An irak4 kinase inhibitor

Abstract

The application discloses a novel IRAK4 inhibitor compound shown in formula (I) and use of the compound for preventing or treating IRAK4-mediated diseases, which include but are not limited to rheumatoid arthritis, lupus erythematosus and other autoimmune diseases, activated B-cell-like diffuse large B-cell lymphoma, chronic lymphocytic leukemia, relapsed non-Hodgkin's lymphoma and other lymphomas.

Description

Technical Field

[0001] This invention relates to a novel IRAK4 inhibitor compound and the use of the compound for the prevention or treatment of IRAK4-mediated diseases. Background Technology

[0002] Chronic inflammatory diseases and autoimmune diseases threaten the lives of millions of people worldwide, and these diseases are associated with abnormal inflammation-mediated signaling. In addition, some diseases, such as type 2 diabetes and cardiovascular disease, are also related to abnormal inflammation-mediated signaling.

[0003] Interleukin-1 receptor-associated kinase 4 (IRAK4) is a member of the intracellular serine-threonine kinase family, the IRAK family. Other members of this kinase family include IRAK2, IRAK-M, and IRAK3. IRAK4 mediates signal transduction and activates the expression of downstream inflammatory factors after the interleukin-1 receptor (IL-1R) or Toll-like receptor (TLR) binds to its ligand. The TLR receives ligand signals from interactions with microorganisms or endogenous stimuli, as well as the initial wave of inflammatory signals and innate immune responses triggered by these stimuli. The TLR plays a crucial role in many diseases, including infectious and autoinflammatory diseases, and many other human diseases. Like tumor necrosis factor-α (TNF-α) and other major cytokines, interleukin-1 (IL-1) is a key factor in inflammatory pathways, capable of propagating and amplifying signals. Because TLR, IL-1R and other cytokine receptor-mediated signaling pathways are cross-linked, IRAK4, a key downstream signaling factor of the TLR and IL-1R inflammatory pathway, plays a significant role in systemic inflammatory responses and can serve as an effective potential target for the treatment of various inflammation-related diseases. Summary of the Invention

[0004] This invention provides a novel class of IRAK4 inhibitor compounds, their uses, and pharmaceutical compositions containing them. These compounds exhibit superior inhibitory effects on IRAK4 kinase.

[0005] This invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0006]

[0007] Wherein, R1 is H or a halogen, and R2 is H or -NH2.

[0008] The compound represented by formula (I) or its pharmaceutically acceptable salt may be one of the following compounds:

[0009]

[0010] This invention also provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof in the preparation of IRAK4 inhibitors.

[0011] The present invention also provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for the prevention or treatment of diseases mediated by abnormal expression of IRAK4.

[0012] The “diseases mediated by abnormal IRAK4 expression” include, but are not limited to, autoimmune diseases such as rheumatoid arthritis and lupus erythematosus, activated B-cell-like diffuse large B-cell lymphoma, chronic lymphocytic leukemia, relapsed non-Hodgkin lymphoma and other lymphomas.

[0013] The present invention also provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0014] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of the compounds of the present invention.

[0015] As used herein, the term “pharmaceutical acceptable” means that the substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or mammals treated with it.

[0016] Certain compounds in this invention have chiral carbon atoms, double bonds, carbocyclic rings, or heterocyclic rings, and the resulting configurational isomers {optical isomers (e.g., enantiomers, diastereomers, etc.), cis-trans isomers, etc.} and mixtures thereof (e.g., racemic mixtures) are all within the scope of protection of this invention. When certain compounds in this invention specify a particular configuration, it means that the configurational isomer is present and there are substantially no other isomers.

[0017] As used herein, the term "inhibitor" refers to a molecule that reduces, blocks, prevents, delays activation, inactivates, desensitizes, or downregulates, for example, genes, proteins, ligands, receptors, or cells.

[0018] As used in this article, the term “IRAK4 aberrant expression” refers to an increase in IRAK4 activity caused by IRAK4 signaling. Detailed Implementation

[0019] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0020] Example 1

[0021]

[0022] To a solution of 2,6-dichloro-4-methylnicotinonitrile (5000 mg, 26.73 mmol) in isopropanol (50 mL), N,N-dimethylformamide dimethyl acetal (3.55 mL, 26.73 mmol) was added. The reaction mixture was heated to 65 °C and stirred for 18 hours, then cooled to room temperature. The mixture was filtered, and the filter cake was washed with isopropanol (20 mL) and dried to give 0004A (2200 mg, 33%). LCMS(ESI)[M+H] + =242 (LC-MS method A).

[0023] A mixture of 0004A (2200 mg, 9.1 mmol) and concentrated hydrochloric acid (5 mL) was heated to 45 °C and stirred for 18 hours. The reaction mixture was then poured into ice water, resulting in the precipitation of a solid. This solid was filtered and dried to obtain 0004B (1000 mg, 62%). LCMS(ESI)[M+H] + =215.0@1.58min (LC-MS method A).

[0024] 0004B (800 mg, 3.74 mmol) was dissolved in isopropanol (10 mL). The reaction solution was cooled to 0 °C, and hydrazine monohydrate (1869 mg, 37.4 mmol) was added. The mixture was then heated to 55 °C and stirred overnight. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with methanol (5 mL) and dried to obtain 0004C (300 mg, 38%). LCMS(ESI)[M+H] + =211(LC-MS method A).

[0025] Add sodium hydroxide solution (7.1 mL, 1 mol / L, 7.14 mmol) to a 40 mL solution of 0004C (600 mg, 2.86 mmol), then add water (10 mL). Heat the reaction mixture to 55 °C and stir until the solution becomes clear. Cool the reaction mixture to 0 °C, slowly add 7% sodium hypochlorite solution (532 mg, 7.14 mmol), and stir overnight at room temperature. Cool the reaction mixture to 0 °C, adjust the pH to 6 with 1 mol / L hydrochloric acid solution, extract with ethyl acetate (50 mL × 2), wash the organic phase with water (20 mL × 3) and saturated brine (20 mL), dry to anhydrous sodium sulfate, filter and concentrate to obtain 0004D (130 mg, 25%), which can be used directly in the next reaction without purification. LCMS(ESI)[M+H] + =181.1@1.24min (LC-MS method A).

[0026] 0004D (130 mg, 0.72 mmol) was dissolved in phosphorus oxychloride (10 mL), and the reaction mixture was heated to 105 °C and stirred for 18 hours. The reaction mixture was concentrated, and saturated sodium bicarbonate solution (10 mL) was added with stirring. Extraction was performed with ethyl acetate (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid chromatography (ethyl acetate / petroleum ether = 0-35%) to give 0004E (40 mg, 28%). LCMS (ESI) [M+H] + =199.0@1.809min (LC-MS method A).

[0027] To a solution of 0003B (40 mg, 0.248 mmol) in N,N-dimethylformamide (5 mL), 0004E (49 mg, 0.248 mmol) and cesium carbonate (161 mg, 0.496 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then poured into water and extracted with ethyl acetate (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was plated using rapid chromatography (ethyl acetate / petroleum ether = 1 / 1) to give 0004F (30 mg, 38%). LCMS (ESI) [M+H] + =324.1@1.617min (LC-MS method A).

[0028] To a solution of 0004F (30 mg, 0.093 mmol) in N,N-dimethylacetamide (3 mL), tris(dibenzylacetone)dipalladium (0) (8.5 mg, 0.0093 mmol), 1,1'-bis(diphenylphosphine)ferrocene (10 mg, 0.0186 mmol), zinc powder (1.2 mg, 0.0186 mmol), and zinc cyanide (22 mg, 0.186 mmol) were added. The reaction mixture was microwaved to 150 °C and stirred for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated. The residue was purified by preparative chromatography using a rapid chromatography plate (ethyl acetate / petroleum ether = 1 / 1) to give 0004G (25 mg, 86%) LCMS (ESI) [M+H]. + =315.1@1.537min (LC-MS method A).

