Benzimidazole derivatives as adenosine receptor antagonists
11453647 · 2022-09-27
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C07D491/107
CHEMISTRY; METALLURGY
C07D491/113
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A61P31/00
HUMAN NECESSITIES
A61K45/06
HUMAN NECESSITIES
C07D491/052
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C07D413/04
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C07D403/12
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C07D401/12
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C07D405/04
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C07D235/32
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C07D403/04
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C07D403/10
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C07D491/048
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C07D235/30
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International classification
C07D235/30
CHEMISTRY; METALLURGY
C07D491/048
CHEMISTRY; METALLURGY
C07D413/04
CHEMISTRY; METALLURGY
C07D405/04
CHEMISTRY; METALLURGY
C07D403/12
CHEMISTRY; METALLURGY
C07D403/10
CHEMISTRY; METALLURGY
C07D403/04
CHEMISTRY; METALLURGY
C07D401/12
CHEMISTRY; METALLURGY
A61K45/06
HUMAN NECESSITIES
C07D491/113
CHEMISTRY; METALLURGY
C07D491/107
CHEMISTRY; METALLURGY
Abstract
The invention relates to benzimidazole derivatives of the general formula I, ##STR00001##
and the use of the compounds of the present invention for the treatment and/or prevention of hyperproliferative or infectious diseases and disorders in mammals, especially humans, and pharmaceutical compositions containing such compound.
Claims
1. A compound of formula I, ##STR00379## wherein Q, Y are CH, R.sup.1 is Br or one of the following structures: ##STR00380## which is unsubstituted or mono-, di- or trisubstituted with R.sup.4, R.sup.2 is one of the following structures: ##STR00381## which is unsubstituted or mono-, di- or trisubstituted with R.sup.5 R.sup.3 is OCH.sub.3, R.sup.4 is H, R.sup.5, ═S, ═NR.sup.5, ═O, OH, COOH, Hal, NH.sub.2, SO.sub.2CH.sub.3, SO.sub.2NH.sub.2, CN, CONH.sub.2, NHCOCH.sub.3, NHCONH.sub.2, NO.sub.2, or linear or branched alkyl having 1-10 C atoms which is unsubstituted or mono-, di- or trisubstituted by R.sup.5 and in which 1-4 C atoms may be replaced, independently of one another, by O, S, SO, SO.sub.2, NH, NCH.sub.3, —OCO—, —NHCONH—, —NHCO—, —COO—, —CONH—, —NCH.sub.3CO—, —CONCH.sub.3—, —C≡C— groups and/or —CH═CH— groups, and/or, in addition, 1-10 H atoms may be replaced by F and/or CI, or mono-or bicyclic cyclic alkyl having 3-7 C atoms which is unsubstituted or mono-, di- or trisubstituted by R.sup.5 and in which 1-4 C atoms may be replaced, independently of one another, by O, S, SO, SO.sub.2, NH, NCH.sub.3, —OCO—, —NHCONH—, —NHCO—, —COO—, —CONH—, —NCH.sub.3CO—, —CONCH.sub.3—, —C≡C— groups and/or by —CH═CH— groups and/or, in addition, 1-10 H atoms may be replaced by F and/or CI, or mono- or bicyclic heteroaryl, heterocyclyl, aryl or cyclic alkylaryl, containing 3 to 14 carbon atoms and 0-4 heteroatoms, independently selected from N, O and S, which is unsubstituted or mono-, di- or trisubstituted by R.sup.5, R.sup.5, R.sup.6 are independently of one another selected from the group consisting of H, ═S, ═NH, ═O, OH, COOH, Hal, NH.sub.2, SO.sub.2CH.sub.3, SO.sub.2NH.sub.2, CN, CONH.sub.2, NHCOCH.sub.3, NHCONH.sub.2, NO.sub.2 and linear or branched alkyl having 1-10 C atoms in which 1-4 C atoms may be replaced, independently of one another, by O, S, SO, SO.sub.2, NH, NCH.sub.3, —OCO—, —NHCONH—, —NHCO—, —COO—, —CONH—, —NCH.sub.3CO—, —CONCH.sub.3—, —C≡C— groups and/or —CH═CH— groups, and/or, in addition, 1-10 H atoms may be replaced by F and/or CI, Hal is F, C, Br, or I, or physiologically acceptable salts, solvates, prodrugs or stereoisomers thereof, including mixtures thereof in all ratios.
2. The compound according to claim 1, wherein R.sup.1 is ##STR00382##
3. Compound according to claim 1, wherein R.sup.1 is Br or one of the following structures: ##STR00383## which is unsubstituted or mono-, di- or trisubstituted with R.sup.5 and physiologically acceptable salts, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.
4. A compound selected from the group consisting of: TABLE-US-00009 No. IUPAC-Name 2 4-Fluoro-N-(7-methoxy-4-phenyl-1H-benzoimidazol-2-yl)- benzamide, 3 2-Bromo-N-(7-methoxy-4-phenyl-1H-benzoimidazol-2-yl)- isonicotinamide, 4 2-Bromo-N-(4-bromo-7-methoxy-1H-benzoimidazol-2-yl)- isonicotinamide, 5 6-Bromo-N-(7-methoxy-4-phenyl-1H-benzoimidazol-2-yl)- nicotinamide, 6 6-Bromo-N-(4-bromo-7-methoxy-1H-benzoimidazol-2-yl)- nicotinamide, 7 N-(7-Methoxy-4-phenyl-1H-benzoimidazol-2-yl)-2-morpholin-4-yl- isonicotinamide, 8 N-(7-Methoxy-4-phenyl-1H-benzoimidazol-2-yl)-6-morpholin-4-yl- nicotinamide, 9 N′-(7-Methoxy-4-phenyl-1H-benzoimidazol-2-yl)-N,N-dimethyl- formamidine, 10 4-Chloromethyl-N-(7-methoxy-4-phenyl-1H-benzoimidazol-2-yl)- benzamide, 11 4-Ethylaminomethyl-N-(7-methoxy-4-phenyl-1H-benzoimidazol-2- yl)-benzamide, 12 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid (7-methoxy-4- phenyl-1H-benzoimidazol-2-yl)-amide, 13 4-Aminomethyl-N-(7-methoxy-4-phenyl-1H-benzoimidazol-2-yl)- benzamide, 15 4-Imidazol-1-ylmethyl-N-(7-methoxy-4-phenyl-1H-benzoimidazol-2- yl)-benzamide, 16 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid (4-cyclohexyl-7- methoxy-1H-benzoimidazol-2-yl)-amide, 17 N-(4-Cyclohexyl-7-methoxy-1H-benzoimidazol-2-yl)-2-morpholin-4- yl-isonicotinamide, 21 4-hydroxy-N-(7-methoxy-4-morpholino-1H-benzimidazol-2-yl)-4- methyl-piperidine-1-carboxamide, 22 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid [7-methoxy-4-(1- methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]-amide, 23 N-(7-Methoxy-4-morpholin-4-yl-1H-benzoimidazol-2-yl)-2- morpholin-4-yl-isonicotinamide, 24 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid [7-methoxy-4- (tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 26 N-[7-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]- 2-morpholin-4-yl-isonicotinamide, 28 4-Methyl-piperidine-1-carboxylic acid (7-methoxy-4-phenyl-1H- benzoimidazol-2-yl)-amide, 29 N-[7-Methoxy-4-(tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-yl]-6- morpholin-4-yl-nicotinamide, 30 2-(3-Hydroxy-3-methyl-pyrrolidin-1-yl)-N-[7-methoxy-4-(1-methyl- 1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]-isonicotinamide, 31 3-Hydroxy-3-methyl-pyrrolidine-1-carboxylic acid [7-methoxy-4-(1- methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]-amide, 32 4-Hydroxy-4-trifluoromethyl-piperidine-1-carboxylic acid [7- methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]- amide, 33 2-Oxa-7-aza-spiro[3.5]nonane-7-carboxylic acid [7-methoxy-4-(1- methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]-amide, 34 4-Difluoromethyl-4-hydroxy-piperidine-1-carboxylic acid [7- methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]- amide, 35 4-Hydroxymethyl-4-methyl-piperidine-1-carboxylic acid [7-methoxy- 4-(1-methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]-amide, 36 4-Fluoromethyl-4-hydroxy-piperidine-1-carboxylic acid [7-methoxy- 4-(1-methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]-amide, 37 4-Methoxy-piperidine-1-carboxylic acid [7-methoxy-4-(1-methyl-1H- pyrazol-4-yl)-1H-benzoimidazol-2-yl]-amide, 38 3-Oxa-9-aza-spiro[5.5]undecane-9-carboxylic acid [7-methoxy-4- (1-methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]-amide, 39 4-Methyl-piperidine-1-carboxylic acid [7-methoxy-4-(1-methyl-1H- pyrazol-4-yl)-1H-benzoimidazol-2-yl]-amide, 40 4-Hydroxy-piperidine-1-carboxylic acid [7-methoxy-4-(1-methyl-1H- pyrazol-4-yl)-1H-benzoimidazol-2-yl]-amide, 41 4-Benzyl-4-hydroxy-piperidine-1-carboxylic acid [7-methoxy-4-(1- methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]-amide, 42 N-[4-methoxy-7-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- c]pyridin-2-yl]-2-(morpholin-4-yl)pyridine-4-carboxamide, 43 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-2-oxa-6-azaspiro[3.4]octane-6-carboxamide, 44 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxamide, 45 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxamide, 46 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]morpholine-4-carboxamide, 47 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide, 48 4-[(dimethylamino)methyl]-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4- yl)-1H-1,3-benzodiazol-2-yl]benzamide, 49 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-4-(methoxymethyl)benzamide, 50 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide, 51 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-2-oxo-1,8-diazaspiro[4.5]decane-8-carboxamide, 52 4-(2-hydroxyethyl)-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H- 1,3-benzodiazol-2-yl]-1,2,3,6-tetrahydropyridine-1-carboxamide, 53 3-butyl-4-hydroxy-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H- 1,3-benzodiazol-2-yl]piperidine-1-carboxamide, 54 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-4-phenoxypiperidine-1-carboxamide, 55 4-hydroxy-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3- benzodiazol-2-yl]-4-(pyridin-3-yl)piperidine-1-carboxamide, 56 4-hydroxy-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3- benzodiazol-2-yl]-3-(2-methylpropyl)piperidine-1-carboxamide, 57 N-[4-(2,6-dimethylpyridin-4-yl)-7-methoxy-1H-1,3-benzodiazol-2- yl]-2-(morpholin-4-yl)pyridine-4-carboxamide, 58 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-4-oxopiperidine-1-carboxamide, 60 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide, 62 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-1-methyl-5-oxo-1,4,9-triazaspiro[5.5]undecane-9-carboxamide, 63 4-fluoro-N-[7-methoxy-4-(morpholin-4-yl)-1H-1,3-benzodiazol-2- yl]benzamide, 64 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-6-oxaspiro[2.5]octane-1-carboxamide, 65 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-5-{3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy}pyrazine-2- carboxamide, 66 (chloromethyl)({2-[(1-{[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H- 1,3-benzodiazol-2-yl]carbamoyl}-4-methylpiperidin-4- yl)oxy]ethyl})dimethylazanium hydrochloride, 67 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-7-oxa-2-azaspiro[4.5]decane-2-carboxamide, 68 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-8-oxa-2-azaspiro[4.5]decane-2-carboxamide, 69 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-2-oxa-7-azaspiro[4.4]nonane-7-carboxamide, 70 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-3-oxabicyclo[3.1.0]hexane-6-carboxamide, 71 4-[(1H-imidazol-1-yl)methyl]-N-[7-methoxy-4-(1-methyl-1H-pyrazol- 4-yl)-1H-1,3-benzodiazol-2-yl]benzamide, 72 (1S,2S)-2-bromo-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H- 1,3-benzodiazol-2-yl]cyclopropane-1-carboxamide, 73 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-5-(2-methoxyethoxy)pyrazine-2-carboxamide, 74 4-hydroxy-N-[7-methoxy-4-(pyridin-4-yl)-1H-1,3-benzodiazol-2-yl]- 4-methylpiperidine-1-carboxamide, 75 4-benzyl-4-hydroxy-N-[7-methoxy-4-(morpholin-4-yl)-1H-1,3- benzodiazol-2-yl]piperidine-1-carboxamide, 76 4-[(1H-imidazol-1-yl)methyl]-N-[7-methoxy-4-(morpholin-4-yl)-1H- 1,3-benzodiazol-2-yl]benzamide, 77 N-[7-methoxy-4-(morpholin-4-yl)-1H-1,3-benzodiazol-2-yl]-1- benzofuran-5-carboxamide, 78 4-hydroxy-N-{7-methoxy-4-[1-(oxan-2-yl)-1H-pyrazol-4-yl]-1H-1,3- benzodiazol-2-yl}-4-methylpiperidine-1-carboxamide, 79 4-hydroxy-N-[7-methoxy-4-(1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-4-methylpiperidine-1-carboxamide, 80 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-1-benzofuran-5-carboxamide, 81 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-5-(morpholin-4-yl)pyrazine-2-carboxamide, 82 4-hydroxy-N-[4-methoxy-7-(1-methyl-1H-pyrazol-4-yl)-3H- imidazo[4,5-c]pyridin-2-yl]-4-methylpiperidine-1-carboxamide, 83 4-benzyl-4-hydroxy-N-[4-methoxy-7-(1-methyl-1H-pyrazol-4-yl)-3H- imidazo[4,5-c]pyridin-2-yl]piperidine-1-carboxamide, 84 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-1,2-oxazole-3-carboxamide, 85 N-[7-methoxy-4-(pyridin-4-yl)-1H-1,3-benzodiazol-2-yl]-2-oxa-6- azaspiro[3.4]octane-6-carboxamide, 86 1-(1-chloro-3-hydroxypropan-2-yl)-N-[7-methoxy-4-(morpholin-4- yl)-1H-1,3-benzodiazol-2-yl]-1H-pyrazole-4-carboxamide, 87 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-6-(morpholin-4-yl)pyridazine-3-carboxamide, 88 4-[(dimethylamino)methyl]-N-[7-methoxy-4-(oxan-4-yl)-1H-1,3- benzodiazol-2-yl]benzamide, 89 4-[(dimethylamino)methyl]-N-[7-methoxy-4-(pyridin-4-yl)-1H-1,3- benzodiazol-2-yl]benzamide, 90 4-[(dimethylamino)methyl]-N-[7-methoxy-4-(morpholin-4-yl)-1H-1,3- benzodiazol-2-yl]benzamide, 91 N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-6-(morpholin- 4-yl)pyridazine-3-carboxamide, 92 4-hydroxy-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3- benzodiazol-2-yl]-4-(prop-2-yn-1-yl)piperidine-1-carboxamide, 93 N4-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-N1,N1-dimethylbenzene-1,4-dicarboxamide, 94 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-4-(trifluoromethoxy)benzamide, 95 2-bromo-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3- benzodiazol-2-yl]pyridine-4-carboxamide, 96 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-2-methyl-1,3-oxazole-4-carboxamide, 97 4-[(1H-imidazol-1-yl)methyl]-N-[7-methoxy-4-(oxan-4-yl)-1H-1,3- benzodiazol-2-yl]benzamide, 98 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-1,3-benzoxazole-5-carboxamide, 99 3-amino-4-hydroxy-N-[7-methoxy-4-(morpholin-4-yl)-1H-1,3- benzodiazol-2-yl]benzamide, 100 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-4-[(2-oxopyrrolidin-1-yl)methyl]benzamide, 101 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-2,3-dihydro-1-benzofuran-5-carboxamide, 102 4-hydroxy-N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-4- (prop-2-yn-1-yl)piperidine-1-carboxamide, 103 4-benzyl-4-hydroxy-N-[7-methoxy-4-(oxan-4-yl)-1H-1,3- benzodiazol-2-yl]piperidine-1-carboxamide, 104 2-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]-N-[7-methoxy-4-(1- methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2-yl]pyridine-4- carboxamide, 105 2-(4-hydroxy-4-methylpiperidin-1-yl)-N-[7-methoxy-4-(1-methyl-1H- pyrazol-4-yl)-1H-1,3-benzodiazol-2-yl]pyridine-4-carboxamide, 106 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-2-{2-oxa-7-azaspiro[4.4]nonan-7-yl}pyridine-4-carboxamide, 107 2-[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]-N-[7-methoxy-4-(1- methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2-yl]pyridine-4- carboxamide, 108 N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-2,3-dihydro- 1-benzofuran-5-carboxamide, 109 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-3-(methoxymethyl)pyrrolidine-1-carboxamide, 110 N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-2-oxa-7- azaspiro[4.4]nonane-7-carboxamide, 111 N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-8-oxa-2- azaspiro[4.5]decane-2-carboxamide, 112 N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-hexahydro- 1H-furo[3,4-c]pyrrole-5-carboxamide, 113 (5R)-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3- benzodiazol-2-yl]-7-oxa-2-azaspiro[4.5]decane-2-carboxamide, 114 (5S)-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3- benzodiazol-2-yl]-7-oxa-2-azaspiro[4.5]decane-2-carboxamide, 115 (5S)-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3- benzodiazol-2-yl]-2-oxa-7-azaspiro[4.4]nonane-7-carboxamide, 116 (5R)-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3- benzodiazol-2-yl]-2-oxa-7-azaspiro[4.4]nonane-7-carboxamide, 117 N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-3- (methoxymethyl)pyrrolidine-1-carboxamide, 118 2-(4-hydroxy-4-methylpiperidin-1-yl)-N-[7-methoxy-4-(oxan-4-yl)- 1H-1,3-benzodiazol-2-yl]pyridine-4-carboxamide, 119 N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-2-{2-oxa-7- azaspiro[4.4]nonan-7-yl}pyridine-4-carboxamide, 120 2-(4-fluorophenoxy)-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)- 1H-1,3-benzodiazol-2-yl]-2-methylpropanamide, 121 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-hexahydro-1H-furo[3,4-c]pyrrole-5-carboxamide, 122 2-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-[7-methoxy-4-(oxan-4-yl)- 1H-1,3-benzodiazol-2-yl]pyridine-4-carboxamide, 123 N-[7-methoxy-4-(morpholin-4-yl)-1H-1,3-benzodiazol-2-yl]-2-oxa-7- azaspiro[4.4]nonane-7-carboxamide, 124 1-{[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]carbamoyl}piperidine-4-carboxylic acid, 125 N-[7-methoxy-4-(morpholin-4-yl)-1H-1,3-benzodiazol-2-yl]-8-oxa-2- azaspiro[4.5]decane-2-carboxamide, 126 N1-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]piperidine-1,4-dicarboxamide, 127 4-(diethylamino)-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H- 1,3-benzodiazol-2-yl]benzamide, 128 4-hydroxy-N-{7-methoxy-4-[1-(2-methylpropyl)-1H-pyrazol-4-yl]-1H- 1,3-benzodiazol-2-yl}-4-methylpiperidine-1-carboxamide, 129 N-[7-methoxy-4-(pyridin-4-yl)-1H-1,3-benzodiazol-2-yl]-8-oxa-2- azaspiro[4.5]decane-2-carboxamide, 130 2-(1-{[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2- yl]carbamoyl}piperidin-4-yl)acetic acid, 131 4-hydroxy-N-[7-methoxy-4-(2-methylphenyl)-1H-1,3-benzodiazol-2- yl]-4-methylpiperidine-1-carboxamide, 132 2-(1-{[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol- 2-yl]carbamoyl}piperidin-4-yl)acetic acid, 133 N4-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-N1,N1- dimethylbenzene-1,4-dicarboxamide, 134 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-3-(2-methoxyethyl)pyrrolidine-1-carboxamide, 135 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-5-(morpholin-4-yl)pyridine-2-carboxamide, 136 N-[7-methoxy-4-(morpholin-4-yl)-1H-1,3-benzodiazol-2-yl]-1- methyl-1H-pyrazole-4-carboxamide, 137 N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-3-(2- methoxyethyl)pyrrolidine-1-carboxamide, 138 N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-4-[(2- oxopyrrolidin-1-yl)methyl]benzamide, 139 N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-5-(morpholin- 4-yl)pyridine-2-carboxamide, 140 (3R)-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3- benzodiazol-2-yl]-3-(2-methoxyethyl)pyrrolidine-1-carboxamide, 141 (3S)-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3- benzodiazol-2-yl]-3-(2-methoxyethyl)pyrrolidine-1-carboxamide, 142 2-[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]-N-[7-methoxy-4-(oxan-4- yl)-1H-1,3-benzodiazol-2-yl]acetamide, 143 2-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]-N-[7-methoxy-4-(oxan-4- yl)-1H-1,3-benzodiazol-2-yl]acetamide, 144 N-[4-(4-fluorophenyl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-4- hydroxy-4-methylpiperidine-1-carboxamide, 145 tert-butyl 4-(4-{2-[(4-hydroxy-4-methylpiperidine-1-carbonyl)amino]- 4-methoxy-1H-1,3-benzodiazol-7-yl}-1H-pyrazol-1-yl)piperidine-1- carboxylate, 146 4-{[2-amino-7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3- benzodiazol-1-yl]methyl}benzoic acid, 147 (3S)-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3- benzodiazol-2-yl]-3-(methoxymethyl)pyrrolidine-1-carboxamide, 148 (3R)-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3- benzodiazol-2-yl]-3-(methoxymethyl)pyrrolidine-1-carboxamide, 149 (5S)-N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-2-oxa-7- azaspiro[4.4]nonane-7-carboxamide, 150 (5R)-N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-2-oxa-7- azaspiro[4.4]nonane-7-carboxamide, 151 4-hydroxy-N-{7-methoxy-4-[1-(3-methylbutyl)-1H-pyrazol-4-yl]-1H- 1,3-benzodiazol-2-yl}-4-methylpiperidine-1-carboxamide, 152 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-4-[(morpholin-4-yl)methyl]benzamide, 153 N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-2-[(5R)-2- oxa-7-azaspiro[4.4]nonan-7-yl]pyridine-4-carboxamide, 154 N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-2-[(5S)-2- oxa-7-azaspiro[4.4]nonan-7-yl]pyridine-4-carboxamide, 155 N-[4-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-1H-1,3-benzodiazol-2- yl]-4-hydroxy-4-methylpiperidine-1-carboxamide, 156 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-1-methyl-1H-1,2,3-triazole-4-carboxamide, 157 4-hydroxy-N-{4-methoxy-7-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H- 1,3-benzodiazol-2-yl}-4-methylpiperidine-1-carboxamide, 158 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-5-(2-methoxyethoxy)pyridine-2-carboxamide, 159 2-(1-{[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol- 2-yl]carbamoyl}piperidin-3-yl)acetic acid, 160 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-1-methyl-1H-pyrazole-4-carboxamide, 161 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-1-(2-methoxyethyl)-1H-pyrazole-4-carboxamide, 162 N5-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-N2,N2-dimethylpyridine-2,5-dicarboxamide, 163 4-hydroxy-N-[4-methoxy-1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-1H- 1,3-benzodiazol-2-yl]-4-methylpiperidine-1-carboxamide, 164 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-1-(2-methoxyethyl)-1H-1,2,3-triazole-4-carboxamide, 165 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-2-methyl-1,3-thiazole-5-carboxamide, 167 1-(2-Hydroxy-ethyl)-1H-pyrazole-4-carboxylic acid [7-methoxy-4-(1- methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]-amide, 168 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-4-[(4-methylpiperazin-1-yl)methyl]benzamide, 169 1-Methyl-1H-pyrazole-4-carboxylic acid [7-methoxy-4-(1-methyl- 1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]-amide, 170 5-Methyl-isoxazole-4-carboxylic acid [7-methoxy-4-(1-methyl-1H- pyrazol-4-yl)-1H-benzoimidazol-2-yl]-amide, 171 5-Cyclopropyl-isoxazole-4-carboxylic acid [7-methoxy-4-(1-methyl- 1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]-amide, 172 1-Cyano-cyclopropanecarboxylic acid [7-methoxy-4-(1-methyl-1H- pyrazol-4-yl)-1H-benzoimidazol-2-yl]-amide, 173 Thiazole-5-carboxylic acid [7-methoxy-4-(1-methyl-1H-pyrazol-4- yl)-1H-benzoimidazol-2-yl]-amide, 174 5,6,7,8-Tetrahydro-imidazo[1,2-a]pyridine-3-carboxylic acid [7- methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]- amide, 175 4-(4-Methyl-piperazin-1-yl)-but-2-ynoic acid [7-methoxy-4-(1- methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]-amide, 179 (S)-3-Methanesulfonyl-pyrrolidine-1-carboxylic acid [7-methoxy-4- (1-methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]-amide, 180 (S)-3-Fluoro-pyrrolidine-1-carboxylic acid [7-methoxy-4-(1-methyl- 1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]-amide, 181 (S)-3-Cyano-pyrrolidine-1-carboxylic acid [7-methoxy-4-(1-methyl- 1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]-amide, 182 (R)-3-Dimethylaminomethyl-pyrrolidine-1-carboxylic acid [7- methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]- amide, 183 5-Methyl-isoxazole-4-carboxylic acid (7-methoxy-4-morpholin-4-yl- 1H-benzoimidazol-2-yl)-amide, 184 N-[7-methoxy-4-(morpholin-4-yl)-1H-1,3-benzodiazol-2-yl]-1-(2- methoxyethyl)-1H-1,2,3-triazole-4-carboxamide, 185 1-Methyl-1H-[1,2,3]triazole-4-carboxyylic acid (7-methoxy-4- morpholin-4-yl-1H-benzoimidazol-2-yl)-amide, 186 Pyridine-2,5-dicarboxylic acid 2-dimethylamide 5-{[7-methoxy-4- (tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-yl]-amide}, 187 1-(2-Methoxy-ethyl)-1H-pyrazole-4-carboxylic acid [7-methoxy-4- (tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 188 N-[7-Methoxy-4-(tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-yl]-4- morpholin-4-ylmethyl-benzamide, 189 N-[7-Methoxy-4-(tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-yl]-4- (4-methyl-piperazin-1-ylmethyl)-benzamide, 190 1-Methyl-1H-pyrazole-4-carboxylic acid [7-methoxy-4-(tetrahydro- pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 191 5-Methyl-isoxazole-4-carboxylic acid [7-methoxy-4-(tetrahydro- pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 192 5-Cyclopropyl-isoxazole-4-carboxylic acid [7-methoxy-4- (tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 193 1-(2-Methoxy-ethyl)-1H-[1,2,3]triazole-4-carboylic acid [7- methoxy-4-(tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 194 1-Methyl-1H-[1,2,3]triazole-4-carboylic acid [7-methoxy-4- (tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 195 1-Cyano-cyclopropanecarboxylic acid [7-methoxy-4-(tetrahydro- pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 196 Thiazole-5-carboxylic acid [7-methoxy-4-(tetrahydro-pyran-4-yl)- 1H-benzoimidazol-2-yl]-amide, 197 2-Methyl-oxazole-5-carboxylic acid [7-methoxy-4-(tetrahydro- pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 198 2-Methyl-thiazole-5-carboxylic acid [7-methoxy-4-(tetrahydro- pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 199 Imidazo[1,2-a]pyridine-3-carboxylic acid [7-methoxy-4-(tetrahydro- pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 200 5-Amino-2H-[1,2,4]triazole-3-carboxylic acid [7-methoxy-4- (tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 201 (S)-3-Methanesulfonyl-pyrrolidine-1-carboxylic acid [7-methoxy-4- (tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 202 (S)-3-Fluoro-pyrrolidine-1-carboxylic acid [7-methoxy-4-(tetrahydro- pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 203 (S)-3-Cyano-pyrrolidine-1-carboxylic acid [7-methoxy-4- (tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 204 (R)-3-Dimethylaminomethyl-pyrrolidine-1-carboxylic acid [7- methoxy-4-(tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 205 Pyrazolo[1,5-a]pyridine-3-carboxylic acid [7-methoxy-4-(tetrahydro- pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 206 1H-[1,2,4]Triazole-3-carboxylic acid [7-methoxy-4-(tetrahydro- pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 207 5,6,7,8-Tetrahydro-imidazo[1,2-a]pyridine-3-carboxylic acid [7- methoxy-4-(tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 208 2,3-Dimethyl-3H-imidazole-4-sulfonic acid [7-methoxy-4- (tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-yl]-amide, 209 1-[7-Methoxy-4-(tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-yl]-3- thiazol-2-ylmethyl-urea, 210 N-[7-methoxy-4-(morpholin-4-yl)-1H-1,3-benzodiazol-2-yl]-1- methyl-1H-1,2,3-triazole-4-carboxamide, 211 N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-1-(2- methoxyethyl)-1H-1,2,3-triazole-4-carboxamide, 212 N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-1-methyl-1H- 1,2,3-triazole-4-carboxamide, 213 1-cyano-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3- benzodiazol-2-yl]cyclopropane-1-carboxamide, 214 N5-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-N2,N2- dimethylpyridine-2,5-dicarboxamide, 215 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-2-methyl-1,3-oxazole-5-carboxamide, 216 N-[4-(azepan-1-yl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-4-hydroxy- 4-methylpiperidine-1-carboxamide, 217 N-[4-(3-fluorophenyl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-4- hydroxy-4-methylpiperidine-1-carboxamide, 218 N-[4-(2-fluorophenyl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-4- hydroxy-4-methylpiperidine-1-carboxamide, 219 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-1,3-thiazole-5-carboxamide, 220 (3R)-3-methanesulfonyl-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4- yl)-1H-1,3-benzodiazol-2-yl]pyrrolidine-1-carboxamide, 221 (3S)-3-fluoro-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3- benzodiazol-2-yl]pyrrolidine-1-carboxamide, 222 4-hydroxy-N-[7-methoxy-4-(1-methyl-6-oxo-1,6-dihydropyridin-3- yl)-1H-1,3-benzodiazol-2-yl]-4-methylpiperidine-1-carboxamide, 223 (3S)-3-(aminomethyl)-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)- 1H-1,3-benzodiazol-2-yl]pyrrolidine-1-carboxamide, 224 N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-1-methyl-1H- pyrazole-4-carboxamide, 225 N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-1-(2- methoxyethyl)-1H-pyrazole-4-carboxamide, 226 1-cyano-N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2- yl]cyclopropane-1-carboxamide, 227 N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-2-methyl-1,3- thiazole-5-carboxamide, 228 3-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-1-[(1,3- thiazol-2-yl)methyl]urea, 229 N-{7-[1-(difluoromethyl)-1H-pyrazol-4-yl]-4-methoxy-1H-1,3- benzodiazol-2-yl}-4-hydroxy-4-methylpiperidine-1-carboxamide, 230 4-hydroxy-N-(4-methoxy-7-{1-[2-(2-methoxyethoxy)ethyl]-1H- pyrazol-4-yl}-1H-1,3-benzodiazol-2-yl)-4-methylpiperidine-1- carboxamide, 231 4-hydroxy-N-{4-methoxy-7-[1-(pyridin-2-yl)-1H-pyrazol-4-yl]-1H- 1,3-benzodiazol-2-yl}-4-methylpiperidine-1-carboxamide, 232 N-[7-methoxy-4-(1-propylcyclopropyl)-1H-1,3-benzodiazol-2-yl]-1- methyl-1H-pyrazole-4-carboxamide, 233 N-[4-(hexan-3-yl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-1-methyl- 1H-pyrazole-4-carboxamide, 234 N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]-2-methyl-1,3- oxazole-5-carboxamide, 235 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-4-[(4-methylpiperazin-1-yl)methyl]benzamide, 236 4-hydroxy-N-{4-methoxy-7-[3-(2-methoxyethoxy)phenyl]-1H-1,3- benzodiazol-2-yl}-4-methylpiperidine-1-carboxamide, 237 4-hydroxy-N-(4-methoxy-7-{1-[(pyridin-3-yl)methyl]-1H-pyrazol-4- yl}-1H-1,3-benzodiazol-2-yl)-4-methylpiperidine-1-carboxamide, 238 4-hydroxy-N-{7-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-4- methoxy-1H-1,3-benzodiazol-2-yl}-4-methylpiperidine-1- carboxamide, 239 N-[4-(3-fluorophenyl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-1- methyl-1H-pyrazole-4-carboxamide, 240 N4-[4-(3-fluorophenyl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-N1,N1- dimethylbenzene-1,4-dicarboxamide, 241 4-hydroxy-N-{4-methoxy-7-[1-(oxolan-3-yl)-1H-pyrazol-4-yl]-1H- 1,3-benzodiazol-2-yl}-4-methylpiperidine-1-carboxamide, 242 N4-[4-(2-fluorophenyl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-N1,N1- dimethylbenzene-1,4-dicarboxamide, 243 N-[4-(2-fluorophenyl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-1- methyl-1H-pyrazole-4-carboxamide, 244 N-[4-methoxy-1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-1H-1,3- benzodiazol-2-yl]-1-methyl-1H-pyrazole-4-carboxamide, 245 tert-butyl 3-(4-{2-[(4-hydroxy-4-methylpiperidine-1-carbonyl)amino]- 4-methoxy-1H-1,3-benzodiazol-7-yl}-1H-pyrazol-1-yl)azetidine-1- carboxylate, 246 N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-5-oxopyrrolidine-3-carboxamide, 247 3-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2- yl]-1-[(1,3-thiazol-2-yl)methyl]urea, 248 4-(2,5-dioxopyrrolidin-1-yl)-N-[7-methoxy-4-(1-methyl-1H-pyrazol- 4-yl)-1H-1,3-benzodiazol-2-yl]benzamide, 249 1-[(3R,4S)-4-fluoropyrrolidin-3-yl]-3-[7-methoxy-4-(1-methyl-1H- pyrazol-4-yl)-1H-1,3-benzodiazol-2-yl]urea, 250 4-(2,5-dioxopyrrolidin-1-yl)-N-[7-methoxy-4-(oxan-4-yl)-1H-1,3- benzodiazol-2-yl]benzamide, 251 tert-butyl (3S,4R)-3-fluoro-4-({[7-methoxy-4-(1-methyl-1H-pyrazol- 4-yl)-1H-1,3-benzodiazol-2-yl]carbamoyl}amino)pyrrolidine-1- carboxylate, 252 N4-[7-methoxy-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-1,3- benzodiazol-2-yl]-N1,N1-dimethylbenzene-1,4-dicarboxamide, 253 N-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)-1H-imidazole-4- carboxamide, 254 N-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)-1-methyl-1H- imidazole-5-carboxamide, 255 N-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)-2-methyl-1H- imidazole-4-carboxamide, 256 N-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)-1,3-thiazole-5- carboxamide, 257 N-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)-2-methyl-1,3- thiazole-5-carboxamide, 258 2-amino-N-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)-1,3- thiazole-5-carboxamide, 259 N4-[7-methoxy-4-(pyridin-3-yl)-1H-1,3-benzodiazol-2-yl]-N1,N1- dimethylbenzene-1,4-dicarboxamide, 260 N-[7-methoxy-4-(pyridin-3-yl)-1H-1,3-benzodiazol-2-yl]-1-methyl- 1H-pyrazole-4-carboxamide, 261 N4-[4-(2,5-dihydrofuran-3-yl)-7-methoxy-1H-1,3-benzodiazol-2-yl]- N1,N1-dimethylbenzene-1,4-dicarboxamide, 262 N4-[4-(3,6-dihydro-2H-pyran-4-yl)-5-fluoro-7-methoxy-1H-1,3- benzodiazol-2-yl]N1,N1-dimethylbenzene-1,4-dicarboxamide, 263 3-{[dimethyl(oxo)-lambda6-sulfanylidene]amino}-N-[7-methoxy-4- (oxan-4-yl)-1H-1,3-benzodiazol-2-yl]benzamide, 264 N-[4-(3,6-dihydro-2H-pyran-4-yl)-5-fluoro-7-methoxy-1H-1,3- benzodiazol-2-yl]-1-methyl-1H-pyrazole-4-carboxamide, 265 N-[7-(3-fluorophenyl)-4-methoxy-1H-1,3-benzodiazol-2-yl]-1H- imidazole-4-carboxamide, 266 N-[4-methoxy-7-(pyridin-4-yl)-1H-1,3-benzodiazol-2-yl]-1H- imidazole-4-carboxamide, 267 N-{4-methoxy-7-[3-(2-methoxyethoxy)phenyl]-1H-1,3-benzodiazol- 2-yl}-1H-imidazole-4-carboxamide, 268 N-[4-methoxy-7-(pyridin-3-yl)-1H-1,3-benzodiazol-2-yl]-1H- imidazole-4-carboxamide, 269 N-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)-1,3-dimethyl-1H- pyrazole-4-carboxamide, 270 4-hydroxy-N-(7-methoxy-4-{1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-1,3- benzodiazol-2-yl)-4-methylpiperidine-1-carboxamide, 271 4-hydroxy-N-[4-(1H-indazol-4-yl)-7-methoxy-1H-1,3-benzodiazol-2- yl]-4-methylpiperidine-1-carboxamide, 272 4-hydroxy-N-[4-(1H-indol-6-yl)-7-methoxy-1H-1,3-benzodiazol-2- yl]-4-methylpiperidine-1-carboxamide, 273 4-hydroxy-N-[7-methoxy-4-(1-methyl-1H-indazol-5-yl)-1H-1,3- benzodiazol-2-yl]-4-methylpiperidine-1-carboxamide, 274 4-hydroxy-N-[7-methoxy-4-(3-methyl-1H-indazol-5-yl)-1H-1,3- benzodiazol-2-yl]-4-methylpiperidine-1-carboxamide, 275 4-hydroxy-N-(4-{imidazo[1,2-a]pyridin-7-yl}-7-methoxy-1H-1,3- benzodiazol-2-yl)-4-methylpiperidine-1-carboxamide, 277 N4-[5-fluoro-7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]- N1,N1-dimethylbenzene-1,4-dicarboxamide, 278 N-(7-methoxy-4-{1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-1,3-benzodiazol- 2-yl)-1-(2-methoxyethyl)-1H-pyrazole-4-carboxamide, 279 N-[4-(1H-indazol-4-yl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-1-(2- methoxyethyl)-1H-pyrazole-4-carboxamide, 280 N-[4-(1H-indo1-6-yl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-1-(2- methoxyethyl)-1H-pyrazole-4-carboxamide, 281 N-[7-methoxy-4-(1-methyl-1H-indazol-5-yl)-1H-1,3-benzodiazol-2- yl]-1-(2-methoxyethyl)-1H-pyrazole-4-carboxamide, 282 N-[7-methoxy-4-(3-methyl-1H-indazol-5-yl)-1H-1,3-benzodiazol-2- yl]-1-(2-methoxyethyl)-1H-pyrazole-4-carboxamide, 283 N-[4-(2,3-dihydro-1H-indo1-4-yl)-7-methoxy-1H-1,3-benzodiazol-2- yl]-1-(2-methoxyethyl)-1H-pyrazole-4-carboxamide, 284 N2-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)-N5,N5- dimethylpyridine-2,5-dicarboxamide, 285 4-(2,5-dioxopyrrolidin-1-yl)-N-(7-methoxy-4-phenyl-1H-1,3- benzodiazol-2-yl)benzamide, 286 N-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)imidazo[1,2- a]pyridine-3-carboxamide, 287 4,4-difluoro-N-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2- yl)pipendine-1-carboxamide, 288 N-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)imidazo[1,2- b]pyridazine-3-carboxamide, 289 N-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)imidazo[1,2- a]pyrimidine-3-carboxamide, 290 N-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)-2-(pyridin-4-yl)- 1H-imidazole-4-carboxamide, 291 N-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)-5H,6H,7H,8H- imidazo[1,2-a]pyridine-3-carboxamide, 292 N-[4-(2,3-dihydro-1H-indo1-4-yl)-7-methoxy-1H-1,3-benzodiazol-2- yl]-4-hydroxy-4-methylpiperidine-1-carboxamide, 293 N1-(4-methoxy-7-phenyl-1H-1,3-benzodiazol-2-yl)-N4- propylbenzene-1,4-dicarboxamide, 294 N-(4-methoxy-7-phenyl-1H-1,3-benzodiazol-2-yl)-4-(4- methylpiperazine-1-carbonyl)benzamide, 295 N4-(4-methoxy-7-phenyl-1H-1,3-benzodiazol-2-yl)-N1-(2- methoxyethyl)-N1-methylbenzene-1,4-dicarboxamide, 296 N1-[2-(dimethylamino)ethyl]-N4-(4-methoxy-7-phenyl-1H-1,3- benzodiazol-2-yl)-N1-methylbenzene-1,4-dicarboxamide, 297 N4-(4-methoxy-7-phenyl-1H-1,3-benzodiazol-2-yl)-N1-methyl-N1- propylbenzene-1,4-dicarboxamide, 298 N-(4-methoxy-7-phenyl-1H-1,3-benzodiazol-2-yl)-4-(morpholine-4- carbonyl)benzamide, 299 N-[4-methoxy-7-(2-methylpyridin-4-yl)-1H-1,3-benzodiazol-2-yl]- 1H-imidazole-4-carboxamide, 300 N-(5-cyano-7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)-1- methyl-1H-pyrazole-4-carboxamide, 301 N-(4-{imidazo[1,2-a]pyridin-7-yl}-7-methoxy-1H-1,3-benzodiazol-2- yl)-1-(2-methoxyethyl)-1H-pyrazole-4-carboxamide, 302 N-[4-(1H-indo1-5-yl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-1-(2- methoxyethyl)-1H-pyrazole-4-carboxamide, 303 4-hydroxy-N-[4-(1H-indo1-5-yl)-7-methoxy-1H-1,3-benzodiazol-2- yl]-4-methylpiperidine-1-carboxamide, 304 N-[4-(1H-indo1-7-yl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-1-(2- methoxyethyl)-1H-pyrazole-4-carboxamide, 305 4-hydroxy-N-[4-(1H-indo1-7-yl)-7-methoxy-1H-1,3-benzodiazol-2- yl]-4-methylpiperidine-1-carboxamide, 306 N-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)-1-methyl-1H- pyrazole-4-carboxamide, 307 N-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)-1-(2- methoxyethyl)-1H-pyrazole-4-carboxamide, 308 N-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)-2-methyl-1,3- oxazole-5-carboxamide, 309 N4-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)-N1,N1- dimethylbenzene-1,4-dicarboxamide, 310 N-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)-8-oxa-2- azaspiro[4.5]decane-2-carboxamide, 311 N-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)-4-[(2- oxopyrrolidin-1-yl)methyl]benzamide, 312 N1-(2-hydroxyethyl)-N4-(4-methoxy-7-phenyl-1H-1,3-benzodiazol- 2-yl)benzene-1,4-dicarboxamide, 313 N4-[7-methoxy-4-(1,4-oxazepan-4-yl)-1H-1,3-benzodiazol-2-yl]- N1,N1-dimethylbenzene-1,4-dicarboxamide, 314 N-[4-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-1H-1,3-benzodiazol-2- yl]cyclopropanecarboxamide, 315 N-[7-methoxy-4-(pyridin-3-yl)-1H-1,3-benzodiazol-2- yl]cyclopropanecarboxamide, 316 N4-[4-(4-fluorophenyl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-N1,N1- dimethylbenzene-1,4-dicarboxamide, 317 4-(2,5-dioxopyrrolidin-1-yl)-N-[4-(4-fluorophenyl)-7-methoxy-1H- 1,3-benzodiazol-2-yl]benzamide, 318 N-[4-(4-fluorophenyl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-1- methyl-1H-pyrazole-4-carboxamide, 319 N4-[4-(2,6-dimethoxypyridin-3-yl)-7-methoxy-1H-1,3-benzodiazol- 2-yl]-N1,N1-dimethylbenzene-1,4-dicarboxamide, 320 N-[4-(2,6-dimethoxypyridin-3-yl)-7-methoxy-1H-1,3-benzodiazol-2- yl]cyclopropanecarboxamide, 321 N-[7-methoxy-4-(pyridin-3-yl)-1H-1,3-benzodiazol-2-yl]-2-methyl- 1,3-oxazole-5-carboxamide, 322 N-[4-(2,5-dihydrofuran-3-yl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-2- methyl-1,3-oxazole-5-carboxamide, 323 N-[4-(4-fluorophenyl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-2- methyl-1,3-oxazole-5-carboxamide, 324 N4-[4-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-1H-1,3-benzodiazol- 2-yl]-N1,N1-dimethylbenzene-1,4-dicarboxamide, 325 N-[4-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-1H-1,3-benzodiazol-2- yl]-1-methyl-1H-pyrazole-4-carboxamide, 326 (4-{2-[(4-hydroxy-4-methylpiperidine-1-carbonyl)amino]-7-methoxy- 1H-1,3-benzodiazol-4-yl}morpholin-2-yl)methyl carbamate, 327 (1-{2-[(4-hydroxy-4-methylpiperidine-1-carbonyl)amino]-7-methoxy- 1H-1,3-benzodiazol-4-yl}piperidin-3-yl)methyl cyanate, 328 (1-{2-[(4-hydroxy-4-methylpiperidine-1-carbonyl)amino]-7-methoxy- 1H-1,3-benzodiazol-4-yl}piperidin-3-yl)methyl carbamate, 329 N-(7-methoxy-4-phenyl-1H-1,3-benzodiazol-2-yl)-2-oxa-8- azaspiro[4.5]decane-8-carboxamide, 330 N-[4-(1H-indo1-6-yl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-1H- imidazole-4-carboxamide, 331 N-[4-(1H-indo1-6-yl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-1-methyl- 1H-pyrazole-4-carboxamide, 332 N-[4-(4-fluorophenyl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-8-oxa-2- azaspiro[4.5]decane-2-carboxamide, 333 N-[4-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-1H-1,3-benzodiazol-2- yl]-8-oxa-2-azaspiro[4.5]decane-2-carboxamide, 334 N-[4-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-1H-1,3-benzodiazol-2- yl]-4-[(2-oxopyrrolidin-1-yl)methyl]benzamide, 335 N-[4-(4-fluorophenyl)-7-methoxy-1H-1,3-benzodiazol-2-yl]-4-[(2- oxopyrrolidin-1-yl)methyl]benzamide, 336 N-[4-(1H-indo1-6-yl)-7-methoxy-1H-1,3-benzodiazol-2- yl]cyclopropanecarboxamide, and physiologically acceptable salts, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.
5. A process for the preparation of a compound of the formula I, of claim 1, comprising ##STR00384## a) a compound of the formula II undergoes a nitration reaction, followed by a reduction to give a compound of formula IV, a compound of formula IVI is cyclized to give a compound of formula V, a compound of formula V is reacted in a Suzuki type reaction to formula VI employing the use of catalyst and base, a compound of formula VI is converted to a compound of the formula VII by standard amidation or carbamide formation conditions to give a compound of the formula I ##STR00385## b) a compound of the formula III is reacted with a boronic ester or acid under Suzuki-type reaction conditions to give a compound of the formula VII or reacted with an amine in a nucleophilic substitution reaction under increased temperature to form a compound of the formula VII, a compound of formula VII is reduced to a compound of the formula VII and cyclized to a compound of the formula VI and finally reacted with to compound of the formula I under standard amidation or carbamide formation conditions c) the base of a compound of the formula I is converted into one of its salts by treatment with an acid, or d) an acid of a compound of the formula I is converted into one of its salts by treatment with a base.
6. A method of inhibiting adenosine A.sub.2A and/or A.sub.2B receptors in a host in need thereof, comprising administering to said host a compound according to claim 1 or physiologically acceptable salts, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios an amount effective to inhibit adenosine A.sub.2A and/or A.sub.2B receptors.
7. A pharmaceutical preparation comprising at least one compound according to claim 1 and/or physiologically acceptable salts, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.
8. The pharmaceutical preparation according to claim 7 comprising further excipients and/or adjuvants.
9. The pharmaceutical preparation comprising at least one compound according to claim 1 and/or physiologically acceptable salts, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further medicament active compound.
10. A kit consisting of separate packs of a) an effective amount of a compound according to claim 1 and/or physiologically acceptable salts, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, and b) an effective amount of a further medicament active compound.
Description
EXAMPLE 1: EXAMPLES OF COMPOUNDS OF THE PRESENT INVENTION
(1) The invention especially relates to the compounds of table 2 and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.
(2) TABLE-US-00003 TABLE 2 examples of compounds of the present invention No. Structure IUPAC-Name 1
(3) TABLE-US-00004 TABLE 3 NMR profiles of the compounds of the present invention No. MW [M + H] + 1 1 239.28 240 2 361.37 362 3 423.27 424 4 426.07 427 5 423.27 424 6 426.07 427 7 429.48 430 8 429.48 430 9 294.36 295 10 391.86 393 11 400.48 401 12 380.45 381 13 372.43 373 14 245.32 246 15 423.47 424 16 386.49 387 17 435.53 437 18 248.28 249 19 247.30 248 20 243.27 244 21 389.45 390 22 384.44 385 23 438.49 439 24 388.47 389 25 240.26 241 26 433.47 434 27 244.26 245 28 364.45 365 29 437.50 438 30 447.50 448 31 370.41 371 32 438.41 439 33 396.45 397 34 420.42 421 35 398.46 399 36 402.43 403 37 384.44 385 38 424.50 426 39 368.44 369 40 370.41 371 41 460.54 462 42 434.46 435 43 382.42 383 44 425.45 426 45 412.45 413 46 356.38 357 47 423.47 424 48 404.47 405 49 391.43 392 50 438.45 439 51 423.47 424 52 396.45 397 53 426.52 428 54 446.51 448 55 447.50 448 56 426.52 428 57 458.52 460 58 368.40 369 59 285.31 286 60 423.47 424 61 342.40 343 62 452.52 454 63 370.38 371 64 381.43 382 65 483.45 484 66 541.50 543 67 410.48 411 68 410.48 411 69 396.45 397 70 353.38 354 71 427.47 428 72 390.24 391 73 423.43 424 74 381.43 382 75 465.55 467 76 432.48 433 77 392.41 393 78 454.53 456 79 370.41 371 80 387.40 388 81 434.46 435 82 385.43 386 83 461.52 463 84 338.33 339 85 379.42 380 86 434.88 436 87 434.46 435 88 408.50 409 89 401.47 402 90 409.49 410 91 438.49 439 92 408.46 409 93 418.45 419 94 431.37 432 95 427.26 428 96 352.35 353 97 431.49 432 98 388.39 389 99 383.41 384 100 444.49 445 101 389.41 390 102 412.49 413 103 464.56 466 104 447.50 448 105 461.52 463 106 473.53 475 107 447.50 448 108 393.44 394 109 384.44 385 110 400.48 401 111 414.50 416 112 386.45 387 113 410.48 411 114 410.48 411 115 396.45 397 116 396.45 397 117 388.47 389 118 465.55 467 119 477.56 479 120 423.45 424 121 382.42 383 122 451.52 453 123 401.46 402 124 398.42 399 125 415.49 416 126 397.44 398 127 418.50 419 128 426.52 428 129 407.47 408 130 416.48 417 131 394.47 395 132 412.45 413 133 422.48 423 134 398.46 399 135 433.47 434 136 356.38 357 137 402.49 403 138 448.52 450 139 437.50 438 140 398.46 399 141 398.46 399 142 388.47 389 143 388.47 389 144 398.44 399 145 553.66 555 146 377.40 378 147 384.44 385 148 384.44 385 149 400.48 401 150 400.48 401 151 440.54 442 152 446.51 448 153 477.56 479 154 477.56 479 155 386.45 387 156 352.36 353 157 453.54 455 158 422.44 423 159 412.45 413 160 351.37 352 161 395.42 396 162 419.44 420 163 398.46 399 164 396.41 397 165 368.42 369 166 324.34 325 167 381.40 382 168 459.55 461 169 351.37 352 170 352.35 353 171 378.39 379 172 336.35 337 173 354.39 355 174 391.43 392 175 407.48 408 176 325.33 326 177 366.38 367 178 352.40 353 179 418.48 419 180 358.38 359 181 365.40 366 182 397.48 398 183 357.37 358 184 401.42 402 185 357.37 358 186 423.47 424 187 399.45 400 188 450.54 452 189 463.58 465 190 355.40 356 191 356.38 357 192 382.42 383 193 400.44 401 194 356.39 357 195 340.38 341 196 358.42 359 197 356.38 357 198 372.45 373 199 391.43 392 200 357.37 358 201 422.50 424 202 362.40 363 203 369.42 370 204 401.51 403 205 391.43 392 206 342.36 343 207 395.46 396 208 405.48 406 209 387.46 388 210 357.37 358 211 400.44 401 212 356.38 357 213 336.35 337 214 423.47 424 215 352.35 353 216 401.51 403 217 398.44 399 218 398.44 399 219 354.39 355 220 418.48 419 221 358.38 359 222 411.46 412 223 369.43 370 224 355.40 356 225 399.45 400 226 340.38 341 227 372.45 373 228 387.46 388 229 420.42 421 230 472.54 474 231 447.50 448 232 353.42 354 233 355.44 356 234 356.38 357 235 459.55 461 236 454.52 456 237 461.52 463 238 442.52 444 239 365.37 366 240 432.45 433 241 440.50 442 242 432.45 433 243 365.37 366 244 365.40 366 245 525.61 527 246 354.37 355 247 383.43 384 248 444.45 445 249 373.39 374 250 448.48 449 251 473.51 475 252 419.48 420 253 333.35 334 254 347.38 348 255 347.38 348 256 350.40 351 257 364.43 365 258 365.42 366 259 415.45 416 260 348.36 349 261 406.44 407 262 438.46 439 263 442.54 444 264 371.37 372 265 351.34 352 266 334.34 335 267 407.43 408 268 334.34 335 269 361.40 362 270 420.47 421 271 420.47 421 272 419.48 420 273 434.50 435 274 434.50 435 275 420.47 421 276 348.36 349 277 440.47 441 278 431.45 432 279 431.45 432 280 430.47 431 281 445.48 446 282 445.48 446 283 432.48 433 284 415.45 416 285 440.46 441 286 383.41 384 287 386.40 387 288 384.40 385 289 384.40 385 290 410.44 411 291 387.44 388 292 421.50 422 293 428.49 429 294 469.54 471 295 458.52 460 296 471.56 473 297 442.52 444 298 456.50 457 299 348.36 349 300 372.39 373 301 431.45 432 302 430.47 431 303 419.48 420 304 430.47 431 305 419.48 420 306 347.38 348 307 391.43 392 308 348.36 349 309 414.46 415 310 406.48 407 311 440.50 442 312 430.46 431 313 437.50 438 314 313.36 314 315 308.34 309 316 432.45 433 317 458.45 459 318 365.37 366 319 475.50 477 320 368.39 369 321 349.35 350 322 340.34 341 323 366.35 367 324 420.47 421 325 353.38 354 326 462.50 464 327 442.52 444 328 460.53 462 329 406.48 407 330 372.39 373 331 386.41 387 332 424.47 425 333 412.49 413 334 446.50 448 335 458.49 459 336 346.39 347
(4) The Nos. recited herein corresponds to the numbering of the compounds disclosed in table 2
(5) TABLE-US-00005 No. NMR 1 NMR, but no peak listing available 2 1H NMR (400 MHz, DMSO-d6) ppm = 8.22-8.17 (m, 2H), 7.85 (d, J = 7.6 Hz, 2H), 7.51-7.46 (m, 2H), 7.42-7.33 (m, 3H), 7.31 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 3.99 (s, 3H). 3 1H NMR (400 MHz, DMSO-d6) ppm = 12.57-12.34 (m, 1H), 8.58 (d, J = 5.0 Hz, 1H), 8.22-8.20 (m, 1H), 8.00 (dd, J = 5.1, 1.4 Hz, 1H), 7.87-7.64 (m, 2H), 7.56-7.47 (m, 2H), 7.42-7.35 (m, 1H), 7.33 (d, J = 8.3 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 3.99 (s, 3H). 4 1H NMR (400 MHz, DMSO-d6) ppm = 12.57-12.34 (m, 1H), 8.58 (d, J = 5.0 Hz, 1H), 8.22-8.20 (m, 1H), 8.00 (dd, J = 5.1, 1.4 Hz, 1H), 7.87-7.64 (m, 2H), 7.56-7.47 (m, 2H), 7.42-7.35 (m, 1H), 7.33 (d, J = 8.3 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 3.99 (s, 3H). 5 1H NMR (400 MHz, DMSO-d6) ppm = 9.04-9.03 (m, 1H), 8.34 (dd, J = 8.3, 2.6 Hz, 1H), 7.86-7.78 (m, 3H), 7.53-7.48 (m, 2H), 7.39-7.34 (m, 1H), 7.32 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 3.99 (s, 3H). 6 1H NMR (400 MHz, DMSO-d6) ppm = 9.04-9.03 (m, 1H), 8.34 (dd, J = 8.3, 2.6 Hz, 1H), 7.86-7.78 (m, 3H), 7.53-7.48 (m, 2H), 7.39-7.34 (m, 1H), 7.32 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 3.99 (s, 3H). 7 1H NMR (400 MHz, DMSO-d6) ppm = 8.29 (d, J = 5.1 Hz, 1H), 7.89-7.82 (m, 2H), 7.54-7.52 (m, 1H), 7.51-7.46 (m, 2H), 7.38-7.30 (m, 2H), 7.26- 7.23 (m, 1H), 6.92 (d, J = 8.4 Hz, 1H), 3.99 (s, 3H), 3.76-3.72 (m, 4H), 3.59- 3.55 (m, 4H). 8 1H NMR (400 MHz, DMSO-d6) ppm = 8.87 (d, J = 2.5 Hz, 1H), 8.23 (dd, J = 9.1, 2.5 Hz, 1H), 7.88-7.82 (m, 2H), 7.51-7.46 (m, 2H), 7.37-7.32 (m, 1H), 7.30 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 3.98 (s, 3H), 3.72-3.68 (m, 4H), 3.66-3.62 (m, 4H). 9 NMR available, but no peak listing 10 1H NMR (500 MHz, DMSO-d6) ppm = 12.82-11.31 (m, 1H), 8.14-8.11 (m, 2H), 7.87-7.82 (m, 2H), 7.64-7.60 (m, 2H), 7.52-7.47 (m, 2H), 7.38-7.34 (m, 1H), 7.33 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 4.86 (s, 2H), 4.00 (s, 3H). 11 1H NMR (400 MHz, DMSO-d6) ppm = 8.91-8.82 (m, 2H), 8.16-8.12 (m, 2H), 7.86-7.81 (m, 2H), 7.66-7.62 (m, 2H), 7.51-7.45 (m, 2H), 7.37-7.32 (m, 1H), 7.30 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.24-4.19 (m, 2H), 3.97 (s, 3H), 3.06-2.96 (m, 2H), 1.22 (t, J = 7.3 Hz, 3H). 12 1H NMR (400 MHz, DMSO-d6) ppm = 7.73-7.68 (m, 2H), 7.53-7.48 (m, 2H), 7.41-7.36 (m, 1H), 7.31 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 3.98 (s, 3H), 3.87-3.79 (m, 2H), 3.35-3.26 (m, 2H), 1.54-1.41 (m, 4H), 1.15 (s, 3H). 13 #NV 14 1H NMR (400 MHz, DMSO-d6) ppm = 10.72 (s, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.42 (d, J = 8.2 Hz, 1H), 5.79-5.69 (m, 2H), 3.81 (s, 3H), 2.93-2.71 (m, 1H), 1.85-1.67 (m, 5H), 1.54-1.18 (m, 5H). 15 1H NMR (400 MHz, DMSO-d6) ppm = 9.33-9.31 (m, 1H), 8.18-8.14 (m, 2H), 7.88-7.84 (m, 1H), 7.85-7.83 (m, 2H), 7.75-7.73 (m, 1H), 7.57-7.54 (m, 2H), 7.51-7.46 (m, 2H), 7.38-7.33 (m, 1H), 7.32 (d, J = 8.3 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 5.56 (s, 2H), 3.99 (s, 3H). 16 1H NMR (400 MHz, DMSO-d6) ppm = 7.06 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 3.91 (s, 3H), 3.87-3.79 (m, 2H), 3.37-3.27 (m, 2H), 3.05-2.94 (m, 1H), 1.86-1.70 (m, 5H), 1.56-1.20 (m, 9H), 1.16 (s, 3H). 17 1H NMR (400 MHz, DMSO-d6) ppm = 8.29 (d, J = 5.3 Hz, 1H), 7.55 (s, 1H), 7.28 (d, J = 5.3 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 3.91 (s, 3H), 3.77-3.73 (m, 4H), 3.60-3.55 (m, 4H), 3.09-2.99 (m, 1H), 1.91-1.70 (m, 5H), 1.56-1.22 (m, 5H). 18 NMR available, but no peak listing 19 NMR available, but no peak listing 20 1H NMR (400 MHz, DMSO-d6) ppm = 12.76-12.40 (m, 1H), 8.12-8.09 (m, 1H), 7.83-7.80 (m, 1H), 7.67-7.54 (m, 2H), 7.28-7.20 (m, 2H), 6.92 (d, J = 8.6 Hz, 1H), 3.94 (s, 3H), 3.91 (s, 3H). 21 1H NMR (400 MHz, DMSO-d6) ppm = 7.10-7.04 (m, 1H), 6.86 (d, J = 8.7 Hz, 1H), 3.92 (s, 3H), 3.90-3.81 (m, 6H), 3.37-3.21 (m, 6H), 1.57-1.42 (m, 4H), 1.16 (s, 3H). 22 1H NMR (400 MHz, DMSO-d6) ppm = 8.23 (s, 1H), 7.93 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.89-3.82 (m, 2H), 3.39-3.29 (m, 2H), 1.57-1.44 (m, 4H), 1.17 (s, 3H). 23 1H NMR (400 MHz, DMSO-d6) ppm = 8.28 (d, J = 5.6 Hz, 1H), 7.65-7.61 (m, 1H), 7.31-7.27 (m, 1H), 7.27-7.18 (m, 1H), 6.84 (d, J = 8.6 Hz, 1H), 4.00-3.95 (m, 4H), 3.94 (s, 3H), 3.79-3.73 (m, 4H), 3.67-3.62 (m, 4H), 3.61-3.46 (m, 4H). 24 1H NMR (400 MHz, DMSO-d6) ppm = 7.13 (d, J = 8.5 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 4.00-3.91 (m, 5H), 3.89-3.82 (m, 2H), 3.53-3.28 (m, 5H), 1.77-1.69 (m, 4H), 1.57-1.43 (m, 4H), 1.17 (s, 3H). 25 1H NMR (400 MHz, DMSO-d6) ppm = 8.03 (s, 1H), 7.77-7.73 (m, 2H), 7.68- 7.59 (m, 2H), 7.52-7.47 (m, 2H), 7.42-7.37 (m, 1H), 3.97 (s, 3H). 26 1H NMR (400 MHz, DMSO-d6) ppm = 8.30 (s, 1H), 8.26 (d, J = 5.8 Hz, 1H), 8.01 (s, 1H), 7.73-7.71 (m, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.35-7.33 (m, 1H), 6.89 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.79-3.74 (m, 4H), 3.71-3.66 (m, 4H). 27 NMR available, but no peak listing 28 1H NMR (400 MHz, DMSO-d6) ppm = 7.77-7.70 (m, 2H), 7.52-7.46 (m, 2H), 7.39-7.34 (m, 1H), 7.27 (d, J = 8.3 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 4.22-4.13 (m, 2H), 3.97 (s, 3H), 2.91-2.80 (m, 2H), 1.69-1.54 (m, 3H), 1.12-1.00 (m, 2H), 0.92 (d, J = 6.3 Hz, 3H). 29 1H NMR (500 MHz, DMSO-d6) ppm = 13.34-11.32 (m, 1H), 8.90 (d, J = 2.4 Hz, 1H), 8.27 (dd, J = 9.1, 2.5 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.01-3.96 (m, 2H), 3.95 (s, 3H), 3.75- 3.64 (m, 8H), 3.55-3.47 (m, 2H), 3.40-3.33 (m, 1H), 1.83-1.72 (m, 4H). 30 1H NMR (400 MHz, DMSO-d6) ppm = 8.29-8.26 (m, 1H), 8.11 (d, J = 6.5 Hz, 1H), 8.00-7.96 (m, 1H), 7.64-7.60 (m, 1H), 7.37-7.33 (m, 2H), 6.89 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.79-3.73 (m, 2H), 3.63- 3.49 (m, 2H), 2.12-1.97 (m, 2H), 1.42 (s, 3H). 31 1H NMR (400 MHz, DMSO-d6) ppm = 11.61-10.67 (m, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.73-3.19 (m, 4H), 2.00-1.80 (m, 2H), 1.34 (s, 3H). 32 1H NMR (400 MHz, DMSO-d6) ppm = 8.23 (s, 1H), 7.94 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 4.25-4.18 (m, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 3.19-3.10 (m, 2H), 1.77-1.64 (m, 4H). 33 1H NMR (400 MHz, DMSO-d6) ppm = 8.23 (s, 1H), 7.94-7.92 (m, 1H), 7.39 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.71 (s, 2H), 3.66-3.49 (m, 4H), 3.40 (s, 2H), 1.60-1.46 (m, 4H). 34 1H NMR (400 MHz, DMSO-d6) ppm = 8.24 (s, 1H), 7.94 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 5.75 (t, J = 56.0 Hz, 1H), 4.19-4.12 (m, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 3.23-3.12 (m, 2H), 1.61-1.56 (m, 4H). 35 1H NMR (500 MHz, DMSO-d6) ppm = 11.96-10.14 (m, 1H), 8.24 (s, 1H), 7.94 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.83-3.76 (m, 2H), 3.38-3.29 (m, 2H), 3.19 (s, 2H), 1.54- 1.45 (m, 2H), 1.29-1.22 (m, 2H), 0.93 (s, 3H). 36 1H NMR (400 MHz, DMSO-d6) ppm = 8.23 (s, 1H), 7.94-7.92 (m, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 4.19 (d, J = 47.8 Hz, 2H), 4.07- 4.00 (m, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.33-3.22 (m, 2H), 1.64-1.50 (m, 4H). 37 1H NMR (500 MHz, DMSO-d6) ppm = 8.23 (s, 1H), 7.93 (s, 1H), 7.30 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.87-3.81 (m, 2H), 3.46-3.40 (m, 1H), 3.31-3.24 (m, 5H), 1.91-1.84 (m, 2H), 1.48-1.41 (m, 2H). 38 1H NMR (500 MHz, DMSO-d6) ppm = 12.48-10.34 (m, 1H), 8.23 (s, 1H), 7.94-7.92 (m, 1H), 7.40 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.60-3.55 (m, 8H), 1.57-1.51 (m, 4H), 1.50-1.45 (m, 4H). 39 1H NMR (400 MHz, DMSO-d6) ppm = 8.24 (s, 1H), 7.95 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 4.24-4.16 (m, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 2.93-2.83 (m, 2H), 1.71-1.56 (m, 3H), 1.14-1.02 (m, 2H), 0.93 (d, J = 6.3 Hz, 3H). 40 1H NMR (500 MHz, DMSO-d6) ppm = 14.03-10.78 (m, 2H), 8.24 (s, 1H), 7.95-7.93 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 3.97 (s, 3H), 3.93-3.87 (m, 5H), 3.79-3.73 (m, 1H), 3.35-3.25 (m, 2H), 1.84- 1.77 (m, 2H), 1.45-1.36 (m, 2H). 41 1H NMR (500 MHz, DMSO-d6) ppm = 13.52-9.93 (m, 2H), 8.23 (s, 1H), 7.94 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.30-7.25 (m, 2H), 7.25-7.18 (m, 3H), 6.90 (d, J = 8.4 Hz, 1H), 3.98-3.93 (m, 5H), 3.90 (s, 3H), 3.27-3.17 (m, 2H), 2.72 (s, 2H), 1.53-1.41 (m, 4H). 42 NMR available, but no peak listing 43 1H NMR (400 MHz, DMSO-d6) ppm = 11.44-10.20 (m, 1H), 8.26-8.23 (m, 1H), 7.97-7.93 (m, 1H), 7.40-7.36 (m, 1H), 6.96-6.91 (m, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.76 (s, 2H), 3.67-3.56 (m, 2H), 3.45 (s, 2H), 3.43-3.36 (m, 2H), 2.27-1.78 (m, 2H). 44 1H NMR (700 MHz, DMSO-d6) ppm = 13.26-11.37 (m, 1H), 11.36-9.74 (m, 1H), 8.24 (s, 1H), 7.94 (s, 1H), 7.56 (s, 1H), 7.29 (d, J = 8.3 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.84-3.80 (m, 2H), 3.48- 3.41 (m, 2H), 3.29 (s, 2H), 1.86-1.81 (m, 2H), 1.81-1.74 (m, 2H). 45 1H NMR (500 MHz, DMSO-d6) ppm = 8.23 (s, 1H), 7.94 (s, 1H), 7.31 (d, J = 8.3 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 3.94-3.93 (m, 3H), 3.93-3.92 (m, 4H), 3.90-3.89 (m, 3H), 3.64-3.60 (m, 4H), 1.69-1.65 (m, 4H). 46 1H NMR (400 MHz, DMSO-d6) ppm = 8.23 (s, 1H), 7.94 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.67-3.62 (m, 4H), 3.60-3.55 (m, 4H). 47 1H NMR (500 MHz, DMSO-d6) ppm = 12.23-10.69 (m, 1H), 8.25-8.23 (m, 1H), 7.94-7.93 (m, 1H), 7.60-7.57 (m, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.72-3.64 (m, 2H), 3.55-3.46 (m, 2H), 3.10 (s, 2H), 2.15-2.13 (m, 2H), 1.63-1.58 (m, 4H). 48 1H NMR (400 MHz, DMSO-d6) ppm = 10.91-10.81 (m, 1H), 8.33-8.31 (m, 1H), 8.24-8.20 (m, 2H), 8.05-8.04 (m, 1H), 7.81-7.76 (m, 2H), 7.38 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 4.40-4.37 (m, 2H), 3.97 (s, 3H), 3.91 (s, 3H), 2.75-2.71 (m, 6H). 49 1H NMR (400 MHz, DMSO-d6) ppm = 12.17-11.61 (m, 1H), 8.36-8.32 (m, 1H), 8.13-8.10 (m, 2H), 8.07-8.03 (m, 1H), 7.51-7.47 (m, 2H), 7.32 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 4.52 (s, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 3.40-3.34 (m, 3H). 50 1H NMR (500 MHz, DMSO-d6) ppm = 12.11-10.86 (m, 1H), 10.78-10.75 (m, 1H), 8.66-8.63 (m, 1H), 8.23 (s, 1H), 7.93 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 4.15-4.08 (m, 2H), 3.96 (s, 3H), 3.91 (s, 3H), 3.42-3.30 (m, 2H), 1.90-1.81 (m, 2H), 1.70-1.62 (m, 2H). 51 1H NMR (500 MHz, DMSO-d6) ppm = 12.32-10.92 (m, 1H), 8.25-8.23 (m, 1H), 8.16-8.13 (m, 1H), 7.94-7.93 (m, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 3.74-3.66 (m, 2H), 3.65-3.57 (m, 2H), 2.26-2.21 (m, 2H), 1.90 (t, J = 8.0 Hz, 2H), 1.69-1.59 (m, 4H). 