US 9,290,467 B2Granted

Cyclic amides

AssigneeHoffmann-La Roche Inc.

InventorsLilli Anselm, David Banner, Jean-Baptiste Blanc, Delphine Gaufreteau, Wolfgang Haap, Guido Hartmann, Bernd Kuhn, Thomas Luebbers, Jens-Uwe Peters, Beat Spinnler

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Abstract

The invention relates to a compound of formula (I) wherein A, B, D and R1 to R6 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.

Claims11

Dependent claims

A compound of formula (I)

wherein
A is —O—, —S—, —CH2—, —NH— or —SO2—;
B is phenyl, substituted phenyl, pyrrolidinyl, substituted pyrrolidinyl, pyridinyl, substituted pyridinyl, pyrimidinyl, substituted pyrimidinyl, 1,2,3,4-tetrahydronaphtalenyl, bicyclo[4.2.0]octa-1(6),2,4-trienyl, indanyl or 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, wherein substituted phenyl is phenyl substituted with one or two substituents each of which is independently halogen, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, alkoxy, haloalkyl, azetidinyl, alkylsulfanyl or cyano, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one or two substituents each of which is independently halogen, alkyl, alkoxy, haloalkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, alkylsulfanyl, alkylsulfonyl, cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl, cyclohexylsulfanyl, cycloheptylsulfanyl, cyclooctylsulfanyl, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, cycloheptylsulfonyl and cyclooctylsulfonyl, wherein substituted pyridinyl is pyridinyl substituted with halogen, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, alkoxy or haloalkoxy, and wherein substituted pyrimidinyl is pyrimidinyl substituted with halogen, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, alkoxy or haloalkoxy;
D is —O—, —S—, —CH2—, —NH— or —SO2—;
one of R1, R2, R3 and R4 is hydrogen and the other ones are independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl;
or R5 and R6 together with the carbon atom to which they are attached form cyclopropyl;
and
is a carbon-carbon single bond or a carbon-carbon double bond;
or a pharmaceutically acceptable salt or ester thereof.

6 more elements

A compound selected from

(E)-(S)-5-Oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6(11),7,9,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-5-Oxo-11,16-dioxa-4-aza-tricyclo[15.2.2.1*6,10*]docosa-1(20),6,8,10(22),13,17(21),18-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-5-Oxo-17-oxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-19-Chloro-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6(11),7,9,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-19-Chloro-5-oxo-17-oxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-18-Chloro-5-oxo-11,16-dioxa-4-aza-tricyclo[15.2.2.1*6,10*]docosa-1(20),6,8,10(22),13,17(21),18-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(S)-19-Chloro-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,18(22),19-hexaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-8-Bromo-19-chloro-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(S)-8-Bromo-19-chloro-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,18(22),19-hexaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-8,19-Dichloro-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(S)-8,19-Dichloro-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,18(22),19-hexaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-18-Chloro-5-oxo-16-oxa-4,10-diaza-tricyclo[15.2.2.0*6,10*]henicosa-1(20),13,17(21),18-tetraene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(3S,8S)-18-Chloro-8-fluoro-5-oxo-16-oxa-4,10-diaza-tricyclo[15.2.2.0*6,10*]henicosa-1(20),13,17(21),18-tetraene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-18-Chloro-8,8-difluoro-5-oxo-16-oxa-4,10-diaza-tricyclo[15.2.2.0*6,10*]henicosa-1(20),13,17(21),18-tetraene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-18-Chloro-8,8-dimethyl-5-oxo-16-oxa-4,10-diaza-tricyclo[15.2.2.0*6,10*]henicosa-1(20),13,17(21),18-tetraene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-19-Chloro-8-methoxy-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(S)-19-Chloro-8-methoxy-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,18(22),19-hexaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-19-Chloro-9-methoxy-5-oxo-17-oxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-19-Chloro-9-methyl-5-oxo-17-oxa-12-thia-4,10-diaza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-19-Chloro-5-oxo-9-trifluoromethyl-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-19-Chloro-5-oxo-17-oxa-4,12-diaza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(S)-19-Chloro-9-methoxy-5-oxo-17-oxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,18(22),19-hexaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(S)-19-Chloro-5-oxo-9-trifluoromethyl-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,18(22),19-hexaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-19-Iodo-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-19-Iodo-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide, stereoaxis R;
(E)-(S)-19-Iodo-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide, stereoaxis S;
(3E,12S)-22-chloro-N-(1-cyanocyclopropyl)-14-oxo-2,5,11,12,13,14,16,17,18,19-decahydro-7,10-ethenonaphtho[2,3-b][1,12,5]dioxazacyclohexadecine-12-carboxamide;
(E)-(S)-8-Chloro-19-iodo-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(12S)-22-chloro-N-(1-cyanocyclopropyl)-14-oxo-2,3,4,5,11,12,13,14,16,17,18,19-dodecahydro-7,10-ethenonaphtho[2,3-b][1,12,5]dioxazacyclohexadecine-12-carboxamide;
(S)-19-Iodo-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6(11),7,9,18(22),19-hexaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(S)-8-Chloro-19-iodo-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6(11),7,9,18(22),19-hexaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide
(E)-(S)-19-Chloro-8-fluoro-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-9,19-Dichloro-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-19-Chloro-5-oxo-8-trifluoromethyl-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(S)-19-Chloro-8-fluoro-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,18(22),19-hexaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(S)-9,19-Dichloro-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,18(22),19-hexaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(S)-19-Chloro-5-oxo-8-trifluoromethyl-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,18(22),19-hexaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
and
(E)-(S)-8-Bromo-19-chloro-5-oxo-17-oxa-4,12-diaza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
3-[(E)-(S)-19-Chloro-3-(1-cyano-cyclopropylcarbamoyl)-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester;
(E)-(S)-19-Chloro-8-cyano-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-8-Azetidin-3-yl-19-chloro-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
3-[(S)-19-Chloro-3-(1-cyano-cyclopropylcarbamoyl)-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,18(22),19-hexaen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester;
(S)-8-Azetidin-3-yl-19-chloro-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,18(22),19-hexaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E-Z)—(S)-19-Chloro-8,10-difluoro-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-19-Chloro-7,8-difluoro-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(Z)—(S)-19-Chloro-7,8-difluoro-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-19-Chloro-8-methylsulfanyl-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(E)-(S)-10,19-Dichloro-8-fluoro-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(S)-19-Chloro-8-cyano-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,18(22),19-hexaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
(S)-19-Chloro-7,8-difluoro-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8,10,18(22),19-hexaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide;
and
(S)-19-Chloro-8-methylsulfanyl-5-oxo-12,17-dioxa-4-aza-tricyclo[16.2.2.0*6,11*]docosa-1(21),6,8, 10,18(22),19-hexaene-3-carboxylic acid (1-cyano-cyclopropyl)-amide.

50 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/738,649Filed 10 Jan 2013
Priority: EP 1215074011 Jan 2012
Published: US 2013/0196965 A11 Aug 2013
Granted: 22 Mar 2016
Term ends: Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 273/01
Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 -…:…
A61P 1/18
Drugs for disorders of the alimentary tract or the digestive system: for pancreatic disorders, e.g. pancreatic enzymes
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/00
Drugs for disorders of the cardiovascular system

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US 2013/0196965 A1Pre-grant publication · published 1 Aug 2013
US 9,290,467 B2This patent

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

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Abstract

The invention relates to a compound of formula (I) wherein A, B, D and R1 to R6 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.

A compound of formula (I)

wherein
A is —O—, —S—, —CH2—, —NH— or —SO2—;
B is phenyl, substituted phenyl, pyrrolidinyl, substituted pyrrolidinyl, pyridinyl, substituted pyridinyl, pyrimidinyl, substituted pyrimidinyl, 1,2,3,4-tetrahydronaphtalenyl, bicyclo[4.2.0]octa-1(6),2,4-trienyl, indanyl or 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, wherein substituted phenyl is phenyl substituted with one or two substituents each of which is independently halogen, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, alkoxy, haloalkyl, azetidinyl, alkylsulfanyl or cyano, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one or two substituents each of which is independently halogen, alkyl, alkoxy, haloalkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, alkylsulfanyl, alkylsulfonyl, cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl, cyclohexylsulfanyl, cycloheptylsulfanyl, cyclooctylsulfanyl, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, cycloheptylsulfonyl and cyclooctylsulfonyl, wherein substituted pyridinyl is pyridinyl substituted with halogen, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, alkoxy or haloalkoxy, and wherein substituted pyrimidinyl is pyrimidinyl substituted with halogen, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, alkoxy or haloalkoxy;
D is —O—, —S—, —CH2—, —NH— or —SO2—;
one of R1, R2, R3 and R4 is hydrogen and the other ones are independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl;
or R5 and R6 together with the carbon atom to which they are attached form cyclopropyl;
and
is a carbon-carbon single bond or a carbon-carbon double bond;
or a pharmaceutically acceptable salt or ester thereof.

6 more elements

Facts

Application

13/738,649Filed 10 Jan 2013

Priority

EP 1215074011 Jan 2012

Published

US 2013/0196965 A11 Aug 2013

Granted

22 Mar 2016

Term ends

Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 273/01
Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 -…:…
A61P 1/18
Drugs for disorders of the alimentary tract or the digestive system: for pancreatic disorders, e.g. pancreatic enzymes
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/00
Drugs for disorders of the cardiovascular system