US 12,312,362 B2Granted

Spiro derivatives of Alpha-D-galactopyranosides

AssigneeIdorsia Pharmaceuticals Ltd

InventorsMartin Bolli, John Gatfield, Corinna Grisostomi, Lubos Remen, Christoph Sager, Cornelia Zumbrunn

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Abstract

The present invention relates to compounds of Formula (I) wherein Ar1, A, B, and R1 are as described in the description, their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of Formula (I), and especially to their use as Galectin-3 inhibitors.

Claims18

Dependent claims

A compound of Formula (I)

wherein
Ar1 represents
aryl which is unsubstituted, or mono-, di-, tri-, tetra-, or penta-substituted, wherein the substituents are independently selected from halogen, methyl, cyano, methoxy, trifluoromethyl, and trifluoromethoxy;
5- or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl independently is unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from halogen, methyl, cyano, and methoxy;
or
9- or 10-membered heteroaryl, wherein said 9- or 10-membered heteroaryl independently is unsubstituted, or mono-substituted with methyl;
R1 represents
hydroxy;
C1-4-alkoxy;
—O—CO—C1-3-alkyl;
O—CO—NH—RN11 wherein RN11 represents hydrogen or C1-3-alkyl;
—O—CH2—C1-fluoroalkyl;
or
—O—CH2—CO—R1X wherein R1X represents
hydroxy;
C1-3-alkoxy;
morpholin-4-yl;
or
—NRN21RN22 wherein RN21 and RN22 both independently represent hydrogen or methyl;
and
represents a spirocyclic fragment, wherein:
ring A represents a heterocycloalkylene selected from
wherein X represents nitrogen or oxygen, and n represents the integer 0 or 1;
and wherein in case X represents nitrogen, said nitrogen is unsubstituted or mono-substituted with C1-4-alkyl;
and
wherein R2 represents hydrogen or C1-4-alkyl;
and
ring B represents
C4-7-cycloalkane-diyl wherein said C4-7-cycloalkane-diyl is unsubstituted, mono-, or di-substituted wherein the substituents are independently selected from C1-4-alkyl;
C1-3-fluoroalkyl;
C1-4-alkoxy;
halogen;
cyano;
oxo;
hydroxy;
hydroxy-C1-4-alkyl;
hydroxyimino;
morpholin-4-yl;
and —NH—RN11 wherein RN11 represents C1-6-alkyl, C2-4-alkoxy, C3-6-cycloalkyl, C2-3-fluoroalkyl, —CO—C1-4-alkyl, or —CO—C1-4-alkoxy;
4- to 7-membered heterocycloalkane-diyl wherein said heterocycloalkane-diyl contains one ring oxygen atom;
4- to 7-membered heterocycloalkane-diyl wherein said heterocycloalkane-diyl contains one ring nitrogen atom, wherein said ring nitrogen atom is unsubstituted or mono-substituted with C1-4-alkyl, —CO—C1-4-alkyl, —SO2—C1-4-alkyl, —CO—C1-4-alkoxy, or —CO—NH—C1-4-alkyl;
and wherein said 4- to 7-membered heterocycloalkane-diyl carries no further substituent in addition to said substituent on the ring nitrogen atom, or carries one further substituent on a ring carbon atom that is attached to said ring nitrogen atom wherein said substituent is oxo, or —CO—OH;
or
bridged bicyclic C6-9-cycloalkane-diyl;
or a pharmaceutically acceptable salt thereof.

42 more elements

A compound wherein said compound is:

(2R,3R,4S,5R,6R)-2-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate;
(2R,3R,4R,5R,6R)-2-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol;
(2R,3R,4S,5R,6R)-2-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylph enyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate;
(2R,3R,4R,5R,6R)-2-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylph enyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol;
(2R,3R,4R,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluoroph enyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol;
(2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;
tert-butyl (3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;
(2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol;
tert-butyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;
(2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-6-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylph enyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-6-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(2, 3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-6-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1, 2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-6-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.6]undec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3, 4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;
(5s,8S)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;
(5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;
tert-butyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;
tert-butyl ((5s,8S)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;
tert-butyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydrox ymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;
tert-butyl ((5s,8S)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydrox ymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;
tert-butyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydrox ymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;
tert-butyl ((5s,8S)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydrox ymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;
3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;
3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;
3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;
(2R,3R,4S,5R,6R)-2-(hydroxymethyl)-6-(((5r,8R)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-2-(hydroxymethyl)-6-(((5s,8S)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6-((8-(2-hydr oxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol;
(5s,8S)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydrox ymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;
(5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydrox ymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;
(5s,8S)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;
(5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;
(5s,8S)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxy methyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;
(5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxy methyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;
(2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6-(((5r,8R)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6-(((5s,8S)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6-(((5s,8S)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol;
3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-one;
(2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-(2,2-difluoroethoxy)-2-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;
methyl 2-(((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3, 4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetate;
(2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-ethoxy-2-(hydroxymethyl)-4-(4-(3,4,5-tr ifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;
2-(((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3, 4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)-N-methylacetamide;
2-(((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3, 4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)-1-morpholinoethan-1-one;
methyl 2-(((2R,3R,4S,5R,6R)-2-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-meth ylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetate;
(2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl carbamate;
(2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-6-(((5r,8R)-8-((2,2-difluoroethyl) amino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol;
tert-butyl (RS)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxym ethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,8-diazaspiro[4.6]undec-2-ene-8-carboxylate;
(RS)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxym ethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,8-diazaspiro[4.6]undec-2-en-9-one;
(RS)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxym ethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-8-methyl-1-oxa-2,8-diazaspiro[4.6]undec-2-en-9-one;
(5RS,8S)-7-(tert-butoxycarbonyl)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,7-diazaspiro[4.4]no n-2-ene-8-carboxylic acid;
3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-ol;
(5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-ol;
N-((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1, 2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide;
N-((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydr oxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide;
N-((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydr oxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide;
N-((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1, 2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide;
ethyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydrox ymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;
ethyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;
ethyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydrox ymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;
(2R,3R,4S,5R,6R)-2-(hydroxymethyl)-6-(((5r,8R)-8-(isopropylamino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)me thyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-6-((8-((2,2-difluoroethyl)amino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxym ethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-6-((8-(cyclopropylamino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-2-(hydroxymethyl)-5-methoxy-6-((8-((2,2,2-trifluoroethyl)amino)-1-oxa-2-azaspiro[4.5]de c-2-en-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-6-(((5r,8R)-8-((2,2-difluoroethyl)amino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hy droxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;
(2R,3R,4S,5R,6R)-6-(((5r,8R)-8-(cyclopropylamino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxy methyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;
2-(((2R,3R,4S,5R,6R)-2-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetic acid;
2-(((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetic acid;
2-(((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3, 4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetic acid;
(2R,3R,4S,5R,6R)-6-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylph enyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol;
N-(tert-butyl)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1, 2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxamide;
1-(3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triaz ol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl)ethan-1-one;
tert-butyl 3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate;
3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-3-azaspiro[4.5]decan-2-one;
3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1, 8-dioxa-3-azaspiro[4.5]decan-2-one;
3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1,3-diazaspiro[4.5]decan-2-one;
2-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-2,4-diazaspiro[5.5]undecan-3-one;
(2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxy-6-((2-methyl-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)tetrahydro-2H-pyran-3-ol;
or
(2R,3R,4S,5R,6R)-6-((1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol;
or a pharmaceutically acceptable salt thereof.

84 more elements

Dependencies are inferred from the claim text.

Facts

Application: 18/248,007Filed 5 Oct 2021
Priority: WO PCT/EP2020/0779686 Oct 2020
Published: US 2023/0295182 A121 Sep 2023
Granted: 27 May 2025
Term ends: Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07D 498/10
In which the condensed system contains two hetero rings: spiro-condensed systems
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 13/12
Drugs for disorders of the urinary system: of the kidneys

Family

US 2023/0295182 A1Pre-grant publication · published 21 Sep 2023
US 12,312,362 B2This patent

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

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Abstract

A compound of Formula (I)

wherein
Ar1 represents
aryl which is unsubstituted, or mono-, di-, tri-, tetra-, or penta-substituted, wherein the substituents are independently selected from halogen, methyl, cyano, methoxy, trifluoromethyl, and trifluoromethoxy;
5- or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl independently is unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from halogen, methyl, cyano, and methoxy;
or
9- or 10-membered heteroaryl, wherein said 9- or 10-membered heteroaryl independently is unsubstituted, or mono-substituted with methyl;
R1 represents
hydroxy;
C1-4-alkoxy;
—O—CO—C1-3-alkyl;
O—CO—NH—RN11 wherein RN11 represents hydrogen or C1-3-alkyl;
—O—CH2—C1-fluoroalkyl;
or
—O—CH2—CO—R1X wherein R1X represents
hydroxy;
C1-3-alkoxy;
morpholin-4-yl;
or
—NRN21RN22 wherein RN21 and RN22 both independently represent hydrogen or methyl;
and
represents a spirocyclic fragment, wherein:
ring A represents a heterocycloalkylene selected from
wherein X represents nitrogen or oxygen, and n represents the integer 0 or 1;
and wherein in case X represents nitrogen, said nitrogen is unsubstituted or mono-substituted with C1-4-alkyl;
and
wherein R2 represents hydrogen or C1-4-alkyl;
and
ring B represents
C4-7-cycloalkane-diyl wherein said C4-7-cycloalkane-diyl is unsubstituted, mono-, or di-substituted wherein the substituents are independently selected from C1-4-alkyl;
C1-3-fluoroalkyl;
C1-4-alkoxy;
halogen;
cyano;
oxo;
hydroxy;
hydroxy-C1-4-alkyl;
hydroxyimino;
morpholin-4-yl;
and —NH—RN11 wherein RN11 represents C1-6-alkyl, C2-4-alkoxy, C3-6-cycloalkyl, C2-3-fluoroalkyl, —CO—C1-4-alkyl, or —CO—C1-4-alkoxy;
4- to 7-membered heterocycloalkane-diyl wherein said heterocycloalkane-diyl contains one ring oxygen atom;
4- to 7-membered heterocycloalkane-diyl wherein said heterocycloalkane-diyl contains one ring nitrogen atom, wherein said ring nitrogen atom is unsubstituted or mono-substituted with C1-4-alkyl, —CO—C1-4-alkyl, —SO2—C1-4-alkyl, —CO—C1-4-alkoxy, or —CO—NH—C1-4-alkyl;
and wherein said 4- to 7-membered heterocycloalkane-diyl carries no further substituent in addition to said substituent on the ring nitrogen atom, or carries one further substituent on a ring carbon atom that is attached to said ring nitrogen atom wherein said substituent is oxo, or —CO—OH;
or
bridged bicyclic C6-9-cycloalkane-diyl;
or a pharmaceutically acceptable salt thereof.

42 more elements

Facts

Application

18/248,007Filed 5 Oct 2021

Priority

WO PCT/EP2020/0779686 Oct 2020

Published

US 2023/0295182 A121 Sep 2023

Granted

27 May 2025

Term ends

Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07D 498/10
In which the condensed system contains two hetero rings: spiro-condensed systems
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 13/12
Drugs for disorders of the urinary system: of the kidneys