IP Library › Granted Patent US 8,034,822

Granted Patent B2

US 8,034,822 · App. 11/683,955 · Granted Oct 11, 2011

Glucokinase activators

Assignee: Takeda San Diego, Inc.

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Quick Facts

Patent No.: US 8,034,822
App. No.: 11/683,955
Granted: Oct 11, 2011
Kind: B2

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Abstract

Compounds are provided for use with glucokinase that comprise the formula: wherein the variables are as defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods and intermediates useful for making the compounds; and methods of using said compounds.

Claims (293)

1. A compound comprising:

or a pharmaceutically acceptable salt thereof, wherein

Q 1 is selected from the group consisting of CO, CS and CR 7 R 8 ;

R 1 is selected from the group consisting of hetero(C 3-12 )cycloalkyl, hetero(C 3-12 )bicycloalkyl, heteroaryl, and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted;

R 2 is hydrogen;

R 3 ′ is hydrogen;

R 3 is selected from the group consisting of (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, and heteroaryl(C 1-5 )alkyl, each substituted or unsubstituted;

R 6 is selected from the group consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )alkyl, halo(C 1-10 )alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1-3 )alkyl, sulfonyl(C 1-3 )alkyl, sulfinyl(C 1-3 )alkyl, amino(C 1-10 )alkyl, amino(C 1-3 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl, heteroaryl, (C 9-12 )bicycloaryl and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted, with the proviso that R 6 is absent when the atom to which it is bound forms part of a double bond;

R 7 and R 8 are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )alkyl, halo(C 1-10 )alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1-3 )alkyl, sulfonyl(C 1-3 )alkyl, sulfinyl(C 1-3 )alkyl, amino(C 1-10 )alkyl, imino(C 1-3 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl, heteroaryl, (C 9-12 )bicycloaryl and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted, or R 7 and R 6 are taken together to form a substituted or unsubstituted ring, with the proviso that R 8 is absent when the atom to which it is bound forms part of a double bond;

n is selected from the group consisting of 0, 1, 2, 3 and 4; and

R 9 is selected from the group consisting of hydrogen, halo, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )alkyl, halo(C 1-10 )alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1-3 )alkyl, sulfonyl(C 1-3 )alkyl, sulfinyl(C 1-3 )alkyl, amino(C 1-10 )alkyl, imino(C 1-3 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl, heteroaryl, (C 9-12 )bicycloaryl and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted, or R 9 and R 6 or two R 9 are taken together to form a substituted or unsubstituted ring.

2. The compound of claim 1 comprising:

3. The compound of claim 1 comprising:

wherein

R 7b is selected from the group consisting of hydrogen, halo, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )alkyl, halo(C 1-10 )alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1-3 )alkyl, sulfonyl(C 1-3 )alkyl, sulfinyl(C 1-3 )alkyl, amino(C 1-10 )alkyl, imino(C 1-3 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl, heteroaryl, (C 9-12 )bicycloaryl and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted.

4. The compound of claim 1 comprising:

wherein

m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11;

is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation between the C and the ring to which L is attached, wherein the atoms of the linker providing the separation are carbon;

R 10 is selected from the group consisting of hydrogen, halo, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )alkyl, halo(C 1-10 )alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1-3 )alkyl, sulfonyl(C 1-3 )alkyl, sulfinyl(C 1-3 )alkyl, amino(C 1-10 )alkyl, iminio(C 1-3 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl, heteroaryl, (C 9-12 )bicycloaryl and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted, or two R 10 are taken together to form a substituted or unsubstituted ring.

5. The compound of claim 1 comprising:

wherein

m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11;

L is a linker providing 0, 1, 2, 3, 4, 5 or 6 atom separation between the C and the ring to which L is attached, wherein the atoms of the linker providing the separation are carbon;

R 7b is selected from the group consisting of hydrogen, halo, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )alkyl, halo(C 1-10 )alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1-3 )alkyl, sulfonyl(C 1-3 )alkyl, sulfinyl(C 1-3 )alkyl, amino(C 1-10 )alkyl, iminio(C 1-3 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl, heteroaryl, (C 9-12 )bicycloaryl and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted; and

R 10 is selected from the group consisting of hydrogen, halo, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )alkyl, halo(C 1-10 )alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1-3 )alkyl, sulfonyl(C 1-3 )alkyl, sulfinyl(C 1-3 )alkyl, amino(C 1-10 )alkyl, imino(C 1-3 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl, heteroaryl, (C 9-12 )bicycloaryl and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted, or two R 10 are taken together to form a substituted or unsubstituted ring.

6. The compound of claim 1 comprising:

wherein

p is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8 and 9;

L is a linker providing 0, 1, 3, 4, 5 or 6 atom separation between the C and the ring to which L is attached, wherein the atoms of the linker providing the separation are carbon;

R 10 is selected from the group consisting of hydrogen, halo, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )alkyl, halo(C 1-10 )alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1-3 )alkyl, sulfonyl(C 1-3 )alkyl, sulfinyl(C 1-3 )alkyl, amino(C 1-10 )alkyl, imino(C 1-3 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl, heteroaryl, (C 9-12 )bicycloaryl and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted, or two R 10 are taken together to form a ringform a substituted or unsubstituted ring.

7. A compound selected from the group consisting of:

(S)-2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-4-methylpentanoic acid;

(S)-2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-4-methyl-N-(thiazol-2-yl)pentanamide;

(S)-4-methyl-2-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)pentanoic acid;

(S)-4-methyl-2-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(thiazol-2-yl)pentanamide;

2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-phenyl-N-(thiazol-2-yl)acetamide;

2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-3-phenyl-N-(pyridin-2-yl)propanamide;

2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(5-methylthiazol-2-yl)-3-phenylpropanamide;

2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-3-phenyl-N-(thiazol-2-yl)propanamide;

2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-3-(1H-imidazol-4-yl)-N-(5-methylthiazol-2-yl)propanamide;

2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-3-(1H-imidazol-4-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl-N-(pyridin-2-yl)propanamide;

3-cyclohexyl-2-(2,4-dioxo-1,2-dihydroquinazolin-3 (4H)-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(7-(methylsulfonyl)-2,4-dioxo-1,2-dihydroquinazolin-3(4H) yl)-N-(5-methylthiazol-2-yl)propanamide;

(S)-methyl 3-cyclohexyl-2-(4-oxoquinazolin-3(4H)-yl)propanoate;

(S)-3-cyclohexyl-2-(4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-yl)propan-amide;

(S)-3-cyclohexyl-N-(5-methylthiazol-2-yl)-2-(4-oxoquinazolin-3(4H)-yl)propanamide;

(S)-cyclohexyl-2-(4-oxoquinazolin-3(4H)-yl)-N-(pyridin-2-yl)propanamide;

(R)-3-cyclohexyl-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-yl)propanamide;

(R)-3-cyclohexyl-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(pyridin-2-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(5-(hydroxymethyl)thiazol-2-yl)propanamide;

methyl 2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-3-(1-methyl-1H-imidazol-2-yl)propanoate;

2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-3-(1-methyl-1H-imidazol-2-yl)propanoic acid;

2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-3-(1-methyl-1H-imidazol-2-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(5-methylthiazol-2-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(5-methylthiazol-2-yl)propanamide;

N-(benzo[d]thiazol-2-yl)-3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(pyridin-2-yl)propanamide;

2-(6-chloro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

N-(5-chlorothiazol-2-yl)-3-cyclohexyl-2-(6-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)propanamide;

2-(6-chloro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

6-(3-cyclohexyl-2-(6-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)propanamido)picolinic acid;

3-cyclohexyl-2-(6-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(1-methyl-1H-pyrazol-3-yl)propanamide;

2-(6-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-3-(tetrahydro-2H-pyran-4-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(5-methylthiazol-2-yl)propanamide;

2-(6-Chloro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-3-(tetrahydro-pyran-4-yl)-N-thiazol-2-yl-propionamide;

2-(6-Methanesulfonyl-1,3-dioxo-3,4-dihydro-1H-isoquinolin-2-yl)-3-(tetrahydro-pyran-4-yl)-N-thiazol-2-yl-propionamide;

2-(6-Fluoro-4-oxo-4H-quinazolin-3-yl)-3-(tetrahydro-pyran-4-yl)-N-thiazol-2-yl-propionamide;

2-(6-Chloro-4-oxo-4H-quinazolin-3-yl)-N-(5-chloro-thiazol-2-yl)-3-cyclohexyl-propionamide;

2-(6-Chloro-4-oxo-4H-quinazolin-3-yl)-3-cyclohexyl-N-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionamide;

2-(6-Chloro-4-oxo-4H-quinazolin-3-yl)-3-cyclohexyl-N-(5-methyl-[1,3,4]thiadiazol-2-yl)-propionamide;

N-(5-Chloro-thiazol-2-yl)-3-cyclohexyl-2-(6-fluoro-4-oxo-4H-quinazolin-3-yl)-propionamide;

N-(5-chlorothiazol-2-yl)-2-(6-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

N-(5-Chloro-thiazol-2-yl)-2-(6-fluoro-4-oxo-4H-quinazolin-3-yl)-3-(tetrahydro-pyran-4-yl)-propionamide;

N-(5-Chloro-thiazol-2-yl)-3-cyclopentyl-2-(6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-propionamide;

N-(5-Chloro-thiazol-2-yl)-3-cyclopentyl-2-(6-fluoro-4-oxo-4H-quinazolin-3-yl)-propionamide;

N-(5-Chloro-thiazol-2-yl)-3-cyclohexyl-2-(7-methanesulfonyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-propionamide;

N-(5-Chloro-thiazol-2-yl)-3-cyclohexyl-2-(7-methanesulfonyl-4-oxo-4H-quinazolin-3-yl)-propionamide;

3-Cyclohexyl-2-(6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-N-(5-fluoro-thiazol-2-yl)-propionamide;

3-Cyclopentyl-2-(6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-N-(5-fluoro-thiazol-2-yl)-propionamide;

N-(5-Chloro-thiazol-2-yl)-3-cyclohexyl-2-(7-methanesulfonyl-4-oxo-4H-quinazolin-3-yl)-propionamide;

3-Cyclohexyl-2-(7-methanesulfonyl-4-oxo-4H-quinazolin-3-yl)-N-pyridin-2-yl-propionamide;

3-Cyclohexyl-2-(7-methanesulfonyl-4-oxo-4H-quinazolin-3-yl)-N-(5-methyl-thiazol-2-yl)-propionamide;

3-Cyclohexyl-2-(7-methanesulfonyl-4-oxo-2-thioxo-1,4-dihydro-2H-quinazolin-3-yl)-N-thiazol-2-yl-propionamide;

3-Cyclohexyl-2-(7-methanesulfonyl-4-oxo-2-thioxo-1,4-dihydro-2H-quinazolin-3-yl)-N-pyridin-2-yl-propionamide;

6-[3-Cyclohexyl-2-(7-methanesulfonyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-propionylamino]-nicotinic acid;

6-[3-Cyclohexyl-2-(7-methanesulfonyl-4-oxo-4H-quinazolin-3-yl)-propionylamino]-nicotinic acid;

3-Cyclohexyl-2-(6-fluoro-4-oxo-4H-quinazolin-3-yl)-N-(5-hydroxymethyl-pyridin-2-yl)-propionamide;

3-cyclohexyl-N-(5-(hydroxymethyl)pyridin-2-yl)-2-(7-(methylsulfonyl)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)propanamide;

3-Cyclohexyl-2-(6-fluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-N-(5-hydroxymethyl-pyridin-2-yl)-propionamide;

3-Cyclohexyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(7-methanesulfonyl-4-oxo-4H-quinazolin-3-yl)-propionamide;

3-Cyclohexyl-N-(5-fluoro-pyridin-2-yl)-2-(7-methanesulfonyl-4-oxo-4H-quinazolin-3-yl)-propionamide;

3-Cyclohexyl-2-(7-ethanesulfonyl-4-oxo-4H-quinazolin-3-yl)-N-(5-fluoro-pyridin-2-yl)-propionamide;

N-(5-Chloro-pyridin-2-yl)-3-cyclohexyl-2-(7-ethanesulfonyl-4-oxo-4H-quinazolin-3-yl)-propionamide;

3-Cyclohexyl-2-(7-ethanesulfonyl-4-oxo-4H-quinazolin-3-yl)-N-(5-hydroxymethyl-thiazol-2-yl)-propionamide;

3-Cyclohexyl-2-(7-cyclopropanesulfonyl-4-oxo-4H-quinazolin-3-yl)-N-(5-fluoro-pyridin-2-yl)-propionamide;

N-(5-Chloro-pyridin-2-yl)-3-cyclohexyl-2-(7-cyclopropanesulfonyl-4-oxo-4H-quinazolin-3-yl)-propionamide;

3-{6-[3-Cyclohexyl-2-(7-methanesulfonyl-4-oxo-4H-quinazolin-3-yl)-propionylamino]-pyridin-3-yl}-propionic acid ethyl ester;

N-(5-Chloro-pyridin-2-yl)-3-(2,6-difluoro-phenyl)-2-(7-methanesulfonyl-4-oxo-4H-quinazolin-3-yl)-propionamide;

methyl 6-(3-cyclohexyl-2-(7-(cyclopropylsulfonyl)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)propanamido)nicotinate;

N-(5-Chloro-pyridin-2-yl)-3-cyclohexyl-2-(6-methanesulfonyl-4-oxo-4H-quinazolin-3-yl)-propionamide;

6-[3-Cyclohexyl-2-(7-cyclopentanesulfonyl-4-oxo-4H-quinazolin-3-yl)-propionylamino]-nicotinamide;

6-[3-Cyclohexyl-2-(7-ethanesulfonyl-4-oxo-4H-quinazolin-3-yl)-propionylamino]-nicotinamide;

N-(5-Chloro-pyridin-2-yl)-3-cyclohexyl-2-(6-methanesulfonyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-propionamide;

6-[3-Cyclohexyl-2-(7-cyclopentanesulfonyl-4-oxo-4H-quinazolin-3-yl)-propionylamino]-nicotinic acid methyl ester;

N-(5-Chloro-pyridin-2-yl)-3-cyclohexyl-2-[4-oxo-6-(propane-2-sulfonyl)-4H-quinazolin-3-yl]-propionamide;

