Pyrrolopyrimidine compounds and their uses

Patent metadata

Field	Value
Publication number	US-2018155351-A1
Application number	US-201815886014-A
Country	US
Kind code	A1
Filing date	Feb 1, 2018
Priority date	Aug 22, 2008
Publication date	Jun 7, 2018
Grant date	—

Abstract

The disclosed compounds relate to treatments and therapies for protein kinase-associated disorders. There is also a need for compounds useful in the treatment or prevention or amelioration of one or more symptoms of cancer, transplant rejections, and autoimmune diseases. Furthermore, there is a need for methods for modulating the activity of protein kinases, such as CDK1, CDK2, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, using the compounds provided herein.

First claim

What is claimed is:

1 . A compound of formula I:

or a pharmaceutically acceptable salt, wherein
X is CR 9 , or N;
R 1 is C 1-8 alkyl, CN, C(O)OR 4 or CONR 5 R 6 , a 5-14 membered heteroaryl group, or a 3-14 membered cycloheteroalkyl group;
R 2 is C 1-8 alkyl, C 3-14 cycloalkyl, or a 5-14 membered heteroaryl group, and wherein R 2 may be substituted with one or more C 1-8 alkyl, or OH;
L is a bond, C 1-8 alkylene, C(O), or C(O)NR 10 , and wherein L may be substituted or unsubstituted;
Y is H, R 11 , NR 12 R 13 , OH, or Y is part of the following group

where Y is CR 9 or N;
where 0-3 R 8 may be present, and R 8 is C 1-8 alkyl, oxo, halogen, or two or more R 8 may form a bridged alkyl group;
W is CR 9 , or N;
R 3 is H, C 1-8 alkyl, C 1-8 alkylR 14 , C 3-14 cycloalkyl, C(O)C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkylOH, C(O)NR 14 R 15 , C 1-8 cyanoalkyl, C(O)R 14 , C 0-8 alkylC(O)C 0-8 alkylNR 14 R 15 , C 0-8 alkylC(O)OR 14 , NR 14 R 15 , SO 2 C 1-8 alkyl, C 1-8 alkylC 3-14 cycloalkyl, C(O)C 1-8 alkylC 3-14 cycloalkyl, C 1-8 alkoxy, or OH which may be substituted or unsubstituted when R 3 is not H.
R 9 is H or halogen;
R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 are each independently selected from H, C 1-8 alkyl, C 3-14 cycloalkyl, a 3-14 membered cycloheteroalkyl group, a C 6-14 aryl group, a 5-14 membered heteroaryl group, alkoxy, C(O)H, C(N)OH, C(N)OCH 3 , C(O)C 1-3 alkyl, C 1-8 alkylNH 2 , C 1-6 alkylOH, and wherein R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , and R 13 , R 14 , and R 15 when not H may be substituted or unsubstituted;
m and n are independently 0-2; and
Wherein L, R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , and R 13 , R 14 , and R 15 may be substituted with one or more of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-14 cycloalkyl, 5-14 membered heteroaryl group, C 6-14 aryl group, a 3-14 membered cycloheteroalkyl group, OH, (O), CN, alkoxy, halogen, or NH 2 .

2 . The compound of formula I according to claim 1 wherein R 3 is H, C 1-8 alkyl, C 3-14 cycloalkyl, C(O)C 1-8 alkyl, C 1-8 alkylOH, C 1-8 cyanoalkyl, C 0-8 alkylC(O)C 0-8 alkylNR 14 R 15 , C 0-8 alkylC(O)OR 14 , NR 14 R 15 , C 1-8 alkylC 3-14 cycloalkyl, C(O)C 1-8 alkylC 3-14 cycloalkyl, C 0-8 alkoxy, C 1-8 alkylR 14 , C 1-8 haloalkyl, or C(O)R 14 , which may be substituted with one or more of OH, CN, F, or NH 2 , and wherein R 14 and R 15 are each independently selected from H, C 1-8 alkyl, C 3-14 cycloalkyl, alkoxy, C(O)C 1-3 alkyl, C 1-8 alkylNH 2 , or C 1-6 alkylOH.

3 . The compound of formula I according to any of claims 1 - 2 wherein R 3 is H, C 1-8 alkyl, or C 1-8 alkylOH.

4 . The compound of formula I according any of claims 1 - 3 wherein Y is H, OH, or Y is part of the following group

where Y is N and W is CR 9 , or N;
where 0-2 R 8 may be present, and R 8 is C 1-8 alkyl, oxo, or two or more R 8 may form a bridged alkyl group.

5 . The compound of formula I according to any of claims 1 - 4 wherein L is a bond, C 1-8 alkylene, or C(O)NH, or C(O).

6 . The compound of formula I according to any of claims 1 - 5 wherein R 2 is C 3-14 cycloalkyl.

7 . The compound of formula I according to any of claims 1 - 6 wherein R 2 is cyclopentane.

8 . The compound of formula I according to any of claims 1 - 7 wherein R 1 is CN, C(O)OR 4 , CONR 5 R 6 , or a 5-14 membered heteroaryl group.

9 . The compound of formula I according to any of claims claim 1 - 8 wherein R 1 is CONR 5 R 6 , and R 5 and R 6 are C 1-8 alkyl.

10 . The compound of formula I according to any of claims 1 - 9 wherein X is CR 9 .

11 . The compound of formula I according to any of claims 1 - 10 wherein one X is N and the other X is CR 9 .

12 . The compound of formula I according to any of claims 1 - 11 wherein X is CR 9 and Y is

where m and n are 1, and Y and W are N.

13 . A method of treating a disease, disorder or syndrome associated with CDK 4 inhibition, said method comprising administering a compound according to any one of claims 1 - 12 or its prodrug or pharmaceutical composition comprising the compound of formula I or its prodrug and pharmaceutically acceptable excipients to a subject in need thereof.

14 . The method of treating as claimed in claim 13 , wherein the disease, disorder or syndrome is hyperproliferative in a subject, wherein subject is an animal including humans, selected from a group comprising cancer and inflammation.

15 . A method of inhibiting a cyclin dependent kinase (e.g. cdk-4), which method comprises contacting the kinase with a kinase-inhibiting compound according to any one of claims 1 to 12 .

16 . A method of modulating a cellular process (for example cell division) by inhibiting the activity of a cyclin dependent kinase using a compound according to any one of claims 1 to 12 .

17 . A compound according to any one of claims 1 to 12 for use in the prophylaxis or treatment of a disease state as described herein.

18 . The use of a compound according to any one of claims 1 to 12 for the manufacture of a medicament, wherein the medicament is for any one or more of the uses defined herein.

19 . A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier.

20 . A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier in a form suitable for oral administration.

21 . A compound of formula I(a):

or a pharmaceutically acceptable salt thereof, wherein:
R 50 is CONR 54 R 55 , or CN;
R 51 is C 3-14 cycloalkyl which may be unsubstituted or substituted by C 1-3 alkyl, or OH;
Z is CH or N; and
V is NR 56 or CHR 57 ;
R 54 and R 55 are independently H, C 1-3 alkyl,
R 52 , R 53 R 56 , and R 57 are independently H, C 1-8 alkyl, C 3-14 cycloalkyl, C 1-8 haloalkyl, NR 58 R 59 , C(O)OR 60 , C(O)C 1-8 alkyl, C 0-8 alkylC(O)C 0-8 alkyl-NR 61 R 62 , C 1-8 alkoxy, C 1-8 alkylOR 63 , C(O)-5-14cycloheteroalkyl group, C 3-14 cycloalkyl group, each of which when not H may be substituted by one or more of C 1-8 alky, OH, or CN;
R 58 , R 59 , R 60 , R 61 , R 62 , and R 63 are H or C 1-8 alkyl.

22 . A compound selected from:
7-Cyclopentyl-2-[5-(3-methyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3d]pyrimidine-6-carbonitrile; 7-Cyclopentyl-2-{5-[4-(2-fluoro-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-(4-dimethylamino-3, 4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 2-[5-(4-Carbamoylmethyl-piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 2-{5-[4-(2-Amino-acetyl)-piperazin-1-yl]-pyridin-2-ylamin

Assignees

• Novartis Ag
• Astex Therapeutics Ltd

Inventors

• Besong Gilbert
• Brain Christopher Thomas
• Brooks Clinton A
• Congreve Miles Stuart
• Dagostin Claudio
• He Guo
• Hou Ying
• Howard Steven
• Li Yue
• Lu Yipin
• Mortenson Paul
• Smith Troy
• Sung Moo Je
• Woodhead Steven
• Wrona Wojciech
• Lagu Bharat

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title