Pyrazinamide derivatives

Abstract

The present invention relates to pyrazinamide derivative compounds, such as those according to formula (I), and compositions comprising said compounds. The present invention also provides such pyrazinamide derivative compounds for use in the treatment of Plasmodium-associated diseases, such as malaria. [Formula 1] JPEG2025509917000222.jpg35170

Description

[Technical field]

[0001] The present invention provides pyrazinamide derivative compounds, and compositions comprising said compounds. The present invention also provides such pyrazinamide derivative compounds for use in the treatment of parasite-related diseases, such as malaria. [Background technology]

[0002] Malaria is an infectious disease caused by four parasitic protozoan species: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malaria. These four parasites are typically transmitted by the bite of infected female Anopheles mosquitoes. Malaria is a problem in many parts of the world, and the burden of malaria has been steadily increasing over the past few decades. An estimated 1-3 million people die from malaria each year, mostly children under the age of five. This rising mortality from malaria is due in part to the fact that the most deadly malaria parasite, Plasmodium falciparum, has developed resistance to nearly all available antimalarial drugs, and resistance to even artemisinin is emerging.

[0003] WO 2011 / 143419 discloses various pyrazines used as ataxia telangiectasia mutated (ATM) and Rad3-related (together ATR) kinase inhibitors.However, in the case of treating malaria, there is a need for targeted therapy that can be selective (i.e., can more selectively inhibit a certain target molecule compared to other molecular targets (e.g., ATR kinase), as described below), which can have the advantage of reducing side effects and can selectively treat malaria.

[0004] In view of the above, there remains a need to develop new compounds as selective antiparasitic agents. The present invention provides such compounds, their pharmaceutically acceptable salts, their solid forms, their pharmaceutical compositions, and their combinations. The present invention further provides a method of treating, preventing, or ameliorating a parasitic disease, comprising administering to a subject in need thereof an effective amount of a compound of the present invention. Summary of the Invention

[0005] According to one aspect of the present invention, a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, R 1 is i) H or ii) (C1-C3) alkyl; portion: [ka] teeth, [ka] is selected from the group consisting of R 2 is i) C1-C3 alkyl, ii) halo, iii) hydrogen, iv) C1-C3 haloalkyl, or v) cyano; each X 2 are independently N and CR 3 With the proviso that at least one X 2 CR 3 and; Each R 3are independently hydrogen, halo, SF5, C1-C3 alkyl, hydroxyl, cyano, O-C1-C3 alkyl, SO2-C1-C3 alkyl, C(O)O-C1-C3 alkyl, O-C1-C3 haloalkyl, C1-C3 haloalkyl, CH2NH2, OCH2C6H5, C(O)-N(H)-C1-C4 alkylene-NH2, and [ka] is selected from the group consisting of R 4 is C1-C3 alkyl, C(O)N(R 5 )2, or CO2C1-C3 alkyl; Each R 5 is independently H or C1-C3 alkyl; Each R 6 is H or two R 6 the groups together form an oxo; Each R 7 is independently selected from the group consisting of H and C1-C3 alkyl; L 1 is i) absent or ii) optionally OH or C 3~ C1-C5 alkylene substituted with C6 cycloalkyl; X 1 i) H, ii) OH, iii) NH2, iv) a) a C3-C6 cycloalkyl substituted with an NH2 substituent, b) a C3-C6 cyclohaloalkyl substituted with an NH2 substituent, or c) a 4-6 membered heterocyclyl containing one heteroatom selected from O and N, wherein the 4-6 membered heterocyclyl is substituted with NH2, or [ka] (wherein Z is N or CH, Y is O or NH, n is 1 or 2, and m is 1 or 2). and However, L1 If does not exist, then X 1 is not H, OH, or NH2, A compound or a pharma- ceutically acceptable salt thereof is provided.

[0006] According to a second aspect of the present invention there is provided a compound according to the first aspect of the present invention, or a pharma- ceutically acceptable salt thereof, for use as a medicament.

[0007] According to a third aspect of the present invention there is provided a compound according to the first aspect of the present invention, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a Plasmodium associated disease.

[0008] According to a fourth aspect of the invention there is provided the use of a compound according to the first aspect of the invention, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a Plasmodium associated disease.

[0009] According to a fifth aspect of the present invention there is provided a method of treating a Plasmodium associated disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the first aspect of the present invention, or a pharma- ceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] According to a sixth aspect of the present invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect of the present invention, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers.

[0011] Accordingly, the present invention provides the following numbered embodiments: It will be appreciated that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention.

[0012] Embodiment 1. Formula (I): [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, R 1 is i) H or ii) (C1-C3) alkyl; portion: [ka] teeth, [ka] is selected from the group consisting of R 2 is i) C1-C3 alkyl, ii) halo, iii) hydrogen, iv) C1-C3 haloalkyl, or v) cyano; each X 2 are independently N and CR 3 With the proviso that at least one X 2 CR 3 and; Each R 3 are independently hydrogen, halo, SF5, C1-C3 alkyl, hydroxyl, cyano, O-C1-C3 alkyl, SO2-C1-C3 alkyl, C(O)O-C1-C3 alkyl, O-C1-C3 haloalkyl, C1-C3 haloalkyl, CH2NH2, OCH2C6H5, C(O)-N(H)-C1-C4 alkylene-NH2, and [ka] is selected from the group consisting of R 4 is C1-C3 alkyl, C(O)N(R 5 )2, or CO2C1-C3 alkyl; Each R 5 is independently H or C1-C3 alkyl; Each R 6 is H or two R 6 the groups together form an oxo; Each R 7is independently selected from the group consisting of H and C1-C3 alkyl; L 1 is i) absent or ii) optionally OH or C 3~ C1-C5 alkylene substituted with C6 cycloalkyl; X 1 i) H, ii) OH, iii) NH2, iv) a) a C3-C6 cycloalkyl substituted with an NH2 substituent, b) a 3-C6 cyclohaloalkyl substituted with an NH2 substituent, or c) a 4-6 membered heterocyclyl containing one heteroatom selected from O and N, and substituted with NH2; or [ka] (wherein Z is N or CH, Y is O or NH, n is 1 or 2, and m is 1 or 2). and However, L 1 If does not exist, then X 1 is not H, OH, or NH2, A compound or a pharma- ceutically acceptable salt thereof.

[0013] Embodiment 3. At least two X 2 CR 3 or a pharma- ceutically acceptable salt thereof.

[0014] Embodiment 4. At least three X 2 CR 3 or a pharma- ceutically acceptable salt thereof.

[0015] Embodiment 5.R 1 is H; or a pharma- ceutically acceptable salt thereof.

[0016] Embodiment 6.L 1 or a pharma- ceutically acceptable salt thereof.

[0017] Embodiment 7.L 1 is unsubstituted C1-C5 alkylene; or a pharma- ceutically acceptable salt thereof.

[0018] Embodiment 8.L 1 is unsubstituted C4 alkylene; or a pharma- ceutically acceptable salt thereof.

[0019] Embodiment 9.X 1 teeth, i) NH2, ii) a) a C3-C6 cycloalkyl substituted with NH2, b) a C3 cyclohaloalkyl substituted with NH2, or c) a 4-6 membered heterocyclyl containing one heteroatom selected from O and N, wherein the 4-6 membered heterocyclyl is substituted with NH2, or [ka] (wherein Z is CH, Y is NH, n is 1 or 2, and m is 1 or 2). or a pharma- ceutically acceptable salt thereof.

[0020] Embodiment 10.X 1 is NH2, or a pharma- ceutically acceptable salt thereof.

[0021] Embodiment 11. Part: [ka] teeth, [ka] or a pharma- ceutically acceptable salt thereof.

[0022] Embodiment 12. Part [ka] teeth, [ka] or a pharma- ceutically acceptable salt thereof.

[0023] Embodiment 13. R 2 is CH3, or a pharma- ceutically acceptable salt thereof.

[0024] Embodiment 14. portion: [ka] teeth, [ka] or a pharma- ceutically acceptable salt thereof.

[0025] Embodiment 15. Part: [ka] teeth, [ka] or a pharma- ceutically acceptable salt thereof.

[0026] Embodiment 16. Part: [ka] teeth, [ka] or a pharma- ceutically acceptable salt thereof.

[0027] Embodiment 17. Part: [ka] teeth, [ka] or a pharma- ceutically acceptable salt thereof.

[0028] Embodiment 18. Part: [ka] teeth, [ka] or a pharma- ceutically acceptable salt thereof.

[0029] Embodiment 19. Part: [ka] teeth, [ka] or a pharma- ceutically acceptable salt thereof.

[0030] 20. Part of embodiment 20: [ka] teeth, [ka] and p is 0, 1, 2, 3, or 4; 3 are independently halo, SF5, methyl, hydroxyl, cyano, OMe, SO2Me, C(O)OMe, O-C1 haloalkyl, C1 haloalkyl, CH2NH2, OCH2C6H5, C(O)-N(H)-C1-C4 alkylene-NH2, and [ka] or a pharma- ceutically acceptable salt thereof.

[0031] Embodiment 21. A compound according to any of the embodiments herein, wherein p is 0, 1, or 2; or a pharma- ceutically acceptable salt thereof.

[0032] Embodiment 22. A compound according to any of the embodiments herein, wherein p is 1 or 2; or a pharma- ceutically acceptable salt thereof.

[0033] Embodiment 23. Each R 3 or a pharma- ceutically acceptable salt thereof.

[0034] 24. Part of embodiment 24: [ka] teeth, [ka] or a pharma- ceutically acceptable salt thereof.

[0035] 25. Part of embodiment 25: [ka] teeth, [ka] or a pharma- ceutically acceptable salt thereof.

[0036] Embodiment 26.R 3 is halo, OCF3, SF5, or OCHF2, or a pharma- ceutically acceptable salt thereof.

[0037] Embodiment 27.R 3 or a pharma- ceutically acceptable salt thereof.

[0038] 28. Part of embodiment 28: [ka] teeth, [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0039] 29. N-(2-amino-2-methylpropyl)-6-(6-chloro-7-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-methyl-5-(pentafluoro-lambda 6 -sulfanayl)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-chloro-7-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-chloro-5-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-chloro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-((1-aminocyclobutyl)methyl)-6-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-methyl-6-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-((1S,2S)-2-aminocyclopentyl)-6-(6-chloro-5-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(3-amino-3-methylbutyl)-6-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-methyl-6-(pentafluoro-lambda 6 -sulfanayl)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-chloro-6-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-chloro-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3,6-dimethyl-1H-indol-2-yl)pyrazine-2-carboxamide; Ethyl 5-(6-((2-amino-2-methylpropyl)carbamoyl)pyrazin-2-yl)-6-methyl-4H-thieno[3,2-b]pyrrole-2-carboxylate; N-(2-amino-2-methylpropyl)-6-(5-bromo-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-(4-aminopiperidin-1-yl)ethyl)-6-(6-chloro-5-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-chloro-7-fluoro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-chloro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-chloro-7-fluoro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-(difluoromethoxy)-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-cyclopropylethyl)-6-(6-chloro-5-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-(difluoromethoxy)-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-(pentafluoro-lambda 6 -sulfanayl)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-aminoethyl)-6-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-chloro-5-fluoro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3,5-dimethyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-((4-aminotetrahydro-2H-pyran-4-yl)methyl)-6-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-((4-aminotetrahydro-2H-pyran-4-yl)methyl)-6-(6-chloro-5-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; (S)-N-(2-amino-2-cyclopropylethyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; Methyl 2-(6-((2-amino-2-methylpropyl)carbamoyl)pyrazin-2-yl)-3-methyl-1H-indole-5-carboxylate; (R)-N-(2-amino-2-cyclopropylethyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-isopropyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-((1-aminocyclopropyl)methyl)-6-(6-chloro-5-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-((1-aminocyclobutyl)methyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-((1-amino-3,3-difluorocyclobutyl)methyl)-6-(6-chloro-5-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(2,6-dimethyl-4H-thieno[3,2-b]pyrrolo-5-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-chloro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-N-methyl-6-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-chloro-6-fluoro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-(trifluoromethyl)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-chloro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(3-aminopropyl)-6-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(3-amino-3-methylbutyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-ethyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5,6-difluoro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-isopropyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-fluoro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(3-aminobicyclo[1.1.1]pentan-1-yl)-6-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-(benzyloxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5,7-difluoro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(7-fluoro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-fluoro-1H-indol-2-yl)pyrazine-2-carboxamide; Ethyl 5-(6-((2-amino-2-methylpropyl)carbamoyl)pyrazin-2-yl)-4H-thieno[3,2-b]pyrrole-2-carboxylate; N-(2-aminoethyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(3-aminobicyclo[1.1.1]pentan-1-yl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(1-amino-2-methylpropan-2-yl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(7-chloro-1H-indol-2-yl)pyrazine-2-carboxamide; N-((4-aminotetrahydro-2H-pyran-4-yl)methyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; Methyl 2-(6-((2-amino-2-methylpropyl)carbamoyl)pyrazin-2-yl)-1H-indole-6-carboxylate; N-((1r,4r)-4-aminocyclohexyl)-6-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; Methyl 2-(6-((2-amino-2-methylpropyl)carbamoyl)pyrazin-2-yl)-1H-indole-5-carboxylate; N-(2-amino-2-methylpropyl)-6-(3-(trifluoromethyl)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(3-aminopropyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(azetidin-3-yl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(4-methoxy-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-methoxy-1H-indol-2-yl)pyrazine-2-carboxamide; N-(3-aminocyclopentyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(4,5,6,7-tetrahydro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-methoxy-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-N-methyl-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-cyano-1H-indol-2-yl)pyrazine-2-carboxamide; 6-(3-methyl-1H-indol-2-yl)-N-(piperidin-4-yl)pyrazine-2-carboxamide; N-(2-amino-3-hydroxypropyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-((3-aminooxetan-3-yl)methyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-cyano-1H-indol-2-yl)pyrazine-2-carboxamide; 6-(3-methyl-1H-indol-2-yl)-N-(2-methyl-2-morpholinopropyl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-fluoro-6-methoxy-1H-indol-2-yl)pyrazine-2-carboxamide; N-((1r,4r)-4-aminocyclohexyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)pyrazine-2-carboxamide; N-((1r,4r)-4-aminocyclohexyl)-6-(5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5,7-dichloro-1H-pyrrolo[2,3-c]pyridin-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-chloro-1H-pyrrolo[3,2-c]pyridin-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(4-chloro-1H-pyrrolo[3,2-c]pyridin-2-yl)pyrazine-2-carboxamide; (rac)-N-((1r,2s)-2-aminocyclohexyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; (rac)-N-((3r,4s)-4-aminotetrahydrofuran-3-yl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-cyano-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-methyl-5-(2-oxopyrrolidin-1-yl)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-methyl-5-(methylsulfonyl)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-hydroxy-2-methylpropyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; (rac)-N-((1r,2r)-2-aminocyclohexyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; 6-(3-methyl-1H-indol-2-yl)-N-neopentylpyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(7-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(1H-pyrrolo[2,3-c]pyridin-2-yl)pyrazine-2-carboxamide; 5-(6-((2-amino-2-methylpropyl)carbamoyl)pyrazin-2-yl)-4H-thieno[3,2-b]pyrrole-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-(aminomethyl)-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-phenyl-1H-pyrrol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-fluoro-6-hydroxy-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(7-methoxy-1H-indol-2-yl)pyrazine-2-carboxamide; 5-(6-((2-amino-2-methylpropyl)carbamoyl)pyrazin-2-yl)-N,N-dimethyl-4H-thieno[3,2-b]pyrrole-2-carboxamide; and pharma- ceutically acceptable salts thereof. The compound according to any of the embodiments herein selected from the group consisting of:

[0040] Embodiment 30. Formula (IIa): (IIa). [ka] or a pharma- ceutically acceptable salt thereof, according to any of the embodiments herein.

