t =0.89min,m / z=152.36[M+H] + .

[0292] A mixture of 3-bromopyridin-4-amine (10.0 g, 57.8 mmol) and diethyl 2-(ethoxymethylene)malonate (32.8 mL, 173 mmol) was heated to 120°C for 16 hours. The reaction mixture was allowed to reach room temperature, reduced to dryness in vacuo and purified by column chromatography eluting with 0-50% EtOAC / petroleum ether to give diethyl 2-[[(3-bromo-4-pyridinyl)amino]methylene]malonate. LCMS (Method C) R t =1.71min, m / z=343.19[M+H] + .

[0293] A solution of 2-[[(3-bromo-4-pyridinyl)amino]methylene]malonate (2.8 g, 8.12 mmol) in diphenyl ether (42 mL) was heated to 250 °C for 30 minutes. The reaction mixture was allowed to cool 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 vacuum to give ethyl 8-bromo-4-hydroxy-1,6-naphthyridine-3-carboxylate. LCMS (Method C) R t =1.16min, m / z=297.11[M+H] + .

[0294] 8-Bromo-4-hydroxy-1,6-naphthyridine-3-carboxylic acid ethyl ester (4.3 g, 14.5 mmol) was added to POCl3 (43 mL) and heated to 90 ° C for 6 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted in EtOAc (100 mL), washed with saturated NaHCO3 aqueous solution (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 / petroleum ether. LCMS (Method C) R t =2.30min, m / z=315.09[M+H] + .

[0295] To a stirred solution of 8-bromo-4-chloro-1,6-naphthyridine-3-carboxylic acid ethyl ester (3 g, 9.5 mmol) in THF (60 mL) was added morpholine (4.1 g, 47.5 mmol) at room temperature and 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 / petroleum ether to give 8-bromo-4-morpholino-1,6-naphthyridine-3-carboxylic acid ethyl ester. LCMS (Method C) R t =1.65min, m / z=366.24[M+H] + .

[0296] To a stirred 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 added Cs2CO3 (2.13 g, 6.55 mmol), followed by tri-tert-butylphosphonium tetrafluoroborate (0.127 g, 0.43 mmol) and degassed under N2 for 10 minutes. PdCl2(dppf) (0.16 g, 0.21 mmol) was added to the reaction mixture and heated to 90°C for 16 hours. The reaction mixture was dissolved in EtOAc (30 mL), washed with water (15 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to dryness. The crude product was purified by column chromatography eluting with 0-50% EtOAc / petroleum ether. LCMS (Method C) R t =2.33min, m / z=432.30[M+H] + .

[0297] To a stirred 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 added LiOH.H2O (0.16 g, 3.81 mmol) at room temperature and heated to 70°C for 4 hours. The reaction mixture was allowed to cool to room temperature and then concentrated to remove the solvent. The pH was adjusted to 6-7 with 0.5 M aqueous HCl under cooling conditions (0°C) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to dryness. LCMS (Method C) R t =2.15min, m / z=403.9[M+H] + .

[0298] To a stirred 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-benzoxazine-4-amine (134 mg, 0.89 mmol) in DMF (5 mL) was 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 hours. The reaction mixture was quenched by the addition of water (5 mL) and extracted with EtOAc (3×15 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 / petroleum ether to give the title compound. LCMS (Method D) R t =2.12min, m / z=536.24[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ [ppm]: 10.75 (s, 1H), 9.03 (s, 1H), 8.84 (s, 1H), 7.77 (d, J = 2Hz, 2H), 7.72 (t, J = 2Hz, 1H), 7.03(m,1H),6.85(td,J=2,7.2Hz,1H),6.72-6.78(m,2H),4.38(t,J=4.4Hz,2H),3.92(t,J=3.6Hz,4H),3.69(br s, 2H), 3.39 (t, J = 4Hz, 4H).

[0299] Example 8.1

[0300] N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-2-methyl-4-morpholino-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide

[0301]

[0302] To a stirred 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 added NaOH (0.132 g, 3.3 mmol). The resulting reaction mixture was stirred at 100 °C for 12 h. The mixture was quenched by the addition of water (200 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers 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 give ethyl 8-bromo-4-hydroxy-2-methyl-quinoline-3-carboxylate. LCMS (Method C) R t =1.54min, m / z=310.22[M+H] + .

[0303] To a stirred solution of 8-bromo-4-hydroxy-2-methyl-quinoline-3-carboxylic acid ethyl ester (0.3 g, 0.96 mmol) in EtOH (5 mL) was added KOH (0.814 g, 14.5 mmol) at room temperature and heated to 80° C. for 24 hours. The reaction mixture was allowed to reach room temperature and concentrated. The pH of the residue was adjusted to 1-2 using 2N HCl aqueous solution and the precipitated solid was filtered, washed with water (10 mL) and dried to give 8-bromo-4-hydroxy-2-methyl-quinoline-3-carboxylic acid. LCMS (Method C) R t =1.46min, m / z=280.05[MH] - .

