1258856-65-3

Upstream product

• 1165923-94-3 1,1-dimethylethyl 6-[(hydroxyamino)(imino)methyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate 
• 1165923-51-2 2-isopropoxy-5-(3-(5-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1,2,4-oxadiazol-5-yl)benzonitrile trifluoroacetate 
• 96-32-2 bromoacetic acid methyl ester 
• 1258855-37-6 2-[(1-methylethyl)oxy]-5-[3-(5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl)-1,2,4-oxadiazol-5-yl]benzonitrile hydrochloride 
• 1165924-06-0 1,1-dimethylethyl 6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate 
• 1165923-92-1 1,1-dimethylethyl 6-cyano-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate 
• 1165923-91-0 1,1-dimethylethyl 5-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2(1H)-isoquinolinecarboxylate 
• 1165923-89-6 1,1-dimethylethyl 6-hydroxy-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate 
• 1072948-37-8 3-cyano-4-[(1-methylethyl)oxy]benzoyl chloride 
• 258273-31-3 3-cyano-4-isopropoxybenzoic acid 
• 1165923-94-3 1,1-dimethylethyl 6-[(hydroxyamino)(imino)methyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate 

Downstream Products

• 1258855-38-7 sodium 2-(6-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydroisoquinolin-2(1H)-yl)acetate 
• 1258853-46-1 (S)-2-(6-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(1-hydroxypropan-2-yl)acetamide hydrochloride 
• 1167416-53-6 1,1-dimethylethyl 9-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate 
• 1333996-49-8 2-[(1-methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)-1,2,4-oxadiazol-5-yl]benzonitrile trifluoroacetate 
• 1333996-51-2 5-{3-[4-(2,2-dimethyl-1,3-dioxan-5-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl]-1,2,4-oxadiazol-5-yl}-2-[(1-methylethyl)oxy]benzonitrile 
• 1333995-60-0 5-(3-{4-[2-hydroxy-1-(hydroxymethyl)ethyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl}-1,2,4-oxadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile 
• 1165923-53-4 2-(6-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydroisoquinolin-2(1H)-yl)acetic acid 

Relevant academic research and scientific papers

Discovery of a brain-penetrant S1P3-sparing direct agonist of the S1P1 and S1P5 receptors efficacious at low oral dose

2-Amino-2-(4-octylphenethyl)propane-1,3-diol 1 (fingolimod, FTY720) has been recently marketed in the United States for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). Its efficacy has been primarily linked to the agonism on

Discovery of a selective S1P1 receptor agonist efficacious at low oral dose and devoid of effects on heart rate

Gilenya (fingolimod, FTY720) was recently approved by the U.S. FDA for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). It is a potent agonist of four of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors (S1P1 and S1P3-5). It has been postulated that fingolimod's efficacy is due to S1P1 agonism, while its cardiovascular side effects (transient bradycardia and hypertension) are due to S1P3 agonism. We have discovered a series of selective S1P 1 agonists, which includes 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy] phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl] propanoate, 20, a potent, S1P3-sparing, orally active S1P1 agonist. Compound 20 is as efficacious as fingolimod in a collagen-induced arthritis model and shows excellent pharmacokinetic properties preclinically. Importantly, the selectivity of 20 against S1P3 is responsible for an absence of cardiovascular signal in telemetered rats, even at high dose levels.

S1P1 AGONISTS COMPRISING A BICYCLIC N-CONTAINING RING

The present invention relates to novel compounds of formula (I) having S1P1 agonist activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.