Small molecule inhibitors of NF-[kappa] B-inducing kinases

A technology of -NH2, -CF3, applied in the field of compounds that inhibit NIK

Pending Publication Date: 2022-03-22
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, transfer of NIK+ / + splenocytes or T cells to Rag2- / - mice confers susceptibility to AIA whereas transfer of NIK- / - cells does not

Method used

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  • Small molecule inhibitors of NF-[kappa] B-inducing kinases
  • Small molecule inhibitors of NF-[kappa] B-inducing kinases
  • Small molecule inhibitors of NF-[kappa] B-inducing kinases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[2249] Example 1: (R)-3-[2-[3-(8-aminopyrido[3,4-d]pyrimidin-2-yl)phenyl]ethynyl]-3-hydroxy yl-1-methyl-pyrrolidin-2-one .

[2250]

[2251] A 500 mL round bottom flask was charged with a stir bar, 2-(3-iodophenyl)pyrido[3,4-d]pyrimidin-8-amine (15 g, 43 mmol), Pd(PPh 3 ) 2 Cl 2 (3.0g, 4.3mmol), CuI (0.9g, 4.3mmol), DIPEA (11g, 85mol), (R)-3-ethynyl-3-hydroxyl-1-methylpyrrolidin-2-one (14g, 99 mmol) and THF (300 mL). The resulting mixture was stirred at 60 °C for 2 h, then cooled to 20 °C. The product was isolated by filtration and purified by FCC to afford (R)-3-[2-[3-(8-aminopyrido[3,4-d]pyrimidin-2-yl)phenyl] as a light yellow solid Ethynyl]-3-hydroxy-1-methyl-pyrrolidin-2-one (9.0 g, 58%). MS (ESI): C 20 h 17 N 5 o 2 The mass calculated value is 359.14; m / z measured value is 360.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.53(s,1H),8.76–8.71(m,1H),8.70–8.67(m,1H),8.02(d,J=5.6Hz,1H),7.62–7.53(m,2H),7.45 (s,2H),7.04(d,J=5.6Hz,1H),6.50(s,1H),3.42–3.36(m,2H),2...

Embodiment 2

[2252] Example 2: (S)-3-[2-[3-(8-aminopyrido[3,4-d]pyrimidin-2-yl)phenyl]ethynyl]-3-hydroxy yl-1-methyl-pyrrolidin-2-one .

[2253]

[2254] The title compound was obtained using similar conditions as described in Example 1 and utilizing 2-(3-iodophenyl)pyrido[3,4-d]pyrimidin-8-amine and (S)-3-ethynyl-3-hydroxy -1-methylpyrrolidin-2-one to obtain (S)-3-[2-[3-(8-aminopyrido[3,4-d]pyrimidin-2-yl)phenyl]acetylene base]-3-hydroxy-1-methyl-pyrrolidin-2-one. MS (ESI): C 20 h 17 N 5 o 2 The mass calculated value is 359.14; m / z measured value is 360.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.53(s,1H),8.76–8.71(m,1H),8.70–8.67(m,1H),8.02(d,J=5.6Hz,1H),7.62–7.53(m,2H),7.45 (s,2H),7.04(d,J=5.6Hz,1H),6.50(s,1H),3.42–3.36(m,2H),2.83(s,3H),2.50–2.44(m,1H), 2.28–2.17(m,1H).

Embodiment 3

[2255] Example 3: (R)-3-[2-[3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-4-methyl-phenyl]acetylene Base] -3-hydroxy-1-methyl-pyrrolidin-2-one .

[2256]

[2257] A 20 mL microwave vial was charged with 6-chloropyrimido[3,2-d]pyrimidin-4-amine (75.0 mg, 0.42 mmol), (R)-3-hydroxy-1-methyl-3-((4- Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethynyl)pyrrolidin-2-one (148mg , 0.42mmol), K 3 PO 4 (264mg, 1.24mmol), 1,4-dioxane (5mL) and H 2 O (1 mL). The resulting mixture was aerated with argon for 5 min, and then treated with [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (PdCl 2 (dtbpf)) (27.0 mg, 0.04 mmol) treatment. The mixture was aerated with argon for another 5 min, and the resulting mixture was subjected to microwave irradiation at 85 °C for 1 h, then it was cooled to RT. The resulting mixture was poured into water (30 mL), and extracted with ethyl acetate (30 mL×3). The combined organic extracts were subjected to anhydrous Na 2...

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Abstract

The present invention relates to compounds that inhibit NIK and pharmaceutical compositions comprising such compounds and methods of use thereof. These compounds and pharmaceutical compositions are contemplated to be useful in the prevention or treatment of diseases such as cancer (such as B-cell malignancies, including leukemia, lymphoma and myeloma), inflammatory disorders, autoimmune disorders, immunodermatological disorders such as palmoplantar pustulopathy and hidradenitis suppurativa, and metabolic disorders such as obesity and diabetes.

Description

technical field [0001] The NF-κB-inducing kinase (termed NIK, also known as MAP3K14) is a regulator and driver of the non-canonical NIK cascade and thus represents an attractive target for therapeutic intervention. The present invention relates to compounds that inhibit NIK and pharmaceutical compositions comprising such compounds. It is envisioned that these compounds and pharmaceutical compositions are useful in the prophylaxis or treatment of diseases such as cancers (such as B cell malignancies, including leukemia, lymphoma and myeloma), inflammatory disorders, autoimmune disorders, immunodermatological disorders such as palmoplantar pus Herpes and hidradenitis suppurativa, and metabolic disorders such as obesity and diabetes. The present invention also relates to methods of preventing or treating such diseases. Background technique [0002] NIK is a serine / threonine kinase transcription factor that promotes the expression of various genes involved in immune response d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/10C07D487/04C07D513/04A61K31/4709A61K31/5025A61K31/519A61P35/00C07D403/10C07D413/10C07D417/10
CPCC07D487/04C07D513/04C07D403/10C07D401/10C07D417/10C07D413/10A61P35/00C07D471/04C07D495/04A61K31/4365A61P25/24
Inventor J·K·巴贝柴文英W·埃克莱斯M·D·哈克A·T·赫尔曼W·M·琼斯P·J·克劳丘克K·D·克鲁特A·D·勒贝克D·J·皮佩尔A·R·罗维拉R·L·沃林
Owner JANSSEN PHARMA NV
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