[0304] A mixture of 8-bromo-4-hydroxy-2-methyl-quinoline-3-carboxylic acid (0.2 g, 0.7 mmol) and POCl (10 mL) was heated to 90° C. for 2 h. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to give 8-bromo-4-chloro-2-methyl-quinoline-3-carbonyl chloride.

[0305] To a stirred solution of 2,3-dihydro-1,4-benzoxazin-4-amine (0.188 g, 1.25 mmol) in THF (3 mL) was added DIPEA (0.342 g, 2.5 mmol) and cooled to 0-5 °C. To the reaction mixture was added a solution of 8-bromo-4-chloro-2-methyl-quinoline-3-carbonyl chloride (0.2 g, 0.62 mmol) in 2 mL of THF and allowed to stir at room temperature. The reaction mixture was quenched by the addition of 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 give 8-bromo-4-chloro-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-methyl-quinoline-3-carboxamide. LCMS (Method C) Rt = 2.12 min, m / z = 432.06 [M+H] + .

[0306] To a stirred 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) in THF (5 mL) was added Et3N (0.116 g, 1.15 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by the addition of 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 ether (30 mL) to give 8-bromo-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-methyl-4-morpholino-quinoline-3-carboxamide. LCMS (Method C) Rt=2.25 min, m / z=483.49 [M+H] + .

[0307] To a stirred solution of 8-bromo-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-methyl-4-morpholino-quinoline-3-carboxamide (0.3 g, 0.62 mmol) and (2,3,5-trifluorophenyl)boronic acid (0.656 g, 3.72 mmol) in 1,4-dioxane (12 mL): water (3 mL) was added CsCO, the reaction mixture was degassed with N gas for 10 min, then [(t-Bu)PH]BF (0.036 g, 0.12 mmol) and PdCl(dppf) (0.045 g, 0.06 mmol) were added and heated to 90 °C for 16 h. The reaction mixture was quenched by the addition of water (200 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO and concentrated under reduced pressure. The crude compound was purified by column chromatography and eluted with 10% EtOAc / petroleum ether to give Example 8.1. LCMS (Method C) Rt=2.29 min, m / z=535.22 [M+H] + . 1 H NMR (400MHz, DMSO) δ [ppm]: 10.57 (s, 1H), 8.31 (d, J = 7.6Hz, 2H) 7.79 (d, J = 6.4Hz, 2H), 7.69 (t, J = 8.4Hz, 1H), 7.59-7.61 (m, 1H), 7.20-7.21 (m ,1H),6.99(d,J=6.8Hz,1H),6.85(td,J=1.6,6.8Hz,1H),6.74-6.79(m,2H),4.39(t,J=4Hz,2H),3.87(t,J=4Hz,4H),3.72(brs,2H),3.32(br s,4H),2.55(s,3H).

[0308] Example 8.2

[0309] N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-morpholino-2-(trifluoromethyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide

[0310]

[0311] Step 1: To a stirred solution of 7-bromoindoline-2,3-dione (2.5 g, 11.06 mmol) and ethyl 4,4,4-trifluorobut-2-ynoate (1.83 g, 11.06 mmol) in DMF (15 mL) was added Na2CO3 (2.34 g, 22.12 mmol) followed by 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 the addition of water (20 mL) and extracted with ethyl (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 / petroleum ether to give ethyl 8-bromo-4-hydroxy-2-(trifluoromethyl)quinoline-3-carboxylate. LCMS (Method C) Rt = 2.29 min, m / z = 364.14

[0312] [M+H] + .

[0313] Step 2: To a stirred solution of ethyl 8-bromo-4-hydroxy-2-(trifluoromethyl)quinoline-3-carboxylate (1.75 g, 4.80 mmol) in EtOH (10 mL) was added KOH (5.39 g, 96.12 mmol) at room temperature and heated to 90°C for 24 hours. The reaction mixture was allowed to reach room temperature and concentrated. The pH of the residue was adjusted to 1-2 using 2N HCl aqueous solution and the precipitated solid was filtered, washed with water (10 mL), ether (20 mL) and dried to give 8-bromo-4-hydroxy-2-(trifluoromethyl)quinoline-3-carboxylic acid. LCMS (Method C) Rt = 1.79 min, m / z = 335.99 [M+H] + .

[0314] 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 to 90°C for 2 hours. The reaction mixture was allowed to reach room temperature and concentrated under reduced pressure to give 8-bromo-4-chloro-2-(trifluoromethyl)quinoline-3-carbonyl chloride.

[0315] Step 4: To a stirred solution of 2,3-dihydro-1,4-benzoxazin-4-amine (0.8 g, 5.36 mmol) in THF (5 mL) was added DIPEA and cooled to 0-5°C. To the reaction mixture was added a solution of 8-bromo-4-chloro-2-(trifluoromethyl)quinoline-3-carbonyl chloride (1 g, 2.68 mmol) in 4 mL THF and allowed to stir at room temperature for 16 hours. The reaction was quenched by the addition of water (20 mL) and 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 / petroleum ether to give 8-bromo-4-chloro-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-(trifluoromethyl)quinoline-3-carboxamide. LCMS (Method C) Rt = 2.23 min, m / z = 486.04 [M+H] + .

[0316] Step 5: To a stirred 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 added morpholine (1.5 mL, 17.34 mmol) at room temperature and stirred for 16 hours. The reaction mixture was concentrated to dryness. The crude material was purified by column chromatography eluting with 0-50% EtOAc / petroleum ether to give 8-bromo-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-2-(trifluoromethyl)quinoline-3-carboxamide. LCMS (Method C) Rt=2.18 min, m / z=537.08 [M+H] + .

[0317] Step 6: To a stirred 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 added Cs2CO3 (0.636 g, 1.95 nmmol). 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 the addition of 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 / petroleum ether to afford Example 8.2 as a white solid. LCMS (Method C) Rt=2.27 min, m / z=589.39 [M+H]+. 1H NMR (400MHz, DMSO) δ [ppm]: 10.62 (s, 1H), 8.45 (d, J = 8.4Hz, 2H), 8.03 (d, J = 7.2Hz, 2H), 7.94 (t, J = 8.4Hz, 1H), 7.65-7.67 (m,1H),7.29-7.31(m,1H),7.03(d,J=7.6Hz,1H),6.83-6.87(mz,1H),6.76-6.80(m,2H),4.39(t,J=3.6Hz,2H),3.87(br s,4H),3.64(br s,2H),3.43(br s,4H).

[0318] Experimental details of the compounds are in the table:

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338] The compounds of formula (I) according to the invention can be used for the treatment and / or control of helminths, in particular, of which endoparasitic nematodes and flukes can be the cause of serious diseases in mammals and poultry. Typical nematodes for this indication are: Filariidae, Setariidae, Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostomum, Oesophagostonum, Charbertia, Trichuris, The nematodes include the genera of Fasciolideae, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris. Trematodes include in particular the family Fasciolideae, especially Fasciola hepatica.

[0339] Some parasites of the genera of Nematode, Cooperia, and Nodosa live on the intestinal tract of the host animal, while others of the genera of Haemonchus and Osterlegia live in the stomach, and those of the genera of Dictyocaulus live in the lung tissue. Parasites of these families can be found in internal cellular tissues and in organs such as the heart, blood vessels, lymphatic vessels, and subcutaneous tissue. One parasite of particular concern is the dog's heartworm: Dirofilaria immitis.

[0340] Parasites that can be treated and / or controlled by the compounds of formula (I) also include those from the class of Cestoda (tapeworms), for example the family Mesocestoidae, in particular Mesocestoides, in particular M. lineatus; Dipylidiidae, in particular Dipylidium caninum, Joyeuxiella spp., in particular Joyeuxiella pasquali and Diplopylidium spp., and Taeniidae, in particular Taenia pisformis, Taenia cervi, Taenia spp. ovis), Taenia hydatigena, Taenia multiceps, Taenia taeniaeformis, Taenia serialis and Echinococcus spp., most particularly Taenia hydatigena, Taenia ovis, Taenia multiceps, Taenia taeniaeformis, Taenia serialis and Echinococcus spp., most particularly Echinococcus granulosus and Echinococcus multilocularis.

[0341] In addition, the compounds of formula (I) are suitable for treating and / or controlling human pathogenic parasites. Among these, the typical representatives that appear in the digestive tract are those of Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Trichuris and Enterobius. The compounds of the present invention can also resist the parasites of Wuchereria, Brugia, Onchocerca and Loa from the Dracunculus family and the parasites of Strongyloides and Trichinella (which particularly infect the gastrointestinal tract).

[0342] One specific parasite to be treated and / or controlled by the compounds of the present invention is heartworm (Dirofilaria immitis). Specific subjects for such treatment are dogs and cats.

[0343] 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., mixed with at least one acceptable excipient. The proportion and nature of any acceptable excipient are determined by the properties of the selected compound of the present invention, the selected route of administration, and standard practices such as those in veterinary and pharmaceutical fields.

[0344] In one embodiment, the present invention provides a composition comprising: a compound of the present invention and at least one acceptable excipient.

[0345] In achieving such treatment and / or control, the compounds of the present invention can be administered in any form and route that makes the compound bioavailable. The compounds of the present invention can be administered by a variety of routes, including oral, particularly by tablets and capsules. The compounds of the present invention can be administered parenterally, more particularly by inhalation, subcutaneous, intramuscular, intravenous, intraarterial, transdermal, intranasal, rectal, vaginal, ocular, topical, sublingual and buccal, intraperitoneal, intrafat, intrathecal and via local delivery such as by catheter or stent. Those skilled in the art can easily select suitable forms of administration and routes according to the specific characteristics of the selected compound, the disease or condition to be treated, the stage of the disease or condition and other relevant circumstances. The pharmaceutical composition of the present invention can be administered to a subject, for example, in the form of tablets, capsules, cachets, papers, lozenges, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, drenches for animals, solutions and suspensions.

[0346] The term "acceptable excipient" refers to those commonly used in the preparation of veterinary and pharmaceutical compositions and should be pure and non-toxic in the amount used. They are generally solid, semi-solid or liquid materials, which together can serve as a vehicle or medium for the active ingredient. Some examples of acceptable excipients are found in Remington's Pharmaceutical Sciences and Handbook of Pharmaceutical Excipients and include diluents, vehicles, carriers, ointment bases, binders, disintegrants, lubricants, glidants, sweeteners, flavoring agents, gel bases, sustained release matrices, stabilizers, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, etc.

[0347] In one embodiment, the composition is suitable for oral administration, such as a tablet or capsule or a liquid preparation, such as a solution or suspension suitable for oral administration. In one embodiment, the composition is suitable for oral administration, such as a chewable preparation suitable for oral administration. In another embodiment, the composition is a liquid or semisolid preparation suitable for parenteral administration, such as a solution or suspension or paste.

[0348] Specific compositions for use on a subject to treat and / or control nematodes / helminths include: solutions; emulsions, including classical emulsions, microemulsions, and self-emulsifying compositions, which are anhydrous organic, preferably oily compositions that form an emulsion with body fluids after addition to the subject's body; suspensions (drench formulations); pour-on formulations; food additives; powders; tablets, including effervescent tablets; boluses; capsules, including microcapsules; and chewable treats. In particular, the composition is in the form of a tablet, capsule, food additive, or chewable treat.

[0349] The compositions of the present invention are prepared in a manner known in the veterinary and pharmaceutical fields and include at least one compound of the present invention as an active ingredient. The amount of the compound of the present invention may vary depending on its specific form and may conveniently be between 1% and about 50% by weight of the unit dosage form. The pharmaceutical compositions of the present invention are preferably formulated in a unit dosage form, each dose typically containing about 0.5 mg to about 100 mg of the compound of the present invention. One or more unit dosage forms may be used to affect the therapeutic dose.

[0350] In one embodiment, the present invention also provides a method for treating parasites, comprising: administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.

[0351] In one embodiment, the present invention also provides a method of controlling parasites, comprising: administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.

[0352] In one embodiment, the present invention also provides a method of treating or controlling parasites, comprising contacting the environment of a subject with an effective amount of a compound of formula (I) or a salt thereof, optionally further comprising an effective amount of at least one additional active compound.

[0353] Therefore, the present invention provides the use of the compounds of the present invention as medicines, including the manufacture of medicines. In one embodiment, the present invention provides the manufacture of medicines comprising compounds of formula (I) or salts thereof for treating parasites. In one embodiment, the present invention provides the manufacture of medicines comprising compounds of the present invention or salts thereof for controlling parasites.

[0354] The terms "treating / to treat / treated / treatment" include, but are not limited to, inhibiting, slowing, stopping, alleviating, ameliorating, reversing the progression or severity of existing symptoms, or preventing a disorder, condition or disease. For example, an adult heartworm infection would be treated by administering a compound of the invention. Treatment may be applied or administered therapeutically.

[0355] The terms "control", "controlling", "controlled" refer to, but are not limited to, reducing, alleviating or ameliorating the risk of a symptom, symptom, condition or disease, as well as protecting an animal from a symptom, symptom, condition or disease. Control may refer to therapeutic, prophylactic or preventive administration. It is well known that an infection with larval or immature heartworms may be asymptomatic, while an infection with mature parasites is symptomatic and / or debilitating. Thus, for example, a heartworm infection would be controlled by acting on the larval or immature parasites, thereby preventing the infection from developing into an infection with mature parasites.

[0356] Thus, the use of the compounds of the invention in the treatment and / or control of parasites, in particular helminths (among which are endoparasitic nematodes and trematodes) refers to the use of the compounds of the invention to act on all forms of the parasite throughout its life cycle, regardless of whether the subject exhibits symptoms (including morbidity or mortality) and regardless of the stage of the parasite attack.

[0357] As used herein, "administering to a subject" includes, but is not limited to, administration on the skin, subcutaneously, intramuscularly, mucosally, submucosally, transdermally, orally, or intranasally. Administration may include injection or topical administration.

[0358] The terms "subject" and "patient" are meant to include human and non-human mammals, such as dogs, cats, mice, rats, guinea pigs, rabbits, ferrets, cattle, horses, sheep, goats and pigs. It should be understood that a more specific subject is a human. In addition, a more specific subject is a mammalian pet or companion animal such as dogs and cats and also mice, guinea pigs, ferrets and rabbits.

[0359] The term "effective amount" refers to an amount that confers the desired benefit to a subject, and includes administration for both treatment and management. This amount will vary between individual subjects and will depend on a variety of factors, including the subject's overall physical condition and the severity of the underlying cause of the condition to be treated, concomitant treatments, and the amount of the compound of the invention used to maintain the desired response at a beneficial level.

[0360] As a person skilled in the art, the attending diagnostician can easily determine the effective amount by using known techniques and by observing the results obtained in similar situations. When determining the effective amount and dosage, the attending diagnostician will consider many factors, including but not limited to: the species of the patient; its physique, age and general health; the specific condition, illness, infection or disease involved; the degree or degree of involvement or severity of the condition, illness or disease; the response of individual patients; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered preparation; the selected dosing regimen; the use of concomitant medication; and other relevant circumstances. The effective amount of the present invention, i.e. the therapeutic dose, is expected to be in the range of 0.5 mg to 100 mg. The specific amount can be determined by a technician. Although these doses are based on subjects with a body weight of about 1 kg to about 20 kg, the diagnostician will be able to determine the appropriate dose for subjects whose body weight falls outside this weight range. The effective amount of the present invention, i.e. the therapeutic dose, is expected to be in the range of 0.1 mg / kg to 10 mg / kg of the subject. The dosing regimen is expected to be administered daily, weekly or monthly.

[0361] The compounds of the present invention can be used in combination with one or more other active compounds or therapies to treat one or more disorders, diseases or conditions, including parasitic treatments that require them. The compounds of the present invention can be administered simultaneously, sequentially or separately with one or more compounds or therapies for the treatment of parasites and other disorders.

[0362] For example, when used to treat parasites including heartworms, the compounds of the invention can be used in combination with macrolides such as ivermectin, moxidectin or milbemycin oxime, or with imidacloprid. A specific combination for treating parasites includes a compound of the invention and ivermectin. Another specific combination for treating parasites includes a compound of the invention and milbemycin oxime.

[0363] Thus, it is to be understood that the compositions and methods of the present invention optionally include the inclusion of an effective amount of at least one additional active compound.

[0364] The activity of a compound as a parasiticide can be determined by a variety of methods, both in vitro and in vivo.

[0365] Example A

[0366] Dog Heartworm Microfilariae

[0367] Dirofilariae are isolated by filtration from infected donor beagle blood and incubated in an appropriate medium. Test compounds are diluted in DMSO and added to 96-well plates containing parasites. Plates are incubated for the desired time and motility is assessed using an LCD camera imaging system. The effect of serum is tested by adding up to 20% fetal bovine serum to the assay. Motility inhibition percentage values ​​are generated relative to the mean of DMSO-only wells.

[0368] For example, in this test, the following compound 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.

[0369] Example B1

[0370] Ruminant gastrointestinal tract (H. contortus larval development assay (Hc LDA)):

[0371] Haemonchus contortus eggs were isolated from lamb feces and allowed to hatch overnight. Test compounds were diluted in DMSO and added to 96-well plates containing appropriate medium. Haemonchus contortus larvae were added to each well and the plates were incubated for the desired time. Motility was assessed using an LCD camera imaging system. Motility inhibition percentage values ​​were generated relative to the mean of the DMSO-only wells.

[0372] For example, in this test, the following compound 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.

[0373] Example B2

[0374] Other nematode in vitro tests

[0375] Caenorhabditis elegans (Ce): The Caenorhabditis elegans development assay (Ce DA) measures the effects of compounds on developing nematodes. Eggs of C. elegans are placed in 384-well plates along with food (E. coli) and treatments formulated in DMSO. The plates are incubated at 25°C for 48 hours to allow the nematodes to develop to the L4-stage. The effect of the compound is measured as a reduction in motility. Efficacy is expressed as a % reduction in motility compared to a negative control.

[0376] For example, in this test, the following compound from the preparation examples showed an EC 90 <1μg / 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.

[0377] Example C

[0378] Gastrointestinal nematodes

[0379] Gerbils (Merciurus unguiculatus) are artificially infected with third instar larvae of each of T. colubriformis (Tc) and H. contortus (Hc) by gavage. The test compound is then orally treated with a dose ranging from 1×3 mg / kg to 1×32 mg / kg on day 6 post infection, formulated in, for example, DMSO / PEG 2 / 1. Three days after treatment, the gerbils are euthanized and dissected to recover H. contortus from the stomach and T. colubriformis from the small intestine. Efficacy is expressed as a % reduction in the number of worms compared to the placebo-treated group using the Abbot formula.

