4-oxo-3,5,7,8-tetrahydro-4H-pyrano[4,3-d]pyrminidinyl compounds for use as tankyrase inhibitors

Patent metadata

Field	Value
Publication number	US-9227982-B2
Application number	US-201214154170-A
Country	US
Kind code	B2
Filing date	Jul 13, 2012
Priority date	Jul 13, 2011
Publication date	Jan 5, 2016
Grant date	Jan 5, 2016

Abstract

The present invention provides for compounds of formula (I)

wherein R 1 and R 2 are defined herein. The present invention also provides for pharmaceutical compositions and combinations comprising a compound of formula (I) as well as for the use of such compounds as tankyrase inhibitors and in the treatment of Wnt signaling and tankyrase 1 and 2 signaling related disorders which include, but are not limited to, cancer.

First claim

What is claimed is:

1. A compound according to formula (I)

wherein:
R 1 is hydrogen or C 1-4 haloalkyl, or C 1-4 alkyl optionally substituted with one substituent selected from the group consisting of: hydroxy, cyano, C(O)R a , C 3-5 cycloalkyl, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl,
wherein said phenyl and 5-6 member heteroaryl are each optionally substituted with one or two substituents each independently selected from the group consisting of: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, and cyano;

R 2 is R 3 —C 1-2 alkylene-C(O)—, R 3 —C 1-2 alkylene-S(O) 2 —, or R 3 —C 1-2 alkylene-COO—;
R 3 is optionally substituted phenyl, optionally substituted 6 membered heteroaryl, or optionally substituted indolyl,
wherein said phenyl, heteroaryl and indolyl are each optionally substituted with one to three substitutents each independently selected from the group consisting of: halo, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C(O)R a , COOR a , NR a R b , NHC(O)R a , and C(O)NR a R b ;

R a is H or C 1-6 alkyl; and
R b is H or C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein R 1 is optionally substituted C 1-4 alkyl; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein R 1 is substituted methyl or substituted ethyl; or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 wherein R 1 is methyl substituted by an optionally substituted 5 membered heteroaryl; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 wherein R 1 is ethyl substituted by an optionally substituted phenyl; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 wherein R 2 is R 3 -ethylene-C(O)—, R 3 -methylene-S(O) 2 —, or R 3 —C 1-2 methylene-COO—; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 wherein R 2 is R 3 —C 1-2 alkylene-C(O)—; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 wherein R 3 is optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted indolyl; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8 wherein the optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted indolyl are each optionally substituted with one to three substitutents each independently selected from the group consisting of: halo and hydroxy; or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9 wherein R 1 is C 1-4 alkyl, particularly methyl, substituted with one 2- or 3-thienyl, 2-, 4-, or 5-imidazolyl, 2-, 4-, or 5-thiazolyl, or 2-, 4-, or 5-oxazolyl optionally substituted with one halo group; or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 which is:
N-((4-Oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)-3-phenyl-N-(thiophen-2-ylmethyl)propanamid;
3-(4-Fluoro-phenyl)-N-(4-oxo-3,5,7,8-tetrahydro-4H-pyrano[4,3-d]pyrimidin-2-ylmethyl)-N-thiophen-2-ylmethyl-propionamide;
3-(1H-Indol-3-yl)-N-(4-oxo-3,5,7,8-tetrahydro-4H-pyrano[4,3-d]pyrimidin-2-ylmethyl)-N-thiophen-2-ylmethyl-propionamid;
3-(2-Fluoro-phenyl)-N-(4-oxo-3,5,7,8-tetrahydro-4H-pyrano[4,3-d]pyrimidin-2-ylmethyl)-N-thiophen-2-ylmethyl-propionamide;
3-(3-Fluorophenyl)-N-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)-N-(thiophen-2-ylmethyl)propanamide;
3-(2-Hydroxy-phenyl)-N-(4-oxo-3,5,7,8-tetrahydro-4H-pyrano[4,3-d]pyrimidin-2-ylmethyl)-N-thiophen-2-ylmethyl-propionamide;
3-(3-Hydroxy-phenyl)-N-(4-oxo-3,5,7,8-tetrahydro-4H-pyrano[4,3-d]pyrimidin-2-ylmethyl)-N-thiophen-2-ylmethyl-propionamide;
3-(4-Hydroxy-phenyl)-N-(4-oxo-3,5,7,8-tetrahydro-4H-pyrano[4,3-d]pyrimidin-2-ylmethyl)-N-thiophen-2-ylmethyl-propionamide;
N-((4-Oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)-1-phenyl-N-(thiophen-2-ylmethyl)methanesulfonamide;
2-Phenyl-ethanesulfonic acid (4-oxo-3,5,7,8-tetrahydro-4H-pyrano[4,3-d]pyrimidin-2-ylmethyl)-thiophen-2-ylmethyl-amide;
N-((4-Oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)-3-(pyridin-4-yl)-N-(thiophen-2-ylmethyl)propanamide;
N-((4-Oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)-3-(pyridin-4-yl)-N-(thiophen-2-ylmethyl)propanamide;
N-Cyclopentylmethyl-N-(4-oxo-3,5,7,8-tetrahydro-4H-pyrano[4,3-d]pyrimidin-2-ylmethyl)-3-phenyl-propionamide;
Cyclopentylmethyl-N-(4-oxo-3,5,7,8-tetrahydro-4H-pyrano[4,3-d]pyrimidin-2-ylmethyl)-3-phenyl-propionamide;
N-(2-Fluorobenzyl)-N-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)-3-phenylpropanamide;
N-Ethyl-N-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)-3-phenylpropanamide;
N-Isopropyl-N-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)-3-phenylpropanamide;
N-(3,3-Dimethyl-2-oxobutyl)-N-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)-3-phenylpropanamide;
N-((4-Oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)-3-phenyl-N-(thiophen-3-ylmethyl)propanamide;
N-((4-Oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)-3-phenyl-N-(thiazol-2-ylmethyl)propanamide;
N-(Oxazol-2-ylmethyl)-N-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)-3-phenylpropanamide;
N-((5-Chlorothiophen-2-yl)methyl)-N-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)-3-phenylpropanamide;
N-((4-Oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)-3-phenyl-N-(thiazol-5-ylmethyl)propanamide;
N-(2-Hydroxy-ethyl)-N-(4-oxo-3,5,7,8-tetrahydro-4H-pyrano[4,3-d]pyrimidin-2-ylmethyl)-3-phenyl-propionamide;
(S)—N-((4-Oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)-1-phenyl-N-(1-phenylethyl)methanesulfonamide; or
(R)—N-((4-Oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)-1-phenyl-N-(1-phenylethyl)methanesulfonamide; or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

13. A method for the treatment of cancer selected from the group consisting of colon, pancreas and breast comprising administration of a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

Assignees

• Cheung Atwood Kim
• Chin Donovan Noel
• Fan Jianmei
• Shultz Michael David
• Tomlinson Ronald Charles
• Novartis Ag

Inventors

• Cheung Atwood Kim
• Chin Donovan Noel
• Fan Jianmei
• Shultz Michael David
• Tomlinson Ronald Charles

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D491/052 Primary

  the oxygen-containing ring being six-membered · CPC title