6-[2-(7-Methanesulfonyl-4-oxo-4H-quinazolin-3-yl)-3-(tetrahydro-furan-2-yl)-propionylamino]-nicotinic acid methyl ester;

6-[2-(7-Cyclopentanesulfonyl-4-oxo-4H-quinazolin-3-yl)-3-(tetrahydro-furan-2-yl)-propionylamino]-nicotinic acid methyl ester;

N-(5-Fluoro-pyridin-2-yl)-3-furan-2-yl-2-(7-methanesulfonyl-4-oxo-4H-quinazolin-3-yl)-propionamide;

N-(5-fluoropyridin-2-yl)-2-(7-(methylsulfonyl)-4-oxoquinazolin-3(4H)-yl)-3-(tetrahydrofuran-2-yl)propanamide;

2-(7-Cyclopentanesulfonyl-4-oxo-4H-quinazolin-3-yl)-N-(5-fluoro-pyridin-2-yl)-3-(tetrahydro-pyran-4-yl)-propionamide;

6-[3-Cyclohexyl-2-(7-cyclopropylmethanesulfonyl-4-oxo-4H-quinazolin-3-yl)-propionylamino]-nicotinic acid methyl ester;

6-[3-Cyclohexyl-2-(7-cyclopropanesulfonyl-4-oxo-4H-quinazolin-3-yl)-propionylamino]-nicotinamide;

6-[2-(8-Chloro-6-methanesulfonyl-4-oxo-4H-quinazolin-3-yl)-3-cyclohexyl-propionylamino]-nicotinamide;

6-[3-Cyclohexyl-2-(6-methanesulfonyl-4-oxo-4H-quinazolin-3-yl)-propionylamino]-nicotinamide;

N-(5-fluoropyridin-2-yl)-2-(7-(methylsulfonyl)-4-oxoquinazolin-3(4H)-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

3-(4,4-Difluorocyclohexyl)-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-yl)propanamide;

N-cyclopropyl-3-(1-(5-fluoropyridin-2-ylamino)-1-oxo-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)-4-oxo-3,4-dihydroquinazoline-7-carboxamide;

3-(3-Cyclohexyl-1-(5-fluoropyridin-2-ylamino)-1-oxopropan-2-yl)-N-cyclopropyl-4-oxo-3,4-dihydroquinazoline-7-carboxamide;

3-(3-cyclohexyl-1-(5-fluoropyridin-2-ylamino)-1-oxopropan-2-yl)-N-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide;

N-cyclopropyl-3-(3-(3,5-difluorophenyl)-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-4-oxo-3,4-dihydroquinazoline-7-carboxamide;

N-cyclopropyl-3-(3-(3,5-difluorophenyl)-1-oxo-1-(thiazol-2-ylamino) propan-2-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide;

3-(1-(5-Carbamoylpyridin-2-ylamino)-3-(3,5-difluorophenyl)-1-oxopropan-2-yl)-N-cyclopropyl-4-oxo-3,4-dihydroquinazoline-7-carboxamide;

N-cyclopropyl-3-(3-(4-fluorophenyl)-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-4-oxo-3,4-dihydroquinazoline-7-carboxamide;

N-cyclopropyl-3-(3-(3-fluorophenyl)-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-4-oxo-3,4-dihydroquinazoline-7-carboxamide;

3-cyclohexyl-2-(7-fluoro-6-(1-methyl-1H-imidazol-2-ylthio)-4-oxoquinazolin-3(4H)-yl)-N-(5-methylthiazol-2-yl)propan amide;

3-Cyclohexyl-2-(7-fluoro-6-(1-methyl-1H-imidazol-2-ylthio)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(5-methylthiazol-2-yl)propanamide;

3-cyclohexyl-2-(8-methoxy-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-yl)propanamide;

2-(6-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-3-(piperidin-1-yl)-N-(thiazol-2-yl)propanamide;

Benzyl 4-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-4-(thiazol-2-ylcarbamoyl)piperidine-1-carboxylate;

3-cyclohexyl-2-(8-methoxy-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(6-methoxy-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(6-methoxy-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(6-methoxy-2-methyl-4-oxoquinazolin-3(4-H)-yl)-N-(thiazol-2-yl)propanamide;

1-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-yl)cyclopentanecarboxamide;

3-cyclohexyl-2-(8-methyl-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(6-methyl-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-yl)propanamide;

2-(6-acetamido-4-oxoquinazolin-3(4H)-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(4-oxo-8-(trifluoromethyl)quinazolin-3(4H)-yl)-N-(thiazol-2-yl)propanamide;

2-(8-chloro-4-oxoquinazolin-3(4H)-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(6,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-yl)propanamide;

2-(6-chloro-8-methyl-4-oxoquinazolin-3(4H)-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

