CN114957280A - Thiophene [2,3-d ] pyrimidine derivatives and uses thereof - Google Patents

Thiophene [2,3-d ] pyrimidine derivatives and uses thereof Download PDF

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CN114957280A
CN114957280A CN202210636856.2A CN202210636856A CN114957280A CN 114957280 A CN114957280 A CN 114957280A CN 202210636856 A CN202210636856 A CN 202210636856A CN 114957280 A CN114957280 A CN 114957280A
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陈俐娟
陈永
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Chengdu Zeiling Biomedical Technology Co ltd
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Abstract

The invention belongs to the field of chemical medicine, and provides a compound shown as a formula I or a pharmaceutically acceptable salt thereof. The invention provides a thiophene [2,3-d ]]The pyrimidine derivative can be used for preparing an RIPK2 inhibitor, and provides a new choice for preparing a medicament for treating related diseases caused by abnormal activation of RIPK 2.

Description

Thiophene [2,3-d ] pyrimidine derivatives and uses thereof
Technical Field
The invention belongs to the field of chemical medicine, and particularly relates to a thiophene [2,3-d ] pyrimidine derivative, a preparation method thereof and application thereof in medicine.
Background
RIPK2(RIP2, RICK, cardik, CARD3) is a bispecific serine/threonine and tyrosine kinase that modulates the pro-inflammatory signals mediated by NOD1 and NOD2, and is an emerging therapeutic target for autoimmune and inflammatory diseases. The nucleotide binding oligomerization domain (NOD) protein family is an important intracellular pattern recognition receptor, and NOD1 and NOD2 are representative two receptors of the protein family, as reported in Nod2-dependent regulation of origin and adaptive immunity in the intracellular pathway (Science 2005,307, 731-734). Nod-like proteins in inflammation and disease (J.Pathol.2008,214,136-148) and Nod-like proteins in immunity, inflammation and disease (Nat.Immunol.2006,7,1250-1257) report that RIPK2 binds to NOD1 or NOD2 after being activated, and mainly functions as a molecular scaffold, activates NF-kappa B and MAPK signal pathways, further recruits downstream kinases such as TAK1, IKK alpha, IKK beta and IKK xi, and causes the increase of immune-related signal factors such as IL-beta, IL-6, IL-12, TNF alpha and the like.
RIPK 2-dependent signaling disorders have been shown to be associated with autoimmune diseases. Patients with NOD2 gene mutations are susceptible to the induction of Crohn's disease, Blau syndrome, early-onset sarcoidosis, dermatitis, arthritis, and the like. The mutation of NOD1 is closely related to asthma and intestinal inflammatory diseases. Therefore, the pharmacological targeting of the NOD/RIPK2 signal channel, the direct inhibition of the kinase activity of RIPK2, the attenuation of proinflammatory signals through bacterial induction pathways triggered by the stimulation of NOD1 and NOD2, and the reduction of inflammatory response and injury caused by inflammation become a promising new drug target for treating autoimmune and inflammatory diseases.
Disclosure of Invention
It is an object of the present invention to provide potent, selective small molecule inhibitors of RIPK2 kinase activity that can specifically block RIPK 2-dependent pro-inflammatory signaling, providing therapeutic benefits for the treatment of autoinflammatory diseases.
The invention firstly provides a compound shown in a formula I or pharmaceutically acceptable salt, solvate, hydrate, isomer, ester, acid, metabolite or prodrug thereof, wherein the structure of the compound is as follows:
Figure BDA0003680695020000011
x, Y one of which is S and the other is N;
R 1 selected from H, halogen;
R 2 is selected from
Figure BDA0003680695020000021
Figure BDA0003680695020000022
Wherein Z, W is independently selected from O, S, CR 13 R 14 ；
R 3 ～R 12 Independently selected from H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 3-8 membered cycloalkyl,
Figure BDA0003680695020000023
R 3 ～R 12 Wherein the 3-to 8-membered cycloalkyl group contains 0 to 2 heteroatoms, and the heteroatoms are N, S, O; n ═0～1；
R 3 ～R 12 Wherein the substituent of the substituted C1-C8 alkyl is selected from halogen, C2-C6 alkenyl, 3-8 membered cycloalkyl, and 6-10 membered aryl substituted or unsubstituted by halogen;
R 3 ～R 12 wherein the substituent of the substituted 3-to 8-membered cycloalkyl is selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, 3-to 8-membered cycloalkyl, and halogen substituted or unsubstituted 6-to 10-membered aryl;
R 15 selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 3-8 membered cycloalkyl, and substituted or unsubstituted C2-C8 alkenyl;
R 15 wherein the substituent of the substituted C1-C8 alkyl is selected from halogen, C2-C6 alkenyl, 3-8 membered cycloalkyl, and 6-10 membered aryl substituted or unsubstituted by halogen;
R 15 wherein the substituent of the substituted 3-to 8-membered cycloalkyl is selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, 3-to 8-membered cycloalkyl, and halogen substituted or unsubstituted 6-to 10-membered aryl;
R 15 wherein, the substituent of the substituted C2-C8 alkenyl is selected from halogen, 3-8 membered cycloalkyl, and 6-10 membered aryl substituted or unsubstituted by halogen;
R 13 、R 14 independently selected from halogen, hydroxyl, C1-C8 alkyl, C1-C8 alkoxy, or R 13 And R 14 The ring formation is 3-8 membered epoxy group.
Wherein, in the above compounds, R 1 Selected from H, F.
Wherein, in the above compounds, R 3 ～R 12 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl; r 3 ～R 12 Wherein the 3-to 6-membered cycloalkyl group contains 0 to 1 hetero atom(s) N, S, O; r 3 ～R 12 Wherein the substituent of the substituted C1-C6 alkyl is selected from halogen, C2-C4 alkenyl, 3-6 membered cycloalkyl, and 6-10 membered aryl substituted or unsubstituted by halogen; r 3 ～R 12 Wherein the substituent of the substituted 3-to 6-membered cycloalkyl group is selected fromHalogen, C1-C4 alkyl, C2-C4 alkenyl, 3-6 membered cycloalkyl, and halogen substituted or unsubstituted 6-10 membered aryl.
Preferably, in the above compounds, R 3 ～R 12 Independently selected from H, substituted or unsubstituted C1-C4 alkyl, and substituted or unsubstituted 5-6 membered cycloalkyl; r 3 ～R 12 Wherein the 5-6 membered cycloalkyl group contains 0-1 hetero atom(s) N, S, O; r 3 ～R 12 Wherein the substituent of the substituted C1-C4 alkyl group is selected from F, C2 alkenyl, cyclopropyl, fluoro-substituted or unsubstituted 6-membered aryl; r 3 ～R 12 Wherein the substituent of the substituted 5-to 6-membered cycloalkyl is selected from F, C1-C4 alkyl, C2 alkenyl, cyclopropyl, and fluorine substituted or unsubstituted 6-to 10-membered aryl.
Wherein, in the above compounds, R 15 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, and substituted or unsubstituted C2-C6 alkenyl; r 15 Wherein the substituent of the substituted C1-C6 alkyl is selected from halogen, C2-C4 alkenyl, 3-6 membered cycloalkyl, and 6-10 membered aryl substituted or unsubstituted by halogen; r 15 Wherein the substituent of the substituted 3-to 6-membered cycloalkyl is selected from halogen, C1-C4 alkyl, C2-C4 alkenyl, 3-to 6-membered cycloalkyl, and halogen substituted or unsubstituted 6-to 10-membered aryl; r 15 Wherein the substituent of the substituted C2-C6 alkenyl is selected from halogen, 3-6 membered cycloalkyl, and 6-10 membered aryl substituted or unsubstituted by halogen.
Preferably, in the above compounds, R 15 Selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, and substituted or unsubstituted C2-C4 alkenyl; r 15 Wherein the substituent of the substituted C1-C4 alkyl is selected from F, C2 alkenyl, 3-6 membered cycloalkyl, and fluorine substituted or unsubstituted 6 membered aryl; r 15 Wherein the substituent of the substituted 3-to 6-membered cycloalkyl is selected from F, C1-C4 alkyl, C2 alkenyl, 3-to 6-membered cycloalkyl, and fluorine substituted or unsubstituted 6-membered aryl; r 15 Wherein the substituent of the substituted C2-C6 alkenyl is selected from halogen, 3-6 membered cycloalkyl and 6 membered aryl substituted or unsubstituted by fluorine.
Wherein, in the above compounds, R 13 、R 14 Independently selected from halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, or R 13 And R 14 The ring formation is 3-6 membered epoxy group.
Preferably, in the above compounds, R 13 、R 14 Independently selected from halogen, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, or R 13 And R 14 The ring formation is 5-6 membered epoxy group.
More preferably, in the above compounds, R 13 、R 14 Independently selected from F, hydroxy, methyl, methoxy, or R 13 And R 14 Form a ring 5-membered epoxy group.
Most preferably, in the above compounds, R 2 Is selected from
Figure BDA0003680695020000031
Figure BDA0003680695020000032
Figure BDA0003680695020000041
The invention also provides specific compounds having the following structural formula:
Figure BDA0003680695020000042
Figure BDA0003680695020000051
the invention also provides a pharmaceutical composition which is prepared by taking the compound or the pharmaceutically acceptable salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary ingredients.
The invention also provides the compound or the pharmaceutically acceptable salt thereof and the application of the pharmaceutical composition in preparing an RIPK2 inhibitor.
The invention also provides the application of the compound or the pharmaceutically acceptable salt thereof and the pharmaceutical composition in preparing medicaments for treating autoimmune diseases and/or allergic diseases.
Further, in the above use, the autoimmune disease and/or allergic disorder is selected from the group consisting of: inflammatory bowel disease, sepsis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, lupus nephritis, scleroderma, asthma, allergic rhinitis, allergic eczema, multiple sclerosis, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, reactive arthritis, crohn's disease, ulcerative colitis, uveitis, and the like.
The invention also provides pharmaceutically acceptable salts of the thiophene [2,3-d ] pyrimidine derivatives. Wherein the salt with an acid is obtained by reacting the free base of the parent compound with an inorganic or organic acid. The inorganic acid includes hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid and the like. The organic acid includes acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, γ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid, malonic acid, or the like.
The term "pharmaceutically acceptable" as used herein, means that which, within the scope of sound medical judgment, is suitable for use in contact with the tissues of human beings and other mammals without undue toxicity, irritation, allergic response and the like, and which, when administered to a recipient, provides, directly or indirectly, a compound of the invention or a prodrug of the compound.
The invention also provides pharmaceutically acceptable solvates of the thienopyrimidine derivatives. The term "solvate" refers to an association of one or more solvent molecules with a compound of the invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and the like.
The invention also provides pharmaceutically acceptable hydrates of the thiophene [2,3-d ] pyrimidine derivatives. The term "hydrate" refers to a compound that further binds stoichiometric or non-stoichiometric water by non-covalent intermolecular forces.
The invention also provides pharmaceutically acceptable isomers of the thiophene [2,3-d ] pyrimidine derivative. The term "isomers" refers to compounds that are identical in chemical composition but differ in the arrangement of atoms or groups in space, including diastereomers, enantiomers, regioisomers, structural isomers, rotamers, tautomers, and the like.
The invention also provides pharmaceutically acceptable polymorphic substances of the thiophene [2,3-d ] pyrimidine derivative. The term "polymorph" denotes a solid crystalline form of a compound or complex thereof, which may be characterized by physical means, such as X-ray powder diffraction patterns or infrared spectroscopy.
The invention also provides the thiophene [2,3-d ]]The pyrimidine derivative pharmaceutically acceptable pharmaceutical composition is prepared by adding pharmaceutically acceptable auxiliary components into 4-amino-5-aryl-7-cyclohexyl-pyrimido nitrogen heterocyclic derivatives shown in formula I or salts or hydrates thereof. The auxiliary component is cyclodextrin, arginine or meglumine. The cyclodextrin is selected from alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin and (C) 1-4 Alkyl) -alpha-cyclodextrin, (C) 1-4 Alkyl) -beta-cyclodextrin, (C) 1-4 Alkyl) -gamma-cyclodextrin, (hydroxy-C) 1-4 Alkyl) -alpha-cyclodextrin, (hydroxy-C) 1-4 Alkyl) -beta-cyclodextrin, (hydroxy-C) 1-4 Alkyl) -gamma-cyclodextrin, (carboxy-C) 1-4 Alkyl) -alpha-cyclodextrin, (carboxy-C) 1-4 Alkyl) -beta-cyclodextrin, (carboxy-C) 1-4 Alkyl) -gamma-cyclodextrin, saccharide ethers of alpha-cyclodextrin, saccharide ethers of beta-cyclodextrin, saccharide ethers of gamma-cyclodextrin, sulfobutyl ethers of alpha-cyclodextrin, sulfobutyl ethers of beta-cyclodextrin and sulfobutyl ethers of gamma-cyclodextrin. The auxiliary components also comprise pharmaceutically acceptable carriers, adjuvants or vehicles. Can be used in pharmaceutically acceptable pharmaceutical composition, and also comprises ion exchanger, aluminum oxide, aluminum stearate, and lecithin; the buffer substance comprises phosphate,Glycine, arginine, sorbic acid, and the like.
The pharmaceutical composition may be in liquid form or solid form. Wherein the liquid form may be an aqueous solution. The solid form may be in the form of a powder, granules, tablets or lyophilized powder. The pharmaceutical composition further comprises water for injection, saline solution, aqueous glucose solution, saline for injection/infusion, glucose for injection/infusion, Grignard solution or Grignard solution containing lactate.
In the present invention, when Z, W is selected from CR 7 R 8 And R is 7 、R 8 And OH, one molecule of water is removed, which means that Z and W together form a carbonyl group.
The invention has the beneficial effects that:
the invention provides a thiophene [2,3-d ] pyrimidine derivative which can be used for preparing a potent and selective small-molecule RIPK2 kinase activity inhibitor for specifically blocking RIPK 2-dependent proinflammatory signaling, and provides a novel treatment way for treating autoimmune diseases and/or allergic diseases.
Detailed Description
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available. In the examples, the reaction temperature is, without particular mention, room temperature, i.e.from 20 to 30 ℃.
The general synthetic method is described as follows: preparation method of CLJ-1-CLJ-23
Figure BDA0003680695020000071
Step a: preparation of intermediate M1
The starting materials SM1(25g,100mmol), SM2(16.5,110mmol) and p-toluenesulfonic acid were weighed(1.7g,10mmol) was added to a 500mL round bottom flask and 250mL of isopropanol was counted and the temperature was set to 80 ℃. After 2h of reaction, TLC detection shows that the reaction is complete and a large amount of solid is separated out. After filtration, the cake was rinsed with diethyl ether to give high purity intermediate M1. 1 H NMR(400MHz,DMSO-d 6 )δ10.16(s,1H),9.32(s,1H),8.78(d,J＝2.1Hz,1H),8.56(s,1H),8.28(s,1H),8.09(d,J＝8.8Hz,1H),7.90(dd,J＝8.8,2.2Hz,1H).
Step b: preparation of intermediate M2
Intermediate M1(18.2g,50mmol) in the previous step, SM3(N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester) (17g,55mmol), potassium carbonate (13.8g,100mmol) and dppf (Pd) 2 Cl 2 ) (1.8g,2.5mmol) was charged into a 500mL three-necked flask, dioxane/ethanol/water (7: 3:4 in total 200mL) was added as a solvent, nitrogen was replaced three times, and the mixture was put into an oil bath at 80 ℃ for reaction for 2 hours. After the reaction is finished, a large amount of solid is separated out, and after the solid is filtered, a small amount of ethanol is used for leaching a filter cake to obtain a high-purity intermediate M2. 1 H NMR(400MHz,DMSO-d 6 )δ9.26(s,1H),8.73(d,J＝2.1Hz,1H),8.45(s,1H),8.05(d,J＝8.9Hz,1H),7.84–7.79(m,2H),6.21(s,1H),4.12–3.99(m,2H),3.60(t,J＝5.7Hz,2H),2.57(s,2H),1.44(s,9H).
Step c: preparation of intermediate M3(CLJ-1)
Intermediate M2(11.6g,25mmol) from the previous step was dissolved in 100mL of dichloromethane and 50mL of trifluoroacetic acid was added portionwise. After 0.5 hour at room temperature, the reaction was completed, and the reaction solution was concentrated. Dispersing the concentrated solution in water, adding appropriate amount of potassium hydroxide to adjust pH to pH>9, and a large amount of solid precipitated, and was filtered and the cake was rinsed with diethyl ether to give intermediate M3(CL-1) in high purity without further purification. 1 H NMR(400MHz,DMSO-d6)δ9.77(s,1H),9.40(s,1H),8.74(d,J＝2.1Hz,1H),8.52(s,1H),8.14(d,J＝8.7Hz,1H),7.88(dd,J＝8.8,2.1Hz,1H),7.83(s,1H),6.29(t,J＝3.5Hz,1H),3.41(d,J＝3.1Hz,2H),2.97(t,J＝5.6Hz,2H),2.46(s,2H).ESI-MS m/z:366.1[M+H] +
Step d: the reaction is continuously split into two different reaction conditions
Reaction conditions 1: example Synthesis of CLJ-2
Intermediate M3(183mg,0.5mmol) and paraformaldehyde (150mg,5mmol) were weighed and dissolved in 10mL of methanol. After 2h of reaction, NaBH3CN (63mg, 1mmol) was added. After reacting for 2h, detecting that the reaction is complete, mixing the sample with crude silica gel, and separating by using a Flash column to obtain the final product CLJ-2. 1 H NMR(400MHz,DMSO-d 6 )δ10.05(s,1H),9.40(s,1H),8.76(d,J＝2.0Hz,1H),8.52(s,1H),8.13(d,J＝8.7Hz,1H),7.94–7.88(m,2H),6.22(s,1H),3.07(d,J＝3.2Hz,2H),2.65–2.57(m,4H),2.30(s,3H).ESI-MS m/z:380.1[M+H] +
Other compounds were prepared with reference to the synthesis of CLJ-2 except that formaldehyde was replaced with the other corresponding aldehydes or ketones, and the structural characterization is shown in table 1:
TABLE 1 Compounds CLJ-3 to CLJ-10
Figure BDA0003680695020000081
Figure BDA0003680695020000091
Figure BDA0003680695020000101
The other part of the product adopts the following preparation method: intermediate M3(183mg,0.5mmol) from the previous step was dissolved in dichloromethane and the corresponding anhydride or isocyanate was added to the system. After 0.5h of reaction, the detection reaction was complete and a large amount of solid was precipitated. The filter cake is obtained by suction filtration and is rinsed by ether to obtain the pure final product CLJ-11-CLJ-23. Structural characterization table 2 shows:
TABLE 2 Compounds CLJ-11 to CLJ-23
Figure BDA0003680695020000102
Figure BDA0003680695020000111
Figure BDA0003680695020000121
The general synthetic method is described as follows: preparation method of CLJ-24-CLJ-39
Figure BDA0003680695020000122
Referring to the synthetic routes of examples CLJ-1, CLJ-2 and CLJ-11, CLJ-24-CLJ-39 was prepared using the same synthetic method except that N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester was replaced with 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester in reaction b, the structural characterization of which is shown in table 3:
TABLE 3 Compounds CLJ-24 to CLJ-39
Figure BDA0003680695020000123
Figure BDA0003680695020000131
Figure BDA0003680695020000141
Figure BDA0003680695020000151
The general synthetic method is described as follows: preparation method of CLJ-40-CLJ-48
Figure BDA0003680695020000152
Referring to the synthetic routes for examples CLJ-1, CLJ-2 and CLJ-11, CLJ-40-CLJ-48 was prepared using the same synthetic method except that in reaction b N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester was replaced with tert-butyl (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-en-1-yl) carbamate, the structural characterization is shown in Table 4:
TABLE 4 Compounds CLJ-40 to CLJ-48
Figure BDA0003680695020000153
Figure BDA0003680695020000161
The general synthetic method is described as follows: preparation method of CLJ-49-CLJ-56
Figure BDA0003680695020000171
Referring to the synthetic routes of examples CLJ-1, CLJ-2 and CLJ-11, CLJ-49-CLJ-56 was prepared using the same synthetic method except that in reaction b, N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester was replaced with 1-tert-butoxycarbonyl-2, 5-dihydro-1H-pyrrole-3-boronic acid pinacol ester, and the structural characterization was as shown in table 5:
TABLE 5 Compounds CLJ-49 to CLJ-56
Figure BDA0003680695020000172
Figure BDA0003680695020000181
The general synthetic method is described as follows: preparation method of CLJ-57-CLJ-63
Figure BDA0003680695020000182
The preparation of this series of compounds is identical to that of preparation example CLJ-1, except that SM3(1, 3-benzothiazol-5-amine) is replaced by SM4 (6-aminobenzothiazole) and the structural characterization is shown in table 6:
TABLE 6 Compounds CLJ-57 to CLJ-63
Figure BDA0003680695020000183
Figure BDA0003680695020000191
The general synthetic method is described as follows: preparation method of CLJ-64-CLJ-68
Figure BDA0003680695020000192
The preparation of this series of compounds was identical to that of preparation example CLJ-1, except that N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester was replaced with the corresponding boronic acid pinacol ester, the structural characterization of which is shown in table 7:
TABLE 7 Compounds CLJ-64 to CLJ-68
Figure BDA0003680695020000193
Figure BDA0003680695020000201
The general synthetic method is described as follows: preparation method of CLJ-69-CLJ-71
Figure BDA0003680695020000202
Step (ii) ofa: intermediate M1(3.63g,10mmol), 1, 4-dioxa-spiro [4,5 ]]Dec-7-ene-8-boronic acid pinacol ester (2.93g,11mmol), potassium carbonate (2.76g,20mmol) and dppf (PdCl) 2 ) (366mg,0.5mmol) was charged into a 100mL three-necked flask, dioxane/ethanol/water (7: 3:4 in total 50mL) was added as a solvent, nitrogen was replaced three times, and the mixture was put into an oil bath at 80 ℃ for reaction for 2 hours. After the reaction is finished, a large amount of solids are separated out, and after filtration, a small amount of ethanol is used for leaching a filter cake to obtain the high-purity CLJ-71 without further purification. 1 H NMR(400MHz,DMSO-d 6 )δ9.75(s,1H),9.41(s,1H),8.75(d,J＝2.0Hz,1H),8.52(s,1H),8.14(d,J＝8.7Hz,1H),7.89(dd,J＝8.8,2.1Hz,1H),7.83(s,1H),6.14(t,J＝4.1Hz,1H),3.57(s,4H),2.69(d,J＝6.8Hz,2H),2.47–2.41(m,2H),1.90(t,J＝6.5Hz,2H)。
Step b: the intermediate of the previous step was dispersed in 50mL of water and 10mL of concentrated HCl was added to deprotect. After the reaction is continued for 5 hours, a large amount of solid is separated out, a filter cake is obtained by suction filtration, the filter cake is dispersed in 50mL of water, the pH value is adjusted to be more than 9, and the filter cake is dried after suction filtration to obtain the high-purity CLJ-69. 1 H NMR(400MHz,DMSO-d 6 )δ9.95(s,1H),9.41(s,1H),8.75(d,J＝2.1Hz,1H),8.55(s,1H),8.15(d,J＝8.7Hz,1H),7.98(s,1H),7.90(dd,J＝8.7,2.1Hz,1H),6.31(t,J＝4.1Hz,1H),3.11(dd,J＝4.2,2.1Hz,2H),3.00–2.94(m,2H),2.64(t,J＝6.9Hz,2H).
Step c: CLJ-69(378mg,1mmol) was weighed out and dissolved in 20mL of methanol, and sodium borohydride (57mg,1.5mmol) was added. After the reaction is completed for 5 hours, the reaction is completed, and the crude silica gel is used for sample mixing and then is separated by a Flash column to obtain the final product CLJ-70. 1 H NMR(400MHz,DMSO-d 6 )δ9.73(s,1H),9.36(s,1H),8.71(d,J＝1.9Hz,1H),8.48(d,J＝0.9Hz,1H),8.10(d,J＝8.7Hz,1H),7.84(dd,J＝8.7,2.0Hz,1H),7.77(s,1H),6.12(t,J＝4.1Hz,1H),4.78(d,J＝4.0Hz,1H),4.52(s,1H),3.81(s,1H),2.66–2.56(m,1H),2.42(s,0H),2.14–2.04(m,1H),1.95–1.86(m,1H).
The preparation process of 6-fluoro-5-amino-1, 3-benzothiazole is as follows:
Figure BDA0003680695020000211
step a: 2-fluoro-5-nitroaniline (15.6g,100mmol) was dissolved in 200mL acetonitrile, BzCl (12.8mL,110mol) was added in portions, and the reaction was allowed to warm to 50 ℃ for 4 h. The system precipitates a large amount of solid, and the pure intermediate is obtained after filtration and leaching of the filter cake with acetonitrile.
Step b: the intermediate (22.1g,85mmol) obtained in the previous step, Fe powder (9.5g,170mmol) and ammonium chloride (9.1g,170mmol) were mixed in a mixed solvent of methanol/water at 4:1 and heated to 65 ℃. After 1h the reaction was complete by TLC and the reaction suspension was filtered through celite, the mother liquor was retained. And (3) concentrating the mother liquor, dispersing the concentrated mother liquor in 100mL of water for pulping, and performing suction filtration to obtain a relatively pure intermediate.
Step c: the intermediate (13.8g,60mmol) from the previous step and KSCN (8.75g,90mmol) were mixed in 100mL of acetic acid, and Br-containing solution was added dropwise to the system 2 (4.5mL,90mmol) in acetic acid. After 5h of reaction, a large amount of solid is separated out, and a relatively pure intermediate is obtained after suction filtration. 1 H NMR(400MHz,DMSO-d 6 )δ10.16(s,1H),8.66(s,2H),7.99–7.91(m,2H),7.78(d,J＝9.9Hz,1H),7.66(d,J＝6.5Hz,1H),7.61–7.55(m,1H),7.51(t,J＝7.5Hz,2H).
Step d: the intermediate from the previous step (14.3g,50mmol) was dissolved in 150mL tetrahydrofuran and placed under ice-bath conditions. Isoamyl nitrite (10mL,75mmol) was added dropwise. After the dropwise addition, the reaction is carried out for 2 hours at room temperature, a large amount of solid is separated out, and a relatively pure intermediate is obtained after suction filtration.
Step e: the intermediate from the previous step (10.9g,40mmol) was dissolved in 70% concentrated sulfuric acid (100mL) and heated to 100 ℃. After 4h of reaction, TLC was carried out to detect the completion of the reaction, the reaction solution was cooled to room temperature and slowly diluted into ice water, and the pH was adjusted to 10 or more with sodium hydroxide. Then, the mixture was extracted twice with 500mL of ethyl acetate, and the organic phases were combined and concentrated. The concentrated crude product was dispersed in 100mL of diethyl ether and filtered off with suction to give the purer product. 1 H NMR(400MHz,DMSO-d 6 )δ9.13(d,J＝1.1Hz,1H),7.77(d,J＝10.9Hz,1H),7.35(dd,J＝8.2,1.1Hz,1H),5.35(s,2H).
The general synthetic method is described as follows: preparation method of CLJ-72-CLJ-77
Figure BDA0003680695020000221
This series of compounds was similar to the synthetic method of examples CLJ-1 and CLJ-11 except that starting material SM2(1, 3-benzothiazol-5-amine) was replaced with 6-fluoro-5-amino-1, 3-benzothiazole, the other reaction conditions were consistent and the structural characterization is shown in table 8:
TABLE 8 Compounds CLJ-72 to CLJ-77
Figure BDA0003680695020000222
Figure BDA0003680695020000231
The general synthetic method is described as follows: preparation method of CLJ-78-CLJ-83
Figure BDA0003680695020000232
This series of compounds is similar to the synthetic procedures for the examples CLJ-1 and CLJ-11 except that N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester is replaced by tert-butyl (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-en-1-yl) carbamate, the other reaction conditions are identical and the structural characterization is as shown in Table 9:
TABLE 9 Compounds CLJ-78 to CLJ-83
Figure BDA0003680695020000233
Figure BDA0003680695020000241
The general synthetic method is described as follows: preparation method of CLJ-84-CLJ-90
Figure BDA0003680695020000242
This series of compounds was similar to the synthesis of the following CLJ-1 and CLJ-11 except that N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester was replaced with 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester under otherwise identical reaction conditions and the structural characterization was as shown in Table 10:
TABLE 10 Compounds CLJ-84 to CLJ-90
Figure BDA0003680695020000243
Figure BDA0003680695020000251
Pharmacodynamics experimental part
The following representative experiments, without limitation, were used to analyze the biological activity of the compounds of the present invention.
In vitro kinase inhibition assay
In one reaction tube, RIPK2 was in buffer (20mM MOPS, pH 8.5,0.2mM EDTA,10mM MnCl) 2 ) And adding 0.33mg/mL myelin basic protein, 10mM magnesium acetate and [ gamma- 33 P-ATP]And different concentrations of compound, then Mg/ATP was added to the reaction to start the enzymatic process and incubated for 120 min at room temperature. RIPK1 was incubated in buffer (8mM MOPS pH 7.0,0.2mM EDTA) and 0.33mg/mL myelin basic protein, 10mM magnesium acetate and [ gamma- 33 P-ATP]And different concentrations of compound, then Mg/ATP was added to the reaction to start the enzymatic process and incubated for 120 min at room temperature. The reaction was finally stopped by dilution to 0.5% strength with phosphate buffer, 10. mu.l of the reaction was titrated onto a P30 membrane, washed four times with 0.425% phosphate solution, 5 minutes each, with methanol, and finally dried and flashed on a P30 membraneCounting, and the size of the scintillation counting value reflects the degree of phosphorylation of the substrate, so that the inhibition of the kinase activity can be characterized. Fitting IC according to inhibition of 9 concentrations 50 Value, duplicate wells test. A: 1-10 nM; b: 10-100 nM; c: 100-; d: 200 and 500 nM.
TABLE 11 inhibitory Activity of the Compound of the invention RIPK2 kinase
Figure BDA0003680695020000261
Figure BDA0003680695020000271
Note: RIPK2 is IC 50 nM; the RIPK1 inhibition rate was 1 μ M,%.
The results show that most of the compounds of the invention have better in-vitro enzymological inhibitory activity on RIPK2, and the IC of the compounds 50 In the range of 1-100nM and with high selectivity for the family member RIPK1 kinase.
Metabolic stability test
The incubation system was 100. mu.L in volume and included 0.1M PBS pH 7.4, NADPH generating system (1mM NADP, 5mM glucose-6-phosphate, 1U/mL glucose-6-phosphate dehydrogenase, 3.3mM MgCl 2 ) (ii) a Adding 1 mu L k56 solution (concentration is 1 mu M/L) on an ice bath, pre-incubating for 5min by adopting water bath at 37 ℃, adding 2.5 mu L of various genus liver microsome solutions, continuously incubating for 0, 5, 15, 30, 45, and 60min, adding 200 mu L of glacial acetonitrile containing 20ng/mL of internal standard SAHA to terminate the reaction, vortexing and uniformly mixing for 30s, centrifuging at 13000rpm for 10min, taking supernatant, and injecting a sample.
Table 12 liver microsome stability data for partial compounds
Figure BDA0003680695020000272
Figure BDA0003680695020000281
The results show that part of the compounds have good in vitro liver microsome stability and better pharmacokinetic properties.

Claims (10)

1. A compound of formula I or a pharmaceutically acceptable salt thereof, having the structure:
Figure FDA0003680695010000011
x, Y one of which is S and the other is N;
R 1 selected from H, halogen;
R 2 is selected from
Figure FDA0003680695010000012
Figure FDA0003680695010000013
Wherein Z, W is independently selected from O, S, CR 13 R 14 ；
R 3 ～R 12 Independently selected from H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 3-8 membered cycloalkyl,
Figure FDA0003680695010000014
R 3 ～R 12 Wherein the 3-to 8-membered cycloalkyl group contains 0 to 2 heteroatoms, and the heteroatoms are N, S, O; n is 0 to 1;
R 3 ～R 12 wherein the substituent of the substituted C1-C8 alkyl is selected from halogen, C2-C6 alkenyl, 3-8 membered cycloalkyl and 6-10 membered aryl substituted or unsubstituted by halogen;
R 3 ～R 12 wherein the substituent of the substituted 3-to 8-membered cycloalkyl is selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, 3-to 8-membered cycloalkyl, and halogