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3-(2-aminopyrimidin-4-yl)-5-(3-hydroxypropynyl)-1h-pyrrolo[2,3-c]pyridine derivatives as nik inhibitors for the treatment of cancer

A technology of pyrrolidinyl and alkyl, applied in the field of pharmaceutical reagents, can solve the problems of defective B and T cells, weakened receptor activators, and lack of peripheral lymph nodes, etc.

Active Publication Date: 2015-12-09
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Mice lacking functional NIK have no peripheral lymph nodes, defective B and T cells, and a receptor activator of NF-κB ligand-stimulated osteoclastogenesis is impaired

Method used

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  • 3-(2-aminopyrimidin-4-yl)-5-(3-hydroxypropynyl)-1h-pyrrolo[2,3-c]pyridine derivatives as nik inhibitors for the treatment of cancer
  • 3-(2-aminopyrimidin-4-yl)-5-(3-hydroxypropynyl)-1h-pyrrolo[2,3-c]pyridine derivatives as nik inhibitors for the treatment of cancer
  • 3-(2-aminopyrimidin-4-yl)-5-(3-hydroxypropynyl)-1h-pyrrolo[2,3-c]pyridine derivatives as nik inhibitors for the treatment of cancer

Examples

Experimental program
Comparison scheme
Effect test

example A1

[1041] a) Preparation of Intermediate 1

[1042]

[1043] A stirred mixture of 5-bromo-1H-pyrrolo[2,3-c]pyridine (2.00 g, 10.2 mmol) in anhydrous DCM (65 ml) was dissolved with aluminum chloride (2.70 g, 20.3 mmol) at ambient temperature Collated. After stirring for 15 minutes, the mixture was treated dropwise with acetyl chloride (1.44ml, 20.3mmol), and the resulting mixture was stirred at ambient temperature for 24 hours. The mixture was carefully treated with MeOH until no further bubbling was observed. The mixture was then concentrated in vacuo, and the residue was partitioned between 2.0M aqueous sodium hydroxide and EtOAc. The organic phase was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was washed with Et 2 O was triturated to obtain the desired product (2.12 g, 87%).

[1044] LCMS (Method B): R t =2.29min, m / z[M+H] + =239 / 241

[1045] b) Preparation of Intermediate 2

[1046]

[1047] Intermediate 1 (2.12g, 8....

example A2

[1050] a) Preparation of Intermediate 3

[1051]

[1052] A stirred mixture of Intermediate 2 (0.98 g, 2.50 mmol) and tert-butoxybis(dimethylamino)methane (1.03 ml, 5.0 mmol) was heated at 100°C for 2.5 hours. The mixture was cooled to ambient temperature and allowed to stand for 18 hours. A second aliquot of tert-butoxybis(dimethylamino)methane (0.52ml, 2.50mmol) was added and the mixture was heated at 100°C for 2.5 hours. The mixture was cooled to ambient temperature and concentrated in vacuo to obtain the desired product (1.40 g) as a brown semi-solid.

[1053] LCMS (Method D): R t =2.04min, m / z[M+H] + =294 / 296

[1054] b) Preparation of Intermediate 4

[1055]

[1056] A stirred mixture of guanidine hydrochloride (2.38 g, 25.0 mmol) and 1-butanol (9.0 ml) was treated portionwise with sodium methoxide (1.35 g, 25.0 mmol) at ambient temperature under a nitrogen atmosphere. After stirring for 30 minutes, a slurry of Intermediate 3 (1.40 g, 4.75 mmol) in 1-buta...

example A3

[1063] a) preparation of intermediate 6

[1064]

[1065]A stirred mixture of N-methylguanidine hydrochloride (1.99 g, 18.2 mmol) and 1-butanol (8.0 ml) was treated with sodium methoxide (0.98 g, 18.2 mmol) at ambient temperature under a nitrogen atmosphere. After stirring for 30 minutes, the mixture was treated with a slurry of Intermediate 3 (1.05 g, 3.57 mmol) in 1-butanol (3.0 ml), and the resulting mixture was heated at 100 °C for 16 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was diluted with water and extracted sequentially with EtOAc and then with a mixture of EtOAc and MeOH (9:1 by volume). The combined extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a mixture of MeOH and EtOAc (0:1 to 1:9 by volume), followed by EtOAc. 2 O was triturated to obtain the desired product (0.12 g, 22%).

[1066] LCMS (Method C): R t =1....

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Abstract

The present invention relates to compounds of formula (I) which are inhibitors of NF-KB-inducing kinase (NIK - also known as MAP3K14) useful for treating diseases such as cancer, inflammatory disorders, metabolic disorders and autoimmune disorders. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds or pharmaceutical compositions for the prevention or treatment of diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders.

Description

field of invention [0001] The present invention relates to pharmaceutical agents useful for treatment and / or prophylaxis in a mammal, and in particular to pharmaceutical agents useful for the treatment of diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders Inhibitor of NF-κB-induced kinase (NIK, also known as MAP3K14). The invention is also directed to pharmaceutical compositions comprising such compounds; to methods of preparing such compounds and compositions; and to such compounds or pharmaceutical compositions for use in the prevention or treatment of diseases such as cancer, inflammatory disorders, including obesity and metabolic disorders of diabetes and autoimmune disorders). Background of the invention [0002] The present invention relates to pharmaceutical agents useful for treatment and / or prophylaxis in a mammal, and in particular to NF-κB-induced kinase (NIK, also known as MAP3K14 ) usefu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61P35/00
CPCC07D471/04A61P35/00A61P43/00
Inventor G.海恩德S.普赖斯J.库拉戈维斯基C.马克勒奧德S.E.马恩T.A.潘查尔P.蒂斯塞里J.G.蒙塔纳
Owner JANSSEN PHARMA NV
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