US 7,547,701 B2Granted

Haloalkyl containing compounds as cysteine protease inhibitors

AssigneeViroBay, Inc.

InventorsJohn O. Link, Craig J. Mossman, Soon H. Woo, Sheila M. Zipfel

Life of this patent

Estimating the term…

Abstract

The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present invention is directed to pharmaceutical compositions comprising these compounds and processes for preparing them.

Claims23

Dependent claims

A compound of Formula (I):

R1 and R2 taken together with the carbon atom to which both R1 and R2 are attached form (i) cycloalkylene optionally substituted with one or two Rb independently selected from alkyl, halo, alkylamino, dialkylamino, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, alkoxycarbonyl, or aryloxycarbonyl or (ii) heterocyclylalkylene optionally substituted with one to four Rc which are independently selected from alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkyloxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, aminoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, —S(O)n2R14, -alkylene-S(O)n2—R15, —COOR16, -alkylene-COOR17, —CONR18R19, or -alkylene-CONR20R21 (where n2 is 0-2 and R14-R17, R18 and R20 are independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, or heterocyclyl and R19 and R21 are independently hydrogen or alkyl) wherein the aromatic or alicyclic ring in the groups attached to cycloalkylene or heterocyclylalkylene is optionally substituted with one, two, or three substituents independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monsubstituted amino, disubstituted amino, or acyl;
R3 is hydrogen or alkyl;
R4 is aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylalkyl, or -alkylene-X1—R22 (wherein X1 is —NR23—, —O—, —S(O)n3—, —CO—, —COO—, —OCO—, —NR23CO—, —CONR23—, —NR23SO2—, —SO2NR23—, —NR23COO—, —OCONR23—, —NR23CONR24, or —NR23SO2NR24— where R23 and R24 are independently hydrogen, alkyl, or acyl, n3 is 0-2, and R22 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl) wherein said alkylene chain in R4 is optionally substituted with one to six halo and wherein the aromatic or alicyclic ring in R4 is optionally substituted with one, two, or three Rd independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, amino, monsubstituted amino, disubstituted amino, or acyl;
R5 is hydrogen or alkyl;
R6 is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or -alkylene-X2—R25 (wherein X2 is —NR26—, —O—, —S(O)n4—, —CO—, —COO—, —OCO—, —NR26CO—, —CONR26—, —NR26SO2—, —SO2NR26—, —NR26COO—, —OCONR26—, —NR26CONR27—, or —NR26SO2NR27— where R26 and R27 are independently hydrogen, alkyl, or acyl, n4 is 0-2, and R25 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) wherein said alkylene chain in R6 is optionally substituted with one to six halo and the aromatic or alicyclic rings in R6 are optionally substituted by one, two, or three Re independently selected from alkyl, halo, hydroxy, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, nitro, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, carboxy, or alkoxycarbonyl and further where the aromatic or alicyclic rings in Re is optionally substituted by one, two or three Rf independently selected from alkyl, alkoxy, haloalkyl, haloalkoxy, halo, hydroxy, carboxy, cyano, nitro, aryl or cycloalkyl;
R7 is haloalkyl;
and
R8 is hydrogen, alkyl, alkoxyalkyl or haloalkyl;
or
R6 and R8 together with the carbon atom to which they are attached form cycloalkylene or heterocyclylalkylene wherein said cycloalkylene is optionally substituted with one or two substituents independently selected from alkyl, haloalkyl, hydroxy, or alkoxy and heterocyclylalkylene is optionally substituted with one or two substituents independently selected from alkyl, haloalkyl, hydroxy, or alkoxy;
or
a pharmaceutically acceptable salt thereof.

9 more elements

A compound of Formula (I):

wherein:
R1 and R2 taken together with the carbon atom to which both R1 and R2 are attached form (i) cycloalkylene optionally substituted with one or two Rb independently selected from alkyl, halo, alkylamino, dialkylamino, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, alkoxycarbonyl, or aryloxycarbonyl, (ii) a four atom heterocyclylalkylene ring, or (iii) heterocyclylalkylene optionally substituted with one to four Rc independently selected from alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkyloxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, aminoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, —S(O)n2R14, -alkylene-S(O)n2—R15, —COOR16,
-alkylene-COOR17, —CONR18R19, or -alkylene-CONR20R21 (where n2 is 0-2 and R14-R17, R18 and R20 are independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, or heterocyclyl and R19 and R21 are independently hydrogen or alkyl) wherein the aromatic or alicyclic ring in the groups attached to cycloalkylene or heterocyclylalkylene is optionally substituted with one, two, or three substituents independently selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryloxycarbonyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monsubstituted amino, disubstituted amino, or acyl;
R3 is hydrogen or alkyl;
R4 is -alkylene-S(O)2—R22 where R22 is aralkyl, heteroaryalkyl, or cycloalkylalkyl wherein the alkylene chain in R4 is optionally substituted with one to six halo and further wherein the aromatic or alicyclic ring in R4 is optionally substituted with one, two, or three Rd independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, amino, monsubstituted amino, disubstituted amino, or acyl;
R5 is hydrogen or alkyl;
R6 is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or -alkylene-X2—R25 (where X2 is —NR26—, —O—, —S(O)n4—, —CO—, —COO—, —OCO—, —NR26CO—, —CONR26—, —NR26SO2—, —SO2NR26—, —NR26COO—, —OCONR26—, —NR26CONR27—, or —NR26SO2NR27— where R26 and R27 are independently hydrogen, alkyl, or acyl, n4 is 0-2, and R25 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) wherein said alkylene chain in R6 is optionally substituted with one to six halo and the aromatic or alicyclic rings in R6 are optionally substituted by one, two, or three Re independently selected from alkyl, halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, alkoxy, alkoxyalkyl, alkoxyalkyloxy, haloalkyl, haloalkoxy, oxo, cyano, nitro, acyl, aryl, aralkyl, aryloxy, aralkyloxy, arylsulfonyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkyloxy, heteroarylsulfonyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, carboxy, alkoxycarbonyl, alkylsulfonyl, aminosulfonyl, or aminoalkyl and further where the aromatic or alicyclic rings in Re is optionally substituted with one, two or three Rf independently selected from alkyl, alkoxy, haloalkyl, haloalkoxy, halo, hydroxy, carboxy, cyano, nitro, aryl or cycloalkyl;
R7 is haloalkyl optionally substituted with alkoxy or alkoxyalkyloxy;
and R8 is hydrogen, alkyl, alkoxyalkyl or haloalkyl;
or
R6 and R8 together with the carbon atom to which they are attached form cycloalkylene or heterocyclylalkylene wherein said cycloalkylene is optionally substituted with one to four substituents independently selected from alkyl, halo, haloalkyl, hydroxy, or alkoxy and heterocyclylalkylene is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkyl, cycloalkyl, hydroxy, or alkoxy;
or
a pharmaceutically acceptable salts thereof.

10 more elements

A compound selected from the group consisting of:

N-(1-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-phenylethylamino)-propionamide;
N-(4-cyano-1-ethylpiperidin-4-yl)-3-(phenylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-phenyl-ethylamino)propionamide;
N-(4-cyano-1,1-dioxohexahydro-1λ6-thiopyran-4-yl)-3-phenylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-phenylethylamino)-propionamide;
N-(1-cyanocyclopropyl)-3-phenylmethanesulfanyl-2(R)-(2,2,2-trifluoro-1(S)-4-hydroxyphenyl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-phenylethyl-amino)propionamide;
N-(1-cyanocyclopropyl)-3-phenylmethanesulfanyl-2(R)-(2,2,2-trifluoro-1(RS)-furan-2-ylethyl-amino)propionamide;
N-(1-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(RS)-furan-2-ylethyl-amino)propionamide;
N-(1-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-3-bromophenyl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-phenylmethanesulfanyl-2(R)-(2,2,2-trifluoro-1(RS)-indol-3-ylethyl-amino)propionamide;
N-(1-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(RS)-indol-3-ylethyl-amino)propionamide;
N-(1-cyanocyclopropyl)-3-phenylmethanesulfanyl-2(R)-(2,2,2-trifluoro-1(RS)-thiophen-2-ylethyl-amino)propionamide;
N-(1-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(RS)-thiophen-2-ylethyl-amino)propionamide;
N-(1-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-methylethylamino)-propionamide;
N-(1-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-1-methylpyrrol-2-yl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-(1-methylcyclopentyl)-2(S)-(2,2,2-trifluoro-1(S)-thiophen-2-ylethyl-amino)propionamide;
N-(1-cyanocyclopropyl)-3-(1-methylcyclopentyl)-2(S)-(2,2,2-trifluoro-1(R)-thiophen-2-ylethyl-amino)propionamide;
N-(1-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethyl-amino)propionamide;
N-(1-cyanocyclopropyl)-3-pyridin-2-ylmethanesulfanyl-2(R)-(2,2,2-trifluoro-1(RS)-phenylethyl-amino)propionamide;
N-(1-cyanocyclopropyl)-3-pyridin-2-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-phenylethyl-amino)propionamide;
N-(1-cyanocyclopropyl)-3-(1-methylcyclopentyl)-2(S)-(2,2,2-trifluoro-1(S)-2-hydroxyphenyl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-(1-methylcyclopentyl)-2(S)-(2,2,2-trifluoro-1(R)-4-hydroxyphenyl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-pyridin-2-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(R)-phenylethyl-amino)propionamide;
N-(1-cyanocyclopropyl)-3-(1-methylcyclopentyl)-2(S)-(2,2,2-trifluoro-1(S)-4-hydroxyphenyl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-(2-chlorophenyl)-2(S)-(2,2,2-trifluoro-1(RS)-phenylethylamino)-propionamide;
N-(1-cyanocyclopropyl)-3-(2-chlorophenyl)-2(S)-(2,2,2-trifluoro-1(RS)-4-fluorophenyl-ethylamino)-propionamide;
N-(1-cyanocyclopropyl)-3-pyridin-2-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(RS)-4-fluorophenyl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-hydroxyphenyl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-phenylmethanesulfanyl-2(R)-(2,2,2-trifluoro-1(R)-3-chloro-4-hydroxy-phenylethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-phenylmethanesulfanyl-2(R)-(2,2,2-trifluoro-1(S)-3-chloro-4-hydroxy-phenylethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(R)-3-chloro-4-hydroxy-phenylethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-3-chloro-4-hydroxy-phenylethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-(1-methylcyclopentyl)-2(S)-(2,2-difluoro-1(R)-thiophen-2-ylethyl-amino)propionamide;
N-(1-cyanocyclopropyl)-3-phenylmethanesulfanyl-2(R)-(2,2-difluoro-1(RS)-thiophen-2-ylethyl-amino)propionamide;
N-(1-cyanocyclopropyl)-3-(1-methylcyclopentyl)-2(S)-(2,2,2-trifluoro-1(S)-3-fluoro-4-hydroxy-phenylethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-phenylmethanesulfanyl-2(R)-(2,2,2-trifluoro-1(RS)-pyridin-2-ylethyl-amino)propionamide;
N-(1-cyanocyclopropyl)-4-pyridin-2-ylsulfanyl-2(S)-(2,2,2-trifluoro-1(RS)-4-fluorophenyl-ethylamino)butyramide;
N-(1-cyanocyclopropyl)-4-pyridin-2-ylsulfonyl-2(S)-(2,2,2-trifluoro-1(RS)-4-fluorophenyl-ethylamino)butyramide;
N-(1-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(RS)-pyridin-2-yl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(R)-(2,2-difluoro-1(R)-thiophen-2-yl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-(2-difluoromethoxyphenylmethanesulfanyl)-2(R)-(2,2,2-trifluoro-1(RS)-thiophen-2-ylethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-(2-difluoromethoxyphenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(RS)-thiophen-2-ylethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-pyridin-2-ylmethanesulfanyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-pyridin-2-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-pyridin-2-ylmethanesulfanyl-2(R)-(2,2,2-trifluoro-1(R)-4-fluorophenyl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-pyridin-2-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(R)-4-fluorophenyl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-thiophen-3-ylethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-cyclopropylmethanesulfanyl-2(R)-(2,2,2-trifluoro-1(RS)-thiophen-2-yl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(RS)-thiophen-2-yl-ethylamino)propionamide;
N-(1-cyanotetrahydropyran-4-yl)-3-cyclopropylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-3,4-difluoro-phenylethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-1-methylpyrrol-2-ylethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-1-oxo-1-methyl-pyrrol-2-ylethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-3,4,5-trifluoro-phenylethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-(4-fluorophenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluoro-phenylethylamino)propionamide;
N-(1-cyanotetrahydrothiopyran-4-yl)-3-(4-fluorophenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;
N-(1cyanocyclopropyl)-3-(4-fluorophenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-3-phenoxy-phenylethylamino)propionamide;
N-(1-cyano-1,1-dioxohexahydro-1λ6-thiopyran-4-yl)-3-(4-fluorophenylmethane-sulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-(2-difluoromethoxyphenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(RS)-1-phenylsulfonylpyrrol-2-ylethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-(2-difluoromethoxyphenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-(2-trifluoromethylpyridin-6-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(RS)-4-fluorophenyl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(RS)-1-phenyl-sulfonylpyrrol-2-yl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-pyrazin-2-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(R)-4-fluorophenyl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-pyrazin-2-ylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;
N-(1-cyanotetrahydropyran-4-yl)-3-(2-difluoromethoxyphenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;
N-(1-cyano1,1-dioxohexahydro-1λ6-thiopyran-4-yl)-3-(2-difluoromethoxyphenyl-methanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-(2-trifluoromethylpyridin-6-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-pyrazin-2-ylmethanesulfanyl-2(R)-(2,2,2-trifluoro-1(R)-4-fluorophenyl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-pyrazin-2-ylmethanesulfanyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;
N-(1-cyanocyclopropyl)-3-(1-oxopyridin-2-ylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide;
and
N-(1-cyanocyclopropyl)-3-(pyridin-2-ylmethanesulfonyl)-2-(2,2,2-trifluoro-1-phenyl-1-trifluoromethylethylamino)-propionamide;
or
a pharmaceutically acceptable salt thereof.

71 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/943,768Filed 17 Sep 2004 · us provisional application
Priority: 18 Sep 2003
Published: US 2005/0182096 A118 Aug 2005
Granted: 16 Jun 2009
Term ends: Not estimatedThe source records don’t support an estimate.

Classification35 codes

C07D 333/20
Radicals substituted by singly bound hetero atoms other than halogen: by nitrogen atoms
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 5/14
Drugs for disorders of the endocrine system: of the thyroid hormones, e.g. T3, T4
A61P 9/00
Drugs for disorders of the cardiovascular system

Family

Application60/504,680Us provisional application · filed 18 Sep 2003
Application60/561,062Us provisional application · filed 9 Apr 2004
US 2005/0182096 A1Pre-grant publication · published 18 Aug 2005
US 7,547,701 B2This patent

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

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

A compound of Formula (I):

R1 and R2 taken together with the carbon atom to which both R1 and R2 are attached form (i) cycloalkylene optionally substituted with one or two Rb independently selected from alkyl, halo, alkylamino, dialkylamino, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, alkoxycarbonyl, or aryloxycarbonyl or (ii) heterocyclylalkylene optionally substituted with one to four Rc which are independently selected from alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkyloxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, aminoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, —S(O)n2R14, -alkylene-S(O)n2—R15, —COOR16, -alkylene-COOR17, —CONR18R19, or -alkylene-CONR20R21 (where n2 is 0-2 and R14-R17, R18 and R20 are independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, or heterocyclyl and R19 and R21 are independently hydrogen or alkyl) wherein the aromatic or alicyclic ring in the groups attached to cycloalkylene or heterocyclylalkylene is optionally substituted with one, two, or three substituents independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, alkoxycarbonyl, amino, monsubstituted amino, disubstituted amino, or acyl;
R3 is hydrogen or alkyl;
R4 is aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylalkyl, or -alkylene-X1—R22 (wherein X1 is —NR23—, —O—, —S(O)n3—, —CO—, —COO—, —OCO—, —NR23CO—, —CONR23—, —NR23SO2—, —SO2NR23—, —NR23COO—, —OCONR23—, —NR23CONR24, or —NR23SO2NR24— where R23 and R24 are independently hydrogen, alkyl, or acyl, n3 is 0-2, and R22 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl) wherein said alkylene chain in R4 is optionally substituted with one to six halo and wherein the aromatic or alicyclic ring in R4 is optionally substituted with one, two, or three Rd independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, amino, monsubstituted amino, disubstituted amino, or acyl;
R5 is hydrogen or alkyl;
R6 is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or -alkylene-X2—R25 (wherein X2 is —NR26—, —O—, —S(O)n4—, —CO—, —COO—, —OCO—, —NR26CO—, —CONR26—, —NR26SO2—, —SO2NR26—, —NR26COO—, —OCONR26—, —NR26CONR27—, or —NR26SO2NR27— where R26 and R27 are independently hydrogen, alkyl, or acyl, n4 is 0-2, and R25 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl) wherein said alkylene chain in R6 is optionally substituted with one to six halo and the aromatic or alicyclic rings in R6 are optionally substituted by one, two, or three Re independently selected from alkyl, halo, hydroxy, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, nitro, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, carboxy, or alkoxycarbonyl and further where the aromatic or alicyclic rings in Re is optionally substituted by one, two or three Rf independently selected from alkyl, alkoxy, haloalkyl, haloalkoxy, halo, hydroxy, carboxy, cyano, nitro, aryl or cycloalkyl;
R7 is haloalkyl;
and
R8 is hydrogen, alkyl, alkoxyalkyl or haloalkyl;
or
R6 and R8 together with the carbon atom to which they are attached form cycloalkylene or heterocyclylalkylene wherein said cycloalkylene is optionally substituted with one or two substituents independently selected from alkyl, haloalkyl, hydroxy, or alkoxy and heterocyclylalkylene is optionally substituted with one or two substituents independently selected from alkyl, haloalkyl, hydroxy, or alkoxy;
or
a pharmaceutically acceptable salt thereof.

9 more elements

Facts

Application

10/943,768Filed 17 Sep 2004 · us provisional application

Priority

18 Sep 2003

Published

US 2005/0182096 A118 Aug 2005

Granted

16 Jun 2009

Term ends

Not estimatedThe source records don’t support an estimate.

Classification35 codes

C07D 333/20
Radicals substituted by singly bound hetero atoms other than halogen: by nitrogen atoms
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 5/14
Drugs for disorders of the endocrine system: of the thyroid hormones, e.g. T3, T4
A61P 9/00
Drugs for disorders of the cardiovascular system