New insect repellent compounds

Abstract

The present invention relates to novel compounds of general formula (I), wherein A is A1 or A2, and wherein T, X, Y, Ro, R 1 、R 10 and R 11 As defined herein; relates to methods for preparing the compounds; intermediate compounds that can be used to prepare the compounds; pharmaceutical compositions and combinations comprising the compounds; and the use of the compounds as sole agents or in combination with other active ingredients for the treatment, control and / or prevention of diseases, particularly helminth infections. #imgabs0##imgabs1#

Description

[0001] The present invention encompasses novel compounds of general formula (I) as described and defined herein; processes for the preparation of said compounds; intermediate compounds useful in the preparation of said compounds; pharmaceutical compositions and combinations comprising said compounds; and the use of said compounds for the manufacture of pharmaceutical compositions for the control, treatment and / or prevention of disease, in particular for the control, treatment and / or prevention of helminth infections, more particularly gastrointestinal and extraintestinal nematode infections, in animals and humans; formulations containing such compounds; and methods for the control, treatment and / or prevention of helminth infections, more particularly gastrointestinal and extraintestinal nematode infections, in animals and humans, as sole agents or in combination with other active ingredients. Background Art

[0002] The emergence of resistance to all commercial anthelmintics appears to be a growing problem in veterinary medicine. The widespread use of anthelmintics to try to control nematodes has led to significant selection for highly resistant worm populations. Consequently, the spread of resistance to all anthelmintic drug classes threatens effective worm control in cattle, goats, sheep, and horses. Furthermore, the current successful prevention of canine heartworm disease, which currently relies solely on the use of macrolides, is in jeopardy because loss of efficacy of multiple macrolides has been described in some areas of the United States, particularly in areas with a high incidence of heartworm challenge infection. Finally, experimental infection studies with canine heartworm (Dirofilaria immitis) larvae from field cases with suspected loss of efficacy in the lower Mississippi Delta region have provided in vivo confirmation of the presence of macrolide resistance.

[0003] Although resistance to anthelmintics in human helminths currently appears to be rare, the spread of anthelmintic resistance in veterinary medicine, as previously described, needs to be considered in the treatment of human helminthiasis. Persistent inadequate treatment of filariasis can lead to the emergence of highly resistant genotypes, and resistance to certain anthelmintics (e.g., praziquantel, benzimidazole, and niclosamide) has been described.

[0004] Therefore, there is an urgent need for anthelmintics with new molecular modes of action that block resistance.

[0005] The object of the present invention is to provide compounds which can be used as anthelmintics in medicine, in particular in veterinary medicine, having satisfactory or improved anthelmintic activity against a broad spectrum of helminths, in particular at relatively low doses, for the control, treatment and / or prevention of helminthic infections in animals and humans, preferably without any adverse toxic effects on the organisms to be treated.

[0006] WO 2005012283 describes the preparation of certain benzothiophene carboxamides as IKK kinase inhibitors for the treatment of inflammation, cancer and autoimmune diseases. US20140235612 describes new azabenzimidazole compounds as PDE4 inhibitors. WO 2009155388 discloses imidazopyridine and imidazopyrazine compounds as kinase inhibitors. WO2016123392 describes pyrazolopyrimidines as inhibitors of glucocorticoid receptor translocation and their preparation. WO2007092403 discloses new N-phenylbenzotriazoles as c-Kit inhibitors. Naumchuk et al. describe the inhibitory activity of imidazolinone derivatives and their precursors on human protein kinase CK2 (Ukrainica Bioorganica Acta 2015, 13 (1), 32-38). US 20080242695 discloses the preparation of 1H-imidazo[4,5-b]pyridin-2-ol derivatives that regulate skeletal muscle. WO 2012106472 describes naphthyridine derivatives as inhibitors of hypoxia-inducible factor (HIF) hydroxylase, their preparation, and their use in treating HIF-mediated diseases. In addition, WO2009100250 summarizes chromene-3-ylamide derivatives as hypoxia-inducible factor hydroxylase inhibitors. (Bioorganic & Medicinal Chemistry Letters (2002), 12(7), 1063-1066) discloses 2-oxo-1,2-dihydroquinoline-3-carboxamides as effective and novel small molecule inhibitors of plasminogen activator inhibitor-1. WO 2009100250 discloses chromene-3-ylamide derivatives as hypoxia-inducible factor hydroxylase inhibitors. Furthermore, WO 2002070509 describes benzodioxanes, quinoxalines, benzoxazines and related compounds as MCP-1 antagonists for the treatment of inflammatory and autoimmune diseases.

[0007] WO 2017178416 describes new pyrazolopyrimidine derivatives and their anthelmintic activity.

[0008] WO 2018087036 describes new quinoline-3-carboxamide derivatives and their anthelmintic activity.

[0009] However, the prior art does not describe the novel compounds of general formula (I) of the present invention as described and defined herein.

[0010] It has now been found that the compounds according to the invention have surprising and advantageous properties, and this forms the basis of the present invention.

[0011] In particular, it has surprisingly been found that the compounds of the present invention effectively interact with Slo-1 of nematodes. This interaction is characterized by paralysis / inhibition of, in particular, gastrointestinal nematodes, free-living nematodes, and filarial nematodes, data for which are given in the biological experiments section. Therefore, the compounds of the present invention can be used as anthelmintics for controlling, treating, and / or preventing gastrointestinal and extraintestinal helminth infections, in particular gastrointestinal and extraintestinal nematode infections (including filarial infections). Summary of the Invention

[0012] According to a first aspect, the present invention encompasses compounds of general formula (I) and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof:

[0013]

[0014] in:

[0015] A is A1 or A2,

[0016]

[0017] o is 0, 1, 2, 3, or 4;

[0018] R is selected from the group consisting of: hydrogen, halogen, cyano, nitro, -OH, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl; -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl and -SO2-C1-C4 haloalkyl;

[0019] X and Y are independently selected from: CR 7 R 8 , O, S and NR 9 , where at least one of X and Y is CR 7 R 8 ,

[0020] or

[0021] X and Y together form a ring member selected from the group consisting of: -C(O)-O-, -C(O)-NR 9 -、-S(O)-NR 9 -、-SO2-NR 9 -and-SO2-O-;

[0022] T is selected from: 10-membered aryl and 8- to 10-membered heteroaryl, each of which is optionally partially saturated and optionally substituted by 1, 2, 3, 4, 5 or 6 members selected from R 2 、R 3 、R 4 、R 5 、R 6 and Q is substituted with a substituent,

[0023] or

[0024] T is selected from T 1 、T 2 、T 3 、T 4 、T 5 、T 6 、T 7 、T 8a 、T 8b and T 9 :

[0025]

[0026] L is selected from: O and NR 9 ;

[0027] M is selected from: C=O and CR 7 R 8 ;

[0028] U selected from: CR 7 and N;

[0029] V is selected from: CR 7 and N;

[0030] R 1Selected from: hydrogen, cyano, -CHO, -OH, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, C3-C6 halocycloalkyl having 1 to 5 halogen atoms, C3-C4 alkenyl, C3-C4 alkynyl, C1-C4 alkoxy-C1-C4 alkyl, C3-C6 cycloalkyl-C1-C3 alkyl, cyano-C1-C4 alkyl, -NH-C1-C4 alkyl, -N(C1-C4 alkyl)2, NH2-C1-C4 alkyl-, C1-C4 alkyl-NH-C1-C4 alkyl-, (C1-C4 alkyl)2N-C1-C4 alkyl-, C1-C4 Alkyl-C(O)-, C1-C4-haloalkyl-C(O)- having 1 to 5 halogen atoms, C1-C4-alkoxy-C(O)-, benzyloxy-C(O)-, C1-C4-alkoxy-C1-C4-alkyl-C(O)-, -SO2-C1-C4-alkyl and -SO2-C1-C4-haloalkyl having 1 to 5 halogen atoms;

[0031] Phenyl-C1-C4-alkyl, which is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halogen, -OH, -NO2, cyano, C1-C4-haloalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-haloalkoxy having 1 to 5 halogen atoms, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -S-C1-C4-alkyl, -S(O)-C1-C4-alkyl, -SO2-C1-C4-alkyl, -S-C1-C4-haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4-haloalkyl having 1 to 5 halogen atoms and -SO2-C1-C4-haloalkyl having 1 to 5 halogen atoms;

[0032] Heterocyclyl-C1-C4 alkyl, wherein the heterocyclyl substituent is selected from: 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heteroaryl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, -NO2, cyano, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 alkyl having 1 to 5 halogen atoms, haloalkyl and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms,

[0033] R 2 Selected from:

[0034] Hydrogen, halogen, cyano, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2;

[0035] -NR 12 R 13 ;

[0036] -OR 14 ;

[0037] -SR 15 、-S(O)R 15 、-SO2 R 15 ;

[0038] C1-C6 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, C3-C6 cycloalkenyl, C2-C4 alkynyl or phenyl-C1-C4 alkyl, each of which is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halogen, -OH, -NO2, cyano, C1-C4 alkyl-C(O)-, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 Alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0039] heterocyclyl-C1-C4 alkyl, wherein the heterocyclyl substituent is selected from the group consisting of 4- to 10-membered heterocyclyl, 5-membered heteroaryl and 6-membered heteroaryl, and wherein the heterocyclyl substituent and / or the C1-C4 alkyl group is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, -NO2, cyano, -COOH, C1-C4 alkyl-C(O)-, C1-C4 alkoxy-C(O)-, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 Alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0040] Phenyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms; or

[0041] a monocyclic or bicyclic heterocycle selected from the group consisting of: a 4- to 10-membered heterocycloalkyl group, a heterospirocycloalkyl group, a 5-membered heteroaryl group, and a 6-membered heteroaryl group, each of which is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, oxo, thiocarbonyl, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkyl-C(O)-, a C1-C4 haloalkyl group having 1 to 5 halogen atoms, a C1-C4 alkoxy group, a hydroxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy group having 1 to 5 halogen atoms, a C3-C6 Cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms, and 4- to 10-membered heterocycloalkyl;

[0042] R 3 Selected from: hydrogen, halogen or C1-C4 alkyl;

[0043] R 4Selected from: hydrogen, halogen, -OH, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C1-C4 alkyl-C(O)-, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl;

[0044] R 5 Selected from: hydrogen, halogen, -OH, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl-C(O)-, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl;

[0045] R 6 Selected from: hydrogen, halogen, -OH, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C1-C4 alkyl-C(O)-, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl;

[0046] R 7 Selected from: hydrogen, -OH, halogen, C1-C4 alkyl and C1-C4 alkoxy;

[0047] R 8 Selected from: hydrogen, -OH, halogen, C1-C4 alkyl and C1-C4 alkoxy;

[0048] or R 7 and R 8 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered ring selected from the group consisting of C3-C6 cycloalkyl and 3- to 6-membered heterocycloalkyl;

[0049] R 9is selected from the group consisting of: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, and C1-C4 alkoxy;

[0050] R 10 Selected from: hydrogen, -OH, C1-C4 alkyl and C1-C4 alkoxy;

[0051] R 11 selected from the group consisting of: hydrogen, C1-C4 alkyl and C1-C4 alkoxy;

[0052] or R 10 and R 11 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered ring selected from the group consisting of C3-C6 cycloalkyl and 3- to 6-membered heterocycloalkyl,

[0053] R 12 and R 13 Independently selected from:

[0054] Hydrogen, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NH(-C(O)-C1-C4 alkyl), -N(C1-C4 alkyl)(-C(O)-C1-C4 alkyl), C1-C4 alkoxy, C1-C4 alkoxy-C(O)-;

[0055] C1-C4 alkyl, C3-C6 cycloalkyl, phenyl-C1-C4 alkyl, each of which is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, -NH-C(O)-C1-C4 alkyl, -N(C1-C4 alkyl)(-C(O)-C1-C4 alkyl), C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 -C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms and (C1-C4 alkoxy)2P(=O)-;

[0056] Heterocyclyl-C1-C4 alkyl, wherein the heterocyclyl substituent is selected from: 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heteroaryl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, oxo, thiocarbonyl, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, hydroxy-C1-C4 alkyl, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 -C1-C4 alkyl, -S-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0057] Phenyl, benzo-C5-C6 cycloalkyl, each of which is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms and -SO2-C1-C4 alkyl having 1 to 5 halogen atoms alkyl halide;

[0058] a monocyclic or bicyclic heterocycle selected from the group consisting of: a 4- to 10-membered heterocycloalkyl group, a 5-membered heteroaryl group, and a 6-membered heteroaryl group, each of which is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of: halogen, cyano, nitro, -OH, oxo, thiocarbonyl, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, hydroxy-C1-C4 alkyl, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 , -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms,

[0059] R 14 Selected from:

[0060] -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2;

[0061] C1-C4 alkyl, C3-C6 cycloalkyl, phenyl-C1-C4 alkyl, each of which is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 Alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0062] Heterocyclyl-C1-C4 alkyl, wherein the heterocyclyl substituent is selected from: 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heteroaryl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, oxo, thiocarbonyl, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, hydroxy-C1-C4 alkyl, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 -C1-C4 alkyl, -S-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0063] Phenyl, which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms; and

[0064] a monocyclic or bicyclic heterocycle selected from the group consisting of: a 4- to 10-membered heterocycloalkyl group, a 5-membered heteroaryl group, and a 6-membered heteroaryl group, each of which is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of: halogen, cyano, nitro, -OH, oxo, thiocarbonyl, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, hydroxy-C1-C4 alkyl, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 , -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms,

[0065] R 15 Selected from:

[0066] C1-C4 alkyl, C3-C6 cycloalkyl, phenyl-C1-C4 alkyl, each of which is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 Alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0067] Heterocyclyl-C1-C4 alkyl, wherein the heterocyclyl substituent is selected from: 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heteroaryl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, oxo, thiocarbonyl, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, hydroxy-C1-C4 alkyl, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 -C1-C4 alkyl, -S-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0068] Phenyl, which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms; and

[0069] a monocyclic or bicyclic heterocycle selected from the group consisting of: a 4- to 10-membered heterocycloalkyl group, a 5-membered heteroaryl group, and a 6-membered heteroaryl group, each of which is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of: halogen, cyano, nitro, -OH, oxo, thiocarbonyl, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, hydroxy-C1-C4 alkyl, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 , -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms,

[0070] R 16 is selected from the group consisting of: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, and C1-C4 alkoxy;

[0071] R 17 is selected from the group consisting of: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, and C1-C4 alkoxy;

[0072] Q is selected from: 6 to 10 membered aryl and 5 to 10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen; SF5; cyano; -CHO; nitro; oxo; C1-C4 alkyl; C1-C4 hydroxyalkyl; C1-C4 haloalkyl having 1 to 5 halogen atoms; -OH; C1-C4 alkoxy; C3-C6 cycloalkyl-C1-C4 alkoxy; cyano-C1-C4 alkoxy; C1-C4 haloalkoxy having 1 to 5 halogen atoms; -NH(C1-C4 alkyl); -N(C1-C4 alkyl)2; -NH-SO2-(C1-C4 alkyl); -N(SO2-[C1-C4 alkyl])(C1-C4 alkyl); (C1-C4 alkoxyimino)-C1-C4 alkyl; a 4- to 6-membered heterocyclic group optionally substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, methyl and cyano; -CH2-O-(C1-C4 alkyl), -CH2-NH(C1-C4 alkyl), -CH2-N(C1-C4 alkyl)2; a methyl group substituted by a 4- to 6-membered heterocyclic group, the 4- to 6-membered heterocyclic group itself optionally substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, methyl and cyano; -CH2-S-(C1-C4 alkyl); -CH2-S(O)-(C1-C4 alkyl); -CH2-SO2-(C1-C4 alkyl); -S-(C1-C4 alkyl); -S(O)-(C1-C4 alkyl); -SO2-(C1-C4 alkyl); -S-(C1-C4 alkyl) having 1 to 5 halogen atoms -S(O)-(C1-C4 haloalkyl) having 1 to 5 halogen atoms; -SO2-(C1-C4 haloalkyl) having 1 to 5 halogen atoms; -CONH(C1-C4 alkyl); -CONH(C3-C6 cycloalkyl); -NHCO(C1-C4 alkyl); -NHCO(C3-C6 cycloalkyl); -NHCO(C1-C4 haloalkyl) having 1 to 5 halogen atoms;

[0073] When Y is O, S or NR 9 When R 7 、R 8 、R 10 and R 11 are not -OH, and when X is O, S or NR 9 When R 7 and R 8 None of them are -OH.

[0074] definition

[0075] The term "substituted" means that one or more hydrogen atoms on the designated atom or group is replaced with a substituent selected from the designated group, provided that the normal valency of the designated atom in the existing circumstances is not exceeded. Combinations of substituents and / or variables are permitted.

[0076] The term "optionally substituted" means that the number of substituents may be equal to or different from zero. Unless otherwise indicated, an optionally substituted group may be substituted with as many optional substituents as can be accommodated, and these optional substituents are accommodated by replacing hydrogen atoms with non-hydrogen substituents on any available carbon or nitrogen atom. Typically, the number of optional substituents, if present, may be 1, 2, 3, 4 or 5, especially 1, 2 or 3.

[0077] As used herein, the term "one or more", for example in the definition of substituents of the compounds of general formula (I) of the present invention, means "1, 2, 3, 4 or 5, in particular 1, 2, 3 or 4, more in particular 1, 2 or 3, even more in particular 1 or 2".

[0078] As used herein, an oxo substituent represents an oxygen atom bonded to a carbon atom or a sulfur atom via a double bond.

[0079] The term "ring substituent" means a substituent attached to an aromatic or non-aromatic ring that replaces an available hydrogen atom on the ring.

[0080] If a composite substituent consists of more than one part, for example (C1-C4 alkoxy)-(C1-C4 alkyl)-, the position of a given part may be at any suitable position of the composite substituent, i.e., the C1-C4 alkoxy part may be attached to any carbon atom of the C1-C4 alkyl part of the (C1-C4 alkoxy)-(C1-C4 alkyl)- group. A hyphen at the beginning or end of such a composite substituent indicates the point of attachment of the composite substituent to the rest of the molecule. If a ring comprising carbon atoms and optionally one or more heteroatoms (such as nitrogen, oxygen or sulfur atoms) is, for example, substituted by a substituent, the substituent may be bonded to any suitable position of the ring, being bonded to a suitable carbon atom and / or a suitable heteroatom.

[0081] As used herein, the position in a drawn structure through which each substituent is attached to the rest of the molecule can be indicated by a pound sign (#) or a dashed line through the substituent.

[0082] The term "comprising" when used in this specification includes "consisting of.

[0083] If any item in the context of the present invention is referred to as "as mentioned herein", it means that it can be mentioned anywhere in the context of the present invention.

[0084] As used herein, the terms have the following meanings:

[0085] The term "halogen atom" means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom, more particularly chlorine or fluorine.

[0086] The term "C1-C6 alkyl" means a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, or 6 carbon atoms. The term "C1-C4 alkyl" means a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, or 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, or the like, or isomers thereof. In particular, the radical has 1, 2, or 3 carbon atoms ("C1-C3 alkyl"), such as methyl, ethyl, n-propyl, or isopropyl.

[0087] The term "C1-C4 hydroxyalkyl" means a linear or branched saturated monovalent hydrocarbon radical, wherein the term "C1-C4 alkyl" is as defined above, and wherein 1 or 2 hydrogen atoms are replaced by hydroxy groups, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 1-hydroxyprop-2-yl, 2-hydroxyprop-2-yl, 2,3-dihydroxypropyl, 1,3-dihydroxyprop-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1-hydroxy-2-methyl-propyl.

[0088] The term "-NH(C1-C4 alkyl)" or "-N(C1-C4 alkyl)2" means a linear or branched saturated monovalent group, wherein the term "C1-C4 alkyl" is as defined above, for example, methylamino, ethylamino, n-propylamino, isopropylamino, N,N-dimethylamino, N-methyl-N-ethylamino or N,N-diethylamino.

[0089] The term "-S-C1-C4 alkyl", "-S(O)-C1-C4 alkyl" or "-SO2-C1-C4 alkyl" means a linear or branched saturated group, wherein the term "C1-C4 alkyl" is as defined above, for example, methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl, isobutylsulfanyl or tert-butylsulfanyl, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl, isobutylsulfinyl or tert-butylsulfinyl, or methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, isobutylsulfinyl or tert-butylsulfonyl.

[0090] The term "S-C1-C4 haloalkyl" means a straight-chain or branched group, wherein the term "C1-C4 haloalkyl" is as defined below and wherein one or more hydrogen atoms are replaced identically or differently by halogen atoms. In particular, the halogen atoms are fluorine atoms. More particularly, all the halogen atoms are fluorine atoms ("C1-C4 fluoroalkyl"). The C1-C4 haloalkyl is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoroprop-2-yl, with trifluoromethyl being particularly preferred.

[0091] The term "C1-C4 haloalkyl" means a linear or branched saturated monovalent hydrocarbon radical, wherein the term "C1-C4 alkyl" is as defined above and wherein one or more hydrogen atoms are replaced identically or differently by halogen atoms. In particular, the halogen atoms are fluorine atoms. More particularly, all the halogen atoms are fluorine atoms ("C1-C4 fluoroalkyl"). The C1-C4 haloalkyl is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoroprop-2-yl, with trifluoromethyl being particularly preferred.

[0092] The term "C1-C4 alkoxy" means a linear or branched saturated monovalent group of the formula (C1-C4 alkyl)-O-, wherein the term "C1-C4 alkyl" is as defined above, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy or isomers thereof, with methoxy being particularly preferred.

[0093] The term "C1-C4 haloalkoxy" refers to a linear or branched, saturated, monovalent C1-C4 alkoxy group as defined above, in which one or more hydrogen atoms are replaced by halogen atoms, identical or different. In particular, the halogen atoms are fluorine atoms. The C1-C4 haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, or pentafluoroethoxy.

[0094] The term "C2-C4 alkenyl" means a linear or branched monovalent hydrocarbon radical containing one double bond and having 2, 3 or 4 carbon atoms. The C2-C4 alkenyl is, for example, ethenyl (or "vinyl"), prop-2-en-1-yl (or "allyl"), prop-1-en-1-yl, but-3-enyl, but-2-enyl, but-1-enyl, prop-1-en-2-yl (or "isopropenyl"), 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl or 1-methylprop-1-enyl. In particular, the group is allyl.

[0095] The term "C2-C4 alkynyl" refers to a straight-chain monovalent hydrocarbon radical containing one triple bond and containing 2, 3 or 4 carbon atoms. The C2-C4 alkynyl radical is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl (or "propargyl"), but-1-ynyl, but-2-ynyl, but-3-ynyl or 1-methylprop-2-ynyl. In particular, the alkynyl radical is prop-1-ynyl or prop-2-ynyl.

[0096] The term "C3-C6 cycloalkyl" means a saturated monovalent monocyclic hydrocarbon ring containing 3, 4, 5 or 6 carbon atoms ("C3-C6 cycloalkyl"). The C3-C6 cycloalkyl is, for example, a monocyclic hydrocarbon ring such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0097] The term "C3-C6 halocycloalkyl" means a saturated monovalent monocyclic hydrocarbon ring, wherein the term "C3-C6 cycloalkyl" is as defined above and wherein one or more hydrogen atoms are replaced identically or differently by halogen atoms. In particular, the halogen atoms are fluorine or chlorine atoms. The C3-C6 halocycloalkyl is, for example, a monocyclic hydrocarbon ring substituted by one or two fluorine or chlorine atoms, such as 1-fluoro-cyclopropyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, 1-chlorocyclopropyl, 2-chlorocyclopropyl, 2,2-dichlorocyclopropyl, 2,3-dichlorocyclopropyl, 2-fluoro-2-chlorocyclopropyl and 2-fluoro-3-chlorocyclopropyl.

[0098] The term "heterocyclyl-C1-C4 alkyl" means a linear or branched saturated monovalent group, wherein the term "C1-C4 alkyl" is as defined above, and wherein 1 or 2 hydrogen atoms are replaced by a heterocyclyl group as defined below.

[0099] The term “—NH(C3-C6 cycloalkyl)” or “—N(C1-C4 alkyl)(C3-C6 cycloalkyl)” means a linear or branched saturated monovalent group, wherein the term “C1-C4 alkyl” and the term “C3-C6 cycloalkyl” are each as defined above, for example, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, N-methyl-N-cyclopropylamino, N-ethyl-N-cyclopropylamino, N-methyl-N-cyclobutylamino, N-ethyl-N-cyclobutylamino, N-methyl-N-cyclopentylamino, N-ethyl-N-cyclopentylamino, N-methyl-N-cyclohexylamino or N-ethyl-N-cyclohexylamino.

[0100] The term "benzo-C5-C6 cycloalkyl" refers to a monovalent bicyclic hydrocarbon ring in which a saturated monovalent monocyclic hydrocarbon ring containing 5 or 6 carbon atoms ("C5-C6 cycloalkyl") is fused to a benzene ring. The benzo-C5-C6 cycloalkyl group is, for example, a bicyclic hydrocarbon ring such as an indane (i.e., 2,3-dihydro-1H-indene) or tetralin (i.e., 1,2,3,4-tetralin) group.

[0101] The term "spiroalkyl" means a saturated monovalent bicyclic hydrocarbon radical wherein the two rings share a common ring carbon atom, and wherein the bicyclic hydrocarbon radical contains 5, 6, 7, 8, 9, 10 or 11 carbon atoms, and the spiroalkyl radical can be connected to the remainder of the molecule via any carbon atom other than the spiral carbon atom. The spiroalkyl radical is, for example, spiral [2.2] pentyl, spiral [2.3] hexyl, spiral [2.4] heptyl, spiral [2.5] octyl, spiral [2.6] nonyl, spiral [3.3] heptyl, spiral [3.4] octyl, spiral [3.5] nonyl, spiral [3.6] decyl, spiral [4.4] nonyl, spiral [4.5] decyl, spiral [4.6] undecyl or spiral [5.5] undecyl.

[0102] The term “heterocycloalkyl” means a monocyclic or bicyclic saturated or partially saturated heterocycle having a total of 4, 5, 6, 7, 8, 9 or 10 ring atoms (a “4- to 10-membered heterocycloalkyl” group), in particular 4, 5 or 6 ring atoms (a “4- to 6-membered heterocycloalkyl” group), which contains one or two identical or different ring heteroatoms selected from N, O and S, and which may be attached to the remainder of the molecule via any of the carbon atoms or, if present, the nitrogen atom.

[0103] The heterocycloalkyl group may be, but is not limited to, a 4-membered ring such as, for example, azetidinyl, oxetanyl, or thietanyl; or a 5-membered ring such as, for example, tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxathiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,3-thiazolidinyl, or 1,2,4-triazolidinyl; or a 6-membered ring such as, for example, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl, or 1,2-oxazahexyl; or a 7-membered ring such as For example, azepanyl, 1,4-diazepanyl or 1,4-oxaazepanyl; or a bicyclic 7-membered ring, such as, for example, 6-oxa-3-azabicyclo[3.1.1]heptane; or a bicyclic 8-membered ring, such as, for example, 5,6-dihydro-4H-furo[2,3-c]pyrrole or 8-oxa-3-azabicyclo[3.2.1]octane; or a bicyclic 9-membered ring, such as, for example, octahydro-1H-pyrrolo[3,4-b]pyridine, 1,3-dihydro-isoindole, 2,3-dihydro-indole or 3,9-dioxa-7-azabicyclo[3.3.1]nonane; or a bicyclic 10-membered ring, such as, for example, decahydroquinoline or 3,4-dihydroisoquinoline.

[0104] The term "heterospirocycloalkyl" means a bicyclic saturated heterocycle having a total of 6, 7, 8, 9, 10 or 11 ring atoms, wherein the two rings share a common ring carbon atom, the "heterospirocycloalkyl" containing one or two identical or different ring heteroatoms selected from N, O, S; the heterospirocycloalkyl may be attached to the remainder of the molecule via any carbon atom other than the spiro carbon atom or the nitrogen atom (if present).

[0105] The heterospirocycloalkyl group is, for example, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, oxazaspiro[2.5]octyl, azaspiro[4.5]decyl, oxazaspiro[5.5]undecyl, diazaspiro[5.5]undecyl, diazaspiro[4.3]octyl, oxazaspiro[2.5]octyl, diazaspiro[4.5]decyl, di ...5.3]undecyl, diazaspiro[4.3]octyl, oxazaspiro[2.5]octyl, diazaspiro[4.5]decyl, diazaspiro[5.5]undecyl, diazaspiro[5.5]undecyl, diazaspiro[5.3]undecyl, diazaspiro[5.3]undecyl, diazaspiro[5.3]undecyl, diazaspiro[4.3]octyl azaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, azaspiro[5.5]undecyl or one of other homologous scaffolds such as spiro[3.4]-, spiro[4.4]-, spiro[2.4]-, spiro[2.5]-, spiro[2.6]-, spiro[3.5]-, spiro[3.6]-, spiro[4.5]- and spiro[4.6]-.

[0106] The term "6- to 10-membered aryl" refers to a monovalent monocyclic or bicyclic aromatic ring having 6 to 10 carbon ring atoms, and particularly includes phenyl and naphthyl.

[0107] The term "heteroaryl" is intended to mean a monovalent monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 9 or 10 ring atoms (a "5- to 10-membered heteroaryl" group), in particular 5 or 6 ring atoms (a "5- to 6-membered heteroaryl" group), which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms selected from the series N, O and / or S and which is bonded via a ring carbon atom or, if valence permits, via a ring nitrogen atom.

[0108] The heteroaryl group may be a 5-membered heteroaryl group, such as, for example, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl.

[0109] The term "heterocyclyl" means a heterocycle selected from heterocycloalkyl and heteroaryl. In particular, the term "4- to 6-membered heterocyclyl" means a heterocycle selected from 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl.

[0110] In general and unless otherwise mentioned, a heteroaryl or heteroarylene group includes all possible isomeric forms thereof, for example, tautomers and positional isomers relative to the site of attachment to the rest of the molecule. Thus, for some illustrative, non-limiting examples, the term pyridyl includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.

[0111] As used in the context of the present invention, for example, in the context of the definition of "C1-C4 alkyl", "C1-C4 haloalkyl", "C1-C4 hydroxyalkyl", "C1-C4 alkoxy" or "C1-C4 haloalkoxy", the term "C1-C4" means an alkyl group having a finite number of carbon atoms of 1 to 4, i.e., 1, 2, 3 or 4 carbon atoms.

[0112] Furthermore, as used herein, as used in the context of the present invention, for example in the context of the definition of "C3-C6 cycloalkyl" or C3-C6 halocycloalkyl, the term "C3-C6" means a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e., 3, 4, 5 or 6 carbon atoms.

[0113] When a range of values ​​is given, that range encompasses every value and sub-range within that range.

[0114] For example:

[0115] "C1-C4" includes C1, C2, C3, C4, C1-C4, C1-C3, C1-C2, C2-C4, C2-C3 and C3-C4;

[0116] "C2-C6" includes C2, C3, C4, C5, C6, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;

[0117] "C3-C4" includes C3, C4, and C3-C4;

[0118] "C3-C 10 " includes C3, C4, C5, C6, C7, C8, C9, C 10 、C3-C 10 、C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C 10 、C4-C9, C4-C8, C4-C7, C4-C6, C4-C5, C5-C 10 、C5-C9, C5-C8, C5-C7, C5-C6, C6-C 10 、C6-C9, C6-C8, C6-C7, C7-C 10 、C7-C9, C7-C8, C8-C 10 、C8-C9, and C9-C 10 ;

[0119] "C3-C8" includes C3, C4, C5, C6, C7, C8, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C8, C4-C7, C4-C6, C4-C5, C5-C8, C5-C7, C5-C6, C6-C8, C6-C7, and C7-C8;

[0120] "C3-C6" includes C3, C4, C5, C6, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;

[0121] "C4-C8" includes C4, C5, C6, C7, C8, C4-C8, C4-C7, C4-C6, C4-C5, C5-C8, C5-C7, C5-C6, C6-C8, C6-C7, and C7-C8;

[0122] "C4-C7" includes C4, C5, C6, C7, C4-C7, C4-C6, C4-C5, C5-C7, C5-C6, and C6-C7;

[0123] "C4-C6" includes C4, C5, C6, C4-C6, C4-C5, and C5-C6;

[0124] "C5-C 10 " Including C5, C6, C7, C8, C9, C 10 、C5-C 10 ,C5-C9,C5-C8,C5-C7,C5-C6,C6-C 10 ,C6-C9,C6-C8,C6-C7,C7-C 10 、C7-C9、C7-C8、C8-C 10 , C8-C9 and C9-C 10 ;

[0125] "C6-C 10 " Including C6, C7, C8, C9, C 10 、C6-C 10 ,C6-C9,C6-C8,C6-C7,C7-C 10 、C7-C9、C7-C8、C8-C 10 , C8-C9 and C9-C 10 .

[0126] As used herein, the term "leaving group" means an atom or group of atoms that is displaced along with the bound electrons in a chemical reaction to form a stable species. In particular, such leaving groups are selected from: halides, in particular fluoride, chloride, bromide or iodide; (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

[0127] An oxo substituent in the context of the present invention is intended to mean an oxygen atom which is bonded to a carbon atom via a double bond.

[0128] The compounds of general formula (I) may exist as isotopic variations. Therefore, the present invention includes one or more isotopic variations of the compounds of general formula (I), in particular deuterated compounds of general formula (I).

[0129] The term "isotopic variant" of a compound or agent is defined as a compound that exhibits unnatural ratios of one or more of the isotopes that constitute such compound.

[0130] The term "isotopic variation of a compound of formula (I)" is defined as a compound of formula (I) that exhibits an unnatural ratio of one or more of the isotopes that constitute such compound.

[0131] The expression "unnatural proportion" means a proportion of such an isotope that is higher than its natural abundance. In this case, the natural abundance of the isotope to be used is described in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70 (1), 217-235, 1998.

[0132] Examples of such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 P. 33 P. 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I.

[0133] For the treatment and / or prevention of the conditions specified herein, isotopic variations of the compounds of formula (I) preferably contain deuterium ("deuterated compounds of formula (I)"). Incorporation of one or more radioactive isotopes (such as 3 H or 14 C) Isotopic variants of compounds of formula (I) are useful, for example, in drug and / or matrix tissue distribution studies. These isotopes are particularly preferred due to their ease of incorporation and detectability. Positron-emitting isotopes such as 18 F or 11 C is incorporated into the compounds of formula (I). These isotopic variants of the compounds of formula (I) are useful for in vivo imaging applications. 13 Compounds of general formula (I) of C can be used for mass spectrometry analysis in the context of preclinical or clinical research.

[0134] Isotopic variants of compounds of general formula (I) can generally be prepared by methods known to those skilled in the art, such as those described in the schemes and / or embodiments herein, by replacing the reagent with an isotopic variant of a reagent, preferably a deuterated reagent. Depending on the desired deuteration site, in some cases, deuterium from D2 O can be directly incorporated into the compound or incorporated into a reagent that can be used to synthesize such a compound. Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic and acetylenic bonds is a fast way to incorporate deuterium. In the presence of deuterium gas, metal catalysts (i.e., Pd, Pt, and Rh) can be used to directly exchange hydrogen in hydrocarbons containing functional groups for deuterium. Various deuterated reagents and synthetic building blocks can be commercially available from, for example, the following companies: C / D / N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.

[0135] The term "compound of the general formula (I) containing deuterium" is defined as a compound of the general formula (I), wherein one or more hydrogen atoms are replaced by one or more deuterium atoms and wherein the abundance of deuterium at each deuterated position of the compound of the general formula (I) is higher than the natural abundance of deuterium, which is about 0.015%. In particular, in the compound of the general formula (I) containing deuterium, the abundance of deuterium at each deuterated position of the compound of the general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at the position. It should be understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated positions.

[0136] The selective incorporation of one or more deuterium atoms into compounds of general formula (I) can alter the physicochemical properties of the molecule (such as, for example, acidity [CL Perrin et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [CL Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271]) and / or metabolic profile and can result in a change in the ratio of parent compound to metabolite or in the amount of metabolite formed. Such changes may result in certain therapeutic advantages and may therefore be preferred in some cases. Reduced rates of metabolism and metabolic turnover have been reported, where the ratio of metabolites is altered (AE Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in exposure to the parent drug and metabolites can have important consequences for the pharmacodynamics, tolerability, and efficacy of deuterium-containing compounds of general formula (I). In some cases, deuterium substitution reduces or eliminates the formation of unwanted or toxic metabolites and promotes the formation of desired metabolites (e.g., nevirapine: AM Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: AEMutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases, the primary effect of deuteration is to reduce systemic clearance. As a result, the biological half-life of the compound is increased. Potential clinical benefits would include the ability to maintain similar systemic exposure while reducing peak levels and increasing trough levels. Depending on the pharmacokinetic / pharmacodynamic relationship of the particular compound, this could lead to lower side effects and enhanced efficacy. ML-337 (CJ Wenthur et al., J. Med. Chem., 2013, 56, 5208) and odanacatib (K. Kassahun et al., WO 2012 / 112363) are examples of this deuterium effect. Other cases have also been reported where reduced metabolic rate leads to increased drug exposure without altering systemic clearance (e.g., rofecoxib: F. Schneider et al., Arzneim. Forsch. / Drug. Res., 2006, 56, 295; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993).Deuterated drugs that exhibit this effect may have reduced dosing requirements (eg, fewer administrations or lower dosages to achieve the desired effect) and / or may produce a lower metabolite burden.

[0137] Compounds of general formula (I) may have multiple potential metabolic attack sites. In order to optimize the above-mentioned effects on physicochemical properties and metabolic profiles, deuterated compounds of general formula (I) with a certain pattern of one or more deuterium hydrogen exchanges may be selected. In particular, one or more deuterium atoms of the deuterated compound of general formula (I) are attached to carbon atoms and / or are located at the site of a metabolic enzyme (such as, for example, cytochrome P) in the compound of general formula (I). 450 ) at the location of the attack site.

[0138] When the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like is used herein, this is also intended to refer to the individual compounds, salts, polymorphs, isomers, hydrates, solvates and the like.

[0139] By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0140] Depending on the position and nature of the various desired substituents, the compounds of the present invention optionally contain one or more asymmetric centers. One or more asymmetric carbon atoms may exist in the (R) or (S) configuration, which may produce a racemic mixture in the case of a single asymmetric center and a diastereomeric mixture in the case of multiple asymmetric centers. In some cases, asymmetry may also exist due to restricted rotation around a given bond (e.g., a central bond adjacent to two substituted aromatic rings of a given compound).

[0141] Preferred compounds are those that produce the more desired biological activity. Also included within the scope of the present invention are separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention. The purification and separation of such materials can be accomplished by standard techniques known in the art.

[0142] Preferred isomers are those that produce more desirable biological activity. These separated, pure or partially purified isomers or racemic mixtures of the compounds of the invention are also included within the scope of the present invention. The purification and separation of such materials can be accomplished by standard techniques known in the art.

[0143] Optical isomers can be obtained by splitting the racemic mixture according to conventional methods, for example, by forming diastereomeric salts using optically active acids or bases, or forming covalent diastereoisomers to obtain. Examples of suitable acids are tartaric acid, diacetyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. A mixture of diastereoisomers can be separated into their individual diastereoisomers based on their physical and / or chemical differences by methods known in the art (for example, by chromatography or fractional crystallization). The optically active base or acid is then released by the separated diastereomeric salts. The different methods of separating optical isomers involve using chiral chromatography (for example, using an HPLC column of a chiral phase) with or without conventional derivatization, and the best choice is to maximize the separation of enantiomers. Suitable HPLC columns using chiral phases are commercially available, such as those manufactured by Daicel, for example Chiracel OD and Chiracel OJ, and many other columns, which are all conventionally selectable. With or without derivatization, enzymatic separation is also useful. The optically active compounds of the present invention can also be obtained by chiral synthesis using optically active starting materials.

[0144] In order to distinguish different types of isomers from each other, reference is made to IUPAC rules, Section E (Pure Appl Chem 45, 11-30, 1976).

[0145] The present invention includes all possible stereoisomers of the compounds of the present invention, as single stereoisomers or as any mixture of any ratio of said stereoisomers (e.g., (R) or (S) isomers). Separation of single stereoisomers (e.g., single enantiomers or single diastereomers) of the compounds of the present invention is achieved by any suitable state of the art method such as, for example, chromatography (particularly chiral chromatography).

[0146] In addition, the compounds of the present invention may exist as tautomers. For example, any compound of the present invention containing a substitution pattern that produces an α-CH-moiety on an azaquinoline with increased CH acidity may exist as a tautomer or even as a mixture of two tautomers in any amount.

[0147] The present invention includes all possible tautomers of the compounds of the present invention, either as single tautomers or as any mixture of said tautomers in any ratio.

[0148] Additionally, the compounds of the present invention may exist as N-oxides, which are defined as at least one nitrogen atom of the compounds of the present invention being oxidized. The present invention includes all such possible N-oxides.

[0149] The present invention also encompasses useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts (especially pharmaceutically acceptable salts) and / or coprecipitates.

[0150] The compounds of the present invention may exist as hydrates or as solvates, wherein the compounds of the present invention contain polar solvents (especially, for example, water, methanol or ethanol) as structural elements of the compound lattice. The amount of polar solvent (especially water) may be present in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates (such as hydrates), hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates are each possible. The present invention includes all such hydrates or solvates.

[0151] Furthermore, the compounds of the present invention may exist in free form (e.g., as a free base or as a free acid) or as a zwitterion, or in the form of a salt. The salt may be any salt commonly used in pharmacy or for, for example, isolating or purifying the compounds of the present invention, an organic or inorganic addition salt, in particular any pharmaceutically acceptable organic or inorganic addition salt.

[0152] The term "pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see SM Berge et al. "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19.

[0153] Suitable pharmaceutically acceptable salts of the compounds of the invention may be acid addition salts of compounds of the invention with nitrogen atoms in the chain or ring, for example, which are sufficiently basic, such as acid addition salts with inorganic acids or "mineral acids", such as, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, bisulfuric acid, phosphoric acid or nitric acid; or acid addition salts with organic acids, such as, for example, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, 3-phenylpropionic acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, or thiocyanic acid.

[0154] In addition, another suitable pharmaceutically acceptable salt of a sufficiently acidic compound of the present invention is an alkali metal salt, such as a sodium or potassium salt; an alkaline earth metal salt, such as a calcium, magnesium or strontium salt; or an aluminum or zinc salt; or an ammonium salt derived from ammonia or an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, acid, 1,2-ethylenediamine, N-methylpiperidine, N-methyl-glucamine, N,N-dimethyl-glucamine, N-ethyl-glucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol; or a salt with a quaternary ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline or benzalkonium chloride.

[0155] Those skilled in the art will further recognize that acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable inorganic or organic acid via any of a variety of known methods. Alternatively, alkali metal salts and alkaline earth metal salts of the acidic compounds of the present invention can be prepared by reacting the compounds of the present invention with a suitable base via a variety of known methods.

[0156] The present invention includes all possible salts of the compounds of the present invention, either as single salts or as any mixture of said salts in any ratio.

[0157] In the context of the present invention, in particular in the experimental part, for the synthesis of the intermediates and examples according to the invention, when the compounds are mentioned as salts with the corresponding bases or acids, the exact stoichiometric composition of the salt forms as obtained by the respective preparation and / or purification processes is in most cases not known.

[0158] Unless otherwise specified, suffixes referring to chemical names or formulae of salts, such as, for example, "hydrochloride," "trifluoroacetate," "sodium salt," or "x HCl," "x CF3 COOH," "x Na + ” means a salt form, the stoichiometry of which is unspecified.

[0159] This applies analogously to the case where synthesis intermediates or example compounds or salts thereof are obtained by the described preparation and / or purification processes in the form of solvates, such as hydrates, of (if defined) unknown stoichiometric composition.

[0160] Furthermore, the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, either as single polymorphs or as mixtures of more than one polymorph in any ratio.

[0161] In addition, the present invention also includes prodrugs of the compounds according to the invention. The term "prodrug" here indicates a compound which itself may be biologically active or inactive but which is converted (e.g. metabolically or hydrolytically) into a compound according to the invention during its residence time in the body.

[0162] According to a second embodiment of the first aspect, the present invention covers compounds of the general formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

[0163] A is A1 or A2,

[0164]

[0165] o is 0, 1, 2, 3, or 4;

[0166] R is selected from the group consisting of: hydrogen, halogen, cyano, nitro, -OH, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl; -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl and -SO2-C1-C4 haloalkyl;

[0167] X and Y are independently selected from: CR 7 R 8 , O, S and NR 9 , where at least one of X and Y is CR 7 R 8 ,

[0168] or

[0169] X and Y together form a ring member selected from the group consisting of: -C(O)-O-, -C(O)-NR 9 -、-S(O)-NR 9 -、-SO2-NR 9 -and-SO2-O-;

[0170] T is selected from T as defined above 1 、T 2 、T 3 、T 4 、T 5 、T 6 、T 7 、T 8a 、T 8b and T 9 ;

[0171] R 1Selected from: hydrogen, cyano, -CHO, -OH, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, C3-C6 halocycloalkyl having 1 to 5 halogen atoms, C3-C4 alkenyl, C3-C4 alkynyl, C1-C4 alkoxy-C1-C4 alkyl, C3-C6 cycloalkyl-C1-C3 alkyl, cyano-C1-C4 alkyl, -NH-C1-C4 alkyl, -N(C1-C4 alkyl)2, NH2-C1-C4 alkyl-, C1-C4 alkyl-NH-C1-C4 alkyl-, (C1-C4 alkyl)2N-C1-C4 alkyl-, C1-C4 Alkyl-C(O)-, C1-C4 haloalkyl-C(O)- having 1 to 5 halogen atoms, C1-C4 alkoxy-C(O)-, benzyloxy-C(O)-, C1-C4 alkoxy-C1-C4 alkyl-C(O)-, -SO2-C1-C4 alkyl and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0172] Phenyl-C1-C4 alkyl, which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halogen, -OH, -NO2, cyano, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0173] Heterocyclyl-C1-C4 alkyl, wherein the heterocyclyl substituent is selected from: 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heteroaryl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, -NO2, cyano, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 alkyl having 1 to 5 halogen atoms, haloalkyl and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms,

[0174] R 2 Selected from:

[0175] Hydrogen, halogen, cyano, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2;

[0176] -NR 12 R 13 ;

[0177] -OR 14 ;

[0178] -SR 15 、-S(O)R 15 、-SO2 R 15 ;

[0179] C1-C6 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, C3-C6 cycloalkenyl, C2-C4 alkynyl or phenyl-C1-C4 alkyl, each of which is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halogen, -OH, -NO2, cyano, C1-C4 alkyl-C(O)-, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 Alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0180] Heterocyclyl-C1-C4 alkyl, wherein the heterocyclyl substituent is selected from: 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heteroaryl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, -NO2, cyano, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 alkyl having 1 to 5 halogen atoms, Haloalkyl and -SO2-C1-C4-haloalkyl having 1 to 5 halogen atoms;

[0181] Phenyl, which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms; and

[0182] a monocyclic or bicyclic heterocycle selected from the group consisting of: a 4- to 10-membered heterocycloalkyl group, a heterospirocycloalkyl group, a 5-membered heteroaryl group, and a 6-membered heteroaryl group, each of which is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, oxo, thiocarbonyl, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkyl-C(O)-, a C1-C4 haloalkyl group having 1 to 5 halogen atoms, a C1-C4 alkoxy group, a hydroxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy group having 1 to 5 halogen atoms, a C3-C6 Cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms, and 4- to 10-membered heterocycloalkyl;

[0183] R 3 Selected from: hydrogen, halogen or C1-C4 alkyl;

[0184] R 4 Selected from: hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms;

[0185] R 5Selected from: hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy;

[0186] R 6 Selected from: hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms;

[0187] R 7 Selected from: hydrogen, -OH, halogen, C1-C4 alkyl and C1-C4 alkoxy;

[0188] R 8 Selected from: hydrogen, -OH, halogen, C1-C4 alkyl and C1-C4 alkoxy;

[0189] R 9 is selected from the group consisting of: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, and C1-C4 alkoxy;

[0190] R 10 Selected from: hydrogen, -OH, C1-C4 alkyl and C1-C4 alkoxy;

[0191] R 11 selected from the group consisting of: hydrogen, C1-C4 alkyl and C1-C4 alkoxy;

[0192] R 12 and R 13 Independently selected from:

[0193] Hydrogen, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NH(-C(O)-C1-C4 alkyl), C1-C4 alkoxy;

[0194] C1-C4 alkyl, C3-C6 cycloalkyl, phenyl-C1-C4 alkyl, each of which is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, -NH-C(O)-C1-C4 alkyl, -N(C1-C4 alkyl)(-C(O)-C1-C4 alkyl), C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 -C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms and (C1-C4 alkoxy)2P(=O)-;

[0195] Heterocyclyl-C1-C4 alkyl, wherein the heterocyclyl substituent is selected from: 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heteroaryl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, oxo, thiocarbonyl, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, hydroxy-C1-C4 alkyl, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 -C1-C4 alkyl, -S-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0196] Phenyl, benzo-C5-C6 cycloalkyl, each of which is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms and -SO2-C1-C4 alkyl having 1 to 5 halogen atoms alkyl halide;

[0197] a monocyclic or bicyclic heterocycle selected from the group consisting of: a 4- to 10-membered heterocycloalkyl group, a 5-membered heteroaryl group, and a 6-membered heteroaryl group, each of which is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of: halogen, cyano, nitro, -OH, oxo, thiocarbonyl, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, hydroxy-C1-C4 alkyl, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 , -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms,

[0198] R 14 Selected from:

[0199] -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2;

[0200] C1-C4 alkyl, C3-C6 cycloalkyl, phenyl-C1-C4 alkyl, each of which is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 Alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0201] Heterocyclyl-C1-C4 alkyl, wherein the heterocyclyl substituent is selected from: 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heteroaryl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, oxo, thiocarbonyl, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, hydroxy-C1-C4 alkyl, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 -C1-C4 alkyl, -S-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0202] Phenyl, which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms; and

[0203] a monocyclic or bicyclic heterocycle selected from the group consisting of: a 4- to 10-membered heterocycloalkyl group, a 5-membered heteroaryl group, and a 6-membered heteroaryl group, each of which is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of: halogen, cyano, nitro, -OH, oxo, thiocarbonyl, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, hydroxy-C1-C4 alkyl, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 , -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms,

[0204] R 15 Selected from:

[0205] C1-C4 alkyl, C3-C6 cycloalkyl, phenyl-C1-C4 alkyl, each of which is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 Alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0206] Heterocyclyl-C1-C4 alkyl, wherein the heterocyclyl substituent is selected from: 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heteroaryl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, oxo, thiocarbonyl, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, hydroxy-C1-C4 alkyl, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 -C1-C4 alkyl, -S-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0207] Phenyl, which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms; and

[0208] a monocyclic or bicyclic heterocycle selected from the group consisting of: a 4- to 10-membered heterocycloalkyl group, a 5-membered heteroaryl group, and a 6-membered heteroaryl group, each of which is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of: halogen, cyano, nitro, -OH, oxo, thiocarbonyl, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, hydroxy-C1-C4 alkyl, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 , -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms,

[0209] R 16 is selected from the group consisting of: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, and C1-C4 alkoxy;

[0210] R 17 is selected from the group consisting of: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, and C1-C4 alkoxy;

[0211] Q is selected from: 6-membered aryl and 5- to 6-membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen; SF5; cyano; -CHO; nitro; oxo; C1-C4 alkyl; C1-C4 hydroxyalkyl; C1-C4 haloalkyl having 1 to 5 halogen atoms; -OH; C1-C4 alkoxy; C3-C6 cycloalkyl-C1-C4 alkoxy; cyano-C1-C4 alkoxy; C1-C4 haloalkoxy having 1 to 5 halogen atoms; -NH(C1-C4 alkyl); -N(C1-C4 alkyl)2; -NH-SO2-(C1-C4 alkyl); -N(SO2-[C1-C4 alkyl])(C1-C4 alkyl); (C1-C4 alkoxyimino)-C1-C4 alkyl; a 4- to 6-membered heterocyclic group optionally substituted by 1 or 2 substituents selected from fluorine, chlorine, bromine, methyl and cyano; -CH2-O-(C1-C4 alkyl), -CH2-NH(C1-C4 alkyl), -CH2-N(C1-C4 alkyl)2; a methyl group substituted by a 4- to 6-membered heterocyclic group, the 4- to 6-membered heterocyclic group itself optionally substituted by 1 or 2 substituents selected from fluorine, chlorine, bromine, methyl and cyano; -CH2-S-(C1-C4 alkyl); -CH2-S(O)-(C1-C4 alkyl); -CH2-SO2-(C1-C4 alkyl); -S-(C1-C4 alkyl); -S(O)-(C1-C4 alkyl); -SO2-(C1-C4 alkyl); -S-(C1-C4 alkyl) having 1 to 5 halogen atoms -S(O)-(C1-C4 haloalkyl) having 1 to 5 halogen atoms; -SO2-(C1-C4 haloalkyl) having 1 to 5 halogen atoms; -CONH(C1-C4 alkyl); -CONH(C3-C6 cycloalkyl); -NHCO(C1-C4 alkyl); -NHCO(C3-C6 cycloalkyl); -NHCO(C1-C4 haloalkyl) having 1 to 5 halogen atoms;

[0212] When Y is O, S or NR 9 When R 7 、R 8 、R 10 and R 11 are not -OH, and when X is O, S or NR 9 When R 7 and R 8 None of them are -OH.

[0213] According to a third embodiment of the first aspect, the present invention covers compounds of the general formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

[0214] A is A1 or A2,

[0215]

[0216] o is 0, 1, or 2;

[0217] R is selected from the group consisting of: hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy;

[0218] X and Y are independently selected from: CR 7 R 8 , O, S and NR 9 , where at least one of X and Y is CR 7 R 8 ;

[0219] T is selected from T as defined above 1 、T 2 、T 3 、T 4 、T 5 、T 6 、T 7 、T 8a 、T 8b and T 9 ;

[0220] R 1 Selected from: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy;

[0221] R 2 Selected from:

[0222] Hydrogen, halogen, cyano, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2;

[0223] -NR 12 R 13 ;

[0224] -OR 14 ;

[0225] -SR 15 、-S(O)R 15 、-SO2 R 15 ;

[0226] C1-C6 alkyl, C3-C6 cycloalkyl, C2-C4 alkenyl, C3-C6 cycloalkenyl, C2-C4 alkynyl or phenyl-C1-C4 alkyl, each of which is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halogen, -OH, -NO2, cyano, C1-C4 alkyl-C(O)-, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 Alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, and -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0227] a monocyclic or bicyclic heterocycle selected from the group consisting of: a 4- to 10-membered heterocycloalkyl group, a heterospirocycloalkyl group, a 5-membered heteroaryl group, and a 6-membered heteroaryl group, each of which is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, oxo, thiocarbonyl, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 alkyl-C(O)-, a C1-C4 haloalkyl group having 1 to 5 halogen atoms, a C1-C4 alkoxy group, a hydroxy-C1-C4 alkyl group, a C1-C4 alkoxy-C1-C4 alkyl group, a C1-C4 haloalkoxy group having 1 to 5 halogen atoms, a C3-C6 Cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms, and 4- to 10-membered heterocycloalkyl;

[0228] R 3 Selected from: hydrogen, halogen or C1-C4 alkyl;

[0229] R 4Selected from: hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms;

[0230] R 5 Selected from: hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy;

[0231] R 6 Selected from: hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms;

[0232] R 7 Selected from: hydrogen, halogen, C1-C4 alkyl;

[0233] R 8 Selected from: hydrogen, halogen, C1-C4 alkyl;

[0234] R 9 Selected from: hydrogen, C1-C4 alkyl;

[0235] R 10 Selected from: hydrogen, -OH, C1-C4 alkyl and C1-C4 alkoxy;

[0236] R 11 Selected from: hydrogen;

[0237] R 12 and R 13 Independently selected from:

[0238] hydrogen;

[0239] C1-C4 alkyl, C3-C6 cycloalkyl, phenyl-C1-C4 alkyl, each of which is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano, -COOH, C1-C4 alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, -NH-C(O)-C1-C4 alkyl, -N(C1-C4 alkyl)(-C(O)-C1-C4 alkyl), C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 -C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-C1-C4 haloalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4 haloalkyl having 1 to 5 halogen atoms, -SO2-C1-C4 haloalkyl having 1 to 5 halogen atoms and (C1-C4 alkoxy)2P(=O)-;

[0240] Heterocyclyl-C1-C4 alkyl, wherein the heterocyclyl substituent is selected from the group consisting of 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl, and 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, cyano, -OH, oxo, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, and C1-C4 haloalkoxy having 1 to 5 halogen atoms;

[0241] Phenyl, benzo-C5-C6 cycloalkyl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms;

[0242] a monocyclic or bicyclic heterocycle selected from the group consisting of 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl, and 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, cyano, -OH, oxo, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, hydroxy-C1-C4 alkyl, C1-C4 haloalkoxy having 1 to 5 halogen atoms;

[0243] R 14 Selected from:

[0244] C1-C4 alkyl, C3-C6 cycloalkyl, phenyl-C1-C4 alkyl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl;

[0245] Heterocyclyl-C1-C4 alkyl, wherein the heterocyclyl substituent is selected from the group consisting of 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl, and 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, cyano, -OH, oxo, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, and C1-C4 haloalkoxy having 1 to 5 halogen atoms;

[0246] R 15 Selected from:

[0247] C1-C4 alkyl, phenyl-C1-C4 alkyl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms;

[0248] Heterocyclyl-C1-C4 alkyl, wherein the heterocyclyl substituent is selected from: 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl, and 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, and C1-C4 haloalkoxy having 1 to 5 halogen atoms;

[0249] R 16 is selected from the group consisting of: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, and C1-C4 alkoxy;

[0250] R 17 is selected from the group consisting of: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, and C1-C4 alkoxy;

[0251] Q is selected from: 6-membered aryl and 5- to 6-membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4 or 5 substituents selected from the following: halogen, cyano, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, -OH, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, 4- to 6-membered heterocyclyl, which is optionally substituted by 1 or 2 substituents selected from the following: fluorine, chlorine, bromine, methyl and cyano;

[0252] When Y is O, S or NR 9 When R 7 、R 8 、R 10 and R 11 are not -OH, and when X is O, S or NR 9 When R 7 and R 8 None of them are -OH.

[0253] According to a fourth embodiment of the first aspect, the present invention covers compounds of the general formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

[0254] A is A1 or A2,

[0255]

[0256] o is 0 or 1;

[0257] R is selected from the group consisting of: hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy;

[0258] X is selected from: CR 7 R 8 , O, S and NR 9 ,

[0259] Y is CR 7 R 8 ;

[0260] T is selected from T as defined above 1 、T 2 、T 3 、T 4 、T 5 、T 6 、T 7 、T 8a 、T 8b and T9 ;

[0261] R 1 Selected from: hydrogen and C1-C4 alkyl;

[0262] R 2 Selected from:

[0263] Hydrogen, halogens;

[0264] -NR 12 R 13 ;

[0265] -OR 14 ;

[0266] -SR 15 、-S(O)R 15 、-SO2 R 15 ;

[0267] C1-C6 alkyl or C3-C6 cycloalkyl, each of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halogen, cyano, C1-C4 alkyl;

[0268] a monocyclic or bicyclic heterocycle selected from the group consisting of: 4- to 10-membered heterocycloalkyl, heterospirocycloalkyl, 5-membered heteroaryl, and 6-membered heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, -OH, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, hydroxy-C1-C4 alkyl, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 haloalkoxy having 1 to 5 halogen atoms;

[0269] R 3 Selected from: hydrogen, halogen or C1-C4 alkyl;

[0270] R 4 Selected from: hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0271] R 5 Selected from: hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0272] R 6 Selected from: hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0273] R 7 Selected from: hydrogen, halogen, C1-C4 alkyl;

[0274] R8 Selected from: hydrogen, halogen, C1-C4 alkyl;

[0275] R 9 Selected from: hydrogen, C1-C4 alkyl;

[0276] R 10 Selected from: hydrogen, C1-C4 alkyl;

[0277] R 11 Selected from: hydrogen;

[0278] R 12 and R 13 Independently selected from:

[0279] hydrogen;

[0280] C1-C4 alkyl, C3-C6 cycloalkyl, phenyl-C1-C4 alkyl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl;

[0281] Heterocyclyl-C1-C4 alkyl, wherein the heterocyclyl substituent is selected from 4- to 10-membered heterocyclylalkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms;

[0282] Phenyl, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms;

[0283] a monocyclic or bicyclic heterocycle selected from the group consisting of 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl, and 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, and C1-C4 haloalkoxy having 1 to 5 halogen atoms;

[0284] R 14 Selected from:

[0285] C1-C4 alkyl, C3-C6 cycloalkyl, phenyl-C1-C4 alkyl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms;

[0286] Heterocyclyl-C1-C4 alkyl, wherein the heterocyclyl substituent is selected from the group consisting of 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl, and 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, and C1-C4 haloalkoxy having 1 to 5 halogen atoms;

[0287] R 15 Selected from:

[0288] C1-C4 alkyl, phenyl-C1-C4 alkyl, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms;

[0289] Heterocyclyl-C1-C4 alkyl, wherein the heterocyclyl substituent is selected from the group consisting of 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl, and 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, and C1-C4 haloalkoxy having 1 to 5 halogen atoms;

[0290] R 16 Selected from: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0291] R 17 Selected from: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms;

[0292] Q is selected from: 6-membered aryl and 5- to 6-membered heteroaryl, each of which is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, and C1-C4 haloalkoxy having 1 to 5 halogen atoms;

[0293] When Y is O, S or NR 9 When R 7 、R8 、R 10 and R 11 are not -OH, and when X is O, S or NR 9 When R 7 and R 8 None of them are -OH.

[0294] According to a fifth embodiment of the first aspect, the present invention encompasses compounds of formula (I) as defined in any one of the first to fourth embodiments above, and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

[0295] Q is a substituted benzene ring of formula (Q1)

[0296]

[0297] in:

[0298] Z 1 、Z 2 、Z 3 、Z 4 and Z 5independently selected from: hydrogen; halogen; SF5; cyano; -CHO; nitro; C1-C4 alkyl; C1-C4 haloalkyl having 1 to 5 halogen atoms; hydroxy; C1-C4 alkoxy; C3-C6 cycloalkyl-C1-C4 alkoxy; cyano-C1-C4 alkoxy; C1-C4 haloalkoxy having 1 to 5 halogen atoms; -NH(C1-C4 alkyl); -N(C1-C4 alkyl)2; -NH-SO2-(C1-C4 alkyl); -N(SO2-[C1-C4 alkyl])(C1-C4 alkyl); (C1-C4 alkoxyimino)-C1-C4 alkyl; 4 to 6 membered heterocyclic group, which is optionally substituted by 1 or 2 substituents selected from fluorine, chlorine, bromine, methyl and cyano; -CH2-O-(C1-C4 alkyl); -CH2-NH(C1-C4 alkyl); -CH2-N(C1-C4 alkyl)2; methyl substituted by a 4- to 6-membered heterocyclic group, which itself is optionally substituted by 1 or 2 substituents selected from fluorine, chlorine, bromine, methyl and cyano; -CH2-S-(C1-C4 alkyl); -CH2-S(O)-(C1-C4 alkyl); -CH2-SO2-(C1-C4 alkyl); -S-(C1-C4 alkyl); -S(O)-(C1-C4 alkyl); -SO2-(C1-C4 alkyl); -S-(C1-C4 haloalkyl) having 1 to 5 halogen atoms; -S(O)-(C1-C4 haloalkyl) having 1 to 5 halogen atoms; -SO2-(C1-C4 haloalkyl); -CONH(C1-C4 alkyl); -CONH(C3-C6 cycloalkyl); -NHCO(C1-C4 alkyl); -NHCO(C3-C6 cycloalkyl); -NHCO(C1-C4 haloalkyl) having 1 to 5 halogen atoms, or

[0299] Z 1 and Z 2 together with the carbon atoms to which they are attached form a 5- or 6-membered saturated or partially saturated heterocyclic ring, a 5-membered heteroaryl group or a 6-membered heteroaryl group, each of which may be optionally substituted by one or two substituents selected from the group consisting of methyl, fluoro and oxo, and

[0300] Z 3 、Z 4 and Z 5independently selected from the group consisting of: hydrogen; halogen; SF5; cyano; CHO; nitro; C1-C4 alkyl; C1-C4 haloalkyl having 1 to 5 halogen atoms; hydroxy; C1-C4 alkoxy; C3-C6 cycloalkyl-C1-C4 alkoxy; cyano-C1-C4 alkoxy; C1-C4 alkoxy-C(O)-; C1-C4 haloalkoxy having 1 to 5 halogen atoms; -NH(C1-C4 alkyl); -N(C1-C4 alkyl)2; -NH-SO2-(C1-C4 alkyl); -N(SO2-[C1-C4 alkyl])(C1-C4 alkyl); (C1-C4 alkoxyimino)-C1-C4 alkyl; 4- to 6-membered heterocycloalkyl optionally substituted by 1 or 2 substituents selected from fluorine, methyl or cyano; -CH2-O-(C1-C4 alkyl); -CH2-NH(C1-C4 alkyl); -CH2-N(C1-C4 alkyl)2; methyl substituted by 4- to 6-membered heterocycloalkyl, which itself is optionally substituted by 1 or 2 substituents selected from fluorine, methyl or cyano; -CH2-S-(C1-C4 alkyl); -CH2-S(O)-(C1-C4 alkyl); -CH2-SO2-(C1-C4 alkyl); -S-(C1-C4 alkyl); -S(O)-(C1-C4 alkyl); -SO2-(C1-C4 alkyl); -S-(C1-C4 alkyl) having 1 to 5 halogen atoms haloalkyl); -S(O)-(C1-C4 haloalkyl) having 1 to 5 halogen atoms; -SO2-(C1-C4 haloalkyl) having 1 to 5 halogen atoms; -CONH(C1-C4 alkyl); -CONH(C3-C6 cycloalkyl); -NHCO(C1-C4 alkyl); -NHCO(C3-C6 cycloalkyl); -NHCO(C1-C4 haloalkyl) having 1 to 5 halogen atoms, or

[0301] Z 2 and Z 3 together with the carbon atoms to which they are attached form a 5- or 6-membered saturated or partially saturated heterocyclic ring, a 5-membered heteroaryl group or a 6-membered heteroaryl group, each of which may be optionally substituted by one or two substituents selected from the group consisting of methyl, fluoro and oxo, and

[0302] Z 1 、Z 4 and Z 5independently selected from the group consisting of: hydrogen; halogen; SF5; cyano; CHO; nitro; C1-C4 alkyl; C1-C4 haloalkyl having 1 to 5 halogen atoms; hydroxy; C1-C4 alkoxy; C3-C6 cycloalkyl-C1-C4 alkoxy; cyano-C1-C4 alkoxy; C1-C4 haloalkoxy having 1 to 5 halogen atoms; -NH(C1-C4 alkyl); -N(C1-C4 alkyl)2; -NH-SO2-(C1-C4 alkyl); -N(SO2-[C1-C4 alkyl])(C1-C4 alkyl); (C1-C4 alkyl); -C1-C4 alkyl; -C1-C4 alkyl; -C1-C4 alkyl; -CH2-NH(C1-C4 alkyl); -CH2-N(C1-C4 alkyl)2; -C1-C4 alkyl; -CH2-S(C1-C4 alkyl); -CH2-S(O)-(C1-C4 alkyl); -CH2-SO2-(C1-C4 alkyl); -S-(C1-C4 alkyl); -S(O)-(C1-C4 alkyl); -SO2-(C1-C4 alkyl); -S-(C1-C4 alkyl) having 1 to 5 halogen atoms; -C1-C4 alkyl ... haloalkyl); -S(O)-(C1-C4 haloalkyl) having 1 to 5 halogen atoms; -SO2-(C1-C4 haloalkyl) having 1 to 5 halogen atoms; -CONH(C1-C4 alkyl); -CONH(C3-C6 cycloalkyl); -NHCO(C1-C4 alkyl); -NHCO(C3-C6 cycloalkyl); -NHCO(C1-C4 haloalkyl) having 1 to 5 halogen atoms, or

[0303] Q is a pyridine ring of formula (Q2)

[0304]

[0305] in:

[0306] Z 6 、Z 7 、Z 8 and Z 9independently selected from the group consisting of hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C1-C4 hydroxyalkyl, NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), -NH-CO-C1-C4 alkyl, and a monocyclic heterocycle selected from the group consisting of a 4- to 7-membered heterocycloalkyl group or a 5-membered heteroaryl group having at least one nitrogen atom, the heteroaryl ring being attached to the pyridine ring via the at least one nitrogen atom, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, oxo, thiocarbonyl, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S-C1-C4 alkyl, -S(O)-C1-C4 alkyl, -SO2-C1-C4 alkyl, -S-(C1-C4 haloalkyl) having 1 to 5 halogen atoms, -S(O)-(C1-C4 haloalkyl) having 1 to 5 halogen atoms, -SO2-(C1-C4 haloalkyl) having 1 to 5 halogen atoms, or

[0307] Q is a pyrimidine ring of formula (Q3)

[0308]

[0309] in:

[0310] Z 10 、Z 11 and Z 12 independently selected from: hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, or

[0311] Q is a pyridine ring of formula (Q4)

[0312]

[0313] in:

[0314] Z 13 、Z 14 、Z 15 and Z 16independently selected from: hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, or

[0315] Q is a pyridine ring of formula (Q5)

[0316]

[0317] in:

[0318] Z 17 、Z 18 、Z 19 and Z 20 independently selected from: hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, or

[0319] Q is a 5-membered aromatic heterocycle of formula (Q6)

[0320]

[0321] in:

[0322] G 1 -G 4 Independently selected from: N, O, S, CZ 21 and New Zealand 22 , where G 1 -G 4 No more than one of them is O, G 1 -G 4 No more than one of them is S, G 1 -G 4 No more than one of them is NZ 22 , and among them

[0323] Each Z 21 independently selected from the group consisting of hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, C1-C4 haloalkoxy having 1 to 5 halogen atoms, and

[0324] Each Z 22independently selected from: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkyl-C3-C6 cycloalkyl, C1-C4 alkoxy-C1-C4 alkyl, or

[0325] Q is a 5-membered aromatic heterocycle of formula (Q7)

[0326]

[0327] in:

[0328] U 1 -U 4 Independently selected from: N and CZ 23 , where U 1 -U 4 No more than three of them are N, and

[0329] Each Z 23 Independently selected from the group consisting of hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, C1-C4 alkoxy, and C1-C4 haloalkoxy having 1 to 5 halogen atoms.

[0330] Among them, the 5-membered aromatic heterocycle of formula (Q6) can be preferably selected from:

[0331]

[0332]

[0333] in:

[0334] Each Z 21 are independently selected from the group consisting of hydrogen, fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy and

[0335] Z 22 is hydrogen, methyl, or

[0336] The 5-membered aromatic heterocycle of formula (Q7) can be preferably selected from:

[0337]

[0338] in:

[0339] Each Z 23 are independently selected from: hydrogen, fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy, or

[0340] Q can be selected from:

[0341] .

[0342] According to a sixth embodiment of the first aspect, the present invention covers compounds of the above-mentioned general formula (I) and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

[0343] A is selected from:

[0344] ,

[0345] T is selected from T as defined above 1 、T 2 、T 3 、T 4 、T 5 、T 6 、T 7 、T 8a 、T 8b and T 9 ;

[0346] R 1 Selected from: hydrogen or methyl;

[0347] R 2 Selected from:

[0348] Hydrogen, chlorine, fluorine, bromine;

[0349] -NR 12 R 13 ;

[0350] -OR 14 ;

[0351] methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclohexyl, each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, chloro, cyano, methyl, ethyl, propyl and isopropyl;

[0352] a monocyclic or bicyclic heterocycle selected from the group consisting of azetidine, pyrrolidine, pyrazolidine, imidazolidine, 1,2,4-triazolidine, piperidine, piperazine, tetrahydropyridine, dihydro-2H-pyran, tetrahydropyran, 1,2-oxazolidine, 1,2-oxazine, morpholine, thiomorpholine, 3,4-dihydroisoquinoline, 2,3-dihydro-indole, 1,3-dihydro-isoindole, 3,9-dioxa-7-azabicyclo[3.3.1]nonane; alkane, 6-oxa-3-azabicyclo[3.1.1]heptane, 8-oxa-3-azabicyclo[3.2.1]octane, imidazole, pyrazole, 1,2,4-triazole, 1,2,3-triazole, 4-oxa-7-azaspiro[2.5]octane, each of which is optionally substituted with 1, 2, 3 or 4 substituents independently selected from fluoro, chloro, -OH, methyl, trifluoromethyl, methoxymethyl, trifluoromethoxymethyl;

[0353] R3 Selected from: hydrogen, chlorine or methyl;

[0354] R 4 Selected from: hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl, trifluoromethoxy;

[0355] R 5 Selected from: hydrogen, fluorine, chlorine, methyl, trifluoromethyl;

[0356] R 6 Selected from: hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl, trifluoromethoxy;

[0357] R 7 Selected from: hydrogen, fluorine, chlorine, methyl;

[0358] R 8 Selected from: hydrogen, fluorine, chlorine, methyl;

[0359] R 9 Selected from: hydrogen, methyl;

[0360] R 10 Selected from: hydrogen, methyl;

[0361] R 11 Selected from: hydrogen;

[0362] R 12 and R 13 Independently selected from:

[0363] hydrogen and methyl;

[0364] R 14 is methyl;

[0365] R 16 Selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl;

[0366] R 17 Selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl;

[0367] Q is a benzene ring of formula (Q1)

[0368]

[0369] in:

[0370] Z 1 to Z 5 independently selected from the group consisting of: hydrogen, fluorine, chlorine, methyl and trifluoromethyl;

[0371] or

[0372] Q is a benzene ring of formula (Q2)

[0373]

[0374] in:

[0375] Z 6 to Z 9 Independently selected from the group consisting of: hydrogen, fluorine, chlorine, methyl and trifluoromethyl.

[0376] According to a seventh embodiment of the first aspect, the present invention encompasses compounds of general formula (I) and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, as defined in any one of the first to sixth embodiments above, wherein:

[0377] Q is a benzene ring of formula (Q1)

[0378]

[0379] in:

[0380] Z 1 , Z3 and Z 5 independently selected from: hydrogen, fluorine and chlorine;

[0381] Z 2 and Z 4 independently selected from: hydrogen, fluorine, chlorine and trifluoromethyl;

[0382] or

[0383] Q is a benzene ring of formula (Q2)

[0384]

[0385] in:

[0386] Z 6 to Z 9 Independently selected from: hydrogen, fluorine and chlorine.

[0387] According to an eighth embodiment of the first aspect, the present invention encompasses compounds of formula (I) and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, as defined in any one of the first to seventh embodiments above, wherein:

[0388] A is selected from:

[0389] .

[0390] According to a ninth embodiment of the first aspect, the present invention encompasses compounds of the general formula (I) above and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, wherein:

[0391] A is selected from:

[0392]

[0393] T is selected from T as defined above 1 、T 2 、T 3 、T 4 、T 5 、T 6 、T 7 、T 8a 、T 8b and T 9 ;

[0394] R 1 is hydrogen;

[0395] R 2 Selected from

[0396] hydrogen, chlorine;

[0397] -NR 12 R 13 ;

[0398] -OR 14 ;

[0399] methyl, isopropyl;

[0400] Morpholine;

[0401] R 3 is hydrogen or methyl;

[0402] R 4 is hydrogen or fluorine;

[0403] R 5 is hydrogen or methyl;

[0404] R 6 is hydrogen or fluorine;

[0405] R 7 is hydrogen or methyl;

[0406] R 8 is hydrogen;

[0407] R 9 is hydrogen;

[0408] R 10 is hydrogen;

[0409] R 11 is hydrogen;

[0410] R 12 and R 13 Independently selected from:

[0411] hydrogen and methyl;

[0412] R 14 is methyl;

[0413] R 16 is methyl or isopropyl;

[0414] R 17 is methyl;

[0415] Q is a benzene ring of formula (Q1)

[0416]

[0417] in:

[0418] Z 1 、Z 3 and Z 5 independently selected from: hydrogen, fluorine and chlorine;

[0419] Z 2 and Z 4 independently selected from: hydrogen, fluorine, chlorine and trifluoromethyl;

[0420] or

[0421] Q is a benzene ring of formula (Q2)

[0422]

[0423] in:

[0424] Z 6 to Z 9 are independently selected from hydrogen and chlorine.

[0425] According to a tenth embodiment of the first aspect, the present invention encompasses compounds of formula (I) and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, as defined in any one of the first to ninth embodiments above, wherein:

[0426] A is selected from:

[0427] ,

[0428] Preferably, A is

[0429] .

[0430] According to another particular embodiment of the first aspect, the present invention encompasses compounds of general formula (I) and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, as defined in any one of the first to tenth embodiments above, wherein:

[0431] T is T as defined above 1 :

[0432] ,and

[0433] A, U, Q, and R 1 to R 15 has the meaning as defined above for any embodiment of the first aspect.

[0434] According to another particular embodiment of the first aspect, the present invention encompasses compounds of general formula (I) and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, as defined in any one of the first to tenth embodiments above, wherein:

[0435] T is T as defined above 2 :

[0436] ,and

[0437] A, U, V, Q, and R 1 to R 16 has the meaning as defined above for any embodiment of the first aspect.

[0438] According to another particular embodiment of the first aspect, the present invention encompasses compounds of general formula (I) and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, as defined in any one of the first to tenth embodiments above, wherein:

[0439] T is T as defined above 3 :

[0440] ,and

[0441] A, Q, and R 1 to R 15 has the meaning as defined above for any embodiment of the first aspect.

[0442] According to another particular embodiment of the first aspect, the present invention encompasses compounds of general formula (I) and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, as defined in any one of the first to tenth embodiments above, wherein:

[0443] T is T as defined above 4 :

[0444] ,and

[0445] A, U, V, Q, and R 1 to R 15 has the meaning as defined above for any embodiment of the first aspect.

[0446] According to another particular embodiment of the first aspect, the present invention encompasses compounds of general formula (I) and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, as defined in any one of the first to tenth embodiments above, wherein:

[0447] T is T as defined above 5 :

[0448] ,and

[0449] A, Q, and R 1 to R 17 has the meaning as defined above for any embodiment of the first aspect.

[0450] According to another particular embodiment of the first aspect, the present invention encompasses compounds of general formula (I) and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, as defined in any one of the first to tenth embodiments above, wherein:

[0451] T is T as defined above 6 :

[0452] ,and

[0453] A, U, Q, and R 1 to R 15 has the meaning as defined above for any embodiment of the first aspect.

[0454] According to another particular embodiment of the first aspect, the present invention encompasses compounds of general formula (I) and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, as defined in any one of the first to tenth embodiments above, wherein:

[0455] T is T as defined above 7 :

[0456] ,and

[0457] A, U, V, Q, and R 1 to R 15 has the meaning as defined above for any embodiment of the first aspect.

[0458] According to another particular embodiment of the first aspect, the present invention encompasses compounds of general formula (I) and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, as defined in any one of the first to tenth embodiments above, wherein:

[0459] T is T as defined above 8a :

[0460] ,and

[0461] A, L, M, Q, and R 1 to R 15 has the meaning as defined above for any embodiment of the first aspect.

[0462] According to another particular embodiment of the first aspect, the present invention encompasses compounds of general formula (I) and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, as defined in any one of the first to tenth embodiments above, wherein:

[0463] T is T as defined above 8b :

[0464] ,and

[0465] A, Q, and R 1 to R 15 has the meaning as defined above for any embodiment of the first aspect.

[0466] According to another particular embodiment of the first aspect, the present invention encompasses compounds of general formula (I) and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof, as defined in any one of the first to tenth embodiments above, wherein:

[0467] T is T as defined above 9 :

[0468] ,and

[0469] A, Q, and R 1 to R 15 has the meaning as defined above for any embodiment of the first aspect.

[0470] In particular further embodiments of the first aspect, the invention encompasses combinations of two or more of the embodiments described above under the heading "Further embodiments of the first aspect of the invention".

[0471] The present invention encompasses any subcombination within any embodiment or aspect of the invention of compounds of formula (I) above.

[0472] The present invention encompasses compounds of formula (I) disclosed herein below in the Examples section. Such as, in particular, Example compounds S1-1, S1-2, S1-3, S1-4, S1-5, S1-6, S1-7, S1-8, S1-9, S1-10, S1-11, S1-12, S1-13, S1-14, S1-15, S1-16, S1-17, S1-18, S2-1, S2-2, S2-3, S2-4, S2-5, S2-6, S2-7, S3-1, S4-1, S4-2, S4-3, S4-4, S4-5, S4-6, S4-7, S4-8, S4-9, S4-10, S5-1, S6-1, S6-2, S7-1, S7-2, S8a-1, S8a-2, S8a-3, S8a-4, S8a-5, S8a-6, S8b-1, S8b-2, S8b-3, S9-1, S9-2, S9-3, S9-4, S9-5, S9-6.

[0473] The compounds according to the invention of general formula (I) can be prepared according to schemes 1 to 10 (general synthesis schemes) as shown in the experimental part of the present invention. The described schemes and procedures illustrate the synthetic routes of the compounds of general formula (I) of the present invention and are not intended to be limiting. It is clear to those skilled in the art that the transformation sequence as illustrated in schemes 1 to 10 can be modified in various ways. Therefore, the transformation sequence illustrated in these schemes is not intended to be limiting. In addition, the substituents T, Q, A, R can be realized before and / or after the illustrated transformations. 1 、R 2 、R 3 、R 4 、R 5 or R 6The interconversion of any of these. These modifications may be, for example, the introduction of protecting groups, the cleavage of protecting groups, reduction or oxidation functional groups, halogenation, metallation, substitution or other reactions known to those skilled in the art. These conversions include those that introduce functional groups that allow further interconversion of substituents. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.

[0474] In the following, several routes to prepare compounds of general formula (I) are described in Schemes 1 to 10.

[0475] According to a second aspect, the present invention encompasses a process for preparing a compound of formula (I) as defined above, said process comprising the steps of reacting an intermediate compound of formula Int-I-T1, Int-I-T2, Int-I-T3, Int-I-T4, Int-I-T5, Int-I-T6, Int-I-T7, Int-I-T8a, Int-I-T8b or Int-I-T9:

[0476]

[0477]

[0478] Among them L, M, U, V, A, R 1 、R 2 、R 3 、R 4 、R 5 and R 6 As defined for compounds of general formula (I) as defined above, and wherein Hal is halogen, in particular chlorine, bromine or iodine,

[0479] React with a compound of formula 1H:

[0480] QB(OR)2

[0481] 1H,

[0482] wherein Q is as defined for the compound of general formula (I) as defined above, and each R may individually be H or Me, or both R are pinacol esters,

[0483] Thus, a compound of general formula (I) is obtained:

[0484]

[0485] Among them T, L, M, U, A, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and Q are as defined above.

[0486] According to an alternative embodiment of the second aspect, the present invention encompasses a process for the preparation of a compound of formula (I) as defined above, said process comprising the steps of reacting an intermediate compound of formula Int-II-T1, Int-II-T2, Int-II-T3, Int-II-T4, Int-II-T5, Int-II-T6, Int-II-T7, Int-II-T8a, Int-II-T8b or Int-II-T9:

[0487]

[0488] Among them, L, M, U, V, Q, R 2 、R 3 、R 4 、R 5 and R 6 As defined for the compounds of general formula (I) as defined above,

[0489] Reaction with a compound of formula 1V:

[0490] ,

[0491] where R 1 and A is as defined for the compound of general formula (I) as defined above,

[0492] Thus, a compound of general formula (I) is obtained:

[0493]

[0494] Among them, T, A and R 1 As defined above.

[0495] According to a third aspect, the present invention encompasses a process for preparing a compound of general formula (I) as defined above, said process comprising the steps of preparing an intermediate compound as described above and then converting the resulting compound into a solvate, salt and / or solvate thereof using the corresponding (i) solvent and / or (ii) base or acid.

[0496] The present invention encompasses a process for preparing the compounds of the invention of general formula (I) comprising the steps as described in the experimental section hereinafter.

[0497] According to a fourth aspect, the present invention encompasses intermediate compounds for the preparation of compounds of general formula (I) above.

[0498] In particular, the present invention encompasses intermediate compounds having the following general formula and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and mixtures thereof:

[0499]

[0500] Among them L, M, U, V, A, R 1 、R 2 、R 3 、R 4 、R 5 and R 6 As defined above for compounds of formula (I), and Hal is halogen.

[0501] Furthermore, the present invention encompasses intermediate compounds having the following general formula and stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, and mixtures thereof:

[0502]

[0503] Among them, L, M, U, V, Q, R 2 、R 3 、R 4 、R 5 and R 6 As defined for the compounds of general formula (I) as defined above.

[0504] The present invention particularly encompasses the intermediate compounds disclosed in the Examples section herein below.

[0505] The compounds of the general formula (I) of the present invention can be converted into any salt, preferably a pharmaceutically acceptable salt, as described herein by any method known to those skilled in the art. Similarly, any salt of the compounds of the general formula (I) of the present invention can be converted into a free compound by any method known to those skilled in the art.

[0506] The compounds of the general formula (I) according to the present invention exhibit an unexpectedly valuable spectrum of pharmacological actions. It has surprisingly been found that the compounds according to the present invention interact effectively with Slo-1 and, therefore, can be used for the treatment or prevention of diseases, preferably helminth infections, in particular gastrointestinal and extraintestinal helminth infections, more particularly gastrointestinal and extraintestinal nematode infections, in humans and animals.

[0507] The compounds of the present invention are useful for controlling, treating, and / or preventing helminth infections, particularly gastrointestinal and extraintestinal helminth infections. The method comprises administering to a mammal in need thereof an amount of a compound of the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate, or ester thereof, effective for treating the condition.

[0508] In an alternative aspect, the method comprises administering to a bird in need thereof, i.e., a caged bird, or particularly poultry, an amount of a compound of the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; effective to treat the condition.

[0509] In particular, in the field of veterinary medicine, the compounds of the invention are suitable for controlling parasites, especially helminths, in warm-blooded animals with a favorable toxicity profile in animal breeding and animal husbandry, in livestock, breeding, zoo, laboratory, experimental and domestic animals. They are active against all or specific developmental stages of parasites, especially helminths.

[0510] Agricultural livestock include, for example, mammals such as sheep, goats, horses, donkeys, camels, buffaloes, rabbits, reindeer, red deer, and especially cattle and pigs; or poultry such as turkeys, ducks, geese, and especially chickens; or fish or crustaceans, for example in aquaculture.

[0511] Domestic animals include, for example, mammals, such as hamsters, guinea pigs, rats, mice, chinchillas, ferrets or, in particular, dogs, cats; caged birds; reptiles; amphibians or aquarium fish.

[0512] The present invention also provides methods for treating helminth infections, particularly gastrointestinal and extraintestinal helminth infections, and more particularly gastrointestinal and extraintestinal nematode infections.

[0513] These disorders have been well characterized in animals and can be treated by administering the pharmaceutical compositions of the present invention.

[0514] As used in the context of the present invention, the term "treating" or "treatment" is used conventionally, e.g., to manage or care for a subject for the purpose of combating, slowing down, reducing, alleviating, or ameliorating the symptoms of a disease or condition, such as a nematode infection. In particular, and especially in the field of animal health or veterinary medicine, the term "treating" or "treatment" includes preventative, metaphylactic, or therapeutic treatment.

[0515] Helminths that are pathogenic to humans or animals include, for example, acanthocephala, nematodes, pentastoma, and platyhelmintha (eg, monogenea, tapeworms, and flukes).

[0516] Exemplary worms include, but are not limited to:

[0517] Solitary parasites: for example, Dactylogyrus spp., Gyrodactylus spp., Microbothrium spp., Polystoma spp., Troglocephalus spp.;

[0518] Tapeworms: from the order of the Pseudophyllidea, for example: Bothridium spp., Diphyllobothrium spp., Diplogonoporus spp., Ichthyobothrium spp., Ligulas spp., Schistocephalus spp., Spirometra spp.;

[0519] From the order of the Cyclophyllida, for example: Andyras spp., Anoplocephala spp., Avitellina spp., Bertiella spp., Cittotaenia spp., Davainea spp., Diorchis spp., Diplopylidium spp., Dipylidium spp., Echinococcus spp., Echinocotyles spp., Echinolepis spp., Hydatigera spp.), Hymenolepis spp., Joyeuxiella spp., Mesocestoides spp., Moniezias spp., Paranoplocephala spp., Raillietinas spp., Stilesia spp., Taenia spp., Thysaniezia spp., and Thysanosoma spp.

[0520] Trematodes: from the class of the Digenea, for example: Austrobilharzia spp., Brachylaima spp., Calicophoron spp., Catatropis spp., Clonorchis spp., Collyriclum spp., Cotylophoron spp., Cyclocoelum spp., Dicrocoelium spp., Diplostomum spp., Echinochasmus spp., Echinoparyphium spp., Echinostoma spp., Eurytrema spp.), Fasciola spp., Fasciolides spp., Fasciolopsis spp., Fischoederius spp., Gastrothylacus spp., Gigantobilharzia spp., Gigantocotyle spp., Heterophyes spp., Hypoderaeum spp., Leucochloridium spp., Metagonimus spp., Metorchis spp., Nanophyetus spp., Notocotylus spp.), Opisthorchis spp., Ornithobilharzia spp., Paragonimus spp., Paramphistomum spp., Plagiorchis spp., Posthodiplostomum spp., Prosthogonimus spp., Schistosoma spp., Trichobilharzia spp., Troglotrema spp.), Typhlocoelum spp.;.

[0521] Nematodes: from the order of the Trichinellida, for example: Capillaria spp., Eucoleus spp., Paracapillaria spp., Trichinella spp., Trichomosoides spp., Trichuris spp.;

[0522] From the order of the Tylenchida, for example: Micronemas spp., Parastrongyloides spp., Strongyloides spp.;

[0523] From the order of the Rhabditina, for example: Aelurostrongylus spp., Amidostomum spp., Ancylostomas spp., Angiostrongylus spp., Bronchonema spp., Bunostomum spp., Chabertia spp., Cooperia spp., Cooperioides spp., Crenosoma spp., Cyathostomum spp., Cyclococercus spp., Cyclodontostomum spp.), Cylicocyclus spp., Cylicostephanus spp., Cylindropharynx spp., Cystocaulus spp., Dictyocaulus spp., Elaphostrongylus spp., Filaroides spp., Globocephalus spp., Graphidium spp., Gyalocephalus spp., Haemonchus spp., Heligmosomoides spp., Hyostrongylus spp., Marshallagia spp., Metastrongylus spp.), Muellerius spp., Necator spp., Nematodirus spp., Neostrongylus spp., Nippostrongylus spp., Obeliscoides spp., Oesophagodontus spp., Oesophagostomum spp., Ollulanus spp.; Ornithostrongylus spp.), Oslerus spp., Ostertagia spp., Paracooperia spp., Paracrenosoma spp., Parafilaroides spp., Parelaphostrongylus spp., Pneumocaulus spp., Pneumostrongylus spp., Poteriostomum spp., Protostrongylus spp., Spicocaulus spp., Stephanurus spp., Strongylus spp., Syngamus spp., Teladorsagia spp.), Trichonema spp., Trichostrongylus spp., Triodontophorus spp., Troglostrongylus spp., and Uncinaria spp.;

[0524] From the order of the Spirurida, for example: Acanthocheilonema spp., Anisakis spp., Ascaridis spp.; Ascaris spp., Ascarops spp., Aspiculuris spp., Baylisascaris spp., Brugia spp., Cercopithifilaria spp., Crassicauda spp., Dipetalonema spp., Dirofilaria spp., Dracunculus spp.; Drashia spp. spp.), Enterobius spp., Filaria spp., Gnathostoma spp., Gongylonema spp., Habronema spp., Heterakis spp.; Litomosoides spp., Loa spp., Onchocerca spp., Oxyuris spp., Parabronema spp., Parafilaria spp., Parascaris spp., Passalurus spp., Physaloptera spp., Probstmayria spp.), Pseudofilaria spp., Setaria spp., Skjrabinema spp., Spirocerca spp., Stephanofilaria spp., Strongyluris spp., Syphacia spp., Thelazia spp., Toxascaris spp., Toxocara spp., Wuchereria spp.;

[0525] Acantocephala: from the order of the Oligacanthorhynchida, for example, Macracanthorhynchus spp., Prosthenorchis spp.; from the order of the Moniliformida, for example, Moniliformis spp.;

[0526] From the order of the Polymorphida, for example, Filicollis spp.; from the order of the Echinorhynchida, for example, Acanthocephalus spp., Echinorhynchus spp., Leptorhynchoides spp.;

[0527] Pentastoma: From the order of the Porocephalida, for example, Linguatula spp.

[0528] The compounds of the present invention are particularly useful for the treatment and prevention, ie control of, helminth infections, especially gastrointestinal and extraintestinal helminth infections, more particularly gastrointestinal and extraintestinal nematode infections.

[0529] The control of animal parasites, especially helminths, by using the compounds of the invention is intended to reduce or prevent disease, mortality and performance impairment (in the case of meat, milk, wool, hides, eggs, honey, etc.), thereby enabling more economical and simpler animal husbandry and achieving better animal well-being.

[0530] As used herein in the field of animal health, the term "control" or "controlling" means that the compounds of the present invention are effective in reducing the incidence of the respective parasite in an animal infected with a parasite to a harmless level. More specifically, "control" as used herein means that the compounds of the present invention are effective in killing the respective parasite, inhibiting its growth, or inhibiting its proliferation.

[0531] According to another aspect, the present invention encompasses compounds of general formula (I) as described above or their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular pharmaceutically acceptable salts or mixtures thereof, for use in the treatment or prevention of diseases, in particular helminth infections, in particular gastrointestinal and extraintestinal helminth infections, more in particular gastrointestinal and extraintestinal nematode infections.

[0532] The pharmaceutical activity of the compounds according to the invention can be explained by their interaction with the Slo-1 ion channel.

[0533] According to another aspect, the present invention encompasses the use of a compound of formula (I) as described above or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts (especially pharmaceutically acceptable salts thereof), or mixtures thereof, for treating or preventing diseases, especially helminth infections, especially gastrointestinal and extraintestinal helminth infections, more especially gastrointestinal and extraintestinal nematode infections.

[0534] According to another aspect, the present invention encompasses the use of a compound of formula (I) as described above or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts (especially pharmaceutically acceptable salts thereof), or mixtures thereof, in a method for treating or preventing diseases, especially helminthic infections, especially gastrointestinal and extraintestinal helminthic infections, more especially gastrointestinal and extraintestinal nematode infections.

[0535] According to another aspect, the present invention encompasses the use of a compound of formula (I) as described above or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts (especially pharmaceutically acceptable salts thereof), or mixtures thereof, for the preparation of a pharmaceutical composition, preferably a medicament, for the treatment or prevention of diseases, especially helminth infections, especially gastrointestinal and extraintestinal helminth infections, more especially gastrointestinal and extraintestinal nematode infections.

[0536] According to another aspect, the present invention encompasses a method for treating or preventing diseases, in particular helminth infections, in particular gastrointestinal and extraintestinal helminth infections, more in particular gastrointestinal and extraintestinal nematode infections, using an effective amount of a compound of general formula (I) as described above or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts (in particular pharmaceutically acceptable salts thereof), or mixtures thereof.

[0537] According to another aspect, the present invention encompasses a compound of formula (I) as described above or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts (especially pharmaceutically acceptable salts thereof), or mixtures thereof, for use as an antiendoparasitical agent.

[0538] According to another aspect, the present invention encompasses a compound of formula (I) as described above or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts (especially pharmaceutically acceptable salts thereof), or mixtures thereof, for use as an anthelmintic, especially as a nematocide, flatwormicide, acanthocephalicidal or linguisticidal agent.

[0539] According to another aspect, the present invention encompasses pharmaceutical compositions, in particular veterinary formulations, comprising a compound of formula (I) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, salt (in particular a pharmaceutically acceptable salt thereof), or a mixture thereof, and one or more excipients, in particular one or more pharmaceutically acceptable excipients. Such pharmaceutical compositions can be prepared into suitable dosage forms using conventional procedures.

[0540] According to another aspect, the present invention encompasses a process for preparing a pharmaceutical composition, in particular a veterinary formulation, comprising the step of mixing a compound of general formula (I) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, salt (in particular a pharmaceutically acceptable salt) or a mixture thereof, with one or more excipients (in particular one or more pharmaceutically acceptable excipients).

[0541] According to another aspect, the present invention encompasses a method for treating or preventing diseases, in particular helminth infections, in particular gastrointestinal and extraintestinal helminth infections, more in particular gastrointestinal and extraintestinal nematode infections, comprising a pharmaceutical composition, in particular a veterinary formulation, comprising an effective amount of a compound of general formula (I) as described above or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts (in particular pharmaceutically acceptable salts thereof) or mixtures thereof.

[0542] Thus, the present invention encompasses a method of controlling helminth infections in humans and / or animals by administering to a human or animal in need thereof an anthelmintically effective amount of at least one compound of general formula (I) above.

[0543] The invention further encompasses pharmaceutical compositions, especially veterinary preparations, comprising at least one compound according to the invention, usually together with one or more pharmaceutically suitable excipients, and their use for the purposes mentioned above.

[0544] The compounds according to the present invention may have systemic and / or local activity. For this purpose, they may be administered in a suitable manner, such as, for example, via oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic routes or as implants or stents. Such administration may be prophylactic, remedial, preventative or therapeutic.

[0545] For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

[0546] For oral administration, the compound according to the present invention can be formulated into dosage forms known in the prior art for delivering the compound of the present invention quickly and / or in a modified manner, such as tablets (uncoated or coated tablets, for example, with delayed dissolution or insoluble enteric or controlled release coatings), orally disintegrating tablets, films / films (wafers), films / lyophylisates, capsules (for example, hard or soft gelatin capsules), sugar-coated tablets, granules, pills, chewable tablets (for example, soft chewable tablets), powders, emulsions, suspensions, aerosols or solutions. The compound according to the present invention can be incorporated into the dosage form in crystalline and / or amorphous and / or dissolved form.

[0547] Parenteral administration can be achieved by avoiding an absorption step (e.g. intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or by including absorption (e.g. intramuscularly, subcutaneously, intradermally, transdermally or intraperitoneally). Suitable administration forms for parenteral administration are especially preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilized powders or sterile powders.

[0548] Examples of suitable other routes of administration are pharmaceutical forms for inhalation [especially powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets / films / films / capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eyewashes, eye inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampon; vaginal capsules, aqueous suspensions (lotions, shake mixtures (mixturae agitandae)), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milks, pastes, foams, spot-ons, powders, implants or stents.

[0549] The compounds according to the invention can be incorporated into the administration forms described. This can be done in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, in particular:

[0550] • Fillers and carriers (e.g. cellulose, microcrystalline cellulose (such as Avicel ® ), lactose, mannitol, starch, calcium phosphate (such as Di-Cafos ® )),

[0551] • Ointment bases (e.g. petrolatum, paraffin, triglycerides, waxes, wool wax, wool alcohol, lanolin, hydrophilic ointments, polyethylene glycol),

[0552] • suppository bases (e.g. polyethylene glycol, cocoa butter, hard fat),

[0553] • Solvents (e.g., water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglyceride fatty oils, liquid polyethylene glycol, paraffin wax),

[0554] • Surfactants, emulsifiers, dispersants or wetting agents (e.g. sodium lauryl sulfate), lecithin, phospholipids, fatty alcohols (such as Lanette ® ), sorbitan fatty acid esters (such as, for example, Span ® ), polyoxyethylene sorbitan fatty acid esters (such as Tween ® ), polyoxyethylene fatty acid glycerides (such as Cremophor ® ), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as Pluronic ® ),

[0555] • buffers, acids and bases (e.g. phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, tromethamine, triethanolamine),

[0556] • Isotonic agents (eg, glucose, sodium chloride),

[0557] • Adsorbents (e.g. highly dispersed silica),

[0558] • Viscosifiers, gel formers, thickeners and / or binders (e.g. polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, starch, carbomers, polyacrylic acids (such as Carbopol ® ); alginate, gelatin),

[0559] • Disintegrants (e.g. modified starch, sodium carboxymethylcellulose, sodium starch glycolate (such as Explotab ® ), cross-linked polyvinyl pyrrolidone, cross-linked carboxymethyl cellulose sodium (such as AcDiSol ® )),

[0560] • Flow regulators, lubricants, glidants and release agents (e.g. magnesium stearate, stearic acid, talc, highly dispersed silica (such as Aerosil ® )),

[0561] • Coating materials (eg sugar, shellac) and film formers for thin or diffusion membranes that dissolve rapidly or in a modified manner (eg polyvinylpyrrolidone (such as Kollidon ® ), polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit ® )),

[0562] • capsule material (e.g., gelatin, hydroxypropyl methylcellulose),

[0563] • Synthetic polymers (e.g. polylactic acid, polyglycolide, polyacrylates, polymethacrylates (such as Eudragit ® ), polyvinylpyrrolidone (such as Kollidon ® ), polyvinyl alcohol, polyvinyl acetate, polyoxyethylene, polyethylene glycol and copolymers and block copolymers thereof,

[0564] • Plasticizers (e.g. polyethylene glycol, propylene glycol, glycerol, triacetin, triacetyl citrate, dibutyl phthalate),

[0565] • Penetration enhancers,

[0566] • stabilizers (e.g. antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate),

[0567] • Preservatives (e.g., parabens, sorbic acid, thimerosal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

[0568] • colorants (e.g. inorganic pigments such as e.g. iron oxide, titanium dioxide),

[0569] • Flavorings, sweeteners, taste and / or odor masking agents.

[0570] Furthermore, the present invention relates to a pharmaceutical composition comprising at least one compound according to the invention, usually together with one or more pharmaceutically suitable excipients, and to the use thereof according to the invention.

[0571] According to another aspect, the present invention encompasses pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) according to the invention and at least one or more further active ingredients, in particular for the treatment and / or prevention of endo- and / or ectoparasitic infections.

[0572] In the present invention, the term "endoparasites" is used as known to the person skilled in the art and refers in particular to helminths. In the present invention, the term "ectoparasites" is used as known to the person skilled in the art and refers in particular to arthropods, in particular insects or mites.

[0573] In particular, the present invention encompasses pharmaceutical combinations, especially veterinary combinations, comprising:

[0574] • one or more first active ingredients, in particular a compound of formula (I) as defined above, and

[0575] • one or more additional active ingredients, in particular one or more endoparasiticides and / or ectoparasiticides.

[0576] In the present invention, the term "combination" is used as known to those skilled in the art, and the combination may be a fixed combination, a non-fixed combination, or a kit of parts.

[0577] In the present invention, a "fixed combination" is used as known to those skilled in the art and is defined as a combination wherein, for example, a first active ingredient (such as one or more compounds of general formula (I) of the invention) and the further active ingredient are present together in one unit dose or one single entity. One example of a "fixed combination" is a pharmaceutical composition wherein the first active ingredient and the further active ingredient are present in an admixture for simultaneous administration, such as a formulation. Another example of a "fixed combination" is a pharmaceutical combination wherein the first active ingredient and the further active ingredient are present in one unit rather than in an admixture.

[0578] A non-fixed combination or "kit of parts" in the present invention is used as known to those skilled in the art and is defined as a combination in which the first active ingredient and the further active ingredient are present in more than one unit. An example of a non-fixed combination or kit of parts is a combination in which the first active ingredient and the further active ingredient are present separately. The components of the non-fixed combination or kit of parts may be administered separately, sequentially, simultaneously, in parallel or in a staggered time sequence.

[0579] The compounds of the present invention can be administered as a single agent or in combination with one or more other pharmaceutically active ingredients, where the combination does not cause unacceptable side effects. Such drug combinations are also encompassed by the present invention. For example, the compounds of the present invention can be combined with known ectoparasiticides and / or endoparasiticides.

[0580] Other or further active ingredients designated herein by their common names are known and described, for example, in the Pesticide Manual ("The Pesticide Manual", 16th edition, British Crop Protection Council 2012), or can be searched on the Internet (e.g., http: / / www.alanwood.net / pesticides). Classification is based on the current IRAC Mode of Action Classification Scheme at the time of filing of this patent application.

[0581] Examples of ectoparasiticides and / or endoparasiticides are insecticides, acaricides and nematicides and include in particular:

[0582] (1) Acetylcholinesterase (AChE) inhibitors, such as, for example, carbamates, for example, alanycarb, aldicarb, bendiocarb, benfuracarb, butocarboxim, butoxycarboxim, carbaryl, carbofuran, carbosulfan, ethiofencarb, fenobucarb, valproate, Formetanate, furathiocarb, isoprocarb, methiocarb, methomyl, metolcarb, oxamyl, pirimicarb, propoxur, thiodicarb, thiofanox, triazamate, trimethacarb, XMC, and xylylcarb;or organophosphates, such as acephate, azamethiphos, azinphos-ethyl, azinphos-methyl, chlorethoxyfos, chlorfenvinphos, chlormephos, chlorpyrifos-methyl, cyanophos, demeton-S-methyl, diazinon, dichlorvos / DDVP DDVP), dicrotophos, dimethoate, dimethylvinphos, disulfoton, EPN, ethion, ethoprophos, famphur, fenitrothion, fenthion, fosthiazate, heptenophos, imicyafos, isofenphos, isopropyl O-(methoxyaminothiophosphoryl) salicylate O-(methoxyaminothiophosphoryl)salicylate), isoxathion, malathion, mecarbam, methidathion, mevinphos, naled, oxydemeton-methyl, phenthoate, phorate, phosalone, phosmet, phoxim, pirimiphos-methyl yl), profenofos, propetamphos, prothiofos, pyraclofos, pyridaphenthion, quinalphos, tebupirimfos, temephos, terbufos, tetrachlorvinphos, thiometon, triazophos, triclorfon, and vamidothion.

[0583] (2) GABA-gated chloride channel blockers, such as, for example, cyclopentadienyl organochlorides, for example chlordane and endosulfan, or phenylpyrazoles (fiproles), for example ethiprole and fipronil.

[0584] (3) Sodium channel modulators, such as, for example, pyrethroids, for example, acrinathrin, allethrin, d-cis-trans allethrin, d-trans allethrin, bifenthrin, bioallethrin, bioallethrin S-cyclopentenyl isomer, bioresmethrin, cycloprothrin, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyfluthrin, gamma-cyfluthrin, cypermethrin, alpha-cypermethrin, beta-cypermethrin, theta-cypermethrin , ζ-cypermethrin, cyphenothrin [(1R)-trans-isomer], deltamethrin, empenthrin [(EZ)-(1R)-isomer], esfenvalerate, etofenprox, fenpropathrin, fenvalerate, flucythrinate flucythrinate, flumethrin, tau-fluvalinate, halfenprox, imiprothrin, kadethrin, momfluorothrin, permethrin, phenothrin [(1R)-trans-isomer], prallethrin, pyrethrins (pyrethrum), resmethrin, silafluofen, tefluthrin, tetramethrin, tetramethrin [(1R)-isomer], tralomethrin and transfluthrin or DDT or methoxychlor.

[0585] (4) Competitive modulators of the nicotinic acetylcholine receptor (nAChR), such as, for example, neonicotinoids, for example acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid and thiamethoxam, or nicotine or sulfoxaflor or flupyradifurone.

[0586] (5) Nicotinic acetylcholine receptor (nAChR) allosteric modulators, such as, for example, the spinosyns, eg, spinetoram and spinosad.

[0587] (6) Glutamate-gated chloride channel (GluCl) allosteric modulators, such as, for example, avermectins / milbemycins, e.g., abamectin, emamectin benzoate, lepimectin, and milbemectin.

[0588] (7) Juvenile hormone mimetics, such as, for example, juvenile hormone analogs, for example hydroprene, kinoprene and methoprene or fenoxycarb or pyriproxyfen.

[0589] (9) Regulators of chordal organs, such as, for example, pymetrozine or flonicamid.

[0590] (10) Mite growth inhibitors, such as, for example, clofentezine, hexythiazox and diflovidazin or etoxazole.

[0591] (12) Inhibitors of mitochondrial ATP synthase, such as ATP disruptors, such as, for example, diafenthiuron or organotin compounds, for example azocyclotin, cyhexatin and fenbutatin oxide, or propargite or tetradifon.

[0592] (13) Oxidative phosphorylation uncouplers via disruption of the proton gradient, such as, for example, chlorfenapyr, DNOC, and sulfluramid.

[0593] (14) Nicotinic acetylcholine receptor channel blockers, such as, for example, bensultap, cartap hydrochloride, thiocyclam and thiosultap-sodium.

[0594] (15) Type O chitin biosynthesis inhibitors, such as, for example, bistrifluron, chlorfluazuron, diflubenzuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, noviflumuron, teflubenzuron and triflumuron.

[0595] (16) Type 1 chitin biosynthesis inhibitors, such as buprofezin.

[0596] (17) Molting disruptors (especially for Diptera, i.e., two-winged creatures), such as, for example, cyromazine.

[0597] (18) Ecdysone receptor agonists, such as, for example, chromafenozide, halofenozide, methoxyfenozide and tebufenozide.

[0598] (19) Octopamine receptor agonists, such as, for example, amitraz.

[0599] (20) Mitochondrial complex III electron transport inhibitors, such as, for example, hydramethylnone or acequinocyl or fluacrypyrim.

[0600] (21) Mitochondrial complex I electron transport inhibitors, such as, for example, from the group of METI acaricides, for example fenazaquin, fenpyroximate, pyrimidifen, pyridaben, tebufenpyrad and tolfenpyrad or rotenone (Derris).

[0601] (22) Voltage-dependent sodium channel blockers, such as, for example, indoxacarb or metaflumizone.

[0602] (23) Inhibitors of acetyl-CoA carboxylase, such as, for example, tetronic acid and tetramic acid derivatives, for example spirodiclofen, spiromesifen and spirotetramat.

[0603] (25) Mitochondrial complex II electron transport inhibitors, such as, for example, β-ketonitrile derivatives, for example, cyenopyrafen and cyflumetofen; and formanilides, such as, for example, pyflubumide.

[0604] (28) Ryanodine receptor modulators, such as, for example, diamides, for example chlorantraniliprole, cyantraniliprole and flubendiamide,

[0605] Additional active ingredients such as, for example, Afidopyropen, Afoxolaner, Azadirachtin, Benclothiaz, Benzoximate, Bifenazate, Broflanilide, Bromopropylate, Chinomethionat, Chloroprallethrin, Cryolite, Cyclaniliprole, Cycloxanil, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cyclohexidine, Cycloxaprid), Cyhalodiamide, Dicloromezotiaz, Dicofol, Epsilon-Metofluthrin, Epsilon-Momfluthrin, Flometoquin, Fluazaindolizine, Fluensulfone, Flufenerim, Flufenoxystrobin, Flufiprole, Fluhexafon, Flupyr Fluopyram, Fluralaner, Fluxametamide, Fufenozide, Guadipyr, Heptafluthrin, Imidaclothiz, Iprodione, kappa-Bifenthrin, kappa-Tefluthrin, Lotilaner, Meperfluthrin, Paichongding, Trifluprofen Pyridalyl, Pyrifluquinazon, Pyriminostrobin, Spirobudiclofen, Tetramethylfluthrin, Tetraniliprole, Tetrachlorantraniliprole, Tioxazafen, Thiofluoximate, Triflumezopyrim, and Iodomethane; based on Bacillus firmusfirmus) (I-1582, BioNeem, Votivo); and the following compounds: 1-{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfinyl]phenyl}-3-(trifluoromethyl)-1H-1,2,4-triazol-5-amine (known in WO2006 / 043635) (CAS 885026-50-6), {1'-[(2E)-3-(4-chlorophenyl)prop-2-en-1-yl]-5-fluorospiro[indole-3,4'-piperidinyl]-1(2H)-yl}(2-chloropyridin-4-yl)methanone (known in WO2003 / 106457) (CAS 637360-23-7), 2-chloro-N-[2-{1-[(2E)-3-(4-chlorophenyl)prop-2-en-1-yl]piperidin-4-yl}-4-(trifluoromethyl)phenyl]isonicotinamide (known in WO2006 / 003494) (CAS 872999-66-1), 3-(4-chloro-2,6-dimethylphenyl)-4-hydroxy-8-methoxy-1,8-diazaspiro[4.5]dec-3-en-2-one (known in WO 2010052161) (CAS 1225292-17-0), 3-(4-chloro-2,6-dimethylphenyl)-8-methoxy-2-oxo-1,8-diazaspiro[4.5]dec-3-en-4-ylethyl carbonate (known in EP 2647626) (CAS 1440516-42-6), 4-(but-2-yn-1-yloxy)-6-(3,5-dimethylpiperidin-1-yl)-5-fluoropyrimidine (known in WO 2004 / 099160) (CAS 792914-58-0), PF1364 (known in JP2010 / 018586) (CAS1204776-60-2), N-[(2E)-1-[(6-chloropyridin-3-yl)methyl]pyridin-2(1H)-ylidene]-2,2,2-trifluoroacetamide (known in WO2012 / 029672) (CAS1363400-41-2), (3E)-3-[1-[(6-chloro-3-pyridinyl)methyl]-2-pyridylidene]-1,1,1-trifluoro-propan-2-one (known in WO20 13 / 144213) (CAS 1461743-15-6), N-[3-(benzylcarbamoyl)-4-chlorophenyl]-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (known in WO2010 / 051926) (CAS 1226889-14-0), 5-bromo-4-chloro-N-[4-chloro-2-methyl-6-(methylcarbamoyl)phenyl]-2-(3-chloro-2-pyridyl)pyrazole-3-carboxamide (known in CN103232431) (CAS1449220-44-3), 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-(cis-1-oxido-3-thietanyl)-benzamide, 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-(trans-1-oxido-3-thietanyl)-benzamide and 4-[(5S)-5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-(cis-1-oxido-3-thietanyl)benzamide (obtained from WO 2013 / 050317A1) (CAS 1332628-83-7), N-[3-chloro-1-(3-pyridyl)-1H-pyrazol-4-yl]-N-ethyl-3-[(3,3,3-trifluoropropyl)sulfinyl]-propionamide, (+)-N-[3-chloro-1-(3-pyridyl)-1H-pyrazol-4-yl]-N-ethyl-3-[(3,3,3-trifluoropropyl)sulfinyl]-propionamide and (-)-N-[3-chloro-1-(3-pyridyl)-1H-pyrazol-4-yl]-N-ethyl-3-[(3,3,3-trifluoropropyl)sulfinyl]-propionamide (known from WO 2013 / 162715 A2, WO 2013 / 162716 A2, US2014 / 0213448 A1) (CAS 1477923-37-7), 5-[[(2E)-3-chloro-2-propen-1-yl]amino]-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile (known in CN 101337937 A) (CAS 1105672-77-2), 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)thiocarbonyl(thioxomethyl)]phenyl]-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxamide, (thiobenzamide, known in CN 103109816 A) (CAS 1232543-85-9); N-[4-chloro-2-[[(1,1-dimethylethyl)amino]carbonyl]-6-methylphenyl]-1-(3-chloro-2-pyridyl)-3-(fluoromethoxy)-1H-pyrazole-5-carboxamide (known in WO 2012 / 034403A1) (CAS 1268277-22-0), N-[2-(5-amino-1,3,4-thiadiazol-2-yl)-4-chloro-6-methylphenyl]-3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxamide (known in WO 2011 / 085575A1) (CAS 1233882-22-8), 4-[3-[2,6-dichloro-4-[(3,3-dichloro-2-propen-1-yl)oxy]phenoxy]propoxy]-2-methoxy-6-(trifluoromethyl)-pyrimidine (known in CN 101337940 A) (CAS 1108184-52-6); (2E)- and 2(Z)-2-[2-(4-cyanophenyl)-1-[3-(trifluoromethyl)phenyl]ethylidene]-N-[4-(difluoromethoxy)phenyl]-hydrazinecarboxamide (known in CN 101715774 A) (CAS 1232543-85-9); 3-(2,2-dichlorovinyl)-2,2-dimethyl-4-(1H-benzimidazol-2-yl)phenyl-cyclopropanecarboxylate (known in CN 103524422A)(CAS 1542271-46-4); (4aS)-7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-[(trifluoromethyl)thio]phenyl]amino]carbonyl]-indeno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylic acid methyl ester (known in CN 102391261 A) (CAS 1370358-69-2); 6-deoxy-3-O-ethyl-2,4-di-O-methyl-, 1-[N-[4-[1-[4-(1,1,2,2,2-pentafluoroethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]carbamate]-α-L-mannopyranose (known in US 2014 / 0275503 A1) (CAS1181213-14-8); 8-(2-cyclopropylmethoxy-4-trifluoromethyl-phenoxy)-3-(6-trifluoromethyl-pyridazin-3-yl)-3-aza-bicyclo[3.2.1]octane (CAS1253850-56-4), (8-trans)-8-(2-cyclopropylmethoxy-4-trifluoromethyl-phenoxy)-3-(6-trifluoromethyl-pyridazin-3-yl)-3-aza-bicyclo[3.2.1]octane (CAS 933798-27-7), (8-cis)-8-(2-cyclopropylmethoxy-4-trifluoromethyl-phenoxy)-3-(6-trifluoromethyl-pyridazin-3-yl)-3-aza-bicyclo[3.2.1]octane (known from WO 2007040280A1, WO 2007040282 A1) (CAS 934001-66-8) and N-[3-chloro-1-(3-pyridyl)-1H-pyrazol-4-yl]-N-ethyl-3-[(3,3,3-trifluoropropyl)thio]-propionamide (known in WO 2015 / 058021 A1, WO2015 / 058028A1) (CAS1477919-27-9) and N-[4-(aminothiocarbonyl)-2-methyl-6-[(methylamino)carbonyl]phenyl]-3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide (known in CN 103265527 A) (CAS1452877-50-7), 5-(1,3-dioxan-2-yl)-4-[[4-(trifluoromethyl)phenyl]methoxy]-pyrimidine (known in WO 2013 / 115391 A1) (CAS1449021-97-9), 3-(4-chloro-2,6-dimethylphenyl)-4-hydroxy-8-methoxy-1-methyl-1,8-diazaspiro[4.5]dec-3-en-2-one (known in WO 2010 / 066780 A1, WO 2011 / 151146 A1) (CAS 1229023-34-0), 3-(4-chloro-2,6-dimethylphenyl)-8-methoxy-1-methyl-1,8-diazaspiro[4.5]decane-2,4-dione (known in WO 2014 / 187846 A1) (CAS 1638765-58-8), 3-(4-chloro-2,6-dimethylphenyl)-8-methoxy-1-methyl-2-oxo-1,8-diazaspiro[4.5]dec-3-en-4-yl-carbonate (known in WO 2010 / 066780 A1, WO 2011 / 151146 A1) (CAS 1229023-34-0), 3-(4-chloro-2,6-dimethylphenyl)-8-methoxy-1-methyl-1,8-diazaspiro[4.5]decane-2,4-dione (known in WO 2014 / 187846 A1) (CAS 1638765-58-8), A1) (CAS1229023-00-0), N-[1-[(6-chloro-3-pyridyl)methyl]-2(1H)-pyridylidene]-2,2,2-trifluoro-acetamide (known in DE 3639877A1, WO 2012029672 A1) (CAS1363400-41-2), [N(E)]-N-[1-[(6-chloro-3-pyridyl)methyl]-2(1H)-pyridylidene]-2,2,2-trifluoro-acetamide (known in WO 2016005276 A1) (CAS1689566-03-7), [N(Z)]-N-[1-[(6-chloro-3-pyridyl)methyl]-2(1H)-pyridylidene]-2,2,2-trifluoro-acetamide, (CAS1702305-40-5), 3-endo-3-[2-propoxy-4-(trifluoromethyl)phenoxy]-9-[[5-(trifluoromethyl)-2-pyridyl]oxy]-9-azabicyclo[3.3.1]nonane (known in WO 2011 / 105506 A1, WO 2016 / 133011 A1) (CAS1332838-17-1).

[0606] Active ingredients with unknown or non-specific modes of action, such as fentrifanil, fenoxacrim, cycloprene, chlorobenzilate, flubenzimine, dicyclanil, amidoflumet, quinomethionate, triarathene, clothiazoben, tetrasul, potassium oleate, petroleum, metoxadiazone, gossyplure, flutenzin, bromopropylate, and cryolite;

[0607] Active ingredients from other classes, such as butacarb, dimetilan, cloethocarb, phosphocarb, pirimiphos(-ethyl), methacrifos, isopropyl o-salicylate, trichlorfon, sulprofos, propaphos, sebufos, pyridathion, prothoate, dichlofenthion, demeton-S-methylsulfone, isazofos, cyanofenphos, dialifos, carbophenothion, temeton-S-methylsulfone, autathiofos), aromfenvinfos(-methyl), azinphos(-ethyl), chlorpyrifos(-ethyl), fosmethilan, iodofenphos, dioxabenzofos, formothion, fonofos, flupyrazofos, fensulfothion, and etrimfos;

[0608] Organochlorines, such as lindane and heptachlor; or phenylpyrazoles, such as acetoprole, pyrafluprole, pyriprole, vaniliprole, and sisapronil; or isoxazolines, such as sarolaner, afoxolaner, lotilaner, and fluralaner;

[0609] Pyrethroids, for example (cis-, trans-), metofluthrin, profluthrin, flufenprox, flubrocythrinate, fubfenprox, fenfluthrin, protrifenbute, pyresmethrin, RU15525, terallethrin, cis-resmethrin ), heptafluthrin, bioethanomethrin, biopermethrin, fenpyrithrin, cis-cypermethrin, cis-permethrin, clocythrin, cyhalothrin (lambda-), chlovaporthrin, or halogenated hydrocarbon compounds (HCHs);

[0610] neonicotinoids, such as nithiazine;

[0611] dicloromezotiaz, triflumezopyrim;

[0612] Macrocyclic lactones, such as nemadectin, ivermectin, latidectin, moxidectin, selamectin, eprinomectin, doramectin, emamectin benzoate; milbemycin oxime;

[0613] Triprene, epofenonane, and diofenolan;

[0614] Biological agents, hormones or pheromones, such as natural products such as thuringiensin, codlemone or neem ingredients;

[0615] Dinitrophenols, such as dinocap, dinobuton, and binapacryl;

[0616] Benzoyl ureas, such as fluazuron and penfluron;

[0617] Amidine derivatives, for example, chlormebuform, cymiazole, demiditraz;

[0618] Beehive varroa acaricides, for example organic acids such as formic acid, oxalic acid.

[0619] Non-limiting examples of insecticides and acaricides of particular interest for use in animal health are and particularly include [i.e., Mehlhorn et al., Encyclpaedic Reference of Parasitology 4th ed. (ISBN 978-3-662-43978-4)]: Effectors of arthropod ligand-gated chloride channels: chlordane, heptachlor, endoculfan, bromocyclen, lindane, fipronil, pyriprole, sisapronil, afoxolaner, fluralaner, sarolaner, lotilaner, fluxametamide, broflanilide, avermectin, doramectin, eprinomectin, ivermectin, milbemycin, moxidectin, selamectin;

[0620] Arthropod octopamine receptor modulators: amitraz, BTS27271, cymiazole, demiditraz;

[0621] Effectors of voltage-gated sodium channels in arthropods: DDT, methoxychlor, metaflumizone, indoxacarb, cinerin I, cinerin II, jasmolin I, jasmolin II, pyrethrin I, pyrethrin II II), allethrin, alphacypermethrin, bioallethrin, beta-cyfluthrin, cyfluthrin, cyhalothrin, cypermethrin, deltamethrin, etofenprox, fenvalerate, flucythrinate, flumethrin, halfenprox, permethrin, phenothrin, resmethrin, tau-fluvalinate, tetramethrin;

[0622] Effectors of arthropod nicotinic cholinergic synapses (acetylcholinesterase, acetylcholine receptors): bromoprypylate, bendiocarb, carbaryl, methomyl, promacyl, propoxur, azamethiphos, chlorfenvinphos, chlorpyrifos, cythioate, diazinon, dichlorvos, dicrotophos, dimethoate, ethion, famphophos r), fenitrothion, fenthion, heptenophos, malathion, naled, phosmet, phoxim, phtalofos, propetamphos, temephos, tetrachlorvinphos, triclorfon, imidacloprid, nitenpyram, dinotefuran, spinosad, and spinetoram;

[0623] Effectors of arthropod development: cyromazine, dicyclanil, diflubenzuron, fluazuron, lufenuron, triflumuron, fenoxycarb, hydroprene, methoprene, pyriproxyfen, fenoxycarb, hydroprene, S-methoprene, pyriproxyfen.

[0624] Exemplary active ingredients from the group of endoparasiticides as additional or further active ingredients in the present invention include, but are not limited to, anthelmintic active compounds and antiprotozoal active compounds.

[0625] Antihelmintic active compounds include, but are not limited to, the following nematicidal, fluke-killing and / or cesticide active compounds:

[0626] From the macrolide class, such as eprinomectin, abamectin, nemadectin, moxidectin, doramectin, selamectin, lepimectin, latidectin, milbemectin, ivermectin, emamectin, and milbemycin;

[0627] From benzimidazoles and probenzimidazole precursors, for example: oxibendazole, mebendazole, triclabendazole, thiophanate, parbendazole, oxfendazole, netobimin, fenbendazole, febantel, thiabendazole, cyclobendazole, cambendazole, albendazole-sulphoxide, albendazole, flubendazole;

[0628] From the depsipeptide class, preferably cyclic depsipeptides, especially 24-membered cyclic depsipeptides, such as emodepside and PF1022A;

[0629] from the tetrahydropyrimidine class, such as morantel, pyrantel, and oxantel;

[0630] From the imidazothiazole class, such as butamisole, levamisole, and tetramisole;

[0631] From the aminophenylamidine class, such as amidantel, deacylated amidantel (dAMD), and tribendimidine;

[0632] From aminoacetonitriles, such as monepantel;

[0633] From the paraherquamides, for example, paraherquamide and derquantel;

[0634] From the salicylanilide class, such as tribromsalan, bromoxanide, brotianide, clioxanide, closantel, niclosamide, oxyclozanide, and rafoxanide;

[0635] From substituted phenols, for example: nitroxynil, bithionol, disophenol, hexachlorophene, niclofolan, meniclopholan;

[0636] From organophosphates, such as trichlorfon, naphthalofos, dichlorvos / DDVP, crufomate, and haloxon;

[0637] From piperazinones / quinolines, such as praziquantel and epsiprantel;

[0638] From the piperazine class, for example: piperazine, hydroxyzine;

[0639] From the tetracycline family, such as tetracycline, chlorotetracycline, doxycycline, oxytetracycline, and rolitetracycline;

[0640] From various other classes, such as bunamidine, niridazole, resorantel, omphalotin, oltipraz, nitroscanate, nitroxynile, oxamniquine, mirasan, miracil, lucanthon, hycanthone, hetolin, emetine, diethylcarbamazine, dichlorophen, diamfenetide, clonazepam, bephenium, amoscanate, and clorsulon.

[0641] The antiprotozoal active ingredients of the present invention include but are not limited to the following active ingredients:

[0642] From the triazines, for example: diclazuril, ponazuril, letrazuril, toltrazuril;

[0643] From the class of polyether ionophores, such as monensin, salinomycin, maduramicin, and narasin;

[0644] From macrolides, such as milbemycin and erythromycin;

[0645] From the quinolone class, such as enrofloxacin and pradofloxacin;

[0646] From the quinine family, such as chloroquine;

[0647] From the pyrimidine class, for example: pyrimethamine;

[0648] From sulfonamides, such as sulfaquinoxaline, trimethoprim, and sulfaclozin;

[0649] From thiamines, such as amprolium;

[0650] From the lincosamides class, such as clindamycin;

[0651] From diphenylureas, such as imidocarb;

[0652] From the nitrofuran class, such as nifurtimox;

[0653] From quinazolinone alkaloids, such as halofuginone;

[0654] From various other classes, for example: oxamniquin, paromomycin;

[0655] From vaccines or antigens derived from microorganisms, such as Babesia canis rossi, Eimeria tenella, Eimeria praecox, Eimeria toxicus, Eimeria mitis, Eimeria maxima, Eimeria brunetti, Eimeria acervulina, Babesia canis vogeli, Leishmania infantum, Babesia canis canis, Dictyocaulus viviparus.

[0656] All named other or additional active ingredients in the present invention can optionally form salts with suitable bases or acids if their functional groups permit.

[0657] The effective dose of the compounds of the present invention for treating each desired indication can be readily determined based on standard laboratory techniques known for evaluating compounds useful for treating helminth infections, by standard toxicity tests, and by standard pharmacological assays for determining treatment of the above-specified conditions in animals, and by comparing these results with the results of known active ingredients or drugs for treating these conditions. The amount of active ingredient to be administered in treating one of these conditions can vary widely depending on considerations such as the specific compound and dosage unit employed, the mode of administration, the duration of treatment, the age and sex of the subject being treated, and the nature and extent of the condition being treated.

[0658] The total amount of active ingredient to be administered is generally about 0.001 mg / kg to about 200 mg / kg body weight per day, and preferably about 0.01 mg / kg to about 20 mg / kg body weight per day. A clinically useful dosing schedule is one to three doses per day to once every four weeks. In addition, a "drug holiday" is possible, wherein the drug is not given to the subject for a specific period of time, thereby benefiting the overall balance between the pharmacological effect and the tolerability. In addition, long-acting treatment can be performed, wherein the subject is treated once for more than four weeks. The unit dose can contain about 0.5 mg to about 1500 mg of active ingredient and can be used once a day or more or less than once a day. The average daily dose administered by injection (including intravenous, intramuscular, subcutaneous and parenteral injections) and using an infusion technique is preferably 0.01 to 200 mg / kg total body weight. The average daily rectal dosage regimen is preferably 0.01 to 200 mg / kg total body weight. The average daily vaginal dosage regimen is preferably 0.01 to 200 mg / kg total body weight. The average daily topical dosage regimen is preferably 0.1 to 200 mg applied one to four times daily. The transdermal concentration is preferably the concentration required to maintain a daily dose of 0.01 to 200 mg / kg. The average daily inhalation dosage regimen is preferably 0.01 to 100 mg / kg of total body weight.

[0659] Of course, for each subject, the specific initial and ongoing dosing regimen will vary depending on the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the subject, the time of administration, the route of administration, the rate of drug excretion, drug combination, etc. The desired mode of treatment and number of doses of the compound of the present invention, or a pharmaceutically acceptable salt or ester thereof, or composition can be determined by those skilled in the art using routine therapeutic testing.

[0660] Experimental part

[0661] The various aspects of the invention described in this application are illustrated by the following examples, which are not meant to limit the invention in any way.

[0662] The example test experiments described herein serve to illustrate the present invention, and the present invention is not limited to the examples given.

[0663] Abbreviations and acronyms

[0664] abbreviation:

[0665] atm standard atmospheric pressure

[0666] DAD diode array detector

[0667] DMSO dimethyl sulfoxide

[0668] DME 1,2-dimethoxyethane

[0669] ELSD Evaporative Light Scattering Detector

[0670] ESI electrospray ionization

[0671] h hour

[0672] LC-MS liquid chromatography-coupled mass spectrometry

[0673] min

[0674] NMR nuclear magnetic resonance spectroscopy

[0675] R t Retention time

[0676] TLC thin-layer chromatography.

[0677] Experimental part-Overview

[0678] All reagents whose synthesis is not described in the experimental part are either commercially available, are known compounds, or can be formed from known compounds by known methods by a person skilled in the art.

[0679] The compounds and intermediates produced according to the methods of the present invention may require purification. Purification of organic compounds is well known to those skilled in the art, and there may be multiple ways to purify the same compound. In some cases, purification may not be necessary. In some cases, the compound may be purified by crystallization. In some cases, an appropriate solvent may be used to stir out the impurities. In some cases, the compound may be purified by chromatography, particularly flash column chromatography, using, for example, a pre-filled silica gel column (e.g., Biotage SNAP column KP-Sil ® or KP-NH ® ) combined with Biotage automated purification system (SP4 ® or Isolera Four ® ) and eluents such as a gradient of hexane / ethyl acetate or dichloromethane / methanol. In some cases, compounds can be purified by preparative HPLC using, for example, a Waters automated purifier equipped with a diode array detector and / or an online electrospray ionization mass spectrometer in combination with a suitable pre-packed reverse phase column and eluents such as a gradient of water and acetonitrile (which may contain additives such as trifluoroacetic acid, formic acid, or aqueous ammonia).

[0680] In some cases, the purification methods described above can provide compounds of the invention having sufficient basic or acidic functionality in the form of salts, such as, for example, trifluoroacetate or formate salts in the case of sufficiently basic compounds of the invention, or as ammonium salts in the case of sufficiently acidic compounds of the invention. Salts of this type can be converted to their free base or free acid forms, respectively, by a variety of methods known to those skilled in the art, or used as salts in subsequent bioassays. It is to be understood that the specific forms of the compounds of the invention (e.g., salts, free bases, etc.) isolated and described herein are not necessarily the only forms in which the compounds can be used in bioassays to quantify specific biological activities.

[0681] Analytical methods

[0682] Analytical liquid chromatography

[0683] Analytical (UP) LC-MS was performed with the aid of different equipment as described below. Masses (m / z) are reported from positive mode electrospray ionization unless negative mode (ESI-) is specified.

[0684] LC-MS method

[0685] Method 1:

[0686] MS instrument type: Agilent Technologies 6130 Quadrupole LC-MS; HPLC instrument type: Agilent Technologies 1260 Infinity; column: Waters XSelect (C18, 30×2.1 mm, 3.5μ); flow rate: 1 mL / min; column temperature: 35°C; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; linear gradient: t=0 min 5% A, t=1.6 min 98% A, t=3 min 98% A; detection: DAD (220–320 nm); detection: MSD (ESI positive / negative (ESI pos / neg)), mass range: 100–800; detection: ELSD (PL-ELS 2100): gas flow rate 1.2 mL / min, gas temperature: 70°C, nebulization (neb): 50°C.

[0687] Method 2:

[0688] MS instrument type: Agilent Technologies 6130 Quadrupole LC-MS; HPLC instrument type: Agilent Technologies 1260 Infinity; column: Waters XSelect (C18, 50×2.1 mm, 3.5 μ); flow rate: 0.8 mL / min; column temperature: 35°C; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; linear gradient: t=0 min 5% A, t=3.5 min 98% A, t=6 min 98% A; detection: DAD (220–320 nm); detection: MSD (ESI positive / negative), mass range: 100–800; detection: ELSD (PL-ELS2100): gas flow rate 1.2 mL / min, gas temperature: 70°C, nebulization: 50°C.

[0689] Method 3:

[0690] MS instrument type: Agilent Technologies LC / MSD SL; HPLC instrument type: Agilent Technologies 1100 series; column: Waters XSelect (C18, 30×2.1 mm, 3.5 μ); flow rate: 1 mL / min; column temperature: 25°C; eluent A: 95% acetonitrile + 5% 10 mM ammonium bicarbonate in water; eluent B: 10 mM ammonium bicarbonate in water, pH=9.0; linear gradient: t=0 min 5% A, t=1.6 min 98% A, t=3 min 98% A; detection: DAD (220-320 nm); detection: MSD (ESI positive / negative) mass range: 100-800.

[0691] Method 4:

[0692] MS instrument type: Agilent Technologies LC / MSD SL; HPLC instrument type: Agilent Technologies 1100 series; column: Waters XSelect (C18, 50×2.1 mm, 3.5 μm); flow rate: 0.8 mL / min; column temperature: 25°C; eluent A: 95% acetonitrile + 5% 10 mM ammonium bicarbonate in water; eluent B: 10 mM ammonium bicarbonate in water, pH = 9.0; linear gradient: t = 0 min 5% A, t = 3.5 min 98% A, t = 6 min 98% A; detection: DAD (220-320 nm); detection: MSD (ESI positive / negative); mass range: 100-800.

[0693] Method 5:

[0694] Instrument type: Reveleris™ Flash Chromatography System; Column: Reveleris™ C18 Flash Cartridge; 4 g, flow rate 18 mL / min; 12 g, flow rate 30 mL / min; 40 g, flow rate 40 mL / min; 80 g, flow rate 60 mL / min; 120 g, flow rate 80 mL / min; Eluent A: 0.1% formic acid in acetonitrile; Eluent B: 0.1% formic acid in water; Gradient: t=0 min 5% A, t=1 min 5% A, t=13 min 100% A, t=16 min 100% A; Detection: UV (200-360 nm), ELSD.

[0695] Method 6:

[0696] Instrument type: Reveris™ Flash Chromatography System; Column: GraceResolv™ Silica Cartridge; 4 g, flow rate 15 mL / min; 12 g, flow rate 28 mL / min; 24 g, flow rate 30 mL / min; 40 g, flow rate 40 mL / min; 80 g, flow rate 55 mL / min; 120 g, flow rate 80 mL / min and Davisil™ Chromatographic Silica Media (LC60A 20-45 μm); 300 g, flow rate 70 mL / min; 500 g, flow rate 70 mL / min; Eluent: see Experimental; Detection: UV (200-360 nm), ELSD.

[0697] Method 7:

[0698] Instrument type: Büchi Pump Manager C-615, Büchi Pump Module C-601; Column: GraceResolv™ Silica Cartridge; 4 g, flow rate 15 mL / min; 12 g, flow rate 28 mL / min; 24 g, flow rate 30 mL / min; 40 g, flow rate 40 mL / min; 80 g, flow rate 55 mL / min; 120 g, flow rate 80 mL / min and Davisil™ Chromatographic Silica Media (LC60A 20–45 μm); 300 g, flow rate 70 mL / min; 500 g, flow rate 70 mL / min; Eluent: see Experimental; Detection: TLC Plate; TLC Silica Gel 60 F254 (Merck).

[0699] Method 8:

[0700] MS instrument type: Agilent Technologies 6130 Quadrupole LC-MS; HPLC instrument type: Agilent Technologies 1260 Infinity; column: Waters XSelect (C18, 50×2.1 mm, 3.5μ); flow rate: 0.8 mL / min; column temperature: 35°C; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; linear gradient: t=0 min 5% A, t=3.5 min 98% A, t=8 min 98% A; detection: DAD (220-320 nm); detection: MSD (ESI positive / negative), mass range: 100-800; detection: ELSD (PL-ELS 2100): gas flow rate 1.2 mL / min, gas temperature: 70°C, nebulization: 50°C.

[0701] Method 9:

[0702] MS instrument type: Agilent Technologies G1956B Quadrupole LC-MS; HPLC instrument type: Agilent Technologies 1200 preparative LC; column: Waters Sunfire (C18, 150 × 19 mm, 5 µm); flow rate: 25 mL / min; column temperature: RT; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; detection: DAD (220–320 nm); detection: MSD (ESI positive / negative), mass range: 100–800; fraction collection based on MS and DAD, or MS instrument type: ACQ-SQD2; HPLC instrument type: Waters Modular preparative HPLC system; column: Waters XSelect (C18, 150 × 19 mm, 10 µm); flow rate: 24 mL / min preparative pump, 1 mL / min loading pump; column temperature: RT; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; detection: DAD (220-320 nm); detection: MSD (ESI positive / negative), mass range: 100-800; fraction collection based on MS and DAD.

[0703] Method 10:

[0704] MS instrument type: Agilent Technologies G1956B Quadrupole LC-MS; HPLC instrument type: Agilent Technologies 1200 preparative LC; column: Waters XSelect (C18, 150 × 19 mm, 5 µm); flow rate: 25 mL / min; column temperature: RT; eluent A: 99% acetonitrile + 1% 10 mM ammonium bicarbonate in water, pH = 9.0; eluent B: 10 mM ammonium bicarbonate in water, pH = 9.0; detection: DAD (220–320 nm); detection: MSD (ESI positive / negative), mass range: 100–800; fraction collection based on MS and DAD, or MS instrument type: ACQ-SQD2; HPLC instrument type: Waters Modular preparative HPLC system; column: Waters XSelect (C18, 150 × 19 mm, 10 µm); flow rate: 24 mL / min preparative pump, 1 mL / min loading pump; column temperature: RT; eluent A: 99% acetonitrile + 1% 10 mM ammonium bicarbonate in water, pH=9.5; eluent B: 10 mM ammonium bicarbonate in water, pH=9.5; detection: DAD (220-320 nm); detection: MSD (ESI positive / negative), mass range: 100-800; fraction collection based on MS and DAD.

[0705] Method 11:

[0706] Instrument type: Reveris preparative; Detection: UV (220-360 nm), ELSD; Column: XSelect TM CSHC18, 145×25 mm, 10µ or GEMINI TM C18, 185×25 mm, 10 µm Flow rate: 40 mL / min; Eluent A: 10 mM ammonium bicarbonate in water (pH 9.0), Eluent B: 99% acetonitrile + 1% 10 mM ammonium bicarbonate in water in acetonitrile or Eluent A: 250 mM ammonia, Eluent B: 250 mM ammonia in acetonitrile.

[0707] Method 12:

[0708] MS instrument type: Agilent Technologies LC / MSD SL; HPLC instrument type: Agilent Technologies 1100 series; column: Phenomenex Gemini NX (C18, 50×2.0 mm, 3.0 μ); flow rate: 0.8 mL / min; column temperature: 25°C; eluent A: 95% acetonitrile + 5% 10 mM ammonium bicarbonate in water, pH = 9.0; eluent B: 10 mM ammonium bicarbonate in water, pH = 9.0; linear gradient: t = 0 min 5% A, t = 3.5 min 98% A, t = 6 min 98% A; detection: DAD (220–320 nm); detection: MSD (ESI positive / negative); mass range: 100–800.

[0709] Method 13:

[0710] Under acidic chromatographic conditions, [M+H] + or M - The determination was performed using 1 ml formic acid / liter acetonitrile and 0.9 ml formic acid / liter Millipore water as eluents. A Zorbax Eclipse Plus C18 column, 50 mm × 2.1 mm, was used. The column oven temperature was 55°C.

[0711] Instrumentation: Agilent 1290 LC, Agilent MSD, HTS PAL autosampler. Linear gradient from 10% acetonitrile to 95% acetonitrile from 0.0 to 1.80 minutes, constant 95% acetonitrile from 1.80 to 2.50 minutes, flow rate 1.0 ml / min.

[0712] In all cases, the retention time indices were calculated based on the same series of linear alkan-2-ones having 3 to 16 carbons, with the index of the first alkanone set to 300 and the index of the last alkanone set to 1600, with the indices between successive alkanones being calculated accordingly by using linear interpolation between them.

[0713] Method 14:

[0714] Under acidic chromatographic conditions, [M+H] + or M - The determination was performed using 1 ml formic acid / L acetonitrile and 0.9 ml formic acid / L Millipore water as eluents. A Zorbax Eclipse Plus C18 column, 50 mm × 2.1 mm, was used. The column oven temperature was 55°C.

[0715] Under neutral chromatographic conditions, [M+H] + The determination was performed using acetonitrile and Millipore water containing 79 mg / l ammonium carbonate as eluents.

[0716] instrument:

[0717] LC-MS3:

[0718] Waters UPLC with SQD2 mass spectrometer and Sample Manager autosampler. Linear gradient: 10% acetonitrile to 95% acetonitrile from 0.0 to 1.70 minutes, constant 95% acetonitrile from 1.70 to 2.40 minutes, flow rate 0.85 ml / min.

[0719] LC-MS5:

[0720] Agilent 1100 LC system with MSD mass spectrometer and HTS PAL autosampler (column: Zorbax XDBC18 1.8 µm 50 mm × 4.6 mm, oven temperature 55°C) Linear gradient: 10% acetonitrile to 95% acetonitrile from 0.0 to 4.25 minutes, constant 95% acetonitrile from 4.25 to 5.80 minutes, flow rate 2.0 ml / min.

[0721] In all cases, the retention time indices were calculated based on the same series of linear alkan-2-ones having 3 to 16 carbons, with the index of the first alkanone set to 300 and the index of the last alkanone set to 1600, with the indices between successive alkanones being calculated accordingly by using linear interpolation between them.

[0722] Method 15: MCW-SQ-HSST3

[0723] Instrument: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLC HSS T3 1.8 µm 50 × 1 mm; eluent A: 1 l water + 0.25 ml 99% formic acid, eluent B: 1 l acetonitrile + 0.25 ml 99% formic acid; gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A, oven: 50°C; flow rate: 0.40 ml / min; UV detection: 210 nm.

[0724] GC-MS method

[0725] Instrument: GC: Agilent 6890N, FID: detection temperature: 300°C and MS: 5973 MSD, EI-positive, detection temperature: 280°C, mass range: 50-550; column: RXi-5MS20m, ID 180µm, df 0.18µm; average velocity: 50 cm / s; injection volume: 1 µl; injector temperature: 250°C; split ratio: 20 / 1; carrier gas: He.

[0726] Method S:

[0727] Initial temperature: 60°C; initial time: 1.0 min; solvent delay: 1.3 min; rate 50°C / min; final temperature 250°C; final time 3.5 min.

[0728] Method A:

[0729] Initial temperature: 100°C; initial time: 1.5 min; solvent delay: 1.3 min; rate 75°C / min; final temperature 250°C; final time 2.5 min.

[0730] Method C:

[0731] Initial temperature: 100°C; initial time: 1.0 min; solvent delay: 1.3 min; rate 75°C / min; final temperature 280°C; final time 2.6 min.

[0732] Method U:

[0733] Initial temperature: 100°C; initial time: 1.0 min; solvent delay: 1.3 min; rate 120°C / min; final temperature 280°C; final time 6.5 min.

[0734] Ion exchange chromatography

[0735] Anion exchange chromatography: ISOLUTE TM SAX; Chemical description: Quaternary amine (non-endcapped) functionalized silica made with trifunctional silane; Adsorbent type: Strong anion exchange; Average particle size: 50 µm; Pore size: 60 Å; Exchange capacity: 0.6 meq / g.

[0736] microwave

[0737] Biotage™ Initiator, microwave synthesizer; temperature range: 40°C-250°C; pressure range: 0-20 bar; power range: 0-400 W.

[0738] Nuclear magnetic resonance spectroscopy

[0739] 1 H-and 13 C-NMR instrument type: Bruker DMX300 ( 1 HNMR: 300 MHz; 13 C NMR: 75 MHz), BrukerAvance III 400 ( 1 HNMR: 400 MHz; 13 C NMR: 100 MHz) or Bruker 400 Ultrashield ( 1 HNMR: 400 MHz; 13 C NMR: 100 MHz); internal standard: tetramethylsilane; chemical shifts (δ) are shown in parts per million [ppm]; the following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br. = broad; coupling constants are shown in Hertz [Hz].

[0740] or, 1 H-NMR data were determined using a Bruker Avance III 400 MHz spectrometer equipped with a 1.7 mm TCI probe head, with tetramethylsilane as a reference (0.00 ppm) and measurements typically recorded using solvents CD3CN, CDCl3 or d6-DMSO. Alternatively, a Bruker Avance III 600 MHz instrument equipped with a 5 mm CPNMP probe head or a Bruker Avance NEO 600 MHz instrument equipped with a 5 mm TCI probe head was used for measurement. Typically, measurements were performed at a probe temperature of 298 K. Other measurement temperatures were noted.

[0741] Experimental Section - General Procedures

[0742] The synthesis of compounds of formula (I) can be carried out according to or in analogy to the following schemes (Schemes 1-10).

[0743] Here and throughout the context of the present invention, cross-links denote cis / trans mixtures.

[0744] General Reaction Scheme-1 (S1): Example compounds S1-1 to S1-4

[0745]

[0746] General Reaction Scheme-2 (S1): Example Compounds S1-5 to S1-8

[0747]

[0748] General Reaction Scheme-3 (S1): Example compounds S1-9 to S1-11

[0749]

[0750] General Synthesis Scheme-4 (S1): Example Compounds S1-12

[0751]

[0752] wherein Rq represents one or more substituents of Q as defined above for the compounds of general formula (I).

[0753] General Synthesis Scheme-5 (S1): Example Compounds S1-13

[0754]

[0755] General Synthesis Scheme-6 (S1): Example Compounds S1-14 to S1-6

[0756]

[0757] wherein Rq represents one or more substituents of Q as defined above for the compounds of general formula (I).

[0758] General Synthesis Scheme-7 (S4): Example Compound S4-1

[0759]

[0760] wherein Rq represents one or more substituents of Q as defined above for the compounds of general formula (I).

[0761] General Synthesis Scheme–8 (S4)

[0762]

[0763] where R 7 have the meanings as defined above for the compounds of general formula (I).

[0764] General Synthesis Scheme-9 (S8a): Example Compound S8a-1

[0765]

[0766] General Synthesis Scheme-10 (S8b): Example Compound S8b-1

[0767]

[0768] Experimental Section - Examples

[0769] Intermediate (S1)

[0770] Example S1-1A

[0771] 1-(3-Bromo-2-fluorophenyl)-2-methylpropan-1-one

[0772]

[0773] Diisopropylamine (740 mg, 7.31 mmol, 1.04 mL) is dissolved in tetrahydrofuran (2 mL). The solution is cooled with an ice bath. N-butyllithium (2.5 M in hexane; 7.31 mmol, 2.93 mL) is slowly added. After 30 min, the mixture is cooled with a dry ice / acetone bath. A solution of 1-bromo-2-fluorobenzene (800 mg, 4.57 mmol) in tetrahydrofuran (8 mL) is slowly added. After 3 h, N-methoxy-N-methylisobutyramide (600 mg, 4.57 mmol) is slowly added. The dry ice / acetone bath is removed after 40 min. Saturated aqueous ammonium chloride solution, water and ether are added. The organic layer is separated and the aqueous layer is extracted with ether. The combined organic layer is dried over sodium sulfate. The solvent is removed in a vacuum to obtain 852 mg (3.48 mmol, 76% of theoretical value) of the title compound.

[0774] GC-MS (Method S): R t = 4.46 min; m / z = 244 / 246 M +

[0775] Example S1-1B

[0776] 7-Bromo-3-isopropyl-1-benzothiophene-2-carboxylic acid ethyl ester

[0777]

[0778] 2-Mercaptoacetic acid ethyl ester (478 mg, 3.98 mmol, 0.44 mL) is added to a mixture of 1-(3-bromo-2-fluorophenyl)-2-methylprop-1-one (848 mg, 3.46 mmol) and potassium carbonate (1435 mg, 10.38 mmol) in N,N-dimethylformamide (8 mL). The mixture is heated to 100 ° C for 10 h and allowed to cool to room temperature. Ethyl acetate and water are added. Hydrochloric acid (1 N) is added until an acidic pH value is obtained. The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic layer is washed with water and salt water. After drying over sodium sulfate, the solvent is removed in a vacuum to obtain 861 mg (2.63 mmol, 76% of theoretical value) of the title compound.

[0779] LC-MS (Method 1): R t = 2.27 min; m / z = 297 / 299 (M-C2H5) -

[0780] Example S1-1C

[0781] 7-Bromo-3-isopropyl-1-benzothiophene-2-carboxylic acid

[0782]

[0783] Ethyl 7-bromo-3-isopropyl-1-benzothiophene-2-carboxylate (861 mg, 2.63 mmol) was dissolved in tetrahydrofuran (8 mL). Aqueous lithium hydroxide monohydrate (1 N; 7.89 mmol, 7.89 mL) was added. After 20 h, hydrochloric acid (1 N) was added until an acidic pH was achieved. Ethyl acetate was added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate. The solvent was removed in vacuo to obtain 718 mg (2.40 mmol, 91% of theoretical value) of the title compound.

[0784] LC-MS (Method 1): R t = 2.28 min; m / z = 297 / 299 (MH) -

[0785] Example S1-1D

[0786] 7-Bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-isopropyl-1-benzothiophene-2-carboxamide

[0787]

[0788] Triethylamine (729 mg, 7.20 mmol, 1.00 mL) is added to a mixture of 7-bromo-3-isopropylbenzo[b]thiophene-2-carboxylic acid (718 mg, 2.40 mmol) and (S)-chroman-4-amine hydrochloride (535 mg, 2.88 mmol) in dichloromethane (20 mL). Diethyl cyanophosphonate (783 mg, 4.80 mmol) is added. After 75 min, the volatiles are removed in vacuo. Purification by flash column chromatography (Method 7; 80 g; heptane, 2%-20% ethyl acetate) gives 442 mg (1.03 mmol, 42% of theoretical value) of the title compound.

[0789] LC-MS (Method 1): R t = 2.32 min; m / z = 430 / 432 (M+H) +

[0790] Example S1-2A

[0791] 3-Amino-7-bromo-1-benzothiophene-2-carboxylic acid ethyl ester

[0792]

[0793] Ethyl 2-mercaptoacetate (0.721 g, 6.00 mmol, 0.66 mL) was added to a mixture of 3-bromo-2-fluorobenzonitrile (1.000 g, 5.00 mmol) and potassium carbonate (2.073 g, 15.00 mmol) in dry N,N-dimethylformamide (4 mL). The reaction mixture was stirred at 100 ° C for 16 h, cooled to room temperature and concentrated in vacuo. Water (50 mL) was added until a precipitate was formed. The solid was filtered off and dried in air. 1.470 g (4.90 mmol, 98% of theoretical value) of the title compound was obtained.

[0794] LC-MS (Method 1): R t = 2.24 min; m / z = 300 / 302 (M+H) +

[0795] 1H NMR (400 MHz, DMSO-d6) δ = 8.21 (d, J = 8.1 Hz, 1H), 7.78 (d, J =7.6 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.24 (s, 2H), 4.28(q, J = 7.1 Hz, 2H),1.30 (t, J = 7.1 Hz, 3H).

[0796] Example S1-2B

[0797] 7-Bromo-3-(dimethylamino)-1-benzothiophene-2-carboxylic acid ethyl ester

[0798]

[0799] Decaborane (0.36 g, 2.94 mmol) was added to a solution of ethyl 3-amino-7-bromo-1-benzothiophene-2-carboxylate (1.47 g, 4.90 mmol) and paraformaldehyde (0.59 g, 19.59 mmol) in methanol (20 mL). The reaction mixture was stirred for 4 h. Decaborane (0.15 g, 1.23 mmol) was added. After 16 h, the reaction mixture was concentrated in vacuo. Purification by flash column chromatography (Method 6; 80 g; heptane, 0%-50% ethyl acetate) gave 1.05 g (3.20 mmol, 65% of theoretical value) of the title compound.

[0800] LC-MS (Method 1): R t= 2.42 min; m / z = 328 / 330 (M+H) +

[0801] 1H NMR (400 MHz, DMSO-d6) δ = 8.05 (d, J = 8.2 Hz, 1H), 7.78 (d, J =7.6 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 4.29 (q, J =7.1 Hz, 2H), 3.08 (s, 6H),1.32 (t, J = 7.1 Hz, 3H).

[0802] Example S1-2C

[0803] 7-Bromo-3-(dimethylamino)-1-benzothiophene-2-carboxylic acid

[0804]

[0805] Lithium hydroxide monohydrate (0.81 g, 19.19 mmol) is added to a suspension of ethyl 7-bromo-3-(dimethylamino)-1-benzothiophene-2-carboxylate (1.05 g, 3.20 mmol) in a mixture of water (20 mL) and tetrahydrofuran (20 mL). The mixture is stirred at room temperature for 16 h. Lithium hydroxide monohydrate (0.81 g, 19.19 mmol) is added and the reaction mixture is stirred at room temperature for 1 h and at 70 ° C for 16 h. The reaction mixture is cooled to room temperature and acidified with hydrochloric acid (2 M) until a precipitate is formed. The solid is filtered off, washed with water and dried in air. 0.93 g (3.10 mmol, 97% of theoretical value) of the title compound is obtained.

[0806] LC-MS (Method 1): R t = 1.78 min; m / z = 300 / 302 (M+H) +

[0807] 1H NMR (400 MHz, DMSO-d6) δ = 13.83 (s, 1H), 8.09 (d, J = 8.1 Hz,1H), 7.79 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 7.9 Hz,1H), 3.06 (s, 6H).

[0808] Example S1-2D

[0809] 7-Bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-(dimethylamino)-1-benzothiophene-2-carboxamide

[0810]

[0811] Diethyl cyanophosphonate (657 mg, 4.03 mmol, 0.6 mL) was added to a solution of 7-bromo-3-(dimethylamino)-1-benzothiophene-2-carboxylic acid (930 mg, 3.10 mmol), (S)-chroman-4-amine hydrochloride (690 mg, 3.72 mmol), and triethylamine (941 mg, 9.29 mmol, 1.3 mL) in dichloromethane (20 mL). The mixture was stirred at room temperature for 16 h. Purification by flash column chromatography (Method 6; 80 g; heptane, 0%-50% ethyl acetate) gave 1080 mg (2.50 mmol, 81% of theory) of the title compound.

[0812] LC-MS (Method 1): R t = 2.36 min; m / z = 431 / 433 (M+H) +

[0813] 1H NMR (400 MHz, DMSO-d6) δ = 9.91 (d, J = 8.0 Hz, 1H), 8.13 (d, J =8.1 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.41 (t, J =7.9 Hz, 1H), 7.31 (d, J =7.4 Hz, 1H), 7.24-7.14 (m, 1H), 6.97-6.88 (m, 1H), 6.83 (d, J = 8.2 Hz, 1H),5.24 (q, J = 6.7 Hz, 1H), 4.32 (ddd, J = 10.7, 7.5,2.9 Hz, 1H), 4.21 (ddd, J= 11.0, 7.5, 3.0 Hz, 1H), 2.88 (s, 6H), 2.24 (ddt, J = 13.1, 8.1, 3.9 Hz, 1H), 2.11 (dtd, J = 14.0, 7.3, 3.0 Hz, 1H).

[0814] Example S1-3A

[0815] 3-Amino-7-bromo-1-benzothiophene-2-carboxylic acid methyl ester

[0816]

[0817] Methyl 2-mercaptoacetate (2.37 g, 22.33 mmol, 2.0 mL) was added to a mixture of 3-bromo-2-fluorobenzonitrile (3.72 g, 18.61 mmol) and potassium carbonate (7.71 g, 55.80 mmol) in N,N-dimethylformamide (20 mL). The reaction mixture was stirred at 100 ° C for 16 h and allowed to cool to room temperature. The mixture was poured into water. The resulting precipitate was filtered and dried in air to give 5.16 g (18.02 mmol, 97% of theory) of the title compound.

[0818] LC-MS (Method 1): R t = 2.12 min; m / z = 286 / 288 (M+H) + .

[0819] Example S1-3B

[0820] 7-Bromo-3-chloro-1-benzothiophene-2-carboxylic acid methyl ester

[0821]

[0822] Copper (II) chloride (1.489 g, 11.07 mmol) was suspended in acetonitrile (100 mL). Isoamyl nitrite (1.621 g, 13.84 mmol, 1.86 mL) was added and the mixture was cooled with an ice bath. 3-amino-7-bromo-1-benzothiophene-2-carboxylic acid methyl ester (2.640 g, 9.23 mmol) was added portionwise. The mixture was allowed to warm to room temperature. After 16 h, volatiles were removed in vacuo. Water and ether were added to the residue. The mixture was filtered through a layer of celite. The organic layer of the filtrate was separated and the aqueous layer was extracted with ether. The combined organic layers were dried over sodium sulfate and the solvent was removed in vacuo. The residue was suspended in dimethyl sulfoxide. The solid was removed by filtration. The filtrate was purified by flash column chromatography (Method 5; 120 g). 0.569 g (1.86 mmol, 20% of theoretical value) of the title compound was obtained.

[0823] LC-MS (Method 1): R t = 2.30 min; m / z = 305 / 307 (M+H) + .

[0824] Example S1-3C

[0825] 7-Bromo-3-methoxy-1-benzothiophene-2-carboxylic acid methyl ester

[0826]

[0827] Sodium hydride (60% in mineral oil; 223 mg, 5.59 mmol) was suspended in anhydrous tetrahydrofuran (4 mL). Methanol (179 mg, 5.59 mmol, 0.23 mL) was added. The reaction mixture was stirred for 30 min. A solution of methyl 7-bromo-3-chloro-1-benzothiophene-2-carboxylate (569 mg, 1.86 mmol) in anhydrous tetrahydrofuran (5 mL) was added. After 20 h, the mixture was added to hydrochloric acid (1 N). The mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and the solvent was removed in vacuo. The residue was applied to a hydromatrix. Purification by flash column chromatography (Method 7; 24 g; heptane, 5% to 40% ethyl acetate containing 1% acetic acid) gave 158 mg (0.53 mmol, 28% of theory) of the title compound.

[0828] LC-MS (Method 1): R t = 2.23 min; m / z = 301 / 303 (M+H) + .

[0829] Example S1-3D

[0830] 7-Bromo-3-methoxy-1-benzothiophene-2-carboxylic acid

[0831]

[0832] Lithium hydroxide monohydrate aqueous solution (1 N; 1.574 mmol, 1.574 mL) was added to a solution of 7-bromo-3-methoxy-1-benzothiophene-2-carboxylic acid methyl ester (158 mg, 0.525 mmol) in tetrahydrofuran (2 mL). The reaction mixture was stirred for 4 h and hydrochloric acid (1 N) was added until an acidic pH value was obtained. Ethyl acetate and water were added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and the solvent was removed in vacuo. 147 mg (0.512 mmol, 98% of theoretical value) of the title compound were obtained.

[0833] LC-MS (Method 1): R t = 2.07 min; m / z = 287 / 289 (M+H) + .

[0834] Example S1-3E

[0835] 7-Bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-methoxy-1-benzothiophene-2-carboxamide

[0836]

[0837] 7-Bromo-3-methoxy-1-benzothiophene-2-carboxylic acid (295 mg, 1.03 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). Triethylamine (260 mg, 2.57 mmol, 0.36 mL) and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro-phosphate) (391 mg, 1.03 mmol) were added. The reaction mixture was stirred for 30 min and (S)-chroman-4-amine hydrochloride (191 mg, 1.03 mmol) was added. Stirring was continued for 16 h. Ethyl acetate and water were added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water and dried over sodium sulfate. The solvent was removed in vacuo to obtain 398 mg (0.951 mmol, 93% of theoretical value) of the title compound.

[0838] LC-MS (Method 1): R t = 2.270 min; m / z = 418 / 420 (M+H) + .

[0839] Example S1-4A

[0840] Ethyl 7-bromo-3-chlorobenzothiophene-2-carboxylate

[0841]

[0842] Copper (II) chloride (1.114 g, 8.28 mmol) was suspended in acetonitrile (80 mL). Isoamyl nitrite (1.213 g, 10.35 mmol, 1.39 mL) was added and the mixture was cooled with an ice bath. Ethyl 3-amino-7-bromobenzothiophene-2-carboxylate (2.072 g, 6.90 mmol) was added portionwise. The mixture was allowed to warm to room temperature. Ether and water were added after 16 h. The organic layer was separated and the aqueous layer was extracted with ether. The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed in vacuo. The residue was purified by flash column chromatography (Method 5; 120 g). 0.860 g (2.69 mmol, 39% of theoretical value) of the title compound was obtained.

[0843] LC-MS (Method 1): R t = 2.41 min; m / z = 319 / 321 (M+H) + .

[0844] Example S1-4B

[0845] 7-Bromo-3-chloro-1-benzothiophene-2-carboxylic acid

[0846]

[0847] Lithium hydroxide monohydrate (1 N; 1.891 mmol, 1.891 mL) was added to a solution of ethyl 7-bromo-3-chlorobenzothiophene-2-carboxylate (403 mg, 1.261 mmol) in tetrahydrofuran (12 mL) at 0°C. After 0.5 h, the reaction mixture was allowed to warm to room temperature. Stirring was continued for 64 h and hydrochloric acid (1 N) was added until an acidic pH was achieved. The formed precipitate was filtered and air-dried to give 351 mg (1.204 mmol, 95% of theory) of the title compound.

[0848] LC-MS (Method 1): R t = 2.23 min; m / z = 245 / 247 (M-COO-H) - .

[0849] Example S1-4C

[0850] 7-Bromo-3-chloro-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-1-benzothiophene-2-carboxamide

[0851]

[0852] Triethylamine (451 mg, 4.46 mmol, 0.62 mL) is added to a mixture of 7-bromo-3-chloro-1-benzothiophene-2-carboxylic acid (433 mg, 1.49 mmol) and (S)-chroman-4-amine hydrochloride (331 mg, 1.78 mmol) in dichloromethane (10 mL). To the resulting solution, diethyl cyanophosphonate (242 mg, 1.49 mmol, 0.23 mL) is added. The reaction mixture is stirred for 16 h. Diethyl cyanophosphonate (242 mg, 1.49 mmol, 0.23 mL) is added. Volatiles are removed in vacuo after 20 h. The residue is purified by flash column chromatography (Method 7; 40 g; heptane, 2%-20% ethyl acetate). 254 mg (0.60 mmol, 40% of theoretical value) of the title compound are obtained.

[0853] LC-MS (Method 1): R t = 2.33 min; m / z = 422 / 424 (M+H) + .

[0854] Example S1-1F

[0855] 3-Chloroisonicotinate Ethyl ester

[0856]

[0857] 3-Chloroisonicotinic acid (5.00 g, 32 mmol) was suspended in ethanol (200 mL). Sulfuric acid (9.34 g, 95 mmol, 5.07 mL) was added and the mixture was stirred at reflux temperature for 64 h. Most of the solvent was removed in vacuo. The residue was distributed between saturated aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (100 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 5.15 g (28 mmol, 87% of theoretical value) of the title compound.

[0858] LC-MS (Method 1): R t = 1.79 min; m / z = 186 (M+1) + .

[0859] Example S1-2F

[0860] 3-Hydroxythieno[2,3-c]pyridine-2-carboxylic acid ethyl ester

[0861]

[0862] 3-Chloroisonicotinate (4.95 g, 27 mmol) was dissolved in N,N-dimethylformamide (50 mL). Ethyl 2-mercaptoacetate (6.40 g, 53 mmol, 5.84 mL) was added and the resulting mixture was cooled with an ice bath. Sodium hydride (2.66 g, 67 mmol; 60% in mineral oil) was added portionwise and the resulting mixture was stirred under ice bath cooling for 45 min. Stirring was continued at room temperature for 2.5 h. Water (500 mL) was added and the mixture was acidified to pH 3 with acetic acid. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (100 mL), water (3×100 mL) and brine. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification was achieved by grinding in diisopropyl ether (100 mL) to obtain 4.17 g (19 mmol, 70% of theoretical value) of the title compound.

[0863] LC-MS (Method 1): R t = 1.65 min; m / z = 224 (M+1) +

[0864] 1H NMR (400 MHz, CHLOROFORM-d) δ 10.07 (s, 1H), 9.09 (s, 1H), 8.58 (d, J =5.4 Hz, 1H), 7.80 (dd, J = 5.5, 0.9 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz,3H).

[0865] Examples S1-3F

[0866] Ethyl 3-(((trifluoromethyl)sulfonyl)oxy)thieno[2,3-c]pyridine-2-carboxylate

[0867]

[0868] Under nitrogen atmosphere, ethyl 3-hydroxythieno[2,3-c]pyridine-2-carboxylate (1.00 g, 4.5 mmol) and N To a stirred solution of 1-phenyltrifluoromethane-sulfonyl imide (1.68 g, 4.7 mmol) in dichloromethane (20 mL) was added triethylamine (1.13 g, 11.2 mmol, 1.56 mL). The resulting mixture was stirred at room temperature for 16 h. N -phenyl trifluoromethanesulfonimide (0.40 g, 1.1 mmol) and triethylamine (0.23 mg, 2.2 mmol, 0.31 mL) and continued stirring for 2 h. The reaction mixture was concentrated in vacuo. Purification by flash column chromatography (Method 6, 40 g; heptane, 5%-100% ethyl acetate) gave 1.51 g (4.3 mmol, 95% of theoretical value) of the title compound.

[0869] LC-MS (Method 1): R t = 2.13 min; m / z = 356 (M+1) +

[0870] 1H NMR (400 MHz, CHLOROFORM-d) δ 9.21 (d, J = 0.9 Hz, 1H), 8.69 (d, J = 5.7 Hz, 1H), 7.70 (d, J = 5.7 Hz, 1H), 4.51 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H).

[0871] Examples S1-4F

[0872] Ethyl 3-(dimethylamino)thieno[2,3-c]pyridine-2-carboxylate

[0873]

[0874] A mixture of ethyl 3-(((trifluoromethyl)sulfonyl)oxy)thieno[2,3-c]pyridine-2-carboxylate (0.50 g, 1.4 mmol), potassium carbonate (1.17 g, 8.4 mmol), and dimethylamine hydrochloride (0.34 g, 4.2 mmol) in N,N-dimethylformamide (5 mL) was stirred at 90°C for 1 h. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (2 x 10 mL). The filtrate was concentrated in vacuo. Purification by flash column chromatography (Method 6, 40 g; heptane, 5%-100% ethyl acetate) afforded 0.20 g (0.8 mmol, 56% of theory) of the title compound.

[0875] LC-MS (Method 1): R t = 1.73 min; m / z = 251 (M+1) +

[0876] 1H NMR (400 MHz, chloroform-d) δ 9.03 (d, J = 1.0 Hz, 1H), 8.49 (d, J = 5.7Hz, 1H), 7.78 (dd, J = 5.7, 1.1 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.14 (s,6H), 1.41 (t, J =7.1 Hz, 3H).

[0877] Example S1-5F

[0878] Ethyl 3-(dimethylamino)-7-iodothieno[2,3-c]pyridine-2-carboxylate

[0879]

[0880] To a stirred solution of ethyl 3-(dimethylamino)thieno[2,3-c]pyridine-2-carboxylate (50 mg, 0.200 mmol) in tetrahydrofuran (1.00 mL) at -78°C was added 2,2,6,6-tetramethyl-piperidinylmagnesium chloride lithium chloride complex (1 M; 0.80 mmol, 0.80 mL). The resulting solution was stirred for 15 min while warming to room temperature. The solution was cooled back to -78°C and a solution of iodine (253 mg, 1.00 mmol) in tetrahydrofuran (1.00 mL) was added. The resulting mixture was stirred at -78°C for 15 min. The reaction mixture was quenched in aqueous sodium thiosulfate (1 M, 10 mL) and extracted with ethyl acetate (2 x 5 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (Method 6, 40 g; heptane, 5%-50% ethyl acetate) gave 23 mg (0.06 mmol, 30% of theory) of the title compound.

[0881] LC-MS (Method 1): R t = 2.25 min; m / z = 377 (M+1) +

[0882] 1H NMR (400 MHz, CHLOROFORM-d) δ 8.24 (d, J = 5.5 Hz, 1H), 7.78 (d, J = 5.5 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.12 (s, 6H), 1.42 (t, J = 7.1 Hz, 3H).

[0883] Example S1-6F

[0884] Ethyl 7-(2,3-dichlorophenyl)-3-(dimethylamino)thieno[2,3-c]pyridine-2-carboxylate

[0885]

[0886] A stirred mixture of ethyl 3-(dimethylamino)-7-iodothieno[2,3-c]pyridine-2-carboxylate (40 mg, 0.11 mmol), sodium carbonate (23 mg, 0.21 mmol) in 1,4-dioxane (1.00 mL) and water (0.15 mL) was flushed with nitrogen. 1,1'-Bis-(diphenylphosphino)-ferrocene)palladium dichloride (5 mg, 0.01 mmol) was added, and the resulting mixture was stirred in a sealed vial at 60°C under a nitrogen atmosphere for 8 hours. After cooling to room temperature, (2,3-dichlorophenyl)boronic acid (21 mg, 0.11 mmol) and sodium carbonate (11 mg, 0.11 mmol) were added. The resulting mixture was flushed with nitrogen. 1,1'-Bis-(diphenylphosphino)-ferrocene)palladium dichloride (5 mg, 0.01 mmol) was added, and the reaction mixture was stirred at 60°C under nitrogen in a sealed vial for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (1 mL), and filtered. The filter cake was washed with ethyl acetate (1 mL). The filtrate was concentrated in vacuo. Purification by flash column chromatography (Method 6, 4 g; heptane, 5%-100% ethyl acetate) afforded 38 mg (0.10 mmol, 90% of theory) of the title compound.

[0887] LC-MS (Method 1): R t = 2.34 min; m / z = 395 / 397 (M+1) +

[0888] 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 5.7 Hz, 1H), 8.05 (d, J =5.7 Hz, 1H), 7.86 (dd, J = 6.3, 3.3 Hz, 1H),7.63-7.49 (m, 2H), 4.25 (q, J =7.1 Hz, 2H), 3.13 (s, 6H), 1.26 (t, J = 7.1 Hz, 3H).

[0889] Example S1-7F

[0890] Lithium 7-(2,3-dichlorophenyl)-3-(dimethylamino)thieno[2,3-c]pyridine-2-carboxylate

[0891]

[0892] To a stirred solution of ethyl 7-(2,3-dichlorophenyl)-3-(dimethylamino)thieno[2,3-c]pyridine-2-carboxylate (34 mg, 0.09 mmol) in tetrahydrofuran (0.20 mL) at room temperature was added aqueous lithium hydroxide monohydrate (1 M; 0.13 mmol, 0.13 ml). The resulting mixture was stirred at 60°C for 16 h. The reaction mixture was cooled to room temperature, diluted with brine (5 mL), and extracted with tetrahydrofuran (3 x 2 mL). The combined organic extracts were concentrated in vacuo to yield 23 mg (0.06 mmol, 71% of theory) of the title compound.

[0893] LC-MS (Method 1): R t = 1.81 min; m / z = 365 / 367 (MH) - [Free acid]

[0894] Example S1-8F

[0895] 3-Methoxythieno[2,3-c]pyridine-2-carboxylic acid ethyl ester

[0896]

[0897] Ethyl 3-hydroxythieno[2,3-c]pyridine-2-carboxylate (2.00 g, 9.0 mmol) was dissolved in tetrahydrofuran (40 mL). Triphenylphosphine (2.82 g, 10.8 mmol) and methanol (0.32 mg, 9.9 mmol, 0.40 mL) were added to the resulting solution. A solution of di-tert-butyl azodicarboxylate (2.48 g, 10.8 mmol) in tetrahydrofuran (10 mL) was slowly added under ice-bath cooling. Stirring was continued under ice-bath cooling for 10 min. The reaction was continued for 1.5 h while warming to room temperature. The reaction mixture was concentrated in vacuo. Ethyl acetate (100 mL) and aqueous sodium hydroxide solution (1 M; 100 mL) were added under stirring. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash column chromatography (Method 6, 120 g; heptane, 7%-60% ethyl acetate) gave 1.94 g (8.2 mmol, 91% of theory) of the title compound.

[0898] LC-MS (Method 1): R t = 1.66 min; m / z = 238 (M+1) + .

[0899] Example S1-9F

[0900] 2-(Ethoxycarbonyl)-3-methoxythieno[2,3-c]pyridine 6-oxide

[0901]

[0902] To a stirred solution of ethyl 3-methoxythieno[2,3-c]pyridine-2-carboxylate (200 mg, 0.84 mmol) in dichloromethane (5 mL) at 0°C was added m-chloroperbenzoic acid (249 mg, 1.01 mmol; 70%). The resulting mixture was stirred for 16 h while warming to room temperature. The reaction mixture was diluted with dichloromethane (20 mL), washed with saturated aqueous sodium bicarbonate (2 x 10 mL), dried over sodium sulfate, and concentrated in vacuo to yield 180 mg (0.71 mmol, 84% of theory) of the title compound.

[0903] LC-MS (Method 1): R t = 1.62 min; m / z = 254 (M+1) + .

[0904] Example S1-10F

[0905] 7-Bromo-3-methoxythieno[2,3-c]pyridine-2-carboxylic acid ethyl ester

[0906]

[0907] Phosphorus oxybromide (473 mg, 1.65 mmol) was added to a stirred solution of 2-(ethoxycarbonyl)-3-methoxythieno[2,3-c]pyridine 6-oxide (209 mg, 0.83 mmol) in dichloromethane (5 mL) at 0 ° C. The resulting mixture was stirred while warming up until room temperature for 16 h. The reaction mixture was slowly poured into a saturated aqueous sodium bicarbonate solution (20 mL). After stirring for 15 min, the layers were separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purified by flash column chromatography (method 6, 12 g; heptane, 5%-50% ethyl acetate) to give 122 mg (0.39 mmol, 47% of theoretical value) of the title compound.

[0908] LC-MS (Method 1): R t = 2.16 min; m / z = 316 / 318 (M+1) +

[0909] 1H NMR (400 MHz, CHLOROFORM-d) δ 8.32 (d, J = 5.4 Hz, 1H), 7.72 (d, J = 5.4 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 4.18 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H).

[0910] Example S1-11F

[0911] 7-Bromo-3-methoxythieno[2,3-c]pyridine-2-carboxylic acid

[0912]

[0913] To a stirred solution of ethyl 7-bromo-3-methoxythieno[2,3-c]pyridine-2-carboxylate (123 mg, 0.28 mmol) in tetrahydrofuran (3 mL) was added aqueous lithium hydroxide monohydrate (1 M; 0.59 mmol, 0.59 mL) at room temperature. The resulting mixture was stirred for 16 h. The reaction mixture was acidified with hydrochloric acid (1 M; 5 mL). The resulting precipitate was filtered and air-dried to yield 104 mg (0.36 mmol, 93% of theory) of the title compound.

[0914] LC-MS (Method 1): R t = 1.90 min; m / z = 288 / 290 (M+1) +

[0915] 1H NMR (400 MHz, DMSO-d6) δ 13.98 (s, 1H), 8.39 (d, J = 5.4 Hz, 1H), 7.93 (d, J = 5.4 Hz, 1H), 4.12 (s, 3H).

[0916] Example S1-12F

[0917] 7-Bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-methoxythieno[2,3-c]pyridine-2-carboxamide

[0918]

[0919] 7-Bromo-3-methoxythieno[2,3-c]pyridine-2-carboxylic acid (100 mg, 0.35 mmol) was added to N , NTo a stirred suspension in dimethylformamide (2 mL) was added triethylamine (105 mg, 1.04 mmol, 0.15 mL). To the resulting clear solution was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (139 mg, 0.36 mmol) and (S)-chroman-4-amine hydrochloride (71 mg, 0.38 mmol). The mixture was stirred in a sealed vial at room temperature for 72 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between dichloromethane (2 mL) and water (3 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (1 mL). The combined organic layers were purified by flash column chromatography (Method 6, 12 g; heptane, 5%-100% ethyl acetate) to yield 83 mg (0.20 mmol, 57% of theory) of the title compound.

[0920] LC-MS (Method 1): R t = 2.16 min; m / z = 419 / 421 (M+1) +

[0921] 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 8.2 Hz, 1H), 8.38 (d, J =5.5 Hz, 1H), 8.02 (d, J = 5.5 Hz, 1H), 7.27 (d, J =7.5 Hz, 1H), 7.23-7.15 (m,1H), 6.95-6.88 (m, 1H), 6.82 (dd, J = 8.2, 1.1 Hz, 1H), 5.29 (q, J = 6.5 Hz,1H), 4.27 (dd, J = 6.3, 4.3 Hz, 2H), 4.12 (s, 3H),2.22-2.14 (m, 2H).

[0922] Intermediate (S4)

[0923] Example S4-1G

[0924] Sodium 1-cyanoprop-1-en-2-ol

[0925]

[0926] To a solution of sodium methoxide (5.4 M in methanol; 320 mmol, 59 mL) in anhydrous methanol (250 mL) was added 5-methyl-isoxazole (25.5 g, 291 mmol, 25 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo. The solid residue was triturated in diethyl ether for 30 min. The solid was filtered off and dried in air. 24.2 g (230 mmol, 79% of theoretical value) of the title compound were obtained as a mixture of E / Z isomers.

[0927] 1H NMR (400 MHz, DMSO-d6) δ 3.12 (s, 0.5H), 2.92 (s, 0.5H), 1.70 (s, 1.5H), 1.48 (s, 1.5H).

[0928] Example S4-2G

[0929] 1-(3,5-Dichlorophenyl)-3-methyl-1H-pyrazol-5-amine

[0930]

[0931] A mixture of sodium 1-cyanoprop-1-ene-2-olate (0.98 g, 9.4 mmol) and 3,5-dichlorophenyl-hydrazine hydrochloride (2.00 g, 9.4 mmol) in ethanol (50 mL) was stirred under reflux for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was poured into water (200 mL). The precipitate was filtered out and dried in air. 1.56 g (6.44 mmol, 68% of theoretical value) of the title compound was obtained.

[0932] LC-MS (Method 1): R t = 1.91 min; m / z = 242 / 244 (M+H) +

[0933] 1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 1.8 Hz, 2H), 7.47 (t, J =1.8 Hz, 1H), 5.54 (s, 2H), 5.37 (s, 1H), 2.06 (s, 3H).

[0934] Example S4-3G

[0935] 1-(2,6-Difluorophenyl)-3-methyl-1H-pyrazol-5-amine

[0936]

[0937] A mixture of sodium 1-cyanoprop-1-en-2-ol (1.4 g, 13.3 mmol) and 2,6-difluorophenyl-hydrazine hydrochloride (2.0 g, 11.1 mmol) in trifluoroacetic acid (20 mL) was stirred at 100 ° C for 1 h. The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with saturated aqueous sodium carbonate solution and brine. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. The crude product was applied to a hydromatrix and purified by flash column chromatography (Method 6; 120 g; heptane, 0%-50% ethyl acetate). 1.97 g (9.4 mmol, 85% of theoretical value) of the title compound was obtained.

[0938] LC-MS (Method 1): R t = 1.96 min; m / z = 210 (M+H) +

[0939] Examples S4-4G

[0940] 1-(3,5-Dichlorophenyl)-1H-pyrazol-5-amine

[0941]

[0942] 3-Methoxyacrylonitrile (0.93 g, 11.2 mmol, 0.94 mL) was added to a suspension of 3,5-dichlorophenylhydrazine hydrochloride (2.00 g, 9.4 mmol) in trifluoroacetic acid (50 mL). The reaction mixture was stirred at 100 ° C for 1 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with saturated aqueous sodium carbonate solution. The layers were separated and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was applied to a hydromatrix and purified by flash column chromatography (Method 6; 80 g; heptane, 0%-40% ethyl acetate). 1.60 g (4.98 mmol, 53% of theoretical value; purity 71%) of the title compound was obtained.

[0943] LC-MS (Method 1): R t = 1.93 min; m / z = 228 / 230 (M+H) + .

[0944] Example S4-5G

[0945] 1-(2,6-Difluorophenyl)-1H-pyrazol-5-amine

[0946]

[0947] 3-Methoxyacrylonitrile (1.1 g, 13.3 mmol, 1.12 mL) was added to a suspension of 2,6-difluorophenylhydrazine hydrochloride (2.0 g, 11.1 mmol) in trifluoroacetic acid (50 mL). The reaction mixture was stirred at 100 ° C for 1 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with a saturated aqueous sodium carbonate solution. The layers were separated and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography (Method 6; 80 g; heptane, 0%-50% ethyl acetate) and (Method 6; 120 g; heptane, 0%-30% ethyl acetate). 1.1 g (5.4 mmol, 48% of theoretical value) of the title compound was obtained.

[0948] LC-MS (Method 3): R t = 1.60 min; m / z = 196 (M+H) +

[0949] 1H NMR (400 MHz, DMSO-d6) δ 7.59 (tt, J = 8.5, 6.4 Hz, 1H), 7.35-7.23(m, 3H), 5.38 (d, J = 1.8 Hz, 1H), 5.35 (s, 2H).

[0950] Examples S4-6G

[0951] Diethyl 2-(((1-(3,5-dichlorophenyl)-3-methyl-1H-pyrazol-5-yl)amino)methylene)malonate

[0952]

[0953] Ethoxymethylene malonate (2.29 g, 10.6 mmol, 2.1 mL) is added to a solution of 1-(3,5-dichlorophenyl)-3-methyl-1H-pyrazole-5-amine (1.28 g, 5.3 mmol) in ethanol (50 mL). The mixture is stirred at reflux for 16 h and cooled to room temperature. The formed precipitate is collected by filtration, washed with ethanol and dried in air. 1.32 g (3.2 mmol, 60% of theoretical value) of the title compound are obtained.

[0954] LC-MS (Method 1): R t = 2.31 min; m / z = 412 / 414 (M+H) +

[0955] Examples S4-7G

[0956] Diethyl 2-(((1-(2,6-difluorophenyl)-3-methyl-1H-pyrazol-5-yl)amino)methylene)malonate

[0957]

[0958] Ethoxymethylene malonate (1.2 g, 5.7 mmol, 1.2 mL) was added to a solution of 1-(2,6-difluorophenyl)-3-methyl-1H-pyrazole-5-amine (1.0 g, 4.8 mmol) in ethanol (20 mL). The mixture was stirred at reflux for 16 h and cooled to room temperature. Volatiles were removed in vacuo. The crude product was purified by flash column chromatography (Method 6; 80 g; heptane, 0%-50% ethyl acetate). 1.6 g (4.2 mmol, 88% of theoretical value) of the title compound were obtained.

[0959] LC-MS (Method 1): R t = 2.17 min; m / z = 380 (M+H) +

[0960] 1H NMR (400 MHz, DMSO-d6) δ 10.47 (d, J = 13.0 Hz, 1H), 8.04 (d, J =13.0 Hz, 1H), 7.68 (ddd, J = 14.8, 8.3, 6.6 Hz, 1H), 7.42 (t, J = 8.5 Hz, 2H), 6.42 (s, 1H), 4.08 (p, J = 6.9 Hz, 4H), 2.21 (s, 3H), 1.17 (dt, J = 29.7, 7.1Hz, 6H).

[0961] Examples S4-8G

[0962] Diethyl 2-(((1-(3,5-dichlorophenyl)-1H-pyrazol-5-yl)amino)methylene)malonate

[0963]

[0964] Ethoxymethylene malonate (1.3 g, 6 mmol, 1.2 mL) was added to a solution of 1-(3,5-dichlorophenyl)-1H-pyrazole-5-amine (1.6 g, 5 mmol; purity 71%) in ethanol (20 mL). The mixture was stirred under reflux for three days and cooled to room temperature. The formed precipitate was filtered out, washed with cold ethanol and dried in air. 1.2 g (3 mmol, 60% of theoretical value) of the title compound was obtained.

[0965] LC-MS (Method 1): R t = 2.25 min; m / z = 398 / 400 (M+H) +

[0966] 1H NMR (400 MHz, DMSO-d6) δ 10.61 (d, J = 11.6 Hz, 1H), 8.04 (d, J =12.7 Hz, 1H), 7.72 (s, 4H), 6.60 (s, 1H), 4.12 (dt,J = 13.9, 7.1 Hz, 4H),1.21 (t, J = 7.1 Hz, 6H).

[0967] Example S4-9G

[0968] Diethyl 2-(((1-(2,6-difluorophenyl)-1H-pyrazol-5-yl)amino)methylene)malonate

[0969]

[0970] Ethoxymethylene malonate (1.4 g, 6.4 mmol, 1.3 mL) was added to a solution of 1-(2,6-difluorophenyl)-1H-pyrazole-5-amine (1.1 g, 5.4 mmol) in ethanol (20 mL). The mixture was stirred at reflux for 16 h and cooled to room temperature. Volatiles were removed in vacuo. The crude product was purified by flash column chromatography (Method 6; 80 g; heptane, 0%-50% ethyl acetate). 1.7 g (4.7 mmol, 88% of theoretical value) of the title compound were obtained.

[0971] LC-MS (Method 1): R t = 2.04 min; m / z = 366 (M+H) +

[0972] 1H NMR (400 MHz, DMSO-d6) δ 10.51 (d, J = 12.9 Hz, 1H), 8.07 (d, J =13.0 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.71 (ddd, J= 14.9, 8.5, 6.4 Hz, 1H), 7.45 (t, J = 8.4 Hz, 2H), 6.68-6.53 (m, 1H), 4.09 (p, J = 7.0 Hz, 4H), 1.18 (dt, J = 28.7, 7.1 Hz, 6H).

[0973] Example S4-10G

[0974] 4-Chloro-1-(3,5-dichlorophenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester

[0975]

[0976] A solution of diethyl 2-(((1-(3,5-dichlorophenyl)-3-methyl-1H-pyrazol-5-yl)amino)methylene)malonate (1.1 g, 2.7 mmol) in phosphorus oxychloride (32.9 g, 215 mmol, 20 mL) was stirred under reflux for 16 h. The volatiles were removed in vacuo. The residue was poured onto ice. The mixture was allowed to warm to room temperature and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed in vacuo. 0.9 g (2.3 mmol, 88% of theory) of the title compound was obtained.

[0977] LC-MS (Method 1): R t = 2.82 min; mass not detected

[0978] 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.34 (d, J = 1.9 Hz, 2H), 7.65 (t, J = 1.8 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 2.79 (s, 3H), 1.37 (t, J =7.1 Hz, 3H).

[0979] Example S4-11G

[0980] 4-Chloro-1-(2,6-difluorophenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester

[0981]

[0982] A solution of diethyl 2-(((1-(2,6-difluorophenyl)-3-methyl-1H-pyrazol-5-yl)amino)methylene)malonate (1.6 g, 4.1 mmol) in phosphorus oxychloride (82.0 g, 536 mmol, 50 mL) was stirred under reflux for 16 h. The volatiles were removed in vacuo. The residue was dissolved in ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed in vacuo. 1.2 g (3.4 mmol, 82% of theory) of the title compound were obtained.

[0983] LC-MS (Method 1): R t = 2.23 min; m / z = 352 (M+H) +

[0984] 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 7.76 (tt, J = 8.5, 6.4 Hz,1H), 7.47 (t, J = 8.4 Hz, 2H), 4.39 (q, J = 7.1 Hz,2H), 2.78 (s, 3H), 1.36(t, J = 7.1 Hz, 3H).

[0985] Example S4-12G

[0986] 4-Chloro-1-(3,5-dichlorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester

[0987]

[0988] A solution of diethyl 2-(((1-(3,5-dichlorophenyl)-1H-pyrazol-5-yl)amino)methylene)malonate (1.2 g, 3.01 mmol) in phosphorus oxychloride (82.0 g, 536 mmol, 50 mL) was stirred under reflux for 16 h. The volatiles were removed in vacuo. The residue was dissolved in ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed in vacuo. 1.1 g (2.97 mmol, 98% of theory) of the title compound was obtained.

[0989] LC-MS (Method 1): R t = 2.65 min; mass not detected

[0990] 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.83 (s, 1H), 8.36 (s, 2H), 7.70 (s, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.38 (t, J= 7.1 Hz, 3H).

[0991] Example S4-13G

[0992] 4-Chloro-1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester

[0993]

[0994] A solution of diethyl 2-(((1-(2,6-difluorophenyl)-1H-pyrazol-5-yl)amino)methylene)malonate (1.7 g, 4.7 mmol) in phosphorus oxychloride (82.0 g, 536 mmol, 50 mL) was stirred under reflux for 16 h. The volatiles were removed in vacuo. The residue was dissolved in ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed in vacuo. 1.4 g (4.0 mmol, 85% of theory) of the title compound was obtained.

[0995] LC-MS (Method 1): R t = 2.18 min; m / z = 338 (M+H) +

[0996] 1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.85 (s, 1H), 7.79 (ddd, J= 15.0, 8.6, 6.4 Hz, 1H), 7.50 (t, J = 8.4 Hz, 2H), 4.41 (d, J = 7.1 Hz, 2H),1.37 (t, J = 7.1 Hz, 3H).

[0997] Example S4-14G

[0998] 4-Chloro-1-(3,5-dichlorophenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

[0999]

[1000] To a suspension of ethyl 4-chloro-1-(3,5-dichlorophenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (700 mg, 1.82 mmol) in a mixture of tetrahydrofuran (20 mL) and water (20 mL) was added lithium hydroxide monohydrate (458 mg, 10.92 mmol). The mixture was stirred at room temperature for 16 h. Hydrochloric acid (2 M) was added until a white precipitate was formed. The solid was filtered off, washed with water and dried in air. 636 mg (1.78 mmol, 98% of theoretical value) of the title compound were obtained.

[1001] LC-MS (Method 1): R t = 2.77 min; m / z = 354 / 356 (MH) -

[1002] 1H NMR (400 MHz, DMSO-d6) δ 13.83 (s, 1H), 9.05 (s, 1H), 8.31 (d, J =1.8 Hz, 2H), 7.61 (t, J = 1.8 Hz, 1H), 2.77 (s, 3H).

[1003] Example S4-15G

[1004] 4-Chloro-1-(2,6-difluorophenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

[1005]

[1006] To a suspension of 4-chloro-1-(2,6-difluorophenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (1.20 g, 3.4 mmol) in a mixture of tetrahydrofuran (20 mL) and water (20 mL) is added lithium hydroxide monohydrate (0.86 g, 20.5 mmol). The mixture is stirred at room temperature for 16 h and concentrated in vacuo. The residue aqueous solution is acidified by adding hydrochloric acid (1 M) until a white precipitate is formed. The solid is filtered off, washed with water and dried in air. 1.06 g (3.2 mmol, 96% of theoretical value) of the title compound is obtained.

[1007] LC-MS (Method 1): R t = 2.04 min; m / z = 324 (M+H) +

[1008] 1H NMR (400 MHz, DMSO-d6) δ 13.77 (s, 1H), 8.94 (s, 1H), 7.81-7.70 (m, 1H), 7.47 (t, J = 8.3 Hz, 2H), 2.78 (s, 3H).

[1009] Example S4-16G

[1010] 4-Chloro-1-(3,5-dichlorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

[1011]

[1012] To a suspension of 4-chloro-1-(3,5-dichlorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (1.10 g, 3.0 mmol) in a mixture of tetrahydrofuran (20 mL) and water (20 mL) was added lithium hydroxide monohydrate (0.75 g, 17.8 mmol). The mixture was stirred at room temperature for 16 h and concentrated in vacuo. The residue aqueous solution was acidified by adding hydrochloric acid (1 M) until a white precipitate was formed. The solid was filtered off, washed with water and dried in air. 0.87 g (2.5 mmol, 86% of theoretical value) of the title compound was obtained.

[1013] LC-MS (Method 1): R t = 2.58 min; m / z = 340 / 342 (MH) -

[1014] 1H NMR (400 MHz, DMSO-d6) δ 13.89 (s, 1H), 9.15 (s, 1H), 8.79 (s,1H), 8.36 (d, J = 1.8 Hz, 2H), 7.69 (s, 1H).

[1015] Example S4-17G

[1016] 4-Chloro-1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

[1017]

[1018] To a solution of ethyl 4-chloro-1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1.35 g, 4.0 mmol) in a mixture of tetrahydrofuran (20 mL) and water (20 mL) was added lithium hydroxide monohydrate (1.00 g, 24.0 mmol). The mixture was stirred at room temperature for 16 h. Hydrochloric acid (1 M) was added until a white precipitate was formed. The solid was filtered off, washed with water and dried in air. 0.97 g (3.1 mmol, 78% of theoretical value) of the title compound was obtained.

[1019] LC-MS (Method 1): R t = 2.02 min; m / z = 310 (M+H) +

[1020] 1H NMR (400 MHz, DMSO-d6) δ 13.86 (s, 1H), 9.03 (s, 1H), 8.83 (s,1H), 7.78 (ddd, J = 14.9, 8.5, 6.4 Hz, 1H), 7.50 (t, J =8.4 Hz, 2H).

[1021] Example S4-18G

[1022] 1-(3,5-Dichlorophenyl)-4-(dimethylamino)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

[1023]

[1024] A suspension of 4-chloro-1-(3,5-dichlorophenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (0.20 g, 0.56 mmol) in a solution of dimethylamine in tetrahydrofuran (2.0 M; 1.78 g, 4.00 mmol, 2.0 mL) was stirred at 80 ° C for 16 h. The reaction mixture was cooled to room temperature and hydrochloric acid (1 M) was added until a white precipitate formed. The solid was filtered off, washed with water and dried in air. 0.20 g (0.54 mmol, 98% of theory) of the title compound was obtained.

[1025] LC-MS (Method 1): R t = 2.51 min; m / z = 365 / 367 (M+H) +

[1026] 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 21.0 Hz, 3H), 7.46 (s, 1H), 3.01 (s, 6H), 2.64 (s, 3H) [no acidic protons detected].

[1027] Example S4-19G

[1028] 1-(2,6-Difluorophenyl)-4-(dimethylamino)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

[1029]

[1030] A solution of 4-chloro-1-(2,6-difluorophenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (0.20 g, 0.62 mmol) in dimethylamine in tetrahydrofuran (2.0 M; 1.78 g, 4.00 mmol, 2.0 mL) was stirred at 80 ° C for 1 h. The reaction mixture was cooled to room temperature and hydrochloric acid (1 M) was added until a white precipitate formed. The solid was filtered off, washed with water and dried in air. 0.14 g (0.43 mmol, 70% of theory) of the title compound was obtained.

[1031] LC-MS (Method 1): R t = 1.93 min; m / z = 333 (M+H) + .

[1032] Example S4-20G

[1033] 1-(3,5-Dichlorophenyl)-4-(dimethylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

[1034]

[1035] A suspension of 4-chloro-1-(3,5-dichlorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (0.20 g, 0.58 mmol) in a solution of dimethylamine in tetrahydrofuran (2.0 M; 1.78 g, 4.00 mmol, 2.0 mL) was stirred at 80 ° C for 1 h. The reaction mixture was cooled to room temperature and hydrochloric acid (1 M) was added until a white precipitate formed. The solid was filtered off, washed with water and dried in air. 0.17 g (0.48 mmol, 83% of theory) of the title compound was obtained.

[1036] LC-MS (Method 1): R t= 2.23 min; m / z = 351 / 353 (M+H) +

[1037] 1H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.66 (s, 1H), 8.58 (s,1H), 8.42 (d, J = 1.8 Hz, 2H), 7.58 (s, 1H), 3.25 (s,6H).

[1038] Example S4-21G

[1039] 1-(2,6-Difluorophenyl)-4-(dimethylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

[1040]

[1041] A solution of 4-chloro-1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (0.20 g, 0.65 mmol) in dimethylamine in tetrahydrofuran (2.0 M; 1.78 g, 4.00 mmol, 2.0 mL) was stirred at 80 ° C for 1 h. The reaction mixture was cooled to room temperature and hydrochloric acid (1 M) was added until a white precipitate formed. The solid was filtered off, washed with water and dried in air. 0.12 g (0.37 mmol, 57% of theory) of the title compound was obtained.

[1042] LC-MS (Method 1): R t = 1.71 min; m / z = 319 (M+H) + .

[1043] Intermediate (S8)

[1044] Example S8a-1A

[1045] 2-Acetoxy-3-bromobenzoic acid

[1046]

[1047] A mixture of 3-bromo-2-hydroxybenzoic acid (10 g, 46 mmol) and phosphoric acid (0.2 mL, 4 mmol) in acetic anhydride (50.0 mL, 530 mmol) was stirred at 50 ° C for 18 h. The reaction mixture was cooled to room temperature and water (120 mL) was added. The resulting mixture was stirred at 50 ° C for 1 h and cooled in an ice-water bath. The solid was filtered out. The filtrate was stirred again at 50 ° C for 1 h. A clear solution was obtained. After cooling in an ice-water bath, a precipitate was formed. The precipitate was filtered off, washed with water and dried in air. 8 g (31 mmol; 68% of theoretical value) of the title compound were obtained.

[1048] LC-MS (Method 1): R t = 1.80 min; m / z = 257 / 259 (MH) -

[1049] 1H NMR (400 MHz, chloroform- d ) δ 10.65 (s, 1H), 8.06 (m, 1H), 7.86 (m, 1H), 7.29-7.19 (m, 1H), 2.40 (s, 3H).

[1050] Example S8a-2A

[1051] 8-Bromo-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester

[1052]

[1053] To a solution of 2-acetoxy-3-bromobenzoic acid (8.1 g, 31.3 mmol) and 1-hydroxy-benzotriazole hydrate (4.8 g, 31.3 mmol) in tetrahydrofuran (120 mL) was added N,N'-dicyclohexylcarbodiimide (6.5 g, 31.7 mmol) at 0°C. After stirring for 5 min, a suspension was obtained. The reaction mixture was stored at 5°C for 20 h. The solid was filtered off and the filtrate was used in subsequent steps (see below).

[1054] To a stirred solution of dimethyl malonate (3.6 mL, 31.3 mmol) in tetrahydrofuran (240 mL), sodium hydride (60% in mineral oil; 2.6 g, 65.7 mmol) was added. The filtrate obtained from the previous step was added (see above). After 2 h, the reaction mixture was concentrated in a vacuum. A mixture of hydrochloric acid (10% (v / v); 120 mL, 390 mmol) and methanol (120 mL) was added to the residue. The mixture was stirred for four days. The precipitate was filtered off, washed with methanol (120 mL) and dried in air. 3.6 g (12.3 mmol; 39% of theoretical value) of the title compound was obtained.

[1055] LC-MS (Method 1): R t = 1.92 min; m / z = 299 / 301 (M+H) +

[1056] 1H NMR (400 MHz, chloroform- d ) δ 14.66 (s, 1H), 7.99 (m, 1H), 7.91 (m, 1H),7.23 (t, J = 7.9 Hz, 1H), 4.05 (s, 3H).

[1057] Example S8a-3A

[1058] (S)-8-Bromo-N-(chroman-4-yl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamide

[1059]

[1060] A mixture of (S)-chroman-4-amine hydrochloride (0.248 g, 1.337 mmol) and sodium methoxide (0.072 g, 1.337 mmol) was stirred in methanol (3 mL) for 1 h. Volatiles were removed in vacuo. A mixture of 8-bromo-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (0.100 g, 0.334 mmol) in tetrahydrofuran (3 mL) was added and the suspension was stirred at 60°C for 72 h. The reaction mixture was cooled to room temperature. Volatiles were removed in vacuo. The residue was triturated in methanol. The solid was filtered off, washed with methanol, and dried in air. 0.068 g of the title compound was obtained. The filtrate was concentrated in vacuo. The residue was triturated in diisopropyl ether. The solid was filtered off, washed with diisopropyl ether and water, and dried in air. 0.077 g of the title compound was obtained. A total of 0.145 g (0.317 mmol; 94% of theory) of the title compound was obtained with a purity of >90% according to LC-MS.

[1061] LC-MS (Method 1): R t = 2.32 min; m / z = 414 / 416 (MH) -

[1062] 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.10 (d, J = 7.5 Hz, 1H),8.00 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H),7.24 (dd, J = 20.5, 7.5Hz, 2H), 6.92 (t, J = 7.3 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 5.30 (d, J = 6.3Hz, 1H), 4.29 (d, J = 7.3 Hz, 1H), 4.20 (d, J = 7.5 Hz,1H), 2.29-2.11 (m,2H). [No OH signal was detected].

[1063] Example S8a-4A

[1064] 8-Bromo-4-chloro-2-oxo-2H-chromene-3-carboxylic acid methyl ester

[1065]

[1066] A mixture of methyl 8-bromo-4-hydroxy-2-oxo-2H-chromene-3-carboxylate (3.64 g, 12.17 mmol), N,N-diisopropylethylamine (2.1 mL, 12.17 mmol) and phosphorus oxychloride (12.48 mL, 134 mmol) was stirred at 110° C. for 1.5 h. The reaction mixture was concentrated in vacuo, flushed with argon and used as is in the next step.

[1067] Example S8a-5A

[1068] 8-Bromo-4-(dimethylamino)-2-oxo-2H-chromene-3-carboxylic acid methyl ester

[1069]

[1070] Under an argon atmosphere, triethylamine (5.1 mL, 36.5 mmol) and dimethylamine (2 M in tetrahydrofuran; 30.4 mL, 60.9 mmol) were added to a solution of crude 8-bromo-4-chloro-2-oxo-2H-chromene-3-carboxylic acid methyl ester (3.86 g, 12.2 mmol) in anhydrous tetrahydrofuran (25 mL). The resulting suspension was stirred at room temperature for 1 h. The solid was filtered off. The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (120 mL). The solution was washed with water (2×100 mL) and brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. 3.85 g (11.6 mmol; 96% of theoretical value over two steps) of the title compound were obtained.

[1071] LC-MS (Method 1): R t = 1.84 min; m / z = 326 / 328 (M+H) +

[1072] 1H NMR (400 MHz, chloroform- d ) δ 7.76 (dd, J = 7.8, 1.2 Hz, 1H), 7.70 (dd, J = 8.2, 1.2 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 3.95 (s, 3H), 3.08 (s, 6H).

[1073] Example S8a-6A

[1074] 8-Bromo-4-isopropyl-2-oxo-2H-chromene-3-carboxylic acid methyl ester

[1075]

[1076] Under a nitrogen atmosphere at 0°C, isopropylmagnesium bromide (1 M in tetrahydrofuran; 3.2 mL, 3.24 mmol) was added dropwise to a solution of methyl 8-bromo-4-(dimethylamino)-2-oxo-2H-chromene-3-carboxylate (0.96 g, 2.94 mmol) in anhydrous tetrahydrofuran (50 mL). The reaction mixture was stirred at 0°C for 30 min. Saturated aqueous ammonium chloride (30 mL) and brine (30 mL) were added. The mixture was allowed to warm to room temperature. The layers were separated. The aqueous layer was extracted with ethyl acetate (30 mL). The combined organic layers were dried over sodium sulfate. The solvent was removed in vacuo. Purification by flash column chromatography (Method 6; 40 g; heptane, 3%-25% ethyl acetate) gave 0.38 g (1.12 mmol; 38% of theory) of the title compound.

[1077] LC-MS (Method 1): R t = 2.06 min; m / z = 325 / 327 (M+H) +

[1078] 1H NMR (400 MHz, chloroform- d ) δ 7.81 (t, J = 8.7 Hz, 2H), 7.20 (t, J = 8.0Hz, 1H), 3.95 (s, 3H), 3.43-3.23 (m, 1H), 1.44 (d, J = 7.1 Hz, 6H).

[1079] Example S8a-7A

[1080] 8-(3,5-Dichlorophenyl)-4-isopropyl-2-oxo-2H-chromene-3-carboxylic acid methyl ester

[1081]

[1082] A mixture of methyl 8-bromo-4-isopropyl-2-oxo-2H-chromene-3-carboxylate (330 mg, 1.02 mmol), (3,5-dichlorophenyl)boronic acid (194 mg, 1.02 mmol), and sodium carbonate (323 mg, 3.04 mmol) in 1,4-dioxane (9.0 mL) and water (1.5 mL) was purged with argon. 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (74 mg, 0.10 mmol) was added. The reaction mixture was stirred at 100°C for 1.5 hours and allowed to cool to room temperature. The reaction mixture was combined with the crude material obtained from the same reaction starting with 50 mg (0.15 mmol) of methyl 8-bromo-4-isopropyl-2-oxo-2H-chromene-3-carboxylate. The resulting mixture was diluted with dichloromethane (20 mL). The layers were separated using a phase separator. The organic layer was concentrated in vacuo. Purification by flash column chromatography (Method 6; 24 g; heptane; 2%-20% ethyl acetate) gave 31 mg (0.79 mmol; 68% based on 1.17 mmol of theory) of the title compound.

[1083] LC-MS (Method 1): R t = 2.33 min; m / z = 391 / 393 (M+H) +

[1084] 1H NMR (400 MHz, chloroform- d ) δ 7.91 (dd, J = 8.3, 1.6 Hz, 1H), 7.53 (dd, J = 7.6, 1.5 Hz, 1H), 7.40 (d, J = 6.4 Hz, 4H), 3.95 (s, 3H), 3.38 (p, J = 7.2Hz, 1H), 1.48 (d, J = 7.1 Hz, 6H).

[1085] Examples S8a-8A

[1086] Lithium 8-(3,5-dichlorophenyl)-4-isopropyl-2-oxo-2H-chromene-3-carboxylate

[1087]

[1088] To a solution of methyl 8-(3,5-dichlorophenyl)-4-isopropyl-2-oxo-2H-chromene-3-carboxylate (310 mg, 0.792 mmol) in a mixture of tetrahydrofuran (5 mL) and water (5 mL) was added lithium hydroxide monohydrate (100 mg, 2.377 mmol). The reaction mixture was stirred at room temperature for 25 min and concentrated in vacuo. The crude product was used as is.

[1089] LC-MS (Method 1): R t = 2.19 min; m / z = 377 / 379 (M+H) + [Free acid].

[1090] (Target) Example compound (S1)

[1091] Example Compound S1-1

[1092] 7-(3,5-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-isopropyl-1-benzothiophene-2-carboxamide

[1093]

[1094] To a mixture of 7-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-isopropyl-1-benzothiophene-2-carboxamide (88 mg, 0.204 mmol), (3,5-dichlorophenyl)boronic acid (43 mg, 0.225 mmol), and sodium carbonate (65 mg, 0.613 mmol) in a degassed mixture of 1,2-dimethoxyethane (4 mL) and water (1 mL) was added bis(triphenylphosphine)palladium(II) chloride (7 mg, 0.010 mmol). The mixture was stirred at 100°C for 16 h. Water and dichloromethane were added. The mixture was passed through a phase separator, and the organic layer was passed through a layer of sodium sulfate. The solvent was removed in vacuo. The residue was purified by flash column chromatography (Method 7; 4 g; heptane, 2%-20% ethyl acetate) to yield 58 mg (0.111 mmol, 54% of theory) of the title compound.

[1095] LC-MS (Method 2): R t = 4.65 min; m / z = 496 / 498 (M+H) +

[1096] 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.06 (dd, J = 8.3, 1.0 Hz, 1H), 7.54-7.45 (m, 3H), 7.42 (t, J = 1.9 Hz, 1H), 7.36 (dd, J = 7.3, 1.0 Hz, 1H), 7.31-7.26 (m, 1H), 7.24-7.16 (m, 1H), 6.98-6.90 (m, 1H), 6.86 (dd, J = 8.2, 1.2 Hz,1H), 6.20 (d, J = 7.2 Hz, 1H), 5.33 (q, J = 5.6 Hz, 1H), 4.37-4.27 (m, 1H),4.26-4.16 (m, 1H), 4.16-4.03 (m, 1H), 2.42-2.27(m, 1H), 2.26-2.13 (m, 1H),1.66-1.48 (m, 6H).

[1097] Example Compound S1-2

[1098] 7-(3-Chlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-isopropyl-1-benzothiophene-2-carboxamide

[1099]

[1100] To a mixture of 7-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-isopropyl-1-benzothiophene-2-carboxamide (88 mg, 0.204 mmol), (3-chlorophenyl)boronic acid (35 mg, 0.225 mmol), and sodium carbonate (65 mg, 0.613 mmol) in a degassed mixture of 1,2-dimethoxyethane (4 mL) and water (1 mL) was added bis(triphenylphosphine)palladium(II) chloride (7 mg, 0.010 mmol). The mixture was stirred at 100°C for 16 h. Water and dichloromethane were added. The mixture was passed through a phase separator, and the organic layer was passed through a layer of sodium sulfate. The solvent was removed in vacuo. The residue was purified by flash column chromatography (Method 7; 4 g; heptane, 2%-20% ethyl acetate) to yield 74 mg (0.155 mmol, 76% of theory) of the title compound.

[1101] LC-MS (Method 2): R t = 4.45 min; m / z = 462 / 463 (M+H) +

[1102] 1H NMR (400 MHz, chloroform-d) δ = 8.10-7.95 (m, 1H), 7.63-7.57 (m, 1H), 7.57-7.45 (m, 2H), 7.45-7.34 (m, 3H), 7.27 (d, J = 6.9 Hz, 1H), 7.23-7.15 (m,1H), 6.96-6.89(m, 1H), 6.89-6.82 (m, 1H), 6.19 (d, J = 7.6 Hz, 1H), 5.41-5.20(m, 1H),4.37-4.25 (m, 1H), 4.25-4.03 (m, 2H), 2.40-2.26 (m, 1H), 2.26-2.13(m, 1H), 1.62-1.47(m, 6H).

[1103] Example Compound S1-3

[1104] 7-(2,3-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-isopropyl-1-benzothiophene-2-carboxamide

[1105]

[1106] To a mixture of 7-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-isopropyl-1-benzothiophene-2-carboxamide (88 mg, 0.204 mmol), (2,3-dichlorophenyl)boronic acid (43 mg, 0.225 mmol), and sodium carbonate (65 mg, 0.613 mmol) in a degassed mixture of 1,2-dimethoxyethane (4 mL) and water (1 mL) was added bis(triphenylphosphine)palladium(II) chloride (7 mg, 0.010 mmol). The mixture was stirred at 100°C for 16 h. Water and dichloromethane were added. The mixture was passed through a phase separator, and the organic layer was passed through a layer of sodium sulfate. The solvent was removed in vacuo. The residue was purified by flash column chromatography (Method 7; 4 g; heptane, 2%-20% ethyl acetate) to yield 32 mg (0.061 mmol, 30% of theory) of the title compound.

[1107] LC-MS (Method 2): R t = 4.45 min; m / z = 496 / 498 (M+H) +

[1108] 1H NMR (400 MHz, chloroform-d) δ = 8.13-8.04 (m, 1H), 7.58-7.52 (m, 1H), 7.52-7.45 (m, 1H), 7.36-7.28 (m, 2H), 7.26 (s, 2H), 7.22-7.14 (m, 1H), 6.91(t, J = 7.5 Hz,1H), 6.87-6.80 (m, 1H), 6.14 (d, J = 7.4 Hz, 1H), 5.35-5.21(m, 1H), 4.35-4.24 (m, 1H), 4.23-4.06 (m, 2H), 2.37-2.24 (m, 1H), 2.24-2.08 (m, 1H), 1.65-1.47 (m, 6H).

[1109] Example Compound S1-4

[1110] 7-(3,4-Difluorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-isopropyl-1-benzothiophene-2-carboxamide

[1111]

[1112] To a mixture of 7-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-isopropyl-1-benzothiophene-2-carboxamide (88 mg, 0.204 mmol), (3,4-difluorophenyl)boronic acid (36 mg, 0.225 mmol), and sodium carbonate (65 mg, 0.613 mmol) in a degassed mixture of 1,2-dimethoxyethane (4 mL) and water (1 mL) was added bis(triphenylphosphine)palladium(II) chloride (7 mg, 0.010 mmol). The mixture was stirred at 100°C for 16 h. Water and dichloromethane were added. The mixture was passed through a phase separator, and the organic layer was passed through a layer of sodium sulfate. The solvent was removed in vacuo. The residue was purified by flash column chromatography (Method 7; 4 g; heptane, 2%-20% ethyl acetate) to yield 68 mg (0.144 mmol, 70% of theory) of the title compound.

[1113] LC-MS (Method 2): R t = 4.33 min; m / z = 464 (M+H) +

[1114] 1H NMR (400 MHz, chloroform-d) δ = 8.08-7.99 (m, 1H), 7.53-7.47 (m, 1H), 7.47-7.40 (m, 1H), 7.39-7.33 (m, 2H), 7.32-7.25 (m, 2H), 7.25-7.17 (m, 1H),6.98-6.90 (m,1H), 6.90-6.82 (m, 1H), 6.18 (d, J = 7.0 Hz, 1H), 5.37-5.25 (m,1H), 4.37-4.27 (m, 1H), 4.26-4.03 (m, 2H), 2.40-2.27 (m, 1H), 2.26-2.13 (m,1H), 1.63-1.46 (m,6H).

[1115] Example Compound S1-5

[1116] 7-(3,5-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-(dimethylamino)-1-benzothiophene-2-carboxamide

[1117]

[1118] A mixture of 3,5-dichlorophenylboronic acid (44 mg, 0.232 mmol), 7-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-(dimethylamino)-1-benzothiophene-2-carboxamide (100 mg, 0.232 mmol), and saturated aqueous sodium carbonate solution (0.34 mL) in 1,2-dimethoxyethane (4 mL) was flushed with argon for 5 min. Tetrakis(triphenylphosphine)palladium(0) (13 mg, 0.012 mmol) was added, and the mixture was stirred at 100°C for 1 h. Dichloromethane (2 mL) was added, and the layers were separated using a phase separator. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (Method 6; 24 g; heptane, 0%-50% ethyl acetate) and by reverse-phase flash column chromatography (Method 10; 24 g). This gave 72 mg (0.14 mmol, 62% of theory) of the title compound.

[1119] LC-MS (Method 2): R t = 4.66 min; m / z = 497 / 499 (M+H) +

[1120] 1H NMR (400 MHz, DMSO-d6) δ = 9.96 (d, J = 8.0 Hz, 1H), 8.14 (dd, J =6.6, 2.6 Hz, 1H), 7.76 (dd, J = 9.7, 1.8 Hz, 3H), 7.64-7.49 (m, 2H), 7.29 (d,J = 7.5 Hz, 1H), 7.25-7.12 (m, 1H), 6.92 (t, J = 7.4 Hz, 1H), 6.83 (d, J =8.2 Hz, 1H), 5.23 (q, J = 6.8 Hz, 1H), 4.31 (ddd, J =10.6, 7.5, 2.8 Hz, 1H),4.21 (ddd, J = 11.0, 7.5, 3.0 Hz, 1H), 2.90 (s, 6H), 2.24 (ddd, J = 12.9,9.0, 4.1 Hz, 1H), 2.09 (dtd, J = 13.9, 7.2, 2.9 Hz, 1H).

[1121] Example Compound S1-6

[1122] 7-(3-Chlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-(dimethylamino)-1-benzothiophene-2-carboxamide

[1123]

[1124] A mixture of 3-chlorophenylboronic acid (36 mg, 0.232 mmol), 7-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-(dimethylamino)-1-benzothiophene-2-carboxamide (100 mg, 0.232 mmol), and saturated aqueous sodium carbonate solution (0.34 mL) in 1,2-dimethoxyethane (4 mL) was flushed with argon for 5 min. Tetrakis(triphenylphosphine)palladium(0) (13 mg, 0.012 mmol) was added, and the mixture was stirred at 100°C for 1 h. Dichloromethane (2 mL) was added, and the layers were separated using a phase separator. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (Method 6; 24 g; heptane, 0%-50% ethyl acetate). 98 mg (0.21 mmol, 91% of theory) of the title compound were obtained.

[1125] LC-MS (Method 2): R t = 4.43 min; m / z = 463 (M+H) +

[1126] 1H NMR (400 MHz, DMSO-d6) δ = 9.97 (d, J = 8.0 Hz, 1H), 8.11 (dd, J =7.1, 2.0 Hz, 1H), 7.75-7.52 (m, 6H), 7.29 (d, J = 7.4Hz, 1H), 7.22-7.15 (m,1H), 6.95-6.88 (m, 1H), 6.83 (d, J = 8.2 Hz, 1H), 5.22 (q, J = 6.7 Hz, 1H), 4.31 (ddd, J = 10.6, 7.5, 2.9 Hz, 1H), 4.21 (ddd, J =11.0, 7.5, 3.0 Hz, 1H), 2.91 (s, 6H), 2.20 (s, 1H), 2.09 (dtd, J = 13.8, 7.2, 2.9 Hz, 1H).

[1127] Example Compound S1-7

[1128] 7-(2,3-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-(dimethylamino)-1-benzothiophene-2-carboxamide

[1129]

[1130] A mixture of 2,3-dichlorophenylboronic acid (44 mg, 0.232 mmol), 7-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-(dimethylamino)-1-benzothiophene-2-carboxamide (100 mg, 0.232 mmol), and saturated aqueous sodium carbonate solution (0.34 mL) in 1,2-dimethoxyethane (4 mL) was flushed with argon for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (13 mg, 0.012 mmol) was added, and the mixture was stirred at 100°C for 1 hour. Dichloromethane (2 mL) was added, and the layers were separated using a phase separator. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (Method 6; 24 g; heptane, 0%-50% ethyl acetate) and by reverse-phase flash column chromatography (Method 10; 24 g). This gave 61 mg (0.12 mmol, 52% of theory) of the title compound.

[1131] LC-MS (Method 2): R t = 4.42 min; m / z = 497 / 499 (M+H) +

[1132] 1H NMR (400 MHz, DMSO-d6) δ = 9.92 (d, J = 7.8 Hz, 1H), 8.14 (d, J =8.1 Hz, 1H), 7.81 (dd, J = 7.8, 1.7 Hz, 1H),7.61-7.41 (m, 4H), 7.27 (d, J =7.5 Hz, 1H), 7.22-7.14 (m, 1H), 6.94-6.87 (m, 1H), 6.82 (d, J = 8.2 Hz, 1H), 5.20 (q, J = 6.5 Hz, 1H), 4.30 (ddd, J = 10.6,7.4, 2.9 Hz, 1H), 4.20 (ddd, J= 10.9, 7.4, 2.9 Hz, 1H), 2.92 (s, 6H), 2.21 (ddd, J = 13.3, 8.1, 3.1 Hz, 1H), 2.12-2.02 (m, 1H).

[1133] Example Compound S1-8

[1134] 7-(3,4-Difluorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-(dimethylamino)-1-benzothiophene-2-carboxamide

[1135]

[1136] A mixture of 3,4-difluorophenylboronic acid (37 mg, 0.232 mmol), 7-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-(dimethylamino)-1-benzothiophene-2-carboxamide (100 mg, 0.232 mmol), and saturated aqueous sodium carbonate solution (0.34 mL) in 1,2-dimethoxyethane (4 mL) was flushed with argon for 5 min. Tetrakis(triphenylphosphine)palladium(0) (13 mg, 0.012 mmol) was added, and the mixture was stirred at 100°C for 1 h. Dichloromethane (2 mL) was added, and the layers were separated using a phase separator. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (Method 6; 24 g; heptane, 0%-50% ethyl acetate). 104 mg (0.22 mmol, 97% of theory) of the title compound were obtained.

[1137] LC-MS (Method 2): R t = 4.30 min; m / z = 465 (M+H) +

[1138] 1H NMR (400 MHz, DMSO-d6) δ = 9.97 (d, J = 8.0 Hz, 1H), 8.14-8.07 (m,1H), 7.78 (ddd, J = 11.3, 7.7, 2.0 Hz, 1H),7.70-7.48 (m, 4H), 7.29 (d, J =7.5 Hz, 1H), 7.23-7.14 (m, 1H), 6.95-6.87 (m, 1H), 6.83 (d, J = 8.1 Hz, 1H), 5.22 (q, J = 6.6 Hz, 1H), 4.31 (td, J = 7.9, 3.7Hz, 1H), 4.25-4.16 (m, 1H), 2.90 (s, 6H), 2.23 (dt, J = 10.1, 5.4 Hz, 1H), 2.11-2.03 (m, 1H).

[1139] Example Compound S1-9

[1140] 7-(3,5-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-methoxy-1-benzothiophene-2-carboxamide

[1141]

[1142] To a mixture of 7-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-methoxy-1-benzothiophene-2-carboxamide (100 mg, 0.239 mmol), (3,5-dichlorophenyl)boronic acid (50 mg, 0.263 mmol), and sodium carbonate (76 mg, 0.717 mmol) in a degassed mixture of 1,2-dimethoxyethane (4 mL) and water (1 mL) was added bis(triphenylphosphine)palladium(II) chloride (8 mg, 0.012 mmol). The mixture was stirred at 100°C for 16 h. Water and dichloromethane were added. The layers were separated using a phase separator. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (Method 7; 4 g; heptane, 2%-20% ethyl acetate). This gave 72 mg (0.146 mmol, 60% of theory) of the title compound.

[1143] LC-MS (Method 2): R t = 4.57 min; m / z = 484 / 486 (M+H) +

[1144] 1H NMR (400 MHz, chloroform-d) δ = 7.80 (dd, J = 8.0, 1.1 Hz, 1H), 7.72 (d,J = 7.7 Hz, 1H), 7.57 (dd, J = 1.9, 0.7 Hz, 2H), 7.54-7.47 (m, 1H), 7.47-7.39(m, 2H),7.35-7.29 (m, 1H), 7.22 (td, J = 8.2, 1.6 Hz, 1H), 6.98-6.83 (m, 2H),5.44-5.35 (m, 1H), 4.38-4.29 (m, 1H), 4.29-4.19 (m, 1H), 4.03 (s, 3H), 2.44-2.31 (m, 1H), 2.26-2.14 (m, 1H).

[1145] Example Compound S1-10

[1146] 7-(3-Chlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-methoxy-1-benzothiophene-2-carboxamide

[1147]

[1148] To a mixture of 7-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-methoxy-1-benzothiophene-2-carboxamide (100 mg, 0.239 mmol), (3-chlorophenyl)boronic acid (41 mg, 0.263 mmol), and sodium carbonate (76 mg, 0.717 mmol) in a degassed mixture of 1,2-dimethoxyethane (4 mL) and water (1 mL) was added bis(triphenylphosphine)palladium(II) chloride (8 mg, 0.012 mmol). The mixture was stirred at 100°C for 16 h. Water and dichloromethane were added. The layers were separated using a phase separator. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (Method 7; 4 g; heptane, 2%-20% ethyl acetate). This gave 57 mg (0.123 mmol, 51% of theory) of the title compound.

[1149] LC-MS (Method 2): R t = 4.36 min; m / z = 450 (M+H) +

[1150] 1H NMR (400 MHz, chloroform-d) δ = 7.78 (dd, J = 7.9, 1.2 Hz, 1H), 7.73 (d,J = 7.8 Hz, 1H), 7.65 (dt, J = 1.7, 1.1 Hz, 1H), 7.61 (dt, J = 6.9, 1.9 Hz,1H), 7.53-7.47(m, 1H), 7.47-7.40 (m, 3H), 7.35-7.29 (m, 1H), 7.21 (dd, J =8.1, 1.0 Hz, 1H), 6.93 (td, J = 7.5, 1.2 Hz, 1H), 6.89 (dd, J = 8.3, 1.2 Hz,1H), 5.45-5.33 (m,1H), 4.39-4.29 (m, 1H), 4.29-4.19 (m, 1H), 4.03 (s, 3H), 2.43-2.30 (m, 1H), 2.26-2.13 (m, 1H).

[1151] Example Compound S1-11

[1152] 7-(2,3-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-methoxy-1-benzothiophene-2-carboxamide

[1153]

[1154] To a mixture of 7-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-methoxy-1-benzothiophene-2-carboxamide (100 mg, 0.239 mmol), (2,3-dichlorophenyl)boronic acid (68 mg, 0.359 mmol), and sodium carbonate (76 mg, 0.717 mmol) in a degassed mixture of 1,2-dimethoxyethane (4 mL) and water (1 mL) was added bis(triphenylphosphine)palladium(II) chloride (8 mg, 0.012 mmol). The mixture was stirred at 100°C for 16 h. Ethyl acetate and water were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate. The solvent was removed in vacuo. The crude product was purified by flash column chromatography (Method 7; 4 g; heptane, 2%-20% ethyl acetate). This gave 73 mg (0.143 mmol, 60% of theory) of the title compound.

[1155] LC-MS (Method 2): R t = 4.37 min; m / z = 484 / 486 (M+H) +

[1156] 1H NMR (400 MHz, chloroform-d) δ = 7.83 (dd, J = 8.1, 1.1 Hz, 1H), 7.72 (d,J = 7.7 Hz, 1H), 7.58 (dd, J = 7.5, 2.1 Hz, 1H), 7.51 (dd, J = 8.1, 7.3 Hz,1H), 7.39 (dd,J = 7.3, 1.1 Hz, 1H), 7.37-7.28 (m, 3H), 7.24-7.18 (m, 1H),6.97-6.90 (m, 1H), 6.88 (dd,J = 8.3, 1.0 Hz, 1H), 5.43-5.31 (m, 1H), 4.38-4.28 (m, 1H), 4.28-4.17(m, 1H), 4.06 (s, 3H), 2.41-2.29 (m, 1H), 2.25-2.11(m, 1H).

[1157] Example Compound S1-12

[1158] 3-Chloro-7-(2,3-dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-1-benzothiophene-2-carboxamide

[1159]

[1160] To a mixture of 7-bromo-3-chloro-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-1-benzothiophene-2-carboxamide (70 mg, 0.166 mmol), (2,3-dichlorophenyl)boronic acid (47 mg, 0.248 mmol), and sodium carbonate (53 mg, 0.497 mmol) in a degassed mixture of 1,2-dimethoxyethane (2 mL) and water (1 mL) was added bis(triphenylphosphine)palladium(II) chloride (6 mg, 0.008 mmol). The mixture was stirred at 100°C for 16 h. Water and dichloromethane were added. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (Method 7; 4 g; heptane, 2%-20% ethyl acetate). This gave 43 mg (0.084 mmol, 51% of theory) of the title compound.

[1161] LC-MS (Method 2): R t = 4.52 min; m / z = 488 / 490 (M+H) +

[1162] 1H NMR (400 MHz, chloroform-d) δ = 7.92 (dd, J = 8.2, 0.9 Hz, 1H), 7.68-7.55 (m, 2H), 7.45 (dd, J = 7.3, 0.9 Hz, 1H), 7.42-7.29 (m, 4H), 7.26-7.18(m, 1H), 7.00-6.82(m, 2H), 5.38 (q, J = 5.7 Hz, 1H), 4.40-4.19 (m, 2H), 2.45-2.31 (m, 1H), 2.29-2.15 (m, 1H).

[1163] Example Compound S1-13

[1164] 7-(2,3-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-(dimethylamino)thieno[2,3-c]pyridine-2-carboxamide

[1165]

[1166] To a stirred suspension of lithium 7-(2,3-dichlorophenyl)-3-(dimethylamino)thieno[2,3-c]pyridine-2-carboxylate (23 mg, 0.06 mmol) in N,N-dimethylformamide (1.00 mL) was added triethylamine (19 mg, 0.19 mmol, 0.03 mL). To the resulting clear solution was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (35 mg, 0.09 mmol) and (S)-chroman-4-amine hydrochloride (17 mg, 0.09 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere in a sealed vessel for 16 hours. The reaction mixture was partitioned between ethyl acetate (5 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 5 mL). The combined organic extracts were washed with brine (3 x 5 mL), dried over sodium sulfate, and concentrated in vacuo. Purification by flash column chromatography (Method 6, 4 g; heptane, 5%-100% ethyl acetate) afforded 18 mg (0.04 mmol, 58% of theory) of the title compound.

[1167] LC-MS (Method 4): R t = 4.16 min; m / z = 498 / 500 (M+1) +

[1168] 1H NMR (400 MHz, DMSO-d6) δ 9.81 (d, J = 8.1 Hz, 1H), 8.64 (d, J =5.6 Hz, 1H), 8.09 (d, J = 5.6 Hz, 1H), 7.90-7.83 (m,1H), 7.61-7.54 (m, 2H),7.26 (d, J = 7.6 Hz, 1H), 7.23-7.15 (m, 1H), 6.94-6.86 (m, 1H), 6.81 (dd, J =8.2, 1.1 Hz, 1H), 5.21 (q, J = 6.5 Hz, 1H), 4.33-4.16(m, 2H), 2.93(s, 6H), 2.27-2.15 (m, 1H), 2.14-2.02 (m, 1H).

[1169] Example Compound S1-14

[1170] 7-(3,5-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-methoxythieno[2,3-c]pyridine-2-carboxamide

[1171]

[1172] A stirred mixture of 7-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-methoxythieno[2,3-c]pyridine-2-carboxamide (40 mg, 0.10 mmol), (3,5-dichlorophenyl)boronic acid (20 mg, 0.11 mmol), and sodium carbonate (20 mg, 0.19 mmol) in 1,4-dioxane (1.00 mL) and water (0.15 mL) was flushed with nitrogen. 1,1'-Bis(diphenylphosphino)ferrocenepalladium dichloride (4 mg, 0.01 mmol) was added, and the resulting mixture was stirred at 60°C under a nitrogen atmosphere in a sealed container for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (1 mL), and filtered. The filter cake was rinsed with ethyl acetate (1 mL), and the filtrate was concentrated in vacuo. Purification by flash column chromatography (Method 6, 12 g; heptane, 5%-100% ethyl acetate) gave 37 mg (0.08 mmol, 80% of theory) of the title compound.

[1173] LC-MS (Method 2): R t = 4.43 min; m / z = 485 / 487 (M+1) +

[1174] 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 5.5 Hz, 1H), 8.60 (d, J =8.2 Hz, 1H), 8.03-7.95 (m, 3H), 7.86 (t, J = 1.9 Hz,1H), 7.27 (d, J = 7.6 Hz,1H), 7.23-7.15 (m, 1H), 6.96-6.87 (m, 1H), 6.82 (dd, J = 8.2, 1.0 Hz, 1H), 5.30 (q, J = 6.5 Hz, 1H), 4.27 (dd, J = 6.3, 4.4 Hz, 2H),4.12 (s, 3H), 2.18(q, J = 6.4 Hz, 2H).

[1175] Example Compound S1-15

[1176] 7-(3-Chlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-methoxythieno[2,3-c]pyridine-2-carboxamide

[1177]

[1178] A stirred mixture of 7-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-methoxythieno[2,3-c]pyridine-2-carboxamide (40 mg, 0.10 mmol), (3-chlorophenyl)boronic acid (16 mg, 0.11 mmol), and sodium carbonate (20 mg, 0.19 mmol) in 1,4-dioxane (1.00 mL) and water (0.15 mL) was flushed with nitrogen. 1,1'-Bis(diphenylphosphino)ferrocenepalladium dichloride (4 mg, 0.01 mmol) was added, and the resulting mixture was stirred at 60°C under a nitrogen atmosphere in a sealed container for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (1 mL), and filtered. The filter cake was rinsed with ethyl acetate (1 mL), and the filtrate was concentrated in vacuo. Purification by flash column chromatography (Method 6, 12 g; heptane, 5%-100% ethyl acetate), preparative HPLC (Method 11) and trituration in diisopropyl ether gave 23 mg (0.05 mmol, 53% of theory) of the title compound.

[1179] LC-MS (Method 2): R t = 4.20 min; m / z = 451 / 453 (M+1) +

[1180] 1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 5.4 Hz, 1H), 8.57 (d, J =8.2 Hz, 1H), 8.04-7.98 (m, 2H), 7.94 (d, J = 5.5 Hz,1H), 7.70-7.63 (m, 2H),7.27 (d, J = 7.6 Hz, 1H), 7.23-7.15 (m, 1H), 6.95-6.88 (m, 1H), 6.82 (dd, J =8.2, 1.0 Hz, 1H), 5.29 (q, J = 6.4 Hz, 1H), 4.27 (dd, J= 6.4, 4.4 Hz, 2H),4.12 (s, 3H), 2.18 (q, J = 6.2 Hz, 2H).

[1181] Example Compound S1-16

[1182] 7-(2,3-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-methoxythieno[2,3-c]pyridine-2-carboxamide

[1183]

[1184] A stirred mixture of 7-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-methoxythieno[2,3-c]pyridine-2-carboxamide (80 mg, 0.19 mmol), (2,3-dichlorophenyl)boronic acid (40 mg, 0.21 mmol), and sodium carbonate (40 mg, 0.38 mmol) in 1,4-dioxane (2.0 mL) and water (0.3 mL) was flushed with nitrogen. 1,1'-Bis(diphenylphosphino)ferrocenepalladium dichloride (9 mg, 0.01 mmol) was added, and the resulting mixture was stirred at 70°C under a nitrogen atmosphere in a sealed container for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (1 mL), and filtered. The filter cake was rinsed with ethyl acetate (1 mL), and the filtrate was concentrated in vacuo. Purification by flash column chromatography (Method 6, 12 g; toluene, 5%-100% diisopropyl ether) gave 68 mg (0.14 mmol, 73% of theory) of the title compound.

[1185] LC-MS (Method 4): R t = 4.08 min; m / z = 485 / 487 (M+1) +

[1186] 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 5.6 Hz, 1H), 8.54 (d, J =8.3 Hz, 1H), 8.01 (d, J = 5.6 Hz, 1H), 7.91-7.83 (m,1H), 7.61-7.55 (m, 2H),7.24 (d, J = 7.5 Hz, 1H), 7.21-7.14 (m, 1H), 6.93-6.86 (m, 1H), 6.84-6.76 (m,1H), 5.26 (q, J = 6.6 Hz, 1H), 4.25 (dd, J = 6.1, 4.5Hz, 2H), 4.15 (s, 3H),2.15 (q, J = 6.2 Hz, 2H).

[1187] Example Compound S1-17

[1188] 7-(2,3-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-fluoro-3-(morpholin-4-yl)-1-benzothiophene-2-carboxamide

[1189]

[1190] LC-MS (Method 15): Rt = 1.41 min; MS (ESI positive (ESIpos)): m / z = 557 [M+H] +

[1191] 1H NMR (peak list): (400 MHz, DMSO-d6) δ [ppm]:-0.149 (1.79),-0.008(16.00), 0.008 (14.78), 0.146(1.88), 1.235 (0.66), 2.162 (7.53), 2.323(1.88), 2.327 (2.64), 2.332 (1.88), 2.366 (2.35), 2.524 (8.85), 2.665 (2.35),2.670 (3.01), 2.674 (2.26), 2.710(2.64), 3.032 (3.48), 4.158 (3.01), 4.173(2.45), 4.302 (4.61), 4.312 (2.82), 4.330 (3.48), 5.099 (4.71), 5.115 (4.61),5.754 (11.76), 6.879 (7.91), 6.899(8.94), 6.915 (4.71), 6.933 (9.51), 6.952(5.55), 7.234 (4.14), 7.238 (4.71), 7.255 (7.25), 7.273 (3.58), 7.276 (3.67),7.324 (2.82), 7.341 (5.08), 7.360(2.64), 7.441 (5.08), 7.462 (9.32), 7.469(5.27), 7.478 (4.89), 7.490 (12.24), 7.506 (8.00), 7.518 (8.28), 7.527(10.92), 7.538 (4.42), 7.547 (10.54), 7.566(4.52), 7.816 (9.60), 7.820(9.79), 7.836 (8.38), 7.840 (8.19), 10.427 (4.14), 10.440 (4.14).

[1192] Example Compound S1-18

[1193] 7-(3,5-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-fluoro-3-(morpholin-4-yl)-1-benzothiophene-2-carboxamide

[1194]

[1195] LC-MS (Method 15): Rt = 1.50 min; MS (ESI positive): m / z = 557 [M+H] +

[1196] 1H NMR (peak list): (600 MHz, DMSO-d6) δ [ppm]:-0.023 (1.36), 0.005(2.27), 1.232 (2.59), 2.157(0.49), 2.164 (0.68), 2.173 (1.33), 2.181 (3.20),2.187 (3.62), 2.195 (2.36), 2.203 (1.61), 2.210 (1.16), 2.219 (0.42), 2.227(0.41), 2.387 (0.51), 2.518(1.40), 2.521 (1.43), 2.524 (1.13), 2.615 (0.66),3.016 (0.53), 4.139 (1.01),4.145 (1.07), 4.158 (1.76), 4.174 (1.43), 4.180 (1.11), 4.317 (1.11), 4.324 (1.98), 4.331 (1.28), 4.336 (1.10), 4.343 (1.70),4.350 (0.87), 5.120 (1.02),5.127 (2.16), 5.138 (2.09), 5.146 (0.92), 5.761 (7.62), 6.892 (3.87), 6.905 (4.13), 6.931 (2.03), 6.943 (3.96), 6.956 (2.20),7.249 (1.87), 7.252 (1.92),7.264 (3.16), 7.275 (1.61), 7.278 (1.66), 7.344 (3.26), 7.357 (3.11), 7.461 (2.42), 7.474 (3.01), 7.480 (2.46), 7.493 (2.72),7.630 (2.85), 7.638 (2.92),7.644 (2.69), 7.651 (2.44), 7.722 (15.12), 7.725 (16.00), 7.785 (4.30), 7.788 (7.12), 7.791 (3.39), 10.462 (3.29), 10.473(3.14).

[1197] (Target) Example compound (S2)

[1198] Example Compound S2-1

[1199] 7-(2,3-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-methyl-3H-imidazo[4,5-b]pyridine-2-carboxamide

[1200]

[1201] Step 1: 7-(2,3-dichlorophenyl)-3-methyl-3H-imidazo[4,5-b]pyridine-2-carboxylic acid ethyl ester

[1202]

[1203] Ethyl 7-bromo-3-methyl-3H-imidazo[4,5-b]pyridine-2-carboxylate [CAS2090992-55-3] (1 g, 3.52 mmol), 2,3-dichlorophenylboronic acid (1 g, 5.28 mmol) and potassium fluoride (0.61 g, 10.5 mmol) were mixed with 50 mL of tetrahydrofuran and 4 mL of water. The mixture was degassed with argon for 5 minutes. Tris(dibenzylideneacetone)dipalladium(0) (0.32 g, 0.35 mmol) and tri-tert-butylphosphine tetrafluoroborate (0.2 g, 0.7 mmol) were added. The mixture was heated to 60°C for 4 hours. After cooling to room temperature, the mixture was diluted with water (10 mL) and extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and evaporated in vacuo. The remaining residue was purified by silica gel chromatography with an ethyl acetate / cyclohexane gradient to give 0.96 g (72.8%) of ethyl 7-(2,3-dichlorophenyl)-3-methyl-3H-imidazo[4,5-b]pyridine-2-carboxylate as a yellow oil.

[1204] LC-MS (Method 13): Retention index 932; m / z = 350.1; 352.0 (M+H) +

[1205] 1 H-NMR (400 MHz, DMSO- d 6) δ 8.68-8.67 (d, 1H), 7.84-7.82 (d, 1H), 7.58-7.50 (m, 2H), 7.47-7.45 (d, 1H), 4.44-4.39 (q, 2H), 1.37-1.31 (t, 3H).

[1206] Step 2: 7-(2,3-dichlorophenyl)-3-methyl-3H-imidazo[4,5-b]pyridine-2-carboxylic acid

[1207]

[1208] Ethyl 7-(2,3-dichlorophenyl)-3-methyl-3H-imidazo[4,5-b]pyridine-2-carboxylate (0.45 g, 1.28 mmol) from step 1 was dissolved in 21 mL of dichloromethane. Boron tribromide (6.42 mL, 1 M in dichloromethane) was added dropwise at -10 °C and maintained at -10 °C for 1 hour. The reaction mixture was allowed to warm to room temperature overnight and slowly quenched with 20 mL of water. The organic layer was separated and the solvent was evaporated under reduced pressure. The crude product contained some decarboxylation impurities and was used as is in the next step.

[1209] LC-MS (Method 13): Retention index 923; m / z = 322.0; 324.0 (M+H) +

[1210] Step 3: 7-(2,3-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-methyl-3H-imidazo-[4,5-b]pyridine-2-carboxamide

[1211]

[1212] To 7-(2,3-dichlorophenyl)-3-methyl-3H-imidazo[4,5-b]pyridine-2-carboxylic acid (crude material 122 mg, 0.34 mmol), (S)-chroman-4-amine hydrochloride (71 mg, 0.38 mmol) and N , N A stirred mixture of diisopropylethylamine (135 mg, 1.04 mmol) in dichloromethane (7.5 mL) was added N -(3-dimethylaminopropyl)- N ' -ethylcarbodiimide hydrochloride (67 mg, 0.34 mmol), 1-hydroxy-1 H -benzotriazole (24 mg, 0.17 mmol) and 4- N , N-dimethylaminopyridine (21 mg, 0.17 mmol). The resulting mixture was stirred overnight. The reaction mixture was mixed with water (10 mL) and the dichloromethane phase was separated. The aqueous phase was extracted again with dichloromethane. The combined organic layer was dried over sodium sulfate / silica gel cartridge and concentrated in vacuo. 46 mg (27.1%) of the title compound was obtained by flash chromatography with ethyl acetate / cyclohexane gradient purification.

[1213] LC-MS (Method 13): Retention index: 1089; m / z = 453.1; 455.1 (M+H) +

[1214] 1 H-NMR (400 MHz, DMSO- d 6) δ 9.24 (d, 1H, NH), 8.61 (d, 1H), 7.75 (d, 1H), 7.53-7.46 (m, 2H), 7.41 (d, 1H), 7.17-7.12 (m, 2H), 6.86-6.83 (t, 1H), 6.77 (d, 1H), 5.33-5.28 (q, 1H), 4.32-4.28 (m, 1H), 4.20-4.16 (m+s, 1H+3H), 2.23-2.18 (m, 1H), 2.09-2.06 (m, 1H).

[1215] Example Compound S2-2

[1216] 7-(2,3-Dichlorophenyl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-3-methyl-3H-imidazo[4,5-b]pyridine-2-carboxamide

[1217]

[1218] This example was prepared similarly to Example S2-1.

[1219] LC-MS (Method 13): Retention index: 1163; m / z = 437.1; 439.1 (M+H) +

[1220] 1 H-NMR (400 MHz, DMSO- d6) δ 9.13 (d, 1H, NH), 8.61 (d, 1H), 7.76(d,1H), 7.54-7.47 (m, 2H), 7.41 (d, 1H), 7.26-7.15 (m, 4H), 5.59-5.52 (q, 1H),4.19 (s, 3H), 3.02-2.95 (m, 1H), 2.86-2.78 (m, 1H), 2.42-2.36 (m, 1H), 2.15-2.10 (m, 1H).

[1221] Example Compound S2-3

[1222] 4-(2,6-Dichloropyridin-4-yl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-1-(propan-2-yl)-1H-indole-2-carboxamide

[1223]

[1224] This example was prepared similarly to Example S2-1.

[1225] Example Compound S2-4

[1226] N-[(4S)-3,4-Dihydro-2H-chromen-4-yl]-1-(propan-2-yl)-4-(2,3,5-trichlorophenyl)-1H-indole-2-carboxamide

[1227]

[1228] This example was prepared similarly to Example S2-1.

[1229] Example Compound S2-5

[1230] 4-(3,5-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-1-(propan-2-yl)-1H-indole-2-carboxamide

[1231]

[1232] This example was prepared similarly to Example S2-1.

[1233] Example Compound S2-6

[1234] N-[(4S)-3,4-Dihydro-2H-chromen-4-yl]-1-(propan-2-yl)-4-(2,3,5-trifluorophenyl)-1H-indole-2-carboxamide

[1235]

[1236] This example was prepared similarly to Example S2-1.

[1237] Example Compound S2-7

[1238] 4-(2,3-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-1-(propan-2-yl)-1H-indole-2-carboxamide

[1239]

[1240] This example was prepared similarly to Example S2-1.

[1241] (Target) Example compound (S3)

[1242] Example Compound S3-1

[1243] 8-(2,3-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-3-(propan-2-yl)imidazo[1,2-a]pyridine-2-carboxamide

[1244] .

[1245] (Target) Example compound (S4)

[1246] Example Compound S4-1

[1247] 4-Chloro-1-(2,6-difluorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

[1248]

[1249] Diethyl cyanophosphonate (69 mg, 0.42 mmol, 0.06 mL) was added to a solution of (S)-chroman-4-amine hydrochloride (72 mg, 0.39 mmol), 4-chloro-1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (100 mg, 0.32 mmol), and triethylamine (98 mg, 0.97 mmol, 0.14 mL) in dichloromethane (4.0 mL). The mixture was stirred at room temperature for 16 h. The volatiles were removed in vacuo. Purification by flash column chromatography (Method 6; 24 g; heptane, 0% to 50% ethyl acetate) gave 110 mg (0.25 mmol, 77% of theory) of the title compound.

[1250] LC-MS (Method 4): Rt = 3.92 min; m / z = 441 (M+H) +

[1251] 1H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J = 8.1 Hz, 1H), 8.78 (s, 1H), 8.69 (s, 1H), 7.77 (ddd, J = 14.9, 8.5, 6.4 Hz, 1H), 7.49 (t, J = 8.4 Hz, 2H),7.36 (d, J = 7.2 Hz, 1H), 7.21-7.13 (m, 1H), 6.97-6.88 (m, 1H), 6.80 (d, J =8.1 Hz, 1H), 5.32-5.17 (m, 1H), 4.36-4.16 (m,2H), 2.21 (ddt, J = 13.5, 8.4, 4.3 Hz, 1H), 2.06 (dtd, J = 13.5, 6.5, 3.0 Hz, 1H).

[1252] Example Compound S4-2

[1253] 1-(3,5-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-(dimethylamino)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

[1254]

[1255] Diethyl cyanophosphonate (58 mg, 0.36 mmol, 0.05 mL) is added to a solution of 1-(3,5-dichlorophenyl)-4-(dimethylamino)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (100 mg, 0.27 mmol), triethylamine (83 mg, 0.82 mmol, 0.11 mL) and (S)-chroman-4-amine hydrochloride (61 mg, 0.33 mmol) in dichloromethane (4.0 mL). The mixture is stirred at room temperature for 16 h. A precipitate is formed. The solid is filtered off and dried. 45 mg (0.09 mmol, 33% of theoretical value) of the title compound are obtained.

[1256] LC-MS (Method 4): R t = 4.58 min; m / z = 496 / 498 (M+H) +

[1257] 1H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 8.2 Hz, 1H), 8.42 (d, J =1.8 Hz, 2H), 8.37 (s, 1H), 7.53 (t, J = 1.8 Hz, 1H), 7.36 (d, J = 7.4 Hz, 1H),7.23-7.12 (m, 1H), 6.93 (t, J = 7.0 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.21(q, J = 6.1 Hz, 1H), 4.33-4.18 (m, 2H), 3.05 (s, 6H),2.68 (s, 3H), 2.18 (dd,J = 8.9, 4.5 Hz, 1H), 2.03 (dd, J = 14.0, 3.3 Hz, 1H).

[1258] Example Compound S4-3

[1259] 1-(2,6-Difluorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-(dimethylamino)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

[1260]

[1261] Diethyl cyanophosphonate (82 mg, 0.50 mmol, 0.08 mL) was added to a solution of (S)-chroman-4-amine hydrochloride (86 mg, 0.46 mmol), 1-(2,6-difluorophenyl)-4-(dimethylamino)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (144 mg, 0.39 mmol; purity 89%) and triethylamine (117 mg, 1.16 mmol, 0.16 mL) in dichloromethane (4.0 mL). The mixture was stirred at room temperature for 16 h and concentrated in vacuo. Purification by flash column chromatography (Method 6; 24 g; heptane, 0%-50% ethyl acetate) gave 78 mg (0.16 mmol, 43% of theory) of the title compound.

[1262] LC-MS (Method 4): R t = 3.75 min; m / z = 464 (M+H) +

[1263] 1H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 8.2 Hz, 1H), 8.16 (s, 1H), 7.67 (ddd, J = 14.8, 8.5, 6.4 Hz, 1H), 7.39 (t, J = 8.6Hz, 2H), 7.32 (d, J =7.4 Hz, 1H), 7.19-7.13 (m, 1H), 6.91 (t, J = 7.1 Hz, 1H), 6.79 (d, J = 8.1Hz, 1H), 5.25-5.14 (m, 1H), 4.24 (qd, J = 12.4, 11.1, 5.3 Hz,2H), 3.07 (s,6H), 2.66 (s, 3H), 2.17 (dq, J = 9.6, 4.6 Hz, 1H), 2.09-1.93 (m, 1H).

[1264] Example Compound S4-4

[1265] 1-(3,5-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-(dimethylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

[1266]

[1267] Diethyl cyanophosphonate (103 mg, 0.63 mmol, 0.10 mL) was added to a solution of (S)-chroman-4-amine hydrochloride (108 mg, 0.58 mmol), 1-(3,5-dichlorophenyl)-4-(dimethylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (170 mg, 0.48 mmol) and triethylamine (147 mg, 1.45 mmol, 0.20 mL) in dichloromethane (4.0 mL). The mixture was stirred at room temperature for 16 h and concentrated in vacuo. The residue was triturated in dichloromethane. The solid was filtered off and dried. 145 mg (0.30 mmol, 62% of theory) of the title compound were obtained.

[1268] LC-MS (Method 4): R t = 4.54 min; m / z = 482 / 484 (M+H) +

[1269] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 8.2 Hz, 1H), 8.62 (s, 1H), 8.46 (d, J = 1.9 Hz, 2H), 8.28 (s, 1H), 7.54 (t, J =1.9 Hz, 1H), 7.33 (d, J =7.3 Hz, 1H), 7.22-7.11 (m, 1H), 6.96-6.87 (m, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.25-5.14 (m, 1H), 4.25 (q, J = 7.9, 6.2 Hz, 2H),3.27 (s, 6H), 2.24-2.10 (m,1H), 2.02 (dq, J = 13.8, 5.3, 4.8 Hz, 1H).

[1270] Example Compound S4-5

[1271] 1-(2,6-Difluorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-(dimethylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide

[1272]

[1273] Diethyl cyanophosphonate (79 mg, 0.48 mmol, 0.07 mL) is added to a solution of (S)-chroman-4-amine hydrochloride (83 mg, 0.45 mmol), 1-(2,6-difluorophenyl)-4-(dimethylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (118 mg, 0.37 mmol) and triethylamine (113 mg, 1.11 mmol, 0.16 mL) in dichloromethane (4.0 mL). The mixture is stirred at room temperature for 16 h and concentrated in vacuo. Purification by flash column chromatography (Method 6; 24 g; heptane, 0%-50% ethyl acetate) and preparative HPLC (Method 10) affords 45 mg (0.10 mmol, 27% of theoretical value) of the title compound.

[1274] LC-MS (Method 4): R t = 3.60 min; m / z = 450 (M+H) + .

[1275] Example Compound S4-6

[1276] 1-(4-Chlorophenyl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-4-(propan-2-yl)-1H-benzotriazole-5-carboxamide

[1277]

[1278] Example Compound S4-7

[1279] N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-1-phenyl-4-(propan-2-yl)-1H-benzotriazole-5-carboxamide

[1280]

[1281] Example Compound S4-8

[1282] 1-(3-Chlorophenyl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-4-(propan-2-yl)-1H-benzotriazole-5-carboxamide

[1283]

[1284] Example Compound S4-9

[1285] N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-4-(propan-2-yl)-1-[3-(trifluoromethyl)phenyl]-1H-benzotriazole-5-carboxamide

[1286]

[1287] Example Compound S4-10

[1288] 1-(2-Chlorophenyl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-4-(propan-2-yl)-1H-benzotriazole-5-carboxamide

[1289]

[1290] (Target) Example compound (S5)

[1291] Example Compound S5-1

[1292] 3-(3,5-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-7-(dimethylamino)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxamide

[1293]

[1294] LC-MS (Method 15): Rt = 1.04 min; MS (ESI positive): m / z = 512 [M+H]+

[1295] 1H NMR (Peak list): (400 MHz, DMSO-d6) δ [ppm]:-0.008 (3.14), 0.008(1.66), 2.523 (1.06), 2.807(16.00), 3.586 (7.10), 4.099 (0.52), 4.107 (0.42),4.124 (0.62), 4.149 (0.43), 4.767 (0.48), 4.786 (0.47), 5.754 (0.50), 6.743(0.83), 6.761 (0.90), 6.872(0.89), 6.890 (0.55), 7.053 (0.80), 7.072 (0.64),7.120 (0.46), 7.140 (0.72), 7.407 (1.44), 7.703 (0.75), 7.707 (1.30), 7.712(0.68), 8.055 (2.97), 8.873(0.76), 8.893 (0.73).

[1296] (Target) Example compound (S6)

[1297] Example Compound S6-1

[1298] 5-(2,3-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]naphthalene-2-carboxamide

[1299]

[1300] Example Compound S6-2

[1301] 1-(2,3-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]isoquinoline-6-carboxamide

[1302] .

[1303] (Target) Example Compound (S7)

[1304] Example Compound S7-1

[1305] 8-(3,5-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-7-oxo-7,8-dihydro-1,8-naphthyridine-3-carboxamide

[1306]

[1307] LC-MS (Method 15): Rt = 1.03 min; MS (ESI positive): m / z = 466 [M+H] +

[1308] 1 H-NMR (400 MHz, DMSO- d 6): δ [ppm]= 9.05 (d, 1H), 8.86 (d, 1H), 8.71(d, 1H), 8.14 (d, 1H), 7.75 (t, 1H), 7.56 (d, 2H), 7.22-7.14 (m, 2H),6.90-6.79 (m, 3H), 5.29 (q, 1H), 4.33-4.22 (m, 2H), 2.19-2.00 (m, 2H)

[1309] Example Compound S7-2

[1310] 1-(4-Chlorobenzyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-5-(dimethylamino)-2-oxo-1,2-dihydro-1,7-naphthyridine-6-carboxamide

[1311]

[1312] (Target) Example compound (S8)

[1313] Example Compound S8a-1

[1314] 8-(3,5-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-(propan-2-yl)-2H-chromen-3-carboxamide

[1315]

[1316] Example Compound S8a-2

[1317] 8-(3,5-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-2-oxo-4-(propan-2-yl)-2H-chromen-3-carboxamide

[1318]

[1319] To a mixture of crude lithium 8-(3,5-dichlorophenyl)-4-isopropyl-2-oxo-2H-chromene-3-carboxylate (303 mg, 0.79 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added triethylamine (0.6 mL, 4.75 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (663 mg, 1.74 mmol). After stirring for 30 min, (S)-chroman-4-amine hydrochloride (323 mg, 1.74 mmol) was added. The reaction mixture was stirred for 1.5 h and water was added. The resulting precipitate was filtered off, washed with water, and air-dried. Purification by flash column chromatography (Method 6; 24 g; heptane, 2%-100% ethyl acetate) gave 125 mg (0.25 mmol; 31% of theory) of the title compound.

[1320] LC-MS (Method 4): R t = 4.18 min; m / z = 506 / 508 (MH) -

[1321] 1H NMR (400 MHz, DMSO- d 6) δ 8.93 (d, J = 8.2 Hz, 1H), 8.13 (d, J = 8.0Hz, 1H), 7.72 (m, 2H), 7.63 (d, J = 1.9 Hz, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.33(d, J = 7.5 Hz, 1H), 7.19-7.11 (m, 1H), 6.90 (t, J = 7.4 Hz, 1H), 6.78 (d, J =8.2 Hz, 1H), 5.18 (q, J = 6.3 Hz, 1H), 4.23 (m, 2H), 3.53-3.38 (m, 1H), 2.21-2.09 (m, 1H), 2.02-1.92 (m, 1H),1.45 (t, J = 7.6 Hz, 6H).

[1322] Example Compound S8a-3

[1323] 8-(2,3-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-2-oxo-2H-chromene-3-carboxamide

[1324]

[1325] Step 1: Ethyl 8-bromo-2-oxo-2H-chromene-3-carboxylate

[1326]

[1327] To a solution of 3-bromo-2-hydroxybenzaldehyde (1.00 g, 5.0 mmol) in ethanol (15 mL) was added diethyl malonate (1.20 g, 7.5 mmol) and piperidine (85 mg, 1.0 mmol). The resulting mixture was stirred at 80 ° C for 6 hours. After cooling to room temperature, the solvent was removed in a vacuum and ethyl acetate was added. The resulting mixture was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3: 1) to give 700 mg (34%) of the product as a white solid.

[1328] LC-MS (Analytical Method A, 0.01-2.00 min 5-95% B): R t = 1.06 min; MS (ESI positive): m / z =297 (M+H) +

[1329] Step 2: 8-Bromo-2-oxo-2H-chromene-3-carboxylic acid

[1330]

[1331] To the solution of 8-bromo-2-oxo-2H-chromene-3-ethyl formate (650 mg, 2.2 mmol) in tetrahydrofuran (13 mL), sodium hydroxide (170 mg, 4.4 mmol) is added. The gained mixture is stirred at room temperature overnight. After the reaction is complete, desolvation is removed in a vacuum. Add water and then add dilute hydrochloric acid (1 N) to adjust pH to 1, collect precipitated solid and dry by filtration, obtain 540 mg (92%) of the product as off-white solid.

[1332] LC-MS (Analytical Method A, 0.01-2.00 min 5-95% B): R t = 0.76 min; MS (ESI positive): m / z =269 (M+H) +

[1333] Step 3: 8-Bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-2-oxo-2H-chromene-3-carboxamide

[1334]

[1335] To 8-bromo-2-oxo-2 H -chromene-3-carboxylic acid (250 mg, 0.93 mmol) in N , N - a solution in dimethylformamide (5 mL) was added HATU (530 mg, 1.4 mmol), N , N -diisopropylethylamine (360 mg, 2.8 mmol) and (S)-chroman-4-amine (166 mg, 1.1 mmol) were added and the resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, water was added and the precipitated solid was collected by filtration, washed with water, and dried in vacuo to give 200 mg (50%) of the product as a yellow solid.

[1336] LC-MS (Analytical Method E, 0.01-2.00 min 5-95% B): R t = 1.20 min; MS (ESI positive): m / z =400 (M+H) +

[1337] Step 4: 8-(2,3-dichlorophenyl)- N -[(4 S )-3,4-dihydro-2H-chromen-4-yl]-2-oxo-2 H -chromene-3-carboxamide

[1338]

[1339] Towards( S )-8-bromo- N -(chroman-4-yl)-2-oxo-2 HTo a solution of 2-chromene-3-carboxamide (100 mg, 0.3 mmol) in a mixed solvent of tetrahydrofuran / water (v:v 4:1, 2.5 mL) were added 2,3-dichlorophenylboronic acid (48 mg, 0.3 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (13 mg, 0.01 mmol), tri-tert-butylphosphine tetrafluoroborate (7 mg, 0.02 mmol), and potassium fluoride (44 mg, 0.8 mmol). The resulting mixture was stirred at 60° C. under a nitrogen atmosphere overnight. After cooling to room temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) and preparative HPLC [column: Xbridge Prep C18, 5 um, 19*150 mm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; gradient: 65% B to 95% B in 8 min;] to give 50.9 mg (43%) of the product as a white solid.

[1340] 1 H-NMR (400 MHz, DMSO- d 6 ) : δ [ppm]= 2.07-2.08 (m, 1H), 2.17-2.19 (m,1H), 4.18-4.20 (m, 1H), 4.25-4.28 (m, 1H), 5.22 (q, 1H), 6.79 (d, 1H), 6.89(t, 1H), 7.18 (t, 1H), 7.24-7.27 (m, 1H), 7.45-7.58(m, 3H), 7.71 (d, 1H), 7.79(d, 1H), 8.10(d, 1H), 8.87 (d, 1H), 8.93 (s, 1H);

[1341] LC-MS (Analytical Method C, 0.01-3.00 min 5-95% B): R t = 2.05 min; MS (ESI positive): m / z= 466 (M+H) + .

[1342] Example Compound S8a-4

[1343] 8-(3,5-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-2H-chromen-3-carboxamide

[1344]

[1345] Towards( S )-8-bromo- N -(chroman-4-yl)-2 H To a solution of 3-chromene-3-carboxamide (100 mg, 0.3 mmol) [described for Example S8a-5, Steps 1-4] in a mixed solvent of tetrahydrofuran / water (v:v = 4:1, 2.5 mL) were added 3,5-dichlorophenylboronic acid (50 mg, 0.3 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (13 mg, 0.01 mmol), tri-tert-butylphosphine tetrafluoroborate (8 mg, 0.01 mmol), and potassium fluoride (45 mg, 0.8 mmol). The resulting mixture was stirred at 60°C under a nitrogen atmosphere overnight. After cooling to room temperature, the solvent was evaporated and the residue was redissolved in ethyl acetate. The mixture was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) and preparative HPLC [column: Kinetex 5 μm EVO C18 OBD, 21.2 x 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; gradient: 10% B to 50% B over 10 minutes] to obtain 53.8 mg (46%) of the product as a white solid. MS (ESI positive): m / z = 452 (M+H). + .

[1346] 1 H-NMR (400 MHz, DMSO- d 6 ) : δ [ppm] = 1.96-2.02 (m, 2H), 4.18-4.31 (m,2H), 5.00 (s, 2H), 5.17 (q,1H), 6.80 (d, 1H), 6.89 (t, 1H), 7.07 (t, 1H),7.15-7.17 (m, 2H), 7.27 (d, 1H), 7.35-7.41 (m, 2H), 7.58-7.61 (m, 3H), 8.64(d, 1H);

[1347] LC-MS (Analytical Method C, 0.01-3.00 min 5-95% B): R t = 1.95 min; MS (ESI positive): m / z= 452 (M+H) + .

[1348] Example Compound S8a-5

[1349] 8-(2,3-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-2H-chromen-3-carboxamide

[1350]

[1351] Step 1: tert-Butyl 2-((3-bromo-2-hydroxyphenyl)(hydroxy)methyl)acrylate

[1352]

[1353] A mixture of 3-bromo-2-hydroxybenzaldehyde (5.00 g, 24.9 mmol), tert-butyl acrylate (15.94 g, 124.4 mmol) and 1,4-diazabicyclo(2.2.2)octane (0.56 g, 5.0 mmol) was stirred at 65 ° C for 2 days. After the reaction was complete, tert-butyl acrylate was removed in vacuo. Water was added and the resulting mixture was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2: 1) to give 3.00 g (37%) of the product as a yellow oil.

[1354] LC-MS (Analytical Method A, 0.01-1.80 min 5-95% B): R t = 0.94 min; MS (ESI positive): m / z =329 (M+H) + .

[1355] Step 2: tert-Butyl 8-bromo-2H-chromene-3-carboxylate

[1356]

[1357] To a solution of tert-butyl 2-((3-bromo-2-hydroxyphenyl)(hydroxy)methyl)acrylate (2.30 g, 7.00 mmol) in a mixed solvent of tetrahydrofuran / water (v:v = 1:2, 30 mL) was added potassium hydroxide (392 mg, 7.0 mmol) and the resulting mixture was stirred at reflux for 5 hours. After cooling to room temperature, the solvent was removed in vacuo. Water was added and the resulting mixture was extracted with ethyl acetate and the combined organic phases were dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1). The collected fractions were concentrated to give 400 mg (18%) of the product as a colorless oil.

[1358] 1 H-NMR (400 MHz, DMSO- d6 ) : δ [ppm]= 1.50 (d, 9H), 5.01 (s, 2H), 6.91 (t, 1H), 7.36 (d, 1H), 7.40 (s, 1H), 7.53 (d, 1H).

[1359] Step 3: 8-Bromo-2H-chromene-3-carboxylic acid

[1360]

[1361] To a solution of 8-bromo-2H-chromene-3-formic acid tert-butyl ester (850 mg, 2.7 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (5 mL) and the resulting mixture was stirred at room temperature for 3 hours. After the reaction was complete, the solvent was removed in a vacuum. Water was added and a saturated sodium bicarbonate solution was added to adjust the pH to 7. The resulting mixture was extracted with dichloromethane; the combined organic phases were dried over anhydrous sodium sulfate and concentrated in a vacuum to give 600 mg (85%) of the product as a yellow solid.

[1362] LC-MS (Analytical Method A, 0.01-2.00 min 5-95% B): R t = 0.90 min; MS (ESI positive): m / z =255 (M+H) + .

[1363] Step 4: 8-Bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-2H-chromene-3-carboxamide

[1364]

[1365] To 8-bromo-2H-chromene-3-carboxylic acid (600 mg, 2.4 mmol) was added N , N -dimethylformamide (10 mL) was added with HATU (1.34 g, 3.53 mmol), N , N To the 4-nitro-2-nitro-1-propanediol (50mg, 1.3mmol) was added diisopropylethylamine (912mg, 7.1mmol) and (S)-chroman-4-amine (421mg, 2.8mmol). The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, saline solution was added to quench the reaction. The precipitated solid was collected by filtration, washed with water, and dried in a vacuum to give 500mg (55%) of the product as a yellow solid.

[1366] LC-MS (Analytical Method E, 0.01-2.00 min 5-95% B): Rt = 1.21 min; MS (ESI positive): m / z =386 (M+H) + .

[1367] Step 5: 8-(2,3-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-2H-chromene-3-carboxamide

[1368]

[1369] To (S)-8-bromo- N -(chroman-4-yl)-2 H To a solution of 2-chromene-3-carboxamide (100 mg, 0.3 mmol) in a mixed solvent of tetrahydrofuran / water (v:v 4:1, 2.5 mL) was added 2,3-dichlorophenylboronic acid (50 mg, 0.3 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (13 mg, 0.01 mmol), tri-tert-butylphosphine tetrafluoroborate (8 mg, 0.01 mmol) and potassium fluoride (45 mg, 0.8 mmol). The resulting mixture was stirred at 60 ° C under a nitrogen atmosphere overnight. After cooling to room temperature, the solvent was evaporated and the residue was redissolved in ethyl acetate. The mixture was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) and preparative HPLC [column: Kinetex 5 um EVO C18 OBD, 21.2*150 mm, 5 um; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; gradient: 10% B to 60% B in 12 min] to give 54.6 mg (46%) of the product as a white solid.

[1370] 1 H-NMR (400 MHz, DMSO- d 6 ) : δ [ppm] = 1.96-2.08 (m, 2H), 4.22-4.29 (m,2H), 4.93 (s, 2H), 5.15 (q,1H), 6.80 (d, 1H), 6.86-6.90 (m, 1H), 7.05 (t,1H), 7.14-7.18 (m, 3H), 7.28(d, 1H), 7.33 (d, 1H), 7.40-7.44 (m, 2H), 7.67(d,1H), 8.64 (d, 1H);

[1371] LC-MS (Analytical Method C, 0.01-3.00 min 5-95% B): R t = 1.95 min; MS (ESI positive): m / z= 452 (M+H) + .

[1372] Example Compound S8a-6

[1373] 8-(3,5-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-(morpholin-4-yl)-2-oxo-1,2-dihydroquinoline-3-carboxamide

[1374]

[1375] Example Compound S8b-1

[1376] 8-(3,5-Dichlorophenyl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-2,4-dimethyl-4H-chromene-3-carboxamide

[1377]

[1378] Step 1: 2-Bromo-6-(1-hydroxyethyl)phenol

[1379]

[1380] At 0 DEG C, under nitrogen atmosphere, to a cold solution of 3-bromo-2-hydroxybenzaldehyde (30.0 g, 150.0 mmol, 1.0 eq) in anhydrous ether (300 mL) was dropwise added methylmagnesium bromide solution (3 M in ether, 150 mL, 450 mmol, 3.0 eq). The resulting reaction mixture was allowed to reach ambient temperature for 2 h. The reaction progress was monitored by TLC. The reaction mixture was cooled to 0 DEG C and quenched with 1 M HCl. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (100-200 silica gel, 50% EtOAc- hexane) to give pure 2-bromo-6-(1-hydroxyethyl) phenol (24.0 g, 74% of theoretical value) as an off-white solid.

[1381] TLC system: 30% EtOAc in petroleum ether

[1382] 1H-NMR (400 MHz, CDCl3) δ 7.61 (broad peak, 1H), 7.40-7.37 (m, 1H), 7.05-7.03 (m, 1H), 6.76-6.72 (m, 1H), 5.08-5.05 (m, 1H), 3.00 (broad peak, 1H), 1.54-1.52 (d, 3H);

[1383] R f Value: 0.9.

[1384] Step 2: Ethyl 8-bromo-2-hydroxy-2,4-dimethylchroman-3-carboxylate

[1385]

[1386] At room temperature, under a nitrogen atmosphere, to a stirred solution of 2-bromo-6-(1-hydroxyethyl)phenol (1.0 g, 4.61 mmol, 1.0 eq) in dichloroethane (15 mL) was added 4 Å molecular sieves (4.60 g), anhydrous FeCl (0.037 g, 0.23 mmol), followed by ethyl acetoacetate (1.20 g, 9.25 mmol) and the resulting solution was irradiated at 60 ° C for 1.30 h in a microwave. The reaction progress was monitored by TLC. After completion, the reaction mixture was filtered through a celite pad and washed thoroughly with dichloromethane. The filtrate was washed with saturated NaHCO 3 solution and brine, dried over Na 2 SO 4 and concentrated to give the crude compound, which was purified by flash chromatography (20% EtOAc-hexanes) to give pure ethyl 8-bromo-2-hydroxy-2,4-dimethylchroman-3-carboxylate (1.40 g, 92.3% of theoretical) as a thick yellow liquid.

[1387] TLC system: 50% EtOAc in petroleum ether

[1388] R f Value: 0.3.

[1389] Step 3: Ethyl 8-bromo-2,4-dimethyl-4H-chromene-3-carboxylate

[1390]

[1391] To a stirred solution of 8-bromo-2-hydroxy-2,4-dimethylchroman-3-ethyl formate (13.8 g, 41.9 mmol, 1.0 eq) in toluene (140 mL), p-toluenesulfonic acid (7.2 g, 41.9 mmol, 1.0 eq) was added and the resulting reaction mixture was refluxed for 1 h. The reaction progress was monitored by TLC. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO 3 and brine solution in sequence. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude compound, which was further purified by flash column chromatography (silica gel, 50% EtOAc / hexane) to obtain pure 8-bromo-2,4-dimethyl-4H-chromene-3-ethyl formate (9.0 g, 68% of theoretical value) as an off-white solid.

[1392] TLC system: 50% EtOAc in petroleum ether

[1393] 1H-NMR (400 MHz, CDCl3) δ 7.61 (broad peak, 1H), 7.40-7.38 (m, 1H), 7.10-7.08 (m, 1H), 6.96-6.92 (m, 1H), 4.25 (m, 2H), 3.89 (q, 1H), 2.45 (s, 3H), 1.36-1.34 (t, 3H), 1.28-1.26 (d, 3H);

[1394] R f Value: 0.8.

[1395] Step 4: 8-Bromo-2,4-dimethyl-4H-chromene-3-carboxylic acid

[1396]

[1397] To a stirred solution of ethyl 8-bromo-2,4-dimethyl-4H-chromene-3-carboxylate (9.0 g, 29.0 mmol) in EtOH (90 mL) was added LiOH•H₂O (2.3 g, 58 mmol) in water (40 mL) and the resulting reaction mixture was refluxed for 4 h. The reaction progress was monitored by TLC. Volatiles were removed under reduced pressure and the resulting crude product was poured into cold water and washed with dichloromethane. The aqueous layer was acidified with 2N aqueous HCl (pH = 2) and extracted with 10% MeOH-CH₂Cl₂ (3 × 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude compound, which was further purified by trituration with 10% EtOAc / diethyl ether to give 8-bromo-2,4-dimethyl-4H-chromene-3-carboxylic acid (5.25 g, 64.1% of theoretical) as an off-white solid. Purity: 99.6%

[1398] LC-MS (Method 14): R t = 2.20 min;

[1399] TLC system: 10% MeOH-CH2Cl2

[1400] 1 H-NMR (400 MHz, DMSO- d 6) δ 7.51-7.49 (m, 1H), 7.31-7.29 (m, 1H), 7.09-7.05 (m, 1H), 3.83 (q, 1H), 2.37 (s, 3H), 1.22-1.20 (d, 3H);

[1401] R f Value: 0.1

[1402] LC-MS method

[1403] Mobile phase-A: 10 mM ammonium formate in water

[1404] Mobile phase-B: ACN

[1405] Column - Xbridge BEH C18 2.5 μm, 2.1 × 50 mm

[1406] Flow rate: 0.7 mL / min, temperature: 40°C

[1407] Time (min) and %B: 0-5; 3.0-100; 3.5-100; 3.8-5; 4.3-5;

[1408] Gas flow rate 1.6 SLM

[1409] Evaporator temperature 40℃.

[1410] Step 5: 8-Bromo-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-2,4-dimethyl-4H-chromene-3-carboxamide

[1411]

[1412] To a suspension of 8-bromo-2,4-dimethyl-4H-chromene-3-carboxylic acid (949 mg, 3.35 mmol) in anhydrous toluene (15 mL) was added 2 drops of DMF. Thionyl chloride (450 mg, 3.78 mmol) was then added dropwise over 2 minutes. After stirring at 70° C. for 4 h, the mixture was cooled to room temperature and stirred at 40° C. for 18 hours after the addition of (1S)-indan-1-amine hydrochloride (460 mg, 3.45 mmol) and N,N-diisopropylethylamine (950 mg, 7.35 mmol).

[1413] The solvent was removed under reduced pressure and the residue was partitioned between water (50 mL) and dichloromethane (50 mL).The combined organic layers were dried under reduced pressure and removed, leaving 924 mg (59% of theory) of the title compound.

[1414] LC-MS3-index = 1033; m / z = 397.1; 399.1 (M+H) +

[1415] 1 H-NMR (400 MHz, DMSO- d 6) δ 8.44-8.40 (m, 1H), 7.48-7.45 (m, 1H), 7.29-7.20 (m, 5H), 7.03-6.99 (m, 1H), 5.46-5.42 (m, 1H), 3.86-1.23 (m, 11H).

[1416] Step 6: 8-(3,5-Dichlorophenyl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-2,4-dimethyl-4H-chromene-3-carboxamide

[1417]

[1418] A mixture of 8-bromo-N-[1S)-2,3-dihydro-1H-inden-1-yl]-2,4-dimethyl-4H-chromene-3-carboxamide (120 mg, 0.301 mmol) and bis(triphenylphosphine)palladium(II) dichloride (21 mg, 0.03 mmol) in 1,4-dioxane (10 mL) was stirred at room temperature for 2 hours. (3,5-dichlorophenyl)boronic acid (100 mg, 0.366 mmol), sodium carbonate (370 mg, 3.49 mmol), and water (1.30 mL) were added, and stirring was continued at 90°C for 18 hours. The mixture was cooled to room temperature, water was added, and the aqueous layer was extracted with dichloromethane (3 x 20 mL). The solvent was dried and removed under reduced pressure. Purification by flash chromatography (cyclohexane, 80%-20% ethyl acetate) gave 3.4 mg (2.4% of theory) of the title compound as a brown solid.

[1419] LC-MS3-index = 1350; m / z = 463.1; 465.1 (M+H) +

[1420] 1 H-NMR (400 MHz, DMSO- d 6) δ 8.37-8.33 (m, 1H), 7.61-7.56 (m, 3H), 7.34-7.15 (m, 7H), 5.48-5.42 (m, 1H), 3.91-3.86 (m, 1H), 2.99-2.93 (m, 1H),2.86-2.78 (m, 1H), 2.46-2.39 (m, 1H), 2.02 (s, 3H), 1.94-1.84 (m, 1H),1.31-1.29 (m, 3H).

[1421] Example Compound S8b-2

[1422] 2,4-Dimethyl-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-8-(2,3,5-trifluorophenyl)-4H-chromene-3-carboxamide

[1423]

[1424] Example compound S8b-2 was prepared in a similar manner to Example compound S8b-1.

[1425] 8-Bromo-2,4-dimethyl-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-4H-chromene-3-carboxamide

[1426]

[1427] To prepare example compound S8b-2, the intermediate compound 8-bromo-2,4-dimethyl-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-4H-chromene-3-carboxamide was prepared in a manner similar to the intermediate compound 8-bromo-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-2,4-dimethyl-4H-chromene-3-carboxamide (step 1 in the preparation of example compound S8b-1).

[1428] LC-MS3-index = 1083; m / z = 411.1; 413.1 (M+H) +

[1429] 1 H-NMR (400 MHz, DMSO- d 6) δ 8.39-8.37 (m, 1H), 7.46-6.98 (m, 7H), 5.14-5.10 (m, 1H), 3.88-3.83 (m, 1H), 2.76-2.72 (m, 2H), 2.08-2.07 (d, 3H),1.94-1.91 (m, 2H), 1.76-1.74 (m, 2H), 1.28-1.27 (d, J = 6.8 Hz, 3H).

[1430] Example Compound S8b-3

[1431] N-[(4S)-3,4-Dihydro-2H-chromen-4-yl]-2,4-dimethyl-8-(2,3,5-trifluorophenyl)-4H-chromene-3-carboxamide

[1432] Step 1: 8-Bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-2,4-dimethyl-4H-chromene-3-carboxamide

[1433]

[1434] To a suspension of 8-bromo-2,4-dimethyl-4H-chromene-3-carboxylic acid (150 mg, 0.53 mmol) in anhydrous tetrahydrofuran (5 mL) was added 1,1'-carbonyldiimidazole (95 mg, 0.586 mmol). After stirring at 60°C for 18 h, the mixture was cooled to room temperature and, after adding (4S)-3,4-dihydro-2H-chromene-4-amine hydrochloride (95 mg, 0.512 mmol) and N,N-diisopropylethylamine (500 mg, 3.869 mmol), stirring was continued at 60°C for 18 hours.

[1435] In 4-nitro-1-oxo-2-nitropropene (5-nitropropene) ...

[1436] LC-MS3-index = 985

[1437] 1 H-NMR (400 MHz, DMSO- d 6) δ 8.58-8.56 (m, 1H), 7.47-6.77 (m, 7H), 5.18 (m, 1H), 4.25-4.21 (m, 2H), 3.88-3.86 (m, 1H), 2.10-2.08 (m, 1H), 2.08(d, 3H), 1.98 (m, 1H), 1.26 (d, 3H).

[1438] Step 2: N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-2,4-dimethyl-8-(2,3,5-trifluorophenyl)-4H-chromene-3-carboxamide S8b-3

[1439]

[1440] A mixture of 8-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-2,4-dimethyl-4H-chromene-3-carboxamide (94 mg, 0.227 mmol) and bis(triphenylphosphine)palladium(II) dichloride (44 mg, 0.062 mmol) in 1,4-dioxane (10 mL) was stirred at room temperature for 2 hours. (2,3,5-trifluorophenyl)boronic acid (300 mg, 1.706 mmol), sodium carbonate (870 mg, 8.21 mmol), and water (3.30 mL) were added, and stirring was continued at 90°C for 18 hours. The mixture was cooled to room temperature, water was added, and the aqueous layer was extracted with dichloromethane (3 x 20 mL). The solvent was dried and removed under reduced pressure. Purification by flash chromatography (cyclohexane, 80%-20% ethyl acetate) afforded 12 mg (10.5% of theory) of the title compound.

[1441] LC-MS 7-index = 1091; m / z = 466.1 (M+H)+

[1442] 1H-NMR (400 MHz, DMSO-d6) δ 8.51-8.49 (m, 1H), 7.62-6.77 (m, 9H), 5.16-5.11 (m, 1H), 4.23-4.20 (m, 2H), 3.91-3.86 (m,1H), 2.12-2.08 (m, 1H),2.00-1.94 (m, 1H), 1.94 (s, 3H), 1.30-1.28(d, J = 6.8 Hz, 3H).

[1443] (Target) Example Compound (S9)

[1444] Example S9-1

[1445] 2-[2-Chloro-3-(trifluoromethyl)phenyl]-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]quinoxaline-6-carboxamide

[1446]

[1447] Example Compound S9-2

[1448] 2-(2-Chlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]quinoxaline-6-carboxamide

[1449]

[1450] Example Compound S9-3

[1451] 2-(2-Chlorophenyl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]quinoxaline-6-carboxamide

[1452]

[1453] Example Compound S9-4

[1454] 2-(2,3-Dichlorophenyl)-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]quinoxaline-6-carboxamide

[1455]

[1456] Example S9-5

[1457] 2-(2,3-Dichlorophenyl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]quinoxaline-6-carboxamide

[1458]

[1459] ...

Claims

1. Compounds of general formula (I) and stereoisomers, tautomers and salts thereof, and mixtures thereof, in: A is A1, o is 0, 1, 2, 3, or 4; R is selected from the group consisting of: hydrogen, halogen, cyano, nitro, -OH, C1-C4 alkyl and -NH2; X, Y are independently selected from: CR 7 R 8 , O and S, wherein at least one of X and Y is CR 7 R 8 ; T is selected from T 1 : U selected from: CR 7 and N; R 1 Selected from: hydrogen, cyano, -OH and C1-C4 alkyl; R 2 Selected from: hydrogen, halogen, cyano; -NR 12 R 13 ; -OR 14 ; -SR 15 ; C1-C6 alkyl, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, -OH, cyano and C1-C4 alkyl, 4- to 10-membered heterocycloalkyl, optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, and C1-C4 alkyl; R 5 Selected from: hydrogen, halogen, -OH, cyano and C1-C4 alkyl; R 6 Selected from: hydrogen, halogen, -OH, cyano and C1-C4 alkyl; R 7 Selected from: hydrogen, -OH, halogen and C1-C4 alkyl; R 8 Selected from: hydrogen, -OH, halogen and C1-C4 alkyl; R 10 Selected from: hydrogen, -OH and C1-C4 alkyl; R 11 Selected from: hydrogen and C1-C4 alkyl; R 12 and R 13 Independently selected from: Hydrogen, -OH, -NH2; C1-C4 alkyl, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano, C1-C4 alkyl and -NH2; R 14 Selected from: -NH2; C1-C4 alkyl, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano, C1-C4 alkyl and -NH2; R 15 yes: C1-C4 alkyl, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano, C1-C4 alkyl and -NH2; Q is selected from: 6 to 10 membered aryl and 5 to 10 membered heteroaryl, each of which is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from: halogen; SF5; cyano; C1-C4 alkyl; C1-C4 hydroxyalkyl; C1-C4 haloalkyl having 1 to 5 halogen atoms and -OH; When Y is O or S, R 7 、R 8 and R 10 are not -OH, and when X is O or S, R 7 and R 8 None of them are -OH.

2. The compound according to claim 1 and its stereoisomers, tautomers and salts, and mixtures thereof, in: A is A1, o is 0, 1, 2, 3, or 4; R is selected from the group consisting of: hydrogen, halogen, cyano, nitro, -OH, C1-C4 alkyl and -NH2; X, Y are independently selected from: CR 7 R 8 , O and S, wherein at least one of X and Y is CR 7 R 8 ; T is selected from T 1 : U selected from: CR 7 and N; R 1 Selected from: hydrogen, cyano, -OH and C1-C4 alkyl; R 2 Selected from: hydrogen, halogen, cyano; -NR 12 R 13 ; -OR 14 ; -SR 15 ; C1-C6 alkyl, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, -OH, cyano and C1-C4 alkyl; 4- to 10-membered heterocycloalkyl, optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, and C1-C4 alkyl; R 5 Selected from: hydrogen, halogen, cyano and C1-C4 alkyl; R 6 Selected from: hydrogen, halogen, cyano and C1-C4 alkyl; R 7 Selected from: hydrogen, -OH, halogen and C1-C4 alkyl; R 8 Selected from: hydrogen, -OH, halogen and C1-C4 alkyl; R 10 Selected from: hydrogen, -OH and C1-C4 alkyl; R 11 Selected from: hydrogen and C1-C4 alkyl; R 12 and R 13 Independently selected from: Hydrogen, -OH, -NH2; C1-C4 alkyl, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano, C1-C4 alkyl and -NH2; R 14 Selected from: -NH2; C1-C4 alkyl, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano, C1-C4 alkyl and -NH2; R 15 yes: C1-C4 alkyl, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano, C1-C4 alkyl and -NH2; Q is selected from: 6-membered aryl and 5 to 6-membered heteroaryl, each of which is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of halogen; SF5; cyano; C1-C4 alkyl; C1-C4 hydroxyalkyl; C1-C4 haloalkyl having 1 to 5 halogen atoms; and -OH; When Y is O or S, R 7 、R 8 and R 10 are not -OH, and when X is O or S, R 7 and R 8 None of them are -OH.

3. The compound according to claim 1 or 2, and stereoisomers, tautomers and salts thereof, and mixtures thereof, wherein: A is A1, o is 0, 1, or 2; R is selected from the group consisting of: hydrogen, halogen, cyano and C1-C4 alkyl; X, Y are independently selected from: CR 7 R 8 , O and S, wherein at least one of X and Y is CR 7 R 8 ; T is selected from T 1 : U selected from: CR 7 and N; R 1 Selected from: hydrogen and C1-C4 alkyl; R 2 Selected from: hydrogen, halogen, cyano; -NR 12 R 13 ; -OR 14 ; -SR 15 ; C1-C6 alkyl, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, -OH, cyano and C1-C4 alkyl; R 5 Selected from: hydrogen, halogen, cyano and C1-C4 alkyl; R 6 Selected from: hydrogen, halogen, cyano, C1-C4 alkyl; R 7 Selected from: hydrogen, halogen and C1-C4 alkyl; R 8 Selected from: hydrogen, halogen and C1-C4 alkyl; R 10 Selected from: hydrogen, -OH and C1-C4 alkyl; R 11 It is hydrogen; R 12 and R 13 Independently selected from: hydrogen; C1-C4 alkyl, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano, C1-C4 alkyl and -NH2; R 14 Selected from: C1-C4 alkyl, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano, C1-C4 alkyl; R 15 is C1-C4 alkyl, which is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano and C1-C4 alkyl; Q is selected from the group consisting of 6-membered aryl and 5- to 6-membered heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of halogen, cyano, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, and -OH; When Y is O or S, R 10 Not -OH.

4. The compound according to claim 1 or 2, and its stereoisomers, tautomers and salts, and mixtures thereof, wherein: A is A1, o is 0 or 1; R is selected from the group consisting of: hydrogen, halogen, and C1-C4 alkyl; X is selected from: CR 7 R 8 , O and S, Y is CR 7 R 8 ; T is selected from T 1 : U selected from: CR 7 and N; R 1 Selected from: hydrogen and C1-C4 alkyl; R 2 Selected from: Hydrogen, halogens; -NR 12 R 13 ; -OR 14 ; -SR 15 ; C1-C6 alkyl, which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, cyano, C1-C4 alkyl; 4- to 10-membered heterocycloalkyl, optionally substituted with 1, 2, 3, or 4 substituents independently selected from halogen, -OH, and C1-C4 alkyl; R 5 Selected from: hydrogen, halogen and C1-C4 alkyl; R 6 Selected from: hydrogen, halogen and C1-C4 alkyl; R 7 Selected from: hydrogen, halogen and C1-C4 alkyl; R 8 Selected from: hydrogen, halogen and C1-C4 alkyl; R 10 Selected from: hydrogen and C1-C4 alkyl; R 11 Selected from: hydrogen; R 12 and R 13 Independently selected from: hydrogen; C1-C4 alkyl, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, -OH, cyano and C1-C4 alkyl; R 14 Selected from: C1-C4 alkyl, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen and C1-C4 alkyl; R 15 yes C1-C4 alkyl, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl; Q is selected from: 6-membered aryl and 5 to 6-membered heteroaryl, each of which is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from: halogen and C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms.

5. The compound according to claim 1 or 2, and stereoisomers, tautomers and salts thereof, and mixtures thereof, wherein: Q is a substituted benzene ring of formula (Q1) in: Z 1 、Z 2 、Z 3 、Z 4 and Z 5 independently selected from: hydrogen; halogen; SF5; cyano; C1-C4 alkyl; and hydroxyl; or Q is a pyridine ring of formula (Q2) in: Z 6 、Z 7 、Z 8 and Z 9 Independently selected from: hydrogen; halogen; cyano; C1-C4 alkyl; C1-C4 hydroxyalkyl; Q is a pyrimidine ring of formula (Q3) in: Z 10 、Z 11 and Z 12 independently selected from: hydrogen, halogen, cyano and C1-C4 alkyl, or Q is a pyridine ring of formula (Q4) in: Z 13 、Z 14 、Z 15 and Z 16 Independently selected from: hydrogen, halogen, cyano and C1-C4 alkyl, or Q is a pyridine ring of formula (Q5) in: Z 17 、Z 18 、Z 19 and Z 20 Independently selected from the group consisting of: hydrogen, halogen, cyano and C1-C4 alkyl.

6. The compound according to claim 1 or 2, and stereoisomers, tautomers and salts thereof, and mixtures thereof, wherein: A is selected from: T is selected from T 1 : U selected from: CR 7 and N; R 1 Selected from: hydrogen or methyl; R 2 Selected from: Hydrogen, chlorine, fluorine, bromine; -NR 12 R 13 ; -OR 14 ; methyl, ethyl, propyl, isopropyl, each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, chloro, cyano, methyl, ethyl, propyl and isopropyl; a monocyclic heterocycle selected from the group consisting of azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, 1,2,4-triazolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydro-2H-pyranyl, tetrahydropyranyl, 1,2-oxazolidinyl, morpholinyl, thiomorpholinyl, each of which is optionally substituted with 1, 2, 3 or 4 substituents independently selected from fluoro, chloro, -OH and methyl; R 5 Selected from: hydrogen, fluorine, chlorine and methyl; R 6 Selected from: hydrogen, fluorine, chlorine and methyl; R 7 Selected from: hydrogen, fluorine, chlorine and methyl; R 8 Selected from: hydrogen, fluorine, chlorine and methyl; R 10 Selected from: hydrogen and methyl; R 11 Selected from: hydrogen; R 12 and R 13 Independently selected from: hydrogen and methyl; R 14 is methyl; Q is a benzene ring of formula (Q1) in: Z 1 to Z 5 independently selected from the group consisting of: hydrogen, fluorine, chlorine, methyl and trifluoromethyl; or Q is a pyridine ring of formula (Q2) in: Z 6 to Z 9 Independently selected from the group consisting of: hydrogen, fluorine, chlorine, methyl and trifluoromethyl.

7. The compound according to claim 1 or 2, and stereoisomers, tautomers and salts thereof, and mixtures thereof, wherein: Q is a benzene ring of formula (Q1) in: Z 1 、Z 3 and Z 5 independently selected from: hydrogen, fluorine and chlorine; Z 2 and Z 4 independently selected from: hydrogen, fluorine, chlorine and trifluoromethyl; or Q is a pyridine ring of formula (Q2) in: Z 6 to Z 9 Independently selected from: hydrogen, fluorine and chlorine.

8. The compound according to claim 1 or 2, and stereoisomers, tautomers and salts thereof, and mixtures thereof, wherein: A is selected from:

9. The compound according to claim 1 or 2, and stereoisomers, tautomers and salts thereof, and mixtures thereof, wherein: A is selected from: T is selected from T 1 : U selected from: CR 7 and N; R 1 is hydrogen; R 2 Selected from: hydrogen, chlorine; -NR 12 R 13 ; -OR 14 ; methyl, isopropyl; Morpholinyl; R 5 is hydrogen or methyl; R 6 is hydrogen or fluorine; R 7 is hydrogen or methyl; R 8 is hydrogen; R 10 is hydrogen; R 11 is hydrogen; R 12 and R 13 independently selected from: hydrogen and methyl; R 14 is methyl; Q is a benzene ring of formula (Q1) in: Z 1 、Z 3 and Z 5 independently selected from: hydrogen, fluorine and chlorine; Z 2 and Z 4 independently selected from: hydrogen, fluorine, chlorine and trifluoromethyl; or Q is a pyridine ring of formula (Q2) in: Z 6 to Z 9 are independently selected from hydrogen and chlorine.

10. The compound according to claim 1 or 2, and stereoisomers, tautomers and salts thereof, and mixtures thereof, wherein: A is:

11. The compound according to claim 1, wherein the compound is selected from the group consisting of:

12. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 11 and one or more pharmaceutically acceptable excipients.

13. Use of a compound of formula (I) according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12 for the preparation of a medicament for controlling helminth infections in humans and / or animals.

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