Quinoxaline derivatives as adenosine receptor antagonists
11192899 · 2021-12-07
Assignee
Inventors
Cpc classification
C07D491/107
CHEMISTRY; METALLURGY
A61P31/00
HUMAN NECESSITIES
A61K45/06
HUMAN NECESSITIES
C07D241/44
CHEMISTRY; METALLURGY
C07D403/12
CHEMISTRY; METALLURGY
C07D401/12
CHEMISTRY; METALLURGY
C07D417/12
CHEMISTRY; METALLURGY
C07D405/04
CHEMISTRY; METALLURGY
C07D403/04
CHEMISTRY; METALLURGY
International classification
C07D405/04
CHEMISTRY; METALLURGY
C07D241/44
CHEMISTRY; METALLURGY
C07D401/12
CHEMISTRY; METALLURGY
C07D403/04
CHEMISTRY; METALLURGY
C07D417/12
CHEMISTRY; METALLURGY
C07D491/107
CHEMISTRY; METALLURGY
Abstract
The invention relates to quinoxaline 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, ##STR00182## wherein Q, Y are independently of one another CH or N, R.sup.1 is Hal or linear or branched alkyl having 1-10 C atoms which is unsubstituted or mono-, di- or trisubstituted by R.sup.4 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—, —NR.sup.5SO.sub.2R.sup.6—, —COO—, —CONH—, —NCH.sub.3CO—, —CONCH.sub.3—, —C≡C— groups and/or —CH═CH— groups, and/or 1-10 H atoms may be replaced by F and/or Cl, or mono- or bicyclic cyclic alkyl having 3-7 C atoms which is unsubstituted or mono-, di- or trisubstituted by R.sup.4 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—, —NR.sup.5SO.sub.2R.sup.6—, —COO—, —CONH—, —NCH.sub.3CO—, —CONCH.sub.3—, —C≡C— groups and/or by —CH═CH— groups and/or 1-10 H atoms may be replaced by F and/or Cl, or mono- or bicyclic heteroaryl, heterocyclyl, aryl or cyclic alkylaryl containing 3 to 14 carbon atoms and 0-4 heteroatoms, independently selected from the group consisting of N, O and S, which is unsubstituted or mono-, di- or trisubstituted by R.sup.4, R.sup.2 is linear or branched alkyl having 1-10 C atoms which is unsubstituted or mono-, di- or trisubstituted by R.sup.4 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—, —NR.sup.5SO.sub.2R.sup.6—, —COO—, —CONH—, —NCH.sub.3CO—, —CONCH.sub.3—, —C≡C— groups and/or —CH═CH— groups, and/or 1-10 H atoms may be replaced by F and/or Cl, or cyclic alkyl having 3-7 C atoms which is unsubstituted or mono-, di- or trisubstituted by R.sup.4 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—, —NR.sup.5SO.sub.2R.sup.6—, —COO—, —CONH—, —NCH.sub.3CO—, —CONCH.sub.3—, —C≡C— groups and/or by —CH═CH— groups and/or 1-11 H atoms may be replaced by F and/or Cl, or mono- or bicyclic heteroaryl, heterocyclyl, aryl or cyclic alkylaryl containing 3 to 14 carbon atoms and 0-4 heteroatoms, independently selected from the group consisting of N, O and S, which is unsubstituted or mono-, di- or trisubstituted by R.sup.4, R.sup.3 is linear or branched alkyl or O-alkyl having 1-6 C atoms or cyclic alkyl having 3-6 C atoms, which is unsubstituted or mono-, di- or trisubstituted by H, ═S, ═NH, ═O, OH, cyclic alkyl having 3-6 C atoms, 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 or NO.sub.2, 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, CON H.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—, —NR.sup.5SO.sub.2R.sup.6—, —COO—, —CONH—, —NCH.sub.3CO—, —CONCH.sub.3—, —C≡C— groups and/or —CH═CH— groups, and/or 1-10 H atoms may be replaced by F and/or Cl, 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—, —NRSO.sub.2R.sup.4—, —COO—, —CONH—, —NCH.sub.3CO—, —CONCH.sub.3—, —C≡C— groups and/or by —CH═CH— groups and/or 1-10 H atoms may be replaced by F and/or Cl, or mono- or bicyclic heteroaryl, heterocyclyl, aryl or cyclic alkylaryl containing 3 to 14 carbon atoms and 0-4 heteroatoms, independently selected from the group consisting of 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 ═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 or 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 1-10 H atoms may be replaced by F and/or Cl, Hal is F, C, Br, or I, or a physiologically acceptable salt, derivative, solvate, prodrug r stereoisomer thereof.
2. The compound according to claim 1, wherein R.sup.1 is linear or branched alkyl having 1-10 C atoms which is unsubstituted or mono-, di- or trisubstituted by R.sup.4 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—, —NR.sup.5SO.sub.2R.sup.6—, —COO—, —CONH—, —NCH.sub.3CO—, —CONCH.sub.3—, —C≡C— groups and/or —CH═CH— groups, and/or 1-10 H atoms may be replaced by F and/or Cl, or one of the following structures: ##STR00183## which is unsubstituted or mono-, di- or trisubstituted with R.sup.4.
3. The compound according to claim 1, wherein Q is CH or N, and Y is CH.
4. The compound according to claim 1, wherein R.sup.2 is one of the following structures: ##STR00184## which is unsubstituted or mono-, di- or trisubstituted with R.sup.5.
5. The compound according to claim 1, wherein R.sup.3 one of the following structures ##STR00185##
6. The compound according to claim 1, wherein R.sup.3 is OMe.
7. A compound selected from the group consisting of: TABLE-US-00009 No. IUPAC-Name 1 N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2-yl]-2-oxa-7- azaspiro[4.4]nonane-7-carboxamide 2 4-hydroxy-N-[8-methoxy-5-(pyridin-4-yl)quinoxalin- 2-yl]-4-methylpiperidine-1-carboxamide 3 3-hydroxy-N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2- yl]-3-methylpyrrolidine-1-carboxamide 4 N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2-yl]-2-methyl- 1,3-oxazole-4-carboxamide 5 4-(hydroxymethyl)-N-[8-methoxy-5-(oxan-4-yl)quinoxalin- 2-yl]-4-methylpiperidine-1-carboxamide 6 N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2-yl]-2,2-dioxo- 2lambda6-thia-6-azaspiro[3.3]heptane-6-carboxamide 7 6-methoxy-N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2- yl]pyridazine-3-carboxamide 8 N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2-yl]-1-(2- methoxyethyl)-1H-pyrazole-4-carboxamide 9 4-hydroxy-N-(8-methoxy-5-phenylquinoxalin-2-yl)- 4-(prop-2-yn-1-yl)piperidine-1-carboxamide 10 3-hydroxy-N-(8-methoxy-5-phenylquinoxalin-2-yl)-3- methylpyrrolidine-1-carboxamide 11 4-(hydroxymethyl)-N-(8-methoxy-5-phenylquinoxalin-2- yl)-4-methylpiperidine-1-carboxamide 12 N-(8-methoxy-5-phenylquinoxalin-2-yl)-8-oxa-2- azaspiro[4.5]decane-2-carboxamide 13 N-(8-methoxy-5-phenylquinoxalin-2-yl)-2-oxa-7- azaspiro[4.4]nonane-7-carboxamide 14 N-(8-methoxy-5-phenylquinoxalin-2-yl)-2,2-dioxo- 2lambda6-thia-6-azaspiro[3.3]heptane-6-carboxamide 15 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid (5-methoxy- 8-phenyl-pyrido[3,4-b]pyrazin-3-yl)-amide 16 3-Hydroxy-3-methyl-pyrrolidine-1-carboxylic acid (5-methoxy- 8-phenyl-pyrido[3,4-b]pyrazin-3-yl)-amide 17 4-Hydroxymethyl-4-methyl-piperidine-1-carboxylic acid (5- methoxy-8-phenyl-pyrido[3,4-b]pyrazin-3-yl)-amide 18 N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2-yl]-8-oxa-2- azaspiro[4.5]decane-2-carboxamide 19 N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2-yl]acetamide 20 2,2,2-trifluoro-N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2- yl]acetamide 21 4-Dimethylaminomethyl-N-(5-methoxy-8-phenyl- pyrido[3,4-b]pyrazin-3-yl)-benzamide 22 4-Hydroxy-4-prop-2-ynyl-piperidine-1-carboxylic acid (5-methoxy- 8-phenyl-pyrido[3,4-b]pyrazin-3-yl)-amide 23 4-Methoxymethyl-N-(5-methoxy-8-phenyl-pyrido[3,4-b]pyrazin- 3-yl)-benzamide 24 1-(2-Methoxy-ethyl)-1H-pyrazole-4-carboxylic acid (5-methoxy- 8-phenyl-pyrido[3,4-b]pyrazin-3-yl)-amide 25 6-hydroxy-N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2-yl]pyridazine- 4-carboxamide 26 8-methoxy-5-(oxan-4-yl)quinoxalin-2-amine 27 (3S)-3-hydroxy-N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2-yl]-3- methylpyrrolidine-1-carboxamide 28 (3R)-3-hydroxy-N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2-yl]-3- methylpyrrolidine-1-carboxamide 29 4-hydroxy-N-[8-methoxy-5-(2-methylphenyl)quinoxalin-2-yl]-4- methylpiperidine-1-carboxamide 30 N-(8-methoxy-5-phenylquinoxalin-2-yl)-1-(2-methoxyethyl)-1H- pyrazole-4-carboxamide 31 N-(8-methoxy-5-phenylquinoxalin-2-yl)-2-methyl-1,3-oxazole-4- carboxamide 32 N-(8-methoxy-5-phenylquinoxalin-2-yl)-1-methyl-1H-pyrazole-4- carboxamide 33 N-(8-methoxy-5-phenylquinoxalin-2-yl)cyclopropanecarboxamide 34 N-(8-methoxy-5-phenylquinoxalin-2-yl)-1-methyl-1H-pyrazole- 5-carboxamide 35 N-(8-methoxy-5-phenylquinoxalin-2-yl)-1,3-thiazole-5-carboxamide 36 N-(8-methoxy-5-phenylquinoxalin-2-yl)-2-methyl-1,3-thiazole- 5-carboxamide 37 N-(8-methoxy-5-phenylquinoxalin-2-yl)-4H-1,2,4-triazole-3- carboxamide 38 N-[5-(4-fluorophenyl)-8-methoxyquinoxalin-2-yl]-4-hydroxy-4- methylpiperidine-1-carboxamide 39 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid [5-methoxy-8- (tetrahydro-pyran-4-yl)-pyrido[3,4-b]pyrazin-3-yl]-amide 40 N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2- yl]cyclopropanecarboxamide 41 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid [8-methoxy-5- (6-methyl-pyridazin-3-yl)-quinoxalin-2-yl]-amide 42 1-(2-Methoxy-ethyl)-1H-pyrazole-4-carboxylic acid [8-methoxy- 5-(6-methyl-pyridazin-3-yl)-quinoxalin-2-yl]-amide 43 1-(2-Methoxy-ethyl)-1H-pyrazole-4-carboxylic acid (8-methoxy-5- pyridin-4-yl-quinoxalin-2-yl)-amide 44 1-(2-Methoxy-ethyl)-1H-pyrazole-4-carboxylic acid [5-methoxy-8- (tetrahydro-pyran-4-yl)-pyrido[3,4-b]pyrazin-3-yl]-amide 45 Isoxazole-4-carboxylic acid (5-methoxy-8-phenyl- pyrido[3,4-b]pyrazin-3-yl)-amide 46 4-Hydroxymethyl-4-methyl-piperidine-1-carboxylic acid [8- methoxy-5-(tetrahydro-pyran-4-yl)-quinoxalin-2-yl]-amide 47 3-Hydroxy-3-methyl-pyrrolidine-1-carboxylic acid [5-methoxy-8- (tetrahydro-pyran-4-yl)-pyrido[3,4-b]pyrazin-3-yl]-amide 48 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid [5-(2-fluoro- phenyl)-8-methoxy-quinoxalin-2-yl]-amide 49 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid [5-(4-fluoro- phenyl)-8-methoxy-quinoxalin-2-yl]-amide 50 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid [5-(3-fluoro- phenyl)-8-methoxy-quinoxalin-2-yl]-amide 51 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid [8-methoxy- 5-(2-oxa-7-aza-spiro[4.4]non-7-yl)-quinoxalin-2-yl]-amide 52 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid (8-methoxy-5- pyridin-3-yl-quinoxalin-2-yl)-amide 53 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid (5-azepan-1-yl- 8-methoxy-quinoxalin-2-yl)-amide 54 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid (8-methoxy-5- phenyl-pyrido[3,4-b]pyrazin-2-yl)-amide 55 Isoxazole-4-carboxylic acid [5-methoxy-8-(tetrahydro-pyran-4-yl)- pyrido[3,4-b]pyrazin-3-yl]-amide 56 1-Methyl-1H-pyrazole-4-carboxylic acid [8-methoxy-5-(tetrahydro- pyran-4-yl)-quinoxalin-2-yl]-amide 