CN117209489A - IRAK kinase inhibitors - Google Patents

IRAK kinase inhibitors Download PDF

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Publication number
CN117209489A
CN117209489A CN202310620527.3A CN202310620527A CN117209489A CN 117209489 A CN117209489 A CN 117209489A CN 202310620527 A CN202310620527 A CN 202310620527A CN 117209489 A CN117209489 A CN 117209489A
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compound
pharmaceutically acceptable
deuterated
acceptable salt
stereoisomer
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卢建
卿亚丽
黄雪惠
任月英
宋娜
杨欣
温俏冬
诸葛定娟
郑鹛
殷建明
吕裕斌
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Hangzhou Bangshun Pharmaceutical Co ltd
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Hangzhou Bangshun Pharmaceutical Co ltd
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Abstract

The application discloses a compound with a structure shown in a formula I, deuterated compound, stereoisomer or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound and application of the compound. The compound provided by the application has good IRAK1/4 kinase inhibition effect, and is a novel IRAK1/4 inhibitor with high activity.

Description

IRAK kinase inhibitors
Technical Field
The application belongs to the field of pharmaceutical chemistry, and relates to an IRAK kinase inhibitor, a pharmaceutical composition, a preparation method and application thereof in preparing, preventing and/or treating medicaments related to IRAK signal channel indications.
Background
IRAK (Interleukin-1 receptor related kinase) is a class of serine-threonine protein kinases that are involved in IL-1R (Interleukin-1 type receptor) and Toll-like receptor (TLR) signaling, and IRAK-1, IRAK-2, IRAK-M and IRAK-4 have been found. Under actual physiological conditions, IRAK4 and MyD88 and IRAK2 are combined with each other through a common death region to form a protein complex Myddosome, the protein complex Myddosome plays a phosphorylation function, and further activation of downstream IRAK1 and related factors 6 (TRAF 6) is completed, so that two signal paths of downstream NF- κB and JNK are activated, related genes related to inflammation and cell proliferation are transcribed, and production of inflammatory cytokines is promoted. Meanwhile, IRAK1/4 signal complex is located at a key signal node, and can drive cancer cells to survive through various mechanisms.
Excessive activation of IRAK1/4, or abnormal activation due to mutations, can lead to the development and progression of inflammatory diseases and tumors. The inflammatory diseases include wind-like diseases, gout, fibrosis diseases, GVHD, SLE, IBD and the like, and the tumors include malignant hematopathy such as myelodysplastic syndrome (MDS), leukemia, lymphoma, various solid tumors and the like. Therefore, IRAK1/4 inhibitor is expected to be a medicament with good prospect in the fields of treatment of various inflammatory diseases and malignant tumors, but IRAK1/4 inhibitor with good effect is still lacking in the market at present.
Disclosure of Invention
In view of the above technical problem, an aspect of the present application provides a compound having a structure represented by general formula (I):
wherein:
ring a is an 8-10 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O, S;
the ring A is optionally substituted with 1-3R 2 Substitution;
the R is 2 Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups;
R 1 selected from C 1-6 Alkyl, C 1-6 A haloalkyl group.
In some preferred embodiments, the ring a is a 9 membered bicyclic heteroaryl containing 1-2 heteroatoms selected from N, O, S;
the ring A is optionally substituted with 1R 2 Substitution;
the R is 2 Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups;
R 1 selected from C 1-6 Alkyl, C 1-6 A haloalkyl group.
In some preferred embodiments, the ring a is selected from Preferably->
Further, the ring A is selected from Preferably->
In some more preferred embodiments, the ring a is selected fromFurther preferred is
In some preferred casesIn an embodiment of (2), said R 2 Selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, preferably F, cl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl;
the R is 1 Selected from C 1-3 Alkyl, C 1-3 Haloalkyl, preferably methyl, ethyl, n-propyl, isopropyl, trifluoromethyl.
In some more preferred embodiments, the R 2 Selected from F, methyl, trifluoromethyl, more preferably F, methyl;
the R is 1 Selected from methyl, ethyl, isopropyl, more preferably ethyl.
In still further accordance with certain embodiments of the present application, the compounds provided herein include any one of the following:
in another aspect, the present application provides a pharmaceutical composition comprising a compound according to any one of the preceding claims, a deuterated compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor.
In another aspect, the application also provides an application of the compound according to any one of the previous technical schemes, deuterated compound, stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to the previous technical scheme in preparing medicines for treating and/or preventing IRAK1 and/or IRAK4 related diseases.
In some preferred embodiments, the IRAK1 and/or IRAK4 related disease comprises an autoimmune disease, an inflammatory disorder, a cardiovascular disease, a neurodegenerative disorder, an allergic disorder, multiple organ failure, a kidney disease, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency, transplant rejection, lung injury, a respiratory disease, an ischemic condition, a bacterial infection, a viral infection, an immunomodulatory disorder, or a combination thereof.
The compound provided by the application creatively introduces a double-ring structure on a main ring structure, and has good IRAK1/4 kinase inhibition effect. Compared with the existing inhibitors such as R835 and the like, the compound has stronger inhibition activity, particularly better IRAK4 inhibition activity, strong drug effect, good drug substitution property and high bioavailability, and is a novel ideal IRAK1/4 inhibitor with high activity and low toxicity. The compounds of the application are useful for the treatment and/or prophylaxis of a range of diseases associated with IRAK1/4, such as autoimmune diseases, inflammatory disorders, cancer, transplantation, sperm motility, erythrocyte deficiency, transplant rejection, lung injury, respiratory diseases, ischemic disorders, bacterial infections, viral infections, and the like.
Detailed Description
Definition of the definition
As used herein, numerical intervals include endpoints and any numerical values between the endpoints. For example, "0-3" may include 0, 1, 2, or 3, and "1-3" may include 1, 2, or 3.
"C" as used herein 1-n "include C 1-2 、C 1-3 、……C 1-n . For example, "C 1-6 "group" means having 1 to 6 carbon atoms in the moiety, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. Thus, for example, "C 1-4 Alkyl "means an alkyl group containing 1 to 4 carbon atoms, i.e. the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Numerical ranges, such as "1-6" herein refer to individual integers in the given range.
The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched saturated aliphatic hydrocarbon. The "alkyl" group herein may preferably have 1 to 6 carbon atoms, for example, 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methylAnd (c) a group selected from the group consisting of a group consisting of l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-l-butyl, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl. In the radicals defined herein, where the number range appears as "alkyl", for example, "C 1-6 Alkyl "refers to an alkyl group that may be made up of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and alkyl groups herein also include those where no numerical range is specified. The alkyl group may be optionally substituted or unsubstituted.
"alkyl" as used herein in combination refers to an alkyl group attached to other groups, e.g., an alkyl group in an alkoxy group, as defined above when used alone.
The term "heteroaryl", as used herein, alone or in combination, refers to an 8 to 10 membered bicyclic heteroatom containing aromatic group wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, while the heteroaryl group also has one or more attachment points attached to the remainder of the molecule. Non-limiting examples of "bicyclic heteroaryl" groups include, but are not limited to: benzimidazolyl, benzofuranyl, benzothienyl, indolyl, oxoindolyl, indolinyl, imidazopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, and the like. Heteroaryl groups may be optionally substituted or unsubstituted.
The term "halogen" as used herein, alone or in combination, refers to fluorine, chlorine, bromine or iodine.
The term "(substituted) or" substituted with … … "as used herein means that one or more hydrogens on a particular atom are replaced with a specific group (e.g., halogen, alkyl, etc.), where the normal valence of the specified atom is not exceeded under the present circumstances, then the result is a stable compound.
The term "pharmaceutically acceptable salt" as used herein is well known to those skilled in the art.
The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
The term "pharmaceutical composition" as used herein refers to a biologically active compound optionally admixed with at least one pharmaceutically acceptable chemical ingredient including, but not limited to, carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents and/or excipients.
The term "carrier" as used herein refers to a relatively non-toxic chemical compound or agent that facilitates the introduction of the compound into a cell or tissue.
The term "stereoisomers" as used herein includes, but is not limited to, enantiomers.
The term "enantiomer" as used herein refers to a compound having the same formula, in which two compounds which are enantiomers are mirror images of each other and cannot coincide, due to isomerism caused by differences in the spatial configuration of atoms or groups of atoms (groups).
The compounds of the application may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present application, including but not limited to diastereomers, enantiomers, sterically hindered isomers and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present application.
The present application will be described in further detail with reference to the following examples, but the present application is not limited to the following examples.
The partial preparation conditions used in the examples are as follows:
preparation of Pre-HPLC conditions: instrument: GILSON-GX281; wavelength: 220nm&254nm; column model: waters X-bridge (30X 100mm,10 μm) or Luna C18 (30X 75mm,3 μm); mobile phase: a:10mM ammonium bicarbonate or H 2 O (0.1% formic acid) or H 2 O (0.1% trifluoroacetic acid), B: acetonitrile; run time: 15min; flow rate: 25mL/min.
Some intermediates of the present application are synthesized as follows:
intermediate 1:2- (1H-pyrazol-4-yl) thiazole-4-carboxylic acid
2-bromothiazole-4-carboxylic acid (1.36 g,6.53 mmol) and 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (3.80 g,19.58 mmol), sodium carbonate (2.08 g,19.58 mmol) and tetrakis (triphenylphosphine) palladium (150 mg,130.56 umol) were successively added to a mixed solvent of 1, 4-dioxabicyclo (10.8 mL) and water (2.7 mL) under nitrogen atmosphere at 20℃and the reaction solution was stirred at 60℃for 12 hours. The reaction solution was concentrated under reduced pressure to remove the solvent to give a crude product, water (50 mL) was added to the crude product and stirred for filtration, then 6M hydrochloric acid solution was added to the filtrate to adjust pH to 1-2, and white solid was precipitated, filtered, and the cake was dried in vacuo to give the title compound (1.00 g,5.12mmol, white solid), yield: 78.4%. MS (ESI) m/z 196.1[ M+H ]] + .
Example 1
N- (1- (trans-4-ethoxycyclohexyl) -3- (1H-indol-6-yl) -1H-pyrazol-4-yl) -2- (1H-pyrazol-4-yl) thiazole-4-carboxamide
(1) 8-ethoxy-1, 4-dioxaspiro [4.5] decane
1, 4-Dioxaspiro [4.5]]Decyl-8-ol (50.0 g,316 mmol) was added to tetrahydrofuran (500 mL) and the reaction temperature was lowered to 0deg.C. Sodium hydride (18.9 g, 470 mmol,60% purity) was added in portions to the reaction solution at this temperature, and stirred at 0℃for 1 hour. Then, ethyl iodide (73.9 g, 470 mmo) was added to the reaction mixture. After the addition was completed, the reaction was carried out at room temperature of 20℃for 2 hours. The reaction mixture was poured into an aqueous ammonium chloride solution (1.0L) and treated with ethyl acetate (0.5L)x 2) extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1 to 3/1) to give the title compound (34.0 g,182mmol, yellow oil), yield: 57.7%. 1 H NMR(400MHz,CDCl 3 )δ4.00-3.91(m,4H),3.50(q,J＝7.0Hz,2H),3.44-3.37(m,1H),1.88-1.80(m,4H),1.76-1.68(m,2H),1.61-1.52(m,2H),1.21(t,J＝7.0Hz,3H).
(2) 4-ethoxycyclohex-1-one
8-ethoxy-1, 4-dioxaspiro [4.5] at room temperature of 20deg.C]Decane (34.0 g,182 mmol) was added to dichloromethane (1.02L). Oxalic acid (65.7 g,730mmol,64.5 mL) was dissolved in water (0.85L) at this temperature, and then slowly dropped into the reaction solution. After the addition was completed, the temperature was raised to 35℃and the reaction was carried out for 48 hours. The reaction solution was cooled to room temperature, and then the organic phase and the aqueous phase were separated. The aqueous phase was extracted with dichloromethane (300 ml x 2), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give the title compound (26.0 g, yellow oil). 1 H NMR(400MHz,CDCl 3 )δ3.72(tt,J＝3.0,5.8Hz,1H),3.56(q,J＝7.0Hz,2H),2.63-2.53(m,2H),2.26(td,J＝14.4,6.1Hz,2H),2.07(qd,J＝12.8,6.2Hz,2H),2.00-1.89(m,2H),1.24(t,J＝7.0Hz,3H).
(3) 4-ethoxycyclohex-1-ol
4-ethoxycyclohex-1-one (26.0 g,182 mmol) was added to anhydrous methanol (260 mL), the reaction solution was cooled to 0deg.C, and sodium borohydride (13.8 g,365 mmol) was added slowly in portions at this temperature. After the addition, the temperature is raised to room temperature of 20 ℃ for reaction for 5 hours. The reaction mixture was quenched with ice water (500 mL) and extracted with ethyl acetate (100 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=3/1 to 1/1) to give the title compound (8.50 g,58.9mmol, colorless oil), yield: 32.2%.
(4) 4-ethoxycyclohexyl 4-methylbenzenesulfonate
4-ethoxycyclohex-1-ol (8.50 g,58.9 mmol) was added to chloroform (255 mL) and the reaction solution was cooled to 0 ℃. A mixture of p-toluenesulfonyl chloride (11.2 g,58.9 mmol) and pyridine (85 mL) was slowly added dropwise at this temperature. After the addition, the temperature was raised to room temperature of 20℃for reaction for 12 hours. Water (100 ml) was added to the reaction mixture, followed by liquid extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=3/1 to 1/1) to give the title compound (11.0 g,36.8mmol, white solid), yield: 62.5%.
(5) 3-bromo-1- (trans-4-ethoxycyclohexyl) -4-nitro-1H-pyrazole
4-ethoxycyclohexyl 4-methylbenzenesulfonate (4.97 g,16.6 mmol) and 3-bromo-4-nitro-1H-pyrazole (4.00 g,20.8 mmol) were added to N, N-dimethylformamide (49.7 mL) at 20℃at room temperature. Potassium carbonate (8.64 g,62.5 mmol) and 18-crown-6 (553mg, 2.08 mmol) were added. After the addition was completed, the reaction was heated to 100℃for 16 hours. After the reaction mixture was cooled to room temperature, water (60 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=3/1 to 1/1) to give the product 3-bromo-1- (4-ethoxycyclohexyl) -4-nitropyrazole (0.85 g,2.67mmol, yellow oil), yield: 12.8%.
(6) 6- (1- (trans-4-ethoxycyclohexyl) -4-nitro-1H-pyrazol-3-yl) -1H-indole
3-bromo-1- (trans-4-ethoxycyclohexyl) -4-nitro-1H-pyrazole (300 mg,942 umol), 6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indole (275 mg,1.13 mmol) and potassium carbonate (261 mg,1.89 mmol) were added to a mixed solvent of toluene (3.0 mL), ethanol (0.6 mL) and water (0.6 mL) at room temperature of 20 ℃. The system was replaced 3 times with nitrogen and 1, 1-bis (diphenylphosphine) ferrocene palladium chloride (69.0 mg,94.2 umol) was added under nitrogen. After the addition, the temperature was raised to 100℃for reaction for 12 hours. After the temperature was lowered to room temperature, the reaction solution was filtered. Water (10 mL) was then added to the filtrate, and the mixture was extracted with ethyl acetate (10 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate=1/1) to give the title compound (220 mg, yellow oil).
(7) 1- (trans-4-ethoxycyclohexyl) -3- (1H-indol-6-yl) -1H-pyrazol-4-amine
6- (1- (trans-4-ethoxycyclohexyl) -4-nitro-1H-pyrazol-3-yl) -1H-indole (220 mg,620 umol) was added to ethanol (2.2 mL). Raney nickel (182 mg,3.10 mmol) was added under nitrogen and replaced 3 times with hydrogen. The reaction mixture was stirred under hydrogen atmosphere at room temperature of 20 ℃ for 6 hours. The reaction solution was filtered through celite and concentrated to give the title compound (100 mg, colorless oil). MS (ESI) m/z 325.2[ M+H ]] + .
(8) N- (1- (trans-4-ethoxycyclohexyl) -3- (1H-indol-6-yl) -1H-pyrazol-4-yl) -2- (1H-pyrazol-4-yl) thiazole-4-carboxamide
1- (trans-4-ethoxycyclohexyl) -3- (1H-indol-6-yl) -1H-pyrazol-4-amine (90.0 mg,277 mol) and intermediate 1 (81.2 mg,416 mol) were added to dichloromethane (0.9 mL) and the temperature was reduced to 0 ℃. N, N-diisopropylethylamine (125 mg, 970umol) and HATU (116 mg,305 umol) were added to the reaction solution. After the addition was completed, the reaction was carried out at this temperature for 15 minutes and then allowed to warm to room temperature of 20℃for 12 hours. The reaction solution is filtered and concentrated to obtain crude products. The crude product was further purified by Prep-HPLC to give the title compound (26.8 mg,53.4umol, white solid), yield: 19.2%. MS (ESI) m/z 502.1[ M+H ]] + . 1 H NMR(400MHz,DMSO-d 6 )δ13.50-13.25(m,1H),11.23(brs,1H),9.68(s,1H),8.55-8.21(m,2H),8.18-7.99(m,2H),7.71(s,1H),7.64(d,J＝8.1Hz,1H),7.42-7.32(m,2H),6.47(brs,1H),4.30-4.20(m,1H),3.54-3.46(m,2H),3.41-3.35(m,1H),2.12(d,J＝10.8Hz,4H),1.96-1.83(m,2H),1.45-1.31(m,2H),1.13(t,J＝7.0Hz,3H).
Example 2
N- (3- (benzofuran-6-yl) -1- (trans-4-ethoxycyclohexyl) -1H-pyrazol-4-yl) -2- (1H-pyrazol-4-yl) thiazole-4-carboxamide
(1) 2- (benzofuran-6-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan
6-bromobenzofuran (1.90 g,9.64 mmol), pinacol biborate (3.67 g,14.4 mmol) and potassium phosphonate (6.14 g,28.9 mmol) were added to anhydrous acetonitrile (19 mL) at 20deg.C. Body1, 1-bis (diphenylphosphine) ferrocene palladium chloride (1.06 g,1.45 mmol) was added under nitrogen by 3-fold displacement with nitrogen. After the addition, the reaction solution was heated to 60℃and stirred for 16 hours. After the reaction mixture was cooled to room temperature, water (20 mL) was added and extracted with ethyl acetate (20 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1 to 3/1) to give the title compound (900 mg,3.69mmol, yellow oil), yield: 38.2%. 1 H NMR(400MHz,CDCl 3 )δ7.89(s,1H),7.62-7.58(m,2H),7.56-7.50(m,1H),6.72-6.67(m,1H),1.29(s,12H).
(2) 3- (benzofuran-6-yl) -1- (trans-4-ethoxycyclohexyl) -4-nitro-1H-pyrazole
Reference to the synthetic procedure of example 1, step 6, starting from 2- (benzofuran-6-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (138 mg, 560 mol) and 3-bromo-1- (trans-4-ethoxycyclohexyl) -4-nitro-1H-pyrazole (150 mg,471 mol), the title compound (120 mg,337 mol, yellow solid) was obtained in the yield: 71.6%. MS (ESI) M/z356.4[ M+H ]] + .
(3) 3- (benzofuran-6-yl) -1- (trans-4-ethoxycyclohexyl) -1H-pyrazol-4-amine
3- (benzofuran-6-yl) -1- (trans-4-ethoxycyclohexyl) -4-nitro-1H-pyrazole (110 mg, 309. Mu. Mol) and ammonium chloride (8238 mg,1.55 mmol) were added to a mixed solvent of ethanol (1.1 mL) and water (0.22 mL) at room temperature. Iron powder (399 mg,928 umol) was added to the reaction solution under nitrogen atmosphere, and the mixture was replaced with nitrogen gas 3 times. After the addition, the temperature was raised to 50℃for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to give the title compound (60 mg, yellow oil). MS (ESI) m/z 326.3[ M+H ]] + .
(4) N- (3- (benzofuran-6-yl) -1- (trans-4-ethoxycyclohexyl) -1H-pyrazol-4-yl) -2- (1H-pyrazol-4-yl) thiazole-4-carboxamide
Reference to the synthetic procedure of example 1, step 8, starting from 3- (benzofuran-6-yl) -1- (trans-4-ethoxycyclohexyl) -1H-pyrazol-4-amine (30.0 mg,92.1 mol) and intermediate 1 (27.0 mg,138 mol), gave the title compound (9.4 mg,18.7 mol, white solid), yield: 20.2%。MS(ESI):m/z 503.1[M+H] + .1H NMR(400MHz,CD 3 OD)δ8.26(brs,1H),8.21(s,1H),8.18(s,1H),8.06(d,J＝5.4Hz,1H),7.90-7.85(m,2H),7.76(d,J＝8.0Hz,1H),7.64(dd,J＝8.0,1.4Hz,1H),6.93(dd,J＝2.1,1.0Hz,1H),4.27(tt,J＝11.8,3.4Hz,1H),3.62(q,J＝7.0Hz,2H),3.47(tt,J＝10.8,3.7Hz,1H),2.26(d,J＝11.2Hz,4H),2.08-1.92(m,2H),1.56-1.43(m,2H),1.23(t,J＝7.0Hz,3H).
Example 3
N- (1- (trans-4-ethoxycyclohexyl) -3- (oxazolo [4,5-b ] pyridin-5-yl) -1H-pyrazol-4-yl) -2- (1H-pyrazol-4-yl) thiazole-4-carboxamide
(1) 5-Bromooxazolo [4,5-b ] pyridine
To 2-amino-6-bromo-pyridin-3-ol (4.50 g,23.81 mmol) was added trimethoxymethane (45 mL) at 20℃and the reaction was allowed to react at 105℃for 12 hours. The reaction solution was cooled to room temperature, and the solvent was removed by concentration under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate=100/1 to 10/1) to give the title compound (3.50 g,17.59mmol, white solid), yield: 73.8%. 1 H NMR(400MHz,DMSO-d 6 )δ9.12(s,1H),8.31-8.25(m,1H),7.81-7.68(m,1H).
(2) 5- (tributylstannyl) oxazolo [4,5-b ] pyridine
Under the protection of nitrogen at 20 ℃, 5-bromooxazolo [4,5-b ]]Pyridine (2.00 g,10.05 mmol), lithium chloride (2.56 g,60.30 mmol), tricyclohexylphosphine (281mg, 1.01 mmol), hexabutylditin (7.00 g,12.06 mmol) and tris (dibenzylideneacetone) dipalladium (460 mg,502.50 umol) were added sequentially to 1, 4-dioxane (20 mL), and the reaction was stirred at 50℃for 12 hours. The reaction was cooled, filtered through celite, the filter cake was washed with ethyl acetate (100 ml x 2) and the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (petroleum ether/ethyl acetate=100/1 to 10/1) to give the title compound (1.30 g,3.18mmol, brown solid), yield: 31.6%. MS (ESI) m/z 411.2[ M+H ]] + .
