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Heteroaryl substituted nicotinamide compounds

A technology of compounds and substituents, applied in the field of nicotinamide compounds, can solve problems such as signal transduction loss

Active Publication Date: 2016-10-26
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Conversely, IRAK1 (Thomas, J.A. et al., J. Immunol., 163:978-984 (1999); Swantek, J.L. et al., J. Immunol., 164:4301-4306 (2000)) or IRAK2 (Wan, Deletion of Y. et al., J. Biol. Chem., 284:10367-10375 (2009)) results in partial loss of signaling

Method used

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  • Heteroaryl substituted nicotinamide compounds
  • Heteroaryl substituted nicotinamide compounds
  • Heteroaryl substituted nicotinamide compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 133

[0405] Molecule / asymmetric unit of Example 133: 2

[0406]

[0407] Density (calculated) = 1.308g / cm 3 ,

[0408] wherein the unit cell parameters of Form N-1 are measured at a temperature of about 296K.

[0409] In another embodiment, the N-1 form of Example 133 is characterized as being substantially the same as figure 1 Simulated powder X-ray diffraction (PXRD) pattern consistent with the pattern shown.

[0410]In another embodiment, Form N-1 of Example 133 is characterized by fractional atomic coordinates substantially as set forth in Table 2.

[0411] Table 2

[0412] Fractional Atomic Coordinates Calculated at 296K for Form N-1 of Example 133

[0413] Atomic coordinates (×10 4 )

[0414] atom

X

Y

Z

atom

X

Y

Z

N(3)

6597

7363

4376

C(4)

6728

10155

3329

N(6)

6232

-333

7366

C(5)

5892

8650

2862

N(2)

5802

7040

3471

C(3)

7161

12160

3061

...

Embodiment 1

[0708] (R)-6-(5-cyano-1H-indol-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotine Amide

[0709]

[0710] Step 1: To a solution of ethyl 4,6-dichloronicotinate (10 g, 45 mmol) in DMA (40 mL) was added propan-2-amine (5.3 g, 91 mmol) and DIPEA (31.7 mL, 182 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with MTBE and extracted with water (3x). The organic layer was washed with Na 2 SO 4 Dry, filter and concentrate to give crude product. The product was purified by flash chromatography over silica gel (10% EtOAc:petroleum ether as eluent) to afford ethyl 6-chloro-4-(isopropylamino)nicotinate (8.3 g, 75% yield) as a crystalline solid. LCMS m / z 243.7 (M+H); 1 H NMR (400MHz, DMSO-d 6 )δ8.54(s,1H),7.98(d,J=7.6Hz,1H),6.85(s,1H),4.29(q,J=7.2Hz,2H),3.86(m,1H),1.32( d, J=6.8Hz, 3H), 1.20(s, 3H), 1.19(s, 3H).

[0711]

[0712] Step 2: To a solution of ethyl 6-chloro-4-(isopropylamino)nicotinate (7 g...

Embodiment 1

[0716] To (R)-6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide (100mg, 0.315mmol) and 1H-indole- To a solution of 5-carbonitrile (44.7 mg, 0.315 mmol) in 1,4-dioxane (5 mL) was added Cs 2 CO 3 (308mg, 0.944mmol) and Xantphos (72.8mg, 0.126mmol). Fill the reaction vessel with N 2 Purge for 20min, then add Pd 2 (dba) 3 (115 mg, 0.126 mmol) and purged again for 5 min. The vessel was heated at 110° C. in a sealed tube for 18 h. The reaction mixture was cooled to room temperature, via Filter and dilute with EtOAc (50 mL). The crude mixture was washed with water (10 mL) and brine (10 mL), then washed with Na 2 SO 4 dry. Concentration of the filtered solution gave crude compound, which was purified via silica gel chromatography (50% EtOAc in hexanes) to afford (R)-6-(5-cyano-1H-indol-1-yl)- N-(2-Fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide (20 mg, 15% yield). LCMS 424.2(M+H) + ; 1 H-NMR (400MHz, DMSO-d 6 )δ8.75(t, J=5.60Hz...

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Abstract

Disclosed are compounds of Formula (I) or salts thereof, wherein: HET is a heteroaryl selected from pyrazolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, imidazo[4,5-b] pyridinyl, and purinyl, wherein said heteroaryl is substituted with Ra and Rb; and R1 and R2 are define herein. Also disclosed are methods of using such compounds as modulators of IRAK4, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Application 61 / 923,403, filed January 3, 2014, which is hereby incorporated in its entirety. technical field [0003] The present application relates generally to heteroaryl-substituted nicotinamide compounds useful as kinase inhibitors, including modulation of IRAK-4. The present application provides heteroaryl-substituted nicotinamide compounds, compositions comprising such compounds, and methods of use thereof. The present application also relates to pharmaceutical compositions comprising at least one compound of the present application and methods of inhibiting the activity of kinases, including IRAK-4, in mammals useful for the treatment of disorders associated with kinase modulation. Background technique [0004] Members of the Toll / IL-1 receptor family are important regulators of inflammation and host resistance. The Toll-like receptor (TLR) family recognizes molecular...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D401/04C07D471/04C07D487/04C07D473/00A61P37/00A61P29/00A61K31/455A61K31/437A61K31/519A61K31/52
CPCC07D401/04C07D401/14C07D471/04C07D487/04C07D519/00A61P1/04A61P11/00A61P11/06A61P13/12A61P17/00A61P17/06A61P19/02A61P19/06A61P25/00A61P25/02A61P25/04A61P29/00A61P37/00A61P37/02A61P37/06A61P43/00A61K31/437A61K31/455A61K31/519A61K31/52A61K31/66C07F9/65616
Inventor J·B·圣泰拉S·R·库马尔J·V·邓西亚D·S·加德纳V·R·佩蒂S·K·奈尔J·海因斯吴红N·穆鲁格桑K·萨尔库南P·阿鲁纳恰拉姆
Owner BRISTOL MYERS SQUIBB CO
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