[0380] The compounds of Examples 3.3, 5.2, 5.3, 5.4, 5.19, 5.23 and 5.47 have an efficacy of >80% on Hc and Tc. The compounds of Examples 3.1, 2.3 and 5.6 have an efficacy of >80% on Hc.

[0381] Example D

[0382] Filarial nematodes

[0383] Av model: Gerbils injected subcutaneously with infective A. viteae (Av) larvae are subsequently treated with the test article formulated in, for example, DMSO / PEG 2 / 1 by oral gavage at doses ranging from 1 x 3 mg / kg to 5 x 32 mg / kg (one dose per day for 5 consecutive days). Efficacy is expressed as the % reduction in worm numbers compared to the placebo-treated group at necropsy 12 weeks post-infection using the Abbot formula.

[0384] 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.

[0385] Example E

[0386] Ls Model

[0387] Mice (BALB / c) were experimentally infected with stage 3 larvae of cotton rat filarial worms (L. sigmodontis, Ls) by subcutaneous injection or by exposure to infecting mites. Treatment was with the test article formulated in DMSO / PEG in a ratio of 2 / 1 by oral gavage or subcutaneous injection, with doses ranging from 1×3 mg / kg (single dose) to 5×32 mg / kg (one dose per day for 5 consecutive days). Worms were counted in the peritoneum and pleural cavity at necropsy 35 to 37 days after infection. Efficacy was expressed as % reduction in the number of worms compared to the placebo-treated group using the Abbot formula. The compounds of Examples 3.3, 5.3, 5.41, 5.47, 5.48 and 5.56 were >80% effective against Ls.

Claims

1. A compound of formula (I) or a salt thereof: in: n is 1; X1 is CR1; X2 is CR2; X3 is CR3; X4 is CR4; X5 is CR5; and X6 is CR6; X1 is CR1; X2 is CR2; X3 is CR3; X4 is CR4; X5 is CR5; and X6 is N; X1 is N; X2 is CR2; X3 is CR3; X4 is CR4; X5 is CR5; and X6 is N; X1 is CR1; X2 is N; X3 is CR3; X4 is CR4; X5 is CR5; and X6 is N; X1 is CR1; X2 is CR2; X3 is N; X4 is CR4; X5 is CR5; and X6 is N; or X1 is N; X2 is CR2; X3 is N; X4 is CR4; X5 is CR5; and X6 is N; G is M is O; Y1 is CR8R9; Y2 is O; Z1 is CR 11 ; Z2 is CR 11 ; Z3 is CR 11 ; Z4 for CR 11 ; R1 is selected from the group consisting of: hydrogen, halogen, hydroxyl, -SH and cyano; R2 is selected from the group consisting of: hydrogen, halogen, hydroxyl, -SH and cyano; R3 is selected from the group consisting of: hydrogen, halogen, hydroxyl, -SH and cyano; R4 is selected from the group consisting of: halogen; cyano; -CHO; hydroxy; C1-C4 alkyl; C3-C6 cycloalkyl; C1-C4 haloalkyl; C1-C4 alkoxy; -NH2; -NH(C1-C4 alkyl); -N(C1-C4 alkyl)2; -N(C1-C4 alkyl)(C1-C4 alkoxy); -C(O)NH(C1-C4 alkyl); -C(O)N(C1-C4 alkyl)2; -SC1-C4 alkyl; -B(OR 15 )(OR 16 ), where R 15 is hydrogen, R 16 is hydrogen; and 4- to 7-membered heterocycloalkyl, optionally substituted by 1, 2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxyl, -NH2; wherein the heterocycloalkyl ring in R4 is also optionally substituted by a spirocyclic group, wherein the spirocyclic 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, wherein the spirocyclic group is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxyl and -NH2; R5 is selected from the group consisting of: hydrogen, halogen, hydroxy, -SH, cyano, C1-C4 alkyl and C1-C4 haloalkyl; R6 is selected from the group consisting of: hydrogen, halogen, hydroxyl, -SH and cyano; R7 is hydrogen; R8 is independently selected at each selection from hydrogen and fluorine; R9 is independently selected at each selection from hydrogen and fluorine; R 11 is independently selected at each selection from hydrogen, halogen, hydroxy, cyano and -NH2; Q is selected from: (i) a 6-membered aryl group optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, cyano, nitro, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -NH2 and -S1-C4 alkyl; and (ii) a 5- or 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from O, S and N, wherein the carbon atoms of the 5- or 6-membered heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, cyano, nitro, hydroxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, benzyloxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 and -SC1-C4 alkyl.

2. The compound or salt thereof according to claim 1, wherein X1 is CR1; X2 is CR2; X3 is CR3; X4 is CR4; X5 is CR5; and X6 is N.

3. The compound or salt thereof according to claim 1, wherein X1 is CR1; X2 is CR2; X3 is CR3; X4 is CR4; X5 is N; and X6 is N.

4. The compound or salt thereof according to claim 1, wherein X1 is CR1; X2 is CR2; X3 is CR3; X4 is CR4; X5 is N; and X6 is CR6.

5. The compound or salt thereof according to any one of claims 1 to 4, wherein Q is a 6-membered aryl group which is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -NH2 and -S1-C4 alkyl.

6. The compound or salt thereof according to any one of claims 1 to 4, wherein Q is a 5- or 6-membered heteroaryl having 1 or 2 heteroatoms selected from O, S and N, and wherein the carbons of the heteroaryl are optionally substituted with 1, 2 or 3 substituents independently selected from halogen, cyano, nitro, -OH, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2.

7. A compound or salt thereof according to any one of claims 1 to 6, wherein R4 is selected from C1-C4 alkyl; C1-C4 haloalkyl; C1-C4 alkoxy; C3-C6 cycloalkyl; -N(C1-C4 alkyl)2; -N(C1-C4 alkyl)(C1-C4 alkoxy); -B(OR 15 )(OR 16 ), where R 15 is hydrogen, R 16 is hydrogen; and 4- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxyl, -NH2; wherein the heterocycloalkyl ring is further optionally substituted with a spirocyclic group, wherein the spirocyclic 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.

8. The compound or salt thereof according to any one of claims 1 to 6, wherein R4 is selected from C1-C4 alkyl, C3-C6 cycloalkyl, -N(C1-C4 alkyl)2 and 4- to 7-membered heterocycloalkyl.

9. The compound of formula (I) or a salt thereof according to claim 1, which has formula (Ia-5), wherein R1, R4 and Q are as defined in claim 1. 10 . The compound of formula (Ia-5) or a salt thereof according to claim 9 , wherein R 1 is hydrogen, halogen or cyano.

11. The compound of formula (Ia-5) or a salt thereof according to claim 9 or claim 10, wherein R1 is hydrogen or fluorine.

12. A compound of formula (Ia-5) or a salt thereof according to any one of claims 9 to 11, wherein R4 is 4-morpholino or dimethylamino.

13. according to the compound of formula (Ia-5) described in any one of claims 9 to 11 or its salt, wherein Q is 6-membered aryl, it is optionally substituted by 1,2,3,4 or 5 substituents independently selected from halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxyl, -NH2 and -SC1-C4 alkyl.

14. A compound of formula (Ia-5) or a salt thereof according to any one of claims 9 to 13, wherein Q is selected from:

15. The compound according to claim 1, wherein the compound is selected from: 8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide; 8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,7-naphthyridine-3-carboxamide; 8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxamide 5-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-1-(dimethylamino)naphthalene-2-carboxamide; and 8-(3,5-Dichlorophenyl)-N-(2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-4-(dimethylamino)quinoline-3-carboxamide; or a salt of any of the foregoing compounds.

16. The compound according to claim 1, wherein the compound is selected from: N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(2,3,5-trifluorophenyl)-1,7-naphthyridine-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-[methoxy(methyl)amino]-8-(2,3,5-trifluorophenyl)-1,7-naphthyridine-3-carboxamide; 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-morpholino-8-(2,3-dichlorophenyl)-1,7-naphthyridine-3-carboxamide; 8-(3,5-Dichloro-4-fluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,7-naphthyridine-3-carboxamide; 8-(5-chloro-3-pyridinyl)-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-thiomorpholino-8-(2,3,5-trifluorophenyl)-1,7-naphthyridine-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(1,1-dioxo-1,4-thiazin-4-yl)-8-(2,3,5-trifluorophenyl)-1,7-naphthyridine-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(3,4,5-trifluorophenyl)-1,7-naphthyridine-3-carboxamide; 8-(2,3-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(dimethylamino)-1,5-naphthyridine-3-carboxamide; 8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,5-naphthyridine-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(2,3,5-trifluorophenyl)-1,5-naphthyridine-3-carboxamide; 8-(2,3-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; 8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; 8-(5-chloro-3-pyridinyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; 8-(3,5-Dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-carboxamide; 8-(3,5-difluorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-carboxamide; N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-pyrimidin-5-yl-quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-thiomorpholino-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; 8-[2-Chloro-6-(trifluoromethyl)-4-pyridinyl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; 8-(2,6-dichloro-4-pyridinyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; 8-(3,5-Dichloro-2-fluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; 8-(5-Chloro-2-fluoro-3-pyridinyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(1,1-dioxo-1,4-thiazin-4-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(2,4,5-trifluorophenyl)quinoline-3-carboxamide; 8-(6-chloropyrazin-2-yl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; 8-(4,5-dichloro-3-pyridinyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; 8-(5-Chloro-2,3-difluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(2,3,4,5-tetrafluorophenyl)quinoline-3-carboxamide; 8-(4-chloro-5-fluoro-3-pyridinyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; 8-[4-Chloro-6-(trifluoromethyl)-2-pyridinyl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; 8-(3,5-Dichloro-2,4-difluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; 8-(4,6-dichloro-2-pyridinyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-(6-fluoropyrazin-2-yl)-4-morpholino-quinoline-3-carboxamide; 8-[2-Chloro-6-(trifluoromethyl)pyrimidin-4-yl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; 8-(6-Chloro-5-fluoro-2-pyridinyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; 8-(6-Chloro-3-fluoro-2-pyridinyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-(6-ethoxypyrazin-2-yl)-4-morpholino-quinoline-3-carboxamide; 4-(azetidin-1-yl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-pyrrolidin-1-yl-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-[2-methoxyethyl(methyl)amino]-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; 7-cyano-8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; 4-Cyclopropyl-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(3-fluoroazetidin-1-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(3-hydroxyazetidin-1-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-oxazolidin-3-yl-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(2-oxa-6-azaspiro[3.3]heptane-6-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-8-(3,4,5-trifluorophenyl)quinoline-3-carboxamide; 4-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-morpholino-pyrido[3,2-d]pyrimidine-7-carboxamide; and 8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-1,6-naphthyridine-3-carboxamide; or a salt of any of the foregoing compounds.

17. The compound according to claim 1, wherein the compound is selected from: N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-isoxazolidin-2-yl-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]quinoline-3-carboxamide; 8-(2,6-dichloropyrimidin-4-yl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-tetrahydropyran-4-yl-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; 8-(3,5-Dichloro-2-fluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-carboxamide; 8-(3,5-Dichloro-2,4-difluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(2,3,6-trifluoro-4-pyridinyl)quinoline-3-carboxamide; N-(2,3-Dihydro-1,4-benzoxazin-4-yl)-8-(4-fluoro-2,6-dimethyl-phenyl)-4-morpholino-quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-[4-ethylsulfanyl-6-(trifluoromethyl)pyrimidin-2-yl]-4-morpholino-quinoline-3-carboxamide; 8-[4-Benzyloxy-6-(trifluoromethyl)pyrimidin-2-yl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; [3-(2,3-Dihydro-1,4-benzoxazin-4-ylcarbamoyl)-8-(2,3,5-trifluorophenyl)-4-quinolyl]boronic acid; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(1-methoxyethyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; 8-(3,5-Dichloro-2,4-difluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(dimethylamino)-7-fluoro-quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-(2,3,5,6-tetrafluorophenyl)quinoline-3-carboxamide; 4-Cyclopropyl-8-(3,5-dichloro-2,4-difluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-quinoline-3-carboxamide; 8-[3,5-Bis(trifluoromethyl)phenyl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-carboxamide; 8-(5-Chloro-2,3-difluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-carboxamide; 8-[3-Chloro-5-(trifluoromethyl)phenyl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-carboxamide; 8-(3,5-dichloro-2,4-difluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-[methoxy(methyl)amino]quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide; 8-[3,5-Dichloro-4-(trifluoromethyl)phenyl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; 8-(3-Chloro-2,5,6-trifluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-7-fluoro-4-morpholino-quinoline-3-carboxamide; 8-(3-Chloro-5-cyano-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; 8-(3-Cyano-2,5-difluoro-phenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(2,2,2-trifluoro-1-methyl-ethyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-methyl-4-morpholino-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; and N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-2-(trifluoromethyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; or a salt of any of the foregoing compounds.

18. A compound selected from the group consisting of: N-[8-(3,5-dichlorophenyl)-4-(dimethylamino)-3-quinolyl]-2,3-dihydro-1,4-benzoxazine-4-carboxamide; 8-(3,5-dichlorophenyl)-N-(3,4-dihydro-2H-quinolin-1-yl)-4-(dimethylamino)-1,7-naphthyridine-3-carboxamide; N-Indolin-1-yl-4-morpholino-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; 4-[Bis(2-methoxyethyl)amino]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; 4-[acetyl(methyl)amino]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide; and 8-(3,5-Dichloro-2,4-difluoro-phenyl)-7-fluoro-N-indolin-1-yl-4-morpholino-quinoline-3-carboxamide.

19. A composition comprising a compound or salt thereof according to any one of claims 1 to 18 and at least one acceptable carrier.

20. Use of a compound or a salt thereof according to any one of claims 1 to 18 in the manufacture of a medicament for treating endoparasites.

21. Use of the compound or salt thereof according to any one of claims 1 to 18 in the manufacture of a medicament for treating heartworms.

22. Use of a compound or a salt thereof according to any one of claims 1 to 18 in the manufacture of a medicament for controlling heartworms.

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