57 5-Methyl-isoxazole-4-carboxylic acid [8-methoxy-5-(tetrahydro- pyran-4-yl)-quinoxalin-2-yl]-amide 58 5-Cyclopropyl-isoxazole-4-carboxylic acid [8-methoxy-5- (tetrahydro-pyran-4-yl)-quinoxalin-2-yl]-amide 59 1-(2-Methoxy-ethyl)-1H-[1,2,3]triazole-4-carboxylic acid [8- methoxy-5-(tetrahydro-pyran-4-yl)-quinoxalin-2-yl]-amide 60 1-Methyl-1H-[1,2,3]triazole-4-carboxylic acid [8-methoxy-5- (tetrahydro-pyran-4-yl)-quinoxalin-2-yl]-amide 61 1-Cyano-cyclopropanecarboxylic acid [8-methoxy-5-(tetrahydro- pyran-4-yl)-quinoxalin-2-yl]-amide 62 Cyclopropanesulfonic acid [8-methoxy-5-(tetrahydro-pyran-4-yl)- quinoxalin-2-yl]-amide 63 [8-Methoxy-5-(tetrahydro-pyran-4-yl)-quinoxalin-2-yl]-carbamic acid isopropyl ester 64 2-Methyl-2H-pyrazole-3-carboxylic acid [8-methoxy-5-(tetrahydro- pyran-4-yl)-quinoxalin-2-yl]-amide 65 Thiazole-5-carboxylic acid [8-methoxy-5-(tetrahydro-pyran-4-yl)- quinoxalin-2-yl]-amide 66 2-Methyl-thiazole-5-carboxylic acid [8-methoxy-5-(tetrahydro- pyran-4-yl)-quinoxalin-2-yl]-amide 67 1H-[1,2,4]Triazole-3-carboxylic acid [8-methoxy-5-(tetrahydro- pyran-4-yl)-quinoxalin-2-yl]-amide 68 2,3-Dimethyl-3H-imidazole-4-sulfonic acid [8-methoxy-5- (tetrahydro-pyran-4-yl)-quinoxalin-2-yl]-amide 69 Imidazo[1,2-a]pyrazine-2-carboxylic acid [8-methoxy-5-(tetrahydro- pyran-4-yl)-quinoxalin-2-yl]-amide 70 Azetidine-3-carboxylic acid [8-methoxy-5-(tetrahydro-pyran-4-yl)- quinoxalin-2-yl]-amide 71 Azetidine-3-carboxylic acid (8-methoxy-5-phenyl-quinoxalin- 2-yl)-amide 72 Imidazo[1,2-a]pyrazine-2-carboxylic acid (8-methoxy-5-phenyl- quinoxalin-2-yl)-amide 73 2,3-Dimethyl-3H-imidazole-4-sulfonic acid (8-methoxy-5-phenyl- quinoxalin-2-yl)-amide 74 (8-Methoxy-5-phenyl-quinoxalin-2-yl)-carbamic acid isopropyl ester 75 Cyclopropanesulfonic acid (8-methoxy-5-phenyl-quinoxalin-2-yl)- amide 76 1-Cyano-cyclopropanecarboxylic acid (8-methoxy-5-phenyl- quinoxalin-2-yl)-amide 77 1-Methyl-1H-[l,2,3]triazole-4-carboxylic acid (8-methoxy-5-phenyl- quinoxalin-2-yl)-amide 78 1-(2-Methoxy-ethyl)-1H[1,2,3]triazole-4-carboxylic acid (8- methoxy-5-phenyl-quinoxalin-2-yl)-amide 79 5-Cyclopropyl-isoxazole-4-carboxylic acid (8-methoxy-5-phenyl- quinoxalin-2-yl)-amide 80 5-Methyl-isoxazole-4-carboxylic acid (8-methoxy-5-phenyl- quinoxalin-2-yl)-amide 81 1-Methyl-1H-pyrazole-4-carboxylic acid (8-methoxy-5-phenyl- quinoxalin-2-yl)-amide 82 6-Oxo-1,6-dihydro-pyridazine-4-carboxylic acid (8-methoxy-5- phenyl-quinoxalin-2-yl)-amide 83 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid (5-butyl-8- methoxy-quinoxalin-2-yl)-amide 84 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid [8-methoxy- 5-(1-propyl-cyclopropyl)-quinoxalin-2-yl]-amide 85 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid [8-methoxy- 5-(1-methoxymethyl-cyclopropyl)-quinoxalin-2-yl]-amide 86 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid [5-(3-amino- phenyl)-8-methoxy-quinoxalin-2-yl]-amide 87 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid (8-methoxy-5- pyridin-2-yl-quinoxalin-2-yl)-amide 88 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid (8-methoxy-5- o-tolyl-quinoxalin-2-yl)-amide 89 1-Cyano-cyclopropanecarboxylic acid (5-methoxy-8-phenyl- pyrido[3,4-b]pyrazin-3-yl)-amide 90 Cyclopropanecarboxylic acid (5-methoxy-8-phenyl-pyrido[3,4- b]pyrazin-3-yl)-amide 91 N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2-yl]-2-oxa-7- azaspiro[4.4]nonane-7-carboxamide 92 4-hydroxy-N-[8-methoxy-5-(pyridin-4-yl)quinoxalin-2-yl]-4- methylpiperidine-1-carboxamide 93 3-hydroxy-N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2-yl]-3- methylpyrrolidine-1-carboxamide 94 N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2-yl]-2-methyl-1,3- oxazole-4-carboxamide 95 4-(hydroxymethyl)-N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2- yl]-4-methylpiperidine-1-carboxamide 96 N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2-yl]-2,2-dioxo-2lambda6- thia-6-azaspiro[3.3]heptane-6-carboxamide 97 6-methoxy-N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2-yl]pyridazine- 3-carboxamide 98 N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2-yl]-1-(2-methoxyethyl)- 1H-pyrazole-4-carboxamide 99 4-hydroxy-N-(8-methoxy-5-phenylquinoxalin-2-yl)-4-(prop-2-yn-1- yl)piperidine-1-carboxamide 100 3-hydroxy-N-(8-methoxy-5-phenylquinoxalin-2-yl)-3- methylpyrrolidine-1-carboxamide 101 4-(hydroxymethyl)-N-(8-methoxy-5-phenylquinoxalin-2-yl)-4- methylpiperidine-1-carboxamide 102 N-(8-methoxy-5-phenylquinoxalin-2-yl)-8-oxa-2- azaspiro[4.5]decane-2-carboxamide 103 4-Hydroxy-4-prop-2-ynyl-piperidine-1-carboxylic acid [5-methoxy- 8-(tetrahydro-pyran-4-yl)-pyrido[3,4-b]pyrazin-3-yl]-amide 104 4-Hydroxymethyl-4-methyl-piperidine-1-carboxylic acid [5- methoxy-8-(tetrahydro-pyran-4-yl)-pyrido[3,4-b]pyrazin-3-yl]-amide 105 N-(8-methoxy-5-phenylquinoxalin-2-yl)-2-methyl-1,3-oxazole-5- carboxamide 106 Cyclopropanecarboxylic acid [5-methoxy-8-(tetrahydro-pyran-4- yl)-pyrido[3,4-b]pyrazin-3-yl]-amide 107 N-(8-butyl-5-methoxyquinoxalin-2-yl)-4-hydroxy-4- methylpiperidine-1-carboxamide 108 N-(5-butyl-8-methoxyquinoxalin-2-yl)-4-hydroxy-4- methylpiperidine-1-carboxamide 109 N-[5-(3,6-dihydro-2H-pyran-4-yl)-8-methoxyquinoxalin-2-yl]-4- hydroxy-4-methylpiperidine-1-carboxamide 110 N-[8-(3-fluorophenyl)-5-methoxyquinoxalin-2-yl]-4-hydroxy-4- methylpiperidine-1-carboxamide 111 N-[8-(2-fluorophenyl)-5-methoxyquinoxalin-2-yl]-4-hydroxy-4- methylpiperidine-1-carboxamide 112 4-hydroxy-N-[5-methoxy-8-(pyridin-3-yl)quinoxalin-2-yl]-4- methylpiperidine-1-carboxamide 113 6-methoxy-N-(8-methoxy-5-phenylquinoxalin-2-yl)pyridazine- 3-carboxamide 114 4-hydroxy-N-(8-methoxy-5-{1-[(pyridin-2-yl)methyl]-1H-pyrazol- 4-yl}quinoxalin-2-yl)-4-methylpiperidine-1-carboxamide 115 4-{2-[(4-hydroxy-4-methylpiperidine-1-carbonyl)amino]-8- methoxyquinoxalin-5-yl}-N-methylpyridine-2-carboxamide 116 tert-butyl 3-(4-{2-[(4-hydroxy-4-methylpiperidine-1- carbonyl)amino]-8-methoxyquinoxalin-5-yl}-1H-pyrazol-1- yl)azetidine-1-carboxylate 117 4-hydroxy-N-{8-methoxy-5-[3-(2-methoxyethoxy)phenyl]quinoxalin- 2-yl}-4-methylpiperidine-1-carboxamide 118 4-hydroxy-N-(8-methoxy-5-{3-[(2- methoxyethoxy)methyl]phenyl}quinoxalin-2-yl)-4-methylpiperidine- 1-carboxamide 119 4-hydroxy-N-(8-methoxy-5-{1-[2-(2-methoxyethoxy)ethyl]-1H- pyrazol-4-yl}quinoxalin-2-yl)-4-methylpiperidine-1-carboxamide 120 N-[5-(2-fluorophenyl)-8-methoxyquinoxalin-2- yl]cyclopropanecarboxamide 121 N-[8-methoxy-5-(pyridin-3-yl)quinoxalin-2- yl]cyclopropanecarboxamide 122 N-[5-(azepan-1-yl)-8-methoxyquinoxalin-2- yl]cyclopropanecarboxamide 123 N-[5-(2,3-difluorophenyl)-8-methoxyquinoxalin-2- yl]cyclopropanecarboxamide 124 N-[5-(2,5-difluorophenyl)-8-methoxyquinoxalin-2- yl]cyclopropanecarboxamide 125 N-[5-(2,3-difluorophenyl)-8-methoxyquinoxalin-2-yl]-2-methyl-1,3- oxazole-5-carboxamide 126 N-[5-(4-fluorophenyl)-8-methoxyquinoxalin-2- yl]cyclopropanecarboxamide 127 N-[8-methoxy-5-(1,2,3,6-tetrahydropyridin-4-yl)quinoxalin-2- yl]cyclopropanecarboxamide 128 N-[5-(2,5-difluorophenyl)-8-methoxyquinoxalin-2-yl]-2-methyl- 1,3-oxazole-5-carboxamide 129 N-[5-(2-fluorophenyl)-8-methoxyquinoxalin-2-yl]-2-methyl-1,3- oxazole-5-carboxamide 130 N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2-yl]-2-methyl-1,3-oxazole- 5-carboxamide 131 N-[5-(4-fluorophenyl)-8-methoxyquinoxalin-2-yl]-2-methyl-1,3- oxazole-5-carboxamide 132 N-[5-(3,6-dihydro-2H-pyran-4-yl)-8-methoxyquinoxalin-2-yl]-2- methyl-1,3-oxazole-5-carboxamide 133 N-{5-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-8-methoxyquinoxalin-2- yl}-4-hydroxy-4-methylpiperidine-1-carboxamide 134 N-[5-(3,6-dihydro-2H-pyran-4-yl)-8-methoxyquinoxalin-2-yl]-2- methyl-1,3-thiazole-5-carboxamide 135 N-[5-(3,6-dihydro-2H-pyran-4-yl)-8-methoxyquinoxalin-2-yl]-1- methyl-1H-pyrazole-4-carboxamide 136 N-[5-(3,6-dihydro-2H-pyran-4-yl)-8-methoxyquinoxalin-2-yl]-1,2- thiazole-4-carboxamide 137 1-amino-N-[5-(3,6-dihydro-2H-pyran-4-yl)-8-methoxyquinoxalin- 2-yl]cyclopropane-1-carboxamide 138 N-[8-methoxy-5-(pyridin-3-yl)quinoxalin-2-yl]-2-methyl-1,3- oxazole-5-carboxamide 139 2-amino-N-[5-(3,6-dihydro-2H-pyran-4-yl)-8-methoxyquinoxalin- 2-yl]-1,3-thiazole-4-carboxamide 140 N-[5-(3,6-dihydro-2H-pyran-4-yl)-8-methoxyquinoxalin-2-yl]-5- (oxolan-3-yl)-1,3-thiazole-2-carboxamide 141 N-[5-(2,5-dihydrofuran-3-yl)-8-methoxyquinoxalin-2- yl]cyclopropanecarboxamide 142 5-(aminomethyl)-N-[5-(3,6-dihydro-2H-pyran-4-yl)-8- methoxyquinoxalin-2-yl]furan-3-carboxamide 143 ethyl 5-({[5-(3,6-dihydro-2H-pyran-4-yl)-8-methoxyquinoxalin-2- yl]carbamoyl}amino)-1,3,4-thiadiazole-2-carboxylate 144 N′1-[5-(3,6-dihydro-2H-pyran-4-yl)-8-methoxyquinoxalin-2-yl]- N1,N1-dimethylcyclopropane-1,1-dicarboxamide 145 N-[5-(3,6-dihydro-2H-pyran-4-yl)-8-methoxyquinoxalin-2-yl]-1- [(dimethylamino)methyl]cyclopropane-1-carboxamide 146 N-[5-(3,6-dihydro-2H-pyran-4-yl)-8-methoxyquinoxalin-2-yl]-5- methyl-1,3,4-thiadiazole-2-carboxamide 147 N-{8-methoxy-5-[3-(2-methoxyethoxy)phenyl]quinoxalin-2- yl}cyclopropanecarboxamide 148 N-{8-methoxy-5-[3-(2-methoxyethoxy)phenyl]quinoxalin-2-yl}- 2-methyl-1,3-oxazole-5-carboxamide 149 N′1-(8-methoxy-5-phenylquinoxalin-2-yl)-N1,N1- dimethylcyclopropane-1,1-dicarboxamide 150 1-[(dimethylamino)methyl]-N-(8-methoxy-5-phenylquinoxalin-2- yl)cyclopropane-1-carboxamide 151 N-{8-methoxy-5-[3-(2-methoxyethoxy)phenyl]quinoxalin-2-yl}- 2-methyl-1,3-thiazole-5-carboxamide 152 N-{8-methoxy-5-[3-(2-methoxyethoxy)phenyl]quinoxalin-2-yl}- 5-methyl-1,3,4-thiadiazole-2-carboxamide 153 4-hydroxy-N-{8-methoxy-5-[1-(pyridin-2-yl)-1H-pyrazol-4- yl]quinoxalin-2-yl}-4-methylpiperidine-1-carboxamide 154 N-[8-methoxy-5-(6-methylpyridazin-3-yl)quinoxalin-2-yl]-2- methyl-1,3-oxazole-5-carboxamide 155 N-[8-methoxy-5-(2-methoxypyrimidin-5-yl)quinoxalin-2-yl]- 2-methyl-1,3-oxazole-5-carboxamide 156 N-[8-methoxy-5-(2-methoxypyrimidin-5-yl)quinoxalin-2- yl]cyclopropanecarboxamide 157 N-{5-[1-(difluoromethyl)-1H-pyrazol-4-yl]-8-methoxyquinoxalin-2- yl}-2-methyl-1,3-oxazole-5-carboxamide 158 N-{5-[1-(difluoromethyl)-1H-pyrazol-4-yl]-8-methoxyquinoxalin-2- yl}-4-hydroxy-4-methylpiperidine-1-carboxamide 159 N-[5-(3,6-dihydro-2H-pyran-4-yl)-8-methoxyquinoxalin-2-yl]-1H- imidazole-5-carboxamide 160 N-(8-methoxy-5-phenylquinoxalin-2-yl)-1H-imidazole-5- carboxamide 161 N-[8-methoxy-5-(1,4-oxazepan-4-yl)quinoxalin-2- yl]cyclopropanecarboxamide or a physiologically acceptable salt, derivative, solvate, prodrug or stereoisomer thereof.
8. A process for the preparation of a compound of the formula I according to claim 1, comprising ##STR00186## 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 IV is cyclized to give a compound of formula V, a compound of formula V is chlorinated followed by a copper catalyzed amination reaction to give compound VII, a compound of formula VII is reacted in a Suzuki type reaction to a compound of formula VIII by a catalyst and base, a compound of formula VIII is converted to a compound of formula I by amidation or carbamide formation conditions wherein Q, Y, R.sup.1, R.sup.2 and R.sup.3 have the meanings as disclosed for the compound of formula I, ##STR00187## 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 formula IX or reacted with an amine in a nucleophilic substitution reaction under increased temperature to form a compound of formula IX, a compound of formula IX is reduced to a compound of formula X and cyclized to a compound of formula XI, a compound of formula XI is chlorinated followed by copper catalyzed amination to give compound VIII and finally compound VIII is reacted to a compound of formula I under amidation or carbamide formation conditions and wherein Q, Y, R.sup.1, R.sup.2 and R.sup.3 have the meanings as disclosed for the compound of formula I, ##STR00188## c) a compound of the formula XIII is reacted with a boronic ester or acid under Suzuki-type reaction conditions to give a compound of formula XIV, a compound of formula XIV is reduced to a compound of formula X and cyclized to a compound of formula XI, a compound of formula XI is tosylated followed by metal catalyzed amination to give compound VIII and finally compound VIII is reacted to a compound of formula I under amidation or carbamide formation conditions and wherein Q, Y, R.sup.1, R.sup.2 and R.sup.3 have the meanings as disclosed for the compound of formula I, d) a base of a compound of formula I is converted into one of its salts by treatment with an acid, or e) an acid of a compound of formula I is converted into one of its salts by treatment with a base.
9. A method for inhibiting an adenosine A.sub.2A and/or A.sub.2B receptor, comprising administering to said receptor a compound of claim 1 or a physiologically acceptable salt, derivative, solvate, prodrug or stereoisomer thereof.
10. A pharmaceutical composition comprising at least one compound according to claim 1 and/or a physiologically acceptable salt, derivative, solvate, prodrug or stereoisomer thereof and at least one excipient and/or adjuvant.
11. The pharmaceutical composition according to claim 10, further comprising at least one further pharmaceutically active compound.
12. A process for the preparation of a pharmaceutical composition according to claim 10, comprising bringing a compound of formula I and/or one of its physiologically acceptable salts, derivatives, solvates, prodrugs or stereoisomers thereof into a dosage form together with a solid, liquid or semi-liquid excipient or adjuvant.
13. A method for the treatment and/or prophylaxis of a physiological and/or pathophysiological state, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 10, wherein an adenosine A.sub.2A and/or A.sub.2B receptor is inhibited.
14. A method for the treatment and/or prophylaxis of a hyperproliferative or infectious disease or disorder, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 10, wherein an adenosine A.sub.2A and/or A.sub.2B receptor is inhibited.
15. The method according to claim 14, wherein the hyperproliferative disease or disorder is cancer.
16. The method according to claim 15, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, adrenal cortex cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, cervical hyperplasia, cervical cancer, chorio cancer, chronic granulocytic leukemia, chronic lymphocytic leukemia, colon cancer, endometrial cancer, esophageal cancer, essential thrombocytosis, genitourinary carcinoma, glioma, glioblastoma, hairy cell leukemia, head and neck carcinoma, Hodgkin's disease, Kaposi's sarcoma, lung carcinoma, lymphoma, malignant carcinoid carcinoma, malignant hypercalcemia, malignant melanoma, malignant pancreatic insulinoma, medullary thyroid carcinoma, melanoma, multiple myeloma, mycosis fungoides, myeloid leukemia, lymphocytic leukemia, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, osteogenic sarcoma, ovarian carcinoma, pancreatic carcinoma, polycythemia vera, primary brain carcinoma, primary macroglobulinemia, prostatic cancer, renal cell cancer, rhabdomyosarcoma, skin cancer, small-cell lung cancer, soft-tissue sarcoma, squamous cell cancer, stomach cancer, testicular cancer, thyroid cancer and Wilms' tumor.
17. The method according to claim 14, wherein the hyperproliferative disease or disorder is selected from the group consisting of age-related macular degeneration, Crohn's disease, cirrhosis, chronic inflammatory-related disorders, proliferative diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, granulomatosis, immune hyperproliferation associated with organ transplantation, immune hyperproliferation associated with tissue transplantation, an immunoproliferative disease, an immunoproliferative disorder, inflammatory bowel disease, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, vascular hyperproliferation secondary to retinal hypoxia and vasculitis.
18. The method according to claim 14, wherein the infectious disease or disorder is selected from the group consisting of a) virally induced infectious diseases which are caused by retroviruses, hepadnaviruses, herpesviruses, flaviviridae and/or adenoviruses wherein the retroviruses are selected from the group consisting of lentiviruses and oncoretroviruses, wherein the lentivirus is selected from the group consisting of HIV-1, HIV-2, FIV, BIV, SIVs, SHIV, CAEV, VMV and EIAV and the oncoretrovirus is selected from the group consisting of HTLV-I, HTLV-II and BLV, the hepadnavirus is selected from the group consisting of HBV, GSHV and WHV, the herpesivirus is selected from the group consisting of HSV I, HSV II, EBV, VZV, HCMV and HHV 8 and the flaviviridae is selected from the group consisting of HCV, West nile and Yellow Fever, b) bacterial infectious diseases which are caused by Gram-positive bacteria wherein the Gram-positive bacteria are selected from the group consisting of methicillin-susceptible staphylococci, methicillin-resistant staphylococci, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, coagulase-negative staphylococci, glycopeptides-intermediate susceptible Staphylococcus aureus, penicillin-susceptible streptococci, penicillin-resistant streptococci, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus avium, Streptococcus bovis, Streptococcus lactis, Streptococcus sanguis, Streptococci Group C, Streptococci Group G, viridans streptococci, enterococci, vancomycin susceptible strains, vancomycin-resistant strains, Enterococcus faecalis, Enterococcus faecium, Clostridium difficile, Listeria monocytogenes, Corynebacterium jeikeium, Chlamydia spp, C. pneumoniae and Mycobacterium tuberculosis, c) bacterial infectious diseases which are caused by Gram-negative bacteria wherein the Gram-negative bacteria are selected from the group consisting of the Genus Enterobacteriacae, Escherichia spp., Escherichia coli, Klebsiella spp., Enterobacter spp., Citrobacter spp., Serratia spp., Proteus spp., Providencia spp., Salmonella spp., Shigella spp., the genus Pseudomonas, P. aeruginosa, Moraxella spp., M. catarrhalis, Haemophilus spp. and Neisseria spp., d) infectious diseases induced by intracellular active parasites selected from the group consisting of phylum Apicomplexa, Sarcomastigophora, Trypanosoma, Plasmodia, Leishmania, Babesia, Theileria, Cryptosporidia, Sacrocystida, Amoebia, Coccidia and Trichomonadia.
19. A kit comprising separate packs of a) a compound according to claim 1 or a physiologically acceptable salt, derivative, solvate, prodrug or stereoisomer thereof, and b) a further pharmaceutically active compound.
20. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
21. The compound according to claim 7 or a pharmaceutically acceptable salt thereof.
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 1 251.29 252 2 392.46 393 3 255.28 256 4 441.49 442 5 400.48 401 6 396.45 397 7 401.46 402 8 441.49 442 9 421.50 422 10 424.50 425 11 408.46 409 12 420.51 422 13 412.49 413 14 393.44 394 15 386.45 387 16 368.39 369 17 414.50 416 18 432.50 433 19 395.42 396 20 411.46 412 21 416.48 417 22 378.43 379 23 406.48 407 24 418.49 419 25 404.47 405 26 424.48 425 27 393.44 394 28 379.42 380 29 407.47 408 30 426.51 428 31 301.34 302 32 355.31 356 33 413.48 414 34 417.47 418 35 400.44 401 36 404.43 405 37 381.39 382 38 259.31 260 39 386.45 387 40 386.45 387 41 406.48 407 42 403.44 404 43 360.37 361 44 359.39 360 45 319.36 320 46 359.39 360 47 362.41 363 48 376.44 377 49 346.35 347 50 410.45 411 51 401.46 402 52 327.38 328 53 408.46 409 54 419.44 420 55 404.43 405 56 412.45 413 57 347.33 348 58 414.51 416 59 387.44 388 60 410.45 411 61 410.45 411 62 410.45 411 63 441.53 443 64 393.45 394 65 413.52 415 66 393.45 394 67 355.35 356 68 367.41 368 69 368.39 369 70 394.43 395 71 412.45 413 72 368.40 369 73 352.39 353 74 363.44 364 75 345.40 346 76 367.41 368 77 370.43 371 78 384.46 385 79 354.37 355 80 417.49 418 81 404.43 405 82 342.40 343 83 334.38 335 84 396.41 397 85 409.47 410 86 337.38 338 87 355.42 356 88 344.37 345 89 360.38 361 90 404.43 405 91 386.41 387 92 360.37 361 93 359.39 360 94 373.37 374 95 372.47 373 96 398.51 400 97 400.48 401 98 407.47 408 99 393.45 394 100 406.49 407 101 345.36 346 102 320.35 321 103 425.49 426 104 415.49 416 105 360.37 361 106 328.37 329 107 372.47 373 108 372.47 373 109 398.46 399 110 410.45 411 111 410.45 411 112 393.44 394 113 387.40 388 114 473.53 475 115 450.50 451 116 537.62 539 117 466.54 468 118 480.56 482 119 484.55 486 120 337.35 338 121 320.35 321 122 340.42 341 123 355.34 356 124 355.34 356 125 396.35 397 126 337.35 338 127 324.38 325 128 396.35 397 129 378.36 379 130 368.39 369 131 378.36 379 132 366.38 367 133 437.50 439 134 382.44 383 135 365.39 366 136 368.42 369 137 340.38 341 138 361.36 362 139 383.43 384 140 438.51 440 141 311.34 312 142 380.40 381 143 456.48 457 144 396.44 397 145 382.46 383 146 383.43 384 147 393.44 394 148 434.45 435 149 390.44 391 150 376.46 377 151 450.52 452 152 451.50 453 153 459.51 461 154 376.37 377 155 392.37 393 156 351.36 352 157 400.34 401 158 432.43 433 159 351.36 352 160 345.36 346 161 342.40 343
(4) The Nos. recited herein corresponds to the numbering of the compounds disclosed in table 2
(5) TABLE-US-00005 No. NMR 2 1H NMR (400 MHz, DMSO-d6) ppm = 9.94 (s, 1H), 9.19 (s, 1H), 7.61-7.55 (m, 3H), 7.49-7.33 (m, 3H), 7.31-7.26 (m, 1H), 4.33 (s, 1H), 3.99 (s, 3H), 3.85- 3.77 (m, 2H), 3.35-3.23 (m, 2H), 1.54-1.45 (m, 4H), 1.16 (s, 3H). 4 1H NMR (500 MHz, DMSO-d6) ppm = 11.79 (s, 1H), 9.61 (s, 1H), 8.27-8.25 (m, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.67-7.64 (m, 1H), 7.64-7.61 (m, 2H), 7.50- 7.46 (m, 2H), 7.41-7.37 (m, 2H), 7.27 (dd, J = 5.5, 1.4 Hz, 1H), 4.03 (s, 3H), 3.78-3.74 (m, 4H), 3.67- 3.63 (m, 4H). 6 1H NMR (500 MHz, DMSO-d6) ppm = 10.28-9.85 (m, 1H), 9.29 (s, 1H), 8.42 (s, 1H), 8.06 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.86-3.80 (m, 2H), 3.34-3.24 (m, 2H), 1.53-1.44(m, 4H), 1.16 (s, 3H). 7 1H NMR (400 MHz, DMSO-d6) ppm = 10.15-9.94 (m, 1H), 9.25 (s, 1H), 7.46-7.35 (m, 1H), 7.22-7.16 (m, 1H), 4.00-3.89 (m, 7H), 3.87-3.76 (m, 2H), 3.53- 3.36 (m, 4H), 3.35-3.23 (m, 2H), 1.54-1.43 (m, 4H), 1.16 (s, 3H). 8 1H NMR (500 MHz, DMSO-d6) ppm = 11.48 (s, 1H), 9.58 (s, 1H), 8.88-8.87 (m, 1H), 8.28 (dd, J = 9.2, 2.5 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.64-7.61 (m, 2H), 7.50-7.46 (m, 2H), 7.42-7.36 (m, 2H), 7.01 (d, J = 9.2 Hz, 1H), 4.03 (s, 3H), 3.74-3.71 (m, 4H), 3.69- 3.65 (m, 4H). 9 1H NMR (300 MHz, DMSO-d6) 11.65 (s, 1H), 9.75 (s, 1H), 8.38-7.92 (m, 3H), 7.42 (d, J = 7.9 Hz, 2H), 4.03 (s, 3H), 4.01-3.88 (m, 2H), 3.76-3.61 (m, 1H), 3.57- 3.41 (m, 4H), 2.14 (s, 6H), 1.98-1.64 (m, 4H). 10 1H NMR (500 MHz, DMSO-d6) ppm = 9.98-9.85 (m, 1H), 9.21 (s, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 4.00-3.94 (m, 2H), 3.93 (s, 3H), 3.92- 3.85 (m, 3H), 3.55 (td, J = 11.5, 2.4 Hz, 2H), 3.23- 3.15 (m, 2H), 2.82 (t, J = 2.6 Hz, 1H), 2.33 (d, J = 2.7 Hz, 2H), 1.84-1.71 (m, 4H), 1.66 (td, J = 12.8, 4.5 Hz, 2H), 1.57-1.51 (m, 2H). 12 1H NMR (500 MHz, DMSO-d6) ppm = 11.61 (s, 1H), 10.49-10.42 (m, 1H), 9.62 (s, 1H), 8.22-8.19 (m, 2H), 7.73-7.70 (m, 2H), 7.55 (d, J = 8.2 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 4.38 (d, J = 5.4 Hz, 2H), 4.03- 3.98 (m, 2H), 3.97 (s, 3H), 3.98-3.91 (m, 1H), 3.61- 3.54 (m, 2H), 2.74 (d, J = 4.8 Hz, 6H), 1.89-1.75 (m, 4H). 13 1H NMR (400 MHz, DMSO-d6) ppm = 9.64-9.44 (m, 1H), 9.36 (s, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 4.01-3.95 (m, 2H), 3.93 (s, 3H), 3.92- 3.84 (m, 1H), 3.83-3.77 (m, 2H), 3.61-3.46 (m, 8H), 1.95-1.70 (m, 8H). 14 1H NMR (500 MHz, DMSO-d6) ppm = 10.14 (s, 1H), 9.30 (s, 1H), 8.97-8.94 (m, 2H), 8.42-8.39 (m, 2H), 7.97 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 4.06 (s, 3H), 3.82 (dt, J = 13.4, 4.3 Hz, 2H), 3.34-3.26 (m, 2H), 1.54-1.44 (m, 4H), 1.16 (s, 3H). 15 1H NMR (400 MHz, DMSO-d6) ppm = 9.55-9.45 (m, 1H), 9.36 (s, 1H), 8.53-8.36 (m, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 4.01-3.95 (m, 2H), 3.93 (s, 3H), 3.92-3.85 (m, 1H), 3.59-3.40 (m, 6H), 1.88-1.71 (m, 6H), 1.31 (s, 3H). 16 1H NMR (400 MHz, DMSO-d6) ppm = 10.57 (s, 1H), 9.63 (s, 1H), 8.87 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 4.02-3.96 (m, 2H), 3.96 (s, 3H), 3.95-3.88 (m, 1H), 3.56 (td, J = 11.3, 2.6 Hz, 2H), 2.52 (s, 3H), 1.88-1.72 (m, 4H). 17 1H NMR (700 MHz, DMSO-d6) ppm = 9.95-9.86 (m, 1H), 9.21 (s, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 3.99-3.96 (m, 2H), 3.92 (s, 3H), 3.91- 3.86 (m, 1H), 3.77-3.73 (m, 2H), 3.56-3.52 (m, 2H), 3.30-3.25 (m, 2H), 3.19 (s, 2H), 1.83-1.76 (m, 2H), 1.77-1.71 (m, 2H), 1.50-1.45 (m, 2H), 1.25-1.21 (m, 2H), 0.92 (s, 3H). 18 1H NMR (500 MHz, DMSO-d6) ppm = 10.13 (s, 1H), 9.46 (s, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 4.47 (s, 4H), 4.33-4.28 (m, 4H), 4.00-3.96 (m, 2H), 3.93 (s, 3H), 3.92-3.86 (m, 1H), 3.55 (td, J = 11.5, 2.4 Hz, 2H), 1.84-1.71 (m, 4H). 19 1H NMR (400 MHz, DMSO-d6) ppm = 11.06 (s, 1H), 9.70 (s, 1H), 8.30 (d, J = 9.1 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 9.2 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 4.18 (s, 3H), 4.03-3.98 (m, 2H), 3.98 (s, 3H), 3.97-3.90 (m, 1H), 3.61-3.53 (m, 2H), 1.89-1.74 (m, 4H). 20 1H NMR (500 MHz, DMSO-d6) ppm = 11.20 (s, 1H), 9.65 (s, 1H), 8.58-8.57 (m, 1H), 8.24-8.23 (m, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 4.33 (t, J = 5.2 Hz, 2H), 4.02-3.97 (m, 2H), 3.96 (s, 3H), 3.96-3.90 (m, 1H), 3.72 (t, J = 5.2 Hz, 2H), 3.56 (td, J = 11.5, 2.5 Hz, 2H), 3.26 (s, 3H), 1.87-1.73 (m, 4H). 21 1H NMR (400 MHz, DMSO-d6) ppm = 9.98 (s, 1H), 9.20 (s, 1H), 7.61-7.56 (m, 3H), 7.48-7.43 (m, 2H), 7.39-7.34 (m, 1H), 7.29 (d, J = 8.3 Hz, 1H), 4.64 (s, 1H), 3.99 (s, 3H), 4.00-3.92 (m, 2H), 3.24-3.14 (m, 2H), 2.82 (t, J = 2.6 Hz, 1H), 2.33 (d, J = 2.7 Hz, 2H), 1.67 (td, J = 12.7, 4.4 Hz, 2H), 1.57-1.51 (m, 2H). 22 1H NMR (400 MHz, DMSO-d6) ppm = 9.55 (s, 1H), 9.34 (s, 1H), 7.60-7.55 (m, 3H), 7.48-7.42 (m, 2H), 7.39-7.34 (m, 1H), 7.29 (d, J = 8.2 Hz, 1H), 4.80 (s, 1H), 3.99 (s, 3H), 3.79-3.29 (m, 4H), 1.91-1.75 (m, 2H), 1.31 (s, 3H). 23 1H NMR (400 MHz, DMSO-d6) ppm = 9.92 (s, 1H), 9.20 (s, 1H), 7.61-7.55 (m, 3H), 7.48-7.42 (m, 2H), 7.39-7.34 (m, 1H), 7.29 (d, J = 8.3 Hz, 1H), 4.59- 4.46 (m, 1H), 3.99 (s, 3H), 3.75 (dt, J = 13.5, 4.8 Hz, 2H), 3.33-3.24 (m, 2H), 3.19 (s, 2H), 1.52-1.43 (m, 2H), 1.27-1.20 (m, 2H), 0.92 (s, 3H). 24 1H NMR (500 MHz, DMSO-d6) ppm = 9.62 (s, 1H), 9.35 (s, 1H), 7.60-7.57 (m, 3H), 7.48-7.43 (m, 2H), 7.39-7.35 (m, 1H), 7.30 (d, J = 8.3 Hz, 1H), 3.99 (s, 3H), 3.68-3.41 (m, 8H), 1.87-1.73 (m, 2H), 1.54- 1.49 (m, 4H). 25 1H NMR (500 MHz, DMSO-d6) ppm = 9.69 (s, 1H), 9.33 (s, 1H), 7.60-7.57 (m, 3H), 7.48-7.43 (m, 2H), 7.39-7.35 (m, 1H), 7.30 (d, J = 8.2 Hz, 1H), 3.99 (s, 3H), 3.84-3.76 (m, 2H), 3.74-3.40 (m, 6H), 1.97- 1.82 (m, 4H). 26 1H NMR (500 MHz, DMSO-d6) ppm = 10.27 (s, 1H), 9.44 (s, 1H) 7.61-7.57 (m, 3H), 7.48-7.44 (m, 2H), 7.39-7.35 (m, 1H), 7.31 (d, J = 8.2 Hz, 1H), 4.48 (s, 4H), 4.37-4.24 (m, 4H), 3.99 (s, 3H). 27 1H NMR (400 MHz, DMSO-d6)10.23 (s, 1H), 9.38 (s, 1H), 8.19 (s, 1H), 7.66-7.60 (m, 2H), 7.53-7.46 (m, 2H), 7.45-7.39 (m, 1H), 4.37 (s, 1H), 4.10 (s, 3H), 3.90-3.75 (m, 2H), 3.31-3.22 (m, 2H), 1.54-1.43 (m, 4H), 1.16 (s, 3H). 28 1H NMR (400 MHz, DMSO-d6) 9.88 (s, 1H), 9.53 (s, 1H), 8.20 (s, 1H), 7.68-7.62 (m, 2H), 7.53-7.47 (m, 2H), 7.46-7.39 (m, 1H), 4.84 (s, 1H), 4.11 (s, 3H), 3.83-3.36 (m, 4H), 2.01-1.73 (m, 2H), 1.32 (s, 3H). 29 1H NMR (400 MHz, DMSO-d6)10.24 (s, 1H), 9.39 (s, 1H), 8.20 (s, 1H), 7.70-7.61 (m, 2H), 7.53-7.47 (m, 2H), 7.45-7.39 (m, 1H), 4.57 (t, J = 5.4 Hz, 1H), 4.10 (s, 3H), 3.76 (dt, J = 13.5, 4.9 Hz, 2H), 3.31-3.24 (m, 1H), 3.20 (d, J = 5.5 Hz, 2H), 1.57-1.37 (m, 2H), 1.28- 1.12 (m, 2H), 0.93 (s, 3H). 30 1H NMR (700 MHz, DMSO-d6) ppm = 9.65-9.51 (m, 1H), 9.38 (s, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 4.01-3.96 (m, 2H), 3.93 (s, 3H), 3.89 (tt, J = 11.8, 3.9 Hz, 1H), 3.66-3.62 (m, 2H), 3.57-3.52 (m, 4H), 3.67-3.27 (m, 4H), 1.87-1.76 (m, 4H), 1.76- 1.71 (m, 2H), 1.55-1.49 (m, 4H). 31 1H NMR (400 MHz, DMSO-d6) ppm = 11.24 (s, 1H), 9.62 (s, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 4.01-3.96 (m, 2H), 3.94 (s, 3H), 3.93-3.86 (m, 1H), 3.55 (td, J = 11.4, 2.7 Hz, 2H), 2.18 (s, 3H), 1.86-1.71 (m, 4H). 32 1H NMR (400 MHz, DMSO-d6) ppm = 8.52 (s, 1H), 8.08-7.69 (m, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 4.00-3.95 (m, 2H), 3.94 (s, 3H), 3.84- 3.75 (m, 1H), 3.51 (td, J = 11.6, 2.2 Hz, 2H), 1.84- 1.73 (m, 2H), 1.72-1.65 (m, 2H). 33 1H NMR (400 MHz, DMSO-d6) ppm = 11.44 (s, 1H), 9.61 (s, 1H), 8.34 (s, 1H), 8.05-8.00 (m, 2H), 7.76-7.72 (m, 2H), 7.52-7.39 (m, 6H), 4.15 (s, 3H), 3.52 (d, J = 5.1 Hz, 2H), 2.20 (s, 6H). 34 1H NMR (400 MHz, DMSO-d6) ppm = 9.39 (s, 1H), 8.20 (s, 1H), 7.67-7.60 (m, 2H), 7.53-7.46 (m, 2H), 7.46-7.38 (m, 1H), 4.67 (s, 1H), 4.11 (s, 3H), 4.05-3.87 (m, 2H), 3.20 (t, J = 12.4 Hz, 2H), 2.85 (t, J = 2.6 Hz, 1H), 2.33 (d, J = 2.7 Hz, 2H), 1.67 (td, J = 12.4, 11.4, 4.0 Hz, 2H), 1.55 (d, J = 13.2 Hz, 2H). 35 1H NMR (400 MHz, DMSO-d6) ppm = 11.77 (d, J = 1.6 Hz, 1H), 9.78 (d, J = 0.8 Hz, 1H), 8.30 (d, J = 1.6 Hz, 1H), 8.12 (d, J = 8.0 Hz, 2H), 7.68 (dt, J = 8.2, 1.2 Hz, 2H), 7.54-7.42 (m, 5H), 4.53 (s, 2H), 4.14 (d, J = 1.1 Hz, 3H), 3.36 (s, 3H). 36 1H NMR (400 MHz, DMSO-d6) 11.47 (s, 1H), 9.82 (s, 1H), 8.60 (s, 1H), 8.26 (d, J = 5.5 Hz, 2H), 7.69- 7.64 (m, 2H), 7.51 (t, J = 7.4 Hz, 2H), 7.46-7.41 (m, 1H), 4.34 (t, J = 5.2 Hz, 2H), 4.14 (s, 3H), 3.73 (t, J = 5.2 Hz, 2H), 3.27 (s, 3H). 37 1H NMR (500 MHz, DMSO-d6) ppm = 13.38 â€″ 13.34 (m, 1H), 11.96 (s, 1H), 9.60 (s, 1H), 8.23 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.48 (t, J = 2.1 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 4.02 â€″ 3.97 (m, 2H), 3.97 (s, 3H), 3.96 â€″ 3.90 (m, 1H), 3.57 (td, J = 11.5, 2.4 Hz, 2H), 1.87 â€″ 1.74 (m, 4H). 41 1H NMR (400 MHz, DMSO-d6) ppm = 10.02-9.90 (m, 1H), 9.10 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.31-7.21 (m, 4H), 7.19-7.15 (m, 1H), 3.99 (s, 3H), 3.79 (dt, J = 13.2, 4.2 Hz, 2H), 3.33-3.23 (m, 2H), 1.95 (s, 3H), 1.51-1.45 (m, 4H), 1.15 (s, 3H). 42 1H NMR (400 MHz, DMSO-d6) ppm = 11.24 (s, 1H), 9.62 (s, 1H), 8.59-8.57 (m, 1H), 8.25-8.23 (m, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.64-7.60 (m, 2H), 7.50- 7.44 (m, 2H), 7.41-7.34 (m, 2H), 4.33 (t, J = 5.2 Hz, 2H), 4.03 (s, 3H), 3.73 (t, J = 5.2 Hz, 2H), 3.26 (s, 3H). 43 1H NMR (400 MHz, DMSO-d6) ppm = 10.64 (s, 1H), 9.61 (s, 1H), 8.89 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.64-7.60 (m, 2H), 7.50-7.45 (m, 2H), 7.42-7.36 (m, 2H), 4.04 (s, 3H), 2.53 (s, 3H). 44 1H NMR (400 MHz, DMSO-d6) ppm = 11.23-11.21 (m, 1H), 9.62 (s, 1H), 8.55-8.53 (m, 1H), 8.22-8.21 (m, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.63-7.60 (m, 2H), 7.50-7.44 (m, 2H), 7.41-7.34 (m, 2H), 4.03 (s, 3H), 3.91 (s, 3H). 45 1H NMR (400 MHz, DMSO-d6) ppm = 11.59 (s, 1H), 9.62 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.61-7.58 (m, 2H), 7.48-7.43 (m, 2H), 7.40-7.35 (m, 1H), 7.34 (d, J =8.3 Hz, 1H), 4.02 (s, 3H), 2.17-2.10 (m, 1H), 0.94- 0.85 (m, 4H). 46 1H NMR (400 MHz, DMSO-d6) ppm = 11.54 (s, 1H), 9.56 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.64-7.61 (m, 2H), 7.57 (d, J = 2.1 Hz, 1H), 7.50-7.45 (m, 2H), 7.42- 7.36 (m, 3H), 4.14 (s, 3H), 4.03 (s, 3H). 47 1H NMR (400 MHz, DMSO-d6) ppm = 11.92 (s, 1H), 9.58 (s, 1H), 9.39-9.37 (m, 1H), 9.03-9.00 (m, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.64-7.60 (m, 2H), 7.51- 7.45 (m, 2H), 7.42-7.37 (m, 2H), 4.04 (s, 3H). 48 1H NMR (400 MHz, DMSO-d6) ppm = 11.79 (s, 1H), 9.56 (s, 1H), 8.76 (s, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.64-7.60 (m, 2H), 7.50-7.45 (m, 2H), 7.41-7.36 (m, 2H), 4.04 (s, 3H), 2.73 (s, 3H). 49 1H NMR (400 MHz, DMSO-d6) ppm = 14.99-14.73 (m, 1H), 10.75-10.59 (m, 1H), 9.62 (s, 1H), 8.85- 8.72 (m, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.65-7.61 (m, 2H), 7.51-7.45 (m, 2H), 7.42-7.37 (m, 2H), 4.04 (s, 3H). 50 1H NMR (400 MHz, DMSO-d6) d 10.03-9.90 (m, 1H), 9.19 (s, 1H), 7.65-7.59 (m, 2H), 7.57 (d, J = 8.2 Hz, 1H), 7.31-7.24 (m, 3H), 3.99 (s, 3H), 3.81 (dt, J = 13.1, 4.2 Hz, 2H), 3.36-3.22 (m, 2H), 1.53-1.45 (m, 4H), 1.16 (s, 3H). 51 1H NMR (400MHz, DMSO, ppm): 10.1 (s, 1H), 9.39 (s, 1H), 8.03 (s, 1H), 4.36 (s, 1H), 4.04 (s, 3H), 3.99-3.96 (m, 2H), 3.82-3.79 (m, 2H), 3.70-3.64 (m, 1H), 3.55-3.50 (m, 2H), 3.29-3.25 (m, 2H), 1.91-1.73 (m, 4H), 1.55-1.45 (m, 4H), 1.15 (s, 3H). 52 1H NMR (400 MHz, DMSO-d6) d 11.54 (s, 1H), 9.65 (s, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 4.01-3.95 (m, 2H), 3.95 (s, 3H), 3.94-3.86 (m, 1H), 3.55 (td, J = 11.4, 2.7 Hz, 2H), 2.16-2.09 (m, 1H), 1.86-1.70 (m, 4H), 0.94-0.85 (m, 4H). 56 1H NMR (400MHz, DMSO, ppm): 11.41 (s, 1H), 9.83 (s, 1H), 8.58 (s, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 4.35 (t, J = 5.2, 2H), 4.06-3.97 (m, 5H), 3.74-3.68 (m, 3H), 3.57-3.52 (m, 2H), 3.26 (s, 3H), 1.95-1.75 (m, 4H). 60 1H NMR (700 MHz, DMSO-d6) d 10.13-9.88 (m, 1H), 9.13 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.48-7.43 (m, 2H), 7.31-7.26 (m, 3H), 4.00 (s, 3H), 3.84-3.77 (m, 2H), 3.31-3.25 (m, 2H), 1.51-1.44 (m, 4H), 1.15 (s, 3H). 62 1H NMR (500 MHz, DMSO-d6) d 10.15-9.91 (m, 1H), 9.21 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.52-7.47 (m, 1H), 7.45-7.41 (m, 2H), 7.30 (d, J = 8.3 Hz, 1H), 7.23- 7.18 (m, 1H), 4.00 (s, 3H), 3.85-3.79 (m, 2H), 3.33- 3.26 (m, 2H), 1.53-1.44 (m, 4H), 1.16 (s, 3H). 64 1H NMR (700 MHz, DMSO-d6) d 10.13 (s, 1H), 9.26 (s, 1H), 9.22-9.20 (m, 1H), 8.91-8.88 (m, 1H), 8.84- 8.81 (m, 1H), 8.14 (dd, J = 8.0, 5.6 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 4.04 (s, 3H), 3.84-3.79 (m, 2H), 3.32-3.25 (m, 2H), 1.52-1.45 (m, 4H), 1.16 (s, 3H). 65 1H NMR (500 MHz, DMSO-d6) d 11.87-11.24 (m, 1H), 10.29-10.21 (m, 1H), 9.35(s, 1H), 8.16-7.79 (m, 1H), 7.27 (d, J = 8.7 Hz, 1H), 3.99 (s, 3H), 3.85- 3.66 (m, 6H), 3.35-3.25 (m, 2H), 2.11-2.00 (m, 4H), 1.79-1.72 (m, 4H), 1.53-1.44 (m, 4H), 1.16 (s, 3H). 68 1H NMR (400 MHz, DMSO-d6) delta 11.22-11.18 (m, 1H), 9.64 (s, 1H), 8.54-8.52 (m, 1H), 8.22-8.20 (m, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 4.01-3.95 (m, 2H), 3.95 (s, 3H), 3.94-3.91 (m, 1H), 3.90 (s, 3H), 3.60-3.52 (m, 2H), 1.87-1.71 (m, 4H). 71 1H NMR (500 MHz, DMSO-d6) d 10.98 (s, 1H), 9.64 (s, 1H), 8.93 (s, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 4.66 (t, J = 5.1 Hz, 2H), 4.02-3.97 (m, 2H), 3.97 (s, 3H), 3.97-3.90 (m, 1H), 3.80 (t, J = 5.3 Hz, 2H), 3.56 (td, J = 11.5, 2.5 Hz, 2H), 3.28 (s, 3H), 1.87-1.74 (m, 4H). 78 1H NMR (500 MHz, DMSO-d6) d 11.75 (s, 1H), 9.58 (s, 1H), 8.74 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 4.04-3.97 (m, 2H), 3.98 (s, 3H), 3.99- 3.90 (m, 1H), 3.71-3.54 (m, 2H), 2.73 (s, 3H), 1.87- 1.73 (m, 4H). 86 1H NMR (400 MHz, DMSO-d6) d 10.80 (s, 1H), 9.39 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.61-7.58 (m, 2H), 7.49-7.43 (m, 2H), 7.40-7.35 (m, 1H), 7.32 (d, J = 8.2 Hz, 1H), 4.96 (hept, J = 6.3 Hz, 1H), 4.00 (s, 3H), 1.28 (d, J = 6.2 Hz, 6H). 88 1H NMR (700 MHz, DMSO-d6) d 11.26 (s, 1H), 9.37 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.61-7.59 (m, 2H), 7.48-7.45 (m, 2H), 7.40-7.37 (m, 2H), 4.03 (s, 3H), 1.85-1.83 (m, 2H), 1.76-1.74 (m, 2H). 89 1H NMR (400 MHz, DMSO-d6) d 10.96-10.90 (m, 1H), 9.62 (s, 1H), 8.88 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.65-7.60 (m, 2H), 7.51-7.44 (m, 2H), 7.42-7.36 (m, 2H), 4.17 (s, 3H), 4.04 (s, 3H). 90 1H NMR (500 MHz, DMSO-d6) d 11.02 (s, 1H), 9.62 (s, 1H), 8.95 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.64- 7.61 (m, 2H), 7.50-7.46 (m, 2H), 7.42-7.37 (m, 2H), 4.68-4.65 (m, 2H), 4.04 (s, 3H), 3.82-3.79 (m, 2H), 3.29 (s, 3H). 94 1H NMR (400 MHz, DMSO-d6) d 13.38-13.32 (m, 1H), 11.98 (s, 1H), 9.57 (s, 1H), 8.23 (d, J = 2.1 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.64-7.60 (m, 2H), 7.50- 7.45 (m, 3H), 7.42-7.37 (m, 2H), 4.04 (s, 3H). 102 1H NMR (400 MHz, DMSO, ppm): 11.82 (s, 1H), 9.79 (s, 1H), 8.25 (s,1H), 7.65 (t, J = 0.8, 2H), 7.51-7.42 (m, 3H), 4.12 (s, 3H), 2.09-2.19 (m, 1H), 0.92-0.91 (m, 4H). 103 1H NMR (400 MHz, DMSO, ppm): 10.19 (s, 1H), 9.40 (s, 1H), 8.04 (s, 1H), 4.67 (s, 1H), 4.03 (s, 3H), 4.01-3.88 (m, 4H), 3.74-3.63 (m, 1H), 3.58-3.45 (m, 2H), 3.19 (t, J = 12.4 Hz, 2H), 2.84 (t, J = 2.6 Hz, 1H), 2.33 (d, J = 2.7 Hz, 2H), 1.88 (dd, J = 12.4, 4.2 Hz, 2H), 1.78 (d, J = 12.6 Hz, 2H), 1.66 (td, J = 12.8, 4.4 Hz, 2H), 1.54 (d, J = 13.3 Hz, 2H). 104 1H NMR (400 MHz, DMSO, ppm): 10.15 (s,1H), 9.40 (s, 1H), 8.04 (s, 1H), 4.56 (t, J = 5.4 Hz, 1H), 4.03 (s, 3H), 3.98 (dd, J = 11.2, 4.1 Hz, 2H), 3.74 (dd, J = 11.9, 6.9 Hz, 2H), 3.66 (d, J = 11.9 Hz, 1H), 3.53 (d, J = 2.2 Hz, 2H), 3.27 (d, J = 10.3 Hz, 2H), 3.19 (d, J = 5.5 Hz, 2H), 1.88 (dd, J = 12.4, 4.2 Hz, 2H), 1.79-1.76 (m, 2H), 1.55-1.40 (m, 2H), 1.31-1.17 (m, 2H), 0.92 (s, 3H). 105 1H NMR (400 MHz, DMSO-d6) d 11.66 (s, 1H), 9.58 (s, 1H), 8.23 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.65- 7.59 (m, 2H), 7.51-7.44 (m, 2H), 7.42-7.35 (m, 2H), 4.03 (s, 3H), 2.54 (s, 3H). 106 1H NMR (400 MHz, DMSO, ppm): 11.74 (s, 1H), 9.81 (s, 1H), 8.09 (s, 1H), 4.07 (s, 3H), 4.00-3.96 (m, 2H), 3.71-3.65 (m, 1H), 3.56-3.50 (m, 2H), 2.11-2.08 (m, 1H), 1.92-1.76 (m, 4H), 0.91-0.95 (m, 4H). 107 1H NMR (500 MHz, DMSO-d6) d 9.62-9.55 (m, 1H), 9.09 (s, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 3.92 (s, 3H), 3.80 (dt, J = 12.6, 4.0 Hz, 2H), 3.33-3.26 (m, 2H), 3.01 (t, J = 7.6 Hz, 2H), 1.67-1.60 (m, 2H), 1.54-1.45 (m, 4H), 1.33 (h, J = 7.3 Hz, 2H), 1.16 (s, 3H), 0.91 (t, J = 7.4 Hz, 3H). 108 1H NMR (500 MHz, DMSO-d6) d 10.02-9.82 (m, 1H), 9.19 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H) 3.91 (s, 3H), 3.80 (dt, J = 13.8, 4.5 Hz, 2H), 3.33-3.24 (m, 2H), 3.04 (t, J = 7.6 Hz, 2H), 1.65-1.58 (m, 2H), 1.52-1.44 (m, 4H), 1.33 (h, J = 7.4 Hz, 2H), 1.15 (s, 3H), 0.90 (t, J = 7.4 Hz, 3H). 110 1H NMR (500 MHz, DMSO-d6) d 9.64-9.56 (m, 1H), 9.11 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.51-7.46 (m, 3H), 7.21-7.15 (m, 2H), 4.01 (s, 3H), 3.79-3.73 (m, 2H), 3.30-3.23 (m, 2H), 1.51-1.42 (m, 4H), 1.14 (s, 3H). 111 1H NMR (700 MHz, DMSO-d6) d 9.60-9.51 (m, 1H), 9.08 (s, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.47-7.41 (m, 2H), 7.29-7.25 (m, 2H), 7.17 (d, J = 8.2 Hz, 1H), 4.01 (s, 3H), 3.74-3.70 (m, 2H), 3.26-3.20 (m, 2H), 1.48- 1.41 (m, 4H), 1.13 (s, 3H). 112 1H NMR (700 MHz, DMSO-d6) d 9.91 (s, 1H), 9.37- 9.36 (m, 1H), 9.20 (s, 1H), 8.94-8.92 (m, 1H), 8.89- 8.87 (m, 1H), 8.15 (dd, J = 8.2, 5.6 Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 4.11-4.04 (m, 2H), 4.05 (s, 3H), 3.23-3.18 (m, 2H), 1.91-1.87 (m, 2H), 1.85-1.80 (m, 2H), 1.65 (s, 3H). 113 1H NMR (700 MHz, DMSO-d6) d 11.12 (s, 1H), 9.67 (s, 1H), 8.29 (d, J = 9.1 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.64-7.62 (m, 2H), 7.51-7.47 (m, 3H), 7.41- 7.39 (m, 2H), 4.18 (s, 3H), 4.05 (s, 3H). 114 1H NMR (500 MHz, DMSO-d6) d 9.98-9.94 (m, 1H), 9.28 (s, 1H), 8.62-8.61 (m, 1H), 8.56-8.54 (m, 1H), 8.15-8.14 (m, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.78 (td, J = 7.7, 1.8 Hz, 1H), 7.33-7.30 (m, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.14-7.12 (m, 1H), 5.51 (s, 2H), 4.36 (s, 1H), 3.96 (s, 3H), 3.84-3.78 (m, 2H), 3.32-3.25 (m, 2H), 1.52-1.45 (m, 4H), 1.16 (s, 3H). 115 1H NMR (400 MHz, DMSO-d6) d 10.05-10.02 (m, 1H), 9.24 (s, 1H), 8.80 (q, J = 4.8 Hz, 1H), 8.70-8.67 (m, 1H), 8.29-8.27 (m, 1H), 7.85 (dd, J = 5.0, 1.8 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 4.35 (s, 1H), 4.02 (s, 3H), 3.85-3.77 (m, 2H), 3.34- 3.25 (m, 2H), 2.86 (d, J = 4.8 Hz, 3H), 1.53-1.44 (m, 4H), 1.16 (s, 3H). 116 1H NMR (400 MHz, DMSO-d6) d 9.95-9.92 (m, 1H), 9.29 (s, 1H), 8.55-8.54 (m, 1H), 8.22-8.21 (m, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 5.35- 5.28 (m, 1H), 4.36-4.29 (m, 3H), 4.24-4.16 (m, 2H), 3.96 (s, 3H), 3.85-3.77 (m, 2H), 3.34-3.26 (m, 2H), 1.53-1.45 (m, 4H), 1.43 (s, 9H), 1.16 (s, 3H). 117 1H NMR (500 MHz, DMSO-d6) d 10.00-9.95 (m, 1H), 9.20 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.37-7.33 (m, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.16-7.13 (m, 2H), 6.97- 6.94 (m, 1H), 4.36 (s, 1H), 4.15-4.12 (m, 2H), 3.99 (s, 3H), 3.84-3.78 (m, 2H), 3.70-3.67 (m, 2H), 3.33- 3.32 (m, 3H), 3.32-3.25 (m, 2H), 1.52-1.44 (m, 4H), 1.16 (s, 3H). 118 1H NMR (500 MHz, DMSO-d6) d 10.00-9.95 (m, 1H), 9.19 (s, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.53-7.51 (m, 1H), 7.51-7.48 (m, 1H), 7.45-7.41 (m, 1H), 7.33- 7.30 (m, 1H), 7.29 (d, J = 8.3 Hz, 1H), 4.56 (s, 2H), 4.36 (s, 1H), 3.99 (s, 3H), 3.83-3.78 (m, 2H), 3.61- 3.59 (m, 2H), 3.51-3.48 (m, 2H), 3.32-3.25 (m, 2H), 3.25 (s, 3H), 1.52-1.44 (m, 4H), 1.15 (s, 3H). 119 1H NMR (700 MHz, DMSO-d6) d 9.96 (s, 1H), 9.29 (s, 1H), 8.45 (s, 1H), 8.08 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 4.37 (s, 1H), 4.32 (t, J = 5.5 Hz, 2H), 3.96 (s, 3H), 3.84-3.79 (m, 4H), 3.55-3.53 (m, 2H), 3.44-3.41 (m, 2H), 3.36-3.27 (m, 2H), 3.21 (s, 3H), 1.52-1.46 (m, 4H), 1.16 (s, 3H). 120 1H NMR (400 MHz, DMSO-d6) d 11.60 (s, 1H), 9.57 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.49-7.43 (m, 2H), 7.34 (d, J = 8.2 Hz, 1H), 7.32-7.25 (m, 2H), 4.03 (s, 3H), 2.16-2.09 (m, 1H), 0.91-0.85 (m, 4H). 121 1H NMR (400 MHz, DMSO-d6) d 11.67 (s, 1H), 9.66 (s, 1H), 9.21-9.19 (m, 1H), 8.89-8.86 (m, 1H), 8.82 (dt, J = 8.2, 1.8 Hz, 1H), 8.13 (dd, J = 8.2, 5.6 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 4.06 (s, 3H), 2.13 (quint, J = 6.3 Hz, 1H), 0.91 (d, J = 6.1 Hz, 4H). 122 1H NMR (400 MHz, DMSO-d6) d 11.78 (s, 1H), 9.76 (s, 1H), 8.17-8.05 (m, 1H), 7.31 (d, J = 8.7 Hz, 1H), 4.01 (s, 3H), 3.88-3.73 (m, 4H), 2.18-2.04 (m, 5H), 1.79-1.74 (m, 4H), 0.92 (d, J = 6.1 Hz, 4H). 123 1H NMR (500 MHz, DMSO-d6) d 11.65 (s, 1H), 9.60 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.51-7.45 (m, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.33-7.26 (m, 2H), 4.04 (s, 3H), 2.15-2.10 (m, 1H), 0.92-0.86 (m, 4H). 124 1H NMR (400 MHz, DMSO-d6) d 11.62 (s, 1H), 9.59 (s, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.38-7.25 (m, 4H), 4.03 (s, 3H), 2.17-2.09 (m, 1H), 0.93-0.85 (m, 4H). 125 1H NMR (500 MHz, DMSO-d6) d 11.73 (s, 1H), 9.55 (s, 1H), 8.23 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.53- 7.47 (m, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.35-7.28 (m, 2H), 4.05 (s, 3H), 2.54 (s, 3H). 126 1H NMR (400 MHz, DMSO-d6) delta 11.61-11.58 (m, 1H), 9.62 (s, 1H), 7.67-7.61 (m, 3H), 7.33 (d, J = 8.3 Hz, 1H), 7.32-7.25 (m, 2H), 4.02 (s, 3H), 2.17-2.10 (m, 1H), 0.94-0.86 (m, 4H). 127 1H NMR (400 MHz, DMSO-d6) d 11.60 (s, 1H), 9.63 (s, 1H), 9.28-9.21 (m, 2H), 7.48 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 5.99-5.96 (m, 1H), 3.98 (s, 3H), 3.81-3.74 (m, 2H), 3.36-3.29 (m, 2H), 2.91- 2.85 (m, 2H), 2.17-2.09 (m, 1H), 0.93-0.86 (m, 4H). 128 1H NMR (400 MHz, DMSO-d6) delta 11.70 (s, 1H), 9.55 (s, 1H), 8.23 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.39-7.27 (m, 3H), 4.05 (s, 3H), 2.54 (s, 3H). 129 1H NMR (400 MHz, DMSO-d6) delta 11.73 (s, 1H), 9.53 (s, 1H), 8.24 (s, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.51-7.44 (m, 2H), 7.39 (d, J = 8.2 Hz, 1H), 7.34- 7.27 (m, 2H), 4.04 (s, 3H), 2.54 (s, 3H). 130 1H NMR (400 MHz, DMSO-d6) delta 11.66 (s, 1H), 9.60 (s, 1H), 8.23 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 4.02-3.97 (m, 2H), 3.96 (s, 3H), 3.96-3.88 (m, 1H), 3.56 (td, J = 11.4, 2.7 Hz, 2H), 2.54 (s, 3H), 1.87-1.72 (m, 4H). 131 1H NMR (400 MHz, DMSO-d6) delta 11.72 (s, 1H), 9.58 (s, 1H), 8.24 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.69-7.63 (m, 2H), 7.37 (d, J = 8.3 Hz, 1H), 7.33- 7.27 (m, 2H), 4.03 (s, 3H), 2.54 (s, 3H). 132 1H NMR (400 MHz, DMSO-d6) delta 11.67 (s, 1H), 9.58 (s, 1H), 8.23 (s, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 6.05-6.02 (m, 1H), 4.26 (q, J = 2.8 Hz, 2H), 3.98 (s, 3H), 3.86 (t, J = 5.4 Hz, 2H), 2.67-2.62 (m, 2H), 2.54 (s, 3H). 133 1H NMR (500 MHz, DMSO-d6) d 10.12-9.94 (m, 1H), 9.50-9.42 (m, 1H), 9.40-9.33 (m, 1H), 9.30 (s, 1H), 8.60 (s, 1H), 8.30 (s, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 5.53 (quint, J = 7.6 Hz, 1H), 4.43-4.36 (m, 4H), 3.96 (s, 3H), 3.85-3.78 (m, 2H), 3.33-3.26 (m, 2H), 1.53-1.44 (m, 4H), 1.16 (s, 3H). 134 1H NMR (400 MHz, DMSO-d6) delta 11.82-11.76 (m, 1H), 9.55 (s, 1H), 8.75 (s, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 6.04-6.01 (m, 1H), 4.26 (q, J = 2.7 Hz, 2H), 3.98 (s, 3H), 3.86 (t, J = 5.4 Hz, 2H), 2.72 (s, 3H), 2.67-2.61 (m, 2H). 135 1H NMR (400 MHz, DMSO-d6) d 11.22 (s, 1H), 9.62 (s, 1H), 8.54-8.53 (m, 1H), 8.22-8.21 (m, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 6.04- 6.01 (m, 1H), 4.26 (q, J = 2.7 Hz, 2H), 3.97 (s, 3H), 3.91 (s, 3H), 3.86 (t, J = 5.4 Hz, 2H), 2.68-2.62 (m, 2H). 136 1H NMR (400 MHz, DMSO-d6) d 11.72 (s, 1H), 10.03 (s, 1H), 9.64 (s, 1H), 9.15 (s, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 6.06-6.03 (m, 1H), 4.27 (q, J = 2.7 Hz, 2H), 3.99 (s, 3H), 3.87 (t, J = 5.4 Hz, 2H), 2.69-2.63 (m, 2H). 137 1H NMR (400 MHz, DMSO-d6) d 10.84 (s, 1H), 9.40 (s, 1H), 8.88-8.80 (m, 3H), 7.54 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 6.04-6.00 (m, 1H), 4.26 (q, J = 2.7 Hz, 2H), 3.97 (s, 3H), 3.85 (t, J = 5.4 Hz, 2H), 2.66-2.61 (m, 2H), 1.83-1.78 (m, 2H), 1.50-1.45 (m, 2H). 138 1H NMR (400 MHz, DMSO-d6) d 11.83 (s, 1H), 9.64 (s, 1H), 9.24-9.21 (m, 1H), 8.92-8.88 (m, 1H), 8.84- 8.80 (m, 1H), 8.26 (s, 1H), 8.15-8.10 (m, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 4.08 (s, 3H), 2.54 (s, 3H). 139 1H NMR (500 MHz, DMSO-d6) d 10.55-10.47 (m, 1H), 9.68 (s, 1H), 7.80 (s, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 6.06-6.03 (m, 1H), 4.26 (q, J = 2.7 Hz, 2H), 3.98 (s, 3H), 3.86 (t, J = 5.4 Hz, 2H), 2.67-2.62 (m, 2H). 140 1H NMR (400 MHz, DMSO-d6) d 11.80 (s, 1H), 9.56 (s, 1H), 8.80 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 6.05-6.02 (m, 1H), 4.26 (q, J = 2.7 Hz, 2H), 4.07 (dd, J = 8.2, 7.0 Hz, 1H), 3.99 (s, 3H), 3.96-3.79 (m, 6H), 2.68-2.62 (m, 2H), 2.47-2.37 (m, 1H), 2.21-2.12 (m, 1H). 141 1H NMR (400 MHz, DMSO-d6) d 11.58 (s, 1H), 9.68 (s, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 6.99-6.97 (m, 1H), 5.12-5.08 (m, 2H), 4.80- 4.76 (m, 2H), 3.99 (s, 3H), 2.17-2.10 (m, 1H), 0.94- 0.86 (m, 4H). 142 1H NMR (400 MHz, DMSO-d6) delta 11.42-11.39 (m, 1H), 9.61 (s, 1H), 8.73-8.72 (m, 1H), 8.54-8.44 (m, 3H), 7.51 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.14-7.12 (m, 1H), 6.05-6.02 (m, 1H), 4.26 (q, J = 2.8 Hz, 2H), 4.15 (q, J = 5.7 Hz, 2H), 3.98 (s, 3H), 3.86 (t, J = 5.4 Hz, 2H), 2.67-2.62 (m, 2H). 143 1H NMR (500 MHz, DMSO-d6) d 13.32-13.16 (m, 1H), 11.16 (s, 1H), 9.01 (s, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 6.06-6.03 (m, 1H), 4.42 (q, J = 7.1 Hz, 2H), 4.26 (q, J = 2.7 Hz, 2H), 4.04 (s, 3H), 3.86 (t, J = 5.4 Hz, 2H), 2.67-2.61 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H). 144 1H NMR (400 MHz, DMSO-d6) d 10.55-10.49 (m, 1H), 9.34 (s, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 6.03-6.00 (m, 1H), 4.25 (q, J = 2.7 Hz, 2H), 3.96 (s, 3H), 3.85 (t, J = 5.5 Hz, 2H), 3.08-2.68 (m, 6H), 2.66-2.60 (m, 2H), 1.61-1.57 (m, 2H), 1.31- 1.27 (m, 2H). 145 1H NMR (400 MHz, DMSO-d6) d 10.83 (s, 1H), 9.68- 9.59 (m, 1H), 9.39 (s, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 6.04-6.00 (m, 1H), 4.26 (q, J = 2.7 Hz, 2H), 3.97 (s, 3H), 3.85 (t, J = 5.4 Hz, 2H), 3.52 (d, J = 5.7 Hz, 2H), 2.81 (d, J = 4.9 Hz, 6H), 2.65- 2.60 (m, 2H), 1.60-1.56 (m, 2H), 1.25-1.21 (m, 2H). 146 1H NMR (400 MHz, DMSO-d6) d 11.57 (s, 1H), 9.48 (s, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 6.06-6.03 (m, 1H), 4.27 (q, J = 2.7 Hz, 2H), 4.00 (s, 3H), 3.87 (t, J = 5.4 Hz, 2H), 2.86 (s, 3H), 2.68- 2.63 (m, 2H). 147 1H NMR (500 MHz, DMSO-d6) d 11.59 (s, 1H), 9.63 (s, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.37-7.33 (m, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.18-7.14 (m, 2H), 6.97- 6.94 (m, 1H), 4.16-4.12 (m, 2H), 4.02 (s, 3H), 3.70- 3.67 (m, 2H), 3.32 (s, 3H), 2.17-2.10 (m, 1H), 0.93- 0.85 (m, 4H). 148 1H NMR (500 MHz, DMSO-d6) d 11.68-11.64 (m, 1H), 9.58 (s, 1H), 8.23 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.39-7.35 (m, 2H), 7.19-7.17 (m, 2H), 6.99-6.96 (m, 1H), 4.16-4.14 (m, 2H), 4.03 (s, 3H), 3.70-3.67 (m, 2H), 3.33 (s, 3H), 2.54 (s, 3H). 149 1H NMR (500 MHz, DMSO-d6) d 10.58-10.51 (m, 1H), 9.34 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.61-7.58 (m, 2H), 7.48-7.44 (m, 2H), 7.40-7.36 (m, 1H), 7.36 (d, J = 8.2 Hz, 1H), 4.01 (s, 3H), 3.09-2.85 (m, 6H), 1.61-1.58 (m, 2H), 1.31-1.28 (m, 2H). 150 1H NMR (500 MHz, DMSO-d6) d 10.87-10.85 (m, 1H), 9.69-9.61 (m, 1H), 9.40 (s, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.61-7.58 (m, 2H), 7.48-7.44 (m, 2H), 7.40- 7.36 (m, 1H), 7.37 (d, J = 8.3 Hz, 1H), 4.02 (s, 3H), 3.53 (d, J = 5.7 Hz, 2H), 2.81 (d, J = 4.8 Hz, 6H), 1.61- 1.57 (m, 2H), 1.25-1.22 (m, 2H). 151 1H NMR (500 MHz, DMSO-d6) d 11.82-11.77 (m, 1H), 9.56 (s, 1H), 8.76 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.39-7.35 (m, 2H), 7.19-7.16 (m, 2H), 6.99-6.96 (m, 1H), 4.16-4.14 (m, 2H), 4.03 (s, 3H), 3.70-3.67 (m, 2H), 3.33 (s, 3H), 2.73 (s, 3H). 152 1H NMR (500 MHz, DMSO-d6) d 11.61-11.59 (m, 1H), 9.49 (s, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.40-7.36 (m, 2H), 7.20-7.17 (m, 2H), 6.99-6.96 (m, 1H), 4.17- 4.14 (m, 2H), 4.04 (s, 3H), 3.70-3.68 (m, 2H), 3.33 (s, 3H), 2.87 (s, 3H). 153 1H NMR (500 MHz, DMSO-d6) d 10.03-9.95 (m, 1H), 9.36 (d, J = 0.7 Hz, 1H), 9.35-9.32 (m, 1H), 8.54- 8.52 (m, 1H), 8.50 (d, J = 0.7 Hz, 1H), 8.05-7.98 (m, 2H), 7.98 (d, J = 8.3 Hz, 1H), 7.40-7.36 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 3.99 (s, 3H), 3.87-3.80 (m, 2H), 3.35-3.27 (m, 2H), 1.54-1.46 (m, 4H), 1.17 (s, 3H). 154 1H NMR (400 MHz, DMSO-d6) d 11.81 (s, 1H), 9.65 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 8.25 (s, 1H), 8.19 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 4.09 (s, 3H), 2.82 (s, 3H), 2.55 (s, 3H). 156 1H NMR (400 MHz, DMSO-d6) d 11.64 (s, 1H), 9.65 (s, 1H), 8.86 (s, 2H), 7.78 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 2.17-2.10 (m, 1H), 0.94-0.86 (m, 4H). 157 1H NMR (700 MHz, DMSO-d6) d 11.72 (s, 1H), 9.71 (s, 1H), 8.97 (s, 1H), 8.49 (s, 1H), 8.25 (s, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.91 (t, J = 59.1 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 4.02 (s, 3H), 2.55 (s, 3H). 158 1H NMR (700 MHz, DMSO-d6) d 10.03-10.00 (m, 1H), 9.32 (s, 1H), 8.90 (s, 1H), 8.45 (s, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.90 (t, J = 59.1 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 4.37 (s, 1H), 3.98 (s, 3H), 3.84-3.80 (m, 2H), 3.32-3.27 (m, 2H), 1.52-1.46 (m, 4H), 1.16 (s, 3H). 160 1H NMR (400 MHz, DMSO-d6) delta 10.79-10.66 (m, 1H), 9.71 (s, 1H), 8.37-8.17 (m, 2H), 7.69 (d, J = 8.2 Hz, 1H), 7.64-7.60 (m, 2H), 7.50-7.45 (m, 2H), 7.42- 7.36 (m, 2H), 4.04 (s, 3H). 161 1H NMR (400 MHz, DMSO-d6) d 11.66 (s, 1H), 9.66 (s, 1H), 7.74-7.48 (m, 1H), 7.23 (d, J = 8.7 Hz, 1H), 4.01-3.95 (m, 2H), 3.96 (s, 3H), 3.83 (t, J = 5.7 Hz, 2H), 3.82-3.69 (m, 4H), 2.26-2.16 (m, 2H), 2.17- 2.10 (m, 1H), 0.94-0.87 (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 a SHIMADZU LC-MS machine consisting of an UFLC 20-AD system and LCMS 2020 MS detector or an Agilent Technologies 1200 series. The column used and the conditions are described in the different 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. N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2-yl]-1-(2-methoxyethyl)-1H-pyrazole-4-carboxamide
a. 1-Bromo-4-methoxy-2,3-dinitro-benzene
(9) Into a 250-mL 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%. Rt 1.73 min (method A). [M+H]+ 276.8, 278.9.
General Procedure for Suzuki Reactions
b. 4-(4-Methoxy-2,3-dinitro-phenyl)-3,6-dihydro-2H-pyran
(10) Into a 350-ml 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)Cl2 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%. Rt 1.17 min (method B). [M+H]+ 281.2.
c. 3-Methoxy-6-(tetrahydro-pyran-4-yl)-benzene-1,2-diamine
(11) 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%. Rt 1.01 min (method C). [M+H]+ 223.1.
General Procedure for Cyclisation to Quinoxaline Ring
d. 8-Methoxy-5-(tetrahydro-pyran-4-yl)-1H-quinoxalin-2-one
(12) 3-Methoxy-6-(tetrahydro-pyran-4-yl)-benzene-1,2-diamine, 97% (3.41 g, 15.8 mmol) was dissolved in methanol (80 ml), ethyl glyoxylate, 50% solution in toluene (9.64 ml, 94.7 mmol) was added and the mixture was stirred at 80° C. for 2 h. The reaction mixture was evaporated to dryness and the crude material was triturated with ethyl acetate. The solid formed was filtered off and purified by flash chromatography (ethyl acetate/cyclohexane, gradient) to yield in 1.62 g (31%) of a colorless solid. HPLC/MS (purity) 80%. Rt 1.79 min (method D). [M+H]+ 261.1.
General Procedure to Introduce Chlorine
e. 2-Chloro-8-methoxy-5-(tetrahydro-pyran-4-yl)-quinoxaline
(13) 8-Methoxy-5-(tetrahydro-pyran-4-yl)-1H-quinoxalin-2-one, 80% (1.62 g, 4.98 mmol) was dissolved in phosphoryl chloride (27.1 g, 177 mmol) at room temperature and the mixture was stirred at 105° C. for 3 h. After cooling to room temperature mixture was partitioned between saturated aqueous NaHCO3 solution and dichloromethane and stirred additional 1 h at RT. The organic layer was separated and the aqueous phase was extracted three times with dichloromethane. The combined organic layer were dried over sodium sulfate, filtered and the filtrate was evaporated to dryness to give 1.74 g (100%) of the title compound as a yellow solid. HPLC/MS (purity) 80%. Rt 2.36 min (method D). [M+H]+ 279.1.
General Procedure to Synthesize Amino-Quinoxalines
f. 8-Methoxy-5-(tetrahydro-pyran-4-yl)-quinoxalin-2-ylamine
(14) In a high-pressure tube 2-chloro-8-methoxy-5-(tetrahydro-pyran-4-yl)-quinoxaline, 80% (1.74 g, 4.98 mmol) was dissolved THF (20 ml). To this mixture ammonia solution in water, 32% (60 ml) and copper(I)iodide (500 mg, 2.62 mmol) were added, the vessel was sealed and the mixture was stirred at 140° C. for 4 h (max. 21 bar pressure). After cooling to room temperature the mixture was evaporated to dryness and purified by flash chromatography (ethyl acetate/cyclohexane, gradient) to yield in 1.00 g (60%) of a colorless solid. HPLC/MS (purity) 79%. Rt 1.71 min (method D). [M+H]+ 260.1.
General Procedure for Amide Formation
g. N-[8-methoxy-5-(oxan-4-yl)quinoxalin-2-yl]-1-(2-methoxyethyl)-1H-pyrazole-4-carboxamide
(15) 8-Methoxy-5-(tetrahydro-pyran-4-yl)-quinoxalin-2-ylamine, 79% (100 mg, 0.305 mmol), 1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid (67.4 mg, 0.396 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (75.9 mg, 0.396 mmol, 1-hydroxybenzotriazole hydrate (53.5 mg, 0.396 mmol) were dissolved in N,N-dimethylformamide (5.00 ml). N-Ethyldiisopropylamine (0.13 ml, 0.762 mmol) was added at room temperature and the mixture stirred at room temperature for 3 days. The reaction mixture was evaporated to dryness and purified by flash chromatography with acetonitrile/water and the prepurified fractions again with dichloromethane/water to yield in 6.00 mg (5%) of the title compound as a light beige solid. 1H NMR (500 MHz, DMSO-d6) ppm=11.20 (s, 1H), 9.65 (s, 1H), 8.58-8.57 (m, 1H), 8.24-8.23 (m, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.24 (d, J=8.2 Hz, 1H), 4.33 (t, J=5.2 Hz, 2H), 4.02-3.97 (m, 2H), 3.96 (s, 3H), 3.96-3.90 (m, 1H), 3.72 (t, J=5.2 Hz, 2H), 3.56 (td, J=11.5, 2.5 Hz, 2H), 3.26 (s, 3H), 1.87-1.73 (m, 4H). HPLC/MS (purity) 100%. Rt 2.26 min (method D). [M+H]+ 272.1
2. 4-Hydroxy-N-[8-methoxy-5-(pyridin-4-yl)quinoxalin-2-yl]-4-methylpiperidine-1-carboxamide
h. 4-(4-Methoxy-2,3-dinitro-phenyl)pyridine
(16) Into a 350-ml pressure tank reactor purged and maintained with an inert atmosphere of argon was placed 1-bromo-4-methoxy-2,3-dinitrobenzene, 95% (5.00 g, 17.2 mmol), 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 95% (4.44 g, 20.6 mmol), Pd(dppf)Cl2 dichloromethane complex, 90% (1.56 g, 1.72 mmol), potassium carbonate (2.99 g, 20.6 mmol, dissolved in water (2 ml)), ethanol (10 ml) and toluene (100 ml). The mixture was stirred for 15 h at 100° C. and after cooling evaporated to dryness. The residue was purified by column chromatography (ethyl acetate/hexane, 80/20) to yield in 4.01 g (81%) of 4-(4-methoxy-2,3-dinitrophenyl)pyridine as a yellow solid. HPLC/MS (purity) 95%. Rt 0.90 min (method E). [M+H]+ 276.1.
General Procedure for Nitro Group Reduction
i. 3-Methoxy-6-pyridin-4-yl-benzene-1,2-diamine
(17) Into a 250-ml round-bottom flask was placed Palladium/carbon, 10% (2.13 g, 19.9 mmol), methanol (60 ml) and 4-(4-methoxy-2,3-dinitrophenyl)pyridine, 95% (4.00 g, 13.8 mmol). The mixture was stirred for 15 h under a hydrogen atmosphere at RT. The solids were filtered off and discarded. The filtrate was evaporated to dryness and the residue was purified by column chromatography (ethyl acetate/MeOH, 95/5) to yield in 2.0 g (52%) of 3-methoxy-6-(pyridin-4-yl)benzene-1,2-diamine as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 8.57 (d, J=1.7 Hz, 2H), 7.42 (d, J=1.7 Hz, 2H), 6.46 (d, J=8.4 Hz, 2H), 4.33 (s, 4H), 3.78 (s, 3H). Melting point: 165-166° C. HPLC/MS (purity) 91%. Rt 0.64 min (method A). [M+H]+ 216.0.
j. 8-Methoxy-5-pyridin-4-yl-1H-quinoxalin-2-one
(18) 3-Methoxy-6-pyridin-4-yl-benzene-1,2-diamine, 91% (1.77 g, 7.48 mmol) and 3-methoxy-6-pyridin-4-yl-benzene-1,2-diamine, 93% (2.00 g, 8.64 mmol) were dissolved in methanol (80 ml), then ethyl glyoxylate, 50% solution in toluene (9.85 mL, 96.7 mmol) were added at room temperature and the reaction mixture was stirred at 80° C. for 3 h. The mixture was evaporated to dryness and the residue was triturated with ethyl acetate to give a precipitation that—after filtration—was further purified flash chromatography dichloromethane/ethanol, gradient) to yield in 1.80 g (44%) of the title compound as a colorless solid. HPLC/MS (purity) 100%. Rt 1.43 min (method D). [M+H]+ 254.1.
k. 2-Chloro-8-methoxy-5-pyridin-4-yl-quinoxaline
(19) 8-Methoxy-5-pyridin-4-yl-1H-quinoxalin-2-one (1,800 g, 7,107 mmol) was dissolved in phosphoryl chloride (32.7 g, 213 mmol) at room temperature and the mixture was stirred at 105° C. for 3 h. After cooling to room temperature mixture was partitioned between saturated aqueous NaHCO3 solution and dichloromethane and stirred additional 1 h at RT. The precipitate was filtered off to give 870 mg (34%) of the title compound as a yellow solid. HPLC/MS (purity) 75%. Rt 1.89 min (method D). [M+H]+ 254.1.
l. 8-Methoxy-5-pyridin-4-yl-quinoxalin-2-ylamine
(20) In a high pressure tube 2-chloro-8-methoxy-5-pyridin-4-yl-quinoxaline, 75% (870 mg, 2.40 mmol) was dissolved THF (20 ml). To this mixture ammonia solution in water, 32% (50 ml) and copper(I)iodide (229 mg, 1.20 mmol) were added, the vessel was sealed and the mixture was stirred at 140° C. for 5 h (max. 21 bar pressure). After cooling to room temperature the mixture was evaporated to dryness and purified by flash chromatography (ethyl acetate/cyclohexane, gradient) to yield in 140 mg (23%) of a colorless solid. HPLC/MS (purity) 100%. Rt 1.33 min (method D). [M+H]+ 253.1.
General Procedure for Urea Formation
m. 4-hydroxy-N-[8-methoxy-5-(pyridin-4-yl)quinoxalin-2-yl]-4-methylpiperidine-1-carboxamide
(21) 8-Methoxy-5-pyridin-4-yl-quinoxalin-2-ylamine (140 mg, 0.555 mmol) and 1,1′-carbonyldiimidazole (117 mg, 0.721 mmol) were suspended in dichloromethane (4 ml) and stirred at 70° C. for 20 h. 4-Methylpiperidin-4-ol (83.1 mg, 0.721 mmol) was then added at 70° C. and the mixture was stirred for additional 3 h at 70° C. The reaction mixture was evaporated to dryness and directly purified by flash chromatography (water/acetonitrile, gradient). A few drops of 1 N HCl solution was added to the product containing wells to yield in 21.0 mg (9%)—after evaporation to dryness—of the hydrochloride salt of the title compound as a yellow solid. 1H NMR (500 MHz, DMSO-d6) ppm=10.14 (s, 1H), 9.30 (s, 1H), 8.97-8.94 (m, 2H), 8.42-8.39 (m, 2H), 7.97 (d, J=8.3 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 4.06 (s, 3H), 3.82 (dt, J=13.4, 4.3 Hz, 2H), 3.34-3.26 (m, 2H), 1.54-1.44 (m, 4H), 1.16 (s, 3H). HPLC/MS (purity) 100%. Rt 1.76 min (method D). [M+H]+ 394.2.
3. 4-Hydroxy-N-[5-methoxy-8-phenylpyrido[3,4-b]pyrazin-3-yl]-4-methylpiperidine-1-carboxamide
n. 5-Bromo-2-methoxy-3-nitropyridin-4-amine
(22) A mixture of fuming nitric acid (109 ml) and concentrated sulfuric acid (160 mL) was added dropwise to a round bottom flask containing 5-bromo-2-methoxypyridin-4-amine (36.00 g, 177 mmol) with stirring at 0° C. The mixture was stirred for 12 h at room temperature and quenched with ice water (400 ml). The mixture was extracted with DCM (4 times with 500 ml each). The organic phases were combined, washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (EtOAc/petrol ether, gradient) to yield 5-bromo-2-methoxy-3-nitropyridin-4-amine as a yellow solid (5.54 g, 13%). MS: m/z=249.8 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.14 (s, 1H), 3.88 (s, 3H).
o. 2-Methoxy-3-nitro-5-phenylpyridin-4-amine
(23) To a solution of 5-bromo-2-methoxy-3-nitropyridin-4-amine (4.95 g, 20.0 mmol) in dioxane (174 ml) was added phenylboronic acid (2.48 g, 20.4 mmol), Pd(dppf)Cl2CH2Cl2 (652 mg, 0.80 mmol), potassium carbonate (5.92 g, 42.9 mmol), and water (37 ml) at room temperature. After bubbling nitrogen into the mixture for 5 minutes, the mixture was stirred for 16 h at 80° C. The solids were filtrated off. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (EtOAc/petrol ether, gradient) to yield 2-methoxy-3-nitro-5-phenylpyridin-4-amine as a yellow solid (3.96 g, 81%). MS: m/z=246.3 [M+H]+.
p. 2-Methoxy-5-phenylpyridine-3,4-diamine
(24) To a solution of 2-methoxy-3-nitro-5-phenylpyridin-4-amine (3.96 g, 16.2 mmol) in MeOH (138 ml) was placed Palladium/carbon, 10% (515 mg, 4.84 mmol). The mixture was stirred for 16 h at room temperature under H2 atmosphere. When the reaction was done, the solids were filtrate out. The filtrate was concentrated under vacuum to yield 2-methoxy-5-phenylpyridine-3,4-diamine as a yellow solid (3.37 g, 97%). MS: m/z=216.3 [M+H]+.
q. 5-Methoxy-8-phenylpyrido[3,4-b]pyrazin-3-ol
(25) To a solution of 2-methoxy-5-phenylpyridine-3,4-diamine (3.37 g, 15.6 mmol) in methanol (181 ml) was added ethyl 2-oxoacetate (10.86 g, 106 mmol) at room temperature. The mixture was stirred for 3 h at 80° C. After cooling to room temperature, it was concentrated under reduced pressure and the residue was purified by flash chromatography (EtOAc/petrol ether, gradient). Two regio-isomers were collected and the first fraction was identified as 5-methoxy-8-phenylpyrido[3,4-b]pyrazin-3-ol as a yellow solid (750 mg, 19%). MS: m/z=254.0 [M+H]+.
r. 5-Methoxy-8-phenylpyrido[3,4-b]pyrazin-3-yl 4-methylbenzene-1-sulfonate
(26) To a solution of 5-methoxy-8-phenylpyrido[3,4-b]pyrazin-3-ol (750 mg, 2.97 mmol) in dichloromethane (24 ml) was added 4-methylbenzene-1-sulfonyl chloride (616 mg, 3.25 mmol), 4-dimethylaminopyridine (39 mg, 0.28 mmol), and triethylamine (414 mg, 4.14 mmol) at room temperature. The solution was stirred for 2 h at room temperature and then quenched with water (50 ml). The mixture was extracted with dichloromethane (3 times with 150 ml) and the organic phases were combined, washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (EtOAc/petrol ether, gradient) to yield 5-methoxy-8-phenylpyrido[3,4-b]pyrazin-3-yl 4-methylbenzene-1-sulfonate as a green solid (806 mg, 67%). MS: m/z=408.2 [M+H]+.
s. 5-Methoxy-8-phenylpyrido[3,4-b]pyrazin-3-amine
(27) To a solution of 5-methoxy-8-phenylpyrido[3,4-b]pyrazin-3-yl 4-methylbenzene-1-sulfonate (806 mg, 1.97 mmol) in dioxane (85 ml) was added tert-butyl carbamate (463 mg, 3.94 mmol), Pd(OAc)2 (47 mg, 0.2 mmol), XPhos (198 mg, 0.39 mmol), and Cs2CO3 (966 mg, 2.97 mmol). After bubbling nitrogen into the mixture for 5 minutes, the mixture was stirred for 16 h at 100° C. When the reaction was done, the solids were filtrated off. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (EtOAc/petrol ether, gradient) to yield 5-methoxy-8-phenylpyrido[3,4-b]pyrazin-3-amine as a black solid (185 mg, 37%). MS: m/z=253.3 [M+H]+.
t. Phenyl N-[5-methoxy-8-phenylpyrido[3,4-b]pyrazin-3-yl]
(28) To a solution of 5-methoxy-8-phenylpyrido[3,4-b]pyrazin-3-amine (120 mg, 0.48 mmol) in THF (50 ml) was added sodium carbonate (252 mg, 2.38 mmol), phenyl chloroformate (744 mg, 4.76 mmol), and pyridine (188 mg, 2.38 mmol) at room temperature. The mixture was stirred for 6 h at 50° C. When the reaction was done, the solids were filtered out. The filtrate was concentrated under reduced pressure to yield phenyl N-[5-methoxy-8-phenylpyrido[3,4-b]pyrazin-3-yl]carbamate as a white solid (300 mg, crude). MS: m/z=373.2 [M+H]+.
u. 4-Hydroxy-N-[5-methoxy-8-phenylpyrido[3,4-b]pyrazin-3-yl]-4-methylpiperidine-1-carboxamide
(29) To a solution of phenyl N-[5-methoxy-8-phenylpyrido[3,4-b]pyrazin-3-yl]carbamate (100 mg, crude) in THF (10 ml) was added 4-methylpiperidin-4-ol (31 mg, 0.27 mmol), and diisopropylyethylamine (34.0 mg, 0.27 mmol) at room temperature. The solution was stirred for 12 h at 60° C. After cooling to the room temperature, the reaction was quenched by the addition of water (20 ml). The mixture was extracted with DCM (3 times with 50 ml). The organic phases were combined, washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by prep-HPLC under the following conditions: Column, XBridge Prep C18 OBD Column, 19×150 mm 5 um; MeCN in water (with 10 mmol/l NH4HCO3+0.1% NH3.H2O), 30% to 50% gradient in 8 min; Detector, UV 254/220 nm to yield in 4-hydroxy-N-[5-methoxy-8-phenylpyrido[3,4-b]pyrazin-3-yl]-4-methylpiperidine-1-carboxamide as a yellow solid (30.0 mg, 47% for 2 steps). HPLC: 99.3% purity, room temperature=4.14 min. MS: m/z=394.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.38 (s, 1H), 8.19 (s, 1H), 7.68-7.60 (m, 2H), 7.54-7.38 (m, 3H), 4.37 (s, 1H), 4.10 (s, 3H), 3.87-3.76 (m, 2H), 3.34-3.24 (m, 2H), 1.56-1.42 (m, 4H), 1.16 (s, 3H).
(30) HPLC Methods:
(31) Method A:
(32) Shimadzu LCMS-2020; Column: Poroshell HPH-C18, 3.0×50 mm, 2.7 μm; mobile phase A: Water/5 mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 1.0 mL/min; Gradient: 10% B to 95% B in 2.2 min, hold 1.0 min; wave length: 254 nm
(33) Method B:
(34) Shimadzu LCMS-2020; Column: Poroshell HPH-C18, 3.0×50 mm, 2.7 μm; mobile phase A: Water/5 mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 1.3 mL/min; Gradient: 10% B to 95% B in 2.1 min, hold 0.6 min; wave length: 254 nm
(35) Method C:
(36) Shimadzu LCMS-2020; Column: Shim-pack XR-ODS, 3.0×50 mm, 2.2 μm; mobile phase A: Water/0.05% TFA, mobile phase B: acetonitrile/0.05% TFA; flow rate: 1.2 mL/min; Gradient: 5% B to 100% B in 2.2 min, hold 1.0 min; wave length: 254 nm
(37) Method D:
(38) Agilent Technologies 1200 series; column: Chromolith Performance RP18e; 100×3 mm; mobile phase AA: 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
(39) Method E:
(40) Shimadzu LCMS-2020; Column: Shim-pack XR-ODS, 3.0×50 mm, 2.2 μm; mobile phase A: Water/0.05% TFA, mobile phase B: acetonitrile/0.05% TFA; flow rate: 1.2 mL/min; Gradient: 5% B to 100% B in 2.0 min, hold 0.5 min; wave length 254 nm
EXAMPLE 3: TESTING COMPOUNDS OF THE PRESENT INVENTION FOR INHIBITORY ACTIVITIES AGAINST HUMAN ADENOSINE RECEPTORS IN RECOMBINANT CELLS
(41) 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.
(42) 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:
(43) 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.
(44) Obtained raw data were normalized against the inhibitor control and the neural control (DMSO) and the normalized data were fitted using GeneData software.
(45) 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)
(46) 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.
(47) 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] 1 B D D D 2 B D D D 5 B D D D 10 B D C D 13 B D D D 14 B D D D 15 B D D 16 B D D D 17 B D D D 18 B D 20 A D D 21 B C C D 23 B D D D 27 B D C D 28 B D C D 29 B C D D 30 B D D 31 A C D D 32 B D D D 34 B C C D 36 A C C D 37 A D D D 38 B D D D 39 B D D D 40 B D D D 42 A C D D 43 B D D C 44 A C C D 45 A B B C 46 B C D C 47 A B B D 48 A B C D 50 A D D D 51 A D D 52 A C C D 56 A D D 60 B D D 62 B D C 64 B D D 68 A D D 78 A C D 86 A C D D 88 B D D C 102 A B C C 103 A D D 104 A 105 A B C C 106 A B C D 108 B D D 109 A D C 112 B D 114 B D C 115 B 116 B D C 117 B D D 118 B D D D 119 B D D 120 A B C C 121 B C C C 122 B D D 123 A B C C 124 A D C C 125 B C 126 A B C C 128 B D C 129 A B 130 A B D 131 A B C C 132 A B C 134 A B C D 135 A B B 136 A B C D 137 A D C 138 B B A D 139 B D D 140 A B C 141 B B C C 142 A D D 143 B D D 144 B D 145 B D 146 B D 147 A B C C 148 A B C D 149 B D C 151 B D C D 152 B D 156 B D C D 158 B D 159 B B C 160 B B D 161 B D 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
(48) 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.
(49) 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.
(50) 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.
(51) 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
(52) 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.
(53) Material and Methods:
(54) Animal Experiments (In-Life Phase)
(55) 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.
(56) Bioanalytics:
(57) 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 LCMS/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.
(58) Pharmacokinetic Evaluation:
(59) 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.
(60) 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.
(61) 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
(62) Background:
(63) 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.
(64) Assay Description:
(65) 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 Δ) 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.
(66) 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 cytokine 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.
(67) TABLE-US-00008 TABLE 7 Mouse T-Cell Mouse IL-2 IFN-γ No. Name Structure [nM] [nM] Tozadenant
EXAMPLE 7: INJECTION VIALS
(68) 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
(69) 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
(70) 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.