Substituted Azoanthracene Derivatives, Pharmaceutical Compositions, and Methods of Use Thereof

A method to lower blood glucose in a human, to increase glucose-dependent insulin secretion by a human pancreatic beta-cell, to suppress glucagon secretion in a human, or to slow gastric emptying in a human comprising administering to a human a compound selected from the group consisting of:

• (S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-(4-pyridin-4-yl-phenyl)-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(3-Chloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(4-Chloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-(4-Cyclopentylmethoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(3,3-Dimethyl-butoxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-3-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-2-{[(3S,8S)-3-(4-isobutoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(Bicyclo[2.2.1]hept-2-yloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2-methyl-pyridin-4-yloxy)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(6,7-dihydro-5H-[1]pyrindin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,5-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2-methyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2-ethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2-fluoromethyl-pyridin-4-yl)-phenyl]propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(3,4-Dimethyl-benzyloxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-thiazol-2-ylmethyl-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((R)-1-phenyl-ethylcarbamoyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-(1-methyl-cyclobutylcarbamoyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-(1,1-dimethyl-propylcarbamoyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(2,5-Dichloro-benzyloxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-{4-[2-(4-Chloro-phenyl)-ethoxy]-phenyl}-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(4-Chloro-cyclohexyloxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(5-Chloro-pyridin-3-ylmethoxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-({(3S,8S)-7-(2,5-Dimethyl-oxazole-4-carbonyl)-3-[4-(trans-4-methyl-cyclohexyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(3,5-Dichloro-benzyloxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-{4-[2-(3,4-Dichloro-phenyl)-ethoxy]-phenyl}-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• (S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-(2-methyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• and
• (S)-2-{[(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-(2,4-dimethyl-oxazole-5-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid;
• or
• a pharmaceutically acceptable salt thereof.

A method of treating a condition selected from the group consisting of metabolic syndrome, glucose intolerance, hyperglycaemia, dyslipidemia, diabetes mellitus type 1, diabetes mellitus type 2, hypertriglyceridemia, syndrome X, insulin resistance, impaired glucose tolerance (IGT), obesity, an eating disorder, diabetic dyslipidemia, hyperlipidemia, arteriosclerosis, atherosclerosis, hypertension, metabolic disorders where activation of the GLP-1 receptor is beneficial, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, and impaired wound healing, comprising administering to a human a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

• wherein
• W and Z are an oxygen atom;
• X is —CH2—;
• Y is —CH(R5)—;
• wherein
• R5 is -G3-L2-Q2-L3-G4, wherein
• G3 is 1,4-phenylene optionally substituted 1 to 4 times with substituents independently selected from halogen, methyl, ethyl, isopropyl, —CF3, —CH2CF3, —CN, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCF3, —OCH2CF3, —S(O)2—CH3, —NH—CH3, —NH—CH2CH3, —N(CH3)2, —N(CH3)(CH2CH3), —N(CH2CH3)2, and —C(O)—CH3;
• L2 is —O—;
• L3 is a direct bond;
• Q2 is —CH2—,
• G4 is phenyl optionally substituted 1 to 4 times with substituents independently selected from halogen, methyl, ethyl, isopropyl, —CF3, —CH2CF3, —CN, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCF3, —OCH2CF3, —S(O)2—CH3, —NH—CH3, —NH—CH2CH3, —N(CH3)2, —N(CH3)(CH2CH3), —N(CH2CH3)2, and —C(O)—CH3;
• R1 is —CO2H;
• R2 is hydrogen;
• R3 is selected from the group consisting of:
• a) —CO2-tert-butyl,
• b) —CO2-n-hexyl,
• c) —CO2-isopropyl,
• d) —CO2-(tert-butylcyclohexyl)
• e) —CO2-tetrahydrofuran-2-yl,
• f) —CO2-tetrahydropyran-4-yl,
• g) —CO2—CH2-cyclopropyl,
• h) —C(O)NH-(tert-butylphenyl),
• i) —C(O)-piperidin-2-yl,
• j) —C(O)—NH-(trifluoromethoxyphenyl),
• k) —C(O)—NH-(1,1-diphenylmethyl),
• l) —C(O)-isopropyl,
• m) —C(O)-phenyl,
• n) —C(O)-(fluorophenyl),
• o) —C(O)-(chlorophenyl),
• p) —C(O)-(cyanophenyl),
• q) —C(O)-pyridin-2-yl,
• r) —C(O)-pyrimidin-4-yl,
• s) —C(O)-furan-2-yl,
• t) —C(O)-cyclobutyl,
• u) —C(O)-cyclopentyl,
• v) —C(O)-cyclohexyl,
• w) —C(O)-thiophene-2-yl,
• x) —C(O)-benzyl,
• y) —C(O)-(fluorobenzyl),
• z) —C(O)-(chlorobenzyl),
• aa) —C(O)-(cyanobenzyl),
• bb) —C(O)-(2,5-dimethyl-oxazol-4-yl),
• cc) —CH2-oxazol-2-yl,
• dd) —CH2-(1-methylimdiazol-2-yl),
• ee) —CH2-pyridin-2-yl,
• ff) —CH2-furan-2-yl,
• gg) —CH2-thiazol-2-yl,
• hh) —CH2—C≡C-pyrimidin-2-yl,
• ii) —CH2—C≡C-phenyl,
• jj) —CH2-thiophene-2-yl,
• kk) —(R)-1-(phenyl)-propyl, and
• ll) —(S)-1-(phenyl)-propyl;
• R is —(CH2)p-G1-L1-G2;
• wherein
• p is 1;
• L1 is a direct bond or —O—;
• G′ is 1,4-phenylene;
• and
• G2 is 2,3-dimethyl-pyridine-4-yl;
• and
• Rq is hydrogen.

A method to lower blood glucose in a human, to increase glucose-dependent insulin secretion by a human pancreatic beta-cell, to suppress glucagon secretion in a human, or to slow gastric emptying in a human comprising administering to a human a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

• wherein
• W and Z are an oxygen atom;
• X is —CH2—;
• Y is —CH(R5)—;
• wherein
• R5 is -G3-L2-Q2-L3-G4, wherein
• G3 is 1,4-phenylene optionally substituted 1 to 4 times with substituents independently selected from halogen, methyl, ethyl, isopropyl, —CF3, —CH2CF3, —CN, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCF3, —OCH2CF3, —S(O)2—CH3, —NH—CH3, —NH—CH2CH3, —N(CH3)2, —N(CH3)(CH2CH3), —N(CH2CH3)2, and —C(O)—CH3;
• L2 is —O—;
• L3 is a direct bond;
• Q2 is —CH2—,
• G4 is phenyl optionally substituted 1 to 4 times with substituents independently selected from halogen, methyl, ethyl, isopropyl, —CF3, —CH2CF3, —CN, —OCH3, —OCH2CH3, —OCH(CH3)2, —OCF3, —OCH2CF3, —S(O)2—CH3, —NH—CH3, —NH—CH2CH3, —N(CH3)2, —N(CH3)(CH2CH3), —N(CH2CH3)2, and —C(O)—CH3;
• R1 is —CO2H;
• R2 is hydrogen;
• R3 is selected from the group consisting of:
• a) —CO2-tert-butyl,
• b) —CO2-n-hexyl,
• c) —CO2-isopropyl,
• d) —CO2-(tert-butylcyclohexyl)
• e) —CO2-tetrahydrofuran-2-yl,
• f) —CO2-tetrahydropyran-4-yl,
• g) —CO2—CH2-cyclopropyl,
• h) —C(O)NH-(tert-butylphenyl),
• i) —C(O)-piperidin-2-yl,
• j) —C(O)—NH-(trifluoromethoxyphenyl),
• k) —C(O)—NH-(1,1-diphenylmethyl),
• l) —C(O)-isopropyl,
• m) —C(O)-phenyl,
• n) —C(O)-(fluorophenyl),
• o) —C(O)-(chlorophenyl),
• p) —C(O)-(cyanophenyl),
• q) —C(O)-pyridin-2-yl,
• r) —C(O)-pyrimidin-4-yl,
• s) —C(O)-furan-2-yl,
• t) —C(O)-cyclobutyl,
• u) —C(O)-cyclopentyl,
• v) —C(O)-cyclohexyl,
• w) —C(O)-thiophene-2-yl,
• x) —C(O)-benzyl,
• y) —C(O)-(fluorobenzyl),
• z) —C(O)-(chlorobenzyl),
• aa) —C(O)-(cyanobenzyl),
• bb) —C(O)-(2,5-dimethyl-oxazol-4-yl),
• cc) —CH2-oxazol-2-yl,
• dd) —CH2-(1-methylimdiazol-2-yl),
• ee) —CH2-pyridin-2-yl,
• ff) —CH2-furan-2-yl,
• gg) —CH2-thiazol-2-yl,
• hh) —CH2—C≡C-pyrimidin-2-yl,
• ii) —CH2—C≡C-phenyl,
• jj) —CH2-thiophene-2-yl,
• kk) —(R)-1-(phenyl)-propyl, and
• ll) —(S)-1-(phenyl)-propyl;
• R is —(CH2)p-G1-L1-G2;
• wherein
• p is 1;
• L1 is a direct bond or —O—;
• G1 is 1,4-phenylene;
• and
• G2 is 2,3-dimethyl-pyridine-4-yl;
• and
• Rq is hydrogen.