IP Library › Granted Patent US 8,957,074

Granted Patent B2

US 8,957,074 · App. 13/579,359 · Granted Feb 17, 2015

Pyrrolopyrimidine compounds as inhibitors of CDK4/6

Inventors: Christopher Thomas Brain (North Reading, MA); Young Shin Cho (Cambridge, MA); John William Giraldes (Quincy, MA); Bharat Lagu (Acton, MA); Julian Roy Levell (Arlington, MA); Michael J. Luzzio (Noank, CT); Lawrence Blas Perez (Hopkinton, MA); Yaping Wang (Boxborough, MA); Fan Yang (West Roxbury, MA)

Assignee: Novartis AG

C07D498/20 C07D487/04 C07D519/00 C07D471/08 C07D471/10 C07D487/08 C07D498/08

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Quick Facts

Patent No.: US 8,957,074
App. No.: 13/579,359
Granted: Feb 17, 2015
Kind: B2

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Abstract

The invention is directed to novel pyrrolopyrimidine compounds of formula (I) wherein R 1 , R 2Y , R 4 , R 8 -R 11 , A and L are defined herein and to salts, including pharmaceutically acceptable salts thereof. The compounds of the present invention are CDK4/6 inhibitors and could be useful in the treatment of diseases and disorders mediated by CDK4/6, such as cancer, including mantle cell lymphoma, liposarcoma, non small cell lung cancer, melanoma, squamous cell esophageal cancer and breast cancer. The invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting CDK4/6 activity and to the treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

Claims (110)

1. A compound according to formula (I)

wherein:

R 1 is C 3-7 alkyl; C 4-7 cycloalkyl optionally substituted with one substituent selected from the group consisting of C 1-6 alkyl and OH; phenyl optionally substituted with one substitutent selected from the group consisting of C 1-6 alkyl, C(CH 3 ) 2 CN, and OH; piperidinyl optionally substituted with one cyclopropyl or C 1-6 alkyl; tetrahydropyranyl optionally substituted with one cyclopropyl or C 1-6 alkyl; or bicyclo[2.2.1]heptanyl;

A is CH or N;

R 11 is hydrogen or C 1-4 alkyl;

L is a bond, C(O), or S(O) 2 ;

R 2Y is

V is NH or CH 2 ;

X is O or CH 2 ;

W is O or NH;

m and n are each independently 1, 2, or 3 provided that m and n are not both 3;

each R 2Y is optionally substituted with one to four substituents each independently selected from the group consisting of: C 1-3 alkyl optionally substituted with one or two substituents each independently selected from the group consisting of hydroxy, NH 2 , and —S—C 1-3 alkyl; CD 3 ; halo; oxo; C 1-3 haloalkyl; hydroxy; NH 2 ; dimethylamino; benzyl; —C(O)—C 1-3 alkyl optionally substituted with one or two substituents each independently selected from the group consisting of NH 2′ —SCH 3 and NHC(O)CH 3 ; —S(O) 2 —C 1-4 -alkyl; and pyrrolidinyl-C(O)—;

R 4 is hydrogen, deuterium, or C(R 5 )(R 6 )(R 7 ); and

R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently H or deuterium; or a pharmaceutically acceptable salt thereof.

2. The compound according claim 1 of formula (I-B)

wherein

L is a bond or C(O);

R 2Y is

V is NH or CH 2 ;

X is O or CH 2 ;

W is O or NH;

m and n are each independently 1, 2, or 3 provided that m and n are not both 3; and

each R 2Y is optionally substituted with one to four substituents each independently selected from the group consisting of: C 1-3 alkyl optionally substituted with one or two substituents each independently selected from the group consisting of hydroxy, NH 2 , and —S—C 1-3 alkyl; CD 3 ; C 1-3 haloalkyl; hydroxy; NH 2 ; dimethylamino; benzyl; —C(O)—C 1-3 alkyl optionally substituted with one or two substituents each independently selected from the group consisting of NH 2′ —SCH 3 and NHC(O)CH 3 ; —S(O) 2 —C 1-4 alkyl; and pyrrolidinyl-C(O)—; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein L is C(O), or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 wherein L is a bond, or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 wherein A is CH and R 11 is hydrogen; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 wherein R 4 is C(R 5 )(R 6 )(R 7 ) and R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are hydrogen, or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 wherein R 1 is C 4-7 cycloalkyl optionally substituted with one C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 wherein R 1 is cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 wherein R 1 is unsubstituted cyclopentyl, or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 wherein R 2Y is unsubstituted, or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 wherein R 2Y is

either of which is optionally substituted with one C 1-3 alkyl, or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 wherein R 2Y is

optionally substituted with one C 1-3 alkyl, or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1 selected from the group consisting of:

2-(5-(2,6-Diazaspiro[3.3]heptane-2-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;

7-(4-tert-Butyl-phenyl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-Cyclopentyl-2-[5-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-Cycloheptyl-2-[5-(2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

2-(5-(2,7-diazaspiro[3.5]nonane-7-carbonyl)pyridin-2-ylamino)-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;

7-cyclopentyl-2-[5-(8-methyl-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-Cyclopentyl-2-[5-((S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide;

7-(3-tert-Butyl-phenyl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

2-(5-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;

7-[4-(Cyano-dimethyl-methyl)-phenyl]-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-Cyclopentyl-2-[5-((1S,6R)-3,9-diaza-bicyclo[4.2.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-Cyclopentyl-2-[5-((1R,6S)-3,9-diaza-bicyclo[4.2.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-Cyclopentyl-2-[5-(3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-cyclopentyl-N,N-dimethyl-2-(5-(5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-1′-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;

7-Cyclopentyl-2-[5-(1-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-cyclopentyl-N,N-dimethyl-2-(5-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;

7-Cyclopentyl-2-[5-((1S,6R)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

2-[5-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; and

7-cyclohexyl-N,N-dimethyl-2-(5-(4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide; or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 selected from the group consisting of:

7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-Cyclopentyl-2-[5-((S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-Cyclopentyl-2-[5-((1S,5S)-3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-Cyclobutyl-2-[5-((1S,6R)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-Cyclohexyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-6-methyl-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-4-methyl-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-Cyclopentyl-2-[5-(3,9-diaza-bicyclo[3.3.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;

7-cyclopentyl-N,N-dimethyl-2-(5-(3-oxo-1,4-diazabicyclo[3.2.2]nonan-4-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide; and

7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide; or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1 selected from the group consisting of:

7-cyclopentyl-N,N-dimethyl-2-(5-((3aS,6aR)-1-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;

7-cyclopentyl-N,N-dimethyl-2-(5-((3aR,6aS)-1-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide; and

7-cyclopentyl-N,N-dimethyl-2-(5-((3aR,6aS)-5-methyl-1-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide; or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1 selected from the group consisting of:

7-cyclopentyl-N,N-dimethyl-2-(5-((1R,3r,5S)-2′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidine]-3′-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;

7-cyclopentyl-N,N-dimethyl-2-(5-(2-oxo-1-oxa-3,8-diazaspiro[4.6]undecan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;

7-cyclopentyl-N,N-dimethyl-2-(5-(2-oxo-1-oxa-3,7-diazaspiro[4.5]decan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;

7-Cyclopentyl-2-[5-((S)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]dec-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; and

7-Cyclopentyl-2-[5-((R)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]dec-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; or a pharmaceutically acceptable salt thereof.

17. A compound 7 cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide having the following formula: