ETHER LINKED TRIAZOLES AS NRF2 ACTIVATORS

Abstract

The present invention relates to ether-linked triazole compounds, methods of making them, pharmaceutical compositions containing them and their use as NRF2 activators. In particular, the invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof:

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Claims

1. A compound selected from: (3R)-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((S)-4-methyl-1,1-dioxido-4,5-dihydropyrido[4,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)propanoic acid; (3R)-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((S)-4-methyl-1,1-dioxido-4,5-dihydropyrido[2,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)propanoic acid; (3S)-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-4,5-dihydropyrido[4,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)propanoic acid; (3S)-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-4,5-dihydropyrido[2,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)propanoic acid; (3S)-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)propanoic acid; (3R)-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-4,5-dihydropyrido[4,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)propanoic acid; R)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-4,5-dihydropyrido[4,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid; (3R)-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-4,5-dihydropyrido[2,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)propanoic acid; (3S)-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-ethyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)propanoic acid; (3R)-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)propanoic acid; (3S)-((1-(2-(2-methoxyethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic acid; (3S)-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((S)-4-methyl-1,1-dioxido-4,5-dihydropyrido[2,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)propanoic acid; (3S)-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-4,5-dihydropyrido[4,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)propanoic acid; 3-(3-(((3-Bromo-N-(pyridin-2-ylmethyl)phenyl)sulfonamido)methyl)-4-methylphenyl)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoic acid; 3S)-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((S)-4-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)propanoic acid; (3R)-(3-(((R)-8-fluoro-4-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid; (3R)-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-ethyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)propanoic acid GSK3802836A (R)-3-(3-((4,4-dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid; (R)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-8-(trifluoromethyl)-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid; (R)-3-((1-(2-(2-methoxyethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic acid; (3S)-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((S)-4-ethyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)propanoic acid; (R)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoic acid; (R)-2,2-dimethyl-3-(4-methyl-3-(((S)-4-methyl-1,1-dioxido-4,5-dihydropyrido[4,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid; (3R)-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((S)-4-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)propanoic acid; (3R)-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((S)-4-ethyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)propanoic acid; (R)-2,2-dimethyl-3-(4-methyl-3-(((S)-4-methyl-1,1-dioxido-8-(trifluoromethyl)-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid; (R)-3-(3-(((S)-8-fluoro-4-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid; (R)-2,2-dimethyl-3-(4-methyl-3-(((S)-4-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid; (R)-2,2-dimethyl-3-(4-methyl-3-(((S)-4-methyl-1,1-dioxido-4,5-dihydropyrido[2,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid; (R)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid; (R)-3-((N-(5-(2-carboxy-1-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2-methylpropyl)-2-methylbenzyl)phenylsulfonamido)methyl)benzoic acid; (R)-3-(N-(5-(2-carboxy-2-methyl-1-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propyl)-2-methylbenzyl)-N-(3-carboxybenzyl)sulfamoyl)benzoic acid; (R)-3-(N-(5-(2-carboxy-1-((1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-methylpropyl)-2-methylbenzyl)-N-(pyridin-2-ylmethyl)sulfamoyl)benzoic acid; (R)-3-(N-benzyl-N-(5-(2-carboxy-1-((1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-methylpropyl)-2-methylbenzyl)sulfamoyl)benzoic acid; 3-(N-benzyl-N-(5-(2-carboxy-1-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2-methylpropyl)-2-methylbenzyl)sulfamoyl)benzoic acid; 3-(3-(((N-cyclohexyl-3-methoxyphenyl)sulfonamido)methyl)-4-methylphenyl)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoic acid; 3-(3-(((N-cyclohexyl-4-methoxyphenyl)sulfonamido)methyl)-4-methylphenyl)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoic acid; 3-(3-((N-cyclohexylphenylsulfonamido)methyl)-4-methylphenyl)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoic acid; 3-(3-((N-benzylphenylsulfonamido)methyl)-4-methylphenyl)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoic acid; 3-((1-((1-Carbamoylpiperidin-4-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic acid; 3-((1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic acid; Rel-(R)-2,2-dimethyl-3-(4-methyl-3-(((S)-4-methyl-1,1-dioxido-4,5-dihydropyrido[4,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-3-((1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid; Rel-(S)-2,2-dimethyl-3-(4-methyl-3-(((S)-4-methyl-1,1-dioxido-4,5-dihydropyrido[4,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-3-((1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid; 2,2-Dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-((1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid; 3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid; 3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-((1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoic acid; 3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-((1-(2-(2-methoxyethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoic acid; (R)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid hydrochloride; (R)-3-(3-(((R)-2-isopropyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid hydrochloride; (R)-3-(3-(((R)-2-Ethyl-7-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid trifluoroacetate; (S)-methyl 3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid, trifluoroacetate; (S)-3-(3-(((R)-2-isopropyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid, trifluoroacetate; (R)-3-((1-Ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid, trifluoroacetate; (S)-methyl 3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid, trifluoroacetate; (R)-methyl 3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(((S)-6-ethyl-6,7-dihydro-5H-pyrido[2,3-c]azepin-8(9H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid, trifluoroacetate; (S)-methyl 3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(((S)-6-ethyl-6,7-dihydro-5H-pyrido[2,3-c]azepin-8(9H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid, trifluoroacetate; (R)-methyl 3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid, trifluoroacetate; (S)-methyl 3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(((R)-2-ethyl-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid, trifluoroacetate; (R)-3-(3-(((S)-4-Ethyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid; (R)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid; (R)-3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid; or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

3. A method of treating respiratory and non-respiratory disorders, including COPD, asthma, ALI, ARDS, fibrosis, chronic asthma and acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, α1 antitrypsin disease, cystic fibrosis, autoimmune diseases, diabetic nephropathy, chronic kidney disease, sepsis-induced acute kidney injury, acute kidney injury (AKI), kidney disease or malfunction seen during kidney transplantation, Pulmonary Arterial Hypertension, atherosclerosis, hypertension, heart failure, acute coronary syndrome, myocardial infarction, myocardial repair, cardiac remodelling, cardiac arrhythmias, Parkinson's disease (PD), Alzheimer's disease (AD), Friedreich's Ataxia (FA), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), inflammatory bowel disease, colon cancer, neovascular (dry) AMD and neovascular (wet) AMD, eye injury, Fuchs Endothelial Corneal Dystrophy (FECD), uveitis or other inflammatory eye conditions, Non-alcoholic Steatohepatitis (NASH), toxin-induced liver disease (e.g., acetaminophen-induced hepatic disease), viral hepatitis, cirrhosis, psoriasis, dermatitis/topical effects of radiation, immunosuppression due to radiation exposure, Preeclampsia, and high altitude sickness, which comprises administering to a human in need thereof, a compound according to claim 1.

4. The method according to claim 3 wherein the compound is administered orally.

5. The method according to claim 3 wherein the compound is administered intravenously.

6. The method according to claim 3 wherein the compound is administered by inhalation.

7. The method according to claim 3 wherein the disease is COPD.

8. The method according to claim 3 wherein the disease is heart failure.

9. A compound which is: (R,rel-(3S,3'S))-3,3′-(((1,1′-(1,4-phenylenebis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(methylene))bis(oxy))bis(2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic acid); (R)-3,3′-(((1,1′-(1,3-phenylenebis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(methylene))bis(oxy))bis(3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid); (R)-3,3′-(((1,1′-(1,4-phenylenebis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(methylene))bis(oxy))bis(2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic acid); (R,rel-(3R,3′R))-3,3′-(((1,1′-(1,4-phenylenebis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(methylene))bis(oxy))bis(2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic acid); (R,rel-3S,rel-3'S)-3,3′-(((1,1′-(oxybis(ethane-2,1-diyl))bis(1H-1,2,3-triazole-4,1-diyl))bis(methylene))bis(oxy))bis(2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic acid); (R,rel-3R,rel-3′R)-3,3′-(((1,1′-(oxybis(ethane-2,1-diyl))bis(1H-1,2,3-triazole-4,1-diyl))bis(methylene))bis(oxy))bis(2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic acid).

10. A method of treating COPD which comprises administering to a human in need thereof, a compound which is (R)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy) propanoic acid, or a pharmaceutically acceptable salt thereof.

11. A method of treating heart failure which comprises administering to a human in need thereof, a compound which is (R)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid, or a pharmaceutically acceptable salt thereof.

12. A method of treating COPD which comprises administering to a human in need thereof, a compound which is (R)-3-((1-Ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid, or a pharmaceutically acceptable salt thereof.

13. A method of treating heart failure which comprises administering to a human in need thereof, a compound which is (R)-3-((1-Ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid, or a pharmaceutically acceptable salt thereof.

Description

EXAMPLES

[0311] The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.

[0312] All temperatures are given in degrees Celsius, all solvents are highest available purity and all reactions run under anhydrous conditions in an argon (Ar) or nitrogen (N.sub.2) atmosphere where necessary.

[0313] Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Both flash and gravity chromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel. The CombiFlash® system used for purification in this application was purchased from Isco, Inc. CombiFlash® purification was carried out using prepacked silica gel columns, a detector with UV wavelength at 254 nm and a variety of solvents or solvent combinations.

[0314] Preparative HPLC was performed using a Gilson Preparative System with variable wavelength UV detection or an Agilent Mass Directed AutoPrep (MDAP) system with both mass and variable wavelength UV detection or Waters Preparative System with UV/PDA detection or an Shimadzu PREP LC 20AP. A variety of reverse phase columns, e.g., Luna 5 m C18(2) 100 A, SunFire C18, XBridge C18, Atlantics T3 were used in the purification with the choice of column support dependent upon the conditions used in the purification. The compounds are eluted using a gradient of CH.sub.3CN and water. Neutral conditions used an CH.sub.3CN and water gradient with no additional modifier, acidic conditions used an acid modifier, 0.1% TFA (added to both the CH.sub.3CN and water) or 0.1% formic acid and basic conditions used a basic modifier, 0.1% NH.sub.4OH (added to the water) or 10 mM ammonium bicarbonate.

[0315] Analytical HPLC was run using an Agilent system, Shimadzu/Sciex LCMS with variable wavelength UV detection using reverse phase chromatography with a CH.sub.3CN and water gradient with a 0.02 or 0.1% TFA modifier (added to each solvent). LC-MS was determined using either a PE Sciex Single Quadrupole 150EX LC-MS, or Waters ZQ Single Quadrupole LC-MS or Agilent 1200 series SL (detectors: Agilent 6140 single quadrupole and Agilent 1200 MWD SL) instruments. The compound is analyzed using a reverse phase column, e.g., Thermo Hypersil Gold C18, eluted using a gradient of CH.sub.3CN and water with a low percentage of an acid modifier such as 0.02% TFA or 0.1% formic acid or a base modifier such as 5 mM ammonium bicarbonate (adjusted to pH 10 with aqueous ammonia). When specified “acid method” refers to 0.1% formic acid in water and CH.sub.3CN gradient (1.8 min. 0.9 mL/min flow) with a Waters Acquity UPLC HSS C18; 1.8; 2.1×50 mm at 50° C.; “basic method” refers to 95:5 H.sub.2O+0.1% NH.sub.4OH:CH.sub.3CN (pH=9.4) and water gradient (1.8 min. 0.9 mL/min flow) with a Waters Acquity UPLC BEH C18; 1.7; 2.1×50 mm at 50° C. and “overnight basic method” refers to 95:5 H.sub.2O+0.1% NH.sub.4OH:CH.sub.3CN (pH=9.4) and water gradient (16 min. 0.8 mL/min flow) with a Waters Acquity UPLC BEH C18; 1.7; 2.1×50 mm at 50° C.

[0316] Preparative Chiral SFC was performed using a Thar/Waters Preparative SFC System with single wavelength UV detection system or PDA detector. A variety of chiral SFC columns, e.g. Chiralpak IA, IC, AY, AD. OD, OJ, C2 were used in the purification. The compounds are eluted using supercritical fluid CO.sub.2 and co-solvents, such as MeOH, EtOH, IPA, and combination of these solvent in different ratio based on the compound selectivity. Modifiers (0.1% of TFA, NH.sub.4OH, DEA) would be used as needed.

[0317] Analytical Chiral SFC was run using a Thar/Waters SFC system with variable wavelength UV detection or PDA detector. A variety of chiral SFC columns, e.g. Chiralpak IA, IB, IC, ID, AY, AD, AS, CCL4 were used in the purification. The compounds are eluted using supercritical fluid CO.sub.2 and co-solvents, such as MeOH, EtOH, IPA, and combination of these solvent in different ratio based on the compound selectivity. Modifiers (0.1% of TFA, NH.sub.4OH, DEA) would be used as needed.

[0318] Celite® is a filter aid composed of acid-washed diatomaceous silica, and is a registered trademark of Manville Corp., Denver, Colo. Isolute® is a functionalized silica gel based sorbent, and is a registered trademark of Biotage AB Corp., Sweden.

[0319] Nuclear magnetic resonance spectra were recorded at 400 MHz using a Bruker AVANCE 400 or Brucker DPX400 or Varian MR400 400 MHz spectrometer. CDCl.sub.3 is deuteriochloroform, DMSO-D.sub.6 is hexadeuteriodimethylsulfoxide, and MeOD is tetradeuteriomethanol, CD.sub.2Cl.sub.2 is deuteriodichloromethane. Chemical shifts are reported in parts per million (δ) downfield from the internal standard tetramethylsilane (TMS) or calibrated to the residual proton signal in the NMR solvent (e.g., CHCl.sub.3 in CDCl.sub.3). Abbreviations for NMR data are as follows: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doublet of triplets, app=apparent, br=broad. J indicates the NMR coupling constant measured in Hertz.

[0320] Heating of reaction mixtures with microwave irradiations was carried out on a Biotage Initiator® or OEM microwave reactor, typically employing the high absorbance setting.

[0321] Cartridges or columns containing polymer based functional groups (acid, base, metal chelators, etc) can be used as part of compound workup. The “amine” columns or cartridges are used to neutralize or basify acidic reaction mixtures or products. These include NH.sub.2 Aminopropyl SPE-ed SPE Cartridges available from Applied Separations and diethylamino SPE cartridges available from United Chemical Technologies, Inc.

TABLE-US-00003 Table of Abbreviations [Rh(cod)Cl].sub.2 or [RhCl(cod)].sub.2: di-μ-chorido-bis[η.sup.2,η.sup.2-(cycloocta-1,5-diene)rhodium ® T3P: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide □ C.: degree Celsius AcOH: acetic acid ADDP: (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) aq= aqueous BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene CDI: Carbonyl dimidazole CH.sub.2Cl.sub.2: dichloromethane CH.sub.3CN: acetonitrile CHCl.sub.3: chloroform Cs.sub.2CO.sub.3: cesium carbonate DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCE: dichloroethane DCM: dichloromethane DIPEA or DIEA: diisopropylethyl amine DME: dimethyl ether DMF: N,N-dimethylformamide DMF-DMA or DMF- N,N-dimethylformaide-dimethyl acetal dimethyl acetal: DMSO: dimethyl sulfoxide EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et.sub.2O: diethyl ether Et.sub.3N: triethylamine EtOAc: ethyl acetate EtOH: ethanol g: gram(s) h: hour(s) HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate HBTU: N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate HCl: hydrochloric acid HOAt: 1-hydroxy-7-azabenzotriazole HPLC: high performance liquid chromatography IPA: isopropyl alcohol K.sub.2CO.sub.3: potassium carbonate KOAc: potassium acetate LAH: lithium aluminum hydride LC: liquid chromatography LC-MS: liquid chromatography-mass spectroscopy LiBH.sub.4: lithium borohydride LiHMDS: lithium hexamethyldisilazane LiOH: lithium hydroxide M: molar MeCN: acetonitrile Mel: methyl iodide MeOH: methanol mg: milligram(s) MgCl.sub.2: magnesium chloride MgSO.sub.4: magnesium sulfate MHz: megahertz min: minute(s) mL: milliliter(s) mmol: millimole(s) MS: mass spectroscopy N.sub.2: nitrogen gas Na.sub.2CO.sub.3: sodium carbonate Na.sub.2SO.sub.4: sodium sulfate NaBH.sub.3CN or NaCNBH.sub.3: sodium cyanoborohydride NaCl: sodium chloride NaH: sodium hydride NaHCO.sub.3: sodium bicarbonate NaHMDS: sodium hexamethyldisilazane NaHSO.sub.4: sodium bisulfate NaOAc: sodium acetate NaOH: sodium hydroxide NBS: N-bromosuccinimide nBuLi: n-butyl lithium NH.sub.4Cl: ammonium chloride NMR: nuclear magnetic resonance P(tBu).sub.3: tri-t-butyl phosphine Pd(PhP.sub.3).sub.4: tetrakistriphenylphosphine palladium Pd/C: pallidium on carbon Pd.sub.2(dba).sub.3: tris(dibenzylideneacetone)-dipalladium(0) PdCl.sub.2(dppf) or Pd(dppf)Cl.sub.2: [1,1′-bis(diphenylphosphino)-ferrocene] dichloropalladium(II) Petrol: petroleum ether PS-PPh.sub.3: polymer supported triphenylphosphine PtO.sub.2: platinum(IV) oxide RT: room temperature T3P: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane- 2,4,6-trioxide solution TEA: triethylamine TFA: trifluoroacetic acid TFFH: tetrafluoroformamidinium hexafluorophosphate THF: tetrahydrofuran triflic anhydride: trifluoromethanesulfonic anhydride TsOH: p-toluenesulfonic acid wt %: weight percent

Intermediates

Intermediate 1: 2-Fluoro-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide

[0322] ##STR00038##

[0323] To a solution of 2-fluorobenzene-1-sulfonyl chloride (15 g, 77 mmol) in tetrahydrofuran (THF) (300 mL) at 0° C. was added potassium carbonate (13.85 g, 100 mmol), water (110 mL) and 1-amino-2-methylpropan-2-ol (6.87 g, 77 mmol) and was stirred for 4 h at 25° C. The reaction mixture was quenched with ice cold water (200 mL) and extracted with ethyl acetate (2×200 mL), washed with brine (100 mL) then concentrated to provide the title compound as a white solid. (17 g, 67.9 mmol, 88% yield). LCMS m/z 248.2 (M+H).sup.+, 1.678 min (ret.time).

Intermediate 2:4,4-Dimethyl-3,4-dihydro-2Hbenzo[b][1,4,5]oxathiazepine 1,1-dioxide

[0324] ##STR00039##

[0325] To a solution of 2-fluoro-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide (10 g, 40.4 mmol) in dimethyl sulfoxide (DMSO) (100 mL) was added potassium tert-butoxide (13.61 g, 121 mmol) at 10° C. then heated to 90° C. for 4 hr in a sealed tube. The reaction mixture was cooled to ambient temperature and poured into ice water (100 mL), then extracted with ethyl acetate (2×200 mL) and concentrated to give the crude compound. The crude residue was purified by flash column chromatography using EtOAc:Hexane (4:6) as solvent, to provide the title compound. (5 g, 21.92 mmol, 54.2% yield). LCMS m/z 228 (M+H).sup.+, 1.73 min (ret.time).

Intermediate 3: 2-Chloropyridine-3-sulfonyl Chloride

[0326] ##STR00040##

[0327] Step A: Thionyl chloride (159 mL, 2178 mmol) was added drop wise over 60 min to water (450 mL) at 0° C. The solution was allowed to stirred at ambient temperature for 17 h then copper(I) chloride (0.554 g, 5.60 mmol) was added to the mixture at −3° C. and the resulting yellow green solution was stirred for 1 hour at −3° C.

[0328] Step B: 37% HCl (503 mL, 6129 mmol) was added with vigorous stirring to 2-chloropyridin-3-amine (40 g, 311 mmol) at −5° C. and a solution of sodium nitrite (37.8 g, 548 mmol) in water (82 mL) was added drop wise over 45 min, the temperature of the reaction mixture was maintained at −5° C. and stirred for 10 min.

[0329] Step C: The mixture obtained from step B was added to the solution obtained from step A over 30 min at −3° C. The reaction mixture was maintained at 0° C. for 75 min with vigorous stirring. The solid was filtered and dried to give the title compound (20 g, 92 mmol, 29.5% yield) as brown color solid. LCMS m/z 212.02 (M+H).sup.+, 2.058 min (ret. time)

Intermediate 4: 2-Chloro-N-(2-methylallyl)pyridine-3-sulfonamide

[0330] ##STR00041##

[0331] To a solution of 2-chloropyridine-3-sulfonyl chloride (20 g, 94 mmol) in dichloromethane (DCM) (200 mL) was added 2-methylprop-2-en-1-amine (7.38 g, 104 mmol) and TEA (26.3 mL, 189 mmol). It was stirred for 1 h at ambient temperature. The reaction mixture was quenched with water (100 mL) and extracted with DCM (3×80 mL). The combined organic layer was washed with brine solution (80 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The crude residue was purified by column chromatography eluting with 25% ethyl acetate in n-hexane. Desired fractions were concentrated to give the title compound (16 g, 63.5 mmol, 67.4% yield). LCMS m/z 246.97 (M+H).sup.+, 1.800 min (ret. time)

Intermediate 5: 4-Methyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2]thiazepine 1,1-dioxide

[0332] ##STR00042##

[0333] To a solution of 2-chloro-N-(2-methylallyl)pyridine-3-sulfonamide (15 g, 60.8 mmol) in toluene (150 mL) was added AIBN (1.997 g, 12.16 mmol) and heated to 75° C. then tri-n-butyltin hydride (48.7 mL, 182 mmol) was added and the reaction mixture was heated to 110° C. for 20 h. The reaction mixture was concentrated. The residue was diluted with ethyl acetate (200 mL), water was added and extracted. The organic layer was washed with brine solution (80 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The crude residue was purified by column chromatography eluting with 25% ethyl acetate in n-hexane. Desired fractions were concentrated to give the title compound (4.27 g, 19.80 mmol, 32.6% yield) LCMS m/z 213.07 (M+H).sup.+, 1.372 min (ret. time)

Intermediate 6: (S)-4-Methyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2]thiazepine 1,1-dioxide and

Intermediate 7: (R)-4-methyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2]thiazepine 1,1-dioxide

[0334] ##STR00043##

[0335] 4-methyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2]thiazepine 1,1-dioxide (4.27 g, 20.12 mmol) was resolved by Chiral SFC (Column: Chiralpak IC 20×150 mm, 5u; co-solvent: 20% IPA; flowrate: 50 g/min; Back pressure: 100 Bar) to give (S)-4-methyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2]thiazepine 1,1-dioxide (1.96 g, 9.23 mmol, 45.9% yield) LC-MS m/z 213.0 (M+H).sup.+, 0.43 min (ret. time) (chiral SFC ret. time: 2.95 min) and (R)-4-methyl-2,3,4,5-tetrahydropyrido[2,3-f][1,2]thiazepine 1,1-dioxide (1.96 g, 9.23 mmol, 45.9% yield) LC-MS m/z 213.0 (M+H).sup.+, 0.44 min (ret. time) (chiral SFC ret. time: 4.09 min)

Intermediate 8: 2-Bromo-N-(2-methylallyl)benzenesulfonamide

[0336] ##STR00044##

[0337] To a solution of 2-bromobenzene-1-sulfonyl chloride (25 g, 98 mmol) in dichloromethane (DCM) (250 mL) at 0° C. was added TEA (13.64 mL, 98 mmol) and 2-methylprop-2-en-1-amine (6.96 g, 98 mmol) and stirred for 10 min. The reaction was then stirred at ambient temperature for 16 h. The reaction mixture was quenched with ice cold water and extracted with DCM (2×200 mL). The combined organic layer was washed with ice cold water (2×100 mL), washed with brine solution (100 mL), and dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (20 g, 68.3 mmol, 69.8% yield). LC-MS m/z 289.81 (M+H).sup.+, 2.20 min (ret. time).

Intermediate 9: 4-Methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide

[0338] ##STR00045##

[0339] To a solution of 2-bromo-N-(2-methylallyl)benzenesulfonamide (16 g, 55.1 mmol) in toluene (160 mL) at ambient temperature was added AIBN (1.811 g, 11.03 mmol). The reaction mixture was heated to 75° C. and tri-n-butyltin hydride (29.4 mL, 110 mmol) was added. It was heated at 110° C. for 18 h. The reaction mixture was cooled to ambient temperature and diluted with ice water (500 mL) and extracted with EtOAc (2×300 mL). The combined organic layer was washed with chilled brine solution (200 mL) and dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The crude residue was purified by flash column chromatography eluting with 15% ethyl acetate in hexane. Desired fractions were concentrated to give the title compound (8.51 g, 39.9 mmol, 72.3% yield) as a white solid. LC-MS m/z 211.11 (M+H).sup.+, 1.826 min (ret. time).

Intermediate 10: (S)-4-Methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide and

Intermediate 11: (R)-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide

[0340] ##STR00046##

[0341] 4-Methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (4000 mg, 18.93 mmol) was resolved by Chiral SFC (Column: Chiralpak AY 20×250 mm, 5u; co-solvent: 20% EtOH; Flow rate: 50 mg/min; Back pressure: 100 Bar) to give (S)-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (2.2996 g, 10.88 mmol, 57.5% yield) (chiral SFC ret. time: 1.85 min) LC-MS m/z 211.9 (M+H).sup.+, 0.72 min (ret. time) and (R)-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (2.2195 g, 10.50 mmol, 55.5% yield) (chiral SFC ret. time: 2.5 min) LC-MS m/z 211.9 (M+H).sup.+, 0.72 min (ret. time).

Intermediate 12: 2-Bromo-5-fluoro-N-(2-methylallyl)benzenesulfonamide

[0342] ##STR00047##

[0343] To a solution of 2,5-dibromobenzene-1-sulfonyl chloride (25 g, 74.8 mmol) in dichloromethane (250 mL) 2-methylprop-2-en-1-amine (5.32 g, 74.8 mmol) and TEA (10.42 mL, 74.8 mmol) was added at 0° C. and stirred for 10 min. The reaction was then stirred at ambient temperature for 16 h. The reaction mixture was quenched with ice cold water (50 mL) and extracted with DCM (2×100 mL). The combined organic layers were washed with ice cold water (2×50 mL), washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the title compound (20 g, 44.3 mmol, 59.3% yield), LCMS m/z 308 (M+H).sup.+, 2.23 min (ret. time).

Intermediate 13: 8-Fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide

[0344] ##STR00048##

[0345] To a solution of 2-bromo-5-fluoro-N-(2-methylallyl)benzenesulfonamide (6.5 g, 20.04 mmol) in toluene (50 mL) was added AIBN (0.617 g, 3.75 mmol) at ambient temperature. The reaction mixture was heated to 75° C. and tri-n-butyltin hydride (7.52 mL, 28.2 mmol) was added and stirred at 110° C. for 18 h. The reaction mixture was quenched with ice cold water (40 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with ice cold water (2×50 mL), brine (50 mL) and dried over anhydrous Na.sub.2SO.sub.4. The solvent was concentrated and the residue was purified by flash chromatography eluting with 12% EtOAc/petroleum ether to provide the title compound. (1.5 g, 33% yield) LC/MS m/z=228 (M+H).sup.+, 1.97 min (ret time).

Intermediate 14: (S)-8-Fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide and

Intermediate 15: (R)-8-fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide N60122-20-A2

[0346] ##STR00049##

[0347] 8-fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (14 g, 59.8 mmol) was purified with chiral SFC (Column: Lux Amylose-2 (250×30) mm, 5p; Co-Solvent: 10% EtOH; Total flow rate: 100 g/min; Pressure: 100 Bar, 90% CO.sub.2) to give (S)-8-fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (5.7 g, 40% yield). LC-MS m/z 228 (M+H).sup.+, 2.42 min (ret. time), and (R)-8-fluoro-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (5.2 g, 36% yield). LCMS m/z 228 (M+H).sup.+, 2.42 min (ret. time).

Intermediate 16: (S)-4-methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide

[0348] ##STR00050##

[0349] (S)-4-Methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide of the invention was made using compounds described in WO 2017/060854 on page 137, published Apr. 13, 2017, and incorporated herein by reference.

Intermediate 17: (R)-4-methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide

[0350] ##STR00051##

[0351] Similar procedure to (S)-4-Methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide of the invention was made using compounds described in WO 2017/060854 on page 137, published Apr. 13, 2017, and incorporated herein by reference.

Intermediate 18: (S)-4-ethyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide

[0352] ##STR00052##

[0353] (S)-4-Ethyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide of the invention was made using compounds described in WO 2017/060854 on page 135, published Apr. 13, 2017, and incorporated herein by reference.

Intermediate 19: (R)-4-ethyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide

[0354] ##STR00053##

[0355] Similar procedure to (S)-4-Ethyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide of the invention was made using compounds described in WO 2017/060854 on page 135, published Apr. 13, 2017, and incorporated herein by reference.

Intermediate 20: 4-Chloropyridine-3-sulfonyl Chloride

[0356] ##STR00054##

[0357] To a suspension of 4-hydroxypyridine-3-sulfonic acid (25 g, 143 mmol) was added PCIs (104 g, 500 mmol) and POCl.sub.3 (26.6 ml, 285 mmol) at 0° C. and stirred at 120° C. for 1 h. The reaction mixture was cool to ambient temperature, the reaction mass was concentrated. The residue was diluted with EtOAc and poured in to ice. Solid NaHCO.sub.3 was added and the aqueous phase was extracted with EtOAc. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and filtered to afford the title compound (25 g, 98 mmol, 68.6% yield). LCMS m/z 212 (M+H).sup.+, 1.93 min (ret. time).

Intermediate 21: 4-Chloro-N-(2-methylallyl)pyridine-3-sulfonamide N53574-21-A1

[0358] ##STR00055##

[0359] To a solution of 4-chloropyridine-3-sulfonyl chloride (25 g, 98 mmol) in dichloromethane (DCM) (200 mL) at 0° C. was added 2-methylprop-2-en-1-amine (7.66 g, 108 mmol) and TEA (27.3 mL, 196 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with cold water, extracted with DCM (2×). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was evaporated under reduced pressure to afford the title compound which was used without further purification for the next step. (21 g, 85 mmol, 87% yield). LCMS m/z 246 (M+H).sup.+, 2.11 min (ret. time).

Intermediate 22: 4-Methyl-2,3,4,5-tetrahydropyrido[4,3-f][1,2]thiazepine 1,1-dioxide N53574-28-A1

[0360] ##STR00056##

[0361] To a solution of 4-chloro-N-(2-methylallyl)pyridine-3-sulfonamide (10 g, 35.7 mmol) in benzene (90 mL) was added AIBN (1.757 g, 10.70 mmol) and heated at 70° C. Tributylstannane (11.42 g, 39.2 mmol) was added at this temperature. The reaction was stirred at 85° C. for 16 h. The reaction mixture was concentrated to get the crude compound of 4-methyl-2,3,4,5-tetrahydropyrido[4,3-f][1,2]thiazepine 1,1-dioxide (10 g, 3.77 mmol, 10.57% yield). LCMS m/z 213 (M+H).sup.+, 1.77 min (ret. time). This batch of compound was combined with other batches prepared by the same method and purified by column chromatography by using EtOAc:Petroleum ether (1:1) to afford the title compound (2.7 g), LCMS m/z 213 (M+H).sup.+, 1.79 min (ret. time).

Intermediate 23: (R)-4-Methyl-2,3,4,5-tetrahydropyrido[4,3-f][1,2]thiazepine 1,1-dioxide and

Intermediate 24: (S)-4-methyl-2,3,4,5-tetrahydropyrido[4,3-f][1,2]thiazepine 1,1-dioxide

[0362] ##STR00057##

[0363] 4-methyl-2,3,4,5-tetrahydropyrido[4,3-f][1,2]thiazepine 1,1-dioxide (2.39 g, 11.28 mmol) was purified with chiral SFC (Column: Chiralpak IC, 20×250 mm, 5u; Co-Solvent: 30% EtOH; Total flow rate: 50 g/min; Pressure: 100 Bar) to give (R)-4-methyl-2,3,4,5-tetrahydropyrido[4,3-f][1,2]thiazepine 1,1-dioxide (1.10 g, 45% yield). LC-MS m/z 213 (M+H).sup.+, 0.49 min (ret. time), and (S)-4-methyl-2,3,4,5-tetrahydropyrido[4,3-f][1,2]thiazepine 1,1-dioxide (1.07 g, 45% yield). LCMS m/z 213 (M+H).sup.+, 0.49 min (ret. time).

Intermediate 25: (R)-1-Azidobutan-2-ol

[0364] ##STR00058##

[0365] To a round bottom flask equipped with a reflux condenser was added (R)-2-ethyloxirane (26.0 g, 361 mmol), sodium azide (28.1 g, 433 mmol) and ammonium chloride (23.15 g, 433 mmol) followed by a solution of ethanol (200 mL) and water (200 mL). The reaction mixture was heated at 100° C. for 24 hr. The reaction mixture was cooled, the ethanol removed under reduced pressure and the residual aqueous layer extracted with diethyl ether (3×250 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure to afford an oil. The oil was purified by silica gel chromatography (0-10% MeOH/DCM) to afford (R)-1-azidobutan-2-ol (19.8 g, 172 mmol, 47.7% yield). .sup.1H NMR (CHCl.sub.3-d) δ: 3.64-3.76 (m, 1H), 3.35-3.46 (m, 1H), 3.20-3.34 (m, 1H), 2.19 (s, 1H), 1.47-1.60 (m, 2H), 0.90-1.06 (m, 3H)

Intermediate 26: (R)-1-Aminobutan-2-ol

[0366] ##STR00059##

[0367] To a solution of (R)-1-azidobutan-2-ol (19.80 g, 172 mmol) in ethanol (250 mL) was added 10% palladium on carbon (1.830 g, 17.20 mmol) and the suspension was placed under a hydrogen atmosphere for 72 hr. Additional 10% palladium on carbon (1.830 g, 17.20 mmol) was added at 24 and 48 hr time points. The reaction mixture was filtered through celite and then evaporated under reduced pressure to afford a light yellow oil (R)-1-aminobutan-2-ol (13.5 g, 151 mmol, 88% yield). .sup.1H NMR (CHCl.sub.3-d) δ: 3.43 (m, 1H), 2.77 (m, 1H), 2.64 (br. s., 3H), 2.52 (m, 1H), 1.36-1.48 (m, 2H), 0.87-0.96 (m, 3H).

Intermediate 27: (R)-3-fluoro-N-(2-hydroxybutyl)pyridine-2-sulfonamide

[0368] ##STR00060##

[0369] To the mixture of isopropyl magnesium chloride (17.05 mL, 34.1 mmol) in tetrahydrofuran (15 mL) was added BuLi (21.31 mL, 34.1 mmol) dropwise under nitrogen atmosphere at ambient temperature and stirred for 15 min. The solution was cooled to −10° C. and 2-bromo-3-fluoropyridine (5 g, 28.4 mmol) in tetrahydrofuran (15 mL) was added dropwise over 5 min and stirred for 45 min. The mixture was then added to a solution of sulfuryl chloride (6.93 mL, 85 mmol) in toluene (15.00 mL) at −10° C. and stirred for 20 min. Then temperature was raised to 10° C. and a mixture of (R)-1-aminobutan-2-ol (380 mg, 4.26 mmol) and DIEA (0.744 mL, 4.26 mmol) in tetrahydrofuran (1.500 mL) was added and stirred at ambient temperature for 18 hr. The reaction mixture was quenched with saturated NH.sub.4Cl solution (15 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (15 mL) and dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure to give the title compound (2.5 g, 7.61 mmol, 26.8% yield). LCMS m/z 248.89 (M+Na).sup.+, 1.33 min (ret. time).

Intermediate 28: (R)-4-ethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazepine 1,1-dioxide

[0370] ##STR00061##

[0371] To the mixture of (R)-3-fluoro-N-(2-hydroxybutyl)pyridine-2-sulfonamide (2.5 g, 8.06 mmol) in DMSO (15 mL) was added potassium tert-butoxide (1.810 g, 16.13 mmol) at 0° C. The reaction mixture was stirred at 100° C. for 16 h after which was added 1N HCl to pH 6-7 and the mixture extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure, purified with flash silica gel column chromatography to give the title compound (750 mg, 3.26 mmol, 40.4% yield). LCMS m/z 229.06 (M+Na).sup.+, 1.50 min (ret. time).

Intermediate 29: Methyl (R)-3-hydroxy-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethylpropanoate

[0372] ##STR00062##

Methyl 3-hydroxy-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethylpropanoate (5.9 g, 15.84 mmol) was purified with chiral SFC (Column: AY, 20×250 mm, 5u; Co-Solvent: 30% EtOH; Total flow rate: 50 g/min; Pressure: 100 Bar) to give the title compound (3.7614 g, 10.10 mmol, 63.8% yield). LC-MS m/z 395.2 (M+Na).sup.+, 1.17 min (ret. time).

Intermediate 30: Methyl (R)-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate

[0373] ##STR00063##

[0374] To a mixture of methyl (R)-3-hydroxy-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethylpropanoate (2.6 g, 6.98 mmol) in N,N-dimethylformamide (30 mL) was added 3-bromoprop-1-yne (80% in toluene) (1.128 mL, 10.47 mmol) followed by NaH (0.251 g, 10.47 mmol). The resulting reaction mixture was stirred at ambient temperature for 30 min after which was added a solution of sodium bicarbonate (0.586 g, 6.98 mmol) in water (40 mL) and extracted with EtOAc (2×40 mL). The combined organic layer was washed with LiCl (30 mL, 5%) then brine (30 mL), dried over MgSO.sub.4, filtered, evaporated down under vacuum, purified via flash chromatography over silica gel to get the title compound (2.2200 g, 5.41 mmol, 77% yield). LC-MS m/z 433.3 (M+Na).sup.+, 1.38 min (ret. time).

Intermediate 31: Methyl (R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate

[0375] ##STR00064##

[0376] To a mixture of methyl (R)-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (2.22 g, 5.41 mmol) in acetonitrile (25 mL) and water (5 mL) was added ceric ammonium nitrate (5.93 g, 10.82 mmol). The resulting reaction mixture was stirred at ambient temperature for 20 min then was evaporated down under vacuum, extracted with DCM (2×30 mL), purified via flash chromatography over silica gel to give the title compound (1.1404 g, 3.93 mmol, 72.6% yield). LC-MS m/z 313.1 (M+Na).sup.+, 0.94 min (ret. time).

Intermediate 32: Methyl (R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate

[0377] ##STR00065##

[0378] To a mixture of methyl (R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (1.12 g, 3.86 mmol) in isopropanol (6 mL), tetrahydrofuran (8 mL) and water (4 mL) was added sodium azide (0.627 g, 9.64 mmol), DIEA (0.135 mL, 0.771 mmol), iodopropane (0.863 mL, 8.87 mmol) and copper(I) iodide (0.110 g, 0.579 mmol). The resulting reaction mixture was heated with microwave at 80° C. for 60 min then was evaporated down under vacuum, purified via flash chromatography over silica gel using ethyl acetate and hexanes as eluent to afford the title compound (825.6 mg, 2.199 mmol, 57.0% yield). LC-MS m/z 376.2 (M+H).sup.+, 0.89 min (ret. time).

Intermediate 33: Methyl 3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate

[0379] ##STR00066##

[0380] To a mixture of methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (1.0 g, 3.44 mmol) in isopropanol (10 mL), tetrahydrofuran (4 mL) and water (4 mL) was added NaN.sub.3 (0.560 g, 8.61 mmol), DIEA (0.120 mL, 0.689 mmol), iodoethane (0.640 mL, 7.92 mmol) and copper(I) iodide (0.098 g, 0.517 mmol). The resulting reaction mixture was heated with microwave at 70° C. for 60 min then was evaporated down under vacuum, purified via flash chromatography over silica gel using ethyl acetate and hexanes as eluent to give the title compound (1.3326 g, 3.69 mmol, 107% yield). LC-MS m/z 362.1 (M+H).sup.+, 0.83 min (ret. time).

Intermediate 34: Methyl (R)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate

[0381] ##STR00067##

[0382] To a mixture of methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (1.12 g, 3.86 mmol) in isopropanol (10 mL), tetrahydrofuran (4 mL) and water (4 mL) was added NaN.sub.3 (0.627 g, 9.64 mmol), DIEA (0.135 mL, 0.771 mmol), iodoethane (0.717 mL, 8.87 mmol) and copper(I) iodide (0.110 g, 0.579 mmol). The resulting reaction mixture was heated with microwave at 70° C. for 60 min then was evaporated down under vacuum, purified by purified via flash chromatography over silica gel then further purified with chiral SFC (Instrument: Thar 80; Column: Chiralpak AY 20×250 mm, 5u; Co-solvent: 20% EtOH; Flow rate: 50 g/min; Back pressure: 100 Bar; UV wavelength: 220 nm; Temperature: 30° C.; Injection vol: 2.5 ml) to give the title chiral compound (0.4838 g, 1.339 mmol, 34.7% yield). LC-MS m/z 362.1 (M+H).sup.+, 0.82 min (ret. time).

[0383] The compounds in Table A were prepared by a method similar to the one described for the preparation of methyl (R)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00004 TABLE A LCMS Retention Structure/Intermediate # Name [M + H].sup.+ Time (min) [00068] Methyl (S)-3-((1-ethyl-1H- 1,2,3-triazol-4-yl)methoxy)- 3-(3-(hydroxymethyl)-4- methylphenyl)-2,2- dimethylpropanoate 362.1 0.82 [00069] Methyl (R)-3-(3- (hydroxymethyl)-4- methylphenyl)-3-((1-(2-(2- methoxyethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)methoxy)- 2,2-dimethylpropanoate 436.3 0.82 [00070] Methyl (S)-3-(3-(hydroxy- methyl)-4-methylphenyl)-3- ((1-(2-(2-methoxyethoxy)- ethyl)-1H-1,2,3-triazol-4- yl)methoxy)-2,2-dimethyl- propanoate 436.2 0.82

Intermediate 38: Methyl (R)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-((1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoate

[0384] ##STR00071##

[0385] To a mixture of 1-bromo-2-methoxyethane (1.068 mL, 11.37 mmol) in N,N-dimethylformamide (6.00 mL) was added sodium azide (0.739 g, 11.37 mmol). The resulting reaction mixture was stirred at 80° C. for 20 h after which was added the mixture of methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (1.10 g, 3.79 mmol) in isopropanol (6 mL) and tetrahydrofuran (6 mL) then DIEA (0.132 mL, 0.758 mmol) and copper(I) iodide (0.108 g, 0.568 mmol). The resulting reaction mixture was heated with microwave at 80° C. for 30 min then a further 60 min. The reaction mixture was evaporated down under vacuum, purified via flash chromatography over silica gel then further purified with chiral SFC (Instrument: Thar 80; Column: Chiralpak IG 20×250 mm, 5u; Co-solvent: 20% EtOH; Flow rate: 50 g/min; Back pressure: 100 Bar) to give the title compound (0.52 g, 1.328 mmol, 35.1% yield). LC-MS m/z 392.2 (M+H).sup.+, 0.81 min (ret. time).

Intermediate 39: Methyl 3-((1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate

[0386] ##STR00072##

[0387] In two 20 mL microwave vials, each was added half amount of methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-(prop-2-yn-1-yloxy)propanoate (2.86 g, 5.89 mmol) in isopropanol (20 mL), tetrahydrofuran (10 mL) and water (8.0 mL) then sodium azide (0.957 g, 14.72 mmol), DIEA (0.206 mL, 1.178 mmol), tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (3.77 g, 13.55 mmol) and copper(I) iodide (0.168 g, 0.883 mmol). The resulting reaction mixture was each heated with microwave at 80° C. for 1 h then heated again with microwave at 80° C. for 30 min. The combined reaction mixture was evaporated down under vacuum, purified via flash chromatography over silica gel using ethyl acetate and hexanes as eluent to give the title compound (0.7197 g, 1.399 mmol, 23.12% yield). LC-MS m/z 529.3 (M+H).sup.+, 1.12 min (ret. time).

Intermediate 40: 3-Bromo-N-(pyridin-2-ylmethyl)benzenesulfonamide

[0388] ##STR00073##

[0389] To the mixture of 2-picolylamine (0.403 mL, 3.91 mmol) in tetrahydrofuran (15 mL) and water (5 mL) was added K.sub.2CO.sub.3 (0.541 g, 3.91 mmol) then 3-bromobenzenesulfonyl chloride (1.0 g, 3.91 mmol) in tetrahydrofuran (5 mL). The resulting reaction mixture was stirred at ambient temperature for 23 h then was extracted with EtOAc (2×20 mL). The combined organic layer was dried over MgSO.sub.4, filtered, evaporated down under vacuum to give the title compound (1.3206 g, 4.04 mmol, 103% yield). LC-MS m/z 326.8 (M+H).sup.+, 0.60 min (ret. time).

Intermediate 41: Rel-(R)-methyl 2,2-dimethyl-3-(4-methyl-3-(((S)-4-methyl-1,1-dioxido-4,5-dihydropyrido[4,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-3-(prop-2-yn-1-yloxy)propanoate

[0390] ##STR00074##

[0391] To the mixture of methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (800 mg, 2.76 mmol) in dichloromethane (4 mL) was added SOCl.sub.2 (0.603 mL, 8.27 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 h before being evaporated down under vacuum to give intermediate.

[0392] To the mixture of (S)-4-methyl-2,3,4,5-tetrahydropyrido[4,3-f][1,2]thiazepine 1,1-dioxide (702 mg, 3.31 mmol) in N,N-dimethylformamide (10 mL) was added NaH (93 mg, 3.86 mmol). The resulting reaction mixture was stirred at ambient temperature for 5 min after which was added the solution of the above intermediate in N,N-dimethylformamide (5 mL). The resulting reaction mixture was stirred at ambient temperature for 2.5 h after which was added more NaH (13.22 mg, 0.551 mmol). The resulting reaction mixture was stirred at ambient temperature for 2.5 h after which was added more NaH (13.22 mg, 0.551 mmol). The resulting reaction mixture was stirred at ambient temperature for 17 h then quenched with HCl (1.0 N) (1.102 mL, 1.102 mmol), diluted with EtOAc (150 mL), washed with H.sub.2O (2×50 mL), brine (50 mL), dried over MgSO.sub.4, filtered, evaporated down under vacuum, purified via flash chromatography over silica gel using ethyl acetate and hexanes as eluent then further purified with chiral SFC (Instrument: Thar 80 Column: Chiralpak OJ 20×250 mm, 5u; Co-solvent: 20% EtOH; Flow rate: 50 g/min; Back pressure: 100 Bar) to give the title compound (555.4 mg, 1.146 mmol, 41.6% yield). LC-MS m/z 485.3 (M+H).sup.+, 1.21 min (ret. time).

[0393] The compounds in Table B were prepared by a method similar to the one described for the preparation of rel-(R)-methyl 2,2-dimethyl-3-(4-methyl-3-(((S)-4-methyl-1,1-dioxido-4,5-dihydropyrido[4,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-3-(prop-2-yn-1-yloxy)propanoate. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00005 TABLE B LCMS Retention Structure/Intermediate # Name [M + H].sup.+ Time (min) [00075] Rel-(S)-methyl 2,2-dimethyl- 3-(4-methyl-3-(((S)-4-methyl- 1,1-dioxido-4,5-dihydropyrido- [4,3-f][1,2]thiazepin-2(3H)- yl)methyl)phenyl)-3-(prop-2- yn-1-yloxy)propanoate 485.3 1.21

Example 1

3-((1-(3-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic Acid

[0394] ##STR00076##

(5-Bromo-2-methylphenyl)methanol

[0395] ##STR00077##

[0396] To a solution of 5-bromo-2-methylbenzoic acid (70 g, 326 mmol) in tetrahydrofuran (THF) (700 mL) stirred under nitrogen at 0° C. was added a toluene solution of borane-methyl sulfide complex (244 mL, 488 mmol) drop wise during 15 min. The reaction mixture was stirred for 16 h. The reaction was cooled to 0° C. and quenched with methanol (500 mL) drop wise. The reaction mixture was stirred at ambient temperature for 3 h and then concentrated. The crude residue was diluted with ethyl acetate (1 L) and washed with 1 N HCl (500 mL), brine solution (500 mL) and dried over Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (49 g, 244 mmol, 74.9% yield). .sup.1H NMR (400 MHz, DMSO) δ=7.52 (d, J=2.6 Hz, 1H), 7.31 (dd, J=8.0, 2.2 Hz, 1H), 7.12-7.03 (m, 1H), 5.22 (td, J=5.5, 1.8 Hz, 1H), 4.48 (dd, J=5.1, 1.8 Hz, 2H), 2.17 (s, 3H).

4-Bromo-2-(((4-methoxybenzyl)oxy)methyl)-1-methylbenzene

[0397] ##STR00078##

[0398] To a stirred solution of (5-bromo-2-methylphenyl)methanol (100 g, 497 mmol) in dry DMF (800 mL) was added NaH (21.88 g, 547 mmol). After the reaction mixture was stirred for 30 minutes, 1-(chloromethyl)-4-methoxybenzene (82 g, 522 mmol) was added at 0° C. and the reaction mixture was stirred for another 2 h at ambient temperature. The reaction was then diluted with Et.sub.2O (200 mL) and water (200 mL). The organic phase was washed with brine (300 mL) and dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified via silica gel column to yield 4-bromo-2-(((4-methoxybenzyl)oxy)methyl)-1-methylbenzene (140 g, 436 mmol, 88% yield) as a clear oil. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.27 (s, 3H) 3.84 (s, 3H) 4.49 (s, 2H), 4.54 (s, 2H), 6.92 (d, J=8.8, 2H), 6.94 (d, J=8.4, 1H), 7.31-7.35 (m, 3H), 7.54 (d, J=2, 1H).

3-(4-Methoxybenzyl)oxy)methyl)-4-methylbenzaldehyde

[0399] ##STR00079##

[0400] To a stirred solution of 4-bromo-2-(((4-methoxybenzyl)oxy)methyl)-1-methylbenzene (80 g, 249 mmol) in THF (800 mL) at −78° C. under N.sub.2, 2.5 M n-BuLi in hexane (120 mL, 299 mmol) was carefully added. The reaction mixture was stirred at −78° C. for 65 min, and then DMF (38.6 mL, 498 mmol) was added. The reaction mixture was stirred at −78° C. to 25° C. for another 30 min. The mixture was quenched with saturated NH.sub.4Cl (300 mL), and extracted with EtOAc (2×500 mL). The organic layer was washed with water (300 mL) and brine (2×100 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was washed with petroleum ether:EtOAc=10/1 (2000 mL) to give the title compound (50 g, 185 mmol, 74.3% yield) as a solid. LC-MS m/z 288.1 (M+H.sub.2O).sup.+, 2.04 min (ret. time).

Methyl 3-hydroxy-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethylpropanoate

[0401] ##STR00080##

[0402] A mixture of 3-(((4-methoxybenzyl)oxy)methyl)-4-methylbenzaldehyde (4 g, 14.80 mmol), 1-methylimidazole (0.118 mL, 1.480 mmol), ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (5.16 g, 29.6 mmol) and lithium chloride (0.125 g, 2.96 mmol) in N,N-dimethylformamide (DMF) (15 mL) was stirred at ambient temperature for 17 h. NaOH (14.80 mL, 14.80 mmol) was added and the reaction mixture was stirred for 2 h. Water (20 mL) and potassium hydrogen fluoride (1.734 g, 22.20 mmol) were added and stirred for 2 h, followed by adding of 1N HCl (14.80 mL, 14.80 mmol). It was stirred for 16 h. The reaction mixture was diluted with ice water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine solution (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude residue was purified with flash column chromatography eluting with EtOAc:Hexane (2:8). Desired fractions were concentrated to give the title compound (2 g, 5.37 mmol, 36.3% yield) as yellow liquid. LCMS m/z 390.23 (M+18).sup.+, 4.07 min (ret. time)

Methyl 3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate

[0403] ##STR00081##

[0404] To a solution of methyl 3-hydroxy-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethylpropanoate (24 g, 64.4 mmol) and 3-bromoprop-1-yne in toluene (14.37 g, 97 mmol) in N,N-dimethylformamide (DMF) (250 mL) at 0° C. was added NaH (2.320 g, 97 mmol) under nitrogen. It was stirred for 30 min. The reaction mixture was quenched with saturated NaHCO.sub.3 solution and extracted with EtOAc. The organic layer was concentrated under vacuum to afford the title compound (26 g, 55.2 mmol, 86% yield) as liquid. LCMS m/z 428.17 (M+18).sup.+, 2.92 min (ret. time)

Methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate

[0405] ##STR00082##

[0406] To a solution of methyl 3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (13 g, 31.7 mmol) in dichloromethane (DCM) (40 mL) and water (10 mL) at 0° C. was added DDQ (10.78 g, 47.5 mmol). It was stirred at ambient temperature for 30 min. It was quenched with ice water, extracted with DCM twice. The organic layer was dried under anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The crude residue was purified on flash column chromatography eluting with EtOAc:hexane (12:88). Desired fractions were concentrated under to give the title compound (8 g, 13.63 mmol, 43.0% yield) as color less liquid. LC MS m/z 291.20 (M+H).sup.+, 2.20 min (ret. time)

(R)-2-Fluoro-N-(2-hydroxypropyl)benzenesulfonamide

[0407] ##STR00083##

[0408] To a suspension of 2-fluorobenzene-1-sulfonyl chloride (28 g, 144 mmol) in tetrahydrofuran (THF) (250 mL) and water (75 mL) at 0° C. was added (R)-1-aminopropan-2-ol (10.81 g, 144 mmol) and K.sub.2CO.sub.3 (19.88 g, 144 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with ice water, extracted with EtOAc twice. The combined organic layer was washed with ice water twice, brine solution. The organic layer was dried under anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (31 g, 129 mmol, 89% yield) as liquid. LCMS m/z 233.88 (M+H).sup.+, 1.46 min (ret. time)

(R)-4-Methyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide

[0409] ##STR00084##

[0410] To a solution of (R)-2-fluoro-N-(2-hydroxypropyl)benzenesulfonamide (31 g, 133 mmol) in dimethyl sulfoxide (DMSO) (200 mL) at 0° C. was added KOtBu (29.8 g, 266 mmol). The reaction mixture was stirred at 80° C. for 6 h. The reaction mixture was neutralized with 1N HCl, extracted with EtOAc twice. The combined organic layer was washed with ice water twice, brine solution, dried under anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The crude product was triturated with diethyl ether to afford the title compound (15.7 g, 73.3 mmol, 55.1% yield) as white solid. LCMS m/z 214.09 (M+H).sup.+, 1.59 min (ret. time)

Methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-(prop-2-yn-1-yloxy)propanoate

[0411] ##STR00085##

[0412] To the mixture of methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (3.59 g, 12.36 mmol) in tetrahydrofuran (175 mL) was added (R)-4-methyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (3.96 g, 18.55 mmol), PS—PPh.sub.3 (11.59 g, 18.55 mmol) and DIAD (3.61 mL, 18.55 mmol). The resulting reaction mixture was stirred at ambient temperature for 21 h. The reaction mixture was filtered, evaporated down under vacuum, purified via flash chromatography to give the title compound (5.7762 g, 11.90 mmol, 96% yield). LCMS m/z 508.2 (M+Na).sup.+, 1.32 min (ret. time).

Methyl 3-((1-(3-bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate

[0413] ##STR00086##

[0414] To the mixture of methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-(prop-2-yn-1-yloxy)propanoate (0.971 g, 2.0 mmol) in isopropanol (9 mL), tetrahydrofuran (3 mL) and water (4 mL) was added sodium azide (0.325 g, 5.00 mmol), DIEA (0.070 mL, 0.400 mmol), 1-bromo-3-(bromomethyl)benzene (1.150 g, 4.60 mmol) and copper(I) iodide (0.057 g, 0.300 mmol). The resulting reaction mixture was heated with microwave at 80° C. for 30 min. The reaction mixture was evaporated down under vacuum, purified via flash chromatography to give the title compound (1.2115 g, 1.737 mmol, 87% yield). LCMS m/z 697.2 (M+H).sup.+, 1.39 min (ret. time).

3-((1-(3-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic Acid

[0415] ##STR00087##

[0416] To the mixture of methyl 3-((1-(3-bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate (50 mg, 0.072 mmol) in methanol (1.0 mL) was added NaOH (3.0 N) (0.119 mL, 0.358 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 1 h. To the reaction mixture was added HCl (3.0 N) (0.119 mL, 0.358 mmol) then was evaporated down under vacuum, purified by reverse phase HPLC (formic acid modifier) to give the title compound (31.9 mg, 0.047 mmol, 65.1% yield). LC/MS: m/z 683.1 (M+H).sup.+, 1.27 min (ret. time).

Example 2

2,2-Dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-(prop-2-yn-1-yloxy)propanoic Acid

[0417] ##STR00088##

[0418] To the mixture of methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (50 mg, 0.172 mmol) in tetrahydrofuran (2 mL) was added (R)-4-methyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (55.1 mg, 0.258 mmol), PS—PPh3 (215 mg, 0.344 mmol) and DIAD (0.067 mL, 0.344 mmol). The resulting reaction mixture was stirred at ambient temperature for 66 h. The reaction mixture was filtered, evaporated down under vacuum. This residue was dissolved in methanol (2.000 mL) then was added NaOH (3.0 N) (0.459 mL, 1.378 mmol). The resulting reaction mixture was heated with microwave at 100° C. for 30 min twice and heated with microwave again at 120° C. for 30 min. To the reaction mixture was added HCl (3.0 N) (0.459 mL, 1.378 mmol), evaporated down under vacuum, purified by reverse phase HPLC (formic acid modifier) to give the title compound (25.6 mg, 0.054 mmol, 31.5% yield). LC/MS: m/z 472.2 (M+H).sup.+, 1.17 min (ret. time).

Example 3

3-((1-(3-(Azidomethyl)benzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic Acid

[0419] ##STR00089##

Methyl 3-((1-(3-(azidomethyl)benzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate

[0420] ##STR00090##

[0421] To the mixture of methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-(prop-2-yn-1-yloxy)propanoate (971 mg, 2.0 mmol) in isopropanol (12 mL) and water (4 mL) was added sodium azide (650 mg, 10.00 mmol), DIEA (0.070 mL, 0.400 mmol), 1,3-bis(bromomethyl)benzene (1214 mg, 4.60 mmol) and copper(I) iodide (57.1 mg, 0.300 mmol). The resulting reaction mixture was heated with microwave at 80° C. for 30 min. The reaction mixture was evaporated down under vacuum, purified via flash chromatography to give the title compound (691.1 mg, 1.026 mmol, 51.3% yield). LC/MS: m/z 674.3 (M+H).sup.+, 1.36 min (ret. time).

3-((1-(3-(Azidomethyl)benzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic Acid

[0422] ##STR00091##

[0423] To the mixture of methyl 3-((1-(3-(azidomethyl)benzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate (50 mg, 0.074 mmol) in methanol (1.0 mL) was added NaOH (3.0 N) (0.124 mL, 0.371 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 1 h. To the reaction mixture was added HCl (3.0 N) (0.124 mL, 0.371 mmol) then was evaporated down under vacuum, purified by reverse phase HPLC (formic acid modifier) to give the title compound (30.6 mg, 0.046 mmol, 62.5% yield). LC/MS: m/z 660.1 (M+H).sup.+, 1.23 min (ret. time).

Example 4

3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic Acid

[0424] ##STR00092##

(R)-2-Fluoro-N-(2-hydroxybutyl)benzenesulfonamide

[0425] ##STR00093##

[0426] To a solution of (R)-1-aminobutan-2-ol (14.66 g, 164 mmol) in tetrahydrofuran (THF) (200 mL) and water (60 mL) at ambient temperature was added K.sub.2CO.sub.3 (14.20 g, 103 mmol) and 2-fluorobenzene-1-sulfonyl chloride (20 g, 103 mmol). It was stirred for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with brine solution (200 mL) and dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (14 g, 53.8 mmol, 52.3% yield) as a gummy liquid. LC-MS m/z 494.83 (2M−H).sup.+, 1.660 min (ret. time).

(R)-4-Ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide

[0427] ##STR00094##

[0428] To a solution of (R)-2-fluoro-N-(2-hydroxybutyl)benzenesulfonamide (14 g, 56.6 mmol) in dimethyl sulfoxide (DMSO) (140 mL) at 0° C. was added potassium tert-butoxide (6.35 g, 56.6 mmol). It was then heated at 80° C. for 4 h. The reaction mixture was cooled and neutralized with 1N HCl, diluted with ice water (500 mL) and extracted with EtOAc (2×400 mL). The combined organic layer was washed with chilled brine solution (200 mL) and dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The crude residue was purified on flash column chromatography eluting with 50% EtOAc in hexane. Desired fractions were concentrated to give the title compound (11.12 g, 48.9 mmol, 86% yield) as a white solid. LC-MS m/z 228.05 (M+H).sup.+, 1.84 min (ret. time).

Methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate

[0429] ##STR00095##

[0430] To the mixture of methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (0.43 g, 1.481 mmol) in isopropanol (6.0 mL) and water (2.0 mL) was added sodium azide (0.241 g, 3.70 mmol), DIEA (0.052 mL, 0.296 mmol), copper(I) iodide (0.042 g, 0.222 mmol) and iodopropane (0.331 mL, 3.41 mmol). The resulting reaction mixture was heated with microwave at 70° C. for 1 h. The reaction mixture was evaporated down under vacuum, extracted with DCM (3×7 mL), dried over Na.sub.2SO.sub.4, filtered, evaporated down under vacuum, purified via flash chromatography to give the title compound (296.1 mg, 0.789 mmol, 53.3% yield). LC/MS: m/z 376.2 (M+H).sup.+, 0.93 min (ret. time).

3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic Acid

[0431] ##STR00096##

[0432] To the mixture of methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate (55 mg, 0.146 mmol) in tetrahydrofuran (2 mL) was added (R)-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (49.9 mg, 0.220 mmol), PS—PPh.sub.3 (183 mg, 0.293 mmol) and DIAD (0.057 mL, 0.293 mmol). The resulting reaction mixture was stirred at ambient temperature for 21 h. The reaction mixture was filtered, evaporated down under vacuum. The residue was redissolved in methanol (2.000 mL) then was added NaOH (3.0 N) (0.391 mL, 1.172 mmol). The resulting reaction mixture was heated with microwave at 100° C. for 30 min then heated again with microwave at 120° C. for 30 min. To the reaction mixture was added HCl (3.0 N) (0.391 mL, 1.172 mmol) then evaporated down under vacuum, purified by reverse phase HPLC (formic acid modifier) to give the title compound (17.5 mg, 0.031 mmol, 20.93% yield). LC/MS: m/z 571.3 (M+H).sup.+, 1.19 min (ret. time).

Example 5

(R)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoic Acid

[0433] ##STR00097##

Methyl 3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate

[0434] ##STR00098##

[0435] To the mixture of methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (3 g, 10.33 mmol) in dichloromethane (30 mL) was added SOCl.sub.2 (3.77 mL, 51.7 mmol). The resulting reaction mixture was stirred at ambient temperature for 17.5 h then was evaporated down under vacuum. The residue was dissolved in N,N-dimethylformamide (20 mL) to give intermediate solution. To (R)-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (2.82 g, 12.40 mmol) in N,N-dimethylformamide (40 mL) was added NaH (0.298 g, 12.40 mmol). The resulting reaction mixture was stirred at ambient temperature for 5 min then was added into the above intermediate solution. The resulting reaction mixture was stirred at ambient temperature for 4 h then was added more NaH (0.050 g, 2.066 mmol). The resulting reaction mixture was stirred at ambient temperature for 22 h. The reaction was quenched with HCl (1.0 N) (2.066 mL, 2.066 mmol), diluted with EtOAc (300 mL), washed with H.sub.2O (2×100 mL), brine (50 mL), dried over MgSO.sub.4, filtered, evaporated down under vacuum, purified by flash chromatography to give the title compound (4.0916 g, 8.19 mmol, 79% yield). LC/MS: m/z 522.1 (M+Na).sup.+, 1.36 min (ret. time).

Methyl 3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoate

[0436] ##STR00099##

[0437] To the mixture of methyl 3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (2.72 g, 5.44 mmol) in isopropanol (18 mL), tetrahydrofuran (12 mL) and water (8 mL) was added sodium azide (0.885 g, 13.61 mmol), DIEA (0.190 mL, 1.089 mmol), ethyl iodide (1.012 mL, 12.52 mmol) and copper(I) iodide (0.156 g, 0.817 mmol). The resulting reaction mixture was heated with microwave at 80° C. for 30 min. The reaction mixture was evaporated down under vacuum, purified by flash chromatography to give the title compound (2.5336 g, 4.44 mmol, 82% yield). LC/MS: m/z 571.2 (M+H).sup.+, 1.26 min (ret. time).

(R)-methyl 3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoate

[0438] ##STR00100##

[0439] Methyl 3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoate (2.53 g, 4.43 mmol) was separated by chiral SFC (Column: Chiralpak IA 20×250 mm, 5u; Co-solvent: 20% MeOH; Flowrate: 50 g/min; Back pressure: 100 Bar) to give the title compound (1.0058 g, 1.762 mmol, 39.8% yield). LC/MS: m/z 571.3 (M+H).sup.+, 1.26 min (ret. time).

[0440] The compounds in Table 1 were prepared by a method similar to the one described for the preparation of (R)-methyl 3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoate. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00006 TABLE 1 LCMS Retention Structure Name [M + H].sup.+ Time (min) [00101] (S)-methyl 3-(3-(((R)-4-ethyl-1,1- dioxido-3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepin-2- yl)methyl)-4-methylphenyl)-3-((1- ethyl-1H-1,2,3-triazol-4- yl)methoxy)-2,2- dimethylpropanoate 571.3 1.25

(R)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoic Acid

[0441] ##STR00102##

[0442] To the mixture of (R)-methyl 3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoate (1.00 g, 1.752 mmol) in methanol (10 mL) was added NaOH (3.0 N) (2.92 mL, 8.76 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 30 min. To the reaction mixture was added HCl (3.0 N) (2.92 mL, 8.76 mmol), evaporated down under vacuum, extracted with EtOAc (3×20 mL). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered, evaporated under vacuum to give the title compound (843.9 mg, 1.516 mmol, 87% yield). LC/MS: m/z 557.3 (M+H).sup.+, 1.15 min (ret. time).

[0443] The compounds in Table 2 were prepared by a method similar to the one described for the preparation of (3R)-3-(3-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1λ.sup.6,2-benzoxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[(1-ethyl-1H-1,2,3-triazol-4-yl)methoxy]-2,2-dimethylpropanoic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00007 TABLE 2 LCMS Retention Ex # Structure Name [M + H].sup.+ Time (min) Ex. 6 [00103] (S)-3-(3-(((R)-4-ethyl-1,1- dioxido-3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepin-2- yl)methyl)-4-methylphenyl)-3- ((1-ethyl-1H-1,2,3-triazol-4- yl)methoxy)-2,2- dimethylpropanoic acid 557.3 1.14

Example 7

3-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic Acid

[0444] ##STR00104##

Methyl 3-((1-(3-bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate

[0445] ##STR00105##

[0446] To the mixture of methyl 3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (1.09 g, 2.182 mmol) in isopropanol (9 mL), tetrahydrofuran (3 mL) and water (4 mL) was added sodium azide (0.355 g, 5.45 mmol), DIEA (0.076 mL, 0.436 mmol), 1-bromo-3-(bromomethyl)benzene (1.254 g, 5.02 mmol) and copper(I) iodide (0.062 g, 0.327 mmol). The resulting reaction mixture was heated with microwave at 80° C. for 30 min. The reaction mixture was evaporated down under vacuum, purified via flash chromatography to give the title compound (1.4913 g, 2.096 mmol, 96% yield). LC/MS: m/z 711.2 (M+H).sup.+, 1.44 min (ret. time).

3-((1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic Acid

[0447] ##STR00106##

[0448] The mixture of methyl 3-((1-(3-bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate (70 mg, 0.098 mmol) in methanol (10 mL) was hydrogenated on H-Cube apparatus at 1 bar H.sub.2, 1 mL/min, on 10% Pd/C cartridge, at 20° C.; 1 run. The reaction mixture was evaporated down under vacuum, redissolved in methanol (2 mL) then was added NaOH (6 N) (0.082 mL, 0.492 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 30 min. To the reaction mixture was added HCl (6 N) (0.082 mL, 0.492 mmol), evaporated down under vacuum, purified by reverse phase HPLC (formic acid modifier) to give the title compound (14.5 mg, 0.023 mmol, 23.83% yield). LC/MS: m/z 619.3 (M+H).sup.+, 1.25 min (ret. time).

Example 8

2,2-Dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic Acid

[0449] ##STR00107##

[0450] To the mixture of methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate (55 mg, 0.146 mmol) in tetrahydrofuran (2 mL) was added (R)-4-methyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (46.9 mg, 0.220 mmol), PS—PPh3 (183 mg, 0.293 mmol) and DIAD (0.057 mL, 0.293 mmol). The resulting reaction mixture was stirred at ambient temperature for 21 h. The reaction mixture was filtered, evaporated down under vacuum. This residue was redissolved in methanol (2.000 mL) then was added NaOH (3.0 N) (0.391 mL, 1.172 mmol). The resulting reaction mixture was heated with microwave at 100° C. for 30 min then heated again with microwave at 120° C. for 30 min. To the reaction mixture was added HCl (3.0 N) (0.391 mL, 1.172 mmol), evaporated under vacuum, purified by reverse phase HPLC (formic acid modifier) to give the title compound (40.5 mg, 0.073 mmol, 49.7% yield). LC/MS: m/z 557.3 (M+H).sup.+, 1.13 min (ret. time).

[0451] The compounds in Table 3 were prepared by a method similar to the one described for the preparation of 2,2-Dimethyl-3-(4-methyl-3-{[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-2H-5,1λ.sup.6,2-benzoxathiazepin-2-yl]methyl}phenyl)-3-[(1-propyl-1H-1,2,3-triazol-4-yl)methoxy]propanoic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00008 TABLE 3 LCMS Retention Ex # Structure Name [M + H].sup.+ Time (min) Ex. 9 [00108] 3-(3-((4,4-Dimethyl-1,1- dioxido-3,4-dihydo-2H- benzo[b][1,4]oxathiazepin- 2-yl)methyl)-4- methylphenyl)-2,2- dimethyl-3-((1-propyl-1H- 1,2,3-triazol-4-yl)methoxy)- propanoic acid G 571.4 1.17

Example 10

3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoic Acid

[0452] ##STR00109##

[0453] To the mixture of methyl 3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (55 mg, 0.152 mmol) in tetrahydrofuran (2 mL) was added (R)-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (51.9 mg, 0.228 mmol), PS—PPh.sub.3 (190 mg, 0.304 mmol) and DIAD (0.059 mL, 0.304 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was filtered, evaporated down under vacuum. This residue was redissolved in methanol (2.000 mL) then was added NaOH (3.0 N) (0.406 mL, 1.217 mmol). The resulting reaction mixture was heated with microwave at 130° C. for 1 h then heated again with microwave at 130° C. for 1 h. To the reaction mixture was added HCl (3.0 N) (0.406 mL, 1.217 mmol) (60-6), evaporated down under vacuum, purified by reverse phase HPLC (formic acid modifier) to give the title compound (30.1 mg, 0.054 mmol, 35.5% yield). LC/MS: m/z 557.3 (M+H).sup.+, 1.13 min (ret. time).

[0454] The compounds in Table 4 were prepared by a method similar to the one described for the preparation of 3-(3-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1λ.sup.6,2-benzoxathiazepin-2-yl]methyl}-4-methylphenyl)-3-[(1-ethyl-1H-1,2,3-triazol-4-yl)methoxy]-2,2-dimethylpropanoic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00009 TABLE 4 LCMS Retention Ex # Structure Name [M + H].sup.+ Time (min) Ex 11 [00110] 3-((1-Ethyl-1H-1,2,3-triazol- 4-yl)methoxy)-2,2-dimethyl- 3-(4-methyl-3-(((R)-4-methyl- 1,1-dioxido-3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepin- 2-yl)methyl)phenyl)propanoic acid 543.4 1.09 Ex 12 [00111] 3-(3-((4,4-dimethyl-1,1- dioxido-3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepin- 2-yl)methyl)-4- methylphenyl)-3-((1-ethyl- 1H-1,2,3-triazol-4- yl)methoxy)-2,2- dimethylpropanoic acid 557.3 1.12

Example 13

Rel-(S)-3-((1-isobutyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic Acid

[0455] ##STR00112##

Rel-(S)-methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-(prop-2-yn-1-yloxy)propanoate

[0456] ##STR00113##

[0457] To the mixture of methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (0.95 g, 3.27 mmol) in tetrahydrofuran (40 mL) was added (R)-4-methyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (1.047 g, 4.91 mmol), PS—PPh.sub.3 (3.07 g, 4.91 mmol) and DIAD (0.954 mL, 4.91 mmol). The resulting reaction mixture was stirred at ambient temperature for 30 min. The reaction mixture was filtered, evaporated down under vacuum, purified via flash chromatography then separated by chiral SFC (Column: Chiralpak AY 20×250 mm, 5u; Co-solvent: 25% IPA; Flowrate: 50 g/min; Back pressure: 100 Bar) to give the title compound (352.0 mg, 0.725 mmol, 22.16% yield). LC/MS: m/z 508.2 (M+Na).sup.+, 1.32 min (ret. time).

[0458] The compounds in the following Table 5 were prepared by a method similar to the one described for the preparation of rel-(S)-methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-(prop-2-yn-1-yloxy)propanoate. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00010 TABLE 5 Ret. Time Product Name Product Structure (M + Na).sup.+ (min) Rel-(R)-methyl 2,2-dimethyl-3- (4-methyl-3-(((R)-4-methyl-1,1- dioxido-3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepin-2- yl)methyl)phenyl)-3-(prop-2-yn- 1-yloxy)propanoate [00114] 508.2 1.30

Rel-(S)-3-((1-isobutyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic Acid

[0459] ##STR00115##

[0460] To the mixture of rel-(S)-methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-(prop-2-yn-1-yloxy)propanoate (48.6 mg, 0.10 mmol) in isopropanol (1.0 mL) and water (0.3 mL) was added sodium azide (16.25 mg, 0.250 mmol), DIEA (3.49 μl, 0.020 mmol), i-butanol (0.026 mL, 0.230 mmol) and copper(I) iodide (2.86 mg, 0.015 mmol). The resulting reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was evaporated down under vacuum. This residue was dissolved in methanol (1.0 mL) then was added NaOH (3.0 N) (0.233 mL, 0.700 mmol). The resulting reaction mixture was heated with microwave at 100° C. for 30 min. To the reaction mixture was added HCl (3.0 N) (0.233 mL, 0.700 mmol), evaporated down under vacuum, purified by reverse phase HPLC (formic acid modifier) to give the title compound (12.7 mg, 0.022 mmol, 22.25% yield). LC/MS: m/z 571.4 (M+H).sup.+, 1.18 min (ret. time).

[0461] The compounds in Table 6 were prepared by a method similar to the one described for the preparation of rel-(3S)-2,2-dimethyl-3-(4-methyl-3-{[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-2H-5,1λ.sup.6,2-benzoxathiazepin-2-yl]methyl}phenyl)-3-{[1-(2-methylpropyl)-1H-1,2,3-triazol-4-yl]methoxy}propanoic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00011 TABLE 6 LCMS Retention Ex # Structure Name [M + H].sup.+ Time (min) Ex 14 [00116] Rel-(S)-3-((1-(2-(2- azidoethoxy)ethyl)-1H- 1,2,3-triazol-4-yl) methoxy)-2,2- dimethyl-3-(4-methyl- 3-(((R)-4-methyl-1,1- dioxido-3,4-dihydro- 2H-benzo[b]- [1,4,5]oxathiazepin-2- yl)methyl)phenyl) propanoic acid 628.2 1.13 Ex 15 [00117] Rel-(R)-3-((1-(2-(2- azidoethoxy)ethoxy)-1H- 1,2,3-triazol-4- yl)methoxy)-2,2- dimethyl-3-(4-methyl- 3-(((R)-4-methyl-1,1- dioxido-3,4-dihydro- 2H-benzo[b]- [1,4,5]oxathiazepin-2- yl)methyl)phenyl) propanoic acid 628.2 1.13 Ex 16 [00118] Rel-(R)-3-((1-isobutyl- 1H-1,2,3-triazol-4- yl)methoxy)-2,2- dimethyl-3-(4-methyl- 3-(((R)-4-methyl-1,1- dioxido-3,4-dihydro- 2H-benzo[b]- [1,4,5]oxathiazepin-2- yl)methyl)phenyl) propanoic acid 571.4 1.18

Example 17

3-((1-Cyclohexyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic Acid

[0462] ##STR00119##

[0463] To the mixture of iodocyclohexane (0.048 mL, 0.371 mmol) in N,N-dimethylformamide (0.500 mL) was added sodium azide (24.10 mg, 0.371 mmol). The resulting reaction mixture was stirred at 80° C. for 23 h. The reaction mixture was cooled down to ambient temperature before was added isopropanol (0.5 mL), methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-(prop-2-yn-1-yloxy)propanoate (60 mg, 0.124 mmol), DIEA (4.32 μl, 0.025 mmol), water (0.3 mL) and copper(I) iodide (3.53 mg, 0.019 mmol). The resulting reaction mixture was heated with microwave at 80° C. for 10 min. The reaction mixture was evaporated down under vacuum, redissolved in methanol (1.0 mL) then was added NaOH (6.0 N) (0.165 mL, 0.988 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 30 min. To the reaction mixture was added more NaOH (6.0 N) (0.062 mL, 0.371 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 1 h. To the reaction mixture was added HCl (6.0 N) (0.227 mL, 1.359 mmol), evaporated down under vacuum, purified by reverse phase HPLC (formic acid modifier) to give the title compound (26.4 mg, 0.044 mmol, 35.8% yield). LC/MS: m/z 597.3 (M+H).sup.+, 1.23 min (ret. time).

Example 18

3-((1-((1-(Tert-butoxycarbonyl)piperidin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic Acid

[0464] ##STR00120##

[0465] To the mixture of methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-(prop-2-yn-1-yloxy)propanoate (48.6 mg, 0.10 mmol) in isopropanol (1.0 mL), tetrahydrofuran (0.3 mL) and water (0.3 mL) was added sodium azide (16.25 mg, 0.250 mmol), DIEA (3.49 μl, 0.020 mmol), tert-butyl 3-(bromomethyl)piperidine-1-carboxylate (64.0 mg, 0.230 mmol) and copper(I) iodide (2.86 mg, 0.015 mmol). The resulting reaction mixture was heated with microwave at 80° C. for 1 h, heated again with microwave at 80° C. for 30 min. The reaction mixture was evaporated down under vacuum. The residue was dissolved in methanol (1.0 mL) then was added NaOH (6.0 N) (0.167 mL, 1.000 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 30 min. To the reaction mixture was HCl (6.0 N) (0.167 mL, 1.000 mmol), evaporated down under vacuum, purified by reverse phase HPLC (formic acid modifier) to give the title compound (13.7 mg, 0.019 mmol, 19.25% yield). LC/MS: m/z 712.4 (M+H).sup.+, 1.26 min (ret. time).

[0466] The compounds in Table 7 were prepared by a method similar to the one described for the preparation of 3-{[1-({1-[(tert-butoxy)carbonyl]piperidin-3-yl}methyl)-1H-1,2,3-triazol-4-yl]methoxy}-2,2-dimethyl-3-(4-methyl-3-{[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-2H-5,1λ.sup.62-benzoxathiazepin-2-yl]methyl}phenyl)propanoic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00012 TABLE 7 LCMS Retention Ex # Structure Name [M + H].sup.+ Time (min) Ex 19 [00121] 3-((1-(4- (Azidomethyl)benzyl)- 1H-1,2,3-triazol-4- yl)methoxy)-2,2- dimethyl-3-(4-methyl-3- (((R)-4-methyl-1,1- dioxido-3,4-dihydro-2H- benzo[b][1,4,5]oxa- thiazepin-2-yl) methyl)phenyl) propanoic acid 660.3 1.24 Ex 20 [00122] 3-((1-((1-(Tert- butoxycarbonyl)piperidin- 4-yl)methyl)-1H- 1,2,3-triazol-4- yl)methoxy)-2,2- dimethyl-3-(4-methyl-3- (((R)-4-methyl-1,1- dioxido-3,4-dihydro-2H- benzo[b][1,4,5] oxathiazepin- 2-yl)methyl)phenyl) propanoic acid 712.3 1.28 Ex 21 [00123] 3-((4-((2-Carboxy-1-(3- (((R)-4-ethyl-1,1- dioxido-3,4-dihydro-2H- benzo[b][1,4,5] oxathiazepin-2-yl) methyl)-4-methylphenyl)- 2-methylpropoxy)methyl)- 1H-1,2,3-triazol-1- yl)methyl)benzoic acid 663.0 1.12

Example 22

3′-((4-((2-Carboxy-1-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2-methylpropoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylic Acid

[0467] ##STR00124##

[0468] To the mixture of methyl 3-((1-(3-bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate (50 mg, 0.070 mmol) in 1,4-dioxane (1.5 mL) and water (0.5 mL) was added 4-boronobenzoic acid (17.49 mg, 0.105 mmol), K.sub.2CO.sub.3 (48.6 mg, 0.351 mmol) and Pd(Ph.sub.3P).sub.4 (4.06 mg, 3.51 μmol). The resulting reaction mixture was heated with microwave at 130° C. for 30 min. The reaction mixture was evaporated down under vacuum then was added methanol (1.5 mL) and NaOH (3.0 N) (0.187 mL, 0.562 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 30 min. To the reaction mixture was added HCl (3.0 N) (0.187 mL, 0.562 mmol), evaporated down under vacuum, purified by reverse phase HPLC (formic acid modifier) to give the title compound (35.1 mg, 0.048 mmol, 67.6% yield). LC/MS: m/z 739.5 (M+H).sup.+, 1.22 mi (ret. time).

[0469] The compounds in Table 8 were prepared by a method similar to the one described for the preparation of 4-{3-[(4-{[2-carboxy-1-(3-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1λ.sup.6,2-benzoxathiazepin-2-yl]methyl}-4-methylphenyl)-2,2-dimethylethoxy]methyl}-1H-1,2,3-triazol-1-yl)methyl]phenyl}benzoic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00013 TABLE 8 LCMS Retention Ex # Structure Name [M + H].sup.+ Time (min) Ex 23 [00125] 3′-((4-((2- Carboxy-1-(3- (((R)-4-ethyl-1,1- dioxido-3,4- dihydro-2H- benzo[b][1,4,5] oxathiazepin-2-yl) methyl)-4- methylphenyl)- 2-methylpropoxy) methyl)- 1H-1,2,3-triazol-1- yl)methyl)-[1,1′- biphenyl]- 3-carboxylic acid 739.5 1.24 Ex 24 [00126] 3′-((4-((2- Carboxy-1-(3- (((R)-4-ethyl-1,1- dioxido- 3,4-dihydro-2H- benzo[b][1,4,5] oxathiazepin-2- yl)methyl)- 4-methylphenyl)-2- methylpropoxy) methyl)- 1H-1,2,3-triazol-1-yl) methyl)-3-fluoro-[1,1′- biphenyl]-4-carboxylic acid 757.4 1.22 Ex 25 [00127] 3′-((4-((2-Carboxy-2- methyl-1-(4-methyl- 3-(((R)- 4-methyl-1,1-dioxido- 3,4-dihydro-2H- benzo[b][1,4,5] oxathiazepin-2- yl)methyl)phenyl) propoxy) methyl)-1H-1,2,3- triazol-1- yl)methyl)-[1,1′- biphenyl]-4- carboxylic acid 725.3 1.17 Ex 26 [00128] 3′-((4-((2-Carboxy-2- methyl-1-(4-methyl- 3-(((R)- 4-methyl-1,1-dioxido- 3,4-dihydro-2H- benzo[b][1,4,5] oxathiazepin- 2-yl)methyl)phenyl) propoxy)methyl)- 1H-1,2,3- triazol-1-yl)methyl)- [1,1′-biphenyl]- 3-carboxylic acid 725.3 1.19

Example 27

3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-((I-(3-((4-(hydroxymethyl)-11H-1,2,3-triazol-1-yl)methyl)-5-methylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoic Acid

[0470] ##STR00129##

(1-(3-(Azidomethyl)-5-methylbenzyl)-1H-1,2,3-triazol-4-yl)methanol

[0471] ##STR00130##

[0472] To the mixture of prop-2-yn-1-ol (0.116 mL, 2 mmol) in isopropanol (15 mL) and water (5 mL) was added sodium azide (650 mg, 10.00 mmol), DIEA (0.070 mL, 0.400 mmol), 1,3-bis(bromomethyl)-5-methylbenzene (1279 mg, 4.60 mmol) and copper(I) iodide (57.1 mg, 0.300 mmol). The resulting reaction mixture was heated with microwave at 70° C. for 60 min. The reaction mixture was evaporated down under vacuum, purified via flash chromatography to give the title compound (297.9 mg, 1.153 mmol, 57.7% yield). LC/MS: m/z 259.0 (M+H).sup.+, 0.72 min (ret. time).

[0473] The compounds in Table 9 were prepared by a method similar to the one described for the preparation of (1-(3-(Azidomethyl)-5-methylbenzyl)-1H-1,2,3-triazol-4-yl)methanol. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00014 TABLE 9 LCMS Retention Structure Name [M + H].sup.+ Time (min) [00131] (1-(3-(azidomethyl) benzyl)-1H-1,2,3- triazol-4-yl)methanol 244.9 0.61

3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-((1-(3-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoic Acid

[0474] ##STR00132##

[0475] To the mixture of methyl 3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (85 mg, 0.170 mmol) in isopropanol (1.5 mL) and tetrahydrofuran (0.7 mL) was added (1-(3-(azidomethyl)-5-methylbenzyl)-1H-1,2,3-triazol-4-yl)methanol (43.9 mg, 0.170 mmol), DIEA (8.91 μl, 0.051 mmol) and copper(I) iodide (6.48 mg, 0.034 mmol). The resulting reaction mixture was heated with microwave at 80° C. for 30 min. The reaction mixture was evaporated down under vacuum then was added methanol (2 mL), tetrahydrofuran (0.7 mL) and NaOH (3.0 N) (0.454 mL, 1.361 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 60 min. To the reaction mixture was added HCl (3.0 N) (0.454 mL, 1.361 mmol), evaporated down under vacuum, purified by reverse phase HPLC (formic acid modifier) to give the title compound (91.3 mg, 0.123 mmol, 72.1% yield). LC/MS: m/z 744.3 (M+H).sup.+, 1.13 min (ret. time).

[0476] The compounds in Table 10 were prepared by a method similar to the one described for the preparation of 3-(3-{[(4R)-4-ethyl-1,1-dioxo-3,4-dihydro-2H-5,1λ.sup.6,2-benzoxathiazepin-2-yl]methyl}-4-methylphenyl)-3-({1-[(3-{[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]methyl}-5-methylphenyl)methyl]-1H-1,2,3-triazol-4-yl}methoxy)-2,2-dimethylpropanoic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00015 TABLE 10 LCMS Retention Ex # Structure Name [M + H].sup.+ Time (min) Ex 28 [00133] 3-(3-(((R)-4-ethyl-1,1-dioxido- 3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepin- 2-yl)methyl)-4-methylphenyl)- 3-((1-(3-((4-(hydroxymethyl)- 1H-1,2,3-triazol-1- yl)methyl)benzyl)-1H-1,2,3- triazol-4-yl)methoxy)-2,2- dimethyl-propanoic acid 730.3 1.10 Ex 29 [00134] 3-((1-(3-((4-(Hydroxy-methyl)- 1H-1,2,3-triazol-1-yl)methyl)- 5-methylbenzyl)-1H-1,2,3- triazol-4-yl)methoxy)-2,2- dimethyl-3-(4-methyl-3-(((R)- 4-methyl-1,1-dioxido-3,4- dihydro-2H-benzo[b]- [1,4,5]oxathiazepin-2- yl)methyl)phenyl)propanoic acid 730.3 1.08

Example 30

3-((1-((1-(Cyclohexanecarbonyl)piperidin-4-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic Acid

[0477] ##STR00135##

tert-Butyl 4-((4-((3-methoxy-2,2-dimethyl-1-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-oxopropoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)piperidine-1-carboxylate

[0478] ##STR00136##

[0479] To the mixture of methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-(prop-2-yn-1-yloxy)propanoate (2.86 g, 5.89 mmol) in isopropanol (20 mL), tetrahydrofuran (10 mL) and water (8.0 mL) was added sodium azide (0.957 g, 14.72 mmol), DIEA (0.206 mL, 1.178 mmol), tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (3.77 g, 13.55 mmol) and copper(I) iodide (0.168 g, 0.883 mmol). The resulting reaction mixture was each heated with microwave at 80° C. for 1 h then heated again with microwave at 80° C. for 30 min. The reaction mixture was evaporated down under vacuum, purified via flash chromatography to give the title compound (1.5552 g, 2.142 mmol, 36.4% yield). LC/MS: m/z 726.5 (M+H).sup.+, 1.36 min (ret. time).

Methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-((1-(piperidin-4-ylmethyl)-1H-1,2,3-triazol-4-yl)methoxy)propanoate, Hydrochloride, 1,4-DIOXANE (SOLVATE)

[0480] ##STR00137##

[0481] To tert-butyl 4-((4-((3-methoxy-2,2-dimethyl-1-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-oxopropoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)piperidine-1-carboxylate (1.5 g, 2.066 mmol) was added HCl (4.0 M in p-dioxane) (2.58 ml, 10.33 mmol). The resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was evaporated down under vacuum to give the title compound (1.4198 g, 1.892 mmol, 92% yield). LC/MS: m/z 626.3 (M+H).sup.+, 1.00 min (ret. time).

3-((1-((1-(Cyclohexanecarbonyl)piperidin-4-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic Acid

[0482] ##STR00138##

[0483] To the mixture of methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-((1-(piperidin-4-ylmethyl)-1H-1,2,3-triazol-4-yl)methoxy)propanoate, hydrochloride (60 mg, 0.091 mmol) in dichloromethane (1.000 mL) was added DIEA (0.040 mL, 0.227 mmol) and cyclohexanecarbonyl chloride (0.015 mL, 0.109 mmol). The resulting reaction mixture was stirred at ambient temperature for 20 min. The reaction mixture was evaporated down under vacuum. The residue was dissolved in methanol (1.0 mL) then was added NaOH (6.0 N) (0.121 mL, 0.725 mmol). The resulting reaction mixture was heated with microwave at 100° C. for 30 min. To the reaction mixture was added HCl (6.0 N) (0.121 mL, 0.725 mmol), evaporated down under vacuum, purified by reverse phase HPLC (neutral), purified by reverse phase HPLC (formic acid modifier) to give the title compound (35.4 mg, 0.049 mmol, 54.1% yield). LC/MS: m/z 722.5 (M+H).sup.+, 1.22 min (ret. time).

[0484] The compounds in Table 11 were prepared by a method similar to the one described for the preparation of 3-({1-[(1-cyclohexanecarbonylpiperidin-4-yl)methyl]-1H-1,2,3-triazol-4-yl}methoxy)-2,2-dimethyl-3-(4-methyl-3-{[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-2H-5,1λ.sup.6,2-benzoxathiazepin-2-yl]methyl}phenyl)propanoic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00016 TABLE 11 LCMS Retention Ex # Structure Name [M + H].sup.+ Time (min) Ex 31 [00139] 3-((1-((1-Benzoylpiperidin-4- yl)methyl)-1H-1,2,3-triazol-4- yl)methoxy)-2,2-dimethyl-3- (4-methyl-3-(((R)-4-methyl- 1,1-dioxido-3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepin- 2-yl)methyl)phenyl)propanoic acid 716.5 1.15 Ex 32 [00140] 3-((1-((1-Acetylpiperidin-4- yl)methyl)-1H-1,2,3-triazol-4- yl)methoxy)-2,2-dimethyl-3- (4-methyl-3-(((R)-4-methyl- 1,1-dioxido-3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepin- 2-yl)methyl)phenyl) propanoic acid 654.4 1.01 Ex 33 [00141] 2,2-Dimethyl-3-(4-methyl-3- (((R)-4-methyl-1,1-dioxido- 3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepin- 2-yl)methyl)phenyl)-3-((1-((1- propionylpiperidin-4- yl)methyl)-1H-1,2,3-triazol-4- yl)methoxy)propanoic acid 668.4 1.06 Ex 34 [00142] 3-((1-((1-Butyrylpiperidin-4- yl)methyl)-1H-1,2,3-triazol-4- yl)methoxy)-2,2-dimethyl-3- (4-methyl-3-(((R)-4-methyl- 1,1-dioxido-3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepin- 2-yl)methyl)phenyl) propanoic acid 682. 1.10 Ex 35 [00143] 2,2-Dimethyl-3-(4-methyl-3- (((R)-4-methyl-1,1-dioxido- 3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepin- 2-yl)methyl)phenyl)-3-((1-((1- (tetrahydro-2H-pyran-4- carbonyl)piperidin-4- yl)methyl)-1H-1,2,3-triazol-4- yl)methoxy)propanoic acid 4724.5 1.04 Ex 36 [00144] 2,2-Dimethyl-3-(4-methyl-3- (((R)-4-methyl-1,1-dioxido- 3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepin- 2-yl)methyl)phenyl)-3-((1-((1- (methylsulfonyl)piperidin-4- yl)methyl)-1H-1,2,3-triazol-4- yl)methoxy)propanoic acid 690.3 1.08

Example 37

3-((1-(3-((4-Isopropyl-1H-1,2,3-triazol-1-yl)methyl)benzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic Acid

[0485] ##STR00145##

Methyl 3-((1-(3-(azidomethyl)benzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate

[0486] ##STR00146##

[0487] To the mixture of methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-(prop-2-yn-1-yloxy)propanoate (971 mg, 2.0 mmol) in isopropanol (12 mL) and water (4 mL) was added sodium azide (650 mg, 10.00 mmol), DIEA (0.070 mL, 0.400 mmol), 1,3-bis(bromomethyl)benzene (1214 mg, 4.60 mmol) and copper(I) iodide (57.1 mg, 0.300 mmol). The resulting reaction mixture was heated with microwave at 80° C. for 30 min. The reaction mixture was evaporated down under vacuum, purified by flash chromatography to give the title compound (691.1 mg, 1.026 mmol, 51.3% yield). LC/MS: m/z 674.3 (M+H).sup.+, 1.36 min (ret. time).

3-((1-(3-((4-Isopropyl-1H-1,2,3-triazol-1-yl)methyl)benzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic Acid

[0488] ##STR00147##

[0489] To the mixture of methyl 3-((1-(3-(azidomethyl)benzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate (50 mg, 0.074 mmol) in isopropanol (1.0 mL) and tetrahydrofuran (0.5 mL) was added 3-methylbut-1-yne (0.023 mL, 0.223 mmol), DIEA (3.89 μl, 0.022 mmol) and copper(I) iodide (2.83 mg, 0.015 mmol). The resulting reaction mixture was heated with microwave at 80° C. for 30 min (48-1). The reaction mixture was evaporated down under vacuum then was added methanol (1.5 mL) and NaOH (3.0 N) (0.198 mL, 0.594 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 60 min. To the reaction mixture was added HCl (3.0 N) (0.198 mL, 0.594 mmol), evaporated down under vacuum, purified by reverse phase HPLC (neutral), purified by reverse phase HPLC (formic acid modifier) to give the title compound (28.0 mg, 0.038 mmol, 51.8% yield). LC/MS: m/z 728.5 (M+H).sup.+, 1.22 min (ret. time).

[0490] The compounds in Table 12 were prepared by a method similar to the one described for the preparation of 2,2-dimethyl-3-(4-methyl-3-{[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-2H-5,1λ.sup.6,2-benzoxathiazepin-2-yl]methyl}phenyl)-3-({1-[(3-{[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]methyl}phenyl)methyl]-1H-1,2,3-triazol-4-yl}methoxy)propanoic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00017 TABLE 12 Re- LCMS tention Ex [M + Time # Structure Name H].sup.+ (min) Ex 38 [00148] 3-((1-((3-((4-Ethyl-1H- 1,2,3-triazol-1-yl) methyl)benzyl)-1H- 1,2,3-triazol-4-yl) methoxy)-2,2-dimethyl- 3-(4-methyl-3-(((R)-4- methyl-1,1-dioxido- 3,4-dihydro-2H-benzo [b][1,4,5]oxathiazepin- 2-yl)methyl)phenyl) propanoic acid 714.4 1.17 Ex 39 [00149] 3-((1-(3-((4-(Hydroxy- methyl)-1H-1,2,3-triazol- 1-yl)methyl)benzyl)- 1H-1,2,3-triazol-4-yl) methoxy)-2,2-dimethyl- 3-(4-methyl-3-(((R)-4- methyl-1,1-dioxido- 3,4-dihydro-2H-benzo [b][1,4,5]oxathiazepin- 2-yl)methyl)phenyl) propanoic acid 716.1 1.06 Ex 40 [00150] 3-((1-(3-((4-(2- Hydroxyethyl)-1H-1,2,3- triazol-1-yl)methyl) benzyl)-1H-1,2,3- triazol-4-yl)methoxy)- 2,2-dimethyl-3-(4- methyl-3-(((R)-4- methyl-1,1-dioxido- 3,4-dihydro-2H-benzo [b][1,4,5]oxathiazepin- 2-yl)methyl)phenyl) propanoic acid 730.5 1.06 Ex 41 [00151] 3-((1-(3-((4-(2- Hydroxypropan-2-yl)- 1H-1,2,3-triazol-1- yl)methyl)benzyl)-1H- 1,2,3-triazol-4-yl) methoxy)-2,2-dimethyl- 3-(4-methyl-3-(((R)-4- methyl-1,1-dioxido- 3,4-dihydro-2H-benzo [b][1,4,5]oxathiazepin- 2-yl)methyl)phenyl) propanoic acid 744.5 1.10 Ex 42 [00152] 3-((1-(3-((4-(4- Hydroxybutyl)-1H- 1,2,3-triazol-1-yl) methyl)benzyl)- 1H-1,2,3-triazol-4-yl) methoxy)-2,2-dimethyl- 3-(4-methyl-3- (((R)-4-methyl- 1,1-dioxido-3,4- dihydro-2H-benzo [b][1,4,5] oxathiazepin- 2-yl)methyl)phenyl) propanoic acid 758.4 1.07 Ex 43 [00153] 1-(3-((4-((2- Carboxy-2-methyl- 1-(4-methyl-3-(((R)-4- methyl-1,1-dioxido-3,4- dihydro-2H-[b][1,4,5] oxathiazepin-2-yl) methyl)phenyl)propoxy) methyl)-1H-1,2,3- triazol-1-yl)methyl) benzyl)-1H-1,2,3- triazole-4-carboxylic acid 730.4 1.06 Ex 44 [00154] 3-((1-(3-((4-(Carboxy- methyl)-1H-1,2,3- triazol-1-yl)methyl) benzyl)-1H-1,2,3- triazol-4-yl)methoxy)- 2,2-dimethyl-3-(4- methyl-3-(((R)-4- methyl-1,1-dioxido-3,4- dihydro-2H-benzo[b] [1,4,5]oxathiazepin- 2-yl)methyl)phenyl) propanoic acid 744.4 1.06 Ex 45 [00155] 3-((1-(3-((4-(2-Carboxy- ethyl)-1H-1,2,3- triazol-1-yl)methyl) benzyl)-1H-1,2,3- triazol-4-yl)methoxy)- 2,2-dimethyl-3-(4- methyl-3-(((R)-4- methyl-1,1-dioxido- 3,4-dihydro-2H-benzo [b][1,4,5]oxathiazepin- 2-yl)methyl)phenyl) propanoic acid 758.5 1.07

Example 46

(R,rel-(3S,3'S))-3,3′-(((1,1′-(1,4-phenylenebis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(methylene))bis(oxy))bis(2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic Acid)

[0491] ##STR00156##

[0492] To the mixture of rel-(S)-methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-(prop-2-yn-1-yloxy)propanoate (214 mg, 0.441 mmol) in isopropanol (4.0 mL) and water (1.2 mL) was added sodium azide (43.0 mg, 0.661 mmol), DIEA (0.015 mL, 0.088 mmol), copper(I) iodide (12.59 mg, 0.066 mmol) and 1,4-bis(bromomethyl)benzene (52.3 mg, 0.198 mmol). The resulting reaction mixture was stirred at 80° C. for 18 h. The reaction mixture was evaporated down under vacuum, extracted with DCM (3×5 mL), dried over Na.sub.2SO.sub.4, filtered, evaporated down under vacuum. The residue was dissolved in methanol (4.00 mL) and tetrahydrofuran (THF) (4.00 mL) then was added NaOH (3.0 N) (0.734 mL, 2.203 mmol). The resulting reaction mixture was heated with microwave at 100° C. for 30 min. The reaction mixture was acidified with HCl (3.0 N) (0.734 mL, 2.203 mmol), evaporated down under vacuum, purified by reverse phase HPLC (formic acid modifier) to give the title compound (69.8 mg, 0.062 mmol, 28.0% yield). LC/MS: m/z 1131.6 (M+H).sup.+, 1.36 min (ret. time).

[0493] The compounds in Table 13 were prepared by a method similar to the one described for the preparation of (3S)-3-{[1-({4-[(4-{[(1S)-2-carboxy-2,2-dimethyl-1-(4-methyl-3-{[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-2H-5,1λ.sup.6 2-benzoxathiazepin-2-yl]methyl}phenyl)ethoxy]methyl}-1H-1,2,3-triazol-1-yl)methyl]phenyl}methyl)-1H-1,2,3-triazol-4-yl]methoxy}-2,2-dimethyl-3-(4-methyl-3-{[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-2H-5,1λ.sup.6,2-benzoxathiazepin-2-yl]methyl}phenyl)propanoic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00018 TABLE 13 Re- LCMS tention Ex [M + Time # Structure Name H].sup.+ (min) Ex 47 [00157] (R)-3,3′- (((1,1′-(1,3- phenylenebis (methylene))bis (1H-1,2,3- triazole-4,1- diyl))bis (methylene)) bis(oxy))bis(3- (3-(((R)-4-ethyl- 1,1-dioxido-3,4- dihydro-2H- benzo[b][1,4,5] oxathiazepin-2- yl)methyl)- 4-methyl- phenyl)-2,2- dimethyl- propanoic acid) 1159.6 1.44 Ex 48 [00158] (R)-3,3′-(((1,1′- (1,4- phenylenebis (methylene))bis (1H-1,2,3- triazole- 4,1-diyl))bi s(methylene)) bis(oxy))bis(2, 2-dimethyl-3-(4- methyl-3-(((R)- 4-methyl-1,1- dioxido- 3,4-dihydro-2H- benzo[b][1,4,5] oxathiazepin-2- yl)methyl) phenyl) propanoic acid) 1131.6 1.36 Ex 49 [00159] (R,rel-(3R,3′R))- 3,3′-(((1,1′-(1,4- phenylenebis (methylene))bis (1H-1,2,3- triazole-4,1- diyl))bis (methylene)) bis(oxy))bis(2, 2-dimethyl-3-(4- methyl-3-(((R)- 4-methyl-1,1- dioxido-3,4- dihydro-2H- benzo[b][1,4,5] oxathiazepin- 2-yl)methyl) phenyl) propanoic acid) 1131.7 1.37 Ex 50 [00160] (R,rel-3S, rel-3′S)- 3,3′-(((1,1′- (oxybis(ethane- 2,1-diyl))bis (1H-1,2,3- triazole-4,1- diyl))bis (methylene)) bis(oxy))bis(2, 2-dimethyl-3-(4- methyl-3-(((R)- 4-methyl-1,1- dioxido- 3,4-dihydro-2H- benzo[b][1,4,5] oxathiazepin- 2-yl)methyl) phenyl) propanoic acid) 1099.7 1.33 Ex 51 [00161] (R,rel-3R, rel-3′R)- 3,3′-(((1,1′- (oxybis(ethane- 2,1-diyl))bis (1H-1,2,3- triazole-4,1- diyl))bis (methylene)) bis(oxy))bis(2, 2-dimethyl-3- (4-methyl- 3-(((R)-4- methyl-1,1- dioxido-3,4- dihydro-2H- benzo[b][1,4,5] oxathiazepin- 2-yl)methyl) phenyl) propanoic acid) 1099.8 1.33

Example 52

2,2-Dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-((1-((I-propylpiperidin-4-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid

[0494] ##STR00162##

[0495] To the mixture of methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-((1-(piperidin-4-ylmethyl)-1H-1,2,3-triazol-4-yl)methoxy)propanoate, hydrochloride (60 mg, 0.091 mmol) in dichloromethane (1.000 mL) was added DIEA (0.040 mL, 0.227 mmol) and iodopropane (10.58 μl, 0.109 mmol). The resulting reaction mixture was heated with microwave at 100° C. for 60 min. To the reaction mixture was added more iodopropane (4.41 μl, 0.045 mmol) and DIEA (0.016 mL, 0.091 mmol). The resulting reaction mixture was heated with microwave at 100° C. for 30 min. The reaction mixture was evaporated under vacuum. The residue was dissolved in methanol (1.0 mL) then was added NaOH (6.0 N) (0.121 mL, 0.725 mmol). The resulting reaction mixture was heated with microwave at 100° C. for 30 min. To the reaction mixture was added HCl (6.0 N) (0.121 mL, 0.725 mmol), evaporated down under vacuum, purified by reverse phase HPLC (neutral) to give the title compound (33.5 mg, 0.051 mmol, 56.6% yield). LC/MS: m/z 654.4 (M+H).sup.+, 0.82 min (ret. time).

Example 53

2,2-Dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-((1-(piperidin-4-ylmethyl)-1H-1,2,3-triazol-4-yl)methoxy)propanoic Acid, Formic Acid Salt

[0496] ##STR00163##

[0497] To the mixture of methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-((1-(piperidin-4-ylmethyl)-1H-1,2,3-triazol-4-yl)methoxy)propanoate, hydrochloride (60 mg, 0.091 mmol) in methanol (1.0 mL) was added NaOH (6.0 N) (0.091 mL, 0.544 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 30 min. To the reaction mixture was added HCl (6.0 N) (0.076 mL, 0.453 mmol), evaporated down under vacuum, purified by reverse phase HPLC (formic acid modifier) to give the title compound (32.1 mg, 0.049 mmol, 53.9% yield). LC/MS: m/z 612.3 (M+H).sup.+, 0.91 min (ret. time).

Example 54

3-(3-((N-(cycloheptylmethyl)acetamido)methyl)-4-methylphenyl)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoic Acid

[0498] ##STR00164##

[0499] To the mixture of methyl 3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (60 mg, 0.166 mmol) in dichloromethane (0.5 mL) was added SOCl.sub.2 (0.024 mL, 0.332 mmol). The resulting reaction mixture was stirred at ambient temperature for 10 min then was evaporated down under vacuum. This residue was dissolved acetonitrile (3.0 mL) and tetrahydrofuran (1.0 mL) then was added cycloheptylmethanamine (0.048 mL, 0.332 mmol) and DIEA (0.116 mL, 0.664 mmol). The resulting reaction mixture was heated with microwave at 100° C. for 1 h. To the reaction mixture was added DIEA (0.058 mL, 0.332 mmol) and acetyl chloride (0.024 mL, 0.332 mmol). The resulting reaction mixture was stirred at ambient temperature for 30 min. The reaction mixture was evaporated down under vacuum, redissolved in methanol (2.0 mL) then was added NaOH (3.0 N) (0.443 mL, 1.328 mmol). The resulting reaction mixture was heated with microwave at 80° C. for 20 min once then heated with microwave at 100° C. for 20 min twice. The reaction mixture was acidified with HCl (3.0 N) (0.443 mL, 1.328 mmol), evaporated down under vacuum, purified by reverse phase HPLC (formic acid modifier) to give the title compound (33.6 mg, 0.067 mmol, 40.6% yield). LC/MS: m/z 499.4 (M+H).sup.+, 1.18 min (ret. time).

Example 55

2,2-Dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-((1-((1′-methyl-[1,4′-bipiperidin]-4-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)propanoic Acid, Formic Acid Salt

[0500] ##STR00165##

[0501] To the mixture of methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-((1-(piperidin-4-ylmethyl)-1H-1,2,3-triazol-4-yl)methoxy)propanoate, hydrochloride (60 mg, 0.091 mmol) in dichloromethane (1.000 mL) was added 1-methylpiperidin-4-one (0.033 mL, 0.272 mmol) and sodium triacetoxyborohydride (57.6 mg, 0.272 mmol). The resulting reaction mixture was stirred at ambient temperature for 77 h. The reaction mixture was evaporated down under vacuum. The residue was dissolved in methanol (1.0 mL) then was added NaOH (6.0 N) (0.121 mL, 0.725 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 30 min. To the reaction mixture was added more NaOH (6.0 N) (0.045 mL, 0.272 mmol) then was heated with microwave at 120° C. for 60 min. To the reaction mixture was added HCl (6.0 N) (0.166 mL, 0.997 mmol), evaporated down under vacuum, purified by reverse phase HPLC (formic acid modifier) to give the title compound (43.7 mg, 0.058 mmol, 63.9% yield). LC/MS: m/z 709.4 (M+H).sup.+, 0.66 min (ret. time).

Example 56

3-((1-(3-Oxa-6-azaspiro[5.5]undecan-6-ium-9-ylmethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((S)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate

[0502] ##STR00166##

[0503] To the mixture of methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-((1-(piperidin-4-ylmethyl)-1H-1,2,3-triazol-4-yl)methoxy)propanoate, hydrochloride (60 mg, 0.091 mmol) in acetonitrile (1.0 mL) was added DIEA (0.063 mL, 0.362 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (9.46 mg, 0.041 mmol). The resulting reaction mixture was heated with microwave at 100° C. for 1 h. To the reaction mixture was added more 1-bromo-2-(2-bromoethoxy)ethane (9.46 mg, 0.041 mmol) and DIEA (0.063 mL, 0.362 mmol). The resulting reaction mixture was heated with microwave at 100° C. for 1 h (2×). The reaction mixture was evaporated down under vacuum. The residue was dissolved in methanol (1.0 mL) then was added NaOH (6.0 N) (0.121 mL, 0.725 mmol). The resulting reaction mixture was heated with microwave at 100° C. for 30 min twice. The reaction mixture was quenched with HCl (6.0 N) (0.121 mL, 0.725 mmol), evaporated under vacuum, purified by reverse phase HPLC (basic condition) to give the title compound (47.2 mg, 0.069 mmol, 76% yield). LC/MS*: m/z 682.3 (M+H).sup.+, 1.73 min (ret. time).

Example 57

4-(3-((4-((3-Methoxy-2,2-dimethyl-1-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-oxopropoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)picolinic Acid

[0504] ##STR00167##

Methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-((1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)methoxy)propanoate

[0505] ##STR00168##

[0506] To the mixture of methyl 3-((1-(3-bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate (0.86 g, 1.233 mmol) in N,N-dimethylformamide (10 mL) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.470 g, 1.849 mmol), PdCl.sub.2(dppf) (0.045 g, 0.062 mmol) and KOAc (0.242 g, 2.465 mmol). The resulting reaction mixture was heated with microwave at 100° C. for 60 min. The reaction mixture was evaporated down under vacuum, purified flash chromatograph to give the title compound (713.2 mg, 0.958 mmol, 78% yield). LC/MS: m/z 619.2 (M+H).sup.+, 1.32 min (ret. time).

4-(3-((4-((3-Methoxy-2,2-dimethyl-1-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-oxopropoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)picolinic Acid

[0507] ##STR00169##

[0508] To the mixture of methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-((1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazol-4-yl)methoxy)propanoate (50 mg, 0.067 mmol) in 1,4-dioxane (1.5 mL) and water (0.5 mL) was added methyl 4-bromopicolinate (17.41 mg, 0.081 mmol), K.sub.2CO.sub.3 (46.4 mg, 0.336 mmol) and Pd(Ph.sub.3P).sub.4 (3.88 mg, 3.36 μmol). The resulting reaction mixture was heated with microwave at 130° C. for 30 min. The reaction mixture was evaporated down under vacuum. To the residue was added methanol (1.5 mL) and then NaOH (3.0 N) (0.179 mL, 0.537 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 60 min. To the reaction mixture was added HCl (3.0 N) (0.179 mL, 0.537 mmol), evaporated down under vacuum, purified by reverse phase HPLC (formic acid modifier) to give the title compound (15.5 mg, 0.021 mmol, 31.2% yield). LC/MS: m/z 740.5 (M+H).sup.+, 1.11 min (ret. time).

[0509] The compounds in Table 14 were prepared by a method similar to the one described for the preparation of 4-{3-[(4-{[3-methoxy-2,2-dimethyl-1-(4-methyl-3-{[(4R)-4-methyl-1,1-dioxo-3,4-dihydro-2H-5,1λ.sup.6,2-benzoxathiazepin-2-yl]methyl}phenyl)-3-oxopropoxy]methyl}-1H-1,2,3-triazol-1-yl)methyl]phenyl}pyridine-2-carboxylic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00019 TABLE 14 Retention LCMS Time Ex # Structure Name [M + H].sup.+ (min) Ex 58 [00170] 6-(3-((4-((3-Methoxy-2,2- dimethyl-1-(4-methyl-3- (((R)-4-methyl-1,1-dioxido- 3,4-dihydro-2H-benzo[b] [1,4,5]oxathiazepin-2- yl)methyl)phenyl)-3- oxopropoxy)methyl)-1H- 1,2,3-triazol-1-yl)methyl)- phenyl)picolinic acid 740.4 1.25 Ex 59 [00171] 6-(3-((4-((3-Methoxy-2,2- dimethyl-1-(4-methyl-3- (((R)-4-methyl-1,1-dioxido- 3,4-dihydro-2H- benzo[b][1,4,5] oxathiazepin-2-yl)methyl) phenyl)-3-oxopropoxy) methyl)-1H-1,2,3- triazol-1-yl)methyl)- phenyl)nicotinic acid 740.5 1.22

Example 60

3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-difluoropropanoic Acid

[0510] ##STR00172##

(5-Bromo-2-methylphenyl)methanol

[0511] ##STR00173##

[0512] To a solution of 5-bromo-2-methylbenzoic acid (70 g, 326 mmol) in tetrahydrofuran (THF) (700 mL) stirred under nitrogen at 0° C. was added a toluene solution of borane-methyl sulfide complex (244 mL, 488 mmol) drop wise during 15 min. The reaction mixture was stirred for 16 h. The reaction was cooled to 0° C. and quenched with methanol (500 mL) drop wise. The reaction mixture was stirred at ambient temperature for 3 h and then concentrated. The crude residue was diluted with ethyl acetate (1 L) and washed with 1N HCl (500 mL), brine solution (500 mL) and dried over Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (49 g, 244 mmol, 74.9% yield). .sup.1H NMR (400 MHz, DMSO) δ=7.52 (d, J=2.6 Hz, 1H), 7.31 (dd, J=8.0, 2.2 Hz, 1H), 7.12-7.03 (m, 1H), 5.22 (td, J=5.5, 1.8 Hz, 1H), 4.48 (dd, J=5.1, 1.8 Hz, 2H), 2.17 (s, 3H).

4-Bromo-2-(((4-methoxybenzyl)oxy)methyl)-1-methylbenzene

[0513] ##STR00174##

[0514] To a solution of (5-bromo-2-methylphenyl)methanol (20 g, 99 mmol) in N,N-dimethylformamide (DMF) (120 mL) at 0° C. under nitrogen, sodium hydride (4.77 g, 119 mmol) was added in two portions. The reaction mixture was stirred at 0° C. for 20 min. Then 1-(chloromethyl)-4-methoxybenzene (17.14 g, 109 mmol) was added and the reaction mixture was stirred at 0° C. to 25° C. for 1 h. The reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (3×200 mL). The organic layer was washed with water (2×200 mL) and brine (2×200 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=4:1) to give the title compound 4-bromo-2-(((4-methoxybenzyl)oxy)methyl)-1-methylbenzene (25 g, 70.0 mmol, 70.4% yield) as yellow oil. LC/MS m/z 321.7 (M+H).sup.+, 1.90 min (ret. time).

3-(((4-Methoxybenzyl)oxy)methyl)-4-methylbenzaldehyde

[0515] ##STR00175##

[0516] To a solution of 4-bromo-2-(((4-methoxybenzyl)oxy)methyl)-1-methylbenzene (80 g, 249 mmol) in tetrahydrofuran (THF) (800 mL) at −78° C. under nitrogen, butyllithium (120 mL, 299 mmol) was carefully added. The reaction mixture was stirred at −78° C. for 65 min, and then DMF (38.6 mL, 498 mmol) was added. The reaction mixture was stirred at −78° C. to 25° C. for another 30 min. It was quenched with saturated NH.sub.4Cl (300 mL), and extracted with ethyl acetate (2×500 mL), the organic layer was washed with water (300 mL) and brine (2×100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was washed with petroleum ether/ethyl acetate=10/1 (2000 mL) to obtain the title compound 3-(((4-methoxybenzyl)oxy)methyl)-4-methylbenzaldehyde (50 g, 185 mmol, 74.3% yield) as a solid. LC-MS m/z 288.1 (M+H.sub.2O), 2.044 min (ret. time).

Ethyl 2,2-difluoro-3-hydroxy-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)propanoate

[0517] ##STR00176##

[0518] To a suspension of zinc dust (0.728 g, 11.14 mmol) in anhydrous THF (10 mL) was added ethyl 2-bromo-2,2-difluoroacetate (1.429 mL, 11.14 mmol) followed by chlorotrimethylsilane (0.095 mL, 0.743 mmol). The reaction mixture was stirred for 10 minutes until it cooled to 23° C. A solution of 3-(((4-methoxybenzyl)oxy)methyl)-4-methylbenzaldehyde (1.004 g, 3.71 mmol) in anhydrous THF (10 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred for 90 minutes at 25° C. The reaction was quenched with saturated NH.sub.4Cl sol. (10 mL), filtered, diluted with EtOAc and H.sub.2O, separated, and the aqueous layer was extracted three times with EtOAc. The combined organic portions were dried over MgSO.sub.4, filtered, and concentrated yielding a light yellow oil. The crude mixture was purified via flash chromatography to afford the title compound as light yellow oil (1.6910 g, 110%). .sup.1H NMR (DMSO-d.sub.6) δ: 7.37 (s, 1H), 7.21-7.32 (m, 3H), 7.17 (d, J=7.8 Hz, 1H), 6.92 (d, J=8.5 Hz, 2H), 6.54 (d, J=5.5 Hz, 1H), 5.02 (dt, J=17.8, 6.8 Hz, 1H), 4.49 (s, 2H), 4.47 (s, 2H), 4.27 (q, J=7.1 Hz, 2H), 3.75 (s, 3H), 2.25 (s, 3H), 1.23 (t, J=7.0 Hz, 3H).

Ethyl 2,2-difluoro-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-3-(prop-2-yn-1-yloxy)propanoate

[0519] ##STR00177##

[0520] To a solution of ethyl 2,2-difluoro-3-hydroxy-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)propanoate (1.16910 g, 4.29 mmol) and propargyl bromide (0.554 mL, 5.14 mmol, 80% solution in toluene) in anhydrous THF (43 mL), NaH (0.141 g, 5.57 mmol, 95%) was added and the reaction mixture was stirred for 20 minutes at 23° C. The reaction was quenched with saturated NH.sub.4Cl solution (10 mL) and diluted with H.sub.2O. The mixture was then separated and the aqueous later extracted with EtOAc three times. The combined organic extracts were concentrated and the residue was purified via flash chromatography to afford the title compound as an oil (502.7 mg, 25%). .sup.1H NMR (DMSO-d.sub.6) δ: 7.35 (s, 1H), 7.19-7.32 (m, 4H), 6.92 (d, J=8.5 Hz, 2H), 5.10 (dd, J=17.9, 7.4 Hz, 1H), 4.51 (s, 2H), 4.48 (s, 2H), 4.22-4.36 (m, 2H), 4.22-4.36 (m, 1H), 3.95 (dd, J=16.1, 2.0 Hz, 1H), 3.75 (s, 3H), 3.53-3.59 (m, 1H), 2.26 (s, 3H), 1.26 (t, J=7.0 Hz, 3H).

Ethyl 3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-difluoro-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)propanoate

[0521] ##STR00178##

[0522] To a suspension of NaN.sub.3 (32 mg, 0.486 mmol) in anhydrous acetonitrile (0.5 mL), iodoethane (0.04 mL, 0.486 mmol) was added and the reaction mixture was heated to reflux at 70° C. for 2 hours in a capped vial. The solution was subsequently cooled to 23° C. and added to a solution of CuI (1.762 mg, 9.25 μmol), DIPEA (3.22 μL, 0.018 mmol), acetic acid (1.058 μL, 0.018 mmol), and ethyl 2,2-difluoro-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-3-(prop-2-yn-1-yloxy)propanoate (100 mg, 0.231 mmol) anhydrous acetonitrile (0.25 mL). The resulting reaction mixture was stirred at 23° C. for 2 hours. Additional DIPEA (6.44 μL, 0.037 mmol), acetic acid (2.12 μL, 0.037 mmol) in anhydrous acetonitrile (few drops) were added to the reaction mixture which was then stirred for another 30 minutes at 23° C. Additional CuI (1.762 mg, 9.25p mol) was added and the reaction mixture was stirred for an additional 1 hour at 23° C. Additional CuI (3.52 mg, 0.018 mmol) was added and the reaction mixture was stirred for an additional 16 hours at 23° C. The solvent was subsequently removed under reduced pressure and the residue was suspended in DCM, filtered, and purified via flash chromatography to afford the title compound (55.7 mg, 45%). LC/MS: m/z 504.3 (M+H).sup.+, 1.26 min (ret. time)

Ethyl 3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-difluoro-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate

[0523] ##STR00179##

[0524] To a solution of ethyl 3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-difluoro-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)propanoate (20 mg, 0.040 mmol) in acetonitrile (0.2 mL) was added a solution of ceric ammonium nitrate (87 mg, 0.159 mmol) in H.sub.2O (0.2 mL) and the reaction mixture was stirred for 60 minutes at 23° C. The reaction mixture was diluted with EtOAc and H.sub.2O, separated, and the aqueous layer was extracted with EtOAc three times. The combined organic extracts were saved. A second batch of the ethyl 3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-difluoro-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)propanoat (23 mg, 0.046 mmol) in acetonitrile (0.2 mL) was prepared to which then a solution of ceric ammonium nitrate (100 mg, 0.183 mmol) in H.sub.2O (0.2 mL) was added and the reaction mixture was stirred for 45 minutes at 23° C. The reaction mixture was diluted with EtOAc and H.sub.2O, separated, and the aqueous layer was extracted with EtOAc four times. The organic extracts were combined with those from the first batch and concentrated under reduced pressure yielding the crude product mixture as a dark orange oil. The crude product was purified via flash chromatography to afford the title compound as a colorless oil (33.4 mg, 97%). LC/MS: m/z 384.2 (M+H).sup.+, 0.89 min (ret. time)

Ethyl 3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-difluoropropanoate

[0525] ##STR00180##

[0526] To a solution of ethyl 3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-difluoro-3-(3-(hydroxymethyl)-4-methylphenyl)propanoate (29.7 mg, 0.077 mmol) and (R)-4-ethyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide (21.13 mg, 0.093 mmol) in anhydrous THF (1.5 mL), (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (39.1 mg, 0.155 mmol) and tributylphosphine (0.04 mL, 0.155 mmol) were added and the reaction was stirred at 23° C. for 16 hours. The solvents were evaporated under reduced pressure and the remaining residue was suspended in DCM, filtered, and purified via flash chromatography to afford the title compound as a light yellow oil (48.5 mg, 100%). LC/MS: m/z 593.3 (M+H).sup.+, 1.26 min (ret. time)

3-(3-(((R)-4-Ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-difluoropropanoic Acid

[0527] ##STR00181##

[0528] To a solution of ethyl 3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-difluoropropanoate (48.5 mg, 0.082 mmol) in EtOH (0.1 mL) was added H.sub.2O (0.1 mL) followed by 2N NaOH (90 μl, 0.180 mmol) and the mixture was heated to 60° C. for 60 minutes. The solvents were evaporated under reduced pressure. A base extraction was attempted; however the desired compound was noted to remain in the organic layer. The solvents were once again removed under reduced pressure with heating. The resulting solid was redissolved in 3 N HCl (6 mL) solution and EtOAc (6 mL). The mixture was separated and the aqueous layer extracted three times with EtOAc. The combined organic extracts were dried over MgSO.sub.4, filtered, and concentrated yielding a light yellow oil (35.8 mg) which was purified via reverse phase chromatography to afford the title compound (9.9 mg, 19%). LC/MS: m/z 565.1 (M+H).sup.+, 1.04 min (ret. time).

Example 61

(3R)-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((S)-4-methyl-1,1-dioxido-4,5-dihydropyrido[4,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)propanoic Acid

[0529] ##STR00182##

[0530] To the mixture of methyl (R)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (54.2 mg, 0.15 mmol) in tetrahydrofuran (2 mL) was added (S)-4-methyl-2,3,4,5-tetrahydropyrido[4,3-f][1,2]thiazepine 1,1-dioxide (47.8 mg, 0.225 mmol), PS—PPh.sub.3 (188 mg, 0.300 mmol) and DIAD (0.058 mL, 0.300 mmol). The resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was then filtered, evaporated down under vacuum. The residue was dissolved in methanol (2.000 mL) after which was added NaOH (6.0 N) (0.200 mL, 1.200 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 30 min. To the reaction mixture was added HCl (6.0 N) (0.200 mL, 1.200 mmol), evaporated down under vacuum, purified with reverse phase HPLC (formic acid modifier) to give the title product (34.2 mg, 0.063 mmol, 42.1% yield). LC/MS: m/z 542.4 (M+H).sup.+, 0.96 min (ret. time).

[0531] The compounds in Table 15 were prepared by a method similar to the one described for the preparation of (3R)-(((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((S)-4-methyl-1,1-dioxido-4,5-dihydropyrido[4,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)propanoic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00020 TABLE 15 LCMS Retention Ex # Structure Name [M + H].sup.+ Time (min) Ex 62 [00183] (3R)-((1-ethyl-1H-1,2,3- triazol-4-yl)methoxy)-2,2- dimethyl-3-(4-methyl-3-(((S)- 4-methyl-1,1-dioxido-4,5- dihydropyrido[2,3- f][1,2]thiazepin-2(3H)- yl)methyl)phenyl)propanoic acid 542.4 0.98 Ex 63 [00184] (3S)-((1-ethyl-1H-1,2,3- triazol-4-yl)methoxy)-2,2- dimethyl-3-(4-methyl-3-(((R)- 4-methyl-1,1-dioxido-4,5- dihydropyrido[4,3- f][1,2]thiazepin-2(3H)- yl)methyl)phenyl)propanoic acid 542.3 0.96 Ex 64 [00185] (3S)-((1-ethyl-1H-1,2,3- triazol-4-yl)methoxy)-2,2- dimethyl-3-(4-methyl-3-(((R)- 4-methyl-1,1-dioxido-4,5- dihydropyrido[2,3- f][1,2]thiazepin-2(3H)- yl)methyl)phenyl)propanoic acid 542.4 0.99 Ex 65 [00186] (3S)-((1-ethyl-1H-1,2,3- triazol-4-yl)methoxy)-2,2- dimethyl-3-(4-methyl-3-(((R)- 4-methyl-1,1-dioxido-4,5- dihydrobenzo[f][1,2] thiazepin-2(3H)-yl)methyl) phenyl)propanoic acid 541.4 1.15 Ex 66 [00187] (3R)-((1-ethyl-1H-1,2,3- triazol-4-yl)methoxy)-2,2- dimethyl-3-(4-methyl-3-(((R)- 4-methyl-1,1-dioxido-4,5- dihydropyrido[4,3- f][1,2]thiazepin-2(3H)- yl)methyl)phenyl)propanoic acid 542.4 0.95 Ex 67 [00188] (R)-2,2-dimethyl-3-(4-methyl- 3-(((R)-4-methyl-1,1-dioxido- 4,5-dihydropyrido[4,3- f][1,2]thiazepin-2(3H)- yl)methyl)phenyl)-3-((1- propyl-1H-1,2,3-triazol-4- yl)methoxy)propanoic acid 556.4 1.01 Ex 68 [00189] (3R)-((1-ethyl-1H-1,2,3- triazol-4-yl)methoxy)-2,2- dimethyl-3-(4-methyl-3-(((R)- 4-methyl-1,1-dioxido-4,5- dihydropyrido[2,3- f][1,2]thiazepin-2(3H)- yl)methyl)phenyl)propanoic acid 542.4 0.99 Ex 69 [00190] (3S)-((1-ethyl-1H-1,2,3- triazol-4-yl)methoxy)-2,2- dimethyl-3-(4-methyl-3-(((R)- 4-ethyl-1,1-dioxido-4,5- dihydrobenzo[f][1,2]thiazepin- 2(3H)- yl)methyl)phenyl)propanoic acid 555.4 1.22 Ex 70 [00191] (3R)-((1-ethyl-1H-1,2,3- triazol-4-yl)methoxy)-2,2- dimethyl-3-(4-methyl-3-(((R)- 4-methyl-1,1-dioxido-4,5- dihydrobenzo[f] [1,2]thiazepin-2(3H)- yl)methyl)phenyl)propanoic acid 541.4 1.16 Ex 71 [00192] (3S)-((1-(2-(2- methoxyethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)methoxy)- 2,2-dimethyl-3-(4-methyl-3- (((R)-4-methyl-1,1-dioxido- 3,4-dihydro-2H-benzo[b] [1,4,5]oxathiazepin-2-yl) methyl)phenyl)propanoic acid 617.4 1.06 Ex 72 [00193] (3S)-((1-ethyl-1H-1,2,3- triazol-4-yl)methoxy)-2,2- dimethyl-3-(4-methyl-3-(((S)- 4-methyl-1,1-dioxido-4,5- dihydropyrido[2,3-f][1,2] thiazepin-2(3H)-yl) methyl)phenyl)propanoic acid 542.4 0.99 Ex 73 [00194] (3S)-((1-ethyl-1H-1,2,3- triazol-4-yl)methoxy)-2,2- dimethyl-3-(4-methyl-3-(((R)- 4-methyl-1,1-dioxido-4,5- dihydropyrido[4,3- f][1,2]thiazepin-2(3H)- yl)methyl)phenyl)propanoic acid 542.4 0.96 Ex 74 [00195] 3-(3-(((3-Bromo-N-(pyridin-2- ylmethyl)phenyl)sulfonamido) methyl)-4-methylphenyl)-3- ((1-ethyl-1H-1,2,3-triazol-4- yl)methoxy)-2,2- dimethylpropanoic acid 658.2 1.09 Ex 75 [00196] (3S)-((1-ethyl-1H-1,2,3- triazol-4-yl)methoxy)-2,2- dimethyl-3-(4-methyl-3-(((S)- 4-methyl-1,1-dioxido-4,5- dihydrobenzo[f][1,2]thiazepin- 2(3H)- yl)methyl)phenyl)propanoic acid 541.4 1.15 Ex 76 [00197] (3R)-(3-(((R)-8-fluoro-4- methyl-1,1-dioxido-4,5- dihydrobenzo[f][1,2]thiazepin- 2(3H)-yl)methyl)-4- methylphenyl)-2,2-dimethyl-3- ((1-propyl-1H-1,2,3-triazol-4- yl)methoxy)propanoic acid 573.4 1.24 Ex 77 [00198] (3R)-((1-ethyl-1H-1,2,3- triazol-4-yl)methoxy)-2,2- dimethyl-3-(4-methyl-3-(((R)- 4-ethyl-1,1-dioxido-4,5- dihydrobenzo[f][1,2] thiazepin-2(3H)- yl)methyl)phenyl)propanoic acid 555.4 1.21 Ex 78 [00199] (R)-3-(3-((4,4-dimethyl-1,1- dioxido-3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepin- 2-yl)methyl)-4-methylphenyl)- 2,2-dimethyl-3-((1-propyl-1H- 1,2,3-triazol-4- yl)methoxy)propanoic acid 571.4 1.15 Ex 79 [00200] (R)-2,2-dimethyl-3-(4-methyl- 3-(((R)-4-methyl-1,1-dioxido- 8-(trifluoromethyl)-4,5- dihydrobenzo[f][1,2]thiazepin- 2(3H)-yl)methyl)phenyl)-3-((1- propyl-1H-1,2,3-triazol-4- yl)methoxy)propanoic acid 623.5 1.32 Ex 80 [00201] (R)-3-((1-(2-(2- methoxyethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)methoxy)- 2,2-dimethyl-3-(4-methyl-3- (((R)-4-methyl-1,1-dioxido- 3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepin- 2-yl)methyl)phenyl)propanoic acid 617.3 1.06 Ex 81 [00202] (3S)-((1-ethyl-1H-1,2,3- triazol-4-yl)methoxy)-2,2- dimethyl-3-(4-methyl-3-(((S)- 4-ethyl-1,1-dioxido-4,5- dihydrobenzo[f][1,2]thiazepin- 2(3H)- yl)methyl)phenyl)propanoic acid 555.4 1.20 Ex 82 [00203] (R)-3-(3-(((R)-4-ethyl-1,1- dioxido-3,4-dihydro-2H- pyrido[3,2- b][1,4,5]oxathiazepin-2- yl)methyl)-4-methylphenyl)-3- ((1-ethyl-1H-1,2,3-triazol-4- yl)methoxy)-2,2- dimethylpropanoic acid 558.4 0.99 Ex 83 [00204] (R)-2,2-dimethyl-3-(4-methyl- 3-(((S)-4-methyl-1,1-dioxido- 4,5-dihydropyrido[4,3- f][1,2]thiazepin-2(3H)- yl)methyl)phenyl)-3-((1- propyl-1H-1,2,3-triazol-4- yl)methoxy)propanoic acid 556.4 1.01 Ex 84 [00205] (3R)-((1-ethyl-1H-1,2,3- triazol-4-yl)methoxy)-2,2- dimethyl-3-(4-methyl-(((S)- 4-methyl-1,1-dioxido-4,5- dihydrobenzo[f][1,2]thiazepin- 2(3H)- yl)methyl)phenyl)propanoic acid 541.4 1.15 Ex 85 [00206] (3R)-((1-ethyl-1H-1,2,3- triazol-4-yl)methoxy)-2,2- dimethyl-3-(4-methyl-3-(((S)- 4-ethyl-1,1-dioxido-4,5- dihydrobenzo[f][1,2]thiazepin- 2(3H)- yl)methyl)phenyl)propanoic acid 555.4 1.21 Ex 86 [00207] (R)-2,2-dimethyl-3-(4-methyl- 3-(((S)-4-methyl-1,1-dioxido- 8-(trifluoromethyl)-4,5- dihydrobenzo[f][1,2]thiazepin- 2(3H)-yl)methyl)phenyl)-3-((1- propyl-1H-1,2,3-triazol-4- yl)methoxy)propanoic acid 623.5 1.32 Ex 87 [00208] (R)-3-(3-(((S)-8-fluoro-4- methyl-1,1-dioxido-4,5- dihydrobenzo[f][1,2]thiazepin- 2(3H)-yl)methyl)-4- methylphenyl)-2,2-dimethyl-3- ((1-propyl-1H-1,2,3-triazol-4- yl)methoxy)propanoic acid 573.4 1.23 Ex 88 [00209] (R)-2,2-dimethyl-3-(4-methyl- 3-(((S)-4-methyl-1,1-dioxido- 4,5- dihydrobenzo[f][1,2]thiazepin- 2(3H)-yl)methyl)phenyl)-3-((1- propyl-1H-1,2,3-triazol-4- yl)methoxy)propanoic acid 555.2 1.18 Ex 89 [00210] (R)-2,2-dimethyl-3-(4-methyl- 3-(((S)-4-methyl-1,1-dioxido- 4,5-dihydropyrido[2,3- f][1,2]thiazepin-2(3H)- yl)methyl)phenyl)-3-((1- propyl-1H-1,2,3-triazol-4- yl)methoxy)propanoic acid 556.2 1.02 Ex 90 [00211] (R)-3-(3-(((R)-4-ethyl-1,1- dioxido-3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepin- 2-yl)methyl)-4-methylphenyl)- 2,2-dimethyl-3-((1-propyl-1H- 1,2,3-triazol-4- yl)methoxy)propanoic acid 571.2 1.16

Example 91

(R)-3-((N-(5-(2-carboxy-1-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2-methylpropyl)-2-methylbenzyl)phenylsulfonamido)methyl)benzoic Acid

[0532] ##STR00212##

Tert-butyl (R)-3-((N-(5-(1-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-methoxy-2,2-dimethyl-3-oxopropyl)-2-methylbenzyl)phenylsulfonamido)methyl)benzoate

[0533] ##STR00213##

[0534] To the mixture of methyl (R)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethylpropanoate (100 mg, 0.277 mmol in dichloromethane (1 mL) was added SOCl.sub.2 (0.101 mL, 1.383 mmol). The resulting reaction mixture was stirred at ambient temperature for 30 min then was evaporated down under vacuum. The residue was dissolved in acetonitrile (4 mL) after which was added tert-butyl 3-(aminomethyl)benzoate (86 mg, 0.415 mmol) and DIEA (0.193 mL, 1.107 mmol). The resulting reaction mixture was heated with microwave at 100° C. for 1 h after which was added benzenesulfonyl chloride (0.054 mL, 0.415 mmol). The resulting reaction mixture was stirred at ambient temperature for 1 h before was quenched with water (0.2 mL), evaporated down under vacuum, purified via flash chromatography over silica gel to give the title compound (95.7 mg, 0.139 mmol, 50.1% yield). LC/MS: m/z 691.4 (M+H).sup.+, 1.47 min (ret. time).

(R)-3-((N-(5-(2-carboxy-1-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-2-methylpropyl)-2-methylbenzyl)phenylsulfonamido)methyl)benzoic Acid

[0535] ##STR00214##

[0536] To tert-butyl (R)-3-((N-(5-(1-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-methoxy-2,2-dimethyl-3-oxopropyl)-2-methylbenzyl)phenylsulfonamido)methyl)benzoate (95 mg, 0.138 mmol) was added HCl (4.0 M in p-dioxane) (0.344 mL, 1.375 mmol). The resulting reaction mixture was stirred at ambient temperature for 2 h then was evaporated down under vacuum. The residue was dissolved in methanol (2 mL) after which was added NaOH (6.0 N) (0.183 mL, 1.100 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 1 h after which was added with HCl (6.0 N) (0.183 mL, 1.100 mmol), evaporated down under vacuum, extracted with DCM (3×5 mL), dried over MgSO.sub.4, filtered, evaporated down under vacuum to give the title product (70.6 mg, 0.114 mmol, 83% yield). LC/MS: m/z 621.3 (M+H).sup.+, 1.05 min (ret. time).

Example 92

(R)-3-(N-(5-(2-carboxy-2-methyl-1-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propyl)-2-methylbenzyl)-N-(3-carboxybenzyl)sulfamoyl)benzoic Acid

[0537] ##STR00215##

Methyl (R)-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate

[0538] ##STR00216##

[0539] To the mixture of methyl (R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate (160 mg, 0.426 mmol) in dichloromethane (1.0 mL) was added thionyl chloride (0.155 mL, 2.131 mmol). The resulting reaction mixture was stirred at ambient temperature for 2 h then was evaporated down under vacuum to give the title compound (185.4 mg, 0.471 mmol, 110% yield). LC/MS: m/z 394.2 (M+H).sup.+, 1.17 min (ret. time).

Tert-butyl (R)-3-(((N-(5-(3-methoxy-2,2-dimethyl-3-oxo-1-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propyl)-2-methylbenzyl)-3-(methoxycarbonyl)phenyl)sulfonamido)methyl)benzoate

[0540] ##STR00217##

[0541] To the mixture of methyl (R)-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate (90 mg, 0.228 mmol) in acetonitrile (3 mL) was added tert-butyl 3-(aminomethyl)benzoate (71.0 mg, 0.343 mmol) and DIEA (0.160 mL, 0.914 mmol). The resulting reaction mixture was heated with microwave at 100° C. for 1 h after which was added methyl 3-(chlorosulfonyl)benzoate (80 mg, 0.343 mmol). The resulting reaction mixture was stirred at ambient temperature for 23 h then was evaporated down under vacuum, purified via flash chromatography over silica gel to give the title compound (103.6 mg, 0.136 mmol, 59.4% yield). LC/MS: m/z 763.5 (M+H).sup.+, 1.48 min (ret. time).

(R)-3-(N-(5-(2-carboxy-2-methyl-1-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propyl)-2-methylbenzyl)-N-(3-carboxybenzyl)sulfamoyl)benzoic Acid

[0542] ##STR00218##

[0543] To tert-butyl (R)-3-(((N-(5-(3-methoxy-2,2-dimethyl-3-oxo-1-((1-propyl-1H-1,2,3-triazol-4-yl)methoxy)propyl)-2-methylbenzyl)-3-(methoxycarbonyl)phenyl)sulfonamido)methyl)benzoate (103 mg, 0.135 mmol) was added HCl (4.0 M in p-dioxane) (0.338 mL, 1.350 mmol). The resulting reaction mixture was stirred at ambient temperature for 3 h then was evaporated down under vacuum. The residue was dissolved in methanol (2 mL) after which was added NaOH (6.0 N) (0.180 mL, 1.080 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 1 h then was quenched with HCl (6.0 N) (0.180 mL, 1.080 mmol), evaporated down under vacuum, extracted with DCM (3×5 mL), dried over MgSO.sub.4, filtered, evaporated down under vacuum to give the title compound (96.5 mg, 0.142 mmol, 105% yield). LC/MS: m/z 679.4 (M+H).sup.+, 1.00 min (ret. time).

Example 93

(R)-3-(N-(5-(2-carboxy-1-((1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-methylpropyl)-2-methylbenzyl)-N-(pyridin-2-ylmethyl)sulfamoyl)benzoic Acid

[0544] ##STR00219##

[0545] To the mixture of methyl (R)-3-(3-(hydroxymethyl)-4-methylphenyl)-3-((1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoate (50 mg, 0.128 mmol) in dichloromethane (0.5 mL) was added SOCl.sub.2 (0.047 mL, 0.639 mmol). The resulting reaction mixture was stirred at ambient temperature for 30 min then was evaporated down under vacuum. The residue was dissolved in acetonitrile (2 mL) after which was added pyridin-2-ylmethanamine (0.020 mL, 0.192 mmol) and DIEA (0.089 mL, 0.511 mmol). The resulting reaction mixture was heated with microwave at 100° C. for 1 h after which methyl 3-(chlorosulfonyl)benzoate (45.0 mg, 0.192 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 30 min after which was added more DIEA (0.089 mL, 0.511 mmol). The resulting reaction mixture was stirred at ambient temperature for 1 h then was evaporated down under vacuum. The residue was dissolved in methanol (1 mL) and was added NaOH (6.0 N) (0.170 mL, 1.022 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 1 h then was quenched with HCl (6.0 N) (0.170 mL, 1.022 mmol), evaporated down under vacuum, purified with reverse phase HPLC (formic acid modifier) to give the title compound (23.7 mg, 0.036 mmol, 28.5% yield). LC/MS: m/z 652.4 (M+H).sup.+, 0.83 min (ret. time).

[0546] The compounds in Table 16 were prepared by a method similar to the one described for the preparation of (R)-3-(N-(5-(2-carboxy-1-((1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-methylpropyl)-2-methylbenzyl)-N-(pyridin-2-ylmethyl)sulfamoyl)benzoic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00021 TABLE 16 Retention LCMS Time Ex # Structure Name [M + H].sup.+ (min) Example 94 [00220] (R)-3-(N-benzyl-N-(5-(2- carboxy-1-((1-(2- methoxyethyl)-1H-1,2,3- triazol-4-yl)methoxy)-2- methylpropyl)-2- methylbenzyl)sulfamoyl) benzoic acid 651.4 1.08 Example 95 [00221] 3-(N-benzyl-N-(5-(2-carboxy- 1-((1-ethyl-1H-1,2,3-triazol-4- yl)methoxy)-2-methylpropyl)- 2-methylbenzyl)sulfamoyl) benzoic acid 621.5 1.11 Example 96 [00222] 3-(3-(((N-cyclohexyl-3- methoxyphenyl)sulfamido) methyl)-4-methylphenyl)-3- ((1-ethyl-1H-1,2,3-triazol-4- yl)methoxy)-2,2- dimethylpropanoic acid 599.3 1.28 Example 97 [00223] 3-(3-(((N-cyclohexyl-4- methoxyphenyl)sulfonamido) methyl)-4-methylphenyl)-3- ((1-ethyl-1H-1,2,3-triazol-4- yl)methoxy)-2,2- dimethylpropanoic acid 599.3 1.26 Example 98 [00224] 3-(3-((N- cyclohexylphenylsulfonamido) methyl)-4-methylphenyl)-3- ((1-ethyl-1H-1,2,3-triazol-4- yl)methoxy)-2,2- dimethylpropanoic acid 569.3 1.26 Example 99 [00225] 3-(3-((N- benzylphenylsulfonamido) methyl)-4-methylphenyl)-3-((1- ethyl-1H-1,2,3-triazol-4- yl)methoxy)-2,2- dimethylpropanoic acid 577.2 1.21

Example 100

3-((1-((1-Carbamoylpiperidin-4-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic Acid

[0547] ##STR00226##

[0548] To the mixture of methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-((1-(piperidin-4-ylmethyl)-1H-1,2,3-triazol-4-yl)methoxy)propanoate, hydrochloride (60 mg, 0.091 mmol) in dichloromethane (1.000 mL) was added DIEA (0.040 mL, 0.227 mmol) and AcCl (9.66 μl, 0.136 mmol). The resulting reaction mixture was stirred at ambient temperature for 20 min then was evaporated down under vacuum. The residue was dissolved in methanol (1.0 mL) after which was added NaOH (6.0 N) (0.121 mL, 0.725 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 30 min twice after which was added HCl (6.0 N) (0.121 mL, 0.725 mmol) and dimethyl sulfoxide (1.000 mL), and evaporated down under vacuum. To the resulting dimethyl sulfoxide solution was added DIEA (0.040 mL, 0.227 mmol) and TMS-NCO (0.025 mL, 0.181 mmol). The resulting reaction mixture was stirred at ambient temperature for 69 h then was quenched with HCl (6.0 N) (0.015 mL, 0.091 mmol), purified by reverse phase HPLC (formic acid modifier) to give the title (8.7 mg, 0.013 mmol, 14.67% yield). LC/MS: m/z 655.4 (M+H).sup.+, 0.97 min (ret. time).

Example 101

3-((1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoic Acid

[0549] ##STR00227##

[0550] To the mixture of methyl 3-((1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)propanoate (60 mg, 0.114 mmol) in methanol (1.0 mL) was added NaOH (6.0 N) (0.095 mL, 0.568 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 30 min after which was added HCl (6.0 N) (0.095 mL, 0.568 mmol), evaporated down under vacuum, purified by reverse phase HPLC (formic acide modifier) to give the title compound (24.9 mg, 0.048 mmol, 42.6% yield). LC/MS: m/z 515.3 (M+H).sup.+, 1.03 min (ret. time).

Example 102

Rel-(R)-2,2-dimethyl-3-(4-methyl-3-(((S)-4-methyl-1,1-dioxido-4,5-dihydropyrido[4,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-3-((1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propanoic Acid

[0551] ##STR00228##

[0552] To the mixture of rel-(R)-methyl 2,2-dimethyl-3-(4-methyl-3-(((S)-4-methyl-1,1-dioxido-4,5-dihydropyrido[4,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-3-(prop-2-yn-1-yloxy)propanoate (50 mg, 0.103 mmol) in isopropanol (0.5 mL) and tetrahydrofuran (0.5 mL) was added DIEA (3.60 μl, 0.021 mmol), 3-azidooxetane (0.5 M in MTBE) (0.619 mL, 0.310 mmol) and copper(I) iodide (2.95 mg, 0.015 mmol). The resulting reaction mixture was heated with microwave at 70° C. for 30 min then was evaporated down under vacuum. To the residue was added methanol (1.5 mL) and then NaOH (6 N) (0.172 mL, 1.032 mmol). The resulting reaction mixture was heated with microwave at 80° C. for 30 min after which was added a solution of HCl (6 N) (0.172 mL, 1.032 mmol) in methanol (1.5 mL), evaporated down under vacuum (80-4) and purified with reverse phase HPLC (with 0.1% formic acid) to give the title compound (43.4 mg, 0.076 mmol, 73.8% yield). LC/MS: m/z 570.4 (M+H).sup.+, 0.94 min (ret. time).

[0553] The compounds in Table 17 were prepared by a method similar to the one described for the preparation of rel-(R)-2,2-dimethyl-3-(4-methyl-3-(((S)-4-methyl-1,1-dioxido-4,5-dihydropyrido[4,3-f][1,2]thiazepin-2(3H)-yl)methyl)phenyl)-3-((1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00022 TABLE 17 Retention LCMS Time Ex # Structure Name [M + H].sup.+ (min) Example 103 [00229] Rel-(S)-2,2-dimethyl-3-(4- methyl-3-(((S)-4-methyl-1,1- dioxido-4,5-dihydropyrido [4,3-f][1,2]thiazepin-2(3H)- yl)methyl)phenyl)-3-((1- (oxetan-3-yl)-1H-1,2,3-triazol- 4-yl)methoxy)propanoic acid 570.3 0.94

Example 104

2,2-Dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-((1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propanoic Acid

[0554] ##STR00230##

[0555] To the mixture of methyl 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-(prop-2-yn-1-yloxy)propanoate (0.060 g, 0.124 mmol) in isopropanol (1.0 mL) and tetrahydrofuran (0.5 mL) was added 3-azidooxetane (3.0 M in MTBE) (0.494 mL, 0.247 mmol), DIEA (4.32 μl, 0.025 mmol) and copper(I) iodide (3.53 mg, 0.019 mmol). The resulting reaction mixture was heated with microwave at 80° C. for 30 min then was evaporated down under vacuum. The residue was dissolved methanol (1.0 mL) after which was added NaOH (6.0 N) (0.165 mL, 0.988 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 30 min after which was added HCl (6.0 N) (0.165 mL, 0.988 mmol), evaporated down under vacuum and purified by reverse phase HPLC (formic acid modifier) to give the title compound (16.5 mg, 0.029 mmol, 23.40% yield). LC/MS: m/z 571.3 (M+H).sup.+, 1.04 min (ret. time).

[0556] The compounds in Table 18 were prepared by a method similar to the one described for the preparation of 2,2-dimethyl-3-(4-methyl-3-(((R)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)phenyl)-3-((1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00023 TABLE 18 Retention LCMS Time Ex # Structure Name [M + H].sup.+ (min) Example 105 [00231] 3-(3-(((R)-4-ethyl-1,1-dioxido- 3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepin- 2-yl)methyl)-4-methylphenyl)- 2,2-dimethyl-3-((1-((oxetan-3- yl)-1H-1,2,3-triazol-4- yl)methoxy)propanoic acid 585.3 1.09

Example 106

3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-((1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoic Acid

[0557] ##STR00232##

[0558] To the mixture of 1-bromo-2-methoxyethane (0.056 mL, 0.600 mmol) in N,N-dimethylformamide (1.0 mL) was added sodium azide (39.0 mg, 0.600 mmol). The resulting reaction mixture was stirred at 80° C. for 5.5 h. The reaction mixture was cooled to ambient temperature after which was added isopropanol (1.0 mL), tetrahydrofuran (1.0 mL), methyl 3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (100 mg, 0.200 mmol), DIEA (6.99 μl, 0.040 mmol), water (0.6 mL) and copper(I) iodide (5.72 mg, 0.030 mmol). The resulting reaction mixture was heated with microwave at 80° C. for 30 min then was evaporated down under vacuum. The residue was dissolved in methanol (4.0 mL) after which was added NaOH (6.0 N) (0.334 mL, 2.002 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 60 min after which was added more NaOH (6.0 N) (0.067 mL, 0.400 mmol). The resulting reaction mixture was heated with microwave at 120° C. for 60 min and heated again with microwave at 130° C. for 60 min after which was added HCl (6.0 N) (0.400 mL, 2.402 mmol), evaporated down under vacuum, purified by reverse phase HPLC (formic acid modifier) to give the title compound (51.6 mg, 0.088 mmol, 43.9% yield). LC/MS: m/z 587.4 (M+H).sup.+, 1.12 min (ret. time).

[0559] The compounds in Table 19 were prepared by a method similar to the one described for the preparation of 3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-((1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethylpropanoic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00024 TABLE 19 Retention LCMS Time Ex # Structure Name [M + H].sup.+ (min) Example 107 [00233] 3-(3-(((R)-4-ethyl-1,1-dioxido- 3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepin- 2-yl)methyl)-4-methylphenyl)- 3-((1-(2-(2- methoxyethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)methoxy)- 2,2-dimethylpropanoic acid 631.4 1.12

Example 108

(R)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic Acid Hydrochloride

[0560] ##STR00234##

(R)-1-(((3-Fluoropyridin-2-yl)methyl)amino)butan-2-ol

[0561] ##STR00235##

[0562] To a solution of (R)-1-aminobutan-2-ol (3.70 g, 41.5 mmol) in methanol (150 mL) was added 3-fluoropicolinaldehyde (4.67 g, 37.4 mmol) followed by magnesium sulfate (4.50 g, 37.4 mmol) and the reaction mixture was stirred at 0° C. for 1 hr. The reaction mixture was filtered through celite and washed with methanol (300 ml). Sodium borohydride (1.413 g, 37.4 mmol) was added in two portions to the filtrate and the reaction mixture was stirred at ambient temperature for 30 min. The reaction mixture was quenched with 10% sodium bicarbonate solution and the methanol evaporated under reduced pressure. The remaining aqueous phase was extracted with ethyl acetate (3×125 mL) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (0-100%/3:1 ethyl acetate:ethanol/hexanes) to afford a yellow oil (R)-1-(((3-fluoropyridin-2-yl)methyl)amino)butan-2-ol (5.3 g, 24.06 mmol, 58.0% yield). .sup.1H NMR (CHCl.sub.3-d) δ: 8.36-8.45 (m, 1H), 7.37-7.45 (m, 1H), 7.22-7.32 (m, 1H), 4.10-4.16 (m, 2H), 3.68-3.77 (m, 1H), 2.89 (m, 1H), 2.64 (m, 1H), 1.43-1.55 (m, 2H), 0.90-1.02 (m, 3H). LC-MS: m/z 199.2 (M+H).sup.+

(R)-Tert-butyl 2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-carboxylate

[0563] ##STR00236##

[0564] To a solution of (R)-1-(((3-fluoropyridin-2-yl)methyl)amino)butan-2-ol (5.20 g, 26.2 mmol) in dimethyl sulfoxide (100 mL) was added potassium tert-butoxide (3.68 g, 32.8 mmol) and the reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was cooled to ambient temperature to afford a deep red-colored solution. Boc-anhydride (6.09 mL, 26.2 mmol) was added and the reaction mixture was allowed to stir for 18 hr. The reaction mixture was diluted with ethyl acetate (500 mL) and the organic phase washed with water (4×200 mL), brine, dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (0-50% ethyl acetate/hexanes) to afford an orange oil (R)-tert-butyl 2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-carboxylate (4.84 g, 17.39 mmol, 66.3% yield). .sup.1H NMR (DMSO-d.sub.6) δ: 8.17 (m, 1H), 7.36 (m, 1H), 7.24 (m, 1H), 4.49-4.76 (m, 2H), 3.93 (br. s., 1H), 3.47-3.74 (m, 2H), 1.52-1.66 (m, 2H), 1.36 (br. s., 4H), 1.25 (s, 5H), 0.96-1.07 (m, 3H). LC-MS: m/z 279.2 (M+H).sup.+.

(R)-2-Ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine, Hydrochloride

[0565] ##STR00237##

[0566] To a solution of (R)-tert-butyl 2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-carboxylate (4.84 g, 17.39 mmol) in 1,4-dioxane (20 mL), at ambient temperature, was added 4N HCl in dioxane (100 mL, 400 mmol) and the reaction mixture was stirred at ambient temperature for 2 h. The solvent was evaporated under reduced pressure and azeotroped with diethyl ether (3×) to afford a cream solid (R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine, hydrochloride (3.55 g, 16.54 mmol, 95% yield). .sup.1H NMR (DMSO-d.sub.6) δ: 9.95-10.36 (m, 2H), 8.38 (m, 1H), 7.66 (m, 1H), 7.51 (m, 1H), 4.39-4.57 (m, 2H), 4.04-4.18 (m, 1H), 3.47-3.60 (m, 1H), 3.24-3.40 (m, 1H), 1.69 (m, 2H), 1.05 (m, 3H). LC-MS: m/z 179.2 (M+H).sup.+

3-(((4-Methoxybenzyl)oxy)methyl)-4-methylbenzaldehyde

[0567] ##STR00238##

[0568] To a solution of 4-bromo-2-(((4-methoxybenzyl)oxy)methyl)-1-methylbenzene (12.6 g, 39.2 mmol) in tetrahydrofuran (THF) (131 ml) at −78° C. was added n-butyllithium (1.6 M in hexanes) (39.2 ml, 62.8 mmol) dropwise. After 60 min at −78° C., DMF (9.11 ml, 118 mmol) was added dropwise. After 2 h at −78° C., the reaction mixture was quenched at −78° C. with 300 mL of saturated aqueous NH.sub.4Cl, removed from the bath and stirred for 10 min. The reaction contents were diluted with 20 mL water and partitioned with 300 mL EtOAc. The layers were separated and the aqueous layer was extracted with 1×150 mL EtOAc. The combined organics were dried over Na.sub.2SO.sub.4, filtered, and concentrated to give an orange oil. Purification by silica gel chromatography (330 g column, 0-25% EtOAc:Hexanes) gave the title compound as a clear, orange oil (7.4 g, 27.4 mmol, 70% yield). LC-MS m/z 241.1 (M-29 (CHO)).sup.+, 1.11 min (ret. time). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.41 (s, 3H) 3.77-3.86 (m, 3H) 4.58 (d, J=6.53 Hz, 4H) 6.83-7.00 (m, 2H) 7.29-7.37 (m, 3H) 7.74 (dd, J=7.78, 1.76 Hz, 1H) 7.90 (d, J=1.25 Hz, 1H) 10.00 (s, 1H).

Methyl (R)-3-hydroxy-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-propanoate

[0569] ##STR00239##

[0570] To a suspension of tosyl-L-valine (5.72 g, 21.09 mmol) in dichloromethane (DCM) (59.7 ml) at 0° C. was added borane tetrahydrofuran complex (21.09 ml, 21.09 mmol) dropwise. Vigorous bubbling occurred initially. After −5 min, bubbling ceased and the suspension dissolved to give a clear, colorless solution. The solution was stirred for 30 min at 0° C., then warmed to ambient temperature and stirred for an additional 1 h. The mixture was subsequently cooled to −78° C. and a solution of 3-(((4-methoxybenzyl)oxy)methyl)-4-methylbenzaldehyde (5.7 g, 21.09 mmol) in dichloromethane (DCM) (26.0 ml) was added dropwise. After 5 min, ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (5.57 ml, 27.4 mmol) was added dropwise and the resulting reaction mixture was allowed to remain stirring at −78° C. After 2 h at −78° C., the reaction was quenched with 20 mL MeOH and 100 mL saturated aqueous NH.sub.4Cl, warmed to ambient temperature, and stirred vigorously for 20 min. The resulting layers were separated and the aqueous layer was extracted with 3×50 mL DCM. The combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated to give a thick, pale yellow oil. Purification by silica gel chromatography (330 g column, 0-70% EtOAc:Hexanes) afforded the title compound as a clear, colorless oil (2.7 g, 7.3 mmol, 34% yield). LC-MS m/z 373.0 (M+H).sup.+, 1.16 min (ret. time). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.14 (s, 3H) 1.17 (s, 3H) 2.33 (s, 3H) 3.74 (s, 3H) 3.84 (s, 3H) 4.48-4.52 (m, 2H) 4.53 (s, 2H) 4.90 (s, 1H) 6.89-6.94 (m, 2H) 7.14-7.17 (m, 2H) 7.31 (d, J=8.78 Hz, 3H).

Methyl (R)-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate

[0571] ##STR00240##

[0572] To a solution of methyl (R)-3-hydroxy-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethylpropanoate (4.8 g, 12.89 mmol) and 3-bromoprop-1-yne (1.831 ml, 19.33 mmol, ˜80% in toluene) in N, N-dimethylformamide (DMF) (25.8 ml) at 0° C. was added sodium hydride (0.773 g, 19.33 mmol, 60% dispersion in mineral oil). After 2 h, the reaction was quenched with 50 mL water and diluted with 100 mL EtOAc. The resulting layers were separated and the aqueous layer was extracted with 1×50 mL EtOAc. The combined organics were sequentially washed with 4×50 mL water and 1×50 mL brine. The combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated to give a pale-yellow oil. Purification by silica gel chromatography (220 g column, 0-30% EtOAc:Hexanes) afforded the title compound as a colorless semi-solid (4.3 g, 10.5 mmol, 81% yield). LC-MS m/z 433.3 (M+Na).sup.+, 1.36 min (ret. time). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.06 (s, 3H) 1.18 (s, 3H) 2.34 (s, 3H) 2.37 (t, J=2.38 Hz, 1H) 3.70-3.74 (m, 3H) 3.81-3.89 (m, 4H) 4.09-4.18 (m, 1H) 4.53 (d, J=4.02 Hz, 4H) 4.86 (s, 1H) 6.83-6.96 (m, 2H) 7.12-7.17 (m, 2H) 7.28 (s, 1H) 7.31 (d, J=8.78 Hz, 2H).

Methyl-(R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate

[0573] ##STR00241##

[0574] To a solution of methyl (R)-3-(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (6.5 g, 15.83 mmol) in acetonitrile (72.0 ml) and water (7.20 ml) was added ceric ammonium nitrate (26.0 g, 47.5 mmol). The resulting solution was allowed to stir at ambient temperature. After 20 min, the reaction mixture was partitioned with 300 mL EtOAc and 300 mL water, and the resulting layers were separated. The aqueous layer was extracted with 3×100 mL EtOAc and the combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated to give a thick, orange oil. Purification by silica gel chromatography (220 g column, 0-50% EtOAc:Hexanes) gave the title compound as a thick, clear, pale yellow oil (3.9 g, 13.4 mmol, 85% yield). LC-MS m/z 313.1 (M+Na).sup.+, 0.94 min (ret. time). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.06 (s, 3H) 1.18 (s, 3H) 1.63 (br. s., 1H) 2.36-2.38 (m, 3H) 3.73 (s, 3H) 3.85 (dd, J=15.81, 2.26 Hz, 1H) 4.15 (dd, J=15.81, 2.51 Hz, 1H) 4.73 (s, 2H) 4.87 (s, 1H) 7.08-7.21 (m, 2H) 7.28 (s, 1H).

Methyl (R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate

[0575] ##STR00242##

[0576] To a solution of methyl (R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (1.1 g, 3.79 mmol) in water (14.57 ml) was added sequentially DIPEA (0.132 ml, 0.758 mmol), copper(I) iodide (0.144 g, 0.758 mmol), iodomethane (0.472 ml, 7.58 mmol) and sodium azide (0.493 g, 7.58 mmol). The resulting reaction mixture was heated to 70° C. After 45 min, the reaction mixture was cooled to ambient temperature and partitioned with 200 mL EtOAc and 150 mL saturated aqueous NaHCO.sub.3. The resulting layers were separated and the aqueous layer was extracted with 3×50 mL EtOAc. The combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated to give a green oil. Purification by silica gel chromatography (40 g column, 0-90% EtOAc:Hexanes) afforded a thick, orange/red oil. Subsequent purification by chiral SFC (Chiralpak IG 20×250 mm, 5u column, 20% EtOH co-solvent) afforded the title compound as a thick, orange/red oil (1.2 g, 3.5 mmol, 91% yield). LC-MS m/z 348.2 (M+H).sup.+, 0.78 min (ret. time). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.06 (s, 3H) 1.18 (s, 3H) 2.38 (s, 3H) 3.69 (s, 3H) 4.18 (d, J=4.77 Hz, 2H) 4.80 (br. s., 3H) 5.32 (s, 3H) 7.19 (br. s., 3H) 7.28 (s, 1H).

Methyl-(R)-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate

[0577] ##STR00243##

[0578] To a solution of methyl (R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate (683 mg, 1.966 mmol) in dichloromethane (DCM) (9830 μl) was added thionyl chloride (287 μl, 3.93 mmol). After 10 min at ambient temperature, the reaction mixture was concentrated to give the title compound as a pale yellow semi-solid, which was carried forward without further purification. LC-MS m/z 366.1 (M+H).sup.+, 1.06 min (ret. time).

Methyl-(R)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate

[0579] ##STR00244##

[0580] To a solution of methyl (R)-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate (360 mg, 0.984 mmol) and (R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-hydrochloride (211 mg, 0.984 mmol) in acetonitrile (3690 μl) and tetrahydrofuran (THF) (1230 μl) was added K.sub.2CO.sub.3 (408 mg, 2.95 mmol) and sodium iodide (73.7 mg, 0.492 mmol). The resulting reaction mixture was heated to 80° C. After 45 min, the reaction contents were cooled to ambient temperature and partitioned with 30 mL EtOAc, 15 mL saturated aqueous NH.sub.4Cl and 5 mL water. The resulting layers were separated and the aqueous layer was extracted with 3×10 mL EtOAc. The combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated to give a yellow oil. Purification by silica gel chromatography (24 g column, 0-80% EtOAc:Hexanes) afforded the title compound as an orange oil (480 mg, 0.95 mmol, 96% yield). LC-MS m/z 508.4 (M+H).sup.+, 0.73 min (ret. time).

(R)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic Acid Hydrochloride

[0581] ##STR00245##

[0582] To a solution of methyl (R)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate (480 mg, 0.946 mmol) in methanol (9456 μl) was added a solution of 1 M aqueous NaOH (9456 μl, 9.46 mmol). The resulting reaction mixture was heated to 100° C. After 1 h, the reaction contents were cooled to ambient temperature and concentrated. Purification by reverse-phase HPLC (10-80% CH.sub.3CN+0.1% TFA:H.sub.2O+0.1% TFA) and concentration of the product-containing fractions gave a colorless oil. Treatment with 2 mL of 6 N aqueous HCl followed by lyophilization afforded the hydrochloride salt of the title compound as a white solid (499.7 mg, 0.94 mmol, 100% yield). LC-MS m/z 494.4 (M+H).sup.+, 0.66 min (ret. time). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 1.05 (s, 3H) 1.12-1.22 (m, 6H) 1.73-1.93 (m, 2H) 2.53 (s, 3H) 3.79-3.86 (m, 2H) 4.16 (s, 3H) 4.36-4.46 (m, 1H) 4.49-4.64 (m, 2H) 4.65-4.69 (m, 2H) 4.81 (s, 2H) 4.89-4.94 (m, 1H) 7.42 (s, 2H) 7.66-7.69 (m, 1H) 7.70-7.74 (m, 1H) 7.85-7.94 (m, 1H) 8.10-8.22 (m, 1H) 8.36-8.47 (m, 1H).

[0583] The compounds in Table 20 were prepared by a method similar to the one described for the preparation of (R)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00025 TABLE 20 Retention Ex LCMS Time # Structure Name [M + 1] (min) 1H NMR Ex 109 [00246] (R)-3-(3-(((R)-2- isopropyl-2,3- dihydropyrido[2,3- b][1,4]-oxazepin- 4(5H)-yl)methyl)- 4-methylphenyl)- 2,2-dimethyl-3-((1- methyl-1H-1,2,3- triazol-4- yl)methoxy) propanoic acid 508.4 0.71 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 1.05 (s, 3 H) 1.12-1.18 (m, 9 H) 2.06-2.12 (m, 1 H) 2.56 (s, 3 H) 3.85-4.03 (m, 2 H) 4.20 (s, 3 H) 4.39-4.48 (m, 1 H) 4.51-4.66 (m, 2 H) 4.74 (d, J = 11.04 Hz, 2 H) 4.82 (s, 2 H) 4.90-4.96 (m, 1 H) 7.40-7.46 (m, 2 H) 7.74 (s, 1 H) 7.77-7.82 (m, 1 H) 7.96- 8.04 (m, 1 H) 8.30 (s, 1 H) 8.43-8.51 (m, 1 H)

Example 110

(R)-3-(3-(((R)-2-Ethyl-7-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic Acid Trifluoroacetate

[0584] ##STR00247##

(R)-1-(((6-Chloro-3-fluoropyridin-2-yl)methyl)amino)butan-2-ol

[0585] ##STR00248##

[0586] To a solution of 6-chloro-3-fluoropicolinaldehyde (5 g, 31.3 mmol) in methanol (50 mL) was added under an atmosphere of nitrogen to a mixture of (R)-1-aminobutan-2-ol (3.35 g, 37.6 mmol) and sodium hydroxide (10 mL, 31.3 mmol). The resulting reaction mixture was stirred at ambient temperature for 16 h. Following this duration, the reaction contents were cooled to 0° C. and NaBH.sub.4 (1.423 g, 37.6 mmol) was added in equal portions over 5 min. The reaction mixture was then warmed to ambient temperature and stirred for 2 h. Following this duration, the reaction mixture was concentrated and purified by silica gel chromatography (0-50% EtOAc:Petroleum ether) to give the title compound as a colorless liquid (2 g, 6.5 mmol, 21% yield). LC-MS m/z 233.0 (M+H).sup.+, 2.8 min (ret. time).

(R)-tert-Butyl 7-chloro-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-carboxylate

[0587] ##STR00249##

[0588] To a solution of (R)-1-(((6-chloro-3-fluoropyridin-2-yl)methyl)amino)butan-2-ol (2 g, 8.60 mmol) in dimethyl sulfoxide (DMSO) (20 mL) under an atmosphere of N.sub.2 was added potassium tert-butoxide (1.447 g, 12.89 mmol) at ambient temperature. The resulting reaction mixture was then heated to 90° C. and stirred for 2 h. Following this duration, the reaction contents were cooled to 0° C. and Boc-anhydride (2.395 mL, 10.31 mmol) and TEA (1.438 mL, 10.31 mmol) were added sequentially. The resulting reaction mixture was warmed to ambient temperature and stirred for 2 h. Following this duration, the reaction contents were poured into ice cold water (50 mL) and extracted with EtOAc (2×50 mL). The organic layer was separated, dried over Na.sub.2SO.sub.4 and concentrated to obtain a yellow oil. Purification by silica gel chromatography (0-15% EtOAc:Petroleum ether) afforded the title compound as a yellow solid (1.0 g, 2.88 mmol, 34% yield). LC-MS m/z 313.0 (M+H).sup.+, 3.9 min (ret. time).

tert-Butyl (R)-2-ethyl-7-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-carboxylate

[0589] ##STR00250##

[0590] Anhydrous 1,4-dioxane (9831 μL) was added to a mixture of tert-butyl (R)-7-chloro-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-carboxylate (492 mg, 1.573 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (592 mg, 4.72 mmol), PdCl.sub.2(dppf) (57.5 mg, 0.079 mmol), and potassium carbonate (652 mg, 4.72 mmol) under an atmosphere of argon. The resulting reaction mixture was heated in a microwave reactor at 120° C. for 30 min. Following this duration, the reaction contents were filtered. The filtrate was diluted with water and extracted twice with EtOAc. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (40 g column, 0-60% EtOAc:Hexanes) to afford the title compound as a yellow oil (460 mg, 1.09 mmol, 70% yield). LC-MS m/z 293.1 (M+H).sup.+, 0.71 min (ret. time). .sup.1H NMR (CHLOROFORM-d) δ ppm 7.20 (d, 1H), 6.98 (d, 1H), 4.79 (d, 1H), 4.50 (m, 1H), 3.65-4.06 (m, 2H), 3.38 (br. s., 1H), 2.42-2.55 (s, 3H), 1.52-1.77 (m, 3H), 1.40 (br. s., 9H), 1.11 (t, 3H).

(R)-2-Ethyl-7-methyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine Hydrochloride

[0591] ##STR00251##

[0592] A solution of 4 N HCl in 1,4-dioxane (4370 μl) was added to tert-butyl (R)-2-ethyl-7-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-carboxylate (319.4 mg, 1.092 mmol) and stirred at ambient temperature. After 1 h, the reaction contents were concentrated by heating at 50° C. under a nitrogen stream for 18 h, providing the title compound as a white solid (281.7 mg, 1.23 mmol, 113% yield) which was carried forward without further purification. LC-MS m/z 194.1 (M+H).sup.+, 0.35 min (ret. time). .sup.1H NMR (400 MHz, METHANOL-d4) δ ppm 7.88 (d, 1H), 7.63 (d, 1H), 4.71 (d, 2H), 4.15-4.29 (m, 1H), 3.64-3.82 (m, 1H), 3.45-3.62 (m, 1H), 2.68 (s, 3H), 1.70-1.93 (m, 2H), 1.18 (m, 3H).

(R)-Methyl-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate

[0593] ##STR00252##

[0594] To a solution of methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (950 mg, 3.27 mmol) in tert-butanol (13 ml) and water (13 ml) was added sodium azide (425 mg, 6.54 mmol), copper(I) iodide (125 mg, 0.654 mmol), DIPEA (114 μl, 0.654 mmol) and iodomethane (1018 μl, 16.36 mmol). The resulting reaction mixture was heated to 70° C. After 45 min, the reaction contents were cooled to ambient temperature and partitioned with 100 mL EtOAc and 50 mL saturated aqueous NaHCO.sub.3. The resulting layers were separated and the aqueous layer was extracted with 3×15 mL EtOAc. The combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated to give a dark orange oil. Purification by silica gel chromatography (40 g column, 0-90% EtOAc:Hexanes) afforded an orange semi-solid (1.1 g, 3.3 mmol). The racemic mixture was subsequently separated by chiral SFC (Chiralpak IG 20×250 mm, 5u column, 25% EtOH co-solvent) to afford the title compound as an orange semi-solid (445.5 mg, 1.3 mmol, 39% yield). LC-MS m/z 348.1 (M+H).sup.+, 0.78 min (ret. time).

(R)-Methyl-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate

[0595] ##STR00253##

[0596] To a solution of (R)-methyl-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate (56.0 mg, 0.161 mmol) in dichloromethane (DCM) (806 μl) was added thionyl chloride (23.53 μl, 0.322 mmol), giving a clear, orange solution. After 10 min at ambient temperature, the reaction mixture was concentrated to give the title compound as an orange oil, which was carried forward without further purification.

(R)-Methyl-3-(3-(((R)-2-ethyl-7-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate

[0597] ##STR00254##

[0598] To a solution of (R)-methyl-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate (59 mg, 0.161 mmol) and (R)-2-ethyl-7-methyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-hydrochloride (36.9 mg, 0.161 mmol) in acetonitrile (605 μl) and tetrahydrofuran (THF) (202 μl) was added K.sub.2CO.sub.3 (66.9 mg, 0.484 mmol) and sodium iodide (12.09 mg, 0.081 mmol). The resulting reaction mixture was warmed to 80° C. After 45 min, the reaction contents were cooled to ambient temperature and partitioned with 10 mL EtOAc, 10 mL saturated aqueous NH.sub.4Cl and 5 mL water. The layers were separated and the aqueous layer was extracted with 3×10 mL EtOAc. The combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated to give a yellow oil. Purification by silica gel chromatography (12 g column, 0-80% EtOAc:Hexanes) afforded the title compound as an orange oil (54.4 mg, 0.10 mmol, 65% yield). LC-MS m/z 522.3 (M+H).sup.+, 0.79 min (ret. time).

(R)-3-(3-(((R)-2-Ethyl-7-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic Acid Trifluoroacetate

[0599] ##STR00255##

[0600] To a solution of (R)-methyl-3-(3-(((R)-2-ethyl-7-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate (54.4 mg, 0.104 mmol) in methanol (1043 μl) was added a 1 M solution of aqueous NaOH (1043 μl, 1.043 mmol). The resulting reaction mixture was warmed to 100° C. After 45 min, the reaction contents were cooled to ambient temperature and purified directly by reverse-phase HPLC (10-80% CH.sub.3CN+0.1% TFA:H.sub.2O+0.1% TFA) to afford the trifluoroacetic acid salt of the title compound as a white solid (51.4 mg, 0.08 mmol, 79% yield). LC-MS m/z 508.3 (M+H).sup.+, 0.69 min (ret. time). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 1.05 (s, 3H) 1.12-1.20 (m, 6H) 1.60-1.76 (m, 1H) 1.77-1.88 (m, 1H) 2.48 (d, J=5.77 Hz, 6H) 3.62-3.70 (m, 2H) 4.08 (s, 3H) 4.11-4.17 (m, 1H) 4.40-4.59 (m, 5H) 4.62-4.71 (m, 1H) 4.78 (s, 1H) 7.38 (s, 3H) 7.55 (s, 1H) 7.57-7.63 (m, 1H) 7.89 (s, 1H).

1-(((3-Fluoropyridin-2-yl)methyl)amino)-3-methylbutan-2-ol

[0601] ##STR00256##

[0602] To a solution of 3-fluoropicolinaldehyde (18 g, 144 mmol) in methanol (200 mL) was added 1-amino-3-methylbutan-2-ol (15.96 g, 155 mmol) and a solution of 1M aqueous sodium hydroxide (28.8 mL, 28.8 mmol). The resulting reaction mixture was stirred under an atmosphere of nitrogen for 16 hr at ambient temperature. Following this duration, sodium borohydride (6.53 g, 173 mmol) was added in equal portions over 15 min and the resulting reaction mixture was stirred at ambient temperature for 4 h. Following this duration, the methanol solvent was evaporated and the resulting mixture was diluted with water (100 ml) and extracted with 10% MeOH in DCM (3×150 ml). The combined organic layers were washed with saturated aqueous sodium chloride (1000 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (95% EtOAc in petroleum ether) provided the title compound as a yellow gum (16 g, 44.1 mmol, 30.6% yield). LC-MS m/z 213.1 (M+H).sup.+, 0.98 min (ret. time).

(R)-tert-Butyl 2-isopropyl-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-carboxylate

[0603] ##STR00257##

[0604] To a stirred solution of 1-(((3-fluoropyridin-2-yl)methyl)amino)-3-methylbutan-2-ol (16 g, 75 mmol) in dimethyl sulfoxide (DMSO) (150 mL) was added potassium tert-butoxide (10.15 g, 90 mmol) in one portion at ambient temperature. The resulting reaction mixture was warmed to 90° C. and stirred for 2 h. Following this duration, the reaction mixture was cooled back to ambient temperature and triethylamine (11.44 g, 113 mmol) and di-tert-butyldicarbonate (19.74 g, 90 mmol) were added sequentially. The resulting mixture was then allowed to stir for 16 h at ambient temperature. Following this duration, it was diluted with ice water (750 mL) and extracted with diethyl ether (2×500 mL). The combined organic layers were washed with saturated aqueous NaCl (250 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to get provide a thick, orange oil. Purification by silica gel chromatography (10% EtOAc in petroleum ether) provided racemic tert-butyl 2-isopropyl-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-carboxylate as an off-white gum (4.4 g, 14.3 mmol, 18.9% yield). Subsequent chiral SFC chromatography (Chiralpak IE (30×250 mm, 5 u) column, 90:10 Hexane:IPA) afforded the title compound as a white solid (2.1 g, 6.48 mmol). LC-MS m/z 293.1 (M+H).sup.+, 2.86 min (ret. time).

(R)-2-Isopropyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine Hydrochloride

[0605] ##STR00258##

[0606] To a solution of (R)-tert-butyl 2-isopropyl-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4(5H)-carboxylate (2.1 g, 7.18 mmol) in 1,4-dioxane (20 mL) at 0° C. was added a solution of 4M hydrochloric acid in 1,4-dioxane (8.98 mL, 35.9 mmol) dropwise over 5 min under an atmosphere of nitrogen. The resulting reaction mixture was stirred at ambient temperature for 3 hr. Following this duration, the reaction mixture was concentrated under reduced pressure. The resulting crude material was triturated with diethyl ether (20 ml), and the resulting solid was isolated and dried to afford the title compound as an off-white solid (1.8 g, 6.9 mmol, 96% yield). LC-MS m/z 193.2 (M+H).sup.+, 1.99 min (ret. time).

3-(Bromomethyl)picolinonitrile

[0607] ##STR00259##

[0608] To a 500 mL single-neck round bottom flash fitted with a reflux condenser and a nitrogen outlet was added 10.1 g (86 mmol) 3-methylpicolinonitrile, 200 mL dimethyl carbonate, 18.2 g (103 mmol) N-bromosuccinimide and 2.1 g (8.5 mmol) benzoyl peroxide. The resulting reaction mixture was heated to 87° C. and stirred for 5 h. Following this duration, the reaction mixture was cooled to ambient temperature and filtered, and the solid was rinsed with Et.sub.2O. DCM was subsequently added to the filtrate and the resulting mixture was filtered. The combined organics were concentrated and the resulting semi-solid was purified by silica gel chromatography (2×330 g column, 5-35% EtOAc/Hexane) followed by reverse-phase HPLC (Waters Xbridge Prep C18 10 μm OBD, 50×250 mm column) to afford the title compound as a yellow solid (6.3 g, 32.0 mmol, 37% yield). LC-MS m/z 196.8 (M+H).sup.+, 0.60 min (ret. time).

Ethyl 2-((2-cyanopyridin-3-yl)methyl)butanoate

[0609] ##STR00260##

[0610] A 1000 mL 3-neck round bottom flash fitted with a 125 mL addition funnel and a temperature probe was flushed with nitrogen and dried using a heat gun. LDA (2M in THF/heptane/ethylbenzene, 18.3 mL, 36.6 mmol) and 46 mL THF were added followed by cooling with a dry ice/acetone bath. Ethyl butyrate (3.5 g, 30.5 mmol) dissolved in 46 mL THF was added over 24 min via the addition funnel while maintaining the internal temperature below −70.9° C. The reaction mixture was stirred for 45 min. Following this duration, 3-(bromomethyl)picolinonitrile (6.0 g, 30.5 mmol) dissolved in 80 mL THF was added to the enolate over 25 min while keeping the internal temperature below −70.8° C. The addition funnel was rinsed with 6 mL THF. After 1 h, the reaction mixture was quenched with 2.6 mL AcOH in 11 mL THF (internal temperature was maintained below −67.4° C.) and then warmed to 0° C. Saturated aqueous NH.sub.4Cl (177 mL) was added (temperature was maintained below 8.4° C.) followed by EtOAc (177 mL). The reaction mixture was warmed to ambient temperature and water was added to dissolve the solids present in the aqueous layer. The layers were separated and the aqueous layer was washed with 70 mL EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over Na.sub.2SO.sub.4, filtered, and concentrated. Purification by silica gel chromatography (330 g column, 5-70% EtOAc/Hex) afforded the title compound as a pale-yellow oil (5.0 g, 21.5 mmol, 70% yield). LC-MS m/z 233.1 (M+H).sup.+, 0.88 min (ret. time).

2-((2-(Aminomethyl)pyridin-3-yl)methyl)butan-1-ol

[0611] ##STR00261##

[0612] A 1 L round bottom flask fitted with an addition funnel and a temperature probe was dried by flushing with nitrogen and heating with a heat gun. THF (160 mL) and LAH (33 mL, 64.4 mmol, 2M in THF) were added followed by cooling with an ice (aq) bath. Ethyl 2-((2-cyanopyridin-3-yl)methyl)butanoate (5.0 g, 21.5 mmol) was dissolved in 160 mL THF and added via an addition funnel over 49 min while maintaining the internal temperature below 5.2° C. The brown reaction mixture was warmed to ambient temperature and stirred for 90 min. The reaction mixture was cooled with an ice (aq) bath and slowly quenched with 11 mL saturated aqueous Na.sub.2SO.sub.4 while keeping the internal temperature below 15° C. The resulting yellow reaction mixture was warmed to ambient temperature and filtered, and the aqueous layer was washed with 3×EtOAc. The organic layer was concentrated to give the title compound as a yellow oil (3.96 g), which was used without further purification. LC-MS m/z 195.2 (M+H).sup.+, 0.28 min (ret. time).

tert-Butyl ((3-(2-(hydroxymethyl)butyl)pyridin-2-yl)methyl)carbamate

[0613] ##STR00262##

[0614] To a 500 mL round bottom flask containing 3.96 g (20.4 mmol) of 2-((2-(aminomethyl)pyridin-3-yl)methyl)butan-1-ol was added 160 mL DCM and 2.89 g (20.4 mmol) BOC.sub.2O. After stirring for 4 h at ambient temperature, the reaction mixture was concentrated and the resulting crude yellow oil was purified using silica gel chromatography (330 g column, 20-90% EtOAc/Hex) to give the title compound as a clear yellow oil (3.2 g, 11.0 mmol, 54% yield). LC-MS m/z 295.2 (M+H).sup.+, 0.47 min (ret. time). 2-((2-(((tert-Butoxycarbonyl)amino)methyl)pyridin-3-yl)methyl)butyl methanesulfonate

##STR00263##

[0615] To a 500 mL (3) neck round bottom flash fitted with a temperature probe was added 3.24 g (11.0 mmol) tert-butyl ((3-(2-(hydroxymethyl)butyl)pyridin-2-yl)methyl)carbamate dissolved in 160 mL DCM and 2.3 mL (16.5 mmol) TEA. The reaction mixture was cooled with an ice(aq) bath followed by the addition of MsCl (1.1 mL, 14.3 mmol) over 7 min. The temperature was held between 3.8 and 6.9° C. during the MsCl addition. The resulting reaction mixture was warmed to ambient temperature and stirred for 1 h. The reaction mixture was concentrated in vacuo (water bath temperature was kept below 26° C.) and the crude material was purified using silica gel chromatography (330 g column, 30-90% EtOAc/Hex) to afford the title compound as a colorless oil (4.05 g, 10.9 mmol, 99% yield). LC-MS m/z 373.2 (M+H).sup.+, 0.58 min (ret. time).

(S)-tert-Butyl 6-ethyl-5,6,7,9-tetrahydro-8H-pyrido[2,3-c]azepine-8-carboxylate

[0616] ##STR00264##

[0617] To a 250 mL 3-neck round bottom flask fitted with a temperature probe was added 2.5 g of KOtBu and 36 mL DMF. The reaction mixture was cooled with an ice (aq) bath. 2-((2-(((tert-Butoxycarbonyl)amino)methyl)pyridin-3-yl)methyl)butyl methanesulfonate (4.05 g) in 46 mL of DMF was added dropwise over 20 min (internal temperature: 2.1-5.8° C.), followed by an 11 mL DMF flask rinse. The reaction mixture was subsequently warmed to ambient temperature. After 1 h, the reaction mixture was transferred to a 1 L 3-neck round bottom flash fitted with a temperature probe and then cooled with an ice(aq) bath. Water (210 mL) and EtOAc (210 mL) were added slowly while keeping the temperature below 21° C. The reaction mixture was then warmed to ambient temperature and the layers were separated. The aqueous layer was extracted with 70 mL EtOAc. The combined organic layers were washed with water (70 mL), brine (159 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. Purification by silica gel chromatography (330 g column, 10%-90% EtOAc/Hex) afforded racemic tert-butyl 6-ethyl-5,6,7,9-tetrahydro-8H-pyrido[2,3-c]azepine-8-carboxylate (3.0 g, 11 mmol, 100% yield). Chiral SFC (Chiralpak IF, 20×250 mm, 5u column) provided the title compound as a thick, pale yellow oil (1.2 g, 4.4 mmol). LC-MS m/z 277.2 (M+H).sup.+, 0.61 min (ret. time).

(S)-6-Ethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-c]azepine hydrochloride

[0618] ##STR00265##

[0619] To a solution of tert-butyl (S)-6-ethyl-5,6,7,9-tetrahydro-8H-pyrido[2,3-c]azepine-8-carboxylate (875 mg, 3.17 mmol) in diethyl ether (10 mL), with a minimum amount of DCM for solubility, was added hydrochloric acid (4N in dioxane) (30 mL, 120 mmol) and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with Et.sub.2O, the solid filtered, washed with Et.sub.2O and dried under vacuo to afford the title compound as a light yellow solid (503.9 g, 2.4 mmol, 75% yield). LC-MS m/z 177.0 (M+H).sup.+, 0.24 min (ret. time).

[0620] The compounds in Table 21 were prepared by a method similar to the one described for the preparation of (R)-3-(3-(((R)-2-ethyl-7-methyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00026 TABLE 21 Retention Ex LCMS Time # Structure Name [M + 1] (min) 1H NMR Ex 111 [00266] (S)-methyl-3-(3-(((R)- 2-ethyl-2,3- dihydropyrido[2,3- f][1,4]oxazepin-4(5H)- yl)methyl)-4-methyl- phenyl)-2,2-dimethyl- 3-((1-methyl-1H- 1,2,3-triazol-4-yl)- methoxy)-propanoic acid 494.4 0.67 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 1.05 (s, 3 H) 1.13 (s, 3 H) 1.20 (t, J = 7.40 Hz, 3 H) 1.71- 1.81 (m, 1 H) 1.82-1.92 (m, 1 H) 2.50 (s, 3 H) 3.67- 3.84 (m, 2 H) 4.05 (s, 3 H) 4.24-4.36 (m, 1 H) 4.45 (d, J = 12.30 Hz, 2 H) 4.58 (br. s., 3 H) 4.72 (s, 1 H) 4.81 (s, 1 H) 7.39 (s, 2 H) 7.43- 7.48 (m, 1 H) 7.58-7.66 (m, 2 H) 7.87 (s, 1 H) 8.17- 8.26 (m, 1 H) Ex 112 [00267] (S)-3-(3-(((R)-2- isopropyl-2,3- dihydropyrido[2,3- f][1,4]oxazepin-4(5H)- yl)methyl)-4- methylphenyl)-2,2- dimethyl-3-((1- methyl-1H-1,2,3- triazol-4-yl)- methoxy)propanoic acid, trifluoroacetate 508.3 0.72 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 1.05 (s, 3 H) 1.12 (s, 3 H) 1.15- 1.20 (m, 6 H) 1.99-2.14 (m, 1 H) 2.51 (s, 3 H) 3.86 (d, J = 6.02 Hz, 2 H) 4.05 (s, 3 H) 4.25 (d, J = 5.52 Hz, 1 H) 4.44 (q, J = 5.52 Hz, 1 H) 4.51-4.57 (m, 1 H) 4.61 (br. s., 2 H) 4.72 (d, J = 14.31 Hz, 1 H) 4.81 (s, 1 H) 7.40 (s, 2 H) 7.43 (dd, J = 8.16, 4.89 Hz, 1 H) 7.58- 7.66 (m, 2 H) 7.86 (s, 1 H) 8.19 (d, J = 4.27 Hz, 1 H)

Example 113

(R)-3-((1-Ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic Acid, Trifluoroacetate

[0621] ##STR00268##

Methyl 3-(3-(chloromethyl-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate

[0622] ##STR00269##

[0623] To a solution of methyl 3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)-propanoate (556 mg, 1.915 mmol) in dichloromethane (DCM) (9574 μl) was added thionyl chloride (279 μl, 3.83 mmol), giving a clear orange solution. After 10 min at ambient temperature, concentrated the reaction contents to give an orange oil (630.7 mg), which was carried forward without further purification. LC-MS m/z 331.0 (M+Na).sup.+, 1.23 min (ret. time). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.06 (s, 3H) 1.19 (s, 3H) 2.39 (s, 1H) 2.45 (s, 3H) 3.73 (s, 3H) 3.86 (d, J=15.81 Hz, 1H) 4.16 (d, J=15.81 Hz, 1H) 4.63 (s, 2H) 4.85 (s, 1H) 7.19 (s, 1H) 7.24 (s, 1H) 7.29 (s, 1H).

Methyl-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate

[0624] ##STR00270##

[0625] To a solution of methyl 3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate (212.5 mg, 0.688 mmol) and (R)-2-ethyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-hydrochloride (148 mg, 0.688 mmol) in acetonitrile (2581 μl) and tetrahydrofuran (THF) (860 μl) was added K.sub.2CO.sub.3 (285 mg, 2.064 mmol) and sodium iodide (51.6 mg, 0.344 mmol). The resulting reaction mixture was heated to 80° C. After 45 min, the reaction contents were cooled to ambient temperature and partitioned with 50 mL EtOAc, 50 mL saturated aqueous NH.sub.4Cl and 10 mL water. The resulting layers were separated and the aqueous layer was extracted with 3×10 mL EtOAc. The combined organics over dried over Na.sub.2SO.sub.4, filtered and concentrated to give a yellow oil. Purification by silica gel chromatography (24 g column, 0-50% EtOAc:Hexanes) afforded the title compound as a thick, clear, colorless oil (287.3 mg, 0.64 mmol, 93% yield). LC-MS m/z 451.2 (M+H).sup.+, 0.87 min (ret. time). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.98-1.09 (m, 6H) 1.15 (d, J=4.77 Hz, 3H) 1.39-1.50 (m, 1H) 1.59 (s, 3H) 1.62-1.74 (m, 1H) 2.36-2.39 (m, 1H) 2.78-2.97 (m, 2H) 3.60-3.71 (m, 2H) 3.72 (s, 3H) 3.86 (br. s., 2H) 4.04-4.10 (m, 1H) 4.13-4.20 (m, 2H) 4.83 (d, J=4.27 Hz, 1H) 7.04-7.11 (m, 1H) 7.12-7.20 (m, 3H) 7.34 (d, J=7.78 Hz, 1H) 8.24 (d, J=3.76 Hz, 1H).

(R)-Methyl-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido-[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate

[0626] ##STR00271##

[0627] To a solution of methyl 3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-(prop-2-yn-1-yloxy)propanoate in tert-butanol (2349 μl) and water (2349 μl) was added sodium azide (79 mg, 1.212 mmol), copper(I) iodide (23.09 mg, 0.121 mmol), DIPEA (21.17 μl, 0.121 mmol), and ethyl iodide (98 μl, 1.212 mmol). The resulting reaction mixture was heated to 70° C. After 50 min, the reaction contents were cooled to ambient temperature and partitioned with 10 mL EtOAc and 10 mL saturated aqueous NaHCO.sub.3. The resulting layers were separated and the aqueous layer was extracted with 3×5 mL EtOAc. The combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated to give a dark green oil. Purification by silica gel chromatography (24 g column, 0-90% EtOAc:Hexanes) afforded a thick, pale yellow oil (223.2 mg). The diastereomeric mixture was separated by chiral reverse-phase HPLC (Chiralpak AS 20×250 mm, 5u column, heptene+0.1% isopropylamine:EtOH+0.1% isopropylamine (80:20)) to give the title compound as a white solid (76.1 mg, 0.15 mmol, 24% yield). LC-MS m/z 522.3 (M+H).sup.+, 0.78 min (ret. time). .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.01 (d, J=15.31 Hz, 3H) 1.03-1.08 (m, 3H) 1.12 (d, J=6.78 Hz, 3H) 1.40-1.49 (m, 1H) 1.55 (t, J=7.40 Hz, 3H) 1.67 (d, J=7.03 Hz, 1H) 2.35 (d, J=2.51 Hz, 3H) 2.80-2.99 (m, 2H) 3.60-3.67 (m, 4H) 3.68-3.73 (m, 1H) 3.80-3.90 (m, 1H) 4.03-4.17 (m, 2H) 4.39 (q, J=7.28 Hz, 3H) 4.57 (d, J=12.55 Hz, 1H) 4.71 (s, 1H) 7.09-7.21 (m, 4H) 7.34 (dt, J=7.91, 1.44 Hz, 1H) 7.49 (s, 1H) 8.18-8.28 (m, 1H).

(R)-3-((1-Ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic Acid, Trifluoroacetate

[0628] ##STR00272##

[0629] To a solution of (R)-methyl-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido-[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoate (65.6 mg, 0.126 mmol) in methanol (1258 μl) was added a solution of 1 M aqueous NaOH (1258 μl, 1.258 mmol). The resulting reaction mixture was heated to 100° C. After 1 h, the reaction contents were cooled to ambient temperature and directly purified by reverse-phase HPLC (10-80% CH.sub.3CN+0.1% TFA:H.sub.2O+0.1% TFA) to give the trifluoroacetic acid salt of the title compound as a white solid (62.2 mg, 0.10 mmol, 80% yield). LC-MS m/z 508.3 (M+H).sup.+, 0.70 min (ret. time). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 1.05 (s, 3H) 1.12-1.20 (m, 6H) 1.49 (t, J=7.28 Hz, 3H) 1.67-1.78 (m, 1H) 1.83 (s, 1H) 2.48 (s, 3H) 3.68-3.73 (m, 2H) 4.12-4.24 (m, 1H) 4.39 (q, J=7.45 Hz, 2H) 4.44-4.53 (m, 2H) 4.56 (br. s., 2H) 4.72 (d, J=18.32 Hz, 2H) 4.78 (s, 1H) 7.37 (s, 2H) 7.47-7.52 (m, 1H) 7.56 (s, 1H) 7.65 (d, J=8.03 Hz, 1H) 7.92 (s, 1H) 8.34 (d, J=4.52 Hz, 1H).

(R)-2-Ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine Hydrochloride

[0630] ##STR00273##

[0631] (R)-2-Ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride of the invention was made using compounds described in WO 2016/202253 on page 146, published Dec. 22, 2016, and incorporated herein by reference.

[0632] The compounds in Table 22 were prepared by a method similar to the one described for the preparation of (R)-3-((1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00027 TABLE 22 Retention LCMS Time Ex # Structure Name [M + 1] (min) 1H NMR Ex 114 [00274] (S)-methyl 3-((1- ethyl-1H-1,2,3- triazol-4-yl)- methoxxy)-3- (3-(((R)-2- ethyl-2,3- dihydropyrido [2,3-f][1,4] oxazepin-4(5H)- yl)methyl)-4- methylphenyl)- 2,2-dimethyl- propanoic acid, trifluoroacetate 508.3 0.71 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 1.06 (s, 3 H) 1.13 (s, 3 H) 1.20 (s, 3 H) 1.49 (t, J = 7.40 Hz, 3 H) 1.71-1.81 (m, 1 H) 1.82-1.93 (m, 1 H) 2.49 (s, 3 H) 3.66-3.84 (m, 2 H) 4.38 (d, J = 7.28 Hz, 4 H) 4.46 (d, J = 2.76 Hz, 2 H) 4.54-4.60 (m, 2 H) 4.67-4.75 (m, 1 H) 4.81 (s, 1 H) 7.38 (s, 2 H) 7.41-7.48 (m, 1 H) 7.62 (s, 2 H) 7.91 (s, 1 H) 8.17-8.23 (m, 1 H) Ex 115 [00275] (R)-methyl 3-((1- ethyl-1H-1,2,3- triazol-4-yl)- methoxy)-3- (3-((S)-6- ethyl-6,7- dihydro-5H- pyrido[2,3-c] azepin-8(9H)- yl)methyl)-4- methylphenyl)- 2,2-dimethyl- propanoic acid, trifluoroacetate 506.3 0.65 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 0.98-1.08 (m, 7 H) 1.16 (s 3 H) 1.50 (s, 5 H) 1.90-2.06 (m, 1 H) 2.39-2.51 (m, 3 H) 3.03- 3.10 (m, 2 H) 3.46-3.53 (m, 1 H) 3.57-3.73 (m, 1 H) 4.32-4.43 (m, 2 H) 4.44-4.55 (m, 3 H) 4.57-4.65 (m, 1 H) 4.73-4.79 (m, 1 H) 7.37-7.40 (m, 2 H) 7.43-7.48 (m, 1 H) 7.52-7.57 (m, 1 H) 7.81-7.87 (m, 1 H) 7.91-7.94 (m, 1 H) 8.39-8.45 (m, 1 H) Ex 116 [00276] (S)-methyl 3-((1- ethyl-1H-1,2,3- triazol-4-yl)- methoxy)-3- (3-(((S)-6- ethyl-6,7- dihydro-5H- pyrido[2,3-c] azepin-8(9H)- yl)methyl)-4- methylphenyl)- 2,2-dimethyl- propanoic acid, trifluoroacetate 506.3 0.66 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 1.02-1.10 (m, 6 H) 1.13 (s, 3 H) 1.50 (t, J = 7.40 Hz, 5 H) 2.10-2.24 (m, 1 H) 2.49 (s, 3 H) 2.97-3.17 (m, 2 H) 3.46-3.52 (m, 1 H) 3.66-3.81 (m, 1 H) 4.29-4.59 (m, 7 H) 4.80 (s, 1 H) 7.39 (s, 3 H) 7.61 (s, 1 H) 7.74-7.83 (m, 1 H) 7.90 (s, 1 H) 8.21-8.32 (m, 1 H) Ex 117 [00277] (R)-methyl 3-((1- ethyl-1H-1,2,3- triazol-4-yl)- methoxy)-3-(3- (((R)-2-ethyl- 2,3-dihydro- benzo[f][1,4] oxazepin-4(5H)- yl)methyl)-4- methylphenyl)- 2,2-dimethyl- propanoic acid, trifluoroacetate 507.3 0.74 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 1.05 (s, 3 H) 1.11-1.21 (m, 6 H) 1.49 (s, 3 H) 1.66-1.74 (m, 1 H) 1.74-1.87 (m, 1 H) 2.37-2.52 (m, 3 H) 3.55-3.69 (m, 2 H) 4.32- 4.42 (m, 2 H) 4.45-4.60 (m, 6 H) 4.65-4.74 (m, 1 H) 4.79 (s, 1 H) 7.14-7.21 (m, 2 H) 7.27-7.33 (m, 1 H) 7.36 (s, 2 H) 7.42-7.49 (m, 1 H) 7.54-7.59 (m, 1 H) 7.92 (s, 1 H) Ex 118 [00278] (S)-methyl 3-((1- ethyl-1H-1,2,3- triazol-4-yl)- methoxy)-3-(3- (((R)-2-ethyl- 2,3-dihydro- benzo[b][1,4] oxazepin-4(5H)- yl)methyl)-4- methylphenyl)- 2,2-dimethyl- propanoic acid, trifluoroacetate 507.3 0.74 .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ ppm 1.05 (s, 3 H) 1.13 (s, 3 H) 1.19 (t, J = 7.40 Hz, 3 H) 1.50 (t, J = 7.40 Hz, 3 H) 1.66-1.76 (m, 1 H) 1.76-1.86 (m, 1 H) 2.47 (br. s., 3 H) 3.63-3.69 (m, 2 H) 4.03-4.21 (m, 1 H) 4.33-4.51 (m, 5 H) 4.69 (d, J = 13.80 Hz, 3 H) 4.81 (s, 1 H) 7.02-7.13 (m, 1 H) 7.17 (d, J = 7.78 Hz, 1 H) 7.19-7.25 (m, 1 H) 7.38 (s, 2 H) 7.42 (br s., 1 H) 7.60 (br. s., 1 H) 7.91 (s, 1 H)

Example 119

(R)-3-(3-(((S)-4-Ethyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic Acid

[0633] ##STR00279##

(R)-Methyl 3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate

[0634] ##STR00280##

[0635] Methyl (R)-3-(3-(hydroxymethyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate (204 mg, 0.587 mmol) was dissolved in dichloromethane (DCM) (2936 μl) and to this solution was added thionyl chloride (86 μl, 1.174 mmol). Upon addition, the solution went from a clear orange to clear light yellow. After 10 minutes at ambient temperature, the completed reaction was washed into a 100 mL flask, evaporated, then 3×(re-dissolved in DCM, evaporated) to give the title compound (198 mg, 0.541 mmol, 92% yield) as a resin solid. LC-MS m/z 366.2 (M+H).sup.+, 1.04 min (ret. time)

(R)-3-(3-(((S)-4-Ethyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic Acid

[0636] ##STR00281##

[0637] Into a 2 mL uW tube was placed (S)-4-ethyl-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide (18.47 mg, 0.082 mmol), methyl (R)-3-(3-(chloromethyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoate (25 mg, 0.068 mmol), and acetonitrile (550 μl), followed by sodium hydride (5.47 mg, 0.137 mmol, 60% wt.). The reaction was heated to 140° C. for a 1 minute hold time in a microwave reactor. To then hydrolyze the methyl ester, NaOH 1 M aqueous (683 μl, 0.683 mmol) was added and the reaction was again heated to 140° C. for a 1 minute hold time in a microwave reactor. The reaction was purified with preparative reversed phase HPLC under acidic (0.1% v/v TFA) conditions to give the title compound (24.8 mg, 67.1% yield). LC-MS m/z 541.3 (M+H).sup.+, 1.17 min (ret. time). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=7.89 (s, 1H), 7.87-7.82 (m, 1H), 7.63-7.57 (m, 1H), 7.55-7.50 (m, 1H), 7.50-7.44 (m, 1H), 7.26-7.22 (m, 1H), 7.22-7.12 (m, 2H), 4.68-4.63 (m, 1H), 4.38-4.19 (m, 3H), 4.01 (s, 3H), 3.78-3.53 (m, 2H), 3.38-3.21 (m, 1H), 2.94 (m, 2H), 2.27 (s, 3H), 1.92-1.79 (m, 1H), 1.26-1.11 (m, 2H), 0.99-0.91 (m, 3H), 0.90-0.80 (m, 6H)

[0638] The compounds in Table 23 were prepared by a method similar to the one described for the preparation of (R)-3-(3-(((S)-4-Ethyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)propanoic acid. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

TABLE-US-00028 TABLE 23 Retention LCMS Time Ex # Structure Name [M + 1] (min) Ex 120 [00282] (R)-3-(3-(((R)-4-Ethyl-1,1- dioxido-3,4-dihydro-2H- benzo[b][1,4,5]oxathiazepin- 2-yl)methyl)-4-methylphenyl)- 2,2-dimethyl-3-((1-methyl-1H- 1,2,3-triazol-4-yl)methoxy) propanoic acid 543.3 1.09 Ex 121 [00283] (R)-3-(3-(((R)-4-Ethyl-1,1- dioxido-3,4-dihydro-2H- pyrido[3,2-b][1,4,5]oxathiazepin- 2-yl)methyl)-4-methylphenyl)- 2,2-dimethyl-3-((1-methyl- 1H-1,2,3-triazol-4-yl) methoxy)propanoic acid 544.3 0.93