US 7,842,685 B2Granted

S1P1 receptor agonists and use thereof

AssigneeAmgen Inc.

InventorsVictor J. Cee, Michael J. Frohn, Brian Alan Lanman, Susana C. Neira, Anthony B. Reed, Kelvin K. C. Sham

Life of this patent

Estimating the term…

Abstract

The present invention relates to compounds of Formula (I): that are have activity as S1P receptor modulating agents, more specifically to specifically compounds that are S1P1 receptor agonists. The invention also related to the use of such compounds to treat diseases associated with inappropriate S1P1 receptor activity such as autoimmune diseases.

Claims32

Dependent claims

A compound of Formula (I):

wherein:
m is 0, 1, 2 or 3;
n is 0, 1, 2 or 3;
o is 0, 1, 2 or 3;
A is a phenyl, heterocyclyl, three to six membered cycloalkyl, or a five or six membered heteroaryl ring;
L is a saturated 3, 4, 5, 6 or 7-member ring containing 0, 1 or 2 atoms selected from N, O and S and optionally containing a double bond, the ring being substituted by 0, 1 or 2 groups selected from F, Cl, C1-4alkyl, C1-4haloalkyl, OH, —OC1-4alkyl, and —OC1-4haloalkyl;
X1 is N or CH;
X2 is N or CH;
X5 is N or CH;
is selected from
R1 is selected from F, Cl, C1-4alkyl, C1-4haloalkyl, OH, —OC1-4alkyl, and —OC1-4haloalkyl;
R2 is selected from F, Cl, C1-4alkyl, C1-4haloalkyl, OH, —OC1-4alkyl, and —OC1-4haloalkyl;
R3 is selected from F, Cl, C1-4alkyl, C1-4haloalkyl, OH, —OC1-4alkyl, amino, and —OC1-4haloalkyl;
Z is:
(i) a cycloalkyl substituted with amino, monoalkylamino or dialkylamino group;
a cycloalkylalkyl substituted with one or two carboxy groups;
a monosubstituted amino, disubstituted amino, carboxyalkylamino, hydroxyalkyl, substituted hydroxyalkyl, hydroxyalkoxy, substituted hydroxyalkoxy, aminoalkyl, aminoalkoxy, carboxyalkyl, substituted carboxyalkyl, carboxyalkyloxy, substituted carboxyalkyloxy, carboxyalkoxyalkyl, substituted carboxyalkoxyalkyl, aminocarbonyl, acylamino, aminosulfonyl, sulfonylamino, heterocycloamino, heterocycloaminoalkyl, heterocycloaminocarbonyl, heterocycloaminooxy, or heteroaralkyl group;
(ii) a group of formula (b):
where:
q is 0, 1 or 2;
R4 is selected from H, C1-3haloalkyl, and C1-6alkyl;
R5 is selected from H, C1-3haloalkyl, and C1-4alkyl;
or
R4 and R5 together with the carbon atom to which they are attached form a 3, 4, 5, 6 or 7-member carbocyclic ring substituted by 0, 1 or 2 groups selected from F, Cl, C1-4haloalkyl, OH, —OC1-4alkyl, and —OC1-4haloalkyl;
R6 is a lone pair of electrons or O;
R7 is H or C1-6alkyl;
R8 is selected from H, F, Cl, C1-4alkyl, C1-4haloalkyl, OH, —OC1-4alkyl, and —OC1-4haloalkyl;
or
R7 and R8, when taken together, form a group that is selected from —(CR10R10)—, —(CR10R10)O—, —O(CR10R10)—, —(CR10R10)(CR10R10)—, and —(CR10R10)3—;
R9 is selected from H, F, C1-3haloalkyl, C1-4alkyl, OH and OC1-4alkyl;
or R8 and R9 together with the carbon atom to which they are attached from cycloalkyl;
and
each R10 is independently in each instance selected from H, F, Cl, C1-4alkyl, C1-4haloalkyl, OH, —OC1-4alkyl, and —OC1-4haloalkyl;
or
(iii) when R3 is on a carbon atom of the phenyl ring that is adjacent to the carbon of the phenyl ring that is bonded to Z, then R3 and Z can combine to form —CH═CH—NR11—, —(CH2)2NR11—, —CH2NR11CH2—, —(CH2)2NR11CH2—, —N═CR11—NH—, or —N═CH—NR11—, where R11 is selected from hydrogen, hydroxyalkyl, aminoalkyl, carboxyalkyl, substituted hydroxyalkyl, substituted carboxyalkyl, or aminocarbonyl;
or
a pharmaceutically acceptable thereof;
provided that when
is selected from
then at least one of X1, X2 and X5 is N.

37 more elements

A compound selected from:

1-((3-fluoro-4-(5(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)methyl)azetidine-3-carboxylic acid;
(R)-1-((3-fluoro-4-(5(1-phenylcyclopropypl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)pyrrolidine-3-carboxylic acid;
(S)-1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)pyrrolidine-3-carboxylic acid;
1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)-3-hydroxyazetidine-3-carboxylic acid;
3-fluoro-1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylic acid;
1-((3-fluoro-4-(5-(1-phenylcyclopent-3-enyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylic acid;
1-((3-fluoro-4-(5-(1-phenylcyclopentyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylic acid;
1-((3-fluoro-4-(5-(1-phenylcyclohexyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylic acid;
(1R,3S)-3-carboxy-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)azetidine 1-oxide;
(1S,3R)-3-carboxy-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)azetidine 1-oxide;
1-((3-fluoro-4-(5-(2-phenyloxetan-2-yl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylic acid;
1-((3-fluoro-4-(6-(1-phenylcyclopropyl)benzo[d]thiazol-2-yl)phenyl)methyl)azetidine-3-carboxylic acid;
(R)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethyl)azetidine-3-carboxylic acid;
(S)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethyl)azetidine-3-carboxylic acid;
3-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methylamino)propanoic acid;
(R)-3-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethylamino)propanoic acid;
(S)-3-(1-(3-fluoro-4-(5-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-phenyl)ethylamino)propanoic acid;
3-(1-(3-fluoro-4-(5(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethylamino)propanoic acid;
3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzamido)propanoic acid;
2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzamido)acetic acid;
4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzamido)butanoic acid;
1-((2,6-dimethyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]-pyridin-2-yl)phenyl-)-methyl)azetidine-3-carboxylic acid;
1-((2-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)-azetidine-3-carboxylic acid;
1-((3-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylic acid;
1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)cyclopropanamine;
3-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)cyclopropylamino)propanoic acid;
2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)propan-2-amine;
3-(2-(3-fluoro-4-(5(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)propan-2-ylamino)propanoic acid;
3-(3-fluoro-4-(5-1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)propanoic acid;
(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methanol;
2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzyl)propane-1,3-diol;
3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzyl)cyclobutane-1,1-dicarboxylic acid;
(cis)-3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzyl)-cyclobutanecarboxylic acid;
(trans)-3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b ]pyridine-2-yl)benzyl)-cyclobutanecarboxylic acid;
(R)-2,2,2-trifluoro-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)ethanolol;
(S)-2,2,2-trifluoro-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethanol;
2(rac)-2,2,2-trifluoro-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethanamine;
1-(3-fluoro-4-(5(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)azetidin-3-ol;
2-(4-((3,3-difluoroazetidin-1yl)methyl)-2-fluorophenyl)-5-(1-phenylcydopropyl)-thiazolo[5,4-b]pyridine;
(R)-1-(1-(3-fluoro-4-(5(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-propyl)azetidine-3-carboxylic acid;
(S)-1-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)propyl)azetidine-3-carboxylic acid;
1-(3-fluoro-4-(5-(1-(2-fluorophenyl)cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzyl)azetidine-3-carboxylic acid;
1-(3-fluoro-4-(5-(1-(4-hydroxyphenyl)cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzyl)azetidine-3-carboxylic acid;
1-(3-fluoro-4-(5-(1-(4-fluorophenyl)cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzyl)azetidine-3-carboxylic acid;
1-(3-fluoro-4-(5-(1-phenylcyclobutyl)thiazolo[5,4-b]pyridine-2-yl)benzyl)azetidine-3-carboxylic acid;
2-amino-2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-phenethyl)-propane-1,3-diol;
(rac)-2-amino-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-phenyl)-2-(hydroxymethyl)butyl dihydrogen phosphate;
1-(3-fluoro-4-(6-(1-phenylcyclopropyl)thiazolo[4,5-c]pyridine-2-yl)benzyl)azetidine-3-carboxylic acid;
1-(3-amino-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)azetidine-3-carboxylic acid;
1-(4-(5-(1-cyclohexylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid;
1-(4-(5-(1-cyclopentylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid;
1-(4-(5-bi(cycloprop)ylthiazolo[5,4-b]pyridine-2-yl)-3-fluorobenzyl)-azetidine-3-carboxylic acid;
1-(4-(5-(1-(4,4-difluorocyclohexyl)cyclopropyl)thiazolo[5 ,4-b]pyridine-2-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid;
(R)-1-(4-(5-(1-(3,3-difluorocyclopentyl)cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid;
(S)-1-(4-(5-(1-(3,3-difluorocyclopentyl)cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid;
1-(3-fluoro-4-(5-(1-(tetrahydro-2H-pyran-4-yl)cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzyl)azetidine-3-carboxylic acid;
(2S,4R)-4-(3-fluoro-4-(5-(-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-4-hydroxypyrrolidine-2-carboxylic acid;
(2S,4R)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4]pyridine-2-yl)phenyl)-pyrrolidine-2-carboxylic acid;
(2S,4R)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-1-methylpyrrolidine-2-carboxylic acid;
((2S,4S)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-phenyl)-pyrrolidin-2-yl)methanol;
((2-(3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)ethyl)amino)(oxo)acetic acid;
2-(2-fluoro-4-((3-fluoroazetidin-1-yl)methyl)-phenyl)-5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine;
N-benzyl-2-(3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)-phenyl)ethanamine;
N-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)-ethyl)methanesulfonamide;
1-((3-fluoro-4-(6-(1-(pyridine-2-yl)cyclopropyl)benzo[d]thiazol-2-yl)phenyl)methyl)azetidine-3-carboxylic acid;
2-(4-(azetidin-1-ylmethyl)-3,5-dimethylphenyl)-5(1-phenyl-cyclopropyl)thiazolo[5,4-b]pyridine;
1-(4-(5(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)azetidine-3-carboxylic acid;
3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-phenylamino)-propanoic acid;
4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-phenylamino)-butanoic acid;
(R)-3-(2,6-dimethyl-4-(5(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenoxy)propane-1 ,2-diol;
(S)-3-(2,6-dimethyl-4-(5(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenoxy)propane-1 ,2-diol;
3-(4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenylamino)propanoic acid;
(S)-2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzylamino)propanoic acid;
(R)-2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzylamino)propanoic acid;
(2S,4R)-4-(4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenoxy)pyrrolidine-2-carboxylic acid;
1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzylamino)cyclopropanecarboxylic acid;
2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzylamino)-2-methylpropanoic acid;
(S)-1-(3-fluoro-4-(5-1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)azetidine-2-carboxylic acid;
(R)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-benzyl)-azetidine-2-carboxylic acid;
(S)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-benzyl)-pyrrolidine-2-carboxylic acid;
(R)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-benzyl)-pyrrolidine-2-carboxylic acid;
2-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-benzyl)azetidin-3-yl)acetic acid;
5-(1-phenylcyclopropyl)-2-(1,2,3,4-tetrahydroisoquinolin-6-yl)thiazolo-[5,4-]-pyridine;
3-(6-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid;
2-(6-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)acetic acid;
1-(4-(5-(1-cyclobutylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-3-fluorobenzyl)-azetidine-3-carboxylic acid;
1-(4-(5-(1-(3,3-difluorocyclobutyl)cyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-3-fluorobenzyl)azetidine-3-carboxylic acid;
2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyloxy)acetic acid;
2-(4-(1-azetidinylmethyl)-2-fluorophenyl)-5-(1-phenyl-cyclopropyl)-[1,3 ]thiazolo-[5,4-b]pyridine;
2-(4-(1-azetidinylmethyl)-2-fluorophenyl)-5-(1-phenyl-cyclopropyl)-[1,3 ]thiazolo-[5,4-b]pyridine;
4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl-amino)butanoic acid;
(rac)-3-(3-fluoro--4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl-amino)butanoic acid;
(S)-3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl-amino)butanoic acid;
(R)-3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl-amino)butanoic acid;
3-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-ethylamino)butanoic acid;
(S)-3-((R)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pridin-2-yl)phenyl)ethylamino)butanoic acid;
(R)-3-((S)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethylamino)butanoic acid;
(R)-3-((R)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethylamino)butanoic acid;
(S)-3-((S)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethylamino)butanoic acid;
(R)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b-]pyridin-2-yl)phenyl)-ethanamine;
(S)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-ethanamine;
4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)butanoic acid;
1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)-1H-imidazole-4-carboxylic acid;
1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)-1H-imidazole-5-carboxylic acid;
1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)-1H-pyrazole-4-carboxylic acid;
1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)-1H-pyrazole-3-carboxylic acid;
1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)-1H-pyrazole-5-carboxylic acid;
(R)-2-amino-3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)propanoic acid;
(S)-2-amino-3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)propanoic acid;
(R)-2-amino-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)butanoic acid;
(S)-2-amino-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)butanoic acid;
(R)-2-amino-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-2-methylbutanoic acid;
(S)-2-amino-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-2-methylbutanoic acid;
2-(4-(1-azetidinylcarbonyl)-2-fluorophenyl)-5-(1-phenylcyclopropyl)-[1,3]thiazolo[5,4-b]pyridine;
(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)(morpholino)methanone;
R-2-(2-fluoro-4-(4-morpholinylcarbonyl)phenyl)-5-(1-phenyl-cyclopropyl)-[1,3]thiazolo[5,4-b]pyridine;
(3R)-1-((3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)-phenyl)-carbonyl)-3-piperidinecarboxylic acid;
3-fluoro-N-(2-hydroxyethyl)-N-methyl-4-(5-(1-phenylcyclopropyl)-[1,3]thiazolo[5,4-b]pyridin-2-yl)benzamide;
3-fluoro-N-(2-methoxyethyl)-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)benzamide;
3-fluoro-N-(2-hydroxyethyl)-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)benzamide;
1-((3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)carbonyl)-3-azetidinecarboxylic acid;
N-cyclopropyl-3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)benzamide;
3-fluoro-N-(2-methoxyethyl)-N-methyl-4-(5-(1-phenylcyclopropyl)-[1,3]thiazolo[5,4-b]pyridin-2-yl)benzamide;
3-(((3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)carbonyl)amino)-3-methylbutanoic acid;
N-((3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)carbonyl)-N-methyl-beta-alanine;
(rac)-3-(((3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)carbonyl)amino)butanoic acid;
2,2,2-trifluoro-N-(3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)-phenyl)acetamide;
1-(3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)-N-methylcyclopropanamine;
3-fluoro-N,N-dimethyl-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)-aniline;
3-fluoro-N-methyl-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)-aniline;
N-(3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)-N-(methylsulfonyl)methanesulfonamide;
4-((3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)amino)-4-oxobutanoic acid;
3-((3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)sulfamoyl)propanoic acid;
1-(3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)-2-pyrrolidinone;
N-(3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4]pyridin-2-yl)phenyl)-D-alpha-asparagine;
N-(3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)-D-asparagine;
N-(3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)-L-alpha-asparagine;
N-(3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)-L-asparagine;
cis-3-((3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)amino)cyclobutanecarboxylic acid;
trans-3-((3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)amino)cyclobutanecarboxylic acid;
(2S)-4-((3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)amino)-2-hydroxy-4-oxobutanoic acid;
(3S)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenylamino)-3-hydroxy-4-oxobutanoic acid;
(2R)-4-((3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)amino)-2-hydroxy-4-oxobutanoic acid;
(3R)-4-((3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)amino)-3-hydroxy-4-oxobutanoic acid;
2-(1H-indol-5-yl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine;
3-(5-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)-1H-indol-1-yl)propanoic acid;
4-(5(5(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)-1H-indol-1-yl)-butanoic acid;
(5-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)-1H-indol-1-yl)acetic acid;
2-(1H-benzimidazol-5-yl)-5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridine;
3-(5-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)-1H-benzimidazol-1-yl)propanoic acid;
3-(6-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)-1H-benzimidazol-1-yl)propanoic acid;
3-(5-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)-1,3-dihydro-2H-isoindol-2-yl)propanoic acid;
(5-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)-1,3-dihydro-2H-isoindol-2-yl)acetic acid;
N-(3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)benzyl)glycine;
2-(3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)ethanamine;
2-(3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)ethanol;
N-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)ethyl)glycine;
2-(3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)-N,N-dimethylethanamine;
N-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)ethyl)acetamide;
and
(2R,4R)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)pyrrolidine-2-carboxylic acid;
2-amino-3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)propan-1-ol;
N-(2,6-dimethyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)-3-(azetidin-1-yl)propan-1-amine;
(2-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)methanol;
(2,6-dimethyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)methanol;
(3-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)methanol;
(4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)methanol;
1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethanol;
2-amino-3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)propanoic acid;
or
a pharmaceutically acceptable salt thereof.

168 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/456,687Filed 18 Jun 2009 · us provisional application
Priority: 20 Jun 2008
Published: US 2010/0029611 A14 Feb 2010
Granted: 30 Nov 2010
Term ends: Not estimatedThe source records don’t support an estimate.

Classification33 codes

C07D 513/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 9/2059
Polysaccharides, e.g. alginate, gums; Cyclodextrin: starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…

Family

Application61/074,476Us provisional application · filed 20 Jun 2008
US 2010/0029611 A1Pre-grant publication · published 4 Feb 2010
US 7,842,685 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of Formula (I):

wherein:
m is 0, 1, 2 or 3;
n is 0, 1, 2 or 3;
o is 0, 1, 2 or 3;
A is a phenyl, heterocyclyl, three to six membered cycloalkyl, or a five or six membered heteroaryl ring;
L is a saturated 3, 4, 5, 6 or 7-member ring containing 0, 1 or 2 atoms selected from N, O and S and optionally containing a double bond, the ring being substituted by 0, 1 or 2 groups selected from F, Cl, C1-4alkyl, C1-4haloalkyl, OH, —OC1-4alkyl, and —OC1-4haloalkyl;
X1 is N or CH;
X2 is N or CH;
X5 is N or CH;
is selected from
R1 is selected from F, Cl, C1-4alkyl, C1-4haloalkyl, OH, —OC1-4alkyl, and —OC1-4haloalkyl;
R2 is selected from F, Cl, C1-4alkyl, C1-4haloalkyl, OH, —OC1-4alkyl, and —OC1-4haloalkyl;
R3 is selected from F, Cl, C1-4alkyl, C1-4haloalkyl, OH, —OC1-4alkyl, amino, and —OC1-4haloalkyl;
Z is:
(i) a cycloalkyl substituted with amino, monoalkylamino or dialkylamino group;
a cycloalkylalkyl substituted with one or two carboxy groups;
a monosubstituted amino, disubstituted amino, carboxyalkylamino, hydroxyalkyl, substituted hydroxyalkyl, hydroxyalkoxy, substituted hydroxyalkoxy, aminoalkyl, aminoalkoxy, carboxyalkyl, substituted carboxyalkyl, carboxyalkyloxy, substituted carboxyalkyloxy, carboxyalkoxyalkyl, substituted carboxyalkoxyalkyl, aminocarbonyl, acylamino, aminosulfonyl, sulfonylamino, heterocycloamino, heterocycloaminoalkyl, heterocycloaminocarbonyl, heterocycloaminooxy, or heteroaralkyl group;
(ii) a group of formula (b):
where:
q is 0, 1 or 2;
R4 is selected from H, C1-3haloalkyl, and C1-6alkyl;
R5 is selected from H, C1-3haloalkyl, and C1-4alkyl;
or
R4 and R5 together with the carbon atom to which they are attached form a 3, 4, 5, 6 or 7-member carbocyclic ring substituted by 0, 1 or 2 groups selected from F, Cl, C1-4haloalkyl, OH, —OC1-4alkyl, and —OC1-4haloalkyl;
R6 is a lone pair of electrons or O;
R7 is H or C1-6alkyl;
R8 is selected from H, F, Cl, C1-4alkyl, C1-4haloalkyl, OH, —OC1-4alkyl, and —OC1-4haloalkyl;
or
R7 and R8, when taken together, form a group that is selected from —(CR10R10)—, —(CR10R10)O—, —O(CR10R10)—, —(CR10R10)(CR10R10)—, and —(CR10R10)3—;
R9 is selected from H, F, C1-3haloalkyl, C1-4alkyl, OH and OC1-4alkyl;
or R8 and R9 together with the carbon atom to which they are attached from cycloalkyl;
and
each R10 is independently in each instance selected from H, F, Cl, C1-4alkyl, C1-4haloalkyl, OH, —OC1-4alkyl, and —OC1-4haloalkyl;
or
(iii) when R3 is on a carbon atom of the phenyl ring that is adjacent to the carbon of the phenyl ring that is bonded to Z, then R3 and Z can combine to form —CH═CH—NR11—, —(CH2)2NR11—, —CH2NR11CH2—, —(CH2)2NR11CH2—, —N═CR11—NH—, or —N═CH—NR11—, where R11 is selected from hydrogen, hydroxyalkyl, aminoalkyl, carboxyalkyl, substituted hydroxyalkyl, substituted carboxyalkyl, or aminocarbonyl;
or
a pharmaceutically acceptable thereof;
provided that when
is selected from
then at least one of X1, X2 and X5 is N.

37 more elements

Facts

Application

12/456,687Filed 18 Jun 2009 · us provisional application

Priority

20 Jun 2008

Published

US 2010/0029611 A14 Feb 2010

Granted

30 Nov 2010

Term ends

Not estimatedThe source records don’t support an estimate.

Classification33 codes

C07D 513/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 9/2059
Polysaccharides, e.g. alginate, gums; Cyclodextrin: starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…