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US 7,169,926 B1Granted
Dipeptidyl peptidase inhibitors
AssigneesTakeda Pharmaceutical Company Limited, Array BioPharma Inc.
InventorsLaurence E. Burgess, Scott D. Cowen, Stephen L. Gwaltney, II, Jeongboeb Seo, Jeffrey A. Stafford
Life of this patent
Estimating the term…
Abstract
Compounds are provided which may be used to inhibit DPP-IV comprising the formula: wherein the substituents are as described in the specification and claims.
Claims72
A compound of the formula:
- wherein
- Q is CO or C═NR5;
- Z is nitrogen;
- R1 is selected from the group consisting of halo, perhalo(C1-10)alkyl, amino, cyano, thio, (C1-10)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, sulfonyl (C1-3)alkyl, sulfinyl (C1-3)alkyl, imino (C1-3)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted;
- R2 is hydrogen or is selected from the group consisting of (C1-6)alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each substituted or unsubstituted;
- R3 and R4 are taken together to form a substituted or unsubstituted 4, 5, 6 or 7 membered ring;
- R5 is hydrogen or is selected from the group consisting of (C1-10)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted;
- R6 is hydrogen or is selected from the group consisting of (C1-10)alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each substituted or unsubstituted;
- L is a substituent linking the ring nitrogen to X that is 1, 2 or 3 atoms in length as measured from the ring nitrogen to X;
- connecting the M substituent to the carbon atom alpha to the L substituent;
- and
- X is selected from the group consisting of (C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, sulfonyl (C1-3)alkyl, sulfinyl (C1-3)alkyl, imino (C1-3)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, cyano, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted;
- with the provisos that (i) R1 is not —SCH3 when Q is CO, Z is N, LX is —CH2—OEt, R2 is H and R3 and R4 are taken together to form indole, and (ii) R1 is not —CH3 or phenyl when Q is CO, Z is N, LX is —CH2—Ph, R2 is phenyl and R3 and R4 are taken together to form pyridine.
10 more elements
A compound of a formula selected from the group consisting of:
- wherein
- each U is independently selected from the group consisting of nitrogen and CR14, provided that no more than two U are nitrogen;
- and
- each Y is independently selected from the group consisting of CO, SO, SO2, NR14, O, S and CR14R14, except if the bond between two adjacent Y is a double bond, then the each of the two Y forming the double bond are independently selected from the group consisting of CR14 and N;
- and
- each R14 is independently selected from the group consisting of hydrogen, halo, perhalo(C1-10)alkyl, CF3, (C1-10)alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, alkoxy, aryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each optionally further substituted, with the proviso that R14 is not alkylthio, arylthio, halo, cyano, nitro, and thio in the case where the ring atom to which R14 is bound is nitrogen.
3 more elements
A compound of a formula selected from the group consisting of:
- wherein
- p is 0–12;
- each U is independently selected from the group consisting of nitrogen and CR14, provided that no more than two U are nitrogen;
- each Y is independently selected from the group consisting of CO, SO, SO2, NR14, O, S and CR14R14, except if the bond between two adjacent Y is a double bond, then the each of the two Y forming the double bond are independently selected from the group consisting of CR14 and N;
- each R12 is independently selected from the group consisting of halo, perhalo(C1-10)alkyl, CF3, (C1-10)alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted;
- and
- each R14 is independently selected from the group consisting of hydrogen, halo, perhalo(C1-10)alkyl, CF3, (C1-10)alkyl, awl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, alkoxy, aryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each optionally further substituted, with the proviso that R14 is not alkylthio, arylthio, halo, cyano, nitro, and thio in the case where the ring atom to which R14 is bound is nitrogen.
4 more elements
A compound of a formula selected from the group consisting of:
- wherein
- p is 0–12;
- each U is independently selected from the group consisting of nitrogen and CR14, provided that no more than two U are nitrogen;
- each Y is independently selected from the group consisting of CO, SO, SO2, NR14, O, S and CR14R14, except if the bond between two adjacent Y is a double bond, then the each of the two Y forming the double bond are independently selected from the group consisting of CR14 and N;
- each R12 is independently selected from the group consisting of halo, perhalo(C1-10)alkyl, CF3, (C1-10)alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted;
- and
- each R14 is independently selected from the group consisting of hydrogen, halo, perhalo(C1-10)alkyl, CF3, (C1-10)alkyl, aryl, heteroaryl aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, alkoxy, aryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each optionally further substituted, with the proviso that R14 is not alkylthio, arylthio, halo, cyano, nitro, and thio in the case where the ring atom to which R14 is bound is nitrogen.
4 more elements
A compound of a formula selected from the group consisting of:
- wherein
- o is 0–4;
- each U is independently selected from the group consisting of nitrogen and CR14, provided that no more than two U are nitrogen;
- each Y is independently selected from the group consisting of CO, SO, SO2, NR14, O, S and CR14R14, except if the bond between two adjacent Y is a double bond, then the each of the two Y forming the double bond are independently selected from the group consisting of CR14 and N;
- each R20 and R21 is independently selected from the group consisting of halo, perhalo(C1-10)alkyl, CF3, (C1-10)alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted;
- and
- each R14 is independently selected from the group consisting hydrogen, halo, perhalo(C1-10)alkyl, CF3, (C1-10)alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, alkoxy, aryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each optionally further substituted, with the proviso that R14 is not alkylthio, arylthio, halo, cyano, nitro, and thio in the case where the ring atom to which R14 is bound is nitrogen.
4 more elements
A compound selected from the group consisting of:
- {3-[3-(2-Cyano-benzyl)-5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl]-cyclohexyl}-carbamic acid benzyl ester;
- {3-[3-(2-Cyano-benzyl)-5-methyl-4-oxo-4,5-dihydro-3H-1,3,5,6-tetraaza-cyclopenta[a]naphthalen-2-yl]-cyclohexyl}-carbamic acid benzyl ester;
- {3-[3-(R)-(2-Cyano-benzyl)-5-methyl-4-oxo-4,5-dihydro-3H-1,3,5,6-tetraaza-cyclopenta[a]naphthalen-2-yl]-cyclohexyl}-carbamic acid benzyl ester;
- 4-(3-Benzyl-5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl)-piperidine-1-carboxylic acid benzyl ester;
- and
- 4-[5-Methyl-3-(3-methyl-but-2-enyl)-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl]-piperidine-1-carboxylic acid benzyl ester.
3 more elements
A compound selected from the group consisting of:
- 2-[2-(3-Amino-cyclohexyl)-5-methyl-4-oxo-4,5-dihydro-1,3,5,6-tetraaza-cyclopenta[a]naphthalen-3-ylmethyl]-benzonitrile;
- 2-(3-Amino-cyclohexyl)-3-benzyl-5-methyl-3,5-dihydro-imidazo[4,5-c]quinolin-4-one;
- 3-Benzyl-5-methyl-2-piperidin-4-yl-3,5-dihydro-imidazo[4,5-c]quinolin-4-one;
- 5-Methyl-3-(3-methyl-butyl)-2-piperidin-4-yl-3,5-dihydro-imidazo[4,5-c]quinolin-4-one;
- 5-Methyl-3-(3-methyl-butyl-2-enyl)-2-piperidin-4-yl-3,5-dihydro-imidazo[4,5-c]quinolin-4-one;
- and
- 2-[2-(3-Amino-cyclohexyl)-5-methyl-4-oxo-4,5-dihydro-imidazo[4,5-c]quinolin-3-ylmethyl]-benzonitrile.
4 more elements
A compound selected from the group consisting of:
- 2-[2-(3-(R)-Amino-cyclohexyl)-5-methyl-4-oxo-4,5-dihydro-1,3,5,6-tetraaza-cyclopenta[a]naphthalen-3-ylmethyl]-benzonitrile;
- 2-(3-(R)-Amino-cyclohexyl)-3-benzyl-5-methyl-3,5-dihydro-imidazo[4,5-c]quinolin-4-one;
- and
- 2-[2-(3-[(R)-Amino-cyclohexyl]-5-methyl-4-oxo-4,5-dihydro-imidazo[4,5-c]quinolin-3-ylmethyl]-benzonitrile.
1 more element
A compound of a formula selected from the group consisting of:
- wherein
- q is 0, 1, 2, 3, 4, 5 or 6;
- Q is CO or C═NR5;
- Z is nitrogen;
- R1 is selected from the group consisting of halo, perhalo(C1-10)alkyl, amino, cyano, thio, (C1-10)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, sulfonyl (C1-3)alkyl, sulfinyl (C1-3)alkyl, imino (C1-3)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted;
- R2 is hydrogen or is selected from the group consisting of (C1-6)alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each substituted or unsubstituted;
- R5 is hydrogen or is selected from the group consisting of (C1-10)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted;
- R6 is hydrogen or is selected from the group consisting of (C1-10)alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each substituted or unsubstituted;
- each R14 is independently selected from the group consisting of hydrogen, halo, perhalo(C1-10)alkyl, CF3, (C1-10)alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, alkoxy, aryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each optionally further substituted, or two R14 are taken together to form a substituted or unsubstituted fused or bridged ring, with the proviso that R14 is not alkylthio, arylthio, halo, cyano, nitro, and thio in the case where the ring atom to which R14 is bound is nitrogen;
- L is a substituent linking the ring nitrogen to X that is 1, 2 or 3 atoms in length as measured from the ring nitrogen to X;
- and
- X is selected from the group consisting of (C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, sulfonyl (C1-3)alkyl, sulfinyl (C1-3)alkyl, imino (C1-3)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, cyano, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted.
9 more elements
A compound of a formula selected from the group consisting of:
- wherein
- q is 0, 1, 2, 3, 4, 5 or 6;
- Q is CO or C═NR5;
- Z is nitrogen;
- R1 is selected from the group consisting of halo, perhalo(C1-10)alkyl, amino, cyano, thio, (C1-10)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, sulfonyl (C1-3)alkyl, sulfinyl (C1-3)alkyl, imino (C1-3)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted;
- R2 is hydrogen or is selected from the group consisting of (C1-6)alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each substituted or unsubstituted;
- R5 is hydrogen or is selected from the group consisting of (C1-10)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted;
- R6 is hydrogen or is selected from the group consisting of (C1-10)alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each substituted or unsubstituted;
- each R14 is independently selected from the group consisting of hydrogen, halo, perhalo(C1-10)alkyl, CF3, (C1-10)alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, alkoxy, aryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each optionally further substituted, or two R14 are taken together to form a substituted or unsubstituted fused or bridged ring, with the proviso that R14 is not alkylthio, arylthio, halo, cyano, nitro, and thio in the case where the ring atom to which R14 is bound is nitrogen;
- L is a substituent linking the ring nitrogen to X that is 1, 2 or 3 atoms in length as measured from the ring nitrogen to X;
- and
- X is selected from the group consisting of (C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, sulfonyl (C1-3)alkyl, sulfinyl (C1-3)alkyl, imino (C1-3)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, cyano, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted,
- with the proviso that R1 is not —CH3 or phenyl when q is 0, Q is CO, Z is N, LX is —CH2—Ph and R2 is phenyl.
10 more elements
A compound of a formula selected from the group consisting of:
- wherein
- q is 0, 1, 2, 3, 4, 5 or 6;
- Q is CO or C═NR5;
- Z is nitrogen;
- R1 is selected from the group consisting of halo, perhalo(C1-10)alkyl, amino, cyano, thio, (C1-10)alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, sulfonyl (C1-3)alkyl, sulfinyl (C1-3)alkyl, imino (C1-3)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted;
- R2 is hydrogen or is selected from the group consisting of (C1-6)alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each substituted or unsubstituted;
- R5 is hydrogen or is selected from the group consisting of (C1-10)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl, and heterobicycloaryl, each substituted or unsubstituted;
- R6 is hydrogen or is selected from the group consisting of (C1-10)alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each substituted or unsubstituted;
- each R14 is independently selected from the group consisting of hydrogen, halo, perhalo(C1-10)alkyl, CF3, (C1-10)alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, alkoxy, aryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each optionally further substituted, or two R14 are taken together to form a substituted or unsubstituted fused or bridged ring, with the proviso that R14 is not alkylthio, arylthio, halo, cyano, nitro, and thio in the case where the ring atom to which R14 is bound is nitrogen;
- L is a substituent linking the ring nitrogen to X that is 1, 2 or 3 atoms in length as measured from the ring nitrogen to X;
- and
- X is selected from the group consisting of (C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, sulfonyl (C1-3)alkyl, sulfinyl (C1-3)alkyl, imino (C1-3)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, cyano, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted,
- with the proviso that R1 is not —SCH3 when Q is CO, Z is N, LX is —CH2—OEt, R2 is H and two R14 are taken together to form indole.
10 more elements
Dependencies are inferred from the claim text.