(3) 3-bromo-1- (trans-4-ethoxycyclohexyl) -1H-pyrazol-4-amine
To a mixed solution of 3-bromo-1- (trans-4-ethoxycyclohexyl) -4-nitro-1H-pyrazole (300 mg,942.90umol, example 1, step 5) in ethanol (2.4 mL) and water (0.3 mL) at 20℃were added iron powder (315 mg,5.66 mmol) and ammonium chloride (504 mg,9.43 mmol), and the reaction mixture was reacted at 70℃for 12 hours. The reaction solution was filtered, water (10 mL) and ethyl acetate (10 mL) were added to the filtrate to extract, and the organic phase was concentrated under reduced pressure to remove the solvent to give the title compound (220 mg,763.40umol, brown solid), yield: 80.9%. MS (ESI) m/z 288.2[ M+H ]] + .
(4) N- (3-bromo-1- (trans-4-ethoxycyclohexyl) -1H-pyrazol-4-yl) -2- (1H-pyrazol-4-yl) thiazole-4-carboxamide
Intermediate 1 (121 mg,624.60 umol) and HATU (356 mg,936.90 umol), N, N-diisopropylethylamine (201 mg,1.56 mmol), 3-bromo-1- (trans-4-ethoxycyclohexyl) -1H-pyrazol-4-amine (180 mg,624.60 umol) were added sequentially to dichloromethane (1.8 mL) at 20℃and the reaction stirred at 20℃for 3 hours. To the reaction mixture were added water (10 mL) and ethyl acetate (10 mL) for liquid extraction, and the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (petroleum ether/ethyl acetate=100/1 to 10/1) to give the title compound (160 mg,343.82umol, yellow solid), yield: 55.0%. MS (ESI): m/z 465.2[ M+H ]] + .
(5) N- (1- (trans-4-ethoxycyclohexyl) -3- (oxazolo [4,5-b ] pyridin-5-yl) -1H-pyrazol-4-yl) -2- (1H-pyrazol-4-yl) thiazole-4-carboxamide
To a solution of N- (3-bromo-1- (trans-4-ethoxycyclohexyl) -1H-pyrazol-4-yl) -2- (1H-pyrazol-4-yl) thiazole-4-carboxamide (160 mg, 343.82. Mu. Mol) in 1, 4-dioxane (1.6 mL) at 25℃was added 5- (tributylstannyl) oxazolo [4,5-b]Pyridine (211 mg, 515.72. Mu. Mol) and tetrakis (triphenylphosphine) palladium (39 mg, 34.38. Mu. Mol) were added under nitrogen, and the reaction solution was stirred at 120℃for 12 hours. The reaction solution was cooled to room temperature and then filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was further purified by Prep-HPLC to give the title compound (2 mg,3.77umol, white solid), yield: 1.1%. MS (ESI) m/z 505.1[ M+H ]] + .1H NMR(400MHz,CDCl 3 )δ12.28(s,1H),8.70-8.61(m,1H),8.41-8.35(m,2H),8.19-8.12(m,1H),7.99(s,1H),7.91(d,J＝8.6Hz,1H),4.20-4.07(m,1H),3.55-3.48(m,2H),3.38-3.26(m,1H),2.27-2.21(m,2H),2.20-2.14(m,2H),1.91-1.80(m,2H),1.41-1.37(m,2H),1.18(d,J＝6.9Hz,3H).
Example 4
N- (1- (trans-4-ethoxycyclohexyl) -3- (1H-indol-7-yl) -1H-pyrazol-4-yl) -2- (1H-pyrazol-4-yl) thiazole-4-carboxamide
(1) 7- (1- (trans-4-ethoxycyclohexyl) -4-nitro-1H-pyrazol-3-yl) -1H-indole
3-bromo-1- (trans-4-ethoxycyclohexyl) -4-nitro-1H-pyrazole (200 mg, 628.60. Mu. Mol, example 1, step 5), (1H-indol-7-yl) boronic acid (183.38 mg, 754.32. Mu. Mol), potassium carbonate (173.76 mg,1.26 mmol) and 1, 1-bis (diphenylphosphine) ferrocene palladium chloride (46.00 mg, 62.86. Mu. Mol) were added sequentially to a mixed solvent of water (0.4 mL)/ethanol (0.4 mL)/toluene (2 mL) under nitrogen protection at 20 ℃. The reaction solution was replaced with nitrogen gas 3 times, heated to 100℃and stirred for 13 hours. The reaction solution was cooled to room temperature and then filtered, and the filtrate was concentrated to give a crude product. The crude product was further purified by Prep-HPLC to give the title compound (170 mg,479.68umol, brown solid), yield: 76.3%. MS (ESI) m/z 355.2[ M+H ]] + .1H NMR(400MHz,CDCl 3 )δ9.45(brs,1H),8.26(s,1H),7.87(d,J＝7.5Hz,1H),7.66(d,J＝7.9Hz,1H),7.22(t,J＝2.7Hz,1H),7.14(t,J＝7.7Hz,1H),6.55(t,J＝2.6Hz,1H),4.15(tt,J＝11.6,3.8Hz,1H),3.50(q,J＝6.9Hz,2H),3.35-3.26(m,1H),2.27(d,J＝12.3Hz,2H),2.19(d,J＝10.8Hz,2H),1.82-1.78(m,2H),1.48-1.37(m,2H),1.17(t,J＝7.0Hz,3H).
(2) 1- (trans-4-ethoxycyclohexyl) -3- (1H-indol-7-yl) -1H-pyrazol-4-amine
7- (1- (trans-4-ethoxycyclohexyl) -4-nitro-1H-pyrazol-3-yl) -1H-indole (170 mg,479.68 umol) was dissolved in ethanol (1.4 mL)/water (0.34 mL) at 20 ℃. To the reaction solution was added ammonium chloride (128.29 mg,2.40 mmol) and iron powder (80.37 mg,1.44 mmol) in this order. The reaction solution was stirred for 13 hours after being heated to 50 DEG CWhen (1). The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. Purification of the residue by Prep-TLC (petroleum ether/ethyl acetate=1/1) gave the title compound (95 mg,292.83umol, brown solid), yield: 61.1%. MS (ESI) m/z 325.2[ M+H ]] + .1H NMR(400MHz,CDCl 3 )δ10.15(brs,1H),7.58(d,J＝7.3Hz,1H),7.53(d,J＝7.9Hz,1H),7.24(t,J＝2.6Hz,1H),7.13-7.07(m,2H),6.51(t,J＝2.6Hz,1H),4.10-3.94(m,1H),3.50(q,J＝7.0Hz,2H),3.36-3.26(m,1H),2.24-2.10(m,4H),1.84-1.71(m,2H),1.47-1.33(m,2H),1.20-1.14(m,3H).
(3) N- (1- (trans-4-ethoxycyclohexyl) -3- (1H-indol-7-yl) -1H-pyrazol-4-yl) -2- (1H-pyrazol-4-yl) thiazole-4-carboxamide
1- (trans-4-ethoxycyclohexyl) -3- (1H-indol-7-yl) -1H-pyrazol-4-amine (95.00 mg,292.83 mol) and intermediate 1 (68.59 mg,351.40 mol) were dissolved in N, N-dimethylformamide (1 mL) at 20 ℃. The reaction temperature was reduced to 0deg.C, HATU (122.48 mg,322.11 mmol) and N, N-diisopropylethylamine (132.46 mg,1.02 mmol) were added sequentially. The reaction solution was stirred for 13 hours at 20 ℃. Water (20 mL) was added to the reaction mixture, which was extracted with ethyl acetate (10 mL. Times.2), and the organic phases were combined and concentrated to give a crude product. Purification of the crude product by Prep-HPLC gave the title compound (10.6 mg, yellow solid), yield: 7.2%. MS (ESI) m/z 502.3[ M+H ]] + .1H NMR(400MHz,CDCl 3 )δ9.85(brs,1H),9.71(s,1H),8.32(s,1H),8.08-7.93(m,3H),7.63(d,J＝7.9Hz,1H),7.53(d,J＝7.3Hz,1H),7.28(t,J＝2.7Hz,1H),7.24-7.20(m,1H),6.56(t,J＝2.6Hz,1H),4.24-4.14(m,1H),3.52(q,J＝7.0Hz,2H),3.38-3.28(m,1H),2.33-2.15(m,4H),1.95-1.82(m,2H),1.50-1.38(m,2H),1.18(t,J＝7.0Hz,3H).
Example 5
N- (3- (benzofuran-7-yl) -1- (trans-4-ethoxycyclohexyl) -1H-pyrazol-4-yl) -2- (1H-pyrazol-4-yl) thiazole-4-carboxamide
Referring to the synthesis of example 4, step 1 was performed with benzofuran-7-yl boronic acid (180.19 mg,111 mmol) as starting material, the title compound (27.2 mg,54.12umol, white solid) was obtained by similar procedure in yield: 20.97%. MS (ESI) m/z 503.3[ M+H ]] + . 1 H NMR(400MHz,CDCl 3 )δ10.16-10.12(m,1H),8.46(s,1H),8.04(s,1H),8.01-7.91(m,2H),7.76(d,J＝7.7Hz,1H),7.74-7.72(m,1H),7.66(d,J＝7.7Hz,1H),7.41-7.35(m,1H),6.96(d,J＝2.0Hz,1H),4.31-4.20(m,1H),3.56(q,J＝7.2Hz,2H),3.43-3.32(m,1H),2.37-2.29(m,2H),2.28-2.18(m,2H),2.00-1.85(m,2H),1.53-1.42(m,2H),1.22(t,J＝7.0Hz,3H).
