CN110835338A - Imidazopyridine derivative, preparation method and medical application thereof - Google Patents
Imidazopyridine derivative, preparation method and medical application thereof Download PDFInfo
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Abstract
The inventionRelates to imidazopyridine derivatives shown in a general formula (I) or pharmaceutically acceptable salts thereof, a preparation method thereof, and application of the imidazopyridine derivatives or the pharmaceutically acceptable salts thereof as a therapeutic agent, particularly as an IRAK4 kinase inhibitor. Wherein R in the general formula (I)1，R2，R3，R4The definitions of (A) are the same as those in the specification.
Description
Technical Field
The invention relates to a novel imidazole [1,2-a ] pyridine derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and application thereof as a therapeutic agent, in particular as an IRAK4 inhibitor.
Technical Field
Interleukin-1 receptor-associated kinase 4(IRAK-4) is one of the members of the IRAK family of intracellular serine-threonine kinases, other members of the kinase family also include IRAK-1, IRAK-2 and IRAK-M. IRAK-M is expressed only in monocytes and macrophages, expression of IRAK-1, IRAK-2 and IRAK4 is ubiquitous IRAK4 is composed mainly of an N-terminal conserved Death Domain (DD), a hinge region, a C-terminal central Kinase Domain (KD), the DD region is the region where IRAK 5 binds to the initial response gene 88(MyD88) of the adaptor myeloid differentiation factor, the KD region is composed of 12 subregions, has typical serine-threonine kinase domain characteristics, IRAK4 functions primarily to phosphorylate its substrate through the KD region, and thus activates downstream signaling molecules IRAK4, which are interleukin-1 receptor (IL-1R)/Toll-like receptor (IL-1R)/T-like receptor (TLR) and which function as key signaling factors in the intracellular signaling pathways that activate IL-1 receptor signaling pathways, which mediate inflammatory signaling and other inflammatory signaling pathways, including intracellular signaling pathways, and other inflammatory signaling pathways, which function as intracellular signaling factors, as intracellular signaling pathways that mediate the intracellular signaling pathways of IRAK-1 receptor, as well as intracellular signaling pathways.
At present, a series of patents reporting IRAK4 inhibitors have been published, such as patents WO2015104662, WO2016083433, WO201709798 and the like, which describe in detail the use of indazole derivatives as IRAK4 inhibitors. However, there is currently no drug on the market for this target, and only PF-06650833 from Pfizer Inc, BAY-1834845 from Bayer AG, and CA-4948 from Aurigene enter the clinical stage. In the first clinical results reported by Pfizer, PF-06650833 used a sustained release formulation, which not only limited its use, but also increased the cost of drug development. No clinical results have been reported for BAY-1834845 from Bayer AG and CA-4948 from Aurigene. The compounds and test drugs disclosed in the prior art are still unsatisfactory in terms of effectiveness, safety or applicability, and there is still a need to continue the research and development of new interleukin-1 receptor-related kinase 4(IRAK4) inhibitors to meet the ever-increasing medical and health needs of people.
Disclosure of Invention
The inventors have unexpectedly found, through a large number of compound screens, that the compounds of formula (I) below have good IRAK4 enzyme inhibitory activity.
Accordingly, in a first aspect, the present invention provides a class of imidazo [1,2-a ] pyridine derivatives represented by general formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
wherein:
R1is selected from C1-C6Alkyl radical, C3-C8Cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein said aryl or heteroaryl is optionally further substituted by one or more groups selected from halogen, hydroxy, amino, -CONRARBCyano, haloalkyl;
R2is selected from C1-C6Alkyl radical, C3-C8Cycloalkyl, halogen, alkoxy, cyano, hydroxy, carboxy, -CONRARB、-NRaRbHaloalkyl, aminoalkyl, hydroxyalkyl, heterocycloalkyl, aryl or heteroaryl;
R3selected from cyano, alkoxy, -NRaRb、-CONRARB、-SO2NRCRD、C1-C6Alkyl radical, C3-C8Cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein said C1-C6Alkyl radical, C3-C8Cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, haloalkyl, oxo (O ═), C1-C6Alkyl, -CORE、-SO2RF、-CONRARB、-SO2NRCRDSubstituted with the substituent(s);
R4selected from hydrogen, halogen, C1-C6Alkyl radical, C3-C8Cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
Raand RbIndependently selected from a hydrogen atom, -CORE、-SO2RF、C1-C6Alkyl radical, C3-C8Cycloalkyl, aryl or heteroaryl; wherein said aryl or heteroaryl is optionally further substituted by one or more groups selected from halogen, hydroxy, amino, cyano, haloalkyl, -CONRARB、-SO2NRCRDSubstituted with the substituent(s); or RaAnd RbForm a 4 to 8 membered carbocyclic ring with the nitrogen atom to which it is attached,a fused ring, spiro ring or a heterocyclic ring having one or more atoms selected from nitrogen, oxygen, sulfur;
RA、RB、RC、RDindependently selected from hydrogen, C1-C6Alkyl or C3-C6A cycloalkyl group; wherein said alkyl or cycloalkyl is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano or haloalkyl;
RE、RFindependently selected from C1-C6Alkyl or C3-C6A cycloalkyl group; wherein said alkyl or cycloalkyl is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano or haloalkyl.
In some preferred embodiments of the invention, the compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R is1Is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally further substituted by one or more groups selected from halogen, hydroxy, amino, -CONRARBCyano, haloalkyl; wherein R isA、RBThe definition of (A) is described in the general formula (I).
In some preferred embodiments of the present invention, the compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof has the structure of formula (II):
wherein R is2，R3，R4The definition of (A) is described in the general formula (I).
In some preferred embodiments of the invention, the compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R is2Is heteroaryl, heterocycloalkyl or hydroxyalkyl.
In some preferred embodiments of the invention, the compound of formula (I) or (II) or a stereoisomer, tautomer or mixture thereofOr a pharmaceutically acceptable salt thereof, wherein R3Is C1-C6Alkyl, heterocycloalkyl or heteroaryl, wherein said C1-C6Alkyl, heterocycloalkyl or heteroaryl is optionally further substituted by one or more groups selected from halogen, hydroxy, amino, cyano, haloalkyl, oxo (O ═ C), C1-C6Alkyl, -CONRARB、-SO2NRCRD、-CORE、-SO2RFSubstituted with the substituent(s); wherein R isA、RB、RC、RD、RE、RFThe definition of (A) is described in the general formula (I).
In some preferred embodiments of the invention, the compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R is4Is hydrogen, C1-C6Alkyl or C3-C8A cycloalkyl group.
In some preferred embodiments of the present invention, the compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof is:
n- (2- (3-hydroxy-3-methylbutyl) -7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide;
n- (7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide;
n- (7- (2-hydroxypropan-2-yl) -2- (1-methylpiperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide;
n- (2- (1- (ethanesulfonyl) piperidin-4-yl) -7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide.
Further, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier, excipient, or combination thereof.
In another aspect, the present invention provides the use of a compound of formula (I) or (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for inhibiting the activity of IRAK4 kinase.
In a further aspect, the present invention provides the use of a compound of formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, for the manufacture of a medicament for the prevention or treatment of an autoimmune disease, an inflammatory disease or a cancer, wherein said autoimmune disease, inflammatory disease or cancer is preferably selected from the group consisting of lymphoma, endometriosis, psoriasis, lupus erythematosus, multiple sclerosis or rheumatoid arthritis; wherein said lymphoma is preferably primary central nervous system lymphoma or diffuse large B-cell lymphoma with a mutation in MYD88L 265P.
Some of the terms used in the specification and claims of the present invention are defined as follows:
"alkyl" when taken as a group or part of a group refers to a straight or branched chain aliphatic hydrocarbon group. Preferably C1-C20Alkyl, more preferably C1-C6An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted or unsubstituted.
"cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged, and spiro carbocyclic rings. Preferably C3-C12Cycloalkyl, more preferably C3-C8Cycloalkyl, most preferably C3-C6A cycloalkyl group. Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, preferably cyclopropyl, cyclohexyl.
"alkoxy" refers to a group of alkyl-O-. Wherein alkyl is as defined herein. C1-C6Alkoxy groups of (4) are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and the like.
"halogen" refers to fluorine, chlorine, bromine and iodine.
"oxo" refers to a group of oxygen atoms (O ═ connected to carbon atoms via double bonds.
"haloalkyl" refers to an alkyl group containing a halogen substitution, wherein halogen and alkyl are as defined herein. C1-C6The haloalkyl group of (1) is preferred. Examples thereof include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, and the like.
"aryl" means a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms, examples of which include, but are not limited to, phenyl, naphthyl, and the like.
"heteroaryl" refers to a 5-membered monocyclic arene, a 6-membered monocyclic arene, a 9-membered bicyclic arene, or a 10-membered bicyclic arene containing at least one heteroatom (O, S or N), examples of which include, but are not limited to, thiophene, furan, pyrrole, thiazole, oxazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, indole, benzothiophene, benzoxazole, benzothiazole, benzimidazole, and the like.
"heterocycloalkyl" refers to a structure in which at least one ring carbon atom of a cycloalkyl group is replaced by a nitrogen, oxygen, or sulfur atom. Cycloalkyl groups are as defined above with the 4 to 8 membered ring being preferred. Examples include, but are not limited to, oxetane, azetidine, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, nitromethylpiperidine, tetrahydrofuran, tetrahydropyran, dioxothiomorpholine, and the like.
"aminoalkyl" refers to an amino-substituted alkyl group. Wherein alkyl is as defined herein. Examples include, but are not limited to, dimethylaminomethylene, aminoethyl, dimethylaminoethyl, azetidine, piperidinyl, morpholinyl, and the like, and quaternary ammonium salt forms thereof.
"hydroxyalkyl" refers to a hydroxy-substituted alkyl group. Wherein alkyl is as defined herein. Examples include, but are not limited to, forms of 3-hydroxy-3-methylbutyl, hydroxyethyl, hydroxybutyl, hydroxycyclopentyl, hydroxycyclohexyl, and the like.
Detailed Description
The examples show the preparation of representative compounds represented by formula (I) and the associated structural identification data. It must be noted that the following examples are only intended to illustrate the invention and are not intended to limit the invention.1H NMR chemical shifts are expressed in ppm, where s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broadened. If a coupling constant is provided, it is in Hz. The starting materials used for the synthesis of the compounds according to the invention derive without particular mention from commercial or known literature synthetic routes. The commercial manufacturers are from Shanghai Bigdai medicine science and technology limited, Shanghai Shaoyuan reagent limited, Shanghai Lingkai medicine science and technology limited, Nanjing Yao stone science and technology limited, and Shanghai hong biological medicine science and technology limited. The raw material 1c is synthesized by referring to patent WO 2010085820.
The present invention uses the following abbreviations:
HATU: o- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
DIEA: n, N-diisopropylethylamine
THF: tetrahydrofuran (THF)
Hex: n-hexane
Example 1
N- (2- (3-hydroxy-3-methylbutyl) -7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide
First step synthesis of 2-amino-5-nitroisonicotinic acid methyl ester
Slowly adding 10g of 2-amino isonicotinic acid methyl ester into 100mL of concentrated sulfuric acid which is mechanically stirred at the temperature of 0 ℃, cooling to-10 ℃ after stirring until the methyl ester is dissolved, slowly dropwise adding mixed acid prepared by 10mL of concentrated nitric acid and 6mL of concentrated sulfuric acid into the reaction (dropwise adding for about 30min), controlling the reaction temperature to be below-5 ℃ after the dropwise adding is finished, and continuously stirring overnight. After the reaction is finished, adding the reaction solution into a large amount of ice, adjusting the pH value to be neutral to be slightly alkaline by using concentrated ammonia water, stirring to separate out a solid, performing suction filtration, and performing vacuum drying at 30 ℃ for 12 hours.
The solid obtained above is added into concentrated sulfuric acid in batches in an ice bath, stirred for 1h in an ice bath, kept at room temperature for 1h, and reacted for 1h at 50 ℃. After the reaction, the reaction solution is poured into ice, the pH value is adjusted to be neutral to be slightly alkaline by concentrated ammonia water, and the precipitated solid is filtered, and then is dried in vacuum. The resulting yellow solid was recrystallized from THF/Hex to give 1b (10.9g) in 83% overall yield over the two steps.
1H NMR(400MHz,DMSO-d6)δ8.82(s,1H),7.87(br,2H),6.51(s,1H),3.84(s,3H).
The second step of synthesizing 2- (3-ethoxy-3-oxycarbonylpropyl) -6-nitroimidazo [1,2-a ] pyridine-7-carboxylic acid methyl ester
1b (1g,5mmol) and 1c (2.2g,10mmol) were weighed, THF (50mL) was added, the reaction was blocked at 100 ℃ for 5 days, a solid precipitated, the reaction was cooled to room temperature, filtered with suction, and washed with cold THF to give 1d (1.15g, 71%).
1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),8.20(s,1H),8.13(s,1H),4.06(q,J＝8.0Hz,2H),3.09(t,J＝8.0Hz,2H),2.79(t,J＝8.0Hz,2H),1.17(t,J＝8.0Hz,3H).
Step three, synthesizing 6-amino-2- (3-ethoxy-3-oxycarbonylpropyl) -imidazole [1,2-a ] pyridine-7-carboxylic acid methyl ester
Weighing 1d (1g,3.4mmol), iron powder (1.9g,34mmol) and ammonium chloride (0.55g,10.2mmol), adding ethanol/water (100mL, volume ratio 4/1), reacting at 90 deg.C until the 1d reaction of the raw material is completed, filtering with diatomaceous earth, spin-drying the filtrate, dissolving with ethyl acetate (100mL), and dissolving with saturated NaHCO3Solution (30 mL. times.3) washed with anhydrous NaSO4Drying, filtering and concentrating to obtain 1e which is directly put into the next reaction.
Fourthly, synthesizing 2- (3-ethoxy-3-oxycarbonylpropyl) -6- (6- (trifluoromethyl) pyridine-2-formamide) imidazole [1,2-a ] pyridine-7-carboxylic acid methyl ester
Dissolving 1f (0.97g,5.1mmol) in 40mL dichloromethane, adding HATU (2.58g,6.8mmol), DIEA (1.32g,10.2mmol), stirring at room temperature for 1h, adding 1e, reacting at room temperature overnight, detecting by TLC until the raw material reaction is complete, adding saturated NaHCO3The solution (30 mL. times.2) was washed, and the organic phase was washed with saturated ammonium chloride (30 mL. times.2), dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography, eluting with methylene chloride/methanol to give 1g (1.1g, 69% yield in two steps).
The fifth step synthesizes N- (2- (3-hydroxy-3-methylbutyl) -7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridine-6-yl) -6- (trifluoromethyl) pyridine-2-formamide
1g (1g,2mmol) was dissolved in ultra dry THF (20mL) and N was bubbled through2MgMeBr (20mL of 1.0M solution in THF) was added slowly to the reaction via syringe, reacted at room temperature for 24h, and quenched with saturated ammonium chloride (30 mL). Adding 100mL of ethyl acetate for extraction, separating an organic layer, and then using saturated NaHCO3The resulting mixture was washed with water (30mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel column with dichloromethane/methanol as eluent to give Compound 1(171mg, 19%).
LCMS m/z(ESI):451.84[M+H]+
1H NMR(400MHz,CDCl3)δ12.30(s,1H),9.51(s,1H),8.38(d,J＝7.6Hz,1H),8.08(t,J＝7.6Hz,1H),7.82(d,J＝7.6Hz,1H),7.42(s,1H),7.26(s,1H),2.83(t,J＝7.2Hz,2H),1.88(t,J＝7.2Hz,2H),1.68(s,6H),1.24(s,6H).
Example 2
N- (7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide
Synthesis of methyl 2- (1- (tert-Butoxycarbonyl) piperidin-4-yl) -6-nitroimidazo [1,2-a ] pyridine-7-carboxylate in the first step
Weighing 1b (1g,5mmol), 2a (2eq,3.1g) and magnesium oxide (2eq,0.4g), adding THF (50mL), sealing the tube at 100 ℃ for reaction for 24h, cooling the reaction solution to room temperature, performing suction filtration, washing with THF, spin-drying the filtrate, purifying with a silica gel column, and eluting with Hex/THF to obtain 2b (1.13g, 56%).
The second step of synthesis of methyl 6-amino-2- (1- (tert-butoxycarbonyl) piperidin-4-yl) imidazo [1,2-a ] pyridine-7-carboxylate
Weighing 2b (1.13g,2.8mmol), iron powder (1.57g,10eq) and ammonium chloride (0.45g,3eq), adding ethanol/water (100mL, volume ratio 4/1), reacting at 90 ℃ until the raw material 2b is completely reacted, filtering with diatomite, spin-drying the filtrate, dissolving with ethyl acetate (100mL), and saturating with NaHCO3Solution (30 mL. times.3) washed with anhydrous NaSO4Drying, filtering and concentrating to obtain 2c which is directly put into the next reaction.
Step three, synthesizing 2- (1- (tert-butyloxycarbonyl) piperidine-4-yl) -6- (6- (trifluoromethyl) pyridine-2-formamide) imidazole [1,2-a ] pyridine-7-carboxylic acid methyl ester
Dissolving 1f (0.8g,1.5eq) in 40mL dichloromethane, adding HATU (2.1g,2eq) and DIEA (1.1g,3eq), stirring at room temperature for 1h, adding 2c, reacting at room temperature overnight, detecting by TLC that the reaction is complete, adding saturated NaHCO3The solution (30 mL. times.2) was washed, and the organic phase was washed with saturated ammonium chloride (30 mL. times.2), dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography, and eluted with methylene chloride/methanol to give 2e (0.55g, 36% yield in two steps).
Step four, synthesizing 4- (7- (2-hydroxypropan-2-yl) -6- (6- (trifluoromethyl) pyridine-2-formamide) imidazole [1,2-a ] pyridine-2-yl) piperidine-1-carboxylic acid tert-butyl ester
LiCl (40mg,3eq) was weighed out and dissolved in ultra dry THF (5mL), MgMeCl (3mL,9eq,3.0M in THF) was added slowly to the reaction with a syringe until no gas was generated, 2e (0.55g,1mmol) was dissolved in ultra dry THF (10mL) and added slowly to the reaction with a syringe, and the reaction was allowed to react at room temperature for 30min, TLC showed completion, and the reaction was quenched with saturated ammonium chloride (30 mL). Ethyl acetate (100mL) was added for extraction, and the organic layer was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and purified with silica gel column, and eluted with methylene chloride/methanol to give Compound 2f (283mg, 51%).
1H NMR(400MHz,CDCl3)δ12.17(s,1H),9.53(s,1H),8.44(d,J＝8.0Hz,1H),8.12(t,J＝8.0Hz,1H),7.86(d,J＝8.0Hz,1H),7.48(s,1H),7.29(s,1H),4.16-4.15(m,2H),2.92-2.70(m,2H),2.10-1.90(m,2H),1.75(s,6H),1.70-1.50(m,2H),1.46(s,9H).
Step five, synthesizing N- (7- (2-hydroxypropan-2-yl) -2- (piperidine-4-yl) imidazole [1,2-a ] pyridine-6-yl) -6- (trifluoromethyl) pyridine-2-formamide
Adding 2f (120mg,0.22mmol) and 4M dioxane/HCl (10mL) as solvent into a 100mL single-neck flask, reacting at room temperature for 1 hour, detecting by TLC until the raw materials completely react, removing the solvent under reduced pressure, and vacuum drying at 30 ℃ to obtain a compound 2(90mg, 92%)
LCMS m/z(ESI):448.2[M+H]+
1H NMR(400MHz,D2O)δ9.66(s,1H),8.35(d,J＝7.6Hz,1H),8.29(t,J＝7.6Hz,1H),8.08(d,J＝7.6Hz,1H),7.93(s,1H),7.80(s,1H),3.76(br,1H),3.66–3.58(m,2H),3.30–3.24(m,2H),2.45–2.35(m,2H),2.05–1.97(m,2H),1.73(s,6H).
Example 3
N- (7- (2-hydroxypropan-2-yl) -2- (1-methylpiperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide
Weighing 2(45mg,0.1mmol) and dissolving in DMF (5mL), adding potassium carbonate (27mg,2eq), reacting at room temperature for 30min, adding iodomethane (21mg,1.5eq), detecting by TLC until the reaction of the raw material 2 is completed, adding saturated saline (20mL) for washing, adding ethyl acetate 100mL for extraction, separating an organic layer, drying over anhydrous sodium sulfate, filtering, concentrating, purifying by silica gel column, and eluting with dichloromethane/methanol to obtain a compound 3(27mg, 60%).1H NMR(400MHz,CDCl3)δδ12.44(s,1H),9.78(s,1H),8.43(d,J＝7.8Hz,1H),8.14(t,J＝7.8Hz,1H),7.90-7.80(m,2H),7.44(s,1H),4.12(br,1H),3.90-3.80(m,2H),2.95-2.84(m,2H),2.81(s,3H),2.35-2.25(m,2H),1.90-1.83(m,2H),1.77(s,6H).
Example 4
N- (2- (1- (ethylsulfonyl) piperidin-4-yl) -7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide
Adding 2(100mg,0.22mmol) and 30mL of water into a reaction bottle, dissolving with potassium carbonate (310mg,2.23mmol), adding ethylsulfonyl chloride (145mg,1.12mmol) under ice bath, reacting at room temperature for 1 hour, detecting by TLC until the raw material is completely reacted, extracting DCM (30mL multiplied by 2), drying an organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, carrying out silica gel column chromatography, and eluting with dichloromethane/methanol to obtain a compound 4(82mg, 68%).
LCMS m/z(ESI):540.2[M+H]+
1H NMR(400MHz,CDCl3)δ12.16(s,1H),9.55(s,1H),8.45(d,J＝7.8Hz,1H),8.13(t,J＝7.8Hz,1H),7.87(d,J＝7.8Hz,1H),7.49(s,1H),7.32(s,1H),3.90-3.80(m,2H),3.05-2.85(m,5H),2.25-2.10(m,2H),1.90-1.80(m,2H),1.75(s,6H),1.38(t,J＝7.4Hz,3H).
Biological evaluation
IRAK4 kinase Activity assay
The following method was used to determine the extent of inhibition of IRAK4 kinase activity by preferred compounds of the invention under in vitro conditions. The method uses Cisbio
KinEASE-STK S1 wire/threonine kinase kit, by measuring biotinylated polypeptide substrate phosphorylation, homogeneous time-resolved fluorescence technology (HTRF) determination.
Detailed methods referring to the kit instructions, the experimental procedures are briefly described as follows: the compounds of the invention were first dissolved in DMSO to a final concentration of 10 mM. Then, the final concentration range of the tested compound in the reaction system is 16000nM to 0.008nM, and the final concentration of DMSO is less than 2% by performing equal gradient dilution with the buffer solution provided in the kit.
The Adenosine Triphosphate (ATP) concentration tested was the corresponding ATP Km value (300 μ M) determined beforehand. The compound, kinase, biotinylated polypeptide substrate and ATP were incubated at 37 ℃ for kinase reaction for 1 hour, then an anti-phosphoserine/threonine antibody conjugated with a europium-based element compound and streptavidin conjugated with modified XL665 were added to the reaction system to terminate the reaction, and the reaction was incubated at room temperature for 1 hour. After the incubation, the excitation wavelength of each well was 337nm and the fluorescence intensity of each well at the emission wavelengths of 615nm and 665nm was read in the HTRF mode on a microplate reader FLUOstar Omega using the formula Ratio (665nm/615nm) × 104A Ratio value is calculated. The inhibition ratio of the compound at each concentration is calculated by comparing the ratio of the fluorescence intensity of the compound with that of a control group, and the IC of the compound is calculated by nonlinear curve fitting of GraphPad Prism5 in terms of logarithmic concentration-inhibition ratio50Values, see table 1 below.
Table 1 IC of the inhibitory activity of the compounds of the invention against IRAK4 kinase50Value of
| Compound (I) | IC50(nM) |
| 1 | 11nM |
| 2 | 12nM |
| 3 | 0.5nM |
| 4 | 0.3nM |
| Control Compound BAY-1834845 | 8.6nM |
The control compound BAY-1834845 has the following structural formula:
as can be seen from Table 1, the preferred compounds of the present invention all have good inhibitory effect on the IRAK4 enzyme, especially compounds 3 and 4, whose IRAK4 enzyme inhibitory activity IC500.5nM and 0.3nM, respectively. Compared with a control compound BAY-1834845(WO2016083433 example 11), the compound 4 has 28-fold improved inhibitory activity on IRAK4 enzyme, and shows more excellent inhibitory activity on IRAK4 enzyme. Imidazole [1,2-a ] we use]As a new skeleton molecule, the pyridine derivative is completely different from an indazole skeleton of BAY-1834845, and the synthetic route is simple, and the isomer problem caused by nitrogen alkylation of the indazole derivative is avoided. Thus, the compounds of the present invention are expected to be useful in the treatment of IRAK4 inhibitors and their related diseases.
Claims (10)
1. A compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:
wherein:
R1is selected from C1-C6Alkyl radical, C3-C8Cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein said aryl or heteroaryl is optionally further substituted by one or more groups selected from halogen, hydroxy, amino, -CONRARBCyano, haloalkyl;
R2is selected from C1-C6Alkyl radical、C3-C8Cycloalkyl, halogen, alkoxy, cyano, hydroxy, carboxy, -CONRARB、-NRaRbHaloalkyl, aminoalkyl, hydroxyalkyl, heterocycloalkyl, aryl or heteroaryl;
R3selected from cyano, alkoxy, -NRaRb、-CONRARB、-SO2NRCRD、C1-C6Alkyl radical, C3-C8Cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein said C1-C6Alkyl radical, C3-C8Cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, haloalkyl, oxo (O ═), C1-C6Alkyl, -CORE、-SO2RF、-CONRARB、-SO2NRCRDSubstituted with the substituent(s);
R4selected from hydrogen, halogen, C1-C6Alkyl radical, C3-C8Cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
Raand RbIndependently selected from a hydrogen atom, -CORE、-SO2RF、C1-C6Alkyl radical, C3-C8Cycloalkyl, aryl or heteroaryl; wherein said aryl or heteroaryl is optionally further substituted by one or more groups selected from halogen, hydroxy, amino, cyano, haloalkyl, -CONRARB、-SO2NRCRDSubstituted with the substituent(s); or RaAnd RbForm a 4-to 8-membered carbocyclic ring, fused ring, spiro ring, or form a heterocyclic ring having one or more atoms selected from nitrogen, oxygen, sulfur, with the nitrogen atom to which it is attached;
RA、RB、RC、RDindependently selected from hydrogen, C1-C6Alkyl or C3-C6A cycloalkyl group; wherein said alkyl or cycloalkyl is optionally further substituted by one or more groups selected from halogen, hydroxy, cyano or haloAlkyl is substituted by a substituent;
RE、RFindependently selected from C1-C6Alkyl or C3-C6A cycloalkyl group; wherein said alkyl or cycloalkyl is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano or haloalkyl.
2. The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R is1Is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally further substituted by one or more groups selected from halogen, hydroxy, amino, -CONRARBCyano, haloalkyl; wherein R isA、RBIs as defined in claim 1.
3. A compound according to claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, having the structure of formula (II):
wherein R is2，R3，R4Is as defined in claim 1.
4. A compound according to any one of claims 1-3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R2Is heteroaryl, heterocycloalkyl or hydroxyalkyl.
5. A compound according to any one of claims 1-3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R3Is C1-C6Alkyl, heterocycloalkyl or heteroaryl, wherein said C1-C6Alkyl, heterocycloalkyl or heteroaryl optionally further substituted with one or more groups selected from halogen, hydroxy, amino, cyanoHaloalkyl, oxo (O ═), C1-C6Alkyl, -CONRARB、-SO2NRCRD、-CORE、-SO2RFSubstituted with the substituent(s); wherein R isA、RB、RC、RD、RE、RFIs as defined in claim 1.
6. A compound according to any one of claims 1-3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R4Is hydrogen, C1-C6Alkyl or C3-C8A cycloalkyl group.
7. The compound according to any one of claims 1-6, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is:
n- (2- (3-hydroxy-3-methylbutyl) -7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide;
n- (7- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide;
n- (7- (2-hydroxypropan-2-yl) -2- (1-methylpiperidin-4-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide;
n- (2- (1- (ethanesulfonyl) piperidin-4-yl) -7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide.
8. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1-7, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier, excipient, or combination thereof.
9. Use of a compound according to any one of claims 1-7, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for inhibiting the activity of IRAK4 kinase.
10. Use of a compound according to any one of claims 1 to 7, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for the prophylaxis or treatment of an autoimmune disease, an inflammatory disease or a cancer, wherein the autoimmune disease, inflammatory disease or cancer is preferably selected from the group consisting of lymphoma, endometriosis, psoriasis, lupus erythematosus, multiple sclerosis or rheumatoid arthritis; wherein said lymphoma is preferably primary central nervous system lymphoma or diffuse large B-cell lymphoma with a mutation in MYD88L 265P.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2020259626A1 (en) * | 2019-06-26 | 2020-12-30 | 南京明德新药研发有限公司 | Imidazopyridine compound as irak4 inhibitor |
| CN113677679A (en) * | 2019-03-29 | 2021-11-19 | 加拉帕戈斯股份有限公司 | Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders |
| JP2022540464A (en) * | 2019-07-10 | 2022-09-15 | メッドシャイン ディスカバリー インコーポレイテッド | Oxazole compounds as IRAK4 and BTK multi-target inhibitors |
| WO2022267673A1 (en) | 2021-06-21 | 2022-12-29 | 上海勋和医药科技有限公司 | Sulfoximide substituted indazole irak4 kinase inhibitor, preparation method therefor, and use thereof |
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| MA54755A (en) * | 2019-01-18 | 2021-11-24 | Biogen Ma Inc | IMIDAZO[1,2-A]PYRIDINYL DERIVATIVES AS IRAK4 INHIBITORS |
| GB201904375D0 (en) * | 2019-03-29 | 2019-05-15 | Galapagos Nv | Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders |
| WO2022135338A1 (en) * | 2020-12-25 | 2022-06-30 | 南京明德新药研发有限公司 | Amide oxazole compound |
| WO2023283372A1 (en) * | 2021-07-07 | 2023-01-12 | Biogen Ma Inc. | Compounds for targeting degradation of irak4 proteins |
| WO2023098857A1 (en) * | 2021-12-03 | 2023-06-08 | 武汉人福创新药物研发中心有限公司 | Irak4 inhibitor and use thereof |
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| JO3705B1 (en) * | 2014-11-26 | 2021-01-31 | Bayer Pharma AG | Novel substituted indazoles, processes for preparation thereof, pharmaceutical preparations comprising them and use thereof for production of medicaments |
| WO2017148902A1 (en) * | 2016-03-03 | 2017-09-08 | Bayer Pharma Aktiengesellschaft | New 2-substituted indazoles, methods for producing same, pharmaceutical preparations that contain same, and use of same to produce drugs |
| EP3464266B1 (en) * | 2016-06-01 | 2021-10-20 | Bayer Animal Health GmbH | Substituted indazoles useful for treatment and prevention of allergic and/or inflammatory diseases in animals |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113677679A (en) * | 2019-03-29 | 2021-11-19 | 加拉帕戈斯股份有限公司 | Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders |
| WO2020259626A1 (en) * | 2019-06-26 | 2020-12-30 | 南京明德新药研发有限公司 | Imidazopyridine compound as irak4 inhibitor |
| CN113825755A (en) * | 2019-06-26 | 2021-12-21 | 南京明德新药研发有限公司 | Imidazopyridines as IRAK4 inhibitors |
| CN113825755B (en) * | 2019-06-26 | 2023-04-25 | 南京明德新药研发有限公司 | Imidazopyridines as IRAK4 inhibitors |
| JP2022540464A (en) * | 2019-07-10 | 2022-09-15 | メッドシャイン ディスカバリー インコーポレイテッド | Oxazole compounds as IRAK4 and BTK multi-target inhibitors |
| JP7340680B2 (en) | 2019-07-10 | 2023-09-07 | メッドシャイン ディスカバリー インコーポレイテッド | Oxazole compounds as IRAK4 and BTK multi-target inhibitors |
| WO2022267673A1 (en) | 2021-06-21 | 2022-12-29 | 上海勋和医药科技有限公司 | Sulfoximide substituted indazole irak4 kinase inhibitor, preparation method therefor, and use thereof |
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