4,5-dihydroisoxazole derivatives as NAMPT inhibitors

A technology for compounds and medicinal salts, applied in the field of compounds for the treatment of nicotinamide phosphoribosyltransferase-related cancers and inflammatory diseases, can solve problems such as unsatisfied

Inactive Publication Date: 2017-05-10
AURIGENE DISCOVERY TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There appears to be an unmet need for newer drugs to treat diseases and / or conditions associated with elevated NAMPT levels

Method used

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  • 4,5-dihydroisoxazole derivatives as NAMPT inhibitors
  • 4,5-dihydroisoxazole derivatives as NAMPT inhibitors
  • 4,5-dihydroisoxazole derivatives as NAMPT inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0227] Example 1: N-((5-(((3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)oxy)methyl)-4,5-dihydroiso Oxazol-3-yl)methyl)imidazo[1,2-a]pyridine-6-carboxamide (±).

[0228] Step 1: 2-(allyloxy)-3-bromopyridine.

[0229]

[0230] To a solution of 3-bromo-2-fluoropyridine (1.0 g, 5.68 mmol) and allyl alcohol (1.96 mL, 5.0 mmol) in dry THF (10 mL) was added sodium hydride (0.55 g, 2.4 mmol, 60%) in portions . The reaction mixture was stirred at room temperature for 16 hours. Water (50 mL) was added to cool the reaction mixture, then extracted with ethyl acetate (2x100 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure to obtain the title compound (1.4 g, 98%) as an oil. The crude product was carried on to the next step without further purification. LCMS: m / z 214[M+2] + ; 1 H NMR (300MHz, chloroform-d) δ8.13-8.00 (dd, J = 4.8, 1.8Hz, 1H), 7.88-7.72 (dd, J = 7.6, 1.7Hz, 1H), 6.88-6.68 (dd, J =7.6, 4.9Hz, 1H), 6.22-5.97 (ddt, J=1...

Embodiment 2

[0252] Example 2: N-((5-(((6'-fluoro-[3,3'-bipyridyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazole-3 -yl)methyl)imidazo[1,2-a]pyridine-6-carboxamide (±).

[0253]

[0254] As described in step 8 of Example 1, (6-fluoropyridin-3-yl)boronic acid (0.207 g, 1.460 mmol) N-((5-(((3-bromopyridin-2-yl)oxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)imidazo [1,2-a]pyridine-6-carboxamide (±) (product of step 7 of Example 1, 0.420 g, 0.980 mmol). The resulting crude product was purified using preparative HPLC to obtain the title compound (0.191 g, 43% W / W) as a white solid. LCMS: m / z 447.1[M+H] + ; HPLC: 94.33%; 1 H NMR (400MHz, chloroform-d) δ9.06-8.90 (d, J = 1.7Hz, 1H), 8.63-8.44 (d, J = 2.5Hz, 1H), 8.31-8.07 (m, 2H), 8.05- 7.88(td, J=8.0, 7.5, 2.6Hz, 1H), 7.82-7.60(m, 5H), 7.15-6.97(m, 2H), 5.15-4.98(m, 1H), 4.76-4.61(dd, J =12.0, 2.6Hz, 1H), 4.52-4.41(dd, J=16.9, 5.8Hz, 1H), 4.39-4.25(m, 2H), 3.35-3.19(m, 1H), 3.10-2.99(dd, J = 17.4, 6.6 Hz, 1H). Preparative HPLC method: Liquid chro...

Embodiment 3

[0255] Example 3: N-((5-(((6'-fluoro-[3,3'-bipyridyl]-4-yl)oxy)methyl)-4,5-dihydroisoxazole-3 -yl)methyl)imidazo[1,2-a]pyridine-6-carboxamide (±).

[0256] Step 1: 4-(allyloxy)-3-iodopyridine.

[0257]

[0258] At reflux temperature, 3-iodo-4-hydroxypyridine (0.500g, 2.250mmol) was mixed with allyl bromide (0.409g, 3.380mmol), potassium carbonate (0.780g, 5.630mmol) and potassium iodide in acetone (20mL) (0.016 g, 0.100 mmol) reacted for 2 hours. The reaction mixture was then cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate=90 / 10) to obtain the target compound (0.400 g, 67%) as a solid. LCMS: m / z261.9[M+1] + ; 1 H NMR (300MHz, DMSO-d 6)δ7.86-7.85(d, J=2.4Hz, 1H), 7.31-7.28(m, 1H), 6.41-6.38(d, J=7.2Hz, 1H), 5.97-5.86(m, 1H), 5.43 -5.40 (dd, J=9.6, 1.5 Hz, 1H), 5.29-5.25 (dd, J=10.8, 1.0 Hz, 1H), 4.40-4.38 (m, 2H).

[0259] Step 2: tert...

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Abstract

The invention discloses 4,5-dihydroisoxazole derivatives as NAMPT inhibitors. The present invention provides 4,5-dihydroisoxazole derivatives of formula (I) (as shown in the description), which may be therapeutically useful, more particularly as NAMPT inhibitors, wherein, ring A, L1, L2, X1, X2, X3, Z, R1, R2, R3, R4, R5, m, n, p and q have the meanings given in the specification and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention of diseases or disorder, caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPT) in a mammal. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of the substituted 4,5-dihydroisoxazole derivatives of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

Description

[0001] This application claims the benefit of Indian Completed Application 3604 / CHE / 2014, filed 23 July 2014, the contents of which are hereby incorporated by reference. [0002] field of invention [0003] The present invention relates to compounds for the treatment of nicotinamide phosphoribosyltransferase (NAMPT)-related cancers and inflammatory diseases, especially compounds for regulating the function of NAMPT. The invention also provides pharmaceutically acceptable compositions comprising compounds of the invention and methods of using said compositions to treat diseases and / or conditions associated with NAMPT modulation. [0004] Background of the invention [0005] NAD + (Nicotinamide adenine dinucleotide) is a coenzyme that plays a key role in many fundamental physiological processes (Ziegler, M. Eur. J. Biochem. 267, 1550-1564, 2000). NAD + Essential for several signaling pathway processes, including poly ADP ribosylation in DNA repair, mono ADP ribosylation in imm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14C07D471/04A61K31/437A61P35/00
CPCC07D413/14C07D471/04A61K31/444A61K31/501A61P1/04A61P11/00A61P11/06A61P11/16A61P13/12A61P17/00A61P17/02A61P17/06A61P19/02A61P19/04A61P19/10A61P25/00A61P25/28A61P29/00A61P3/00A61P31/14A61P31/18A61P31/22A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P9/00A61P9/10A61P9/14A61P3/10A61K45/06
Inventor 迪奈什·奇坎纳维纳亚克·克海尔纳
Owner AURIGENE DISCOVERY TECH
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