US 8,138,168 B1Granted

Renin inhibitors

AssigneeTakeda Pharmaceutical Company Limited

InventorsBenjamin Jones, Stephen W. Kaldor, Walter Keung, Andre A. Kiryanov, Zhe Li, Jeffrey A. Stafford, John Tyhonas, Craig Behnke

Life of this patent

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Abstract

The invention relates to compounds having the formulae: wherein the variables are as defined herein. The invention further relates to methods of making and using these compounds, and pharmaceutical compositions, kits and articles of manufacture comprise the compounds.

Claims90

Dependent claims

A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein
1 is 0, 1, 2, or 3;
p is 0, 1, 2, 3, or 4;
R1 is selected from the group consisting of (C4-12)aryloxy, hetero(C1-10)aryloxy, amino, (C1-10)alkylamino, sulfonamido, (C1-10)alkyl, halo(C1-10)alkyl, hydroxy(C1-10)alkyl, carbonyl(C1-10)alkyl, thiocarbonyl(C1-10)alkyl, sulfonyl(C1-10)alkyl, sulfinyl(C1-10)alkyl, (C1-10)azaalkyl, (C1-10)oxaalkyl, (C1-10)oxoalkyl, amino(C1-10)alkyl, (C3-12)cycloalkyl(C1-10)alkyl, hetero(C3-12)cycloalkyl(C1-10)alkyl, (C4-12)aryl(C1-10)alkyl, hetero(C1-10)aryl(C1-10)alkyl, (C9-12)bicycloaryl(C1-10)alkyl, hetero(C8-12)bicycloaryl(C1-10)alkyl, hetero(C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, (C9-12)bicycloaryl and hetero(C4-12)bicycloaryl, each unsubstituted or substituted;
R2 is selected from the group consisting of (C1-10)alkoxy, (C4-12)aryloxy, hetero(C1-10)aryloxy, carbonyloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (C1-10)alkylamino, sulfonamido, sulfonyl, sulfinyl, (C1-10)alkyl, halo(C1-10)alkyl, hydroxy(C1-10)alkyl, carbonyl(C1-4)alkyl, thiocarbonyl(C1-10)alkyl, sulfonyl(C1-10)alkyl, sulfinyl(C1-10)alkyl, (C1-10)azaalkyl, (C1-10)oxaalkyl, (C1-10)oxoalkyl, imino(C1-10)alkyl, (C3-12)cycloalkyl(C1-10)alkyl, hetero(C3-12)cycloalkyl(C1-10)alkyl, (C4-12)aryl(C1-10)alkyl, hetero(C1-10)aryl(C1-10)alkyl, (C9-12)bicycloaryl(C1-10)alkyl, hetero(C8-12)bicycloaryl(C1-10)alkyl, hetero(C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, (C4-12)aryl, hetero(C1-10)aryl, (C9-12)bicycloaryl and hetero(C4-12)bicycloaryl, each unsubstituted or substituted;
R6 is selected from the group consisting of hydrogen, hydroxyl, unsubstituted and substituted (C1-6)alkyl, —COOR9, and —CH2OR9, where R9 is selected from the group consisting of hydrogen, (C1-6)alkyl, (C6)aryl, (C5-6)heteroaryl, (C3-6)cycloalkyl, and hetero(C2-5)cycloalkyl, each unsubstituted or substituted;
R7 is selected from the group consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C1-10)alkoxy, (C4-12)aryloxy, hetero(C1-10)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (C1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-10)alkyl, halo(C1-10)alkyl, hydroxy(C1-10)alkyl, carbonyl(C1-10)alkyl, thiocarbonyl(C1-10)alkyl, sulfonyl(C1-10)alkyl, sulfinyl(C1-10)alkyl, (C1-10)azaalkyl, (C1-10)oxaalkyl, (C1-10)oxoalkyl, imino(C1-10)alkyl, (C3-12)cycloalkyl(C1-10)alkyl, hetero(C3-12)cycloalkyl(C1-10)alkyl, (C4-12)aryl(C1-10)alkyl, hetero(C1-10)aryl(C1-10)alkyl, (C9-12)bicycloaryl(C1-10)alkyl, hetero(C8-12)bicycloaryl(C1-10)alkyl, hetero(C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, (C4-12)aryl, hetero(C1-10)aryl, (C9-12)bicycloaryl and hetero(C4-12)bicycloaryl, each unsubstituted or substituted;
and
each R10 is independently selected from the group consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C1-10)alkoxy, (C4-12)aryloxy, hetero(C1-10)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (C1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-10)alkyl, halo(C1-10)alkyl, hydroxy(C1-10)alkyl, carbonyl(C1-10)alkyl, thiocarbonyl(C1-10)alkyl, sulfonyl(C1-10)alkyl, sulfinyl(C1-10)alkyl, (C1-10)azaalkyl, (C1-10)oxaalkyl, (C1-10)oxoalkyl, imino(C1-10)alkyl, (C3-12)cycloalkyl(C1-10)alkyl, hetero(C3-12)cycloalkyl(C1-10)alkyl, (C4-12)aryl(C1-10)alkyl, hetero(C1-10)aryl(C1-10)alkyl, (C9-12)bicycloaryl(C1-10)alkyl, hetero(C8-12)bicycloaryl(C1-10)alkyl, hetero(C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, (C4-12)aryl, hetero(C1-10)aryl, (C9-12)bicycloaryl and hetero(C4-12)bicycloaryl, each unsubstituted or substituted, or R10′ is absent when the carbon to which it is bound forms part of a double bond.

6 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/239,538Filed 26 Sep 2008 · us provisional application
Priority: 26 Sep 2007
Granted: 20 Mar 2012
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 235/14
With only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2: radicals substituted by nitrogen atoms
C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 403/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 403/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group…

Family

Application60/975,490Us provisional application · filed 26 Sep 2007
US 8,138,168 B1This patent

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

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Abstract

A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein
1 is 0, 1, 2, or 3;
p is 0, 1, 2, 3, or 4;
R1 is selected from the group consisting of (C4-12)aryloxy, hetero(C1-10)aryloxy, amino, (C1-10)alkylamino, sulfonamido, (C1-10)alkyl, halo(C1-10)alkyl, hydroxy(C1-10)alkyl, carbonyl(C1-10)alkyl, thiocarbonyl(C1-10)alkyl, sulfonyl(C1-10)alkyl, sulfinyl(C1-10)alkyl, (C1-10)azaalkyl, (C1-10)oxaalkyl, (C1-10)oxoalkyl, amino(C1-10)alkyl, (C3-12)cycloalkyl(C1-10)alkyl, hetero(C3-12)cycloalkyl(C1-10)alkyl, (C4-12)aryl(C1-10)alkyl, hetero(C1-10)aryl(C1-10)alkyl, (C9-12)bicycloaryl(C1-10)alkyl, hetero(C8-12)bicycloaryl(C1-10)alkyl, hetero(C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, (C9-12)bicycloaryl and hetero(C4-12)bicycloaryl, each unsubstituted or substituted;
R2 is selected from the group consisting of (C1-10)alkoxy, (C4-12)aryloxy, hetero(C1-10)aryloxy, carbonyloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (C1-10)alkylamino, sulfonamido, sulfonyl, sulfinyl, (C1-10)alkyl, halo(C1-10)alkyl, hydroxy(C1-10)alkyl, carbonyl(C1-4)alkyl, thiocarbonyl(C1-10)alkyl, sulfonyl(C1-10)alkyl, sulfinyl(C1-10)alkyl, (C1-10)azaalkyl, (C1-10)oxaalkyl, (C1-10)oxoalkyl, imino(C1-10)alkyl, (C3-12)cycloalkyl(C1-10)alkyl, hetero(C3-12)cycloalkyl(C1-10)alkyl, (C4-12)aryl(C1-10)alkyl, hetero(C1-10)aryl(C1-10)alkyl, (C9-12)bicycloaryl(C1-10)alkyl, hetero(C8-12)bicycloaryl(C1-10)alkyl, hetero(C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, (C4-12)aryl, hetero(C1-10)aryl, (C9-12)bicycloaryl and hetero(C4-12)bicycloaryl, each unsubstituted or substituted;
R6 is selected from the group consisting of hydrogen, hydroxyl, unsubstituted and substituted (C1-6)alkyl, —COOR9, and —CH2OR9, where R9 is selected from the group consisting of hydrogen, (C1-6)alkyl, (C6)aryl, (C5-6)heteroaryl, (C3-6)cycloalkyl, and hetero(C2-5)cycloalkyl, each unsubstituted or substituted;
R7 is selected from the group consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C1-10)alkoxy, (C4-12)aryloxy, hetero(C1-10)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (C1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-10)alkyl, halo(C1-10)alkyl, hydroxy(C1-10)alkyl, carbonyl(C1-10)alkyl, thiocarbonyl(C1-10)alkyl, sulfonyl(C1-10)alkyl, sulfinyl(C1-10)alkyl, (C1-10)azaalkyl, (C1-10)oxaalkyl, (C1-10)oxoalkyl, imino(C1-10)alkyl, (C3-12)cycloalkyl(C1-10)alkyl, hetero(C3-12)cycloalkyl(C1-10)alkyl, (C4-12)aryl(C1-10)alkyl, hetero(C1-10)aryl(C1-10)alkyl, (C9-12)bicycloaryl(C1-10)alkyl, hetero(C8-12)bicycloaryl(C1-10)alkyl, hetero(C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, (C4-12)aryl, hetero(C1-10)aryl, (C9-12)bicycloaryl and hetero(C4-12)bicycloaryl, each unsubstituted or substituted;
and
each R10 is independently selected from the group consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C1-10)alkoxy, (C4-12)aryloxy, hetero(C1-10)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (C1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C1-10)alkyl, halo(C1-10)alkyl, hydroxy(C1-10)alkyl, carbonyl(C1-10)alkyl, thiocarbonyl(C1-10)alkyl, sulfonyl(C1-10)alkyl, sulfinyl(C1-10)alkyl, (C1-10)azaalkyl, (C1-10)oxaalkyl, (C1-10)oxoalkyl, imino(C1-10)alkyl, (C3-12)cycloalkyl(C1-10)alkyl, hetero(C3-12)cycloalkyl(C1-10)alkyl, (C4-12)aryl(C1-10)alkyl, hetero(C1-10)aryl(C1-10)alkyl, (C9-12)bicycloaryl(C1-10)alkyl, hetero(C8-12)bicycloaryl(C1-10)alkyl, hetero(C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, (C9-12)bicycloalkyl, hetero(C3-12)bicycloalkyl, (C4-12)aryl, hetero(C1-10)aryl, (C9-12)bicycloaryl and hetero(C4-12)bicycloaryl, each unsubstituted or substituted, or R10′ is absent when the carbon to which it is bound forms part of a double bond.

6 more elements

Facts

Application

12/239,538Filed 26 Sep 2008 · us provisional application

Priority

26 Sep 2007

Granted

20 Mar 2012

Term ends

Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 235/14
With only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2: radicals substituted by nitrogen atoms
C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 403/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 403/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group…