Kinase assay methods
Kinase activity was assayed using Mobility shift assay using R835 as a positive control. IRAK1/4 kinase used was purchased from Carna and substrate LIMKtide was purchased from GL.
The compound was diluted to 50 times the desired highest inhibitor concentration with 100% DMSO. 100 μl of the compound dilutions were transferred to wells of a 96-well plate, and the compound was serially diluted 4-fold for a total of 10 concentrations; in a 96-well plate, two wells of 100 μl of 100% DMSO were added and used as control wells without compound and without enzyme, respectively. Mu.l of compound was transferred to a new 96-well plate and 90. Mu.l of 1 Xkinase buffer was added to each well. Mu.l of each well from a 96-well plate was transferred to a 384-well plate. A2.5 Xenzyme solution was prepared and kinase was added to the 1 Xkinase base buffer. A2.5 x substrate solution was prepared and substrate and ATP were added to the 1x kinase base buffer. 10ul of 2.5 Xenzyme solution was added to each 384-plate assay well and incubated at room temperature for 10 minutes. 2.5 Xsubstrate solution was added to 384 plate test wells, incubated at room temperature for the corresponding time, kinase reaction stopped by adding 30. Mu.l stop buffer and the conversion read on a Caliper Reader.
Percent inhibition = (positive control conversion reading-sample conversion reading)/(positive control conversion reading-negative control conversion reading) ×100%. The log value of the concentration is taken as an X axis, the percent inhibition rate is taken as a Y axis, and an analytical software XLfit excel add-in version 4.3.1 is adopted to fit a quantitative response curve, so that the IC50 value of the test object on the enzyme activity is obtained. The results of the compound kinase are shown in Table 1, wherein A represents < 10nM, B represents 10-100nM, and C represents > 100nM.
R835 is IRAK1/4 inhibitor developed by Rigel company, and R835 used in the present application is prepared by referring to the method of patent WO2016172560, compound II-176.
TABLE 1
Examples IRAK1(IC50nM) IRAK4(IC50nM)
1 49B 7.2A
2 87B 8.0A
R835 75B 15B
Unless otherwise defined, all terms used herein are intended to have the meanings commonly understood by those skilled in the art.
The described embodiments of the present application are intended to be illustrative only and not to limit the scope of the application, and various other alternatives, modifications, and improvements may be made by those skilled in the art within the scope of the application, and therefore the application is not limited to the above embodiments but only by the claims.

Claims (10)

1. A compound having the structure of formula I, deuterated, stereoisomer, or pharmaceutically acceptable salt thereof:
wherein:
ring a is an 8-10 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O, S;
the ring A is optionally substituted with 1-3R 2 Substitution;
the R is 2 Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups;
R 1 selected from C 1-6 Alkyl, C 1-6 A haloalkyl group.
2. The compound of claim 1, or a pharmaceutically acceptable salt, deuterated compound thereof, wherein:
the ring A is 9-membered bicyclic heteroaryl containing 1-2 heteroatoms selected from N, O, S;
the ring A is optionally substituted with 1R 2 Substitution;
the R is 2 Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups;
R 1 selected from C 1-6 Alkyl, C 1-6 A haloalkyl group.
3. The compound, deuterated, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 2, wherein:
the ring A is selected from Preferably->Further, the ring A is selected from Preferably->
4. A compound, deuterated, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 3, wherein:
the ring A is selected fromFurther preferably->
5. The compound, deuterated, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 3 or 4, wherein:
the R is 2 Selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, preferably F, cl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl;
the R is 1 Selected from C 1-3 Alkyl, C 1-3 Haloalkyl, preferably methyl, ethyl, n-propyl, isopropyl, trifluoromethyl.
6. The compound, deuterated, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 5, wherein:
the R is 2 Selected from F, methyl, trifluoromethyl, more preferably F, methyl;
the R is 1 Selected from methyl, ethyl, isopropyl, more preferably ethyl.
7. The compound, deuterated, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1, comprising the compound:
8. a pharmaceutical composition comprising a compound according to any one of claims 1 to 7, a deuterated, a stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor.
9. Use of a compound according to any one of claims 1 to 7, a deuterated, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for the treatment and/or prevention of IRAK1 and/or IRAK4 related diseases.
10. Use according to claim 9, characterized in that: the IRAK1 and/or IRAK4 related disease includes autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, allergic disorders, multi-organ failure, kidney diseases, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency, transplant rejection, lung injury, respiratory diseases, ischemic conditions, bacterial infections, viral infections, immunoregulatory disorders, or combinations thereof.
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