52 NMR available, but no peak listing 53 1H NMR (700 MHz, DMSO-d6) ppm = 13.49-10.13 (m, 2H), 8.24 (s, 1H), 7.95 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 4.13-4.08 (m, 1H), 4.08-4.03 (m, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 3.30 (td, J = 9.1, 4.3 Hz, 1H), 3.11-3.03 (m, 1H), 2.79-2.70 (m, 1H), 1.87-1.82 (m, 1H), 1.72- 1.66 (m, 1H), 1.48-1.21 (m, 6H), 1.12-1.05 (m, 1H), 0.89 (t, J = 7.1 Hz, 3H). 54 1H NMR (400 MHz, DMSO-d6) ppm = 8.23 (s, 1H), 7.94 (s, 1H), 7.33-7.27 (m, 3H), 7.02-6.98 (m, 2H), 6.96-6.91 (m, 1H), 6.83 (d, J = 8.4 Hz, 1H), 4.67-4.60 (m, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.47-3.38 (m, 4H), 2.04-1.96 (m, 2H), 1.69-1.59 (m, 2H). 55 1H NMR (700 MHz, DMSO-d6) ppm = 12.42-10.52 (m, 1H), 8.99 (d, J = 2.0 Hz, 1H), 8.83-8.81 (m, 1H), 8.70-8.68 (m, 1H), 8.26 (s, 1H), 8.03 (dd, J = 8.2, 5.6 Hz, 1H), 7.97 (s, 1H), 7.37 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.09-5.67 (m, 1H), 4.27-4.23 (m, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 3.40- 3.30 (m, 2H), 2.11-2.06 (m, 2H), 1.77-1.74 (m, 2H). 56 1H NMR (700 MHz, DMSO-d6) ppm = 13.51-11.54 (m, 1H), 11.52-10.37 (m, 1H), 8.24 (s, 1H), 7.94 (s, 1H), 7.35 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 4.10-4.06 (m, 1H), 4.05-4.00 (m, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.27 (td, J = 8.8, 4.1 Hz, 1H), 3.14-3.06 (m, 1H), 2.77-2.68 (m, 1H), 1.87- 1.82 (m, 1H), 1.79-1.71 (m, 1H), 1.52-1.47 (m, 1H), 1.41-1.34 (m, 2H), 1.02-0.97 (m, 1H), 0.90 (d, J = 6.6 Hz, 3H), 0.86 (d, J = 6.5 Hz, 3H). 57 NMR available, but no peak listing 58 1H NMR (500 MHz, DMSO-d6) ppm = 12.18-10.47 (m, 1H), 8.24 (s, 1H), 7.94 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.90-3.85 (m, 4H), 2.49-2.45 (m, 4H). 59 1H NMR (400 MHz, DMSO-d6) ppm = 11.82-11.70 (m, 1H), 8.26 (s, 1H), 8.00 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 2.20 (s, 3H). 60 1H NMR (700 MHz, DMSO-d6) ppm = 12.74-9.93 (m, 2H), 8.25 (s, 1H), 7.95 (s, 1H), 7.62 (s, 1H), 7.28 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 4.14-4.09 (m, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.20 (t, J = 6.8 Hz, 2H), 3.14- 3.08 (m, 2H), 2.02 (t, J = 6.8 Hz, 2H), 1.67-1.61 (m, 2H), 1.44-1.40 (m, 2H). 61 1H NMR (500 MHz, DMSO-d6) ppm = 11.86-10.17 (m, 1H), 8.26-8.25 (m, 1H), 7.95-7.94 (m, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.50-3.42 (m, 4H), 1.17 (t, J = 7.1 Hz, 6H). 62 1H NMR (500 MHz, DMSO-d6) ppm = 12.04-11.88 (m, 1H), 8.32-8.27 (m, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 4.29-4.02 (m, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.83-3.65 (m, 2H), 3.59- 3.31 (m, 4H), 2.85 (s, 3H), 2.42-2.21 (m, 3H), 2.02-1.87 (m, 1H). 63 1H NMR (400 MHz, DMSO-d6) ppm = 8.22-8.16 (m, 2H), 7.44-7.37 (m, 2H), 7.16-7.09 (m, 1H), 6.82 (d, J = 8.7 Hz, 1H), 3.97-3.91 (m, 7H), 3.70- 3.50 (m, 4H). 64 1H NMR (400 MHz, DMSO-d6) ppm = 12.12-12.02 (m, 1H), 8.28-8.26 (m, 1H), 8.02-7.99 (m, 1H), 7.33 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.75-3.55 (m, 3H), 3.48-3.40 (m, 1H), 2.01-1.95 (m, 1H), 1.77-1.54 (m, 3H), 1.43-1.35 (m, 1H), 1.19 (t, J = 4.7 Hz, 1H), 1.07 (dd, J = 7.8, 4.2 Hz, 1H). 65 NMR available, but no peak listing 66 NMR available, but no peak listing 67 1H NMR (400 MHz, DMSO-d6) ppm = 11.10-9.59 (m, 2H), 8.24-8.22 (m, 1H), 7.95-7.92 (m, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.69-3.16 (m, 8H), 1.92-1.49 (m, 6H). 68 1H NMR (400 MHz, DMSO-d6) ppm = 11.04-9.94 (m, 1H), 8.24 (s, 1H), 7.94 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.69-3.33 (m, 8H), 1.94-1.78 (m, 2H), 1.57-1.50 (m, 4H). 69 1H NMR (400 MHz, DMSO-d6) ppm = 8.25-8.22 (m, 1H), 7.95-7.92 (m, 1H), 7.40 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.84-3.77 (m, 2H), 3.72-3.35 (m, 6H), 2.04-1.84 (m, 4H). 70 1H NMR (500 MHz, DMSO-d6) ppm = 11.98-11.84 (m, 1H), 8.27-8.25 (m, 1H), 8.02-7.99 (m, 1H), 7.29 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.86 (d, J = 8.8 Hz, 2H), 3.71-3.67 (m, 2H), 2.23- 2.20 (m, 2H), 1.95-1.88 (m, 1H). 71 1H NMR (500 MHz, DMSO-d6) ppm = 15.05-14.13 (m, 1H), 12.69-11.24 (m, 1H), 9.35-9.33 (m, 1H), 8.33-8.30 (m, 1H), 8.19-8.16 (m, 2H), 8.06- 8.03 (m, 1H), 7.84 (t, J = 1.7 Hz, 1H), 7.74 (t, J = 1.7 Hz, 1H), 7.59-7.56 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 5.57 (s, 2H), 3.95 (s, 3H), 3.90 (s, 3H). 72 1H NMR (400 MHz, DMSO-d6) ppm = 12.43-11.91 (m, 1H), 8.27 (s, 1H), 8.01 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.46-3.41 (m, 1H), 2.54-2.50 (m, 1H), 1.68-1.54 (m, 2H). 73 1H NMR (400 MHz, DMSO-d6) ppm = 12.11-11.00 (m, 1H), 8.99 (d, J = 1.3 Hz, 1H), 8.52 (d, J = 1.3 Hz, 1H), 8.34-8.31 (m, 1H), 8.02-8.00 (m, 1H), 7.41 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.60-4.55 (m, 2H), 3.97 (s, 3H), 3.92 (s, 3H), 3.76-3.72 (m, 2H), 3.33 (s, 3H). 74 1H NMR (500 MHz, DMSO-d6) ppm = 10.62-10.51 (m, 1H), 8.95-8.91 (m, 2H), 8.86-8.83 (m, 2H), 7.91 (d, J = 8.7 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 4.03 (s, 3H), 3.88-3.82 (m, 2H), 3.33-3.26 (m, 2H), 1.54-1.43 (m, 4H), 1.16 (s, 3H). 75 1H NMR (500 MHz, DMSO-d6) ppm = 11.22-10.61 (m, 1H), 7.29-7.25 (m, 2H), 7.24-7.18 (m, 3H), 7.07-6.98 (m, 1H), 6.85 (d, J = 8.6 Hz, 1H), 3.97- 3.89 (m, 5H), 3.89-3.83 (m, 4H), 3.23 (d, J = 11.3 Hz, 6H), 2.72 (s, 2H), 1.54- 1.41 (m, 4H). 76 1H NMR (400 MHz, DMSO-d6) ppm = 15.23-14.03 (m, 1H), 12.89-11.51 (m, 1H), 9.37-9.35 (m, 1H), 8.19-8.14 (m, 2H), 7.84 (t, J = 1.7 Hz, 1H), 7.74 (t, J = 1.7 Hz, 1H), 7.60-7.55 (m, 2H), 7.17-7.05 (m, 1H), 6.80 (d, J = 8.6 Hz, 1H), 5.57 (s, 2H), 3.98-3.90 (m, 7H), 3.55-3.40 (m, 4H). 77 1H NMR (400 MHz, DMSO-d6) ppm = 8.52-8.49 (m, 1H), 8.15 (d, J = 2.2 Hz, 1H), 8.10 (dd, J = 8.7, 1.9 Hz, 1H), 7.80-7.75 (m, 1H), 7.13 (dd, J = 2.3, 0.9 Hz, 1H), 7.11-7.01 (m, 1H), 6.81 (d, J = 8.6 Hz, 1H), 4.00-3.89 (m, 7H), 3.56-3.41 (m, 4H). 78 1H NMR (500 MHz, DMSO-d6) ppm = 12.37-10.91 (m, 1H), 10.91-9.79 (m, 1H), 8.47 (s, 1H), 8.05 (s, 1H), 7.31 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 5.43 (dd, J = 10.0, 2.1 Hz, 1H), 3.98-3.94 (m, 1H), 3.92 (s, 3H), 3.88-3.81 (m, 2H), 3.70-3.63 (m, 1H), 3.34-3.25 (m, 2H), 2.16-2.07 (m, 1H), 2.01-1.94 (m, 2H), 1.76-1.66 (m, 1H), 1.59-1.53 (m, 2H), 1.53- 1.43 (m, 4H), 1.16 (s, 3H). 79 1H NMR (500 MHz, DMSO-d6) ppm = 12.37-10.91 (m, 1H), 10.91-9.79 (m, 1H), 8.47 (s, 1H), 8.05 (s, 1H), 7.31 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 5.43 (dd, J = 10.0, 2.1 Hz, 1H), 3.98-3.94 (m, 1H), 3.92 (s, 3H), 3.88-3.81 (m, 2H), 3.70-3.63 (m, 1H), 3.34-3.25 (m, 2H), 2.16-2.07 (m, 1H), 2.01-1.94 (m, 2H), 1.76-1.66 (m, 1H), 1.59-1.53 (m, 2H), 1.53- 1.43 (m, 4H), 1.16 (s, 3H). 80 1H NMR (700 MHz, DMSO-d6) ppm = 12.55-11.83 (m, 1H), 8.53 (d, J = 1.5 Hz, 1H), 8.35-8.33 (m, 1H), 8.16-8.15 (m, 1H), 8.12 (dd, J = 8.7, 1.9 Hz, 1H), 8.06-8.04 (m, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.16-7.14 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H). 81 1H NMR (500 MHz, DMSO-d6) ppm = 11.73-11.31 (m, 1H), 8.85 (d, J = 1.2 Hz, 1H), 8.42 (d, J = 1.2 Hz, 1H), 8.32-8.30 (m, 1H), 7.99-7.98 (m, 1H), 7.44 (d, J = 8.3 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.81-3.78 (m, 4H), 3.76-3.73 (m, 4H). 82 1H NMR (400 MHz, DMSO-d6) ppm = 11.19-10.06 (m, 1H), 8.34-8.32 (m, 1H), 8.08 (s, 1H), 8.07-8.06 (m, 1H), 4.08 (s, 3H), 3.91 (s, 3H), 3.89-3.82 (m, 2H), 3.35-3.26 (m, 2H), 1.55-1.42 (m, 4H), 1.16 (s, 3H). 83 1H NMR (400 MHz, DMSO-d6) ppm = 10.83-10.18 (m, 1H), 8.31 (s, 1H), 8.08-8.04 (m, 2H), 7.30-7.17 (m, 5H), 4.04 (s, 3H), 3.99-3.92 (m, 2H), 3.90 (s, 3H), 3.24-3.14 (m, 2H), 2.72 (s, 2H), 1.53-1.39 (m, 4H). 84 1H NMR (500 MHz, DMSO-d6) ppm = 9.18 (d, J = 1.7 Hz, 1H), 8.30 (s, 1H), 8.01 (s, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.14-7.11 (m, 1H), 6.86 (d, J = 8.3 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H). 85 1H NMR (700 MHz, DMSO-d6) ppm = 12.10-11.31 (m, 1H), 10.51-10.44 (m, 1H), 8.97-8.92 (m, 2H), 8.86-8.84 (m, 2H), 7.92 (d, J = 8.6 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 4.03 (s, 3H), 3.75-3.74 (m, 2H), 3.66-3.40 (m, 6H), 1.96-1.79 (m, 2H). 86 1H NMR (700 MHz, DMSO-d6) ppm = 11.94-11.85 (m, 1H), 8.65 (s, 1H), 8.29 (s, 1H), 7.17-6.83 (m, 1H), 6.79-6.75 (m, 1H), 4.63-4.58 (m, 1H), 4.11-4.00 (m, 2H), 3.95-3.88 (m, 9H), 3.82-3.76 (m, 4H). 87 1H NMR (500 MHz, DMSO-d6) ppm = 12.87-11.27 (m, 1H), 8.31-8.30 (m, 1H), 8.07 (d, J = 9.6 Hz, 1H), 7.99-7.98 (m, 1H), 7.49-7.45 (m, 2H), 7.01 (d, J = 8.5 Hz, 1H), 3.99 (s, 3H), 3.93 (s, 3H), 3.81-3.75 (m, 8H). 88 1H NMR (500 MHz, DMSO-d6) ppm = 10.58-10.48 (m, 1H), 8.23-8.20 (m, 2H), 7.75-7.71 (m, 2H), 7.01 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 4.37 (d, J = 5.1 Hz, 2H), 4.00-3.96 (m, 2H), 3.93 (s, 3H), 3.51 (td, J = 11.3, 2.8 Hz, 2H), 3.36-3.29 (m, 1H), 2.74 (d, J = 4.6 Hz, 6H), 1.86-1.74 (m, 4H). 89 1H NMR (500 MHz, DMSO-d6) ppm = 12.34-12.13 (m, 1H), 10.97-10.88 (m, 1H), 8.98-8.94 (m, 2H), 8.91-8.87 (m, 2H), 8.22-8.18 (m, 2H), 7.99 (d, J = 8.6 Hz, 1H), 7.80-7.77 (m, 2H), 7.07 (d, J = 8.7 Hz, 1H), 4.38 (d, J = 5.0 Hz, 2H), 4.08 (s, 3H), 2.73 (d, J = 4.4 Hz, 6H). 90 1H NMR (500 MHz, DMSO-d6) ppm = 12.58-11.92 (m, 1H), 10.99-10.86 (m, 1H), 8.21-8.18 (m, 2H), 7.79-7.76 (m, 2H), 7.28-7.13 (m, 1H), 6.83 (d, J = 8.6 Hz, 1H), 4.38 (d, J = 5.4 Hz, 2H), 3.99-3.95 (m, 4H), 3.95 (s, 3H), 3.62-3.46 (m, 4H), 2.72 (d, J = 4.8 Hz, 6H). 91 1H NMR (500 MHz, DMSO-d6) ppm = 13.15-11.08 (m, 1H), 8.07 (d, J = 9.6 Hz, 1H), 7.47 (d, J = 9.6 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 3.99 (dt, J = 10.9, 3.1 Hz, 2H), 3.97 (s, 3H), 3.82-3.75 (m, 8H), 3.56- 3.50 (m, 2H), 3.42-3.34 (m, 1H), 1.83-1.74 (m, 4H). 92 1H NMR (400 MHz, DMSO-d6) ppm = 8.24-8.22 (m, 1H), 7.93-7.92 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 4.05-3.99 (m, 2H), 3.97 (s, 3H), 3.92 (s, 3H), 3.36-3.19 (m, 2H), 2.83 (t, J = 2.6 Hz, 1H), 2.34 (d, J = 2.7 Hz, 2H), 1.73-1.56 (m, 4H). 93 1H NMR (400 MHz, DMSO-d6) ppm = 8.32 (s, 1H), 8.22-8.17 (m, 2H), 8.04- 8.02 (m, 1H), 8.50-7.02 (m, 2H), 7.62-7.57 (m, 2H), 7.39 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.06-2.89 (m, 6H). 94 1H NMR (500 MHz, DMSO-d6) ppm = 13.28-10.50 (m, 1H), 8.31 (s, 1H), 8.28-8.23 (m, 2H), 8.03 (s, 1H), 7.58-7.53 (m, 2H), 7.33 (d, J = 8.2 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H). 95 1H NMR (400 MHz, DMSO-d6) ppm = 12.69-12.13 (m, 1H), 8.62-8.58 (m, 1H), 8.30-8.25 (m, 1H), 8.25-8.23 (m, 1H), 8.01 (dd, J = 5.0, 1.4 Hz, 1H), 8.00-7.97 (m, 1H), 7.33 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H). 96 1H NMR (400 MHz, DMSO-d6) ppm = 8.90 (s, 1H), 8.30-8.28 (m, 1H), 7.99-7.98 (m, 1H), 7.39 (d, J = 8.3 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 2.55 (s, 3H). 97 1H NMR (500 MHz, DMSO-d6) ppm = 15.08-14.12 (m, 1H), 12.94-11.51 (m, 1H), 9.33-9.31 (m, 1H), 8.19-8.15 (m, 2H), 7.83 (t, J = 1.7 Hz, 1H), 7.73 (t, J = 1.7 Hz, 1H), 7.58-7.53 (m, 2H), 6.99 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 5.55 (s, 2H), 4.00-3.96 (m, 2H), 3.92 (s, 3H), 3.50 (td, J = 11.4, 2.7 Hz, 2H), 3.35-3.28 (m, 1H), 1.86-1.73 (m, 4H). 98 1H NMR (400 MHz, DMSO-d6) ppm = 12.23-11.42 (m, 1H), 11.03-10.94 (m, 1H), 9.72 (s, 1H), 8.82 (d, J = 2.2 Hz, 1H), 8.35 (d, J = 1.8 Hz, 1H), 8.33 (s, 1H), 8.03 (s, 1H), 7.82 (dd, J = 8.4, 2.3 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H). 99 1H NMR (500 MHz, DMSO-d6/TFA) ppm = 8.21-8.15 (m, 2H), 7.42-7.39 (m, 1H), 7.23 (d, J = 8.5 Hz, 1H), 6.96-6.93 (m, 1H), 4.08-4.03 (m, 4H), 4.01 (s, 3H), 3.78-3.71 (m, 4H). 100 1H NMR (500 MHz, DMSO-d6) ppm = 12.66-11.05 (m, 1H), 8.32 (s, 1H), 8.13-8.10 (m, 2H), 8.03 (s, 1H), 7.42-7.39 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 4.47 (s, 2H), 3.96 (s, 3H), 3.91 (s, 3H), 3.29 (t, J = 7.0 Hz, 2H), 2.33 (t, J = 8.1 Hz, 2H), 2.01-1.93 (m, 2H). 101 1H NMR (400 MHz, DMSO-d6) ppm = 12.40-11.15 (m, 1H), 8.32 (s, 1H), 8.06-8.05 (m, 1H), 8.04 (s, 1H), 7.98 (dd, J = 8.4, 2.0 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 4.67 (t, J = 8.8 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.28 (t, J = 8.7 Hz, 2H). 102 1H NMR (400 MHz, DMSO-d6) ppm = 7.04 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 4.04-3.93 (m, 4H), 3.91 (s, 3H), 3.54-3.45 (m, 2H), 3.34- 3.17 (m, 3H), 2.82 (t, J = 2.6 Hz, 1H), 2.33 (d, J = 2.7 Hz, 2H), 1.81-1.52 (m, 8H). 103 1H NMR (400 MHz, DMSO-d6) ppm = 7.30-7.17 (m, 5H), 7.07 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.00-3.91 (m, 4H), 3.91 (s, 3H), 3.53- 3.45 (m, 2H), 3.33-3.16 (m, 3H), 2.72 (s, 2H), 1.80-1.68 (m, 4H), 1.53- 1.41 (m, 4H). 104 1H NMR (700 MHz, DMSO-d6) ppm = 12.00 (s, 1H), 11.87 (s, 1H), 8.40 (s, 1H), 8.24-8.20 (m, 1H), 8.11 (s, 1H), 7.38-7.33 (m, 1H), 7.13-7.06 (m, 2H), 6.82-6.78 (m, 1H), 4.84 (s, 1H), 3.95 (s, 3H), 3.92-3.88 (m, 3H), 3.62- 3.54 (m, 2H), 3.50-3.45 (m, 1H), 3.36-3.33 (m, 1H), 2.00-1.90 (m, 2H), 1.38 (s, 3H). 105 1H NMR (500 MHz, DMSO-d6) ppm = 12.62-11.71 (m, 1H), 8.32 (s, 1H), 8.18 (d, J = 5.9 Hz, 1H), 8.06-8.00 (m, 1H), 7.78-7.73 (m, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.27-7.21 (m, 1H), 6.87-6.83 (m, 1H), 4.03-3.97 (m, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 3.53-3.46 (m, 2H), 1.63-1.54 (m, 4H), 1.18 (s, 3H). 106 1H NMR (500 MHz, DMSO-d6) ppm = 8.30 (s, 1H), 8.13 (d, J = 6.5 Hz, 1H), 8.00 (s, 1H), 7.66 (s, 1H), 7.38-7.34 (m, 2H), 6.90 (d, J = 8.4 Hz, 1H), 3.98- 3.94 (m, 3H), 3.92 (s, 3H), 3.87-3.82 (m, 2H), 3.77-3.69 (m, 2H), 3.69 (d, J = 8.6 Hz, 1H), 3.66-3.62 (m, 2H), 3.60 (d, J = 8.6 Hz, 1H), 2.14-2.09 (m, 2H), 2.04-1.92 (m, 2H). 107 1H NMR (700 MHz, DMSO-d6) ppm = 12.00 (s, 1H), 11.87 (s, 1H), 8.40 (s, 1H), 8.24-8.20 (m, 1H), 8.11 (s, 1H), 7.38-7.33 (m, 1H), 7.13-7.06 (m, 2H), 6.82-6.78 (m, 1H), 4.84 (s, 1H), 3.95 (s, 3H), 3.92-3.88 (m, 3H), 3.62- 3.54 (m, 2H), 3.50-3.45 (m, 1H), 3.36-3.33 (m, 1H), 2.00-1.90 (m, 2H), 1.38 (s, 3H). 108 1H NMR (500 MHz, DMSO-d6) ppm = 12.30-11.36 (m, 1H), 8.04-8.02 (m, 1H), 7.96 (dd, J = 8.4, 2.0 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 4.66 (t, J = 8.8 Hz, 2H), 4.00-3.95 (m, 2H), 3.92 (s, 3H), 3.51 (td, J = 11.4, 2.8 Hz, 2H), 3.36-3.29 (m, 1H), 3.27 (t, J = 8.8 Hz, 2H), 1.86-1.73 (m, 4H). 109 1H NMR (500 MHz, DMSO-d6) ppm = 10.77-10.36 (m, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.70-3.40 (m, 3H), 3.39-3.18 (m, 3H), 3.28 (s, 3H), 2.58- 2.49 (m, 1H), 2.07-1.96 (m, 1H), 1.76-1.63 (m, 1H). 110 1H NMR (500 MHz, DMSO-d6) ppm = 11.25-9.80 (m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 3.99-3.94 (m, 2H), 3.91 (s, 3H), 3.84- 3.76 (m, 2H), 3.59 (d, J = 8.4 Hz, 1H), 3.55 (d, J = 8.5 Hz, 1H), 3.59-3.38 (m, 6H), 3.33-3.25 (m, 1H), 2.01-1.83 (m, 4H), 1.81-1.70 (m, 4H). 111 1H NMR (500 MHz, DMSO-d6) ppm = 11.21-9.86 (m, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 4.01-3.94 (m, 2H), 3.91 (s, 3H), 3.68- 3.60 (m, 2H), 3.57-3.46 (m, 6H), 3.45-3.32 (m, 2H), 3.31-3.24 (m, 1H), 1.92-1.69 (m, 6H), 1.56-1.48 (m, 4H). 112 1H NMR (400 MHz, DMSO-d6) ppm = 7.17 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 4.00-3.94 (m, 2H), 3.94 (s, 3H), 3.84-3.79 (m, 2H), 3.77-3.69 (m, 2H), 3.61-3.55 (m, 2H), 3.55-3.43 (m, 4H), 3.41-3.31 (m, 1H), 3.06- 2.96 (m, 2H), 1.80-1.69 (m, 4H). 113 1H NMR (500 MHz, DMSO-d6) ppm = 12.72-10.62 (m, 1H), 10.49-10.05 (m, 1H), 8.29-8.25 (m, 1H), 8.00-7.96 (m, 1H), 7.27 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.81-3.46 (m, 5H), 3.43 (d, J = 11.2 Hz, 1H), 3.33 (d, J = 11.2 Hz, 1H), 3.26-3.15 (m, 1H), 1.89- 1.50 (m, 6H). 114 1H NMR (500 MHz, DMSO-d6) ppm = 12.72-10.62 (m, 1H), 10.49-10.05 (m, 1H), 8.29-8.25 (m, 1H), 8.00-7.96 (m, 1H), 7.27 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.81-3.46 (m, 5H), 3.43 (d, J = 11.2 Hz, 1H), 3.33 (d, J = 11.2 Hz, 1H), 3.26-3.15 (m, 1H), 1.89- 1.50 (m, 6H). 115 1H NMR (500 MHz, DMSO-d6) ppm = 11.90-10.97 (m, 1H), 10.25-10.06 (m, 1H), 8.30-8.24 (m, 1H), 8.02-7.95 (m, 1H), 7.25 (d, J = 8.3 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.84-3.76 (m, 2H), 3.62- 3.50 (m, 4H), 3.49-3.39 (m, 2H), 1.98-1.82 (m, 4H). 116 1H NMR (500 MHz, DMSO-d6) ppm = 11.90-10.97 (m, 1H), 10.25-10.06 (m, 1H), 8.30-8.24 (m, 1H), 8.02-7.95 (m, 1H), 7.25 (d, J = 8.3 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.84-3.76 (m, 2H), 3.62- 3.50 (m, 4H), 3.49-3.39 (m, 2H), 1.98-1.82 (m, 4H). 117 1H NMR (500 MHz, DMSO-d6) ppm = 3.66-3.41 (m, 4H), 3.40-3.34 (m, 1H), 3.34-3.29 (m, 2H), 3.28 (s, 3H), 3.28-3.16 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 3.99-3.94 (m, 2H), 3.92 (s, 3H), 2.08- 1.94 (m, 1H), 1.81-1.60 (m, 6H). 118 1H NMR (700 MHz, DMSO-d6) ppm = 13.05-11.77 (m, 1H), 8.19-8.13 (m, 1H), 7.80-7.68 (m, 1H), 7.32-7.22 (m, 1H), 7.03 (d, J = 7.9 Hz, 1H), 6.85- 6.79 (m, 1H), 4.00-3.95 (m, 4H), 3.92 (s, 3H), 3.54-3.47 (m, 4H), 3.33- 3.27 (m, 1H), 1.82-1.73 (m, 4H), 1.64-1.55 (m, 4H), 1.18 (s, 3H). 119 1H NMR (700 MHz, DMSO-d6) ppm = 14.36-11.93 (m, 2H), 8.11 (d, J = 6.4 Hz, 1H), 7.62-7.57 (m, 1H), 7.41-7.35 (m, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 3.98 (dt, J = 11.0, 3.1 Hz, 2H), 3.93 (s, 3H), 3.87- 3.81 (m, 2H), 3.77-3.67 (m, 3H), 3.65-3.61 (m, 2H), 3.60 (d, J = 8.6 Hz, 1H), 3.54-3.48 (m, 2H), 3.32-3.26 (m, 1H), 2.15-2.07 (m, 2H), 2.03-1.92 (m, 2H), 1.80-1.72 (m, 4H). 120 1H NMR (700 MHz, DMSO-d6) ppm = 11.66-11.54 (m, 1H), 8.30 (s, 1H), 8.00 (s, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.17-7.13 (m, 2H), 7.10-7.07 (m, 2H), 6.88 (d, J = 8.3 Hz, 1H), 3.95 (s, 3H), 3.89 (s, 3H), 1.56 (s, 6H). 121 1H NMR (700 MHz, DMSO-d6) ppm = 11.04-10.74 (m, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.39 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.81 (dd, J = 8.8, 6.7 Hz, 2H), 3.76-3.70 (m, 2H), 3.58 (dd, J = 8.9, 3.4 Hz, 2H), 3.49-3.43 (m, 2H), 3.04-2.97 (m, 2H). 122 1H NMR (700 MHz, DMSO-d6) ppm = 14.22-12.03 (m, 2H), 8.09 (d, J = 6.4 Hz, 1H), 7.60 (s, 1H), 7.40-7.35 (m, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.00-3.96 (m, 2H), 3.93 (s, 3H), 3.80-3.70 (m, 2H), 3.61- 3.48 (m, 4H), 3.33-3.26 (m, 1H), 2.09-1.99 (m, 2H), 1.80-1.71 (m, 4H), 1.42 (s, 3H). 123 1H NMR (700 MHz, DMSO-d6) ppm = 11.31-10.27 (m, 1H), 7.07-6.96 (m, 1H), 6.83 (d, J = 8.6 Hz, 1H), 3.91 (s, 3H), 3.90-3.84 (m, 4H), 3.83-3.76 (m, 2H), 3.64-3.37 (m, 6H), 3.35-3.19 (m, 4H), 2.04-1.83 (m, 4H). 124 1H NMR (400 MHz, DMSO-d6) ppm = 8.23 (s, 1H), 7.93 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.15-4.07 (m, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.13-3.04 (m, 2H), 2.60-2.50 (m, 1H), 1.93-1.85 (m, 2H), 1.60- 1.48 (m, 2H). 125 1H NMR (700 MHz, DMSO-d6) ppm = 10.61-10.17 (m, 1H), 6.78-6.65 (m, 2H), 3.88 (s, 3H), 3.84-3.80 (m, 4H), 3.68-3.60 (m, 2H), 3.55-3.49 (m, 2H), 3.49-3.28 (m, 4H), 3.28-3.18 (m, 4H), 1.91-1.74 (m, 2H), 1.54- 1.49 (m, 4H). 126 1H NMR (400 MHz, DMSO-d6) ppm = 8.23 (s, 1H), 7.93 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.34-7.27 (m, 1H), 6.98 (d, J = 8.5 Hz, 1H), 6.84-6.76 (m, 1H), 4.23-4.17 (m, 2H), 3.96 (s, 3H), 3.91 (s, 3H), 3.06-2.96 (m, 2H), 2.44-2.35 (m, 1H), 1.83-1.76 (m, 2H), 1.59-1.48 (m, 2H). 127 1H NMR (400 MHz, DMSO-d6) ppm = 12.20-11.42 (m, 1H), 8.31 (s, 1H), 8.04-7.99 (m, 3H), 7.37 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.81- 6.76 (m, 2H), 3.97 (s, 3H), 3.92 (s, 3H), 3.45 (q, J = 7.0 Hz, 4H), 1.14 (t, J = 7.0 Hz, 6H). 128 1H NMR (400 MHz, DMSO-d6) ppm = 8.27 (s, 1H), 7.97 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 3.96 (d, J = 7.2 Hz, 2H), 3.94 (s, 3H), 3.89-3.81 (m, 2H), 3.37-3.27 (m, 2H), 2.17 (hept, J = 6.8 Hz, 1H), 1.56- 1.43 (m, 4H), 1.16 (s, 3H), 0.88 (d, J = 6.6 Hz, 6H). 129 1H NMR (700 MHz, DMSO-d6) ppm = 15.75-15.03 (m, 1H), 12.09-11.45 (m, 1H), 10.43 (s, 1H), 8.98-8.92 (m, 2H), 8.86-8.84 (m, 2H), 7.92 (d, J = 8.7 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 4.03 (s, 3H), 3.71-3.25 (m, 8H), 1.91- 1.75 (m, 2H), 1.56-1.49 (m, 4H). 130 1H NMR (700 MHz, DMSO-d6) ppm = 12.90-11.39 (m, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 4.22-4.15 (m, 2H), 3.99-3.95 (m, 2H), 3.92 (s, 3H), 3.52-3.47 (m, 2H), 3.33-3.26 (m, 1H), 2.99-2.88 (m, 2H), 2.20 (d, J = 7.0 Hz, 2H), 1.97-1.90 (m, 1H), 1.77-1.69 (m, 6H), 1.20-1.12 (m, 2H). 131 1H NMR (700 MHz, DMSO-d6) ppm = 13.55-11.72 (m, 1H), 11.55-10.37 (m, 1H), 7.37-7.33 (m, 2H), 7.31-7.28 (m, 1H), 7.26-7.23 (m, 1H), 7.13- 7.09 (m, 1H), 7.03-6.98 (m, 1H), 4.00 (s, 3H), 3.81-3.76 (m, 2H), 3.32- 3.24 (m, 2H), 2.14 (s, 3H), 1.51-1.47 (m, 2H), 1.46-1.41 (m, 2H), 1.14 (s, 3H). 132 1H NMR (700 MHz, DMSO-d6) ppm = 13.31-10.06 (m, 2H), 8.23 (s, 1H), 7.92 (s, 1H), 7.35 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.24-4.16 (m, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 2.99-2.89 (m, 2H), 2.19 (d, J = 7.0 Hz, 2H), 1.98-1.90 (m, 1H), 1.77-1.72 (m, 2H), 1.21-1.13(m, 2H). 133 1H NMR (400 MHz, DMSO-d6) ppm = 8.19-8.14 (m, 2H), 7.58-7.53 (m, 2H), 6.98 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 4.01-3.94 (m, 2H), 3.92 (s, 3H), 3.55-3.47 (m, 2H), 3.36-3.26 (m, 1H), 3.01 (s, 3H), 2.92 (s, 3H), 1.88-1.73 (m, 4H). 134 1H NMR (400 MHz, DMSO-d6) ppm = 8.19 (s, 1H), 7.91 (s, 1H), 7.33-7.29 (m, 1H), 6.88-6.84 (m, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 3.73 (dd, J = 10.6, 7.3 Hz, 1H), 3.67-3.60 (m, 1H), 3.48-3.39 (m, 3H), 3.28 (s, 3H), 3.27-3.24 (m, 1H), 3.15-3.08 (m, 1H), 2.35-2.25 (m, 1H), 2.14-2.04 (m, 1H), 1.70-1.63 (m, 2H). 135 1H NMR (700 MHz, DMSO-d6) ppm = 11.90-11.57 (m, 1H), 8.45 (d, J = 2.9 Hz, 1H), 8.29 (s, 1H), 8.10 (d, J = 8.9 Hz, 1H), 7.96 (s, 1H), 7.54 (dd, J = 8.9, 2.9 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.80-3.77 (m, 4H), 3.46-3.44 (m, 4H). 136 1H NMR (400 MHz, DMSO-d6) ppm = 11.80-11.70 (m, 1H), 8.47 (s, 1H), 8.18 (s, 1H), 6.67 (d, J = 8.2 Hz, 1H), 6.65-6.59 (m, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.84-3.80 (m, 4H), 3.34-3.25 (m, 4H). 137 1H NMR (400 MHz, DMSO-d6) ppm = 7.02 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 4.00-3.94 (m, 2H), 3.91 (s, 3H), 3.73-3.43 (m, 5H), 3.39- 3.27 (m, 3H), 3.25 (s, 3H), 3.18-2.97 (m, 1H), 2.30-1.99 (m, 2H), 1.83- 1.69 (m, 4H), 1.67-1.51 (m, 3H). 138 1H NMR (700 MHz, DMSO-d6) ppm = 12.28-11.76 (m, 1H), 8.11-8.09 (m, 2H), 7.40-7.38 (m, 2H), 6.99 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 4.47 (s, 2H), 4.00-3.96 (m, 2H), 3.92 (s, 3H), 3.53-3.48 (m, 2H), 3.35-3.30 (m, 1H), 3.28 (t, J = 7.0 Hz, 2H), 2.33 (t, J = 8.1 Hz, 2H), 1.99-1.94 (m, 2H), 1.84-1.75 (m, 4H). 139 NMR available, but no peak listing 144 1H NMR (400 MHz, DMSO-d6, 90° C.) d 11.36-9.96 (m, 2H), 7.90-7.79 (m, 2H), 7.26-7.19 (m, 2H), 7.18-7.12 (m, 1H), 6.78 (d, J = 8.3 Hz, 1H), 4.05 (s, 1H), 3.95 (s, 3H), 3.83-3.74 (m, 2H), 3.38-3.29 (m, 2H), 1.57-1.41 (m, 4H), 1.15 (s, 3H). 151 1H NMR (500 MHz, DMSO-d6) ppm = 11.47-11.27 (m, 1H), 10.35-10.02 (m, 1H), 8.40-8.24 (m, 1H), 8.13-7.96 (m, 1H), 7.29-7.16 (m, 1H), 6.71 (d, J = 8.3 Hz, 1H), 4.36 (s, 1H), 4.18-4.12 (m, 2H), 3.90 (s, 3H), 3.88-3.82 (m, 2H), 3.29-3.24 (m, 2H), 1.75-1.69 (m, 2H), 1.59-1.41 (m, 5H), 1.15 (s, 3H), 0.93 (d, J = 6.6 Hz, 6H). 152 1H NMR (700 MHz, DMSO-d6) d 11.46-11.36 (m, 1H), 8.33 (s, 1H), 8.24- 8.21 (m, 2H), 8.05 (s, 1H), 7.85-7.82 (m, 2H), 7.39 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 4.45 (s, 2H), 3.97 (s, 3H), 3.97-3.93 (m, 2H), 3.92 (s, 3H), 3.85-3.79 (m, 2H), 3.28-3.22 (m, 2H), 3.17-3.10 (m, 2H). 155 1H NMR (500 MHz, DMSO-d6) ppm = 11.68-11.12 (m, 1H), 10.71-10.03 (m, 1H), 6.97 (d, J = 8.3 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 7.38-5.74 (m, 1H), 4.35 (s, 1H), 4.25 (q, J = 2.7 Hz, 2H), 3.89 (s, 3H), 3.87-3.81 (m, 4H), 3.30-3.22 (m, 2H), 2.58-2.50 (m, 2H), 1.50-1.39 (m, 4H), 1.14 (s, 3H). 156 1H NMR (400 MHz, DMSO-d6) d 8.89 (s, 1H), 8.32-8.30 (m, 1H), 8.02- 8.01 (m, 1H), 7.38 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.17 (s, 3H), 3.97 (s, 3H), 3.92 (s, 3H). 157 1H NMR (400 MHz, DMSO-d6) ppm = 8.35-8.32 (m, 1H), 8.00-7.97 (m, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 4.36 (s, 1H), 4.25- 4.16 (m, 1H), 3.90 (s, 3H), 3.89-3.81 (m, 4H), 3.09-3.02 (m, 2H), 2.64- 2.56 (m, 2H), 2.02-1.95 (m, 2H), 1.87-1.75 (m, 2H), 1.53-1.40 (m, 4H), 1.15 (s, 3H). 158 1H NMR (400 MHz, DMSO-d6) d 11.98-11.04 (m, 1H), 8.50 (d, J = 2.8 Hz, 1H), 8.33-8.31 (m, 1H), 8.24-8.20 (m, 1H), 8.01-8.00 (m, 1H), 7.70 (dd, J = 8.8, 2.9 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 4.37- 4.33 (m, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.75-3.72 (m, 2H), 3.34 (s, 3H). 159 1H NMR (400 MHz, DMSO-d6) d 12.58-10.47 (m, 1H), 8.24-8.23 (m, 1H), 7.94-7.93 (m, 1H), 7.41 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 4.15- 4.01 (m, 2H), 3.96 (s, 3H), 3.91 (s, 3H), 3.09-3.00 (m, 1H), 2.85-2.76 (m, 1H), 2.27 (dd, J = 15.6, 6.5 Hz, 1H), 2.16 (dd, J = 15.7, 7.2 Hz, 1H), 1.95- 1.81 (m, 2H), 1.75-1.67 (m, 1H), 1.54-1.41 (m, 1H), 1.32-1.21 (m, 1H). 160 1H NMR (500 MHz, DMSO-d6) d 12.69-11.26 (m, 1H), 8.33 (s, 1H), 8.04 (s, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.34-7.31 (m, 1H), 6.84 (d, J = 8.3 Hz, 1H), 4.17 (s, 3H), 3.95 (s, 3H), 3.90 (s, 3H). 161 1H NMR (500 MHz, DMSO-d6) d 11.78-11.67 (m, 1H), 8.53-8.52 (m, 1H), 8.34-8.32 (m, 1H), 8.22-8.21 (m, 1H), 8.07-8.04 (m, 1H), 7.31 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 4.34 (t, J = 5.1 Hz, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 3.72 (t, J = 5.2 Hz, 2H), 3.26 (s, 3H). 162 1H NMR (500 MHz, DMSO-d6) d 9.24-9.22 (m, 1H), 8.53 (dd, J = 8.1, 2.3 Hz, 1H), 8.33-8.30 (m, 1H), 8.05-8.01 (m, 1H), 7.73-7.70 (m, 1H), 7.34 (d, J = 8.3 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.04 (s, 3H), 2.94 (s, 3H). 163 1H NMR (500 MHz, DMSO-d6) d 10.77-9.85 (m, 1H), 7.87-7.86 (m, 1H), 7.56-7.55 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 4.29 (s, 1H), 3.92 (s, 3H), 4.10-3.80 (m, 2H), 3.89 (s, 3H), 3.38-3.13 (m, 2H), 3.23 (s, 3H), 1.48-1.33 (m, 4H), 1.13 (s, 3H). 164 1H NMR (400 MHz, DMSO-d6) d 12.27-11.35 (m, 1H), 8.90 (s, 1H), 8.34- 8.31 (m, 1H), 8.04-8.02 (m, 1H), 7.36 (d, J = 8.3 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.67 (t, J = 5.1 Hz, 2H), 3.96 (s, 3H), 3.91 (s, 3H), 3.80 (t, J = 5.2 Hz, 2H), 3.28 (s, 3H). 165 1H NMR (400 MHz, DMSO-d6) d 8.54-8.49 (m, 1H), 8.28 (s, 1H), 7.99 (s, 1H), 7.31 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 2.71 (s, 3H). 166 1H NMR (400 MHz, DMSO-d6) d 12.00-11.55 (m, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.31 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 2.89-2.84 (m, 2H), 2.81-2.76 (m, 2H). 168 1H NMR (400 MHz, DMSO-d6, 90° C.) d 8.26-8.24 (m, 1H), 8.20-8.16 (m, 2H), 8.00-7.99 (m, 1H), 7.69-7.65 (m, 2H), 7.32 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 4.05-4.02 (m, 2H), 3.99 (s, 3H), 3.92 (s, 3H), 3.42- 3.31 (m, 4H), 3.14-3.02 (m, 4H), 2.78 (s, 3H). 184 1H NMR (500 MHz, DMSO-d6) d 12.79-10.98 (m, 1H), 8.91 (s, 1H), 7.13- 7.06 (m, 1H), 6.85 (d, J = 8.6 Hz, 1H), 4.67 (t, J = 5.1 Hz, 2H), 3.94 (s, 3H), 3.94-3.91 (m, 4H), 3.80 (t, J = 5.1 Hz, 2H), 3.48-3.42 (m, 4H), 3.27 (s, 3H). 210 1H NMR (400 MHz, DMSO-d6) d 12.37-11.35 (m, 1H), 8.89 (s, 1H), 7.29 (d, J = 8.6 Hz, 1H), 6.89 (d, J = 8.6 Hz, 1H), 4.17 (s, 3H), 4.00-3.96 (m, 4H), 3.95 (s, 3H), 3.55-3.49 (m, 4H). 211 1H NMR (500 MHz, DMSO-d6) d 12.54-11.12 (m, 1H), 8.87 (s, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 4.68-4.65 (m, 2H), 4.00-3.96 (m, 2H), 3.92 (s, 3H), 3.81-3.78 (m, 2H), 3.50 (td, J = 11.4, 2.8 Hz, 2H), 3.34-3.27 (m, 1H), 3.28 (s, 3H), 1.85-1.73 (m, 4H). 212 1H NMR (500 MHz, DMSO-d6) d 13.05-10.88 (m, 1H), 8.88 (s, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 4.17 (s, 3H), 4.01-3.96 (m, 2H), 3.94 (s, 3H), 3.51 (td, J = 11.2, 3.1 Hz, 2H), 3.36-3.29 (m, 1H), 1.84-1.73 (m, 4H). 213 1H NMR (500 MHz, DMSO-d6) d 14.13-10.81 (m, 1H), 8.18 (s, 1H), 7.85 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 1.66-1.60 (m, 4H). 214 1H NMR (400 MHz, DMSO-d6) d 9.26 (d, J = 2.1 Hz, 1H), 8.55 (dd, J = 8.1, 2.2 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 4.01-3.95 (m, 2H), 3.94 (s, 3H), 3.57-3.47 (m, 2H), 3.38-3.29 (m, 1H), 3.04 (s, 3H), 2.95 (s, 3H), 1.84-1.73 (m, 4H). 215 1H NMR (400 MHz, DMSO-d6) d 8.30 (s, 1H), 8.05-8.02 (m, 1H), 8.01 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 2.54 (s, 3H). 216 1H NMR (400 MHz, DMSO-d6) d 7.47 (d, J = 8.7 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 3.93 (s, 3H), 3.87-3.84 (m, 2H), 3.84-3.81 (m, 2H), 3.80-3.75 (m, 2H), 3.34-3.25 (m, 2H), 2.09-2.00 (m, 4H), 1.78-1.72 (m, 4H), 1.55-1.42 (m, 4H), 1.16 (s, 3H). 217 1H NMR (400 MHz, DMSO-d6) d 7.71-7.65 (m, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.55-7.48 (m, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.18 (td, J = 8.7, 2.6 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 3.98 (s, 3H), 3.88-3.80 (m, 2H), 3.35-3.26 (m, 2H), 1.54-1.41 (m, 4H), 1.15 (s, 3H). 218 1H NMR (500 MHz, DMSO-d6) d 11.73-10.00 (m, 1H), 7.57 (td, J = 7.7, 1.8 Hz, 1H), 7.49-7.44 (m, 1H), 7.37-7.31 (m, 2H), 7.23 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 3.98 (s, 3H), 3.84-3.77 (m, 2H), 3.32-3.24 (m, 2H), 1.52-1.40 (m, 4H), 1.14 (s, 3H). 219 1H NMR (500 MHz, DMSO-d6) d 9.34 (s, 1H), 8.82-8.75 (m, 1H), 8.30 (s, 1H), 8.00 (s, 1H), 7.33 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H). 220 1H NMR (700 MHz, DMSO-d6) d 11.30-10.03 (m, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.08-4.02 (m, 1H), 3.93 (s, 3H), 3.95-3.89 (m, 1H), 3.90 (s, 3H), 3.86-3.81 (m, 1H), 3.70-3.65 (m, 1H), 3.61-3.54 (m, 1H), 3.08 (s, 3H), 2.40-2.32 (m, 2H). 221 1H NMR (400 MHz, DMSO-d6) d 8.25 (s, 1H), 7.96 (s, 1H), 7.31 (d, J = 8.3 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 5.49-5.30 (m, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.85-3.68 (m, 4H), 2.29-2.02 (m, 2H). 222 1H NMR (400 MHz, DMSO-d6, 90 ° C.) d 11.21-9.99 (m, 1H), 8.37-8.29 (m, 1H), 8.05-7.98 (m, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 6.45 (d, J = 9.4 Hz, 1H), 5.75-5.67 (m, 1H), 3.93 (s, 3H), 3.83-3.75 (m, 2H), 3.53 (s, 3H), 3.42-3.33 (m, 2H), 1.50-1.43 (m, 4H), 1.17 (s, 3H). 223 1H NMR (500 MHz, DMSO-d6) d 11.51-10.37 (m, 1H), 8.26 (s, 1H), 8.07- 7.99 (m, 3H), 7.97 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.75-3.45 (m, 4H), 3.31-3.17 (m, 1H), 2.94-2.85 (m, 2H), 2.20-2.08 (m, 1H), 1.86-1.75 (m, 1H). 224 1H NMR (400 MHz, DMSO-d6) d 12.17-11.45 (m, 1H), 8.48 (s, 1H), 8.18 (s, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 4.01-3.94 (m, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.54-3.46 (m, 2H), 3.36-3.25 (m, 1H), 1.88- 1.72 (m, 4H). 225 1H NMR (500 MHz, DMSO-d6) d 12.14-11.62 (m, 1H), 8.52 (s, 1H), 8.20 (s, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 4.35 (t, J = 5.1 Hz, 2H), 4.00-3.95 (m, 2H), 3.92 (s, 3H), 3.73-3.70 (m, 2H), 3.50 (td, J = 11.4, 2.6 Hz, 2H), 3.34-3.27 (m, 1H), 3.25 (s, 3H), 1.86-1.73 (m, 4H). 226 1H NMR (400 MHz, DMSO-d6) d 13.40-11.58 (m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H), 3.98-3.93 (m, 2H), 3.89 (s, 3H), 3.53-3.45 (m, 2H), 3.27-3.18 (m, 1H), 1.73-1.66 (m, 4H), 1.59-1.55 (m, 4H). 227 1H NMR (500 MHz, DMSO-d6) d 8.52-8.41 (m, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 3.99-3.95 (m, 2H), 3.91 (s, 3H), 3.53-3.46 (m, 2H), 3.32-3.25 (m, 1H), 2.71 (s, 3H), 1.81-1.71 (m, 4H). 228 1H NMR (500 MHz, Methanol-d4) delta 7.98-7.96 (m, 1H), 7.81-7.80 (m, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 4.94 (s, 2H), 4.10- 4.06 (m, 2H), 4.01 (s, 3H), 3.65 (td, J = 11.6, 2.5 Hz, 2H), 3.30-3.23 (m, 1H), 1.92-1.79 (m, 4H). 229 1H NMR (700 MHz, DMSO-d6) d 11.45-9.57 (m, 2H), 8.86 (s, 1H), 8.44 (s, 1H), 7.86 (t, J = 59.5 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 4.38 (s, 1H), 3.92 (s, 3H), 3.87-3.82 (m, 2H), 3.34-3.25 (m, 2H), 1.52- 1.43 (m, 4H), 1.15 (s, 3H). 230 1H NMR (500 MHz, DMSO-d6) d 11.66-9.66 (m, 2H), 8.34-8.28 (m, 1H), 8.06-7.99 (m, 1H), 7.23 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 4.37 (s, 1H), 4.28 (t, J = 5.4 Hz, 2H), 3.90 (s, 3H), 3.89-3.83 (m, 2H), 3.82-3.79 (m, 2H), 3.53-3.50 (m, 2H), 3.43-3.39 (m, 2H), 3.33-3.25 (m, 2H), 3.20 (s, 3H), 1.52-1.41 (m, 4H), 1.15 (s, 3H). 231 1H NMR (500 MHz, DMSO-d6) d 11.77-10.96 (m, 1H), 10.87-10.05 (m, 1H), 9.45-9.32 (m, 1H), 8.52-8.49 (m, 1H), 8.49-8.43 (m, 1H), 8.03- 7.96 (m, 2H), 7.47 (d, J = 8.2 Hz, 1H), 7.38-7.34 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H), 4.39 (s, 1H), 3.93 (s, 3H), 3.90-3.83 (m, 2H), 3.34-3.25 (m, 2H), 1.54-1.43 (m, 4H), 1.16 (s, 3H). 232 1H NMR (400 MHz, DMSO-d6) d 8.49 (s, 1H), 8.18 (s, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 1.60-1.54 (m, 2H), 1.24-1.14 (m, 2H), 0.77 (t, J = 7.3 Hz, 3H), 0.75-0.73 (m, 4H). 233 1H NMR (400 MHz, DMSO-d6) d 12.19-11.46 (m, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 3.92 (s, 3H), 3.92 (s, 3H), 3.08-2.99 (m, 1H), 1.76-1.62 (m, 4H), 1.25-1.03 (m, 2H), 0.81 (t, J = 7.3 Hz, 3H), 0.73 (t, J = 7.3 Hz, 3H). 234 1H NMR (500 MHz, DMSO-d6) d 12.76-11.68 (m, 1H), 8.00-7.76 (m, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 3.99-3.95 (m, 2H), 3.91 (s, 3H), 3.52-3.46 (m, 2H), 3.29-3.21 (m, 1H), 2.52 (s, 3H), 1.83-1.68 (m, 4H). 235 1H NMR (400 MHz, DMSO-d6, 90° C.) d 8.26-8.24 (m, 1H), 8.20-8.16 (m, 2H), 8.00-7.99 (m, 1H), 7.69-7.65 (m, 2H), 7.32 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 4.05-4.02 (m, 2H), 3.99 (s, 3H), 3.92 (s, 3H), 3.42- 3.31 (m, 4H), 3.14-3.02 (m, 4H), 2.78 (s, 3H). 236 1H NMR (500 MHz, DMSO-d6) d 11.89-11.21 (m, 1H), 10.85-10.21 (m, 1H), 7.61-7.10 (m, 4H), 6.95-6.86 (m, 1H), 6.79 (d, J = 8.3 Hz, 1H), 4.36 (s, 1H), 4.19-4.12 (m, 2H), 3.94 (s, 3H), 3.90-3.78 (m, 2H), 3.71-3.66 (m, 2H), 3.33 (s, 3H), 3.31-3.22 (m, 2H), 1.50-1.39 (m, 4H), 1.16-1.10 (m, 3H). 238 1H NMR (500 MHz, DMSO-d6) d 11.65-11.00 (m, 1H), 10.90-9.85 (m, 1H), 8.40-8.19 (m, 1H), 8.10-7.91 (m, 1H), 7.27-7.21 (m, 1H), 6.71 (d, J = 8.4 Hz, 1H), 4.75 (s, 1H), 4.40 (s, 1H), 4.04 (s, 2H), 3.90 (s, 3H), 3.88- 3.81 (m, 2H), 3.34-3.25 (m, 2H), 1.52-1.41 (m, 4H), 1.15 (s, 3H), 1.10 (s, 6H). 239 1H NMR (700 MHz, DMSO-d6) d 11.96-11.80 (m, 1H), 8.51 (s, 1H), 8.20 (s, 1H), 7.88-7.81 (m, 1H), 7.78-7.74 (m, 1H), 7.52-7.48 (m, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.17-7.13 (m, 1H), 6.90 (d, J = 8.3 Hz, 1H), 3.99 (s, 3H), 3.91 (s, 3H). 240 1H NMR (700 MHz, DMSO-d6) d 12.74-11.46 (m, 1H), 8.18-8.14 (m, 2H), 7.89-7.82 (m, 1H), 7.79-7.74 (m, 1H), 7.58-7.55 (m, 2H), 7.53-7.49 (m, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.16 (td, J = 8.5, 2.7 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 4.00 (s, 3H), 3.02 (s, 3H), 2.91 (s, 3H). 241 1H NMR (500 MHz, DMSO-d6) d 11.54-11.26 (m, 1H), 10.37-10.07 (m, 1H), 8.48-8.30 (m, 1H), 8.20-7.99 (m, 1H), 7.27 (s, 1H), 6.71 (d, J = 8.3 Hz, 1H), 5.09-5.02 (m, 1H), 4.37 (s, 1H), 4.05-3.99 (m, 2H), 3.95 (dd, J = 9.3, 3.9 Hz, 1H), 3.90 (s, 3H), 3.88-3.81 (m, 3H), 2.47-2.25 (m, 4H), 1.52- 1.41 (m, 4H), 1.15 (s, 3H). 242 1H NMR (500 MHz, DMSO-d6) d 8.15-8.12 (m, 2H), 7.63 (td, J = 7.7, 1.9 Hz, 1H), 7.56-7.53 (m, 2H), 7.48-7.43 (m, 1H), 7.37-7.31 (m, 2H), 7.23- 7.20 (m, 1H), 6.94 (d, J = 8.3 Hz, 1H), 4.00 (s, 3H), 3.01 (s, 3H), 2.90 (s, 3H). 243 1H NMR (400 MHz, DMSO-d6) d 12.12-11.68 (m, 1H), 10.60-10.33 (m, 1H), 8.48-8.46 (m, 1H), 8.17-8.16 (m, 1H), 7.62 (td, J = 7.6, 1.7 Hz, 1H), 7.47-7.41 (m, 1H), 7.36-7.29 (m, 2H), 7.21-7.18 (m, 1H), 6.91 (d, J = 8.3 Hz, 1H), 3.99 (s, 3H), 3.90 (s, 3H). 246 1H NMR (400 MHz, DMSO-d6) d 12.07-11.65 (m, 1H), 8.27 (s, 1H), 8.01 (s, 1H), 7.70-7.67 (m, 1H), 7.33 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.59-3.51 (m, 2H), 3.44-3.40 (m, 1H), 2.48- 2.44 (m, 2H). 247 1H NMR (400 MHz, DMSO-d6) delta 8.70-8.64 (m, 1H), 8.20-8.18 (m, 1H), 7.91-7.90 (m, 1H), 7.78 (d, J = 3.3 Hz, 1H), 7.67 (d, J = 3.2 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 4.75 (d, J = 5.8 Hz, 2H), 3.94 (s, 3H), 3.89 (s, 3H). 248 1H NMR (400 MHz, DMSO-d6) delta 8.34-8.32 (m, 1H), 8.25-8.21 (m, 2H), 8.06-8.04 (m, 1H), 7.51-7.47 (m, 2H), 7.35 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 2.83 (s, 4H). 250 1H NMR (500 MHz, DMSO-d6) delta 8.23-8.20 (m, 2H), 7.49-7.46 (m, 2H), 7.01 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 4.00-3.96 (m, 2H), 3.93 (s, 3H), 3.54-3.48 (m, 2H), 3.36-3.29 (m, 1H), 2.82 (s, 4H), 1.85-1.75 (m, 4H). 252 1H NMR (400 MHz, DMSO-d6) delta 11.04-10.82 (m, 1H), 9.32-9.20 (m, 2H), 8.18-8.14 (m, 2H), 7.59-7.55 (m, 2H), 7.16 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H), 6.75-6.67 (m, 1H), 3.96 (s, 3H), 3.83-3.77 (m, 2H), 3.39-3.32 (m, 2H), 3.04-2.89 (m, 6H), 2.87-2.81 (m, 2H). 253 1H NMR (400 MHz, DMSO-d6) d 12.83-12.68 (m, 1H), 11.76-11.57 (m, 1H), 10.99-10.69 (m, 1H), 8.11-7.94 (m, 2H), 7.87 (s, 1H), 7.70-7.14 (m, 5H), 6.86 (d, J = 8.1 Hz, 1H), 3.97 (s, 3H). 254 1H NMR (400 MHz, DMSO-d6) d 12.07-11.85 (m, 1H), 11.73-11.42 (m, 1H), 8.14-7.94 (m, 2H), 7.91 (s, 1H), 7.73-7.13 (m, 5H), 6.88 (d, J = 8.3 Hz, 1H), 3.98 (s, 3H), 3.91 (s, 3H). 255 1H NMR (400 MHz, DMSO-d6) d 12.75-12.40 (m, 1H), 11.86-11.56 (m, 1H), 10.96-10.35 (m, 1H), 8.05-7.98 (m, 1H), 7.96-7.86 (m, 1H), 7.67- 7.14 (m, 5H), 6.89-6.81 (m, 1H), 3.97 (s, 3H), 2.38-2.31 (m, 3H). 256 1H NMR (400 MHz, DMSO-d6) d 12.68-11.66 (m, 2H), 9.35-9.25 (m, 1H), 8.97-8.48 (m, 1H), 8.08-7.60 (m, 2H), 7.56-7.45 (m, 2H), 7.42-7.33 (m, 1H), 7.31 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 3.98 (s, 3H). 257 1H NMR (500 MHz, DMSO-d6) d 12.47-11.62 (m, 2H), 8.72-8.28 (m, 1H), 8.07-7.59 (m, 2H), 7.56-7.43 (m, 2H), 7.41-7.24 (m, 2H), 6.92 (d, J = 8.4 Hz, 1H), 3.97 (s, 3H), 2.71 (s, 3H). 258 1H NMR (400 MHz, DMSO-d6) d 12.02-11.78 (m, 1H), 11.60-11.37 (m, 1H), 8.22-7.79 (m, 4H), 7.67-7.14 (m, 5H), 6.86 (d, J = 8.3 Hz, 1H), 3.97 (s, 3H). 259 1H NMR (400 MHz, DMSO-d6) delta 12.36-12.11 (m, 1H), 9.67-9.59 (m, 1H), 9.23-9.16 (m, 1H), 8.85-8.79 (m, 1H), 8.19-8.10 (m, 3H), 7.71 (d, J = 8.4 Hz, 1H), 7.60-7.55 (m, 2H), 7.02 (d, J = 8.5 Hz, 1H), 4.04 (s, 3H), 3.02 (s, 3H), 2.91 (s, 3H). 260 1H NMR (500 MHz, DMSO-d6) d 11.98-11.87 (m, 1H), 9.62-9.58 (m, 1H), 9.20-9.15 (m, 1H), 8.81-8.79 (m, 1H), 8.51-8.50 (m, 1H), 8.21-8.20 (m, 1H), 8.14-8.09 (m, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 4.02 (s, 3H), 3.92 (s, 3H). 261 1H NMR (400 MHz, DMSO-d6) d 12.55-11.32 (m, 1H), 8.19-8.15 (m, 2H), 7.60-7.55 (m, 2H), 6.99 (d, J = 8.3 Hz, 1H), 6.93-6.84 (m, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.06-5.01 (m, 2H), 4.83-4.78 (m, 2H), 3.96 (s, 3H), 3.02 (s, 3H), 2.92 (s, 3H). 262 1H NMR (400 MHz, DMSO-d6) d 8.17-8.12 (m, 2H), 7.58-7.54 (m, 2H), 6.77 (d, J = 13.4 Hz, 1H), 6.07-6.04 (m, 1H), 4.26 (q, J = 2.6 Hz, 2H), 3.95 (s, 3H), 3.86 (t, J = 5.4 Hz, 2H), 3.04-2.98 (m, 3H), 2.94-2.88 (m, 3H), 2.52-2.47 (m, 2H). 263 1H NMR (400 MHz, DMSO-d6) d 7.63-7.60 (m, 2H), 7.40 (t, J = 8.1 Hz, 1H), 7.23-7.19 (m, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.00-3.95 (m, 2H), 3.94 (s, 3H), 3.55-3.32 (m, 3H), 3.27 (s, 6H), 1.83- 1.73 (m, 4H). 264 1H NMR (400 MHz, DMSO-d6) d 11.97-11.71 (m, 1H), 8.47 (s, 1H), 8.17- 8.16 (m, 1H), 6.71 (d, J = 13.3 Hz, 1H), 6.07-6.04 (m, 1H), 4.25 (q, J = 2.8 Hz, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.85 (t, J = 5.4 Hz, 2H), 2.54-2.48 (m, 2H). 265 1H NMR (400 MHz, DMSO-d6) d 13.10-12.37 (m, 1H), 11.96-11.53 (m, 1H), 11.26-10.59 (m, 1H), 8.07 (s, 1H), 8.06-7.95 (m, 1H), 7.91-7.82 (m, 2H), 7.57-7.36 (m, 2H), 7.28-7.07 (m, 1H), 6.87 (d, J = 8.4 Hz, 1H), 3.98 (s, 3H). 266 1H NMR (500 MHz, DMSO-d6) d 11.53-11.19 (m, 1H), 8.91-8.85 (m, 2H), 8.86-8.83 (m, 2H), 8.21 (s, 1H), 8.18-8.17 (m, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 4.06 (s, 3H). 267 1H NMR (400 MHz, DMSO-d6) d 13.30-12.36 (m, 1H), 11.81-11.52 (m, 1H), 8.10-8.00 (m, 1H), 7.88 (s, 1H), 7.69-7.51 (m, 1H), 7.48-7.29 (m, 2H), 7.26-7.12 (m, 1H), 7.01-6.80 (m, 2H), 4.21-4.14 (m, 2H), 3.97 (s, 3H), 3.73-3.68 (m, 2H), 3.36-3.30 (m, 3H). 268 1H NMR (500 MHz, DMSO-d6) d 9.42 (s, 1H), 8.85-8.81 (m, 1H), 8.71 (dd, J = 5.3, 1.5 Hz, 1H), 8.37 (s, 1H), 8.21-8.18 (m, 1H), 7.87 (dd, J = 8.1, 5.2 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 4.02 (s, 3H). 269 1H NMR (700 MHz, DMSO-d6) delta 11.76-11.46 (m, 2H), 8.58-8.49 (m, 1H), 8.02-7.97 (m, 1H), 7.69-7.12 (m, 5H), 6.86 (d, J = 8.3 Hz, 1H), 3.97 (s, 3H), 3.82 (s, 3H), 2.43-2.37 (m, 3H). 270 1H NMR (700 MHz, DMSO-d6) delta 11.89-11.76 (m, 1H), 11.67-11.38 (m, 1H), 10.61-10.31 (m, 1H), 8.35-8.20 (m, 1H), 7.67-7.37 (m, 2H), 7.34- 7.12 (m, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.58-6.34 (m, 1H), 4.34 (s, 1H), 3.98 (s, 3H), 3.89-3.74 (m, 2H), 3.30-3.17 (m, 2H), 1.51-1.34 (m, 4H), 1.13 (s, 3H). 271 1H NMR (700 MHz, DMSO-d6) d 13.36-13.11 (m, 1H), 12.52-9.90 (m, 1H), 7.99 (s, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.48-7.45 (m, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.34-7.30 (m, 1H), 6.98 (d, J = 8.3 Hz, 1H), 4.00 (s, 3H), 3.82- 3.75 (m, 2H), 3.30-3.22 (m, 2H), 1.50-1.39 (m, 4H), 1.13 (s, 3H). 272 273 1H NMR (700 MHz, DMSO-d6) delta 13.53-9.83 (m, 2H), 8.16-8.08 (m, 1H), 8.09 (s, 1H), 7.80-7.72 (m, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 4.09 (s, 3H), 3.97 (s, 3H), 3.84-3.79 (m, 2H), 3.31-3.24 (m, 2H), 1.51-1.41 (m, 4H), 1.15 (s, 3H). 274 1H NMR (700 MHz, DMSO-d6) d 12.90-12.52 (m, 1H), 11.27-10.02 (m, 1H), 7.98-7.93 (m, 1H), 7.73-7.62 (m, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 3.97 (s, 3H), 3.84-3.78 (m, 2H), 3.33-3.24 (m, 2H), 2.53 (s, 3H), 1.52-1.41 (m, 4H), 1.15 (s, 3H). 275 1H NMR (700 MHz, DMSO-d6) d 14.34-13.99 (m, 1H), 12.14-11.43 (m, 1H), 10.54-10.33 (m, 1H), 8.91-8.89 (m, 1H), 8.84-8.68 (m, 1H), 8.30- 8.28 (m, 1H), 8.32-8.23 (m, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.69-7.64 (m, 1H), 6.94 (d, J = 8.5 Hz, 1H), 4.00 (s, 3H), 3.87-3.82 (m, 2H), 3.32-3.26 (m, 2H), 1.53-1.43 (m, 4H), 1.16 (s, 3H). 277 1H NMR (500 MHz, DMSO-d6) d 12.54-11.55 (m, 1H), 8.18-8.13 (m, 2H), 7.59-7.54 (m, 2H), 6.69 (d, J = 13.6 Hz, 1H), 3.99-3.95 (m, 2H), 3.92 (s, 3H), 3.50-3.40 (m, 3H), 3.04-2.89 (m, 6H), 2.32-2.22 (m, 2H), 1.62- 1.55 (m, 2H). 278 1H NMR (500 MHz, DMSO-d6) d 12.11-12.06 (m, 1H), 12.04-11.82 (m, 1H), 8.51 (s, 1H), 8.38 (d, J = 5.3 Hz, 1H), 8.20-8.18 (m, 1H), 7.70-7.60 (m, 1H), 7.63-7.61 (m, 1H), 7.52 (d, J = 8.3 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.65-6.60 (m, 1H), 4.33 (t, J = 5.2 Hz, 2H), 4.03 (s, 3H), 3.73-3.69 (m, 2H), 3.25 (s, 3H). 279 1H NMR (500 MHz, DMSO-d6) d 13.32-13.01 (m, 1H), 12.00-11.78 (m, 1H), 8.49 (s, 1H), 8.17 (s, 1H), 8.01 (d, J = 1.0 Hz, 1H), 7.56-7.52 (m, 1H), 7.48-7.44 (m, 1H), 7.46-7.40 (m, 1H), 7.38 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 4.32 (t, J = 5.2 Hz, 2H), 4.02 (s, 3H), 3.72-3.68 (m, 2H), 3.24 (s, 3H). 280 1H NMR (500 MHz, DMSO-d6) d 12.05-11.75 (m, 1H), 11.17-11.09 (m, 1H), 8.51 (s, 1H), 8.19 (s, 1H), 7.84-7.74 (m, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.47-7.38 (m, 1H), 7.38 (t, J = 2.7 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.48-6.45 (m, 1H), 4.34 (t, J = 5.2 Hz, 2H), 3.99 (s, 3H), 3.73-3.70 (m, 2H), 3.25 (s, 3H). 281 1H NMR (500 MHz, DMSO-d6) d 12.01-11.76 (m, 1H), 8.52 (s, 1H), 8.28- 8.23 (m, 1H), 8.21-8.20 (m, 1H), 8.10-8.09 (m, 1H), 7.93-7.87 (m, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 4.34 (t, J = 5.2 Hz, 2H), 4.09 (s, 3H), 3.99 (s, 3H), 3.73-3.70 (m, 2H), 3.25 (s, 3H). 282 1H NMR (500 MHz, DMSO-d6) d 12.88-12.40 (m, 1H), 12.11-11.66 (m, 1H), 8.51 (s, 1H), 8.21-8.18 (m, 1H), 8.07-8.03 (m, 1H), 7.87-7.79 (m, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 4.33 (t, J = 5.2 Hz, 2H), 3.99 (s, 3H), 3.73-3.69 (m, 2H), 3.25 (s, 3H), 2.54 (s, 3H). 283 1H NMR (500 MHz, DMSO-d6) d 12.10-11.52 (m, 1H), 8.49-8.48 (m, 1H), 8.18-8.16 (m, 1H), 7.40-7.33 (m, 2H), 7.24-7.18 (m, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 4.33 (t, J = 5.2 Hz, 2H), 3.99 (s, 3H), 3.72- 3.69 (m, 2H), 3.64 (t, J = 7.9 Hz, 2H), 3.24 (s, 3H), 3.13 (t, J = 7.9 Hz, 2H). 284 1H NMR (500 MHz, DMSO-d6) d 11.89-11.21 (m, 1H), 8.81 (dd, J = 2.1, 0.8 Hz, 1H), 8.25 (dd, J = 8.0, 0.8 Hz, 1H), 8.15 (dd, J = 8.0, 2.1 Hz, 1H), 7.89-7.85 (m, 2H), 7.52-7.48 (m, 2H), 7.38-7.34 (m, 1H), 7.35 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.00 (s, 3H), 3.05 (s, 3H), 2.95 (s, 3H). 285 1H NMR (500 MHz, DMSO-d6) d 12.30-11.76 (m, 2H), 8.23-8.19 (m, 2H), 8.11-7.60 (m, 2H), 7.57-7.42 (m, 4H), 7.40-7.24 (m, 2H), 6.90 (d, J = 8.3 Hz, 1H), 3.99 (s, 3H), 2.82 (s, 4H). 286 1H NMR (500 MHz, DMSO-d6) d 12.41-11.59 (m, 2H), 9.66-9.48 (m, 1H), 8.90-8.55 (m, 1H), 8.08-7.90 (m, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.74-7.16 (m, 7H), 6.90 (d, J = 8.3 Hz, 1H), 4.00 (s, 3H). 287 1H NMR (500 MHz, DMSO-d6) d 11.83-10.34 (m, 2H), 7.95-7.57 (m, 2H), 7.51-7.44 (m, 2H), 7.37-7.31 (m, 1H), 7.23-7.17 (m, 1H), 6.84 (d, J = 8.3 Hz, 1H), 3.94 (s, 3H), 3.70-3.63 (m, 4H), 2.04-1.93 (m, 4H). 288 1H NMR (500 MHz, DMSO-d6) d 11.95-11.63 (m, 1H), 11.63-11.48 (m, 1H), 8.95-8.91 (m, 1H), 8.63 (s, 1H), 8.44-8.41 (m, 1H), 8.06-7.62 (m, 2H), 7.58 (dd, J = 9.2, 4.5 Hz, 1H), 7.55-7.44 (m, 2H), 7.41-7.26 (m, 2H), 6.90 (d, J = 8.3 Hz, 1H), 3.99 (s, 3H). 289 1H NMR (500 MHz, DMSO-d6/TFA) d 10.35 (dd, J = 6.9, 1.9 Hz, 1H), 9.07 (dd, J = 4.4, 1.9 Hz, 1H), 8.91 (s, 1H), 7.75 (dd, J = 6.9, 4.4 Hz, 1H), 7.66- 7.63 (m, 2H), 7.56-7.51 (m, 2H), 7.44-7.39 (m, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 4.01 (s, 3H). 290 1H NMR (500 MHz, DMSO-d6/TFA) d 9.09-9.05 (m, 2H), 8.62 (s, 1H), 8.61- 8.58 (m, 2H), 7.67-7.63 (m, 2H), 7.59-7.54 (m, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.48-7.44 (m, 1H), 7.18 (d, J = 8.5 Hz, 1H), 4.04 (s, 3H). 291 1H NMR (500 MHz, DMSO-d6) d 12.15-11.48 (m, 2H), 8.08 (s, 1H), 8.01- 7.58 (m, 2H), 7.53-7.43 (m, 2H), 7.38-7.25 (m, 2H), 6.89 (d, J = 8.3 Hz, 1H), 4.38-4.30 (m, 2H), 4.00-3.94 (m, 3H), 2.89-2.84 (m, 2H), 1.99- 1.92 (m, 2H), 1.88-1.82 (m, 2H). 292 1H NMR (400 MHz, DMSO-d6) d 7.50-7.38 (m, 3H), 7.25 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 4.00 (s, 3H), 3.87-3.79 (m, 2H), 3.71 (t, J = 7.8 Hz, 2H), 3.37-3.26 (m, 2H), 3.13 (t, J = 7.8 Hz, 2H), 1.55-1.41 (m, 4H), 1.15 (s, 3H). 293 1H NMR (500 MHz, DMSO-d6) d 12.28-12.04 (m, 1H), 11.98-11.76 (m, 1H), 8.64-8.57 (m, 1H), 8.20-8.16 (m, 2H), 8.06-7.93 (m, 3H), 7.79- 7.18 (m, 5H), 6.90 (d, J = 8.3 Hz, 1H), 3.99 (s, 3H), 3.27-3.22 (m, 2H), 1.60- 1.52 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). 294 1H NMR (500 MHz, DMSO-d6) d 12.17-11.97 (m, 2H), 8.19-8.15 (m, 2H), 7.97-7.77 (m, 2H), 7.56-7.52 (m, 2H), 7.52-7.45 (m, 2H), 7.37-7.28 (m, 2H), 6.90 (d, J = 8.3 Hz, 1H), 3.99 (s, 3H), 3.70-3.58 (m, 2H), 3.36-3.27 (m, 2H), 2.43-2.24 (m, 4H), 2.20 (s, 3H). 295 1H NMR (500 MHz, DMSO-d6) d 12.26-12.04 (m, 1H), 12.02-11.76 (m, 1H), 8.20-8.11 (m, 2H), 8.11-7.56 (m, 2H), 7.54-7.50 (m, 2H), 7.57- 7.22 (m, 4H), 6.90 (d, J = 8.3 Hz, 1H), 3.99 (s, 3H), 3.68-3.54 (m, 2H), 3.45- 3.34 (m, 2H), 3.34-3.16 (m, 3H), 3.04-2.90 (m, 3H). 296 1H NMR (500 MHz, DMSO-d6) d 12.14-11.97 (m, 2H), 8.15 (d, J = 7.8 Hz, 2H), 7.93-7.81 (m, 2H), 7.54-7.51 (m, 2H), 7.49 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 3.99 (s, 3H), 3.61-3.52 (m, 1H), 3.32-3.22 (m, 1H), 3.03-2.87 (m, 3H), 2.55- 2.32 (m, 2H), 2.24 (s, 3H), 1.98 (s, 3H). 297 1H NMR (500 MHz, DMSO-d6) d 12.25-12.04 (m, 1H), 12.03-11.75 (m, 1H), 8.19-8.13 (m, 2H), 8.09-7.58 (m, 2H), 7.57-7.20 (m, 6H), 6.90 (d, J = 8.3 Hz, 1H), 3.99 (s, 3H), 3.46-3.40 (m, 1H), 3.17-3.10 (m, 1H), 3.00- 2.85 (m, 3H), 1.67-1.47 (m, 2H), 0.96-0.66 (m, 3H). 298 1H NMR (500 MHz, DMSO-d6) d 12.26-12.05 (m, 1H), 12.00-11.78 (m, 1H), 8.20-8.16 (m, 2H), 8.09-7.60 (m, 2H), 7.60-7.54 (m, 2H), 7.55- 7.24 (m, 4H), 6.90 (d, J = 8.3 Hz, 1H), 3.99 (s, 3H), 3.72-3.27 (m, 8H). 299 1H NMR (500 MHz, DMSO-d6) d 13.03-12.47 (m, 1H), 12.01-11.64 (m, 1H), 11.18-10.68 (m, 1H), 8.51-8.42 (m, 1H), 8.10-8.05 (m, 1H), 7.90- 7.87 (m, 1H), 8.02-7.27 (m, 3H), 6.90 (d, J = 8.4 Hz, 1H), 3.99 (s, 3H), 2.54 (s, 3H). 300 301 1H NMR (700 MHz, DMSO-d6) d 14.56-14.02 (m, 1H), 12.33-11.85 (m, 1H), 11.85-11.82 (m, 1H), 8.94-8.92 (m, 1H), 8.79-8.73 (m, 1H), 8.54 (s, 1H), 8.31-8.30 (m, 1H), 8.32-8.27 (m, 1H), 8.23 (s, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 4.35 (t, J = 5.2 Hz, 2H), 4.04 (s, 3H), 3.73 (t, J = 5.2 Hz, 2H), 3.26 (s, 3H). 302 1H NMR (700 MHz, DMSO-d6) d 12.53-11.05 (m, 2H), 11.16-11.13 (m, 1H), 8.51 (s, 1H), 8.19 (s, 1H), 8.01-7.91 (m, 1H), 7.52-7.46 (m, 2H), 7.40-7.38 (m, 1H), 7.26 (d, J = 8.2 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.50-6.48 (m, 1H), 4.34 (t, J = 5.2 Hz, 2H), 3.98 (s, 3H), 3.71 (t, J = 5.2 Hz, 2H), 3.25 (s, 3H). 303 1H NMR (700 MHz, DMSO-d6) d 11.86-11.14 (m, 1H), 11.19-11.05 (m, 1H), 10.74-10.10 (m, 1H), 8.20-7.23 (m, 2H), 7.53-7.45 (m, 1H), 7.38 (s, 1H), 7.19-7.07 (m, 1H), 6.80 (d, J = 8.3 Hz, 1H), 6.47 (s, 1H), 4.39-4.36 (m, 1H), 3.93 (s, 3H), 3.87-3.80 (m, 2H), 3.29-3.23 (m, 2H), 1.48-1.38 (m, 4H), 1.13 (s, 3H). 304 1H NMR (700 MHz, DMSO-d6) d 12.01-11.81 (m, 1H), 12.08-10.92 (m, 1H), 10.80-10.69 (m, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.30-7.28 (m, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 7.2 Hz, 1H), 7.14-7.10 (m, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.52 (s, 1H), 4.32 (t, J = 5.2 Hz, 2H), 4.02 (s, 3H), 3.69 (t, J = 5.2 Hz, 2H), 3.23 (s, 3H). 305 1H NMR (700 MHz, DMSO-d6) d 12.25-11.21 (m, 1H), 10.80 (s, 1H), 10.93- 10.19 (m, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.30 (t, J = 2.8 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 7.1 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.00-6.96 (m, 1H), 6.54-6.52 (m, 1H), 4.00 (s, 3H), 3.80-3.75 (m, 2H), 3.28-3.22 (m, 2H), 1.49-1.38 (m, 4H), 1.13 (s, 3H). 306 1H NMR (700 MHz, DMSO-d6) d 11.99-11.80 (m, 1H), 11.66-11.55 (m, 1H), 8.52-8.46 (m, 1H), 8.21-8.16 (m, 1H), 8.02-7.98 (m, 1H), 7.65- 7.17 (m, 5H), 6.88-6.84 (m, 1H), 3.97 (s, 3H), 3.91 (s, 3H). 307 1H NMR (700 MHz, DMSO-d6) d 11.99-11.81 (m, 1H), 11.65-11.56 (m, 1H), 8.55-8.49 (m, 1H), 8.24-8.18 (m, 1H), 8.01-7.99 (m, 1H), 7.66- 7.17 (m, 5H), 6.88-6.84 (m, 1H), 4.33 (t, J = 5.2 Hz, 2H), 3.97 (s, 3H), 3.72- 3.70 (m, 2H), 3.26-3.24 (m, 3H). 308 1H NMR (700 MHz, DMSO-d6) delta 12.46-11.63 (m, 2H), 8.16-7.23 (m, 7H), 6.95-6.89 (m, 1H), 3.98 (s, 3H), 2.52 (s, 3H). 309 1H NMR (700 MHz, DMSO-d6) delta 12.25-12.04 (m, 1H), 12.03-11.74 (m, 1H), 8.17-8.14 (m, 2H), 8.04-7.95 (m, 1H), 7.56-7.54 (m, 2H), 7.77-7.21 (m, 5H), 6.90 (d, J = 8.3 Hz, 1H), 3.99 (s, 3H), 3.02-2.90 (m, 6H). 310 1H NMR (700 MHz, DMSO-d6) delta 11.63-11.30 (m, 1H), 10.39-10.10 (m, 1H), 8.02-7.92 (m, 1H), 7.69-7.07 (m, 5H), 6.80 (d, J = 8.3 Hz, 1H), 3.94 (s, 3H), 3.66-3.37 (m, 8H), 1.88-1.71 (m, 2H), 1.52-1.47 (m, 4H). 311 1H NMR (700 MHz, DMSO-d6) delta 12.25-11.94 (m, 1H), 11.94-11.63 (m, 1H), 8.11-8.08 (m, 2H), 8.03-7.96 (m, 1H), 7.68-7.19 (m, 5H), 7.38 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.3 Hz, 1H), 4.46 (s, 2H), 3.98 (s, 3H), 3.27 (t, J = 7.0 Hz, 2H), 2.32 (t, J = 8.1 Hz, 2H), 1.98-1.93 (m, 2H). 314 1H NMR (400 MHz, DMSO-d6) d 12.33-11.98 (m, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.64-6.58 (m, 1H), 4.27 (q, J = 2.4 Hz, 2H), 3.93 (s, 3H), 3.86 (t, J = 5.4 Hz, 2H), 2.58-2.52 (m, 2H), 2.03-1.96 (m, 1H), 0.98-0.92 (m, 4H). 315 1H NMR (400 MHz, DMSO-d6) d 12.14 (s, 1H), 9.60-9.58 (m, 1H), 9.18- 9.13 (m, 1H), 8.82-8.79 (m, 1H), 8.11 (dd, J = 8.3, 5.6 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 4.00 (s, 3H), 2.04-1.97 (m, 1H), 0.98- 0.92 (m, 4H). 316 1H NMR (700 MHz, DMSO-d6) delta 12.62-11.53 (m, 1H), 8.16-8.14 (m, 2H), 7.96-7.91 (m, 2H), 7.57-7.55 (m, 2H), 7.33-7.29 (m, 3H), 6.92 (d, J = 8.3 Hz, 1H), 3.99 (s, 3H), 3.03-2.90 (m, 6H). 317 1H NMR (700 MHz, DMSO-d6) delta 12.34-12.04 (m, 1H), 8.22-8.19 (m, 2H), 7.98-7.91 (m, 2H), 7.48-7.46 (m, 2H), 7.33-7.29 (m, 3H), 6.91 (d, J = 8.3 Hz, 1H), 3.99 (s, 3H), 2.82 (s, 4H). 318 1H NMR (500 MHz, DMSO-d6) delta 12.10-11.65 (m, 1H), 8.50-8.48 (m, 1H), 8.19-8.18 (m, 1H), 7.96-7.90 (m, 2H), 7.32-7.27 (m, 3H), 6.89 (d, J = 8.3 Hz, 1H), 3.98 (s, 3H), 3.91 (s, 3H). 319 1H NMR (500 MHz, DMSO-d6) d 12.37-12.03 (m, 1H), 11.92-11.38 (m, 1H), 8.17-8.13 (m, 2H), 7.80-7.73 (m, 1H), 7.55-7.51 (m, 2H), 7.16- 7.08 (m, 1H), 6.89-6.83 (m, 1H), 6.56-6.50 (m, 1H), 3.97 (s, 3H), 4.02- 3.92 (m, 6H), 3.04-2.88 (m, 6H). 320 1H NMR (500 MHz, DMSO-d6) d 12.04-11.90 (m, 1H), 11.29-11.07 (m, 1H), 7.97-7.69 (m, 1H), 7.24-7.00 (m, 1H), 6.78 (d, J = 8.3 Hz, 1H), 6.55- 6.43 (m, 1H), 3.97-3.84 (m, 9H), 1.99-1.90 (m, 1H), 0.94-0.89 (m, 4H). 321 1H NMR (400 MHz, DMSO-d6, 90° C.) d 9.29-9.26 (m, 1H), 8.63 (dd, J = 5.1, 1.5 Hz, 1H), 8.63-8.58 (m, 1H), 8.01 (s, 1H), 7.74-7.69 (m, 1H), 7.48 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 4.04 (s, 3H), 2.54 (s, 3H). 322 1H NMR (500 MHz, DMSO-d6) d 8.07-8.04 (m, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.88-6.83 (m, 1H), 6.79 (d, J = 8.4 Hz, 1H), 5.03-5.00 (m, 2H), 4.81- 4.77 (m, 2H), 3.95 (s, 3H), 2.54 (s, 3H). 323 1H NMR (400 MHz, DMSO-d6, 90° C.) d 7.95 (s, 1H), 7.91-7.84 (m, 2H), 7.30-7.23 (m, 3H), 7.75-6.19 (m, 2H), 6.91 (d, J = 8.4 Hz, 1H), 4.04-3.99 (m, 3H), 2.52 (s, 3H). 324 1H NMR (400 MHz, DMSO-d6) d 8.20-8.14 (m, 2H), 7.61-7.56 (m, 2H), 7.15 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.67-6.56 (m, 1H), 4.31- 4.26 (m, 2H), 3.96 (s, 3H), 3.88 (t, J = 5.4 Hz, 2H), 3.04-2.89 (m, 6H), 2.60- 2.54 (m, 2H). 325 1H NMR (400 MHz, DMSO-d6) d 12.18-11.88 (m, 1H), 8.52 (s, 1H), 8.21 (s, 1H), 7.15 (d, J =8.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.63-6.54 (m, 1H), 4.28 (q, J = 2.7 Hz, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.87 (t, J = 5.4 Hz, 2H), 2.58-2.53 (m, 2H). 329 1H NMR (700 MHz, DMSO-d6) d 12.06-11.36 (m, 1H), 10.63-10.34 (m, 1H), 8.02-7.93 (m, 1H), 7.65-7.07 (m, 5H), 6.84-6.79 (m, 1H), 3.94 (s, 3H), 3.75 (t, J = 7.1 Hz, 2H), 3.64-3.57 (m, 2H), 3.49-3.42 (m, 4H), 1.74 (t, J = 7.1 Hz, 2H), 1.54-1.46 (m, 4H).
EXAMPLE 2: PREPARATION OF THE COMPOUNDS OF THE PRESENT INVENTION AND ANALYTICAL METHODS
(6) All solvents used were commercially available and were used without further purification. Reactions were typically run using anhydrous solvents under an inert atmosphere of nitrogen. Flash column chromatography was generally carried out using Silica gel 60 (0.035-0.070 mm particle size).
(7) All NMR experiments were recorded either on Bruker Mercury Plus 400 NMR Spectrometer equipped with a Bruker 400 BBFO probe at 400 MHz for proton NMR or on Bruker Mercury Plus 300 NMR Spectrometer equipped with a Bruker 300 BBFO probe at 300 MHz for proton NMR. All deuterated solvents contained typically 0.03% to 0.05% v/v tetramethylsilane, which was used as the reference signal (set at ppm=0.00 for both 1H and 13C).
(8) LC-MS analyses were performed on an Agilent Technologies LC-MS 1200 series consisting of a LCMS 6110 Quadrupole MS detector. The column used and the conditions are described in the HPLC methods. The column temperature was at 40° C. with the flow rate stated. The Diode Array detector was scanned from 200-400 nm. The mass spectrometer was equipped with an electro spray ion source (ES) operated in a positive or negative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time of 0.6 s.
1. 4-Ethylaminomethyl-N-(7-methoxy-4-phenyl-1H-benzoimidazol-2-yl)-benzamide, 11
(9) ##STR00348##
General Procedure for Nitration of the Aromatic Ring
a. 1-Bromo-4-methoxy-2,3-dinitro-benzene
(10) 4-Bromo-3-nitroanisole, 97% (10.0 g, 43.1 mmol) was nitrated by dropwise addition of 10 ml of a mixture of nitric acid, fuming 100% (40 ml) and sulfuric acid, 95-98% (6 ml). The mixture was stirred for 1 h at RT. The reaction mixture was poured onto ice water and extracted three times with ethyl acetate. The combined organic layers are washed with water and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness. The crude material was purified by flash chromatography (ethyl acetate/cyclohexane) to yield in 5.30 g (44%) of the title compound as a yellow solid. HPLC/MS (purity) 100%. Rt 2.65 min (method A). [M+H]+ 276.8, 278.9.
General Procedure to Reduce the Nitro Group
b. 3-Bromo-6-methoxy-benzene-1,2-diamine
(11) Into a 250-ml round-bottom flask was placed sponge-Nickel-catalyst, THF wet (2.00 g), THF (60 ml) and 1-bromo-4-methoxy-2,3-dinitro-benzene (5.30 g, 19.1 mmol). The mixture was stirred for 6 h at RT under a hydrogen atmosphere. The solids were filtered off and discarded. The filtrate was evaporated to dryness to yield in 3.90 g (94%) of 3-bromo-6-methoxy-benzene-1,2-diamine as a yellow solid, which was used without further purification. HPLC/MS (purity) 100%. Rt 1.42 min (method A). [M+H]+ 217.0, 218.9.
General Procedure to Form the Benzimidazole Ring
c. 4-Bromo-7-methoxy-1H-benzoimidazol-2-ylamine
(12) To 3-bromo-6-methoxy-benzene-1,2-diamine (3.90 g, 18.0 mmol), dissolved in methanol (50 ml) and water (25 ml), was added cyanogen bromide (2.86 g, 27.0 mmol) at RT and the resulting mixture was stirred at RT for 20 h. The reaction mixture was evaporated to remove the methanol. Under cooling the aqueous solution basified with ammonia. The precipitate was filtered off and crystallized from dichloromethane to yield in 3.90 g (89%) of the title compound as a yellow solid. HPLC/MS (purity) 99%. Rt 1.72 min (method A). [M+H]+ 242.0, 243.9.
General Procedure for Suzuki Reactions
d. 7-Methoxy-4-phenyl-1H-benzoimidazol-2-ylamine
(13) Into pressure tank reactor purged and maintained with an inert atmosphere of argon was placed 4-bromo-7-methoxy-1H-benzoimidazol-2-ylamine, 99% (1.68 g, 7.02 mmol), benzeneboronic acid, 98% (1.05 g, 8.43 mmol), potassium carbonate, 2 M (5 ml, 49.1 mmol), Pd(dppf)Cl.sub.2 dichloromethane complex, 95% (449 mg, 0.562 mmol), ethanol (2.5 ml) and toluene (25 ml) The mixture was stirred for 20 h at 90° C., cooled to room temperature and concentrated to dryness under vacuum. The residue was purified by column chromatography (dichloromethane/ethanol, gradient) to yield in 1.22 g (70%) of the title compound as a yellow solid. HPLC/MS (purity) 97%. Rt 2.09 min (method A). [M+H]+ 240.1.
General Procedure to Form the Amide Bond Formation
e. 4-Chloromethyl-N-(7-methoxy-4-phenyl-1H-benzoimidazol-2-yl)-benzamide
(14) To a stirred solution of 7-methoxy-4-phenyl-1H-benzoimidazol-2-ylamine (300 mg, 1.22 mmol) and N-ethyldiisopropylamin (1.24 ml, 7.30 mmol) in tetrahydrofuran (6 mL) at RT was added dropwise a solution of 4-(chloromethyl)benzoyl chloride, 97% (276 mg, 1.46 mmol) in dichloromethane (3 ml) and stirred for 60 h at RT. The residue was purified by column chromatography (ethyl acetate/cyclohexane, gradient). Three drops of 1 N HCl solution were added to the dissolved pure fraction and evaporated to dryness to yield in 50.0 mg (10%) of the HCl salt of the title compound as a colorless solid. 1H NMR (500 MHz, DMSO-d6) ppm=12.82-11.31 (m, 1H), 8.14-8.11 (m, 2H), 7.87-7.82 (m, 2H), 7.64-7.60 (m, 2H), 7.52-7.47 (m, 2H), 7.38-7.34 (m, 1H), 7.33 (d, J=8.3 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 4.86 (s, 2H), 4.00 (s, 3H). HPLC/MS (purity) 100%. Rt 2.92 min (method A). [M+H]+ 392.0.
f. 4-Ethylaminomethyl-N-(7-methoxy-4-phenyl-1H-benzoimidazol-2-yl)-benzamide
(15) To a stirred solution of 4-chloromethyl-N-(7-methoxy-4-phenyl-1H-benzoimidazol-2-yl)-benzamide, hydrochloride (44.0 mg, 0.103 mmol) in tetrahydrofuran (2 ml), ethylamine, 2 M in THF (1 ml) was added and stirred for 20 h at RT and then for additional 20 h at 50° C. The mixture was evaporated to dryness and the residue was purified by preparative HPLC (acetonitrile/water, gradient). Five drops of 1 N HCl solution were added to the dissolved pure fraction and evaporated to dryness to yield in 10.0 mg (21%) of the dihydrochloride salt of the title compound as a colorless solid. 1H NMR (400 MHz, DMSO-d6) ppm=8.91-8.82 (m, 2H), 8.16-8.12 (m, 2H), 7.86-7.81 (m, 2H), 7.66-7.62 (m, 2H), 7.51-7.45 (m, 2H), 7.37-7.32 (m, 1H), 7.30 (d, J=8.3 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 4.24-4.19 (m, 2H), 3.97 (s, 3H), 3.06-2.96 (m, 2H), 1.22 (t, J=7.3 Hz, 3H). HPLC/MS (purity) 100%. Rt 2.42 min (method A). [M+H]+ 401.1.
2. 4-hydroxy-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2-yl]-4-(prop-2-yn-1-yl)piperidine-1-carboxamide
(16) ##STR00349##
g. 4-(4-Methoxy-2,3-dinitro-phenyl)-1-methyl-1H-pyrazole
(17) Into pressure tank reactor purged and maintained with an inert atmosphere of argon was placed 1-bromo-4-methoxy-2,3-dinitro-benzene, 88% (4.00 g, 12.7 mmol), 1-methyl-1H-pyrazol-4-boronic acid, pinacol ester (3.17 g, 15.2 mmol), potassium carbonate, 2 M (16 ml, 157 mmol), Pd(dppf)Cl.sub.2 dichloromethane complex, (1.01 g, 1.27 mmol), ethanol (8 ml) and toluene (80 ml) The mixture was stirred for 2 h at 90° C., cooled to room temperature and concentrated to dryness under vacuum. The residue was purified by column chromatography (ethyl acetate/cyclohexane, gradient) to yield in 2.70 g (76%) of the title compound as a yellow solid. HPLC/MS (purity) 100%. Rt 2.38 min (method A). [M+H]+ 279.0.
h. 3-Methoxy-6-(1-methyl-1H-pyrazol-4-yl)-benzene-1,2-diamine
(18) Into flask was placed Palladium/carbon, E101 R Noblyst, 5% (1.50 g, 14.1 mmol), tetrahydrofuran (30 ml) and 4-(4-methoxy-2,3-dinitro-phenyl)-1-methyl-1H-pyrazole, (2.70 g, 9.71 mmol). The mixture was stirred for 18 h at RT under a hydrogen atmosphere. The solids were filtered off and discarded. The filtrate was evaporated to dryness and the residue was used without further purification to yield in 2.10 g (91%) of title compound as a brownish solid. HPLC/MS (purity) 92%. Rt 1.44 min (method A). [M+H]+ 219.1.
i. 7-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-ylamine
(19) 3-Methoxy-6-(1-methyl-1H-pyrazol-4-yl)-benzene-1,2-diamine, 92% (2.10 g, 8.85 mmol) was dissolved in methanol (100 ml) and water (20 ml). Cyanogen bromide (1.44 g, 13.3 mmol) was added and the reaction stirred at RT for 2 h. The mixture was evaporated to dryness and purified by column chromatography (dichloromethane/ethanol, gradient) to yield in 2.20 g (100%) of the title compound as a yellow solid. HPLC/MS (purity) 98%. Rt 1.74 min (method A). [M+H]+ 244.1.
General Procedure to Form Ureas
j. 4-hydroxy-N-[7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-1,3-benzodiazol-2-yl]-4-(prop-2-yn-1-yl)piperidine-1-carboxamide
(20) To a stirred solution of 1,1′-carbonyldiimidazole (84.9 mg, 0.524 mmol) in dichloromethane (5 ml) was slowly added 7-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-ylamine, 98% (100 mg, 0.403 mmol) suspended in dichloromethane (1 ml) at 60° C. After 20 h at 70° C., 4-prop-2-ynyl-piperidin-4-ol, hydrochloride (92.0 mg, 0.524 mmol) and triethylamine (0.168 ml, 1.21 mmol) were added and the mixture was stirred for additional 2 h at 60° C. The mixture was evaporated to dryness and the residue was purified by preparative HPLC (acetonitrile/water, gradient). Five drops of 1 N HCl solution were added to the dissolved pure fraction and evaporated to dryness to yield in 30.0 mg (17%) of the hydrochloride salt of the title compound as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ 8.24-8.22 (m, 1H), 7.93-7.92 (m, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 4.05-3.99 (m, 2H), 3.97 (s, 3H), 3.92 (s, 3H), 3.36-3.19 (m, 2H), 2.83 (t, J=2.6 Hz, 1H), 2.34 (d, J=2.7 Hz, 2H), 1.73-1.56 (m, 4H). HPLC/MS (purity) 100%. Rt 2.00 min (method A). [M+H]+ 409.2.
3. 2-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]pyridine-4-carboxamide
(21) ##STR00350##
k. 1-Bromo-4-methoxy-2,3-dinitro-benzene
(22) Into 3-necked round-bottom flask was placed 1-bromo-4-methoxy-2-nitrobenzene (50.0 g, 205 mmol) in sulfuric acid (100 ml). Nitric acid (24 ml, 530 mmol) was added dropwise with stirring at 0° C. The solution was stirred for 1 h at room temperature and quenched with 1000 ml of ice water. The solution was extracted twice with 1000 ml of ethyl acetate, the combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness. The crude material was recrystallized from ethyl acetate/hexane (2:3) to result in 20.0 g (32%) of 1-bromo-4-methoxy-2,3-dinitrobenzene as a yellow solid. Melting point: 150-153° C. 1H NMR (400 MHz, DMSO-d6) ppm=8.19 (d, J=9.3 Hz, 1H), 7.70 (d, J=9.3 Hz, 1H), 4.02 (s, 3H). HPLC/MS (purity) 91%. [M+H]+ 276.8, 278.9.
l. 4-(4-Methoxy-2,3-dinitro-phenyl)-3,6-dihydro-2H-pyran
(23) Into pressure tank reactor purged and maintained with an inert atmosphere of argon, was placed 1-bromo-4-methoxy-2,3-dinitrobenzene, 91% (15.7 g, 51.4 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 95% (13.7 g, 61.7 mmol), Pd(dppf)Cl.sub.2 dichloromethane complex, 95% (4.42 g, 5.14 mmol), potassium carbonate (8.53 g, 61.7 mmol, dissolved in water (12 ml), ethanol (31.6 ml) and toluene (316 ml). The mixture was stirred for 1 h at 100° C., cooled to room temperature and concentrated to dryness under vacuum. The residue was purified by column chromatography (ethyl acetate/petrol ether: 1/1) to yield in 13.0 g (86%) of 4-(4-methoxy-2,3-dinitrophenyl)-3,6-dihydro-2H-pyran as an orange solid. HPLC/MS (purity) 95%. [M+H]+ 281.2.
m. 3-Methoxy-6-(tetrahydro-pyran-4-yl)-benzene-1,2-diamine
(24) Into a 250-ml round-bottom flask was placed Palladium/carbon, 10% (4.00 g, 3.76 mmol), methanol (100 ml) and 4-(4-methoxy-2,3-dinitrophenyl)-3,6-dihydro-2H-pyran, 95% (10.5 g, 33.9 mmol). The mixture was stirred for 15 h at 35° C. under a hydrogen atmosphere. The solids were filtered off and discarded. The filtrate was evaporated to dryness and the residue was purified by column chromatography (ethyl acetate/hexane, 70/30) to yield in 4.51 g (58%) of 3-methoxy-6-(oxan-4-yl)benzene-1,2-diamine as a yellow solid. Melting point: 116-117° C. 1H NMR (400 MHz, Chloroform-d) 6.67 (d, J=8.5 Hz, 1H), 6.45 (d, J=8.5 Hz, 1H), 4.18-4.09 (m, 2H), 3.86 (s, 3H), 3.65-3.53 (m, 2H), 3.46 (s, 4H), 2.82-2.64 (m, 1H), 1.93-1.73 (m, 4H). HPLC/MS (purity) 97%. [M+H]+ 223.1.
n. 7-Methoxy-4-(tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-ylamine
(25) To 3-bromo-6-methoxy-benzene-1,2-diamine, 97% (1.86 g, 8.10 mmol) dissolved in methanol (40 ml) and water (10 ml) was added cyanogen bromide, 98% (1.31 g, 12.2 mmol) at RT and the resulting mixture was stirred at RT for 20 h. The reaction mixture was evaporated to remove the methanol. Under cooling the aqueous solution was basified with ammonia and evaporated to dryness. The residue was taken up in water and extracted 3 times with dichloromethane. The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The residue was purified by column chromatography (dichloromethane/ethanol, gradient) to yield in 2.11 g (100%) of the title compound as a beige solid. HPLC/MS (purity) 95%. Rt 1.74 min (method A). [M+H]+ 248.1.
o. 2-Bromo-N-[7-methoxy-4-(tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-yl]-isonicotinamide
(26) 7-Methoxy-4-(tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-ylamine, 95% (1.00 g, 3.84 mmol), 2-bromopyridine-4-carboxylic acid, 97% (1.01 g, 4.99 mmol) 1-hydroxybenzotriazole hydrate (156 mg, 1.15 mmol) and [dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium, hexafluoro phosphate (HATU, 1.90 g, 4.99 mmol) were dissolved in N,N-dimethylformamide (30 ml). Then 4-methylmorpholine (1.27 ml, 11.5 mmol) was added at RT and the mixture stirred at RT for 3 days. The reaction mixture was evaporated to dryness, taken up in dichloromethane and stirred for 1 h. The precipitate formed was filtered off and discarded. The filtrate was evaporated to dryness and the residue was purified by column chromatography (dichloromethane/ethanol, gradient) to yield in 2.67 g (100%) of the title compound as a light yellow fine powder. HPLC/MS (purity) 62%. Rt 2.34 min (method A). [M+H]+ 201.9, 203.9.
p. 2-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-[7-methoxy-4-(oxan-4-yl)-1H-1,3-benzodiazol-2-yl]pyridine-4-carboxamide
(27) 2-Bromo-N-[7-methoxy-4-(tetrahydro-pyran-4-yl)-1H-benzoimidazol-2-yl]-isonicotinamide, 62% (300 mg, 0.431 mmol), 3-methylpyrrolidin-3-ol (77.2 mg, 0.561 mmol), cesium carbonate (281 mg, 0.863 mmol) and 2,6-di-tert-butyl-4-methylphenol (0.009 ml, 0.043 mmol) were dissolved in 1-methyl-2-pyrrolidone for synthesis (10 ml) and the mixture was stirred at 140° C. for 3 days. The reaction mixture was evaporated to dryness and the residue was purified by preparative HPLC (acetonitrile/water, gradient). Three drops of 1 N HCl solution were added to the dissolved pure fraction and evaporated to dryness to yield in 13.0 mg (6%) of the hydrochloride salt of the title compound as a light beige solid. 1H NMR (700 MHz, DMSO-d6) ppm=14.22-12.03 (m, 2H), 8.09 (d, J=6.4 Hz, 1H), 7.60 (s, 1H), 7.40-7.35 (m, 1H), 7.07 (d, J=8.3 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 4.00-3.96 (m, 2H), 3.93 (s, 3H), 3.80-3.70 (m, 2H), 3.61-3.48 (m, 4H), 3.33-3.26 (m, 1H), 2.09-1.99 (m, 2H), 1.80-1.71 (m, 4H), 1.42 (s, 3H). HPLC/MS (purity) 100%. Rt 2.02 min (method A). [M+H]+ 452.2.
4. 4-[(dimethylamino)methyl]-N-(4-methoxy-7-morpholino-1H-benzimidazol-2-yl)benzamide
(28) ##STR00351##
q. 4-(4-methoxy-2,3-dinitro-phenyl)morpholine
(29) Into a pressure tank reactor was placed 1-bromo-4-methoxy-2,3-dinitrobenzene, 90% (25.0 g, 81.2 mmol), dioxane (300 ml) and morpholine, 95% (29.8 g, 325 mmol). The mixture was stirred for 15 h at 100° C. The solids were filtered off and discarded. The filtrate was concentrated under vacuum and the residue was purified by column chromatography (ethyl acetate/hexane, 60/40) to yield in 13.0 g (51%) of 4-(4-methoxy-2,3-dinitrophenyl)morpholine as a dark red solid. HPLC/MS (purity) 90%. [M+H]+ 284.0.
r. 3-methoxy-6-morpholino-benzene-1,2-diamine
(30) Into a 250-ml round-bottom flask was placed Palladium/carbon, 10% (3.00 g, 2.82 mmol), methanol (100 ml) and 4-(4-methoxy-2,3-dinitrophenyl)morpholine, 90% (12.7 g, 40.3 mmol). The mixture was stirred for 4 h at RT under hydrogen atmosphere. The solids were filtered off and discarded. The filtrate was evaporated to dryness and the residue was purified by column chromatography (ethyl acetate/hexane/NEt.sub.3, 69.5/29.5/1%) to yield in 7.30 g (77%) of 3-methoxy-6-(morpholin-4-yl)benzene-1,2-diamine as a pink solid. 1H NMR (500 MHz, DMSO-d6) ppm=1H NMR (400 MHz, DMSO-d6) 6.34 (d, J=8.6 Hz, 1H), 6.22 (d, J=8.6 Hz, 1H), 4.22 (s, 4H), 3.75-3.71 (m, 4H), 3.70 (s, 3H), 2.73-2.68 (m, 4H). Melting point: 113-115° C., HPLC/MS (purity) 95%. [M+H]+ 224.1
s. 4-methoxy-7-morpholino-1H-benzimidazol-2-amine
(31) To 3-methoxy-6-morpholin-4-yl-benzene-1,2-diamine, 95% (4.90 g, 20.8 mmol) dissolved in methanol (40 ml) and water (10 ml) was added cyanogen bromide, 98% (3.38 g, 31.3 mmol) at RT and the resulting mixture was stirred at RT for 20 h. Under cooling the aqueous solution was basified with ammonia and evaporated to dryness. The residue purified directly by column chromatography (dichloromethane/ethanol, gradient) to yield in 5.28 g (100%) of the title compound as a yellow solid. HPLC/MS (purity) 98%. Rt 1.64 min (method A). [M+H]+ 249.1.
t. 4-[(dimethylamino)methyl]-N-(4-methoxy-7-morpholino-1H-benzimidazol-2-yl)benzamide
(32) 7-Methoxy-4-morpholin-4-yl-1H-benzoimidazol-2-ylamine, 98% (100 mg, 0.395 mmol), 4-[(dimethylamino)methyl]benzoic acid, hydrochloride (111 mg, 0.513 mmol), [dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium, hexafluoro phosphate (HATU, 195 mg, 0.513 mmol), 4-(dimethylamino)pyridine (48.2 mg, 0.395 mmol) and 1-hydroxybenzotriazole hydrate (16.0 mg, 0.118 mmol) were dissolved in N,N-dimethylformamide (5 mL). To this mixture 4-methylmorpholine (0.13 ml, 1.18 mmol) was added and the mixture stirred at RT for 3 days. The reaction mixture was evaporated to dryness and the residue was purified by preparative HPLC (acetonitrile/water, gradient). Three drops of 1 N HCl solution were added to the dissolved pure fraction and evaporated to dryness to yield in 90.0 mg (51%) of the hydrochloride of the title compound as a colorless solid. 1H NMR (500 MHz, DMSO-d6) ppm=12.58-11.92 (m, 1H), 10.99-10.86 (m, 1H), 8.21-8.18 (m, 2H), 7.79-7.76 (m, 2H), 7.28-7.13 (m, 1H), 6.83 (d, J=8.6 Hz, 1H), 4.38 (d, J=5.4 Hz, 2H), 3.99-3.95 (m, 4H), 3.95 (s, 3H), 3.62-3.46 (m, 4H), 2.72 (d, J=4.8 Hz, 6H). HPLC/MS (purity) 100%. Rt 1.74 min (method A). [M+H]+ 410.1.
(33) Method A
(34) Agilent Technologies 1200 series; column: Chromolith Performance RP18e; 100×3 mm; mobile phase A: water/0.1% TFA, mobile phase B: acetonitrile/0.1% TFA; Gradient: 1% B for 0.2 min, 1% B to 100% B in 3.8 min, hold 0.4 min; flow rate: 2 mL/min, wave length: 220 nm
(35) Pd(dppf)Cl.sub.2=1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dihydrochloride
EXAMPLE 3: TESTING COMPOUNDS OF THE PRESENT INVENTION FOR INHIBITORY ACTIVITIES AGAINST HUMAN ADENOSINE RECEPTORS IN RECOMBINANT CELLS
(36) The functional activities of human A.sub.2A, A.sub.2B, A.sub.1 and A.sub.3 receptors were determined by quantification of cAMP, being the second messenger for adenosine receptors. For this purpose recombinant HEK293 cells, expressing either human A.sub.2A or A.sub.2B receptors (both Gs coupled were seeded into 394-well microtiter plates, test compounds and agonist (NECA) were added. After a 15 min incubation, HTRF reagents (cAMP dynamic 2, Cis Bio) were added and the cellular cAMP levels were determined using the ENVISION (Perkin Elmer) plate reader.
(37) For human A.sub.1 and A.sub.3 receptors, recombinant CHO cells, expressing either A.sub.1 or A3-receptor, were used. As both receptors couple to Gi proteins, the assay protocol was adapted:
(38) Cells were seeded into 384-well plates, forskolin, test compounds and agonists (CPA for A.sub.1- and IB-MECA for A.sub.3-receptor) were added. After 30 min incubation, HTRF reagents (cAMP dynamic 2, Cis Bio) were added and the cellular cAMP levels were determined using the ENVISION (Perkin Elmer) plate reader. Obtained raw data were normalized against the inhibitor control and the neural control (DMSO) and the normalized data were fitted using GeneData software.
(39) The compounds of the present invention show a high selectivity for adenosine A.sub.2A and A.sub.2B receptors over adenosine A.sub.1 and A.sub.3 receptors (see e.g. the data of some examples of the compounds of the present invention in table 4) Particularly, in contrast to the known adenosine A.sub.2A receptor antagonist Tozadenant and similar benzothiazole derivatives, the compounds of the present invention surprisingly show an A.sub.2A/A.sub.2B dual activity (see table 4) which is preferred for the treatment and/or prevention of hyperproliferative and infectious diseases and disorders as it is disclosed above or the compounds of the present invention show at least a high A.sub.2A inhibitory activity together with the other surprising advantages disclosed herein leading to a high efficacy in the treatment and/or prevention of hyperproliferative and infectious diseases and disorders.
(40) TABLE-US-00006 TABLE 4 Functional Functional Functional Functional A2A A2B A1 A3 receptor receptor receptor receptor activity, activity, activity, activity, HEK293, HEK293, CHO, CHO, cAMP, cAMP, cAMP, cAMP, No. IC50 [μm] IC50 [μm] IC50 [μm] IC50 [μm] 2 A B A 3 A B A 5 A B A 7 A C D B 8 A D D C 10 A B D 11 A B D D 12 A C C C 13 A C D C 15 A A C B 16 A D D C 17 A D C 26 A D D C 28 A C C 30 A D C 48 A D D D 49 A C D B 54 B C C D 63 A C D B 71 A B D C 76 A C D D 79 B C D D 80 B C D C 84 B C C C 85 B C D D 86 A D D D 88 A D D D 89 B C D 92 A C D D 93 A B D D 94 A C D C 95 A C C A 97 A B D D 98 B C D C 99 A D D D 100 A C D D 101 A C C C 102 A D D D 103 A C C D 104 A D D C 105 A C D C 106 A D D C 107 A C D C 108 A C D C 114 A D D D 118 A D D 119 A D D D 122 A D D D 133 A C D D 134 B C D D 136 A D D D 138 A C D D 144 A C C D 145 A D D D 150 A D D D 151 A D C D 152 B C D C 153 A D D D 154 A D D C 160 A B D B 161 A C D C 162 B C D D 165 A C C A 168 A D D C 215 A B 216 B D D 217 A B C D 218 A B C D 219 A A C 221 A B D D 224 A B D C 225 A B D D 226 B D D 227 A B D 228 B D 229 B D D 230 B D D 231 B C C 232 B D C 233 B D A 234 A D C 235 A C 236 A B C C 237 B B C C 238 B D 239 A A 240 A A C C 241 B D D 242 A A C C 243 A A C 245 B D D 246 B D 247 B D 248 A B D D 249 B 250 A B D 253 A A C C 254 A A C 255 A A C C 256 A A C 257 A A C 258 A A C 259 A A C D 260 A A C 261 A A D C 262 A A D C 263 B D 264 A B D C 265 A B C C 266 B B D 267 A A C 268 A B D D 269 B B D C 270 B D D 271 B B D D 272 B B D 273 B D D 277 B B D 278 B B D C 279 B B C C 280 B B 282 B B C C 283 B B D C 284 B B D D 285 B A C C 286 B B 287 B B C D 288 B B C 289 B A 290 B B 291 B B C 292 B A D 293 B B C 294 B A C 295 B B C 296 B A C 297 B B C 298 B A C 299 B B 300 B B 301 B C 302 B B 303 B D 304 B B C 305 B B D 306 B A 307 B A 308 B B 309 B A 310 B B D 311 B A C 312 A A C C 313 A D D 314 B C D C 315 B B D C 316 A A C C 317 A A C C 318 A A B B A means IC.sub.50 value is <10 nM, B means IC.sub.50 value is <100 nM, C means IC.sub.50 value is <1 μM, D means IC.sub.50 value is >1 μM.
EXAMPLE 4: TESTING THE EFFECTS OF THE COMPOUNDS OF THE PRESENT INVENTION AGAINST ENDOGENOUS HUMAN A.SUB.2A .RECEPTOR
(41) The endogenous functional activity of the Gs-coupled human A.sub.2A receptor was measured in T cells, where this receptor is highly expressed. Determination of receptor activity was done by quantification of cAMP, which is a second messenger for adenosine receptors.
(42) In short, human pan T cells were isolated from human PBMC (MACS Pan T Cell Isolation Kit, Miltenyi Biotec) that have been derived from fresh whole blood. The T cells were seeded in 384-well microtiter plates and treated with test compounds. After 10 min incubation at room temperature, the A.sub.2A adenosine receptor agonist CGS-21680 was added, and the plates were incubated for another 45 min. Finally, HTRF reagents (cAMP Femto Kit, CisBio) were added to the wells, and after 1 h cellular cAMP levels were determined using the ENVISION (Perkin Elmer) plate reader.
(43) The obtained raw data were normalized against the inhibitor control and the neutral control (DMSO) and the normalized data were fitted using Genedata Screener software.
(44) The compounds of the present invention show that they are able to inhibit the A.sub.2A receptor expressed in human T cells which incubated with the A.sub.2A adenosine receptor agonist CGS-21680 (as measured by quantification of cAMP), which is preferred for the treatment and/or prevention of hyperproliferative and infectious diseases and disorders as it is disclosed above. Therefore, the compounds of the present invention surprisingly are able to prevent immunosuppression and thus are able to support anti-tumor T cell induced inhibition of tumor growth, reduction or destruction of metastases and prevention of neovascularization.
EXAMPLE 5: TESTING THE PHARMACOKINETIC PROPERTIES OF THE COMPOUNDS OF THE PRESENT INVENTION IN RAT AND MOUSE
(45) The objective of the study was to obtain information on the pharmacokinetic properties of the compounds of the present invention in female Wistar rats/mice following single intravenous and oral administration.
(46) Material and Methods:
(47) Animal Experiments (In-Life Phase)
(48) Female Wistar rats/mice (n=6) received either a single intravenous (bolus) injection or an oral administration (by gavage) of the tested compound. Doses of 0.2 and 10 mg/kg (per compound) were given intravenously and per os, respectively, as a solution in DMSO (0.2%)/PEG 200 (40%)/water for iv administration and as a suspension in Methocel (0.5%)/Tween 20 (0.25%) in water for oral dosing. Consecutive blood samples were taken sub-lingually under isoflurane inhalation from 3 animals per route of administration after 0.1 (only iv), 0.25 (only po), 0.5, 1, 2, 4, 6 and 24 h and were further processed to obtain plasma. Also, urine and feces samples of 3 rats per route of administration were collected over the time interval from 0-24 h and were pooled for analysis.
(49) Bioanalytics:
(50) The concentrations of the compounds in plasma, feces were quantified using an UPLC method with tandem mass spectrometric detection (LC-MS/MS) previously developed at the ‘Institute of Drug Metabolism and Pharmacokinetics’. The LC-MS/MS system consisted of a Waters Acquity UPLC coupled to an AB Sciex mass spectrometer API 5500 Q-trap. The UPLC separation was carried out on a reversed phase column (HSS T3, 1.8 μM, 2.1×50 mm) using a mobile phase gradient with 0.1% formic acid and acetonitrile as eluents. The detection of the compounds was performed using multiple reaction monitoring in the positive ionization mode. Plasma samples were spiked with internal standard (20 μl) and the analyte was extracted from the matrix using tertiary-butyl methyl ether (tBME). The organic phase was evaporated to dryness under a stream of nitrogen. The residue was dissolved in acetonitrile/0.1% formic acid for LC-MS/MS analysis. Feces samples were homogenized with 4-times their volume of an ethanol/water mixture (4:1, v/v). Aliquots of the aqueous-ethanolic extracts were spiked with internal standard, diluted with acetonitrile/water (1:1, v/v) and directly injected into the LC-MS/MS system.
(51) Pharmacokinetic Evaluation:
(52) Pharmacokinetic parameters C.sub.max and t.sub.max were taken from the observed data. Area under the curve (AUC), clearance (CL), volume (V), half-life (t.sub.1/2), F and all dose-normalized values were calculated using the custom-made software ‘DDS-TOX’. ‘DDS-TOX’ values were evaluated for several compounds and shown comparable to the values given by the validated software WinNonLin. AUC values were calculated by non-compartmental analysis using the linear up/log down method. Numerical data for mean plasma concentrations and derived pharmacokinetic parameters were rounded to 3 significant digits for presentation. Oral bioavailability and excretion data—expressed as % of dose—are displayed using 2 significant digits.
(53) in comparison with the known adenosine A.sub.2A receptor antagonist Tozadenant and similar benzothiazole derivatives, the compounds of the present invention surprisingly show better pharmacokinetic properties in mouse as the animal model relevant for cancer (see table 6), which is preferred for the treatment and/or prevention of hyperproliferative and infectious diseases and disorders as it is disclosed above.
(54) TABLE-US-00007 TABLE 6 PK data in mouse CMax (iv) @ 1 CL t1/2 Vss Feces mg/kg Name, No. Structure [L/h/kg] [h] [L/kg] iv [%] [ng/ml] Tozadenant
EXAMPLE 6: TESTING THE EFFECT OF THE COMPOUNDS OF THE PRESENT INVENTION ON MOUSE T CELLS
(55) Background
(56) Adenosine (Ado) in tumor microenvironment can inhibit T cell activity by signaling through A.sub.2A receptors and suppress cytokine secretion by T cells. A.sub.2A specific agonists like CGS-21680 does similar job of inhibition of T cell cytokine secretion in vitro and in vivo. Potential A.sub.2A antagonists or A.sub.2A/A.sub.2B dual antagonists can rescue T cells from this inhibition. Herein, we describe the in vitro system we established using Pan T cells from mouse spleens to screen potential A.sub.2A antagonists or A.sub.2A/A.sub.2B dual antagonists for their activity. The method described involves the use of CD3/CD28 pre-coated beads to stimulate Pan T cells purified from mouse splenocytes, combined with the addition of A.sub.2A agonist along with potential A.sub.2A or A.sub.2A/A.sub.2B dual antagonists to evaluate potentiation of T cell cytokine production.
(57) Assay Description:
(58) Briefly, mouse Pan T cells are purified from spleens of BALB/c mice using Pan T cell isolation kit Mouse II (MACS Miltenyi biotech Cat # Order no. 130-095-130) according to manufacturer's protocol. The purified T cells are seeded in Nunc™ 96-Well Polystyrene Round Bottom Microwell Plates in RPMI medium with 10% heat inactivated fetal bovine serum. The cells are rested at 37° C. for 1 h before activating with CD3/CD28 pre-coated beads (Dynabeads™ Mouse T-Activator CD3/CD28; Cat #11456D). After 30 min the cells are treated with varying doses of test antagonist(s). The cells are incubated for additional 30 min at 37° C. before treating with A.sub.2A agonist CGS-21680 (1 μM) or neutral control (DMSO). After 24 h incubation IL-2 levels in the supernatants and after 48 h incubation IFN-γ levels in the supernatants are measured by ELISAs according to manufacturer's protocol (R&D systems Cat # DY402 (IL-2); DY485 (IFN-γ)). Once the concentrations are calculated, the difference of cytokine concentration of DMSO control and agonist alone control is calculated (called A) and the percentage of rescue by each concentration of antagonist is calculated by using Microsoft Excel. These percentages of cytokine rescue in a dose dependent manner of antagonist is plotted in GraphPad Prism software and IC.sub.50 is calculated.
(59) In contrast to the known adenosine A.sub.2A receptor antagonist Tozadenant, the compounds of the present invention show that they are able to rescue T cells from inhibition and are able to prevent the suppression of cyctokine secretion as induced by adenosine or A.sub.2A specific agonists like CGS-2168 (see table 7), which is preferred for the treatment and/or prevention of hyperproliferative and infectious diseases and disorders as it is disclosed above. Therefore, the compounds of the present invention surprisingly are able to prevent immunosuppression and thus are able to support anti-tumor T cell induced inhibition of tumor growth, reduction or destruction of metastases and prevention of neovascularization.
(60) TABLE-US-00008 TABLE 7 Mouse T-Cell Mouse IL-2 IFN-γ No. Name Structure [nM] [nM] Tozadenant
EXAMPLE 7: INJECTION VIALS
(61) A solution of 100 g of a compound of the present invention and 5 g of disodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid, filtered under sterile conditions, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of a compound of the present invention.
EXAMPLE 8: SOLUTION
(62) A solution is prepared from 1 g of a compound of the present invention, 9.38 g of NaH.sub.2PO.sub.4 2H.sub.2O, 28.48 g of Na.sub.2HPO.sub.4.12H.sub.2O and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 l and sterilised by irradiation.
EXAMPLE 9: AMPOULES
(63) A solution of 1 kg of a compound of the present invention in 60 l of bidistilled water is filtered under sterile conditions, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of a compound of the present invention.