[0041] Embodiment 31. Formula (IIb): [ka] or a pharma- ceutically acceptable salt thereof, according to any of the embodiments herein.

[0042] Embodiment 32. Formula (IIc): (IIc). [ka] or a pharma- ceutically acceptable salt thereof, according to any of the embodiments herein.

[0043] Embodiment 33. A compound according to any of the embodiments herein or a pharma- ceutically acceptable salt thereof for use as a medicament.

[0044] Embodiment 34. A compound or a pharma- ceutically acceptable salt thereof according to any of the embodiments herein for use in treating a Plasmodium associated disease.

[0045] Embodiment 35. Use of a compound according to any of the embodiments herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a Plasmodium associated disease.

[0046] Embodiment 36. A method of treating a Plasmodium associated disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the embodiments herein.

[0047] Embodiment 37. The compound for use according to any of the embodiments herein, the use according to any of the embodiments herein, wherein the Plasmodium associated disease is malaria.

[0048] Embodiment 38. A compound for use according to any of the embodiments herein, a use according to any of the embodiments herein, or a method according to any of the embodiments herein, wherein the compound according to any of the embodiments herein is administered in combination with one or more therapeutically active agents.

[0049] Embodiment 39. A compound for use according to any of the embodiments herein, a use according to any of the embodiments herein, or a method according to any of the embodiments herein, wherein the compound according to any of the embodiments herein is administered prior to, simultaneously with, or after a therapeutically active agent.

[0050] Embodiment 40. A compound, use, or method for use according to any of the embodiments herein, wherein the therapeutically active agent is selected from a kinase inhibitor, an antimalarial agent, and an anti-inflammatory agent.

[0051] Embodiment 41. The compound, use, or method for use according to any of the embodiments herein, wherein the active agent is an antimalarial selected from proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amoxicilloquine, sulfonamides, artemisinin, artefren, artemether, artesunate, primaquine, pyronaridine, KAE-609, KAF-156, and INE963.

[0052] Embodiment 42 The method according to any of the embodiments herein, wherein the subject is a human.

[0053] Embodiment 43. A pharmaceutical composition comprising a compound according to any of the embodiments herein and one or more pharma- ceutically acceptable carriers.

[0054] It is understood that any of the elements recited in the above numbered embodiments may be selected individually and / or combined with one another, as well as other embodiments of the present invention.

[0055] definition For the purposes of interpreting this specification, the following definitions shall apply unless otherwise specified, and where appropriate, terms used in the singular shall also include the plural and vice versa. It must be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural unless the context clearly dictates otherwise.

[0056] Thus, for example, reference to "a compound" includes reference to one or more compounds, and the like.

[0057] As used herein, the term "substituent" refers to a radical group that replaces a hydrogen atom in a given molecule.

[0058] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation and attached to the remainder of the molecule by a single bond. By way of example, a C1-C3 alkyl contains 1 to 3 carbon atoms. C1-C3-alkyl includes methyl (Me), ethyl (Et), n-propyl, and 1-methylethyl (iso-propyl).

[0059] As used herein, the terms "halogen," "halo," "hal" and the like refer to fluorine, chlorine, bromine, or iodine. Halogen-substituted groups and moieties, such as halogen-substituted alkyls (haloalkyls), can be mono-, poly-, or per-halogenated.

[0060] As used herein, the term "haloalkyl" refers to an alkyl radical, as defined herein, in which one or more of the hydrogen atoms of said alkyl are replaced by a halogen atom. In some embodiments, said one or more halogen atoms are each a fluorine atom, in which case "haloalkyl" is a "fluoroalkyl."

[0061] As used herein, the term "alkylene" refers to a divalent radical of a straight-chain or branched alkyl group. By way of example, a "C1-C5 alkylene" contains 1 to 5 carbon atoms (e.g., -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)2-, -CH(CH3)CH2CH2CH2-, etc.).

[0062] As used herein, the term "cycloalkyl" refers to a saturated carbocyclic ring radical. A C3-C6 cycloalkyl is any such ring radical containing from 4 to 6 carbon atoms (i.e., cyclobutyl, cyclopentyl, and cyclohexyl). A C3 cycloalkyl is a ring radical containing 3 carbon atoms (i.e., cyclopropyl). A cycloalkyl can be a monocyclic or polycyclic ring, such as a fused or bridged bicyclic ring system (e.g., cycloalkyl ... [ka] However, in some embodiments, a cycloalkyl is a monocyclic ring. As used herein, the term "cycloalkylene" refers to a divalent radical of a cycloalkyl group, such as [ka] )

[0063] As used herein, the term "cyclohaloalkyl" refers to a saturated carbocyclic ring radical in which one or more of the hydrogen atoms of the alkyl are replaced by a halogen atom (e.g., fluorine, chlorine). As used herein, the term "cyclohaloalkylene" refers to a divalent radical of a cyclohaloalkyl (e.g., [ka] )

[0064] A cyclohaloalkyl can be a monocyclic ring or a polycyclic ring, such as a fused or bridged bicyclic ring system, hi some embodiments, a cyclohaloalkyl is a monocyclic ring.

[0065] As used herein, terms such as "heterocyclyl", "heterocycle", "heterocyclic" refer to heterocyclic radicals that are saturated or partially unsaturated (in some embodiments, saturated) but not aromatic and may be monocyclic or polycyclic rings, such as fused or bridged bicyclic ring systems. In some embodiments, the heterocycle is a monocyclic ring. In some embodiments, the heterocycle is saturated. A heterocyclyl contains at least one non-carbon atom (typically N, O, or S, unless otherwise specified) as a ring member, and thus the remaining ring atoms are carbon. A (n-unsaturated) heterocyclyl contains S as a heteroatom, which S may be in the form of S, SO, or SO2. In some embodiments, the heteroatom is O or N. The term "4-6 membered heterocyclyl containing one heteroatom selected from O and N" refers to a ring radical containing 4-6 ring atoms, including one heteroatom (either O or N), and the remaining ring atoms are carbon. As used herein, the term "heterocyclylene" refers to a divalent radical of "heterocyclyl." Examples include 4-6 membered heterocyclylene containing one heteroatom selected from O and N: [ka] Examples include:

[0066] Depending on the selection of starting materials and procedures, the compounds may exist in one of the possible stereoisomers or as a mixture thereof, for example as a pure optical isomer depending on the number of asymmetric carbon atoms, or as a mixture of stereoisomers, such as racemic and diastereomeric mixtures. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents or separated using conventional techniques. When the compounds contain double bonds, the substituents may be in the E or Z configuration. When the compounds contain disubstituted cycloalkyl, the cycloalkyl substituents may have the cis or trans configuration. All tautomeric forms are also intended to be included.

[0067] As used herein, the term "salt" or "salts" refers to an acid addition salt or base addition salt of a compound of the invention. "Salt" specifically includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the invention and are typically not biologically or otherwise undesirable. In many cases, the compounds of the invention are capable of forming acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. When both basic and acidic groups are present in the same molecule, the compounds of the invention can also form internal salts (e.g., zwitterionic molecules).

[0068] Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order. The use of any examples or exemplary language (e.g., "etc.") provided herein is intended merely to further clarify the invention and does not limit the scope of the invention unless otherwise asserted.

[0069] Description of the embodiments The present invention provides a novel class of compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with parasites. In particular, the compounds may be used to treat malaria.

[0070] In some embodiments, with respect to compounds of formula (I), R 1 is H or CH. In one embodiment, R 1 is H.

[0071] In some embodiments, with respect to compounds of formula (I), R 2 is selected from C1-C3 alkyl, Cl, hydrogen, C1 fluoroalkyl (e.g., CF3), and cyano. 2 is CH3.

[0072] In some embodiments, with respect to compounds of formula I, the moiety: [ka] For example, [ka] Selected from the group consisting of [ka] It is.

[0073] In some embodiments, with respect to compounds of formula I, the moiety: [ka] For example, [ka] Selected from the group consisting of [ka] It is.

[0074] In some embodiments, the moiety: [ka] teeth, [ka] where each X 2 are independently N and CR 3 With the proviso that at least one X 2 CR 3 In some embodiments, at least two X 2 are CR 3 In some embodiments, at least three X 2 are CR 3 In some embodiments, all four X 2 are CR 3 It is.

[0075] In some embodiments, the moiety: [ka] teeth, [ka] is selected from the group consisting of:

[0076] In some embodiments, the moiety: [ka] teeth, [ka] and p is 0, 1, 2, 3, or 4; 3 are independently halo, SF5, methyl, hydroxyl, cyano, OMe, SO2Me, C(O)OMe, O-C1 haloalkyl, C1 haloalkyl, CH2NH2, OCH2C6H5, C(O)-N(H)-C1-C4 alkylene-NH2, and [ka] is selected from the group consisting of:

[0077] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1 or 2. In some embodiments, each R 3 is independently selected from the group consisting of halo, OC1 haloalkyl, SF5, methyl, and C(O)OMe.

[0078] In some embodiments, the moiety: [ka] teeth, [ka] It is.

[0079] In some embodiments, the moiety: [ka] teeth, [ka] It is.

[0080] In some embodiments, R 3 is halo, OCF, SF, or OCHF. In some embodiments, R3 is SF5.

[0081] In some embodiments, the moiety: [ka] teeth, [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0082] In some embodiments, the moiety: [ka] teeth, [ka] It is.

[0083] In some embodiments, L 1 is C1-C5 alkylene optionally substituted with OH or C3 cycloalkyl. 1 is unsubstituted C1-C5 alkylene. 1 is an unsubstituted C4 alkylene.

[0084] In some embodiments, X 1 teeth, i) NH2, ii) a) a C3-C6 cycloalkyl substituted with NH2, b) a C3-C6 cycloalkyl substituted with NH2 (in some embodiments, a C3-C6 cyclofluoroalkyl), or c) a 4-6 membered heterocyclyl containing one heteroatom selected from O and N, and substituted with NH2; or [ka] wherein Z is CH, Y is NH, n is 1 or 2, and m is 1 or 2 (in some embodiments, n and m are each 1, or n and m are each 2). It is.

[0085] In some embodiments, X 1 is NH2.

[0086] In some embodiments, X 1 teeth, [ka] where Z is CH and Y is NH.

[0087] In some embodiments, [ka] teeth, [ka] [ka] In some embodiments, the moiety is selected from: [ka] teeth, [ka] It is.

[0088] In a further embodiment, the compound is selected from any one of Examples 1-110, or a pharma- ceutically acceptable salt thereof.

[0089] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0090] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0091] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0092] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0093] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table, in certain embodiments the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly suitable salts including the ammonium, potassium, sodium, calcium, and magnesium salts.

[0094] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0095] In another aspect, the present invention provides an ester of an iodide salt, such as acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl salt, or the like. The compound according to any one of the embodiments 1-44+ is provided in the form of a sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate, or xinafoate salt.

[0096] In another aspect, the invention provides a compound according to any one of embodiments 1-44+ in the form of a salt with sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, or tromethamine.

[0097] Any formula shown herein is also intended to represent the unlabeled form of the compound as well as the isotopically labeled form.Isotopically labeled compounds have the structure depicted by the formula shown herein, except that one or more atoms are replaced with atoms having selected atomic mass or mass number.The isotope that can be incorporated in the compound of the present invention includes, for example, hydrogen isotopes.

[0098] Furthermore, the incorporation of certain isotopes, particularly deuterium (i.e., 2H or D), may result in certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life, or reduced dosage requirements, or improved therapeutic index or tolerability). It is understood that deuterium in this context is considered a substituent of the compounds of the invention. The concentration of deuterium may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the invention is designated as deuterium, such compounds have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in a manner similar to that described for deuterium.

[0099] Other examples of isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., 3 H, 11 C. 13 C.14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 Thus, the present invention relates to, for example, 3 H and 14 Radioisotopes such as C, or 2 H and 13 It should be understood to include compounds incorporating one or more of any of the aforementioned isotopes, including those in which non-radioactive isotopes such as C are present. Such isotopically labeled compounds may be used in metabolic studies ( 14 C), reaction rate tests (e.g. 2 H or 3 3H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radiation treatment of patients. 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. The isotopically labeled compounds of the present invention may generally be prepared by conventional techniques known to those skilled in the art, or may be prepared by methods similar to those described in the accompanying examples and preparations, using appropriate isotopically labeled reagents in place of previously used non-labeled reagents.

[0100] Pharmaceutical Compositions As used herein, the term "pharmaceutical composition" refers to a compound of the present invention or a pharma- ceutically acceptable salt thereof, combined with at least one pharma- ceutically acceptable carrier in a form suitable for oral or parenteral administration.

[0101] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful in the preparation or use of a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, as known to those skilled in the art (see, e.g., Remington The Science and Practice of Pharmacy, 22nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

[0102] The term "therapeutically effective amount" of a compound of the invention refers to an amount of a compound of the invention that elicits a biological or medical response in a subject, such as reducing or inhibiting the activity of an enzyme or protein, or ameliorating a symptom, alleviating a condition, slowing or delaying the progression of a disease, or preventing a disease. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that, when administered to a subject, is effective to at least partially alleviate, inhibit, prevent, and / or ameliorate a Plasmodium-associated disease (e.g., malaria).

[0103] As used herein, the term "subject" refers to primates (e.g., humans, male or female), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0104] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the alleviation or suppression of a given condition, symptom, or disorder, or disease, or a significant reduction in the baseline activity of a biological activity or process.

[0105] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or halting the onset of the disease or at least one clinical symptom thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be discernible to the patient.

[0106] As used herein, the terms "prevent", "preventing" or "prevention" with respect to any disease or disorder refers to the prophylactic treatment of the disease or disorder; or the delay in the onset or progression of the disease or disorder.

[0107] As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0108] As used herein, the terms "a," "an," "the," and similar terms used in connection with the present invention, particularly in connection with the claims, are to be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0109] Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order. The use of any examples or exemplary language (e.g., "etc.") provided herein is intended merely to further clarify the invention and does not limit the scope of the invention unless otherwise asserted.

[0110] Any asymmetric atom (e.g., carbon, or the like) of the compounds of the present invention may be present in racemic form or enriched in one enantiomer, for example, in (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has an enantiomeric excess of at least 50%, an enantiomeric excess of at least 60%, an enantiomeric excess of at least 70%, an enantiomeric excess of at least 80%, an enantiomeric excess of at least 90%, an enantiomeric excess of at least 95%, or an enantiomeric excess of at least 99% in the (R)- or (S)-configuration. Substituents at atoms with unsaturated double bonds may be present in cis-(Z)- or trans-(E)-configuration, if possible.

[0111] Thus, as used herein, the compounds of the invention may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof.

[0112] Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional recrystallization on the basis of the physical chemical differences of the constituent components.

[0113] Any resulting racemic forms of the compounds or intermediates of the present invention can be resolved into their optical antipodes by known methods, for example by separating their diastereomeric salts obtained with optically active acids or bases, and liberating the optically active acidic or basic compounds. In particular, compounds of the present invention can be resolved into their optical antipodes by, for example, fractional crystallization of salts formed with optically active acids (e.g., tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid) using such basic moieties. Racemic compounds or racemic intermediates of the present invention can also be resolved by chiral chromatography (e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent).

[0114] Methods of Synthesizing the Compounds of the Invention All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any examples or exemplary language (e.g., "etc.") provided herein is intended merely to further clarify the invention and does not limit the scope of the invention unless otherwise asserted.

[0115] The compounds of the present application may be prepared by one skilled in the art of organic synthesis using commercially available starting materials, using compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art or that will be apparent to the skilled chemist in light of the teachings herein.

[0116] Compounds of formula (I) may be prepared by the methods described in the synthetic reaction schemes below. In the schemes described below, it is fully understood that, in accordance with general principles of chemistry, protective groups for sensitive or reactive groups are used as necessary. Protective groups are manipulated according to standard methods of organic synthesis, for example as described in Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, or Protecting Groups, 3rd edition, Thieme, Stuttgart, 2004. Protective groups are removed at a convenient stage of the compound synthesis using methods readily apparent to those skilled in the art.

[0117] Those skilled in the art will recognize whether a stereocenter exists in the compounds disclosed herein. Resolution of the final product, intermediate, or starting material can be effected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0118] Compounds of the present disclosure may be synthesized according to the steps outlined in Scheme I. Starting materials are either commercially available or prepared by known procedures reported in the literature or as illustrated.

[0119] In the general method below, R 1 , L 1 , X 1 and Ring A are as previously defined in the above embodiments or are limited to the designations in this scheme. Unless otherwise specified, starting materials are commercially available or prepared by known methods.

[0120] Scheme (I). General Method for the Synthesis of Compounds of Formula (I) [ka] Scheme I shows two alternative general methods for synthesizing compounds of formula (I). Alternative 1 begins with the coupling of a 2-halo-pyrazine-6-carboxylic acid with an appropriately substituted amine under standard amide-forming conditions. This amide is then further reacted with an appropriately substituted boronic acid or ester under typical Suzuki coupling conditions. Alternative 2 begins with the transition metal catalyzed coupling of an appropriately substituted boronic acid or ester with a 2-halo-pyrazine-6-carboxylic acid ester, which is simultaneously hydrolyzed to the carboxylic acid. The resulting acid can be reacted with an appropriately substituted amine under standard amide-forming conditions. Finally, the amine resulting from either alternative can be deprotected using conditions typical for the N-Boc group, such as trifluoroacetic acid or formic acid.

[0121] Detailed descriptions of the synthesis of the compounds of the present invention are provided in the Examples below.

[0122] The invention further includes any variation of this process, in which an intermediate product obtained at any stage thereof is used as a starting material to carry out the remaining steps, or the starting material is formed in situ under the reaction conditions, or the reaction components are used in the form of their salts or are optically pure substances. The compounds of the invention and intermediates may also be converted into each other according to methods generally known to those skilled in the art.

[0123] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. In a further embodiment, the composition comprises at least two pharma- ceutically acceptable carriers, such as those described herein. The pharmaceutical composition may be formulated for a particular route of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal, or topical administration), and rectal administration. Topical administration may also be suitable for inhalation or nasal administration. The pharmaceutical composition of the present invention may be composed of a solid formulation (e.g., but is not limited to, capsules, tablets, pills, granules, powders, or suppositories), or a liquid formulation (e.g., but is not limited to, solutions, suspensions, or emulsions). Tablets may be film-coated or enteric-coated according to methods known in the art.

[0124] Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient in combination with one or more of the following: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol; c) in the case of tablets, additional binders, such as, for example, magnesium aluminum silicate, starch paste, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone; if desired, d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) Absorbents, colourants, flavourings and sweeteners.

[0125] Methods of using the present invention The compounds of formula (I), (IIa), (IIb), (IIc) and (IId), in free form or in pharma- ceutically acceptable salt form, exhibit useful pharmacological properties, e.g., in the treatment of Plasmodium-associated diseases (e.g., malaria), as shown, e.g., in the in vitro tests described in the following paragraphs, and are therefore suitable for therapy or adapted for use as research chemicals (e.g., tool compounds).

[0126] The compounds of the invention may have activity against protein kinases, but are relatively inactive against certain protein kinases, such as ataxia telangiectasia mutated (ATM) and Rad3-related (together ATR) kinases.

[0127] The compounds of the invention are useful in the treatment and / or prevention of infections such as those caused by Plasmodium falciparum; Plasmodium vivax; Plasmodium ovale; and Plasmodium malaria, Trypanosoma cruzi, and Leishmania parasites (e.g., Leishmania donovani).

[0128] Malaria is an infectious disease caused by four parasitic protozoan species: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malaria. These four parasites are typically transmitted by the bite of infected female Anopheles mosquitoes. Malaria is a problem in many parts of the world, and the burden of malaria has been steadily increasing over the past few decades. An estimated 1-3 million people die from malaria each year, mostly children under the age of five. This rising mortality from malaria is due in part to the fact that the most deadly malaria parasite, Plasmodium falciparum, has developed resistance to nearly all available antimalarial drugs, and resistance to even artemisinin is emerging.

[0129] The phylum Apicomplexa includes many members that are human or animal pathogens, including, but not limited to, Plasmodium spp. (malaria), Toxoplasma gondii (human congenital neurological disorder), Eimeria spp. (poultry and cattle pathogens), Cryptosporidia (opportunistic human and animal pathogens), Babesia (bovine parasites), and Theileria (bovine parasites). The pathogenesis associated with these parasitic diseases results from repeated cycles of host cell invasion, intracellular replication, and host cell lysis. Thus, understanding parasite proliferation is essential for the development of new drugs and vaccines to treat, for example, malaria.

[0130] In the vertebrate host, the parasite undergoes two main developmental stages, the hepatocellular and the erythrocytic stage of the life cycle, during which the severe pathology occurs. During the erythrocytic stage, the parasite undergoes a complex but well-synchronized series of stages, suggesting the existence of tightly regulated signaling pathways.

[0131] In accordance with the above, the present invention further provides a method of preventing or treating malaria in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), a compound of the Examples, or a pharma- ceutically acceptable salt thereof. The dosage required will vary depending on the mode of administration, the particular condition to be treated, and the effect desired.

[0132] The pharmaceutical composition or combination of the present invention may be, for example, a unit dose of about 1-1000 mg of active ingredient for a subject of about 50-70 kg. The therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition of the subject, the disorder or disease being treated, or its severity. A physician, clinician, or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the progression of the disorder or disease.

[0133] Combination Products and Combination Therapies of the Invention "Combination" refers to a fixed combination in one unit dosage form, or to combined administration in which the compound of the invention and a combination partner (e.g., another drug, as described below, also referred to as a "therapeutic agent" or "adjunct") may be administered independently at the same time or separately within a time interval (especially where these time intervals allow the combination partners to exhibit a cooperative effect, e.g., a synergistic effect). The single components may be packaged as a kit or may be packaged separately. One or both of the components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose before administration. The terms "co-administration" or "combined administration" or the like, as used herein, are meant to encompass administration of selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination" as used herein means a product resulting from the mixing or combination of multiple therapeutic agents, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that both therapeutic agents (e.g., a compound of the present invention and a combination partner) are administered to a patient at the same time in the form of a single entity or dosage. The term "non-fixed combination" means that both therapeutic agents (e.g., a compound of the present invention and a combination partner) are administered to a patient as separate entities simultaneously, in parallel, or sequentially without specific time limitations, such administration resulting in therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy (e.g., administration of three or more therapeutic agents).

[0134] The term "pharmaceutical combination", as used herein, refers to a fixed combination or a non-fixed combination or kit-of-parts in one unit dosage form for combined administration in which two or more therapeutic agents may be administered independently at the same time or separately within time intervals (especially those time intervals which allow the combination partners to exhibit a cooperative effect, e.g., a synergistic effect).

[0135] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration includes co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule with a fixed ratio of active ingredients. Alternatively, such administration includes co-administration in multiple or separate containers (e.g., tablets, capsules, powders, and liquids) for each active ingredient. The powders and / or liquids can be reconstituted or diluted to the desired dose prior to administration.

[0136] In addition, such administration also encompasses the use of each type of therapeutic agent in a sequential manner, either at about the same time or at different times, in either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0137] In further embodiments, the second agent is selected from a kinase inhibitor, an antimalarial agent, and an anti-inflammatory agent. The antimalarial agent is selected from proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amphopiroquine, sulfonamides, artemisinin, artefren, artemether, artesunate, primaquine, pyronaridine, KAE-609, KAF-156, and INE963.

[0138] The compound of the present invention may be administered either simultaneously with, before, or after one or more other therapeutic agents.The compound of the present invention may be administered separately by the same or different administration route as the other agent, or may be administered together in the same pharmaceutical composition as the other agent.The therapeutic agent is, for example, a compound, peptide, antibody, antibody fragment, or nucleic acid that is therapeutically active or enhances therapeutic activity when administered to a patient in combination with the compound of the present invention.

[0139] Therefore, in another aspect, the present invention provides a combination (particularly a pharmaceutical combination) comprising a compound of any one of formulae (I), (IIa), (IIb), (IIc) and (IId) (particularly a compound according to any one of embodiments 1-44+), or a pharma- ceutically acceptable salt thereof (such as a therapeutically effective amount), and one or more other therapeutically active agents.

[0140] In one embodiment, the invention provides a product comprising a compound of any one of formulae (I), (IIa), (IIb), (IIc) and (IId), or a pharma- ceutically acceptable salt thereof (in particular a compound according to any one of embodiments 1-44+), and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.

[0141] In one embodiment, the present invention provides a pharmaceutical combination comprising a compound of any one of formulae (I), (IIa), (IIb), (IIc), and (IId), or a pharma- ceutically acceptable salt thereof, particularly a compound according to any one of embodiments 1-44+, and another therapeutic agent. Optionally, the pharmaceutical combination may include a pharma- ceutically acceptable carrier, as described above.

[0142] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of any one of formulae (I), (IIa), (IIb), (IIc), and (IId), or a pharma- ceutically acceptable salt thereof, particularly a compound according to any one of embodiments 1-44+. In one embodiment, the kit comprises a means for separately holding the compositions, such as a container, a divided bottle, or a divided foil packet. An example of such a kit is a blister pack, such as those commonly used for packaging tablets, capsules, and the like.

[0143] The kits of the invention may be used to administer various dosage forms (e.g., oral and parenteral), may be used to administer separate compositions at various dosage intervals, or may be used to titrate separate compositions from one another. To aid in compliance, the kits of the invention typically include directions for administration.

[0144] In the combination therapy of the invention, the compound of the invention and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compound of the invention and the other therapeutic agent may be combined into a combination therapy: (i) prior to delivery of the combination product to the physician (e.g., in the case of a kit containing the compound of the invention and the other therapeutic agent); (ii) by the physician (or under the physician's guidance) immediately prior to administration; or (iii) in the patient himself, e.g., during sequential administration of the compound of the invention and the other therapeutic agent. EXAMPLES

[0145] The present disclosure is further illustrated by the following examples and synthetic methods, which should not be construed as limiting the present disclosure in scope or spirit to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments, and are not intended to limit the scope of the present disclosure. In addition, it should be understood that various other embodiments, modifications, and equivalents thereof, which may suggest themselves to those skilled in the art, may be used without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0146] The compounds of the invention may be produced by organic synthesis methods known to those skilled in the art, as shown in the examples below. All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the invention are commercially available or may be produced by organic synthesis methods known to those skilled in the art. It is understood that in all methods, protecting groups for sensitive or reactive groups may be used as necessary, in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (TW Green and PG M Huts (2014) Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods readily apparent to those skilled in the art. Unless otherwise noted, reagents and solvents were used as received from commercial suppliers.

[0147] Chemical names were generated using PerkinElmer's ChemDraw Professional v17.1.0.105.

[0148] Temperatures are given in degrees Celsius. As used herein, unless otherwise specified, the term "room temperature" or "ambient temperature" means a temperature between 15°C and 30°C, such as between 20°C and 30°C, for example between 20°C and 25°C. Unless otherwise stated, all evaporations are carried out under reduced pressure, typically between about 15mmHg and 100mmHg (=20-133mbar). The structures of final products, intermediates, and starting materials are confirmed by standard analytical methods, such as microanalysis or spectroscopic characteristics, such as MS, IR, NMR. Abbreviations used are conventional in the art.

[0149] Abbreviation Abbreviations used in the examples below and elsewhere in the specification are as follows: AcOH Acetic acid B2Pin2 Bis(pinacolato)diboron br Wide range of signals B(Oi Pr) 3 Triisopropyl borate (Boc)2O Di-tert-butyl dicarbonate d doublet CH2Cl2Dichloromethane i-Pr2NEt Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF Dimethylformamide DMSO Dimethyl sulfoxide dtbpy Di-tert-butyl-2.2'-dipyridyl eq.equivalent Et3N Triethylamine Et2O Diethyl ether EtOAc Ethyl acetate EtOH Ethanol h time H2O Water HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate i-PrOH 2-Propanol [Ir(cod)OMe]2(1,5-cyclooctadiene)(methoxy)iridium(I) dimer KHSO4 Potassium hydrogen sulfate K2CO3 Potassium Carbonate K3PO4 Tribasic Potassium Phosphate KOAc Potassium Acetate KOH Potassium hydroxide KO t Bu Potassium tert-butoxide LDA Lithium diisopropylamide LiAlH4 Lithium Aluminum Hydride LiBH4 Lithium borohydride LiOH Lithium hydroxide m multiplet CH3CN Acetonitrile MeI Methyl iodide MeOH Methanol MS mass spectrometry MsCl Methanesulfonyl chloride N normality N2 Nitrogen n-BuLi n-Butyl lithium NaH Sodium hydride NaHCO3 Sodium bicarbonate Na2SO4 Sodium Sulfate NCS N-chlorosuccinimide NH4Cl Ammonium chloride NMR nuclear magnetic resonance Pd / C Palladium Carbon PdCl2(Ph3P)2 Bis(triphenylphosphine)palladium(II) dichloride Pd(dppf)Cl2 1,1'-Bis(diphenylphosphino)ferrocene]-palladium(II) dichloride Ph3P Triphenylphosphine q quartet s singlet t triplet t-BuOH tert-butyl alcohol T3P 1-Propanephosphonic anhydride TFA Trifluoroacetic acid THF Tetrahydrofuran

[0150] Synthesis of intermediates Intermediate A1: tert-butyl (1-(6-bromopyrazine-2-carboxamido)-2-methylpropan-2-yl)carbamate [ka] To a solution of 6-bromopyrazine-2-carboxylic acid (1.649 g, 8.12 mmol) and tert-butyl (1-amino-2-methylpropan-2-yl)carbamate (1.606 g, 8.53 mmol) in DMF (10 mL) was added Et3N (1.25 mL, 8.94 mmol) followed by T3P (5.32 mL, 8.94 mmol, 50 w / w% in EtOAc) under cooling in an ice bath. The reaction mixture was stirred at rt for 40 min. After dilution with EtOAc, the mixture was washed with aqueous KHSO4, water, saturated aqueous NaHCO3, water, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-50%) to give the title compound (2.72 g, 90% yield). 1 H NMR(500MHz,DMSO-d6)δ 9.16(d,J=0.5Hz,1H),9.09(d,J=0.5Hz,1H),8.77(t,J=6.7Hz,1H),3.42(d,J=6.6Hz,2H),1.39(s,9H),1.21(s,6H).LCMS(ESI)m / z C 14 H 21 81 Calculated value for BrN4O3: 374.1, Found value: 375.1 (M+H) + .

[0151] [Table 1]

[0152] Method A: Intermediate B1: tert-Butyl 6-chloro-5-fluoro-3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate [ka] The title compound was prepared in the following manner. [ka]

[0153] To a solution of 6-chloro-5-fluoro-1H-indole (5.05 g, 29.8 mmol) in CH3CN (20 mL) was added a suspension of N-(chloromethylene)-N-methylmethanaminium chloride (5.72 g, 44.7 mmol) in CH3CN (10 mL). The reaction mixture was stirred for 20 min at rt. TLC showed complete conversion. Aqueous NaOH (4.76 g NaOH in 60 mL water) was added and the mixture was stirred for 20 min at 100° C. After cooling under an ice bath, water was added to the reaction mixture. The resulting precipitate was collected by filtration, washed with water and CH3CN, and dried. The filtrate was poured into a separatory funnel with water and CH2Cl2. The resulting precipitate was collected by filtration, washed with water, and dried. The filtrate was extracted with CH2Cl2 and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The product from the filtration and residue from the aqueous workup was triturated with CH3CN, collected by filtration, washed with CH3CN and Et2O and dried to give 6-chloro-5-fluoro-1H-indole-3-carbaldehyde (4.6 g, 78% yield). LCMS (ESI) m / z calculated for C9H5ClFNO 197.0, found 197.9 (M+H). + . [ka]

[0154] To a suspension of compound B1-1 (4.6 g, 23.28 mmol) in THF (30 mL) was added a solution of LiAlH4 in THF (18.2 mL, 41.9 mmol, 2.3 M in THF) under ice-water bath. The reaction mixture was stirred at rt for 20 min and at 80 °C for 30 min. The reaction was quenched with Na2SO4·10H2O under ice-water bath, then 2M aqueous NaOH and water were added. The resulting mixture was filtered through a Celite pad and the Al(OH)3 product was washed with EtOAc. The combined filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-20%) to give 6-chloro-5-fluoro-3-methyl-1H-indole (4.53 g, 23.28 mmol). 1 H NMR(500MHz,DMSO-d6)δ 10.94(s,1H),7.48(d,J=6.4Hz,1H),7.45(d,J=10.2Hz,1H),7.23(t,J=1.7Hz,1H),2.22(d,J=1.0Hz,3H). 19 F NMR(470MHz,DMSO-d6)δ -129.1. [ka]

[0155] To a solution of compound B1-2 (4.53 g, 24.67 mmol) in CHCl (10 mL) was added DMAP (0.117 g, 0.958 mmol) and a solution of BocO (5.38 g, 24.67 mmol) in CHCl (5 mL). The reaction mixture was stirred for 40 min at rt. After concentrating most of the CHCl, a solution of BocO (2 g, 10.89 mmol) in CHCl (10 mL) was added. The reaction mixture was stirred for 20 min at rt. The reaction mixture was concentrated in vacuo. The resulting product was triturated with MeOH-CHCN, collected by filtration and washed with MeOH. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-10%) to give the desired product, which was combined with the product obtained by trituration and dried to give tert-butyl 6-chloro-5-fluoro-3-methyl-1H-indole-1-carboxylate (5.79 g, 74% yield). 1 H NMR(500MHz,DMSO-d6)δ 8.12(d,J=6.6Hz,1H),7.65(dd,J=9.5,1.8Hz,1H),7.57(s,1H),2.22(s,3H),1.62(s,9H). 19 F NMR(470MHz,DMSO-d6)δ -123.2. [ka]

[0156] To a solution of compound B1-3 (1.97 g, 6.94 mmol) in THF (20 mL) was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.13 mL, 10.41 mmol). After cooling to -78 °C, LDA (6 mL, 12.00 mmol, 2.0 M in THF / heptane / ethylbenzene) was added to the reaction mixture via syringe. The reaction mixture was stirred at -78 °C to -22 °C for 50 min. The reaction was quenched with aqueous KHSO4 and extracted with EtOAc. The organic layer was washed with water and brine. The combined aqueous layer was extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-10%) to give Intermediate B1 (2.34 g, 82% yield). 1 H NMR(500MHz,DMSO-d6)δ 7.92(d,J=6.3Hz,1H),7.64(d,J=9.3Hz,1H),2.22(s,3H),1.65(s,9H),1.34(s,12H). 19 F NMR(470MHz,DMSO-d6)δ -123.3.

[0157] Method B: Intermediate B2: tert-Butyl 3-methyl-5-(pentafluoro-λ 6 -sulfanyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate [ka] The title compound was prepared in the following manner. [ka]

[0158] 4-(pentafluoro-lambda) in CH2Cl2 6To a solution of 2-bromo-4-(pentafluoro-lambda-sulfanayl)aniline (5.12 g, 23.36 mmol) at 0° C. was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (3.34 g, 11.68 mmol). The reaction mixture was stirred for 45 min at 0° C. and then for 45 min at rt. The reaction mixture was filtered through a pad of Celite and washed with CHCl. ​​The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-50%) to give 2-bromo-4-(pentafluoro-lambda-sulfanayl)aniline (5.12 g, 23.36 ... 6 -Sulfanayl)aniline (6.24 g, 90% yield) was obtained. 1 H NMR (500 MHz, chloroform-d) δ 7.81 (d, J = 2.5 Hz, 1H), 7.49 (dd, J = 8.9, 2.5 Hz, 1H), 6.72 (dt, J = 8.9, 1.0 Hz, 1H), 4.45 (s, 2H). [ka]

[0159] To a solution of compound B2-1 (3.44 g, 11.54 mmol) in THF (40 mL) was added a solution of t-BuOK in THF (13.85 mL, 13.85 mmol, 1M in THF) by syringe over 10 min under ice bath. The reaction mixture was stirred at 0° C. for 15 min. To this mixture was added a solution of allyl bromide (1.2 mL, 13.85 mmol) in THF (11 mL) by syringe over 10 min. The resulting mixture was stirred at 0° C. for 15 min and at rt for 30 min. The reaction was quenched with water and most of the THF was concentrated. The residue was poured into water and extracted with EtOAc. The organic layer was washed with water and brine. The combined aqueous layer was extracted with EtOAc and the organic layer was washed with brine. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-20%) to give N-allyl-2-bromo-4-(pentafluoro-λ 6-sulfanyl)aniline (2.14 g, 55% yield) was obtained as a pale orange oil. 1 H NMR(500MHz,DMSO-d6)δ 7.88(d,J=2.6Hz,1H),7.65(dd,J=9.2,2.7Hz,1H),6.66(d,J=9.2Hz,1H),6.39(t,J=6.0Hz,1H),5.8 5(ddt,J=17.2,9.9,4.7Hz,1H),5.18-5.09(m,2H),3.90(ddd,J=6.5,4.4,2.1Hz,2H).LCMS(ESI)m / z C9H9 81 Calculated value for BrF5NS: 339.0, Found value: 340.0 (M+H) + . [ka]

[0160] Compound B2-2 (4.485 g, 13.26 mmol), tri-o-tolylphosphine (161 mg, 0.531 mmol), and Pd(OAc)2 (44.7 mg, 0.199 mmol) were placed in a 250 mL round-bottom flask. The flask was purged with N2. To the mixture was added CH3CN (40 mL), followed by Et3N (2.8 mL, 19.9 mmol). The reaction mixture was purged again with N2 and stirred at 90 °C under N2 (balloon) for 8 h. The reaction mixture was filtered, washed with heptane / EtOAc, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-20%) to give 3-methyl-5-(pentafluoro-lambda). 6 -sulfanyl)-1H-indole (2.44 g, 72% yield) was obtained. 1 H NMR (500 MHz, chloroform-d) δ 8.10 (s, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.59 (dd, J = 8.9, 2.2 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.11-7.07 (m, 1H), 2.36 (t, J = 0.9 Hz, 3H). LCMS (ESI) m / z calculated for C9H8F5NS 257.0, found 258.1 (M+H). + . [ka]

[0161] Compound B2 (tert-butyl 3-methyl-5-(pentafluoro-lambda)) can be obtained from intermediate B2-3 in a manner similar to that of intermediate B1. 6 -sulfanyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate) was prepared. 1 H NMR (500 MHz, chloroform-d) δ 7.93-7.82 (m, 2H), 7.66 (dd, J = 8.9, 2.4 Hz, 1H), 2.32 (s, 3H), 1.68 (s, 9H), 1.43 (s, 12H).

[0162] Method C: Intermediate B3: (1-(tert-butoxycarbonyl)-6-chloro-7-fluoro-3-methyl-1H-indol-2-yl)boronic acid [ka]

[0163] The title compound was prepared in the following manner. [ka] tert-Butyl 6-chloro-7-fluoro-3-methyl-1H-indole-1-carboxylate was prepared from 6-chloro-7-fluoro-1H-indole (CAS 259860-04-3) in a manner similar to tert-butyl 6-chloro-5-fluoro-3-methyl-1H-indole-1-carboxylate. LCMS (ESI) m / z C 14 H 15 Calculated value of ClFNO2 is 283.1, measured value is 228.0 (M+H- t Bu) + . [ka]

[0164] Compound B3-1 (3.08 g, 10.86 mmol) was placed in a 500 mL flask and THF (30 mL) was added. The flask was placed under N2 atmosphere and triisopropyl borate (8 mL, 34.5 mmol) was added. The flask was then cooled to 0° C. in an ice bath and LDA (16 mL, 32.0 mmol, 2.0 M in THF / heptane / ethylbenzene) was added dropwise over 10 min. The reaction was then stirred at 0° C. for 1 h. Additional triisopropyl borate (1.3 mL, 5.60 mmol) and LDA (2.8 mL, 5.60 mmol) were added. After 5 min, the reaction was quenched with 1 M aqueous KHSO4 (70 mL, pH checked to be about 1) and the mixture was stirred at rt for 10 min. The two layers were separated and a large amount of precipitate was observed in the aqueous layer. Excess water (ca. 50 mL) was added to redissolve all precipitate and transferred to a separatory funnel. The aqueous layer was extracted with EtOAc (2×30 mL) and the organic extract was dried over Na2SO4, filtered and concentrated in vacuo to give Intermediate B3 (3.48 g, 98% yield), which was used directly in the next reaction without further purification. LCMS (ESI) m / z C 14 H 16 Calculated value of BClFNO4 is 327.1, measured value is 254.1 (M- t BuO) + .

[0165] Method D: Intermediate B4: 3,6-Dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole [ka] The title compound was prepared in the following manner. [ka]

[0166] 3,6-Dimethyl-1H-indole (102 mg, 0.702 mmol), B2(Pin)2 (95 mg, 0.374 mmol), [Ir(cod)OMe]2 (2.3 mg, 0.0035 mmol), and dtbpy (1.9 mg, 0.0070 mmol) were placed in an 8 mL vial. The vial was purged with N2 and charged with THF (1.5 mL). N2 was bubbled through the reaction mixture. The reaction mixture was stirred at 90 °C for 3 h. The desired product MS peak was confirmed by LCMS. LCMS (ESI) m / z C 16 H 22 Calculated value of BNO2 is 271.2, measured value is 272.2 (M+H) + This reaction mixture (0.75 mL) was used directly in the next reaction.

[0167] [Table 2]

[0168] [Table 3]

[0169] [Table 4]

[0170] [Table 5]

[0171] [Table 6]

[0172] Synthesis of Examples Example 1: N-(2-amino-2-methylpropyl)-6-(6-chloro-5-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide [ka] The title compound was prepared in the following manner. [ka]

[0173] Compound B1 (3.34 g, 8.15 mmol), compound A2 (2.1 g, 6.39 mmol), and PdCl2(dppf)·CH2Cl2 (0.26 g, 0.32 mmol) were placed in a 100 mL round-bottom flask. To the mixture was added 1,4-dioxane (10 mL), followed by aqueous K3PO4 (9.6 mL, 19.16 mmol, 2 M). The flask was evacuated and backfilled with N2, and then the reaction mixture was stirred at 100 °C for 45 min. After dilution with EtOAc, the mixture was washed with water, aqueous N-acetyl-cysteine ​​(40 mL, 500 mg dissolved in 50 mL water), and saturated NaHCO3. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-50%) to give the coupled product, which was further purified by trituration with MeOH-CH3CN (sonication and stirring overnight at rt) to give tert-butyl 2-(6-((2-((tert-butoxycarbonyl)amino)-2-methylpropyl)carbamoyl)pyrazin-2-yl)-6-chloro-5-fluoro-3-methyl-1H-indole-1-carboxylate (2.06 g, 56% yield). LCMS (ESI) m / z C 28 H 35 Calculated value for ClFN5O5: 575.2, Found value: 576.3 (M+H) + . [ka]

[0174] 1) HCOOH procedure: A mixture of compound 1-1 (1.93 g, 3.35 mmol) in HCOOH (10.1 mL, 268 mmol) was stirred at 70° C. for 7 h, then left at rt overnight. The same reaction was repeated with another two batches (167 mg, 0.29 mmol, and 1.618 g, 2.81 mmol). These reaction mixtures were combined and concentrated in vacuo. The residue was basified with aqueous NaOH. The resulting suspension was sonicated and thoroughly stirred to complete the release form. MeOH was added to this suspension, and the resulting slurry was stirred at rt for 30 min (occasionally sonicated), then filtered, washed with water, and dried. The resulting product was suspended in MeOH-CH3CN and the resulting slurry was stirred for 10 min at rt (with occasional sonication), then filtered, washed with MeOH-CH3CN and dried to give the title compound (2.17 g, 89% yield) as the free base form. 1 H NMR(500MHz,DMSO-d6)δ 11.97(s,1H),9.30(s,1H),9.07(s,1H),8.91-8.80(m,1H),7.74(d,J=10.0 Hz,1H),7.64-7.58(m,1H),3.31(d,J=7.5Hz,2H),2.65(s,3H),1.07(s,6H). 19 F NMR(470MHz,DMSO-d6)δ -127.4.LCMS(ESI)m / z C 18 H 19 Calculated value for ClFNO: 375.1, Found value: 376.2 (M+H) + .

[0175] 2) HCl procedure: A 100 mL round bottom flask containing compound 1-1 (167 mg, 0.290 mmol) was charged with 4 M HCl in 1,4-dioxane (3 mL, 12.00 mmol) and the reaction was stirred at rt for 69 h. The resulting product was collected by filtration, washed with CH3CN and dried to give the title compound (105 mg, 86% yield) as the HCl salt form. 1H NMR(500MHz,DMSO-d6)δ 12.33(s,1H),9.59(t,J=6.6Hz,1H),9.34(s,1H),9.10(s,1H),8.01(s,3H),7.75(d,J =10.1Hz,1H),7.65(d,J=6.3Hz,1H),3.60(d,J=6.6Hz,2H),2.66(s,3H),1.32(s,6H). 19 F NMR(470MHz,DMSO-d6)δ -127.5.LCMS(ESI)m / z C 18 H 19 Calculated value for ClFNO: 375.1, Found value: 376.0 [M+H] + .

[0176] Example 2: N-(2-amino-2-methylpropyl)-6-(5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide [ka]

[0177] The title compound was prepared in the following manner. [ka]

[0178] Compound A1 (190 mg, 0.509 mmol), (1-(tert-butoxycarbonyl)-5-(trifluoromethoxy)-1H-indol-2-yl)boronic acid (211 mg, 0.611 mmol, CAS 1034566-16-9), and PdCl2(Ph3P)2 (18 mg, 0.025 mmol) were placed in a vial. The vial was purged with N2 and capped. To the mixture was added 1,4-dioxane (0.3 mL) and aqueous K3PO4 (0.76 mL, 1.527 mmol, 2 M). The reaction mixture was stirred at 100 °C for 30 min. The reaction mixture was loaded directly onto silica gel and purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-50%) to give tert-butyl 2-(6-((2-((tert-butoxycarbonyl)amino)-2-methylpropyl)carbamoyl)pyrazin-2-yl)-5-(trifluoromethoxy)-1H-indole-1-carboxylate (204 mg, 68% yield). LCMS (ESI) m / z C 28 H 34 Calculated value for F3N5O6: 593.3, Measured value: 594.3 (M+H) + . [ka]

[0179] To a solution of compound 2-1 (204 mmol) in MeOH (2 mL) was added HCl in 1,4-dioxane (5 mL, 20 mmol, 4 M). The reaction mixture was stirred at rt for 39 h. The reaction mixture was concentrated in vacuo. The residue was triturated with MeOH-CH3CN, collected by filtration, washed with CH3CN, and dried to give the title compound (144 mg, 97% yield). 1H NMR(500MHz,DMSO-d6)δ 12.96(s,1H),9.90(t,J=6.6Hz,1H),9.53(d,J=0.5Hz,1H),9.06(d,J=0.5Hz,1H),8.24(s,3H),7.67-7.62 (m,2H),7.54(dd,J=2.2,0.8Hz,1H),7.20(ddd,J=8.9,2.4,1.0Hz,1H),3.62(d,J=6.6Hz,2H),1.33(s,6H). 19 F NMR(470MHz,DMSO-d6)δ -56.9.LCMS(ESI)m / z C 18 H 18 Calculated value for F3N5O2: 393.1, measured value: 394.1 [M+H] + .

[0180] Example 3: N-(2-amino-2-methylpropyl)-6-(3-methyl-5-(pentafluoro-λ 6 -Sulfanayl)-1H-indol-2-yl)pyrazine-2-carboxamide [ka]

[0181] The title compound was prepared in the following manner. [ka]

[0182] Compound B2 (470 mg, 0.972 mmol), compound A1 (300 g, 0.804 mmol), and PdCl2(dppf)·CH2Cl2 (0.033 g, 0.040 mmol) were placed in a 100 mL round-bottom flask. To this mixture was added 1,4-dioxane (2 mL), followed by aqueous K3PO4 (1.2 mL, 2.4 mmol, 2 M). The flask was evacuated and backfilled with N2, then the reaction mixture was stirred at 100 °C for 30 min. The reaction mixture was diluted with EtOAc and washed with water and brine. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-50%) to give tert-butyl 2-(6-((2-((tert-butoxycarbonyl)amino)-2-methylpropyl)carbamoyl)pyrazin-2-yl)-3-methyl-5-(pentafluoro-λ 6 1H-indole-1-carboxylate (448 mg, 84% yield). 28 H 36 Calculated value for F5N5O5S: 649.2; measured value: 650.3 (M+H) + . [ka]

[0183] tert-Butyl 2-(6-((2-((tert-butoxycarbonyl)amino)-2-methylpropyl)carbamoyl)pyrazin-2-yl)-3-methyl-5-(pentafluoro-lambda) in MeOH (5 mL) 6 To a suspension of 1H-indole-1-carboxylate (155 mg, 0.239 mmol) was added HCl in 1,4-dioxane (6 mL, 24 mmol, 4 M). The reaction mixture was stirred at rt for 62 h and concentrated in vacuo. The residue was triturated with MeOH-CH3CN, collected by filtration, washed with MeOH-CH3CN, and dried to give the title compound (89 mg, 76% yield) as the HCl salt form.1 H NMR(500MHz,DMSO-d6)δ 12.37(s,1H),9.46(d,J=6.9Hz,1H),9.40(s,1H),9.14(s,1H),8.31(d,J=2.1Hz,1H),7.92(s,3H), 7.73(dd,J=9.0,2.2Hz,1H),7.67(d,J=8.9Hz,1H),3.60(d,J=6.7Hz,2H),2.76(s,3H),1.33(s,6H). 19 F NMR(470MHz,DMSO-d6)δ 66.9.LCMS(ESI)m / z C 18 H 20 Calculated value of F5N5OS is 449.1, measured value is 450.3 [M+H] + . [ka]

[0184] Step 1: A round-bottom flask containing the crude HCl salt (50 g, 77 mmol from the deprotection of 3-1) was charged with water (1.25 L) and the resulting solution was brought to pH 9-14 by the addition of 10% NaOH solution (150 mL). The mixture was stirred for 5 h and the resulting slurry was filtered, washed with water, dried and purified to give N-(2-amino-2-methylpropyl)-6-(3-methyl-5-(pentafluoro-lambda)-4-(2-methylpropyl)-2-propanediol. 6 To this was obtained (3a) (30.5 g, 88% yield) 1H-sulfanyl-1H-indol-2-yl)pyrazine-2-carboxamide as the free base.

[0185] Step 2: In a round bottom flask, add N-(2-amino-2-methylpropyl)-6-(3-methyl-5-(pentafluoro-lambda 6-sulfanyl)-1H-indol-2-yl)pyrazine-2-carboxamide (3a) (50 g, 111 mmol) and taken up in EtOH (150 mL). The mixture was warmed to 50° C., treated with siliabond thiol resin (5 g) and stirred overnight. The mixture was cooled to room temperature, treated with Jacobi carbon (5 g) and warmed to 50° C. for 4 h. The mixture was filtered through celite at 50° C., washed with additional warm EtOH and the filtrate was transferred to a round bottom flask. The filtrate was diluted with water (50 mL) and the mixture was warmed to 50° C. and treated with 5 mL of a 10% solution of acetic acid in ethanol / water (96:4). Stirred at 50° C. for 2 h and cooled slowly to 10° C. The resulting slurry was collected by filtration, washed with aqueous ethanol (96:4), and dried to give N-(2-amino-2-methylpropyl)-6-(3-methyl-5-(pentafluoro-lambda 6 As a result, 48 g (85% yield) of (1H-sulfanyl)-1H-indol-2-yl)pyrazine-2-carboxamide acetate (3b) was obtained. 1 H NMR(500MHz,DMSO-d6)δ 12.83(s,1H),9.60(m,1H),9.36(s,1H),9.09(s,1H),8.27(d,J=2.2Hz,1H),7.70(dd,J=9.0, 2.2Hz,1H),7.63(d,J=9.0Hz,1H),3.49-3.33(m,2H),2.74(s,3H),1.91(s,3H),1.16(s,6H). 19 F NMR(470MHz,DMSO-d6)δ 67.21,90.85.LCMS(ESI)m / z C 18 H 20 Calculated value of F5N5OS is 449.1, measured value is 450.14 [M+H] + .

[0186] [Table 7]

[0187] [Table 8]

[0188]

Table 9

[0189]

Table 10

[0190]

Table 11

[0191]

Table 12

[0192]

Table 13

[0193]

Table 14

[0194]

Table 15

[0195]

Table 16

[0196]

Table 17

[0197]

Table 18

[0198]

Table 19

[0199] [Table 20]

[0200] [Table 21]

[0201] [Table 22]

[0202] [Table 23]

[0203] [Table 24]

[0204] Example 71: N-(2-amino-2-methylpropyl)-6-(5-(aminomethyl)-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide [ka] The title compound was prepared in the following manner. [ka]

[0205] To a mixture of (3-methyl-1H-indol-5-yl)methanamine (300 mg, 1.872 mmol, CAS 933735-99-0) in CH3CN (2 mL) at rt was added a solution of Boc2O (409 mg, 1.872 mmol) in CH3CN (3 mL). The reaction mixture was sonicated to impinge the starting amine and then stirred for 20 min at rt. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-50%) to give the title compound (517 mg, 95% yield). 1 H NMR(500MHz,DMSO-d6)δ 10.64(s,1H),7.32(s,1H),7.31-7.27(m,1H),7.25(d,J=8.3Hz,1H),7.07(dd,J=2.4,1.2Hz ,1H),6.98(dd,J=8.4,1.6Hz,1H),4.19(d,J=6.2Hz,2H),2.23(d,J=1.0Hz,3H),1.40(s,9H). [ka]

[0206] The title compound was prepared from compound 71-1 in a manner similar to Example 45. 1 H NMR(500MHz,DMSO-d6)δ 12.35(s,1H),9.78(t,J=6.6Hz,1H),9.35(s,1H),9.08(s,1H),8.22(s,3H),8.15(s,3H),7.82(s,1H),7.59(d,J=8.3Hz ,1H),7.34(dd,J=8.5,1.7Hz,1H),4.13(q,J=5.7Hz,2H),3.62(d,J=6.6Hz,2H),2.71(s,3H),1.33(s,6H).LCMS(ESI)m / z C 19 H 24 Calculated value of NO: 352.2, measured value: 353.3 [M+H] + .

[0207] Example 72: Ethyl 5-(6-((2-amino-2-methylpropyl)carbamoyl)pyrazin-2-yl)-6-methyl-4H-thieno[3,2-b]pyrrole-2-carboxylate [ka] The title compound was prepared in the following manner. [ka]

[0208] To a solution of ethyl 4H-thieno[3,2-b]pyrrole-2-carboxylate (300 mg, 1.537 mmol) in CH3CN (1 mL) was added a suspension of N-(chloromethylene)-N-methylmethanaminium chloride (295 mg, 2.305 mmol) in CH3CN (1 mL). The mixture was stirred for 50 min at rt. Water (1 mL) was added, and then the reaction mixture was basified with aqueous NaOH (2 M) to a pH of >6 and stirred for 20 min at 100 °C. After concentration of most of the solvent, the residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-100%) to give ethyl 6-formyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (227 mg). LCMS (ESI) m / z C 10 Calculated value of H9NO3S is 223.0, measured value is 224.0 (M+H) + To a solution of compound 72-1 in THF (3 mL) was added BH3-THF (2 mL, 2 mmol, 1 M) at 0 °C. The reaction mixture was stirred at rt for 1 h. The reaction was quenched with aqueous NH4Cl and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo.

[0209] The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-30%) to give ethyl 6-methyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (46 mg, 14% yield over two steps). LCMS (ESI) m / z C 10 H 11 Calculated value of NO2S: 209.1, measured value: 210.0 (M+H) + . [ka]

[0210] The title compound was prepared from compound 72-2 in a manner similar to Example 45. 1 H NMR(500MHz,DMSO-d6)δ 12.58(s,1H),9.55(t,J=6.6Hz,1H),9.23(s,1H),9.03(s,1H),8.02(s,3H),7.74(s,1H),4.32 (q,J=7.1Hz,2H),3.58(s,2H),2.61(s,3H),1.34(t,J=7.2Hz,3H),1.32(s,6H).LCMS(ESI)m / z C 19 H 23 Calculated value of N5O3S is 401.2, measured value is 402.1 [M+H] + .

[0211] Example 73: N-(2-amino-2-methylpropyl)-6-(2,6-dimethyl-4H-thieno[3,2-b]pyrrolo-5-yl)pyrazine-2-carboxamide [ka] The title compound was prepared in the following manner. [ka]

[0212] To a solution of compound 72-2 (308 mg, 1.472 mmol) in THF (5 mL) at 0 °C was added LiAlH4 (3 mL, 6.90 mmol, 2.3 M in THF). The reaction mixture was stirred at 70 °C for 2.5 h. The reaction was quenched with Na2SO4·10H2O. The mixture was diluted with EtOAc, filtered through a celite pad and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-20%) to give 2,6-dimethyl-4H-thieno[3,2-b]pyrrole (154 mg, 69% yield) as a colorless oil. LCMS (ESI) m / z calculated for C8H9NS 151.1, found 152.1 (M+H). + . [ka]

[0213] The title compound was prepared from compound 73-1 in a manner similar to Example 45. 1 H NMR(500MHz,DMSO-d6)δ 11.94(s,1H),9.49(t,J=6.7Hz,1H),9.08(s,1H),8.88(s,1H),8.01(s,3H),6.86(d,J=1.4Hz,1H),3.57(d,J=6.7Hz,2H),2.54(sx 2,6H),1.31(s,6H).LCMS(ESI)m / z C 17 H 21 N5OS calculated value 343.2, measured value 344.3 [M+H] + .

[0214] Example 74: N-(2-amino-2-methylpropyl)-6-(5-bromo-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide [ka] and Example 75: N-(2-amino-2-methylpropyl)-6-(3-methyl-5-(methylsulfonyl)-1H-indol-2-yl)pyrazine-2-carboxamide [ka] The title compound was prepared in the following manner. [ka]

[0215] B2(Pin)2 (116 mg, 0.457 mmol), [Ir(cod)OMe]2 (10.1 mg, 0.015 mmol), and dtbpy (8.2 mg, 0.030 mmol) were placed in an 8 mL vial, which was purged with N2 and then charged with THF (2.5 mL). After stirring for 5 min at rt, 5-(methylsulfonyl)-1H-indole (160 mg, 0.762 mmol) was charged. N2 was bubbled through the reaction mixture. The reaction mixture was stirred at 85 °C for 13 h and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-40%) to give 5-bromo-3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (64 mg, 25% yield) as a colorless oil. LCMS (ESI) m / z C 15 H 19 B 79 Calculated value for BrNO2: 335.1, Found value: 336.1 (M+H) + . [ka]

[0216] Compound A1 (65 mg, 0.174 mmol), PdCl2(Ph3P)2 (6.1 mg, 0.0087 mmol), and aqueous K3PO4 (0.17 mL, 0.34 mmol, 2 M) were placed in an 8 mL vial. A solution of compound 74-1 (64 mg, 0.19 mmol) in 1,4-dioxane (0.7 mL) was added. The vial was capped and purged with N2, and the reaction mixture was stirred at 100 °C for 30 min. The reaction mixture was loaded directly onto silica gel and purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-50%) to give tert-butyl (1-(6-(5-bromo-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide)-2-methylpropan-2-yl)carbamate (63 mg, 72% yield). LCMS(ESI)m / z C 23 H 28 81 Calculated value for BrN5O3: 503.1, Found value: 504.3 (M+H) + . [ka]

[0217] Compound 74-2 (24 mg, 0.048 mmol) and sodium methanesulfinate (9.8 mg, 0.096 mmol) were placed in an 8 mL vial. The vial was capped, purged with N2, and charged with DMSO (0.3 mL). To this mixture was added trans-1,2-diaminocyclohexane (0.0023 mL, 0.019 mmol), followed by [Cu(I)(OTf)]2·benzene (2.4 mg, 0.0048 mmol). The reaction mixture was stirred at 100 °C for 14 h. After dilution with EtOAc, the mixture was washed with water (×2) and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-100%) to give tert-butyl (2-methyl-1-(6-(3-methyl-5-(methylsulfonyl)-1H-indol-2-yl)pyrazine-2-carboxamide)propan-2-yl)carbamate (3.9 mg, 67% purity, mixture with unreacted -Br). LCMS (ESI) m / z C 24 H 31 Calculated value of N5O5S: 501.2, measured value: 502.3 (M+H) + . [ka]

[0218] A mixture of compound 75-1 and compound 74-2 (19 mg) in TFA (0.4 mL) was stirred at rt for 30 min. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give the title compound.

[0219] Example 74: 1H NMR(500MHz,DMSO-d6)δ 11.87(s,1H),9.35(s,1H),9.33(d,J=6.9Hz,1H),9.10(s,1H),7.92(d,J=1.9Hz,1H),7.88(s,3H),7.47(d ,J=8.6Hz,1H),7.36(dd,J=8.6,1.9Hz,1H),3.59(d,J=6.6Hz,2H),2.67(s,3H),1.33(s,6H).LCMS(ESI)m / z C 18 H 20 81 Calculated value for BrNO: 403.1, Found value: 404.2 [M+H] + .

[0220] Example 75: 1 H NMR(500MHz,DMSO-d6)δ 12.22(s,1H),9.41(s,1H),9.35(t,J=6.7Hz,1H),9.14(s,1H),8.33(d,J=1.7Hz,1H),7.88(s,3H),7.77(dd,J=8. 6,1.7Hz,1H),7.72(d,J=8.6Hz,1H),3.60(d,J=6.7Hz,2H),3.24(s,3H),2.77(s,3H),1.33(s,6H).LCMS(ESI)m / z C 19 H 23 Calculated value of N5O3S is 401.2, measured value is 402.3 [M+H] + .

[0221] Example 76: N-(2-amino-2-methylpropyl)-6-(3,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indol-2-yl)pyrazine-2-carboxamide [ka] The title compound was prepared in the following manner. [ka]

[0222] To a solution of 3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indol-4-one (206 mg, 1.162 mmol) in DMF (3 mL) was added NaH (70 mg, 1.743 mmol, 60% dispersion in mineral oil) at rt. After stirring for 5 min at rt, 4-methylbenzenesulfonyl chloride (332 mg, 1.743 mmol) was added. The reaction mixture was stirred for 1.5 h at rt. After dilution with EtOAc, the mixture was washed with aqueous KHSO4, water, saturated aqueous NaHCO3, water, and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 3,6,6-trimethyl-1-tosyl-1,5,6,7-tetrahydro-4H-indol-4-one (409 mg, quant). The product was used in the next reaction without purification. LCMS(ESI)m / z C 18 H 21 Calculated value of NO3S: 331.1, measured value: 332.3 (M+H) + . [ka]

[0223] To a suspension of compound 76-1 (409 mg) in MeOH at 0° C. was added NaBH4 (80 mg, 2.115 mmol). After stirring for 40 min at rt, NaBH4 (40 mg, 1.058 mmol) was added. After 5 min, NaBH4 (140 mg, 3.701 mmol) and THF (2 mL) were added. After 40 min, NaBH4 (170 mg, 4.494 mmol) was added. The reaction mixture was stirred for 70 min at rt. The reaction was quenched with aqueous KHSO4, and the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-50%) to give 3,6,6-trimethyl-1-tosyl-4,5,6,7-tetrahydro-1H-indol-4-ol (364 mg, 88% yield over two steps). 1H NMR(500MHz,chloroform-d)δ 7.66-7.61(m,2H),7.30-7.26(m,2H),6.96(q,J=1.0Hz,1H),2.53-2.49(m,2H),2.41(s,3H),2.10(d ,J=1.2Hz,3H),1.82(dd,J=13.1,5.9Hz,1H),1.44(dd,J=13.2,7.1Hz,1H),1.03(s,3H),0.86(s,3H). [ka]

[0224] To a solution of compound 76-2 (128 mg, 0.384 mmol) in CH2Cl2 (1 mL) was added Et3SiH (0.31 mL, 1.92 mmol) dropwise, followed by TFA (0.15 mL, 1.92 mmol). The reaction mixture was stirred at rt for 20 min.

[0225] The same reaction was repeated with compound 76-2 (245 mg, 0.735 mmol), Et3SiH (0.31 mL, 1.92 mmol), and TFA (0.15 mL, 1.92 mmol) in CH2Cl2 (2 mL) at rt for 10 min.

[0226] Both reaction mixtures were combined and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-20%) to give 3,6,6-trimethyl-1-tosyl-4,5,6,7-tetrahydro-1H-indole (217 mg, 63% yield). LCMS (ESI) m / z C 18 H 23 Calculated value of NO2S: 317.1, measured value: 318.2 (M+H) + . [ka]

[0227] To a solution of compound 76-3 (217 mg, 0.684 mmol) in THF (2 mL) was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.28 mL, 1.367 mmol). After cooling to -78 °C, LDA (1 mL, 2.0 mmol, 2.0 M in THF / heptane / ethylbenzene) was added to the reaction mixture via syringe. The reaction mixture was stirred at -78 °C to -32 °C for 20 min. The reaction was quenched with aqueous KHSO4 and the resulting mixture was extracted with EtOAc. The organic layer was washed with water and brine. The combined aqueous layers were extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-10%) to give 3,6,6-trimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-4,5,6,7-tetrahydro-1H-indole (71 mg, 23% yield) as a purple oil. LCMS (ESI) m / z C 24 H 34 Calculated value of BNO4S: 443.2, measured value: 444.3 (M+H) + . [ka]

[0228] Compound 76-4 (70 mg, 0.158 mmol), compound A1 (50 mg, 0.134 mmol), and PdCl2(dppf)·CH2Cl2 (5.5 mg, 0.0067 mmol) were placed in a vial. The vial was capped and purged with N2. To the mixture was added 1,4-dioxane (0.4 mL), followed by aqueous K3PO4 (0.32 mL, 0.64 mmol, 2 M). The reaction mixture was stirred at 100 °C for 55 min and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-75%) to give tert-butyl (2-methyl-1-(6-(3,6,6-trimethyl-1-tosyl-4,5,6,7-tetrahydro-1H-indol-2-yl)pyrazine-2-carboxamide)propan-2-yl)carbamate (74 mg, 91% yield) as a yellow oil. LCMS (ESI) m / z C 32 H 43 Calculated value of N5O5S: 609.3, measured value: 610.3 (M+H) + . [ka]

[0229] To a solution of compound 76-5 (70 mg, 0.115 mmol) in MeOH (1 mL) was added Mg powder (28 mg, 1.148 mmol). The reaction mixture was stirred for 30 min at rt (EXP071-2) and then for 30 min at 45° C. The reaction was quenched with aqueous KHSO4, and the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-50%) to give tert-butyl (2-methyl-1-(6-(3,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indol-2-yl)pyrazine-2-carboxamide)propan-2-yl)carbamate (36 mg, 80% purity, 55% yield) as a yellow oil. LCMS (ESI) m / z C 25 H37 Calculated value of N5O3: 455.3, measured value: 456.3 (M+H) + . [ka]

[0230] To a solution of compound 76-6 (36 mg, 0.063 mmol) in MeOH (0.5 mL) was added HCl in 1,4-dioxane (1 mL, 4 mmol, 4 M). The reaction mixture was stirred at rt for 40 min. The reaction mixture was concentrated in vacuo. The residue was triturated with MeOH-CH3CN, collected by filtration, washed with MeOH-CH3CN, and dried to give the title compound. 1 H NMR(500MHz,DMSO-d6)δ 11.38(s,1H),9.49(t,J=6.5Hz,1H),8.91(s,1H),8.75(s,1H),8.06(s,3H),3.55(d,J=6.7Hz,2H),2.45( s,2H),2.40(t,J=6.4Hz,2H),2.29(s,3H),1.51(t,J=6.3Hz,2H),1.29(s,6H),1.00(s,6H).LCMS(ESI)m / z C 20 H 29 Calculated value of N5O: 355.2 Measured value: 356.3 [M+H] + .

[0231] Example 77: N-((1S,2S)-2-aminocyclopentyl)-6-(6-chloro-5-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide [ka] The title compound was prepared in the following manner. [ka]

[0232] To a suspension of 6-bromopyrazine-2-carboxylic acid (25 mg, 0.123 mmol) in CH2Cl2 (0.31 mL) was added oxalyl chloride (0.043 mL, 0.493 mmol) and 1 drop of DMF (exothermic reaction) at 0° C. The reaction mixture was stirred at 40° C. for 20 min and then concentrated in vacuo.

[0233] To a solution of tert-butyl ((1S,2S)-2-aminocyclopentyl)carbamate (0.034 mg, 0.172 mmol, CAS 586961-34-4) and aqueous K3PO4 (0.31 mL, 0.62 mmol, 2 M) in 1,4-dioxane (0.31 mL) was added the prepared solution of -COCl in 1,4-dioxane (0.31 mL) at 0 ° C. The reaction was allowed to warm to rt. After stirring for 30 min, the reaction vessel was flushed with argon, followed by the addition of tert-butyl 6-chloro-5-fluoro-3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (76 mg, 0.185 mmol) and bis(triphenylphosphine)palladium(II) chloride (4.3 mg, 6.16 μmol). The resulting mixture was stirred at 95° C. for 2 h. The organic layer was filtered through an S-TMT cartridge to remove residual Pd and then evaporated to dryness. The resulting crude material was then treated with TFA (0.25 mL) for 2 h until the reaction was complete. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC to give the title compound (19.7 mg, 31% yield). 1H NMR(400MHz,DMSO-d6)δ 11.86(s,1H),9.33(d,J=1.8Hz,1H),9.09(d,J=1.7Hz,1H),9.06(d,J=8.1 Hz,1H),8.08(s,3H),7.75(dd,J=10.2,1.8Hz,1H),7.64(dd,J=6.4,1.8Hz ,1H),6.52(s,2H),4.38(q,J=8.2Hz,1H),3.59(d,J=6.1Hz,2H),2.65(s,3 H),2.13(d,J=9.8Hz,2H),1.90-1.76(m,3H),1.69(dd,J=13.3,7.2Hz,1H). 19 F NMR(376MHz,DMSO-d6)δ -127.3.LCMS(ESI)m / z C 19 H 19 Calculated value for ClFNO: 387.1 Found value: 388.3 [M+H] + .

[0234] [Table 25]

[0235] [Table 26]

[0236] Example 83: N-(2-amino-2-methylpropyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide [ka] The title compound was prepared in the following manner. [ka]

[0237] In a microwave vial, a mixture of (1-(tert-butoxycarbonyl)-3-methyl-1H-indol-2-yl)boronic acid (462 mg, 1.681 mmol, CAS 352359-20-7), methyl 6-bromopyrazine-2-carboxylate (304 mg, 1.401 mmol), and PdCl2(Ph3P)2 (49 mg, 0.070 mmol) in 1,4-dioxane (2 mL)-aqueous K3PO4 (2.1 mL, 4.2 mmol, 2 M) was stirred at 120 °C for 90 min. Aqueous NaOH (1 mL, 2 mmol, 2 M) was added and the reaction mixture was stirred at 60 °C for 12 h. The reaction mixture was transferred to a separatory funnel with water and Et2O and the aqueous layer was separated. The aqueous layer was acidified with aqueous KHSO4 and extracted with EtOAc (x3). The combined organic extracts were washed with aqueous KHSO4 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with CH3CN and the precipitated product was removed by filtration. The filtrate was concentrated in vacuo to give 6-(1-(tert-butoxycarbonyl)-3-methyl-1H-indol-2-yl)pyrazine-2-carboxylic acid (315 mg, 64% yield). LCMS (ESI) m / z C 19 H 19 Calculated value of N3O4: 353.1, Measured value: 354.0 (M+H) + . [ka]

[0238] To a mixture of compound 83-1 (69 mg, 0.195 mmol) and tert-butyl (1-amino-2-methylpropan-2-yl)carbamate (37 mg, 0.195 mmol) in DMF (0.6 mL) was added i-Pr2NEt (0.068 mL, 0.391 mmol) at rt, followed by HATU (89 mg, 0.234 mmol). The reaction mixture was stirred at rt for 3.5 h. After dilution with EtOAc, the mixture was washed with aqueous KHSO4, water, saturated aqueous NaHCO3, water, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-50%) to give tert-butyl 2-(6-((2-((tert-butoxycarbonyl)amino)-2-methylpropyl)carbamoyl)pyrazin-2-yl)-3-methyl-1H-indole-1-carboxylate (62 mg, 60% yield). LCMS (ESI) m / z C 28 H 37 Calculated value of N5O5: 523.3, Measured value: 524.3 (M+H) + . [ka]

[0239] To a solution of compound 83-2 (61 mg, 0.116 mmol) in MeOH (0.2 mL) was added HCl in 1,4-dioxane (1 mL, 4 mmol, 4 M). The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated in vacuo. The residue was triturated with MeOH-CH3CN, collected by filtration, washed with MeOH-CH3CN, and dried to give the title compound (31 mg, 73% yield). 11H NMR (500 MHz, DMSO-d6) δ 12.05 (s, 1H), 9.66 (t, J = 6.6 Hz, 1H), 9.33 (s, 1H), 9.05 (s, 1H), 8.09 (s, 3H), 7.69 (d, J = 8.0 Hz, 1H), 7.57 - 7.51 (m, 1H), 7.24 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.08 (ddd, J = 8.0, 6.9, 1.0 Hz, 1H), 3.61 (d, J = 6.7 Hz, 2H), 2.70 (s, 3H), 1.33 (s, 6H). LCMS (ESI) m / z C 18 H 21 Calculated value of C19H19N5O 323.2, measured value 324.0 [M + H] + 。

[0240]

Table 27

[0241]

Table 28

[0242]

Table 29

[0243]

Table 30

[0244]

Table 31

[0245]

Table 32

[0246] Examples 102 and 103 were prepared by the following method.

Chemical Structure

[0247] In a manner similar to Example 83, tert-butyl 2-(6-((2-((tert-butoxycarbonyl)amino)-2-cyclopropylethyl)carbamoyl)pyrazin-2-yl)-3-methyl-1H-indole-1-carboxylate (compound 105-1) was prepared. LCMS (ESI) m / z C 29 H 37 Calculated value of N5O5: 535.3, Measured value: 536.4 (M+H) + .

[0248] Chiral separation of racemic compound 102-1 was carried out by Preparative Chiral SFC (stationary phase: Chiralpak AD-H, 21×250 mm, 5 μm, mobile phase: A CO2, B i-PrOH, isocratic method=20% B) to give enantiomer A as the first eluting product and enantiomer B as the second eluting product. Each enantiomer was treated with HCl in 1,4-dioxane (1 mL, 4 M) in MeOH (1 mL) at rt for 3 days. After concentration, the residue was triturated with Et2O, collected by filtration, and dried to give examples 102 and 103, respectively.

[0249] Example 102: 1 H NMR(500MHz,DMSO-d6)δ 11.99(s,1H),9.69(t,J=6.2Hz,1H),9.32(s,1H),9.04(s,1H),8.18(s,3H),7.69(d,J =8.0Hz,1H),7.53(d,J=8.2Hz,1H),7.24(ddd,J=8.1,6.9,1.2Hz,1H),7.08(ddd,J=8.0 ,6.9,1.0Hz,1H),3.76(t,J=6.6Hz,2H),2.73-2.70(m,1H),2.69(s,3H),1.05(tt,J=8 .9,3.8Hz,1H),0.67-0.54(m,2H),0.51-0.46(m,1H),0.43-0.38(m,1H).LCMS(ESI)m / z C 19 H 21Calculated value of NO: 335.2, measured value: 336.2 [M+H] + .

[0250] Example 103: 1 H NMR(500MHz,DMSO-d6)δ 11.95(s,1H),9.66(t,J=6.3Hz,1H),9.33(s,1H),9.04(s,1H),8.16(s,3H),7.69(d,J =8.0Hz,1H),7.53(d,J=8.2Hz,1H),7.24(ddd,J=8.2,6.9,1.1Hz,1H),7.08(ddd,J=8.0 ,6.9,1.0Hz,1H),3.76(td,J=6.3,5.8,2.3Hz,2H),2.73-2.70(m,1H),2.69(s,3H),1.1 1-1.00(m,1H),0.66-0.54(m,2H),0.51-0.46(m,1H),0.43-0.37(m,1H).LCMS(ESI)m / z C 19 H 21 Calculated value of NO: 335.2, measured value: 336.2 [M+H] + .

[0251] Examples 104 and 105 were prepared in the following manner. [ka]

[0252] A mixture of (1-(tert-butoxycarbonyl)-5-cyano-1H-indol-2-yl)boronic acid (57 mg, 0.199 mmol, CAS 475102-15-9), compound A2 (42 mg, 0.127 mmol), and PdCl2(Ph3P)2 (4.4 mg, 0.0063 mmol) was placed in a vial. The vial was purged with N2 and capped. To the mixture was added 1,4-dioxane (0.3 mL) and aqueous K3PO4 (0.19 mL, 0.38 mmol, 2 M). The reaction mixture was stirred at 100 °C for 60 min. The reaction mixture was loaded directly onto silica gel and purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-50%) to give tert-butyl 2-(6-((2-((tert-butoxycarbonyl)amino)-2-methylpropyl)carbamoyl)pyrazin-2-yl)-5-cyano-1H-indole-1-carboxylate (37 mg, 54% yield). LCMS (ESI) m / z C 28 H 34 Calculated value of N6O5: 534.3, Measured value: 535.2 (M+H) + . [ka]

[0253] To a suspension of compound 104-1 (37 mg, 0.068 mmol) in MeOH (0.2 mL) was added HCl in 1,4-dioxane (0.7 mL, 2.8 mmol, 4 M). The reaction mixture was stirred at rt for 20 h. After the mixture was concentrated, the residue was purified by preparative HPLC to give Example 104 (14.6 mg, 47% yield) and Example 105 (1.3 mg, 3.6% yield).

[0254] Example 104: 1H NMR(500MHz,DMSO-d6)δ 12.51(s,1H),9.61(s,1H),9.47(t,J=6.7Hz,1H),9.13(s,1H),8.31-8.27(m,1H),7.89(s,3H),7.76-7.73(m,1 H),7.72(dd,J=2.1,0.9Hz,1H),7.61(dd,J=8.5,1.6Hz,1H),3.60(d,J=6.7Hz,2H),1.34(s,6H).LCMS(ESI)m / z C 18 H 18 Calculated value of NO: 334.2, measured value: 335.3 [M+H] + .

[0255] Example 105: 1 H NMR(500MHz,DMSO-d6)δ 12.30(s,1H),9.58(s,1H),9.44(t,J=7.3Hz,1H),9.11(s,1H),7.89(dd,J=8.7,1.7Hz,1H),7.86(s,2 H),7.73(s,1H),7.67(d,J=8.7Hz,1H),3.89(s,3H),3.60(d,J=6.7Hz,2H),1.35(s,6H).LCMS(ESI)m / z C 19 H 21 Calculated value of N5O3 is 367.2, measured value is 368.3 [M+H] + .

[0256] Example 106: N-(2-amino-2-methylpropyl)-6-(3-chloro-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide [ka] The title compound was prepared in the following manner. [ka]

[0257] To a solution of compound 2-1 (500 mg, 0.842 mmol) in acetone (5 mL) was added NCS (248 mg, 1.26 mmol) at 0° C. The reaction mixture was stirred at rt for 16 h. The reaction was quenched with aqueous saturated NaHCO3 and the mixture was extracted with EtOAc. The organic layer was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / hexanes gradient 10-15%) to give tert-butyl 2-(6-((2-((tert-butoxycarbonyl)amino)-2-methylpropyl)carbamoyl)pyrazin-2-yl)-3-chloro-5-(trifluoromethoxy)-1H-indole-1-carboxylate (300 mg, 57% yield). LCMS (ESI) m / z C 28 H 33 Calculated value for ClF3N5O6: 627.2, Found value: 628.2 (M+H) + . [ka]

[0258] To a solution of compound 106-1 (80 mg, 0.608 mmol) in 1,4-dioxane (1 mL) was added HCl in 1,4-dioxane (1 mL, 4N) at 0° C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated in vacuo. The residue was triturated with diethyl ether to give the crude product, which was further purified by preparative HPLC (column: ZORBAX (150 mm×21.2 mm), 5.0 μ), phase A: 0.1% HCl in water; phase B: CH3CN (%A: 0, 2, 10, %B: 30, 35, 55) to give the title compound (20 mg, 37% yield). 1 H NMR(500MHz,DMSO-d6)δ 13.34(s,1H),9.97(t,J=6.6Hz,1H),9.75(s,1H),9.18(s,1H),8.18(s,3H),7.77(d,J=8.9Hz ,1H),7.57(d,J=2.3Hz,1H),7.34(dd,J=8.8,2.4Hz,1H),3.63(d,J=6.6Hz,2H),1.34(s,6H). 19F NMR(470MHz,DMSO-d6)δ -57.0.LCMS(ESI)m / z C 18 H 17 Calculated value for ClF3N5O2: 427.1, Measured value: 428.3 [M+H] + .

[0259] Example 107: N-(2-amino-2-methylpropyl)-2-(6-((2-amino-2-methylpropyl)carbamoyl)pyrazin-2-yl)-3-methyl-1H-indole-5-carboxamide [ka] The title compound was prepared in the following manner. [ka] To a suspension of methyl 2-(6-((2-((tert-butoxycarbonyl)amino)-2-methylpropyl)carbamoyl)pyrazin-2-yl)-3-methyl-1H-indole-5-carboxylate (compound 48-1) (68 mg, 0.141 mmol) in MeOH (1 mL) was added aqueous NaOH (0.4 mL, 0.8 mmol, 2 M). The reaction mixture was stirred overnight at rt and at 80° C. for 1.5 h. THF (1 m) was added and the reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was diluted with water and Et2O and the resulting mixture was acidified with aqueous KHSO4. The resulting product was collected by filtration, washed with water and dried to give 2-(6-((2-((tert-butoxycarbonyl)amino)-2-methylpropyl)carbamoyl)pyrazin-2-yl)-3-methyl-1H-indole-5-carboxylic acid (65 mg, 99% yield). LCMS (ESI) m / z C 24 H 29 Calculated value for N5O5: 467.2, measured value: 468.1 (M+H) + . [ka]

[0260] To a mixture of compound 107-1 (34 mg, 0.093 mmol) and tert-butyl (1-amino-2-methylpropan-2-yl)carbamate (21 mg, 0.111 mmol) in DMF (0.4 mL) was added i-Pr2NEt (0.032 mL, 0.185 mmol), followed by HATU (53 mg, 0.139 mmol). The reaction mixture was stirred at rt for 1.5 h. After dilution with EtOAc, the mixture was washed with aqueous KHSO4, water, saturated aqueous NaHCO3, water, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / heptane gradient 0-80%) to give tert-butyl (1-(6-(5-((2-((tert-butoxycarbonyl)amino)-2-methylpropyl)carbamoyl)-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamido)-2-methylpropan-2-yl)carbamate (LCMS (ESI) m / z C 33 H 47 Calculated value for N7O6: 637.4, Measured value: 638.4 (M+H) + ), which was treated with HCl in 1,4-dioxane in MeOH at rt overnight. After concentration, the residue was triturated with MeOH-CH3CN, collected by filtration, washed with MeOH-CH3CN and dried to give the title compound (11.9 mg, 25% yield for two steps). 1 H NMR(500MHz,DMSO-d6)δ 12.49(s,1H),9.80(t,J=6.6Hz,1H),9.38(s,1H),9.11(s,1H),8.76(t ,J=6.3Hz,1H),8.15(d,J=1.4Hz,1H),8.13(s,3H),7.90(s,3H),7.78(d ,J=8.5Hz,1H),7.68(dd,J=8.5,1.5Hz,1H),3.62(d,J=6.7Hz,2H),3.48(d,J=6.2Hz,2H),2.72(s,3H),1.34(s,6H),1.30(s,6H).LCMS(ESI)m / z C 23 H 31Calculated value for N7O2: 437.3, measured value: 438.2 [M+H] + .

[0261] Example 108: 5-(6-((2-amino-2-methylpropyl)carbamoyl)pyrazin-2-yl)-4H-thieno[3,2-b]pyrrole-2-carboxamide [ka] The title compound was prepared in the following manner. [ka]

[0262] To a solution of ethyl 5-(6-((2-((tert-butoxycarbonyl)amino)-2-methylpropyl)carbamoyl)pyrazin-2-yl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (compound 53-1) (60 mg, 0.123 mmol) in EtOH (0.2 mL)-THF (0.5 mL) was added aqueous NaOH (0.123 mL, 0.246 mmol, 2 M). The reaction mixture was stirred at rt for 13 h, then aqueous KOH (51 mg in 0.13 mL water) and EtOH (0.23 mL) were added. The reaction mixture was stirred at rt for 96 h. The mixture was transferred to a separatory funnel using Et2O and water. The aqueous layer was separated. The Et2O layer was extracted with water. The combined aqueous layers were washed again with Et2O. The aqueous layer was acidified with aqueous KHSO4 and extracted with EtOAc (x2). The organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give 5-(6-((2-((tert-butoxycarbonyl)amino)-2-methylpropyl)carbamoyl)pyrazin-2-yl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid (53 mg, 93% yield). LCMS (ESI) m / z C 21 H 25 Calculated value for N5O5S: 459.2, measured value: 460.2 (M+H) + . [ka]

[0263] To a solution of compound 108-1 (26 mg, 0.057 mmol) and ammonium chloride (6.1 mg, 0.113 mmol) in DMF (0.2 mL) was added i-Pr2NEt (0.039 mL, 0.226 mmol), followed by HATU (32 mg, 0.085 mmol). The reaction mixture was stirred at rt for 30 min. After dilution with EtOAc, the mixture was washed with aqueous KHSO4, water, saturated aqueous NaHCO3, water, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with MeOH-CH3CN, collected by filtration, washed with CH3CN and dried to give tert-butyl (1-(6-(2-carbamoyl-4H-thieno[3,2-b]pyrrol-5-yl)pyrazine-2-carboxamido)-2-methylpropan-2-yl)carbamate (23 mg, 90% yield). LCMS (ESI) m / z C 21 H 26 Calculated value for N6O4S: 458.2, measured value: 459.3 (M+H) + . [ka]

[0264] To a suspension of compound 108-2 (23 mg, 0.050 mmol) in MeOH (0.5 mL) was added HCl in 1,4-dioxane (1 mL, 4 mmol, 4 M). The reaction mixture was stirred at rt for 30 min. The reaction mixture was concentrated in vacuo. The residue was triturated with MeOH-CH3CN, collected by filtration, washed with MeOH-CH3CN, and dried to give the title compound. 1H NMR(500MHz,DMSO-d6)δ 12.54(d,J=2.0Hz,1H),9.62(t,J=6.7Hz,1H),9.38(s,1H),8.97(s,1H),8.09(s,1H),7.97(s,3H), 7.85(s,1H),7.51(d,J=1.8Hz,1H),7.40(s,1H),3.58(d,J=6.7Hz,2H),1.33(s,6H).LCMS(ESI)m / z C 16 H 18 Calculated value of N6O2S is 358.1, measured value is 359.2 [M+H] + .

[0265] Example 109: 5-(6-((2-amino-2-methylpropyl)carbamoyl)pyrazin-2-yl)-N,N-dimethyl-4H-thieno[3,2-b]pyrrole-2-carboxamide [ka] Example 109 was prepared in a similar manner to example 108 from 5-(6-((2-((tert-butoxycarbonyl)amino)-2-methylpropyl)carbamoyl)pyrazin-2-yl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid. 1 H NMR(500MHz,DMSO-d6)δ 12.51(s,1H),9.57(t,J=6.6Hz,1H),9.39(s,1H),8.97(s,1H),7.97(s,3H),7.52(d,J= 1.8Hz,1H),7.49(s,1H),3.58(d,J=6.7Hz,3H),3.18(s,6H),1.33(s,6H).LCMS(ESI)m / z C 18 H 22 Calculated value of N6O2S is 386.2, measured value is 387.2 [M+H] + .

[0266] Example 110: N-(2-amino-2-methylpropyl)-6-(5-fluoro-6-hydroxy-1H-indol-2-yl)pyrazine-2-carboxamide [ka] The title compound was prepared in the following manner. [ka] To a solution of tert-butyl 2-(6-((2-((tert-butoxycarbonyl)amino)-2-methylpropyl)carbamoyl)pyrazin-2-yl)-5-fluoro-6-methoxy-1H-indole-1-carboxylate (compound 37-1) (60 mg, 0.131 mmol) in CHCl (3 mL) at −78° C., BBr (0.3 mL, 0.393 mmol) was added. The reaction mixture was stirred at −78° C. to rt for 16 h. The reaction was quenched with MeOH and the mixture was concentrated in vacuo. The residue was purified by preparative HPLC (mobile phase: A=0.1% HCOOH in water B=CHCN column: LUNA C18 (250 mm×19 mm), 4.0μ flow rate: 15 mL / min) to give the title compound. 19 F NMR(376MHz,DMSO-d6)δ -142.8.LCMS(ESI)m / z C 17 H 18 Calculated value of FN5O2: 343.1 Measured value: 344.1 [M+H] + .

[0267] Biological Assays and Data The activity of the compounds according to the invention may be evaluated by the following in vitro methods: The compounds of formula (I), or pharma- ceutically acceptable salts thereof, exhibit beneficial pharmacological properties, e.g., as shown in the tests described in the following paragraphs, and are therefore therapeutically indicated, e.g., in the treatment of Plasmodium-associated diseases (e.g., malaria).

[0268] The following assay is illustrative of the invention and is not intended to limit the scope of the invention in any way. This parasite proliferation assay measures the increase in parasite DNA content using the DNA intercalating dye SYBR Gree®.

[0269] 3D7 P. falciparum strain is grown in complete culture medium to a parasitemia of 3%-8% in O+ human erythrocytes. 20 μl of screening medium is dispensed into a 384-well assay plate. 50 nl of compounds of the invention in DMSO, including antimalarial controls (mefloquine, pyrimethamine, and artemisinin), and DMSO alone are transferred to serve as a negative control for inhibition. 30 μl of a suspension of 3D7 P. falciparum infected erythrocytes in screening medium is then dispensed into the assay plate to a final hematocrit of 2.5% and a final parasitemia of 0.3%. The plate is placed in a 37° C. incubator for 72 hours in a hypoxic environment containing 93% N2, 4% CO2, and 3% O2 ​​gas mixture. The plate is dispensed with 10 μl of lysis buffer (saponin, Triton-X, EDTA) containing a 10× solution of SYBR Green I® in RPMI medium. The plate is covered and kept at room temperature overnight to allow the infected red blood cells to lyse. Fluorescence intensity is measured (excitation 425 nm, emission 530 nm) using an Envision™ system (Perkin Elmer). For each compound, the 50% inhibition rate (EC 50 ) is calculated.

[0270] The biological activity in certain examples is shown in the table below:+>EC50 0.1 μM;EC50 0.1 μM>++>EC50 0.01 μM;+++ <EC50 0.01μM。

[0271] [Table 33]

[0272] [Table 34]

[0273] [Table 35]

[0274] As shown in the above table, the compounds of the present invention have precise activity: the compounds of the present invention can significantly slow down the increase in parasitemia.

[0275] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and are to be included within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

Claims

1. Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, R １ is i) H or ii) (C １ ~C ３ ) alkyl; portion: 【Chemistry 2】 teeth, 【Transformation 3】 is selected from the group consisting of R ２ i) C １ ~C ３ alkyl, ii) halo, iii) hydrogen, iv) C １ ~C ３ haloalkyl, or v) cyano; Each X ２ are independently N and CR ３ and wherein at least one X is selected from the group consisting of ２ is CR ３ and Each R ３ are independently hydrogen, halo, SF ５ , C １ ~C ３ Alkyl, hydroxyl, cyano, O—C １ ~C ３ Alkyl, SO ２ -C １ ~C ３ Alkyl, C(O)O-C １ ~C ３ Alkyl, O-C １ ~C ３ Haloalkyl, C １ ~C ３ Haloalkyl, CH ２ NH ２ , OCH ２ C ６ H ５ , C(O)-N(H)-C １ ~C ４ Alkylene-NH ２ , and 【Chemistry 4】 is selected from the group consisting of R ４ is C １ ~C ３ Alkyl, C(O)N(R ５ ) ２ , or CO ２ C １ ~C ３ is alkyl; Each R ５ are independently H or C １ ~C ３ is alkyl; Each R ６ is H or two R ６ the groups together form an oxo; Each R ７ are independently H and C １ ~C ３ selected from the group consisting of alkyl; L １ is i) absent or ii) optionally OH or C ３～ C ６ C substituted with cycloalkyl １ ~C ５ alkylene; X １ i) H, ii) OH, iii)NH ２ 、 iv) a) NH ２ C substituted with a substituent ３ ~C ６ cycloalkyl, b) NH ２ C substituted with a substituent ３ ~C ６ c) a 4- to 6-membered heterocyclyl containing one heteroatom selected from O and N, and ２ 4-6 membered heterocyclyl substituted by 【Transformation 5】 (wherein Z is N or CH, Y is O or NH, n is 1 or 2, and m is 1 or 2). and However, L １ If does not exist, then X １ Is H, OH, or NH ２ But not, The compound or a pharmaceutically acceptable salt thereof.

2. R １ is H, or a pharmaceutically acceptable salt thereof.

3. L １ is unsubstituted C １ ~C ５ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is alkylene.

4. X １ teeth, iv)NH ２ 、 v) a) NH ２ C substituted with ３ ~C ６ cycloalkyl, b) NH ２ C substituted with ３ c) a 4- to 6-membered heterocyclyl containing one heteroatom selected from O and N, and ２ 4-6 membered heterocyclyl substituted by 【Transformation 6】 (wherein Z is CH, Y is NH, n is 1 or 2, and m is 1 or 2).

2. The compound of claim 1, wherein:

5. X １ is NH ２ 5. The compound of claim 4, wherein:

6. portion: 【Chemistry 9】 teeth, 【Chemistry 10】 6. The compound of claim 5, wherein:

7. R ２ is CH ３ 2. The compound of claim 1, wherein:

8. The portion: 【Chemistry 17】 teeth, [Chemistry 18] 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

9. The portion: 【Chemistry 19】 teeth, 【Chemistry 20】 2. The compound of claim 1, wherein:

10. The portion: 【Chemistry 23】 teeth, 【Chemistry 24】 and p is 1 or 2, and each R ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is independently selected from the group consisting of halo, SF5, methyl, C(O)OMe, and OC1 haloalkyl.

11. The portion: 【Chemistry 26】 teeth, 【Chemistry 27】 11. The compound of claim 10, wherein:

12. The portion: 【Chemistry 28】 teeth, 【Chemistry 29】 12. The compound of claim 11, wherein:

13. R ３ Ha, Halo, OCF ３ , S.F. ５ , or OCHF ２ 12. The compound of claim 11, wherein:

14. R ３ is SF ５ 14. The compound of claim 13, wherein:

15. N-(2-amino-2-methylpropyl)-6-(6-chloro-7-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-methyl-5-(pentafluoro-λ ６ -sulfanail)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-chloro-7-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-chloro-5-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-chloro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-((1-aminocyclobutyl)methyl)-6-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-methyl-6-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-((1S,2S)-2-aminocyclopentyl)-6-(6-chloro-5-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(3-amino-3-methylbutyl)-6-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-methyl-6-(pentafluoro-λ ６ -sulfanail)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-chloro-6-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-chloro-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3,6-dimethyl-1H-indol-2-yl)pyrazine-2-carboxamide; Ethyl 5-(6-((2-amino-2-methylpropyl)carbamoyl)pyrazin-2-yl)-6-methyl-4H-thieno[3,2-b]pyrrole-2-carboxylate; N-(2-amino-2-methylpropyl)-6-(5-bromo-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-(4-aminopiperidin-1-yl)ethyl)-6-(6-chloro-5-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-chloro-7-fluoro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-chloro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-chloro-7-fluoro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-(difluoromethoxy)-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-cyclopropylethyl)-6-(6-chloro-5-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-(difluoromethoxy)-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-(pentafluoro-λ ６ -sulfanail)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-aminoethyl)-6-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-chloro-5-fluoro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3,5-dimethyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-((4-aminotetrahydro-2H-pyran-4-yl)methyl)-6-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-((4-aminotetrahydro-2H-pyran-4-yl)methyl)-6-(6-chloro-5-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; (S)—N-(2-amino-2-cyclopropylethyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; Methyl 2-(6-((2-amino-2-methylpropyl)carbamoyl)pyrazin-2-yl)-3-methyl-1H-indole-5-carboxylate; (R)—N-(2-amino-2-cyclopropylethyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-isopropyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-((1-aminocyclopropyl)methyl)-6-(6-chloro-5-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-((1-aminocyclobutyl)methyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-((1-amino-3,3-difluorocyclobutyl)methyl)-6-(6-chloro-5-fluoro-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(2,6-dimethyl-4H-thieno[3,2-b]pyrrolo-5-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-chloro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-N-methyl-6-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-chloro-6-fluoro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-(trifluoromethyl)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-chloro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(3-aminopropyl)-6-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(3-amino-3-methylbutyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-ethyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5,6-difluoro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-isopropyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-fluoro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(3-aminobicyclo[1.1.1]pentan-1-yl)-6-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-(benzyloxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5,7-difluoro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(7-fluoro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-fluoro-1H-indol-2-yl)pyrazine-2-carboxamide; Ethyl 5-(6-((2-amino-2-methylpropyl)carbamoyl)pyrazin-2-yl)-4H-thieno[3,2-b]pyrrole-2-carboxylate; N-(2-aminoethyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(3-aminobicyclo[1.1.1]pentan-1-yl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(1-amino-2-methylpropan-2-yl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(7-chloro-1H-indol-2-yl)pyrazine-2-carboxamide; N-((4-aminotetrahydro-2H-pyran-4-yl)methyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; Methyl 2-(6-((2-amino-2-methylpropyl)carbamoyl)pyrazin-2-yl)-1H-indole-6-carboxylate; N-((1r,4r)-4-aminocyclohexyl)-6-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; Methyl 2-(6-((2-amino-2-methylpropyl)carbamoyl)pyrazin-2-yl)-1H-indole-5-carboxylate; N-(2-amino-2-methylpropyl)-6-(3-(trifluoromethyl)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(3-aminopropyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(azetidin-3-yl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(4-methoxy-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-methoxy-1H-indol-2-yl)pyrazine-2-carboxamide; N-(3-aminocyclopentyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(4,5,6,7-tetrahydro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-methoxy-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-N-methyl-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-cyano-1H-indol-2-yl)pyrazine-2-carboxamide; 6-(3-methyl-1H-indol-2-yl)-N-(piperidin-4-yl)pyrazine-2-carboxamide; N-(2-amino-3-hydroxypropyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-((3-aminooxetan-3-yl)methyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-cyano-1H-indol-2-yl)pyrazine-2-carboxamide; 6-(3-methyl-1H-indol-2-yl)-N-(2-methyl-2-morpholinopropyl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-fluoro-6-methoxy-1H-indol-2-yl)pyrazine-2-carboxamide; N-((1r,4r)-4-aminocyclohexyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)pyrazine-2-carboxamide; N-((1r,4r)-4-aminocyclohexyl)-6-(5-(trifluoromethoxy)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5,7-dichloro-1H-pyrrolo[2,3-c]pyridin-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(6-chloro-1H-pyrrolo[3,2-c]pyridin-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(4-chloro-1H-pyrrolo[3,2-c]pyridin-2-yl)pyrazine-2-carboxamide; (rac)-N-((1r,2s)-2-aminocyclohexyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; (rac)-N-((3r,4s)-4-aminotetrahydrofuran-3-yl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-cyano-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-methyl-5-(2-oxopyrrolidin-1-yl)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(3-methyl-5-(methylsulfonyl)-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-hydroxy-2-methylpropyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; (rac)-N-((1r,2r)-2-aminocyclohexyl)-6-(3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; 6-(3-methyl-1H-indol-2-yl)-N-neopentylpyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(7-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(1H-pyrrolo[2,3-c]pyridin-2-yl)pyrazine-2-carboxamide; 5-(6-((2-amino-2-methylpropyl)carbamoyl)pyrazin-2-yl)-4H-thieno[3,2-b]pyrrole-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-(aminomethyl)-3-methyl-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-phenyl-1H-pyrrol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(5-fluoro-6-hydroxy-1H-indol-2-yl)pyrazine-2-carboxamide; N-(2-amino-2-methylpropyl)-6-(7-methoxy-1H-indol-2-yl)pyrazine-2-carboxamide; 5-(6-((2-amino-2-methylpropyl)carbamoyl)pyrazin-2-yl)-N,N-dimethyl-4H-thieno[3,2-b]pyrrole-2-carboxamide; and pharmaceutically acceptable salts thereof 2. The compound of claim 1 selected from the group consisting of:

16. Formula (IIb): 【Transformation 36】 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

17. Formula (IIc): (IIc). 【Chemistry 37】 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

18. 20. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use in the treatment of a Plasmodium-associated disease.

19. 19. The compound for use according to claim 18, wherein the Plasmodium associated disease is malaria.

20. The compound for use according to claim 18, wherein the compound is administered in combination with one or more therapeutically active agents selected from kinase inhibitors, antimalarials, and anti-inflammatory agents.

21. 21. The compound for use of claim 20, wherein the active agent is an antimalarial selected from proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, ampicillin, sulfonamides, artemisinin, artefren, artemether, artesunate, primaquine, pyronaridine, KAE-609, KAF-156, and INE963.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 and one or more pharmaceutically acceptable carriers.

Images