[0029] Potassium carbonate (22 mg, 0.1592 mmol) was added to a 1 mL solution of dimethyl sulfoxide (DMSO) containing 0004 G (25 mg, 0.0796 mmol). The reaction mixture was stirred at room temperature for 1 minute, then hydrogen peroxide solution (0.5 mL) was added, and the reaction was continued to be stirred at room temperature for 10 minutes. The mixture was purified by high-performance reversed-phase column chromatography (Column Xbridge 21.2*250 mm C18, 10 μm, mobile phase A: water (10 mmol / L ammonium bicarbonate), B: acetonitrile) to obtain SB-0004 (24 mg, 90%) as a white solid. LCMS (ESI) [M+H] + =333.1@6.131min(LC-MS method C)1HNMR(400MHz,DMSO-d6)δ9.673(s,1H),8.914( s,1H),8.490(s,1H),8.359(s,1H),8.296(d,J=6.0Hz,1H),7.867(s,1H),7.62 4(d,J=6.4Hz,1H),4.946(d,J=6.0Hz,0.5H),4.813(d,J=5.6Hz,0.5H),4.620( m,1H),4.296(m,1H),4.119(m,1H),2.663(m,1H),1.562(m,2H),1.002(t,3H).

[0030] Example 2

[0031]

[0032] A solution of 0004B (400 mg, 1.87 mmol) in 10 mL of phosphorus oxychloride was heated to 105 °C and stirred for 18 hours. The reaction solution was concentrated. A saturated sodium bicarbonate solution (20 mL) was added and stirred, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid chromatography (ethyl acetate / petroleum ether = 0-10%) to give 0005A (130 mg, 30%). LCMS (ESI) [M+H] + =233 (LC-MS method A).

[0033] A mixture of 0005A (300 mg, 1.29 mmol) and ammonia (7 N methanol solution, 3 mL) was microwaved to 100 °C for 0.5 h. The reaction solution was concentrated, and the residue was purified by rapid chromatography (ethyl acetate / petroleum ether = 0-10%) to give 0005B (130 mg, 48%). LCMS (ESI) [M+H] + =214.0@1.684min (LC-MS method A).

[0034] A solution of 0003B (55 mg, 0.34 mmol), 0005B (72 mg, 0.34 mmol), and cesium carbonate (221 mg, 0.68 mmol) in N,N-dimethylformamide (3 mL) was heated to 70 °C and stirred for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative-TLC (petroleum ether / ethyl acetate = 1 / 1) to give 0005C (60 mg, 52%, white solid). LCMS (ESI) [M+H] + =339.1@1.72min (LC-MS method A).

[0035] 0005C (60 mg, 0.177 mmol), tris(dibenzylacetone)dipalladium(O) (16 mg, 0.0177 mmol), 1,1'-bis(diphenylphosphine)ferrocene (20 mg, 0.0355 mmol), zinc powder (2 mg, 0.0355 mmol), and zinc cyanide (41 mg, 0.355 mmol) were mixed in N,N-dimethylacetamide (4 mL) and microwaved to 150 °C for 1.5 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative-TLC (petroleum ether / ethyl acetate = 1 / 1) to give 0005D (40 mg, 68%, white solid). LCMS (ESI) [M+H] + =330.1@1.54min (LC-MS method A).

[0036] A solution of 0005D (40 mg, 0.121 mmol) and potassium carbonate (33 mg, 0.243 mmol) in dimethyl sulfoxide (1 mL) was stirred at room temperature for 1 minute, followed by the addition of hydrogen peroxide (0.5 mL). The resulting mixture was stirred at room temperature for 10 minutes. The reaction solution was purified by high-performance reversed-phase column chromatography (Column Xbridge 21.2*250 mm C18, 10 μm, mobile phase A: water (10 mmol / L ammonium bicarbonate), B: acetonitrile) to obtain SB-0005 (24 mg, 57%, white solid). LCMS (ESI) [M+H] + =348.1@5.12min (LC-MS method C); 1H NMR(400MHz,DMSO-d6)δ8.925(s,1H),8.094(d,J=5.6Hz,1H),7.797(d,J=2 .8Hz,1H),7.657(d,J=2.4Hz,1H),7.492(s,1H),7.337(d,J=5.6Hz,1H),7. 155(s,2H),4.919(d,J=5.2Hz,0.5H),4.786(d,J=5.2Hz,0.5H),4.597(m,1 H),4.388(m,1H),4.147(m,1H),2.541(m,1H),1.539(m,2H),0.988(t,3H).

[0037] Example 3

[0038]

[0039] A solution of (7R)-7-ethyl-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(1H)-one (100 mg, 0.21 mmol) and 4-toluenesulfonic acid (115 mg, 0.601 mmol) in acetonitrile (3 mL) was heated to 90 °C and reacted for 2 hours. The reaction solution was concentrated, and the residue was purified by rapid chromatography (methanol / dichloromethane = 0-10%) to give 0008A (50 mg, 64%). LCMS (ESI) [M+H] + =144.1@1.26min (LC-MS method A).

[0040] A solution of 0008A (43 mg, 0.303 mmol), 0004E (60 mg, 0.303 mmol), and cesium carbonate (197 mg, 0.606 mmol) in N,N-dimethylformamide (3 mL) was heated to 50 °C and stirred for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative-TLC (petroleum ether / ethyl acetate = 1 / 1) to give 0008B (20 mg, 22%, white solid). LCMS (ESI) [M+H] + =306.1@1.629min (LC-MS method B).

[0041] 0008B (30 mg, 0.1 mmol), tris(dibenzylacetone)dipalladium(O) (10 mg, 0.01 mmol), 1,1'-bis(diphenylphosphine)ferrocene (10 mg, 0.02 mmol), zinc powder (10 mg, 0.02 mmol), and zinc cyanide (30 mg, 0.2 mmol) were mixed in N,N-dimethylacetamide (2 mL) and microwaved to 150 °C for 1.5 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative-TLC (petroleum ether / ethyl acetate = 1 / 1) to give 0008C (6 mg, 22%, white solid). LCMS (ESI) [M+H] + =297.1@1.50min (LC-MS method B).

[0042] A solution of 0008C (6 mg, 0.02 mmol) and potassium carbonate (6 mg, 0.02 mmol) in dimethyl sulfoxide (1 mL) was stirred at room temperature for 1 minute, followed by the addition of hydrogen peroxide (30% aqueous solution, 0.5 mL). The resulting reaction solution was stirred at room temperature for 10 minutes. The reaction solution was purified by high-performance reversed-phase column chromatography (Column Xbridge 21.2*250 mm C18, 10 μm, mobile phase A: water (10 mmol / L ammonium bicarbonate), B: acetonitrile) to obtain SB-0008 (4 mg, 64%, white solid). LCMS (ESI) [M+H] + =315.1@5.30min (Method D); 1 H NMR (400MHz, DMSO-d6) δ9.553(s,1H),8.498(s,1H),8.369(s,1H),8.303(d,J=6.0Hz,1H),8.075(s,1H),7.868(s,1H),7.628(d,J=6.0H z,1H),4.559(m,1H),4.449(m,1H),3.993(m,1H),2.231(m,1H),2.099(m,1H),1.589(m,1H),1.357(m,1H),1.233(s,1H),0.932(t,3H).

[0043] Example 4

[0044]

[0045] A solution of 0008A (47 mg, 0.328 mmol), 0005B (70 mg, 0.328 mmol), and cesium carbonate (213 mg, 0.656 mmol) in N,N-dimethylformamide (2 mL) was heated to 50 °C and stirred for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative-TLC (petroleum ether / ethyl acetate = 1 / 1) to give 0009A (22 mg, 21%, white solid). LCMS (ESI) [M+H] + =321.1@1.575min (LC-MS method A).

[0046] 0009A (22 mg, 0.0687 mmol), tris(dibenzylacetone)dipalladium(O) (6 mg, 0.0069 mmol), 1,1'-bis(diphenylphosphine)ferrocene (7 mg, 0.0137 mmol), zinc powder (1 mg, 0.0137 mmol), and zinc cyanide (16 mg, 0.137 mmol) were mixed in N,N-dimethylformamide (2 mL) and microwaved to 150 °C for two hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative-TLC (petroleum ether / ethyl acetate = 1 / 1) to give 0009B (18 mg, 85%, white solid). LCMS (ESI) [M+H] + =312.1@1.287min (LC-MS method A).

[0047] A solution of 0009B (18 mg, 0.0578 mmol) and potassium carbonate (16 mg, 0.1157 mmol) in dimethyl sulfoxide (1 mL) was stirred at room temperature for 1 minute. Then, hydrogen peroxide (0.5 mL) was added, and the resulting mixture was stirred at room temperature for 10 minutes. The reaction solution was purified by preparative-HPLC (column: Xbridge 21.2*250 mm C18, 10 μm; mobile phase: A: water (10 mM ammonium bicarbonate), B: acetonitrile) to obtain SB-0009 (6 mg, 31%, white solid). LCMS (ESI) [M+H] + =330.2@5.913min (LC-MS method E) 1H NMR(400MHz,DMSO-d6)δ8.086(m,2H),7.808(s,1H),7.651(s,1H),7.499(s,1H),7.336(d,J=5.2Hz,1H),7.13 6(s,1H),4.517(m,2H),4.049(m,1H),2.199(m,1H),2.038(m,1H),1.551(m,1H),1.234(s,1H),0.887(t,3H).

[0048] Analytical methods are attached.

[0049] 1 H NMR and 19 F NMR spectra were detected on a Bruker AVⅢ400.

[0050] LCMS was performed on an Agilent 1200HPLC / 6100SQ system under the following conditions:

[0051] Method A: Mobile phase: A: Water (0.01% TFA), B: Acetonitrile (0.01% TFA); Gradient phase: 5% B increased to 95% B within 1.4 min, 95% B with 1.6 min (total run time: 3 min); Flow rate: 2.3 mL / min; Column type: SunFire C18, 4.6*50 mm, 3.5 μm; Column temperature: 50℃. Detectors: ADC ELSD, DAD (214 nm and 254 nm), ES-API.

[0052] Method B: Mobile phase: A: Water (10mM NH4HCO3) B: Acetonitrile; Gradient phase: 10% to 95% B within 1.5 min, 95% B with 1.5 min (total run time: 3 min); Flow rate: 1.8 mL / min; Column type: XBridge C18, 4.6*50 mm, 3.5 μm; Column temperature: 50℃. Detectors: ADC ELSD, DAD (214 nm and 254 nm), MSD (ES-API).

[0053] Method C: Mobile phase: A: Water (0.01% TFA), B: Acetonitrile (0.01% TFA); Gradient phase: 5% B increased to 95% B within 1.2 min, 95% B with 13.8 min (total run time: 15 min); Flow rate: 2 mL / min; Column type: SunFire C18, 4.6*50 mm, 3.5 μm; Column temperature: 50 °C; Detector: UV (214 nm and 4 nm), MS (ESI, Posmode, 132 to 1500 amu).

[0054] Method D: Mobile phase: A: Water (10mM NH4HCO3) B: Acetonitrile; Gradient phase: 10% to 95% B within 8 min, 95% B with 7 min (total run time: 15 min); Flow rate: 1 mL / min; Column type: XBridge C18, 4.6*50 mm, 3.5 μm; Column temperature: 40℃. Detector: UV (214 nm and 4 nm), MS (ESI, Pos mode, 132 to 1500 amu).

[0055] Method E: Mobile phase: A: Water (0.01% TFA) B: Acetonitrile (0.01% TFA); Gradient phase: 5% B increased to 95% B within 1.2 min, 95% B for 1.8 min, back to 5% B within 0.01 min. (Total run time: 15 min); Flow rate: 2 mL / min; Column type: SunFire C18, 4.6*50 mm, 3.5 μm; Column temperature: 40℃. Detector: UV (214 nm and 4 nm), MS (ESI, Pos mode, 132 to 1500 amu).

[0056] Effect Example: Detection of IRAK4 kinase activity inhibition

[0057] Detection of IC50 of IRAK4 kinase 50 Values ​​were determined. Staurosporine was used as a positive control compound. This experiment employed a mobility shift assay to screen compounds on the IRAK4 kinase.

[0058] Preparation of compound concentration gradients: The test compound was initially diluted 10 μM, 4-fold, to obtain 10 concentrations, with replicates for each well. Ten solutions of different final concentrations (100-fold final concentration) were serially diluted in a 384-well plate. 250 nmol of each solution was then transferred to a 384-well plate using a pipette system (Labcyte, Echo 550). 250 nmol of 100% DMSO was added to each negative and positive control well. A 2.5-fold final concentration of kinase (Carna, 09-145) was prepared using kinase buffer (prepared by Sandia Pharmaceuticals (Shanghai) Co., Ltd.). 10 μL of the 2.5-fold final concentration kinase solution was added to each compound well and positive control well (Staurosporine, Selleckchem, S1421); 10 μL of kinase buffer was added to each negative control well. The plates were centrifuged at 1000 rpm for 30 seconds, vortexed to mix, and incubated at room temperature for 10 minutes. Prepare a 25 / 15 final concentration mixture of ATP (Sigma, A2383) and substrate (Kinase substrate 8, GL, 112396) using kinase buffer. Add 15 μL of the 25 / 15 final concentration mixture to initiate the reaction. Centrifuge the 384-well plate at 1000 rpm for 30 seconds, vortex to mix, and incubate at room temperature for the appropriate time. Add 30 μL of stop assay solution (prepared by Sandia Pharmaceuticals Technology (Shanghai) Co., Ltd.) to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and vortex to mix. Read the conversion rate using a microplate reader (Caliper EZ Reader II).

[0059] Data Analysis:

[0060] Calculation formula:

[0061]

[0062] %Inhibition is the inhibition rate; Conversion%_sample is the conversion rate reading of the sample.

[0063] Conversion%_min: Mean value of negative control wells, representing the conversion rate reading of wells without enzyme activity;

[0064] Conversion%_max: The average ratio of positive control wells, representing the conversion reading of wells without compound inhibition.

[0065] Fitted dose-response curve:

[0066] Plotting the logarithm of concentration on the X-axis and the percentage inhibition rate on the Y-axis, dose-response curves were fitted using the log(inhibitor) vs. response-variable slope method in GraphPad Prism 5 to derive the IC50 values ​​of each compound on enzyme activity. 50 Value. The calculation formula is as follows: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)), and the results are shown in Table 1:

[0067] Table 1

[0068] Compound numbering <![CDATA[IC 50 (nM)]]> SB-0004 178 SB-0005 236 SB-0008 2301 SB-0009 964

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in, R1 is H or a halogen, and R2 is H or -NH2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

3. A pharmaceutical composition comprising the compound as described in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

4. Use of the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 3 in the preparation of an IRAK4 kinase inhibitor.

5. Use of the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 3 in the preparation of a medicament for the treatment of rheumatoid arthritis, lupus erythematosus, activated B-cell-like diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and relapsed non-Hodgkin lymphoma.

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