N-(5-chlorothiazol-2-yl)-3-cyclohexyl-2-(4-oxo-8-(trifluoromethyl)-quinazolin-3(4H)-yl)propanamide;

2-(3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)propanamido)-thiazole-5-carboxylic acid;

6-(3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)propanamido)-nicotinamide;

2-(3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)propanamido)-N,N-diethylthiazole-5-carboxamide;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(5-(morpholine-4-carbonyl)thiazol-2-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(5-(4-methylpiperazine-1-carbonyl)thiazol-2-yl)propanamide;

N-(5-(4-acetylpiperazine-1-carbonyl)thiazol-2-yl)-3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(5-(4-(2-(isopropylamino)-2-oxoethyl)piperazine-1-carbonyl)thiazol-2-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(5-formylthiazol-2-yl)propanamide;

3-cyclohexyl-N-(5-((diethylamino)methyl)thiazol-2-yl)-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(5-(morpholinomethyl)thiazol-2-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4)-yl)-N-(5-((4-methylpiperazin-1-yl)methyl)thiazol-2-yl)propanamide;

N-(5-((4-acetylpiperazin-1-yl)methyl)thiazol-2-yl)-3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(5-((4-(2-(isopropylamino)-2-oxoethyl)piperazin-1-yl)methyl)thiazol-2-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(5-(hydroxymethyl)thiazol-2-yl)propanamide;

2-(3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3 (4H)-yl)propanamido)isonicotinamide;

6-(3-cyclohexyl-2-(7-(methylsulfonyl)-4-oxoquinazolin-3(4H)-yl)propanamido)nicotinamide;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(5-fluoropyridin-2-yl)propanamide;

N-(5-chloropyridin-2-yl)-3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)propanamide;

3-cyclohexyl-N-(4,6-dimethoxypyrimidin-2-yl)-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)propanamide;

ethyl 4-(3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)propanamido)-1-methyl-1H-imidazole-2-carboxy late;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(5-(morpholine-4-carbonyl)pyridin-2-yl)propanamide;

3-cyclohexyl-2-(7-(ethylsulfonyl)-4-oxoquinazolin-3(4H)-yl)-N-(5-(morpholine-4-carbonyl)pyridin-2-yl)propanamide;

N-(5-cyanopyridin-2-yl)-3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)propanamide;

N-(5-cyanopyridin-2-yl)-3-cyclohexyl-2-(7-(methylsulfonyl)-4-oxoquinazolin-3(4H)-yl)propanamide;

6-(3-cyclohexyl-2-(6-methoxy-4-oxoquinazolin-3(4H)-yl)propanamido)nicotinamide;

N-(5-chloropyridin-2-yl)-3-cyclohexyl-2-(6-methoxy-4-oxoquinazolin-3(4H)-yl)propanamide;

3-(1-(5-carbamoylpyridin-2-ylamino)-3-cyclohexyl-1-oxopropan-2-yl)-N-cyclopropyl-4-oxo-3,4-dihydroquinazoline-7-carboxamide;

3-(1-(5-chlorothiazol-2-ylamino)-3-cyclohexyl-1-oxopropan-2-yl)-N-cyclopropyl-4-oxo-3,4-dihydroquinazoline-7-carboxamide;

3-(1-(5-chloropyridin-2-ylamino)-3-cyclohexyl-1-oxopropan-2-yl)-N-cyclopropyl-4-oxo-3,4-dihydroquinazoline-7-carboxamide;

3-(1-(5-chlorothiazol-2-ylamino)-3-cyclohexyl-1-oxopropan-2-yl)-N-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide;

3-(1-(5-chlorothiazol-2-ylamino)-3-cyclohexyl-1-oxopropan-2-yl)-N-cyclopentyl-4-oxo-3,4-dihydroquinazoline-7-carboxamide;

3-cyclohexyl-2-(7-(cyclopropanesulfonamido)-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-yl)propanamide;

3-(1-(5-chlorothiazol-2-ylamino)-3-cyclohexyl-1-oxopropan-2-yl)-N-methyl-4-oxo-3,4-dihydroquinazoline-7-carboxamide;

3-(1-(5-chlorothiazol-2-ylamino)-3-cyclohexyl-1-oxopropan-2-yl)-N-(2-(dimethylamino)ethyl)-4-oxo-3,4-dihydroquinazoline-7-carboxamide;

3-(1-(5-chlorothiazol-2-ylamino)-3-cyclohexyl-1-oxopropan-2-yl)-N-(2-(dimethylamino)ethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide;

3-(1-(5-chlorothiazol-2-ylamino)-3-cyclohexyl-1-oxopropan-2-yl)-N-((1-methylpiperidin-4-yl)methyl)-4-oxo-3,4-dihydroquinazoline-7-carboxamide;

3-(1-(5-chlorothiazol-2-ylamino)-3-cyclohexyl-1-oxopropan-2-yl)-N-((1-methylpiperidin-4-yl)methyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide;

3-(1-(5-chlorothiazol-2-ylamino)-1-oxo-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)-N-cyclopropyl-4-oxo-3,4-dihydroquinazoline-7-carboxamide;

3-(1-(5-chlorothiazol-2-ylamino)-1-oxo-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)-N-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(pyrimidin-2-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(pyrazin-2-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(pyrazin-2-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(1H-pyrazol-5-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(1H-pyrazol-5-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(5-methylpyridin-2-yl)propanamide;

methyl 6-(3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)propanamido)nicotinate;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(isoxazol-3-yl)propanamide;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(quinolin-2-yl)propanamide;

methyl 6-(3-cyclohexyl-2-(4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)propanamido)nicotinate;

3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(oxazol-2-yl)propanamide;

3-cyclohexyl-2-(4-oxo-7-(trifluoromethyl)quinazolin-3(4H)-yl)-N-(thiazol-2-yl)propanamide;

3-cyclohexyl-2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)-N-(thiazol-2-yl)propanamide;

methyl 6-(3-cyclohexyl-2-(6,7-difluoro-4-oxoquinazolin-3(4H)-yl)propanamido)nicotinate;

(S)-methyl 6-(3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)propanamido)nicotinate;

(R)-methyl 6-(3-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)propanamido)nicotinate;

methyl 6-(3-cyclohexyl-2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)propanamido)nicotinate;

methyl 6-(3-cyclohexyl-2-(6,8-dichloro-4-oxoquinazolin-3(4H)-yl)propanamido)nicotinate;

methyl 6-(2-(6-chloro-8-methyl-4-oxoquinazolin-3(4H)-yl)-3-cyclohexylpropanamido)nicotinate;

methyl 6-(3-cyclohexyl-2-(4-oxo-5-(trifluoromethyl)quinazolin-3(4H)-yl)propanamido)nicotinate;

methyl 6-(3-cyclohexyl-2-(4-oxo-8-(trifluoromethyl)quinazolin-3(4H)-yl)propanamido)nicotinate;

(S)-methyl 6-(3-cyclohexyl-2-(4-oxo-8-(trifluoromethyl)quinazolin-3(4H)-yl)propanamido)nicotinate;

(R)-methyl 6-(3-cyclohexyl-2-(4-oxo-8-(trifluoromethyl)quinazolin-3(4)-yl)propanamido)nicotinate;

N-(5-chloropyridin-2-yl)-2-(6-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-3-[4-(1,1-dioxo-(tetrahydro-2H-thiopyran-4-yl)]propanamide;

N-(5-chloropyridin-2-yl)-2-(6-fluoro-4-oxoquinazolin-3(4)-yl)-3-[4-(1,1-dioxo-(tetrahydro-2H-thiopyran-4-yl)]propanamide;

N-(5-chloropyridin-2-yl)-4,4,4-trifluoro-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)butanamide;

N-(5-chloropyridin-2-yl)-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)propanamide;

N-(5-chloropyridin-2-yl)-3-cyclobutyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)propanamide;

N-(5-chloropyridin-2-yl)-3-(4,4-difluorocyclohexyl)-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)propanamide;

N-(5-chloropyridin-2-yl)-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-3-(3-fluoropyridin-2-yl)propanamide;

(S)—N-(5-chloropyridin-2-yl)-4-cyclohexyl-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)butanamide;

N-(5-chloropyridin-2-yl)-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-3-(4-(trifluoromethyl)cyclohexyl)propanamide;

N-(5-chloropyridin-2-yl)-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide;

N-(5-chloropyridin-2-yl)-3-(3,5-dimethylisoxazol-4-yl)-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)propanamide;

N-(5-chlorothiazol-2-yl)-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-3-(1-methyl-1H-pyrazol-4-yl)propanamide; and

N-(5-chloropyridin-2-yl)-3-(3,3-difluorocyclobutyl)-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)propanamide.

8. The compound of claim 1 , wherein R 1 is a substituted or unsubstituted heteroaryl.

9. The compound of claim 1 , wherein R 1 is selected from the group consisting of thiazolyl and pyridyl; each substituted or unsubstituted.

10. The compound of claim 1 , wherein R 1 is selected from the group consisting of thiazol-2-yl; 2-pyridyl; 5-methyl-thiazol-2-yl; 6-methyl-pyrid-2-yl; 4-methyl-pyrid-2-yl; 5-bromo-6-methyl-pyrid-2-yl; 5-phenyl-pyrid-2-yl; benzothiazol-2-yl; a nictoinic acid methyl ester; and 5-bromo-pyrid-2-yl.

11. The compound of claim 1 , wherein R 1 comprises:

wherein

s is selected from the group consisting of 1 and 2;

r is selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6;

X 6 is selected from the group consisting of CR 18 R 19 , NR 20 , O and S;

R 18 is selected from the group consisting of hydrogen, halo, nitro, cyano, thio, hydroxy, carbonyloxy, (C 1-10 )alkoxy, (C 4-12 )aryloxy, hetero(C 1-10 )aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (C 1-10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )alkyl, halo(C 1-10 )alkyl, hydroxy(C 1-10 )alkyl, carbonyl(C 1-10 )alkyl, thiocarbonyl(C 1-10 )alkyl, sulfonyl(C 1-10 )alkyl, sulfinyl(C 1-10 )alkyl, aza(C 1-10 )alkyl, (C 1-10 )oxaalkyl, (C 1-10 )oxoalkyl, imino(C 1-10 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-10 )alkyl, aryl(C 1-10 )alkyl, hetero(C 1-10 )aryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, (C 4-12 )aryl, hetero(C 1-10 )aryl, (C 9-12 )bicycloaryl and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted;

R 19 is selected from the group consisting of hydrogen, halo, nitro, cyano, thio, hydroxy, carbonyloxy, (C 1-10 )alkoxy, (C 4-12 )aryloxy, hetero(C 1-10 )aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (C 1-10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )alkyl, halo(C 1-10 )alkyl, hydroxy(C 1-10 )alkyl, carbonyl(C 1-10 )alkyl, thiocarbonyl(C 1-10 )alkyl, sulfonyl(C 1-10 )alkyl, sulfinyl(C 1-10 )alkyl, aza(C 1-10 )alkyl, (C 1-10 )oxaalkyl, (C 1-10 )oxoalkyl, imino(C 1-10 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-10 )alkyl, aryl(C 1-10 )alkyl, hetero(C 1-10 )aryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, (C 4-12 )aryl, hetero(C 1-10 )aryl, (C 9-12 )bicycloaryl and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted, or R 18 and R 19 are taken together to form a substituted or unsubstituted ring;

R 20 is selected from the group consisting of hydrogen, hydroxy, carbonyloxy, (C 1-10 )alkoxy, (C 4-12 )aryloxy, hetero(C 1-10 )aryloxy, carbonyl, oxycarbonyl, amino, (C 1-10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )alkyl, halo(C 1-10 )alkyl, hydroxy(C 1-10 )alkyl, carbonyl(C 1-10 )alkyl, thiocarbonyl(C 1-10 )alkyl, sulfonyl(C 1-10 )alkyl, sulfinyl(C 1-10 )alkyl, aza(C 1-10 )alkyl, imino(C 1-10 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-10 )alkyl, aryl(C 1-10 )alkyl, hetero(C 1-10 )aryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, (C 4-12 )aryl, hetero(C 1-10 )aryl, (C 9-12 )bicycloaryl and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted;

each R 21 is independently selected from the group consisting of hydrogen, halo, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )alkyl, halo(C 1-10 )alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1-3 )alkyl, sulfonyl(C 1-3 )alkyl, sulfinyl(C 1-3 )alkyl, amino(C 1-10 )alkyl, imino(C 1-3 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl, heteroaryl, (C 9-12 )bicycloaryl and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted, or two R 21 or R 21 and R 18 or R 20 are taken together to form a substituted or unsubstituted ring; and

R 22 is selected from the group consisting of hydrogen, oxy, hydroxy, carbonyloxy, (C 1-10 )alkoxy, (C 4-12 )aryloxy, hetero(C 1-10 )aryloxy, carbonyl, oxycarbonyl, amino, (C 1-10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )alkyl, halo(C 1-10 )alkyl, hydroxy(C 1-10 )alkyl, carbonyl(C 1-10 )alkyl, thiocarbonyl(C 1-10 )alkyl, sulfonyl(C 1-10 )alkyl, sulfinyl(C 1-10 )alkyl, aza(C 1-10 )alkyl, imino(C 1-10 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-10 )alkyl, aryl(C 1-10 )alkyl, hetero(C 1-10 )aryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 1-10 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, (C 4-12 )aryl, hetero(C 1-10 )aryl, (C 9-12 )bicycloaryl and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted, or R 21 and R 22 are taken together to form a substituted or unsubstituted ring, with the proviso that R 22 is absent when the atom to which it is attached forms part of a double bond.

12. The compound of claim 1 , wherein R 1 is selected from the group consisting of thiazolyl and pyridinyl, each substituted or unsubstituted.

13. The compound of claim 1 , wherein R 3 is selected from the group consisting of hexylmethyl; benzyl; imidazol-4-ylmethyl and (tetrahydro-2H-pyran-4-yl)methyl.

14. The compound of claim 1 , wherein R 6 is selected from the group consisting of hydrogen and a substituted or unsubstituted (C 1-10 )alkyl.

15. The compound of claim 1 , wherein R 6 is methyl.

16. The compound of claim 1 , wherein R 7 is selected from the group consisting of hydrogen and a substituted or unsubstituted (C 1-10 )alkyl.

17. The compound of claim 1 , wherein R 7 is methyl.

18. The compound of claim 1 , wherein the compound is in the form of a pharmaceutically acceptable salt.

19. A pharmaceutical composition comprising as an active ingredient a compound according to claim 1 .

20. A process comprising:

reacting a compound comprising the formula

with a compound comprising the formula

under conditions that form a first reaction product comprising the formula

and

treating the first reaction product under conditions that form a second reaction product comprising the formula

wherein

R 3 is selected from the group consisting of hydrogen, (C 1-10 )alkyl, halo(C 1-10 )alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1-3 )alkyl, sulfonyl(C 1-3 )alkyl, sulfinyl(C 1-3 )alkyl, amino(C 1-10 )alkyl, imino(C 1-3 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl, heteroaryl, (C 9-12 )bicycloaryl and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted;

n is selected from the group consisting of 0, 1, 2, 3 and 4; and

21. The process according to claim 20 , comprising:

reacting the second reaction product with a compound comprising the formula

NHR 1 R 2

under conditions that form a third reaction product comprising the formula

wherein

R 1 is selected from the group consisting of hetero(C 3-12 )cycloalkyl, hetero(C 3-12 )bicycloalkyl, heteroaryl, and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted; and

R 2 is selected from the group consisting of hydrogen and a substituent convertible to hydrogen in vivo.

22. The process according to claim 20 , comprising:

reacting the second reaction product with a compound comprising the formula

R 6 -X

under conditions that form a fourth reaction product comprising the formula

and

reacting the fourth reaction product with a compound comprising the formula

NHR 1 R 2

under conditions that form a fifth reaction product comprising the formula

wherein

X is a leaving group;

R 1 is selected from the group consisting of hetero(C 3-12 )cycloalkyl, hetero(C 3-12 )bicycloalkyl, heteroaryl, and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted

R 2 is selected from the group consisting of hydrogen and a substituent convertible to hydrogen in vivo; and

R 6 is selected from the group consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )alkyl, halo(C 1-10 )alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1-3 )alkyl, sulfonyl(C 1-3 )alkyl, sulfinyl(C 1-3 )alkyl, amino(C 1-10 )alkyl, imino(C 1-3 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl, heteroaryl, (C 9-12 )bicycloaryl and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted.

23. A process comprising:

reacting a compound comprising the formula

with a compound comprising the formula

under conditions that form a first reaction product comprising the formula

reacting the first reaction product with a compound comprising the formula

R 7 (OMe) 3

under conditions that form a second reaction product comprising the formula

treating the second reaction product under conditions that form a third reaction product comprising the formula

and

reacting the third reaction product with a compound comprising the formula

NHR 1 R 2

under conditions that form a fourth reaction product comprising the formula

wherein

R 1 is selected from the group consisting of hetero(C 3-2 )cycloalkyl, hetero(C 3-12 )bicycloalkyl, heteroaryl, and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted;

R 2 is selected from the group consisting of hydrogen and a substituent convertible to hydrogen in vivo;

R 7 is selected from the group consisting of hydrogen, halo, nitro, cyano, thio, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, amino, (C 1-10 )alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C 1-10 )alkyl, halo(C 1-10 )alkyl, carbonyl(C 1-3 )alkyl, thiocarbonyl(C 1-3 )alkyl, sulfonyl(C 1-3 )alkyl, sulfinyl(C 1-3 )alkyl, amino(C 1-10 )alkyl, imino(C 1-3 )alkyl, (C 3-12 )cycloalkyl(C 1-5 )alkyl, hetero(C 3-12 )cycloalkyl(C 1-5 )alkyl, aryl(C 1-10 )alkyl, heteroaryl(C 1-5 )alkyl, (C 9-12 )bicycloaryl(C 1-5 )alkyl, hetero(C 8-12 )bicycloaryl(C 1-5 )alkyl, (C 3-12 )cycloalkyl, hetero(C 3-12 )cycloalkyl, (C 9-12 )bicycloalkyl, hetero(C 3-12 )bicycloalkyl, aryl, heteroaryl, (C 9-12 )bicycloaryl and hetero(C 4-12 )bicycloaryl, each substituted or unsubstituted;

n is selected from the group consisting of 0, 1, 2, 3 and 4; and

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 24, 2007

From: CHERUVALLATH, ZACHARIA; FENG, JUN; GUNTUPALLI, PRASUNA; GWALTNEY, STEPHEN L.; KALDOR, STEPHEN W.; MIURA, JOANNE; SABAT, MARK; TANG, MINGNAM; WOLGAST, BEVERLY

To: TAKEDA SAN DIEGO, INC.

Reel/Frame 019340/0630 →

Continuity (2)

Provisional Application 60780339 · Mar 8, 2006

Related Publication 20070213349A1 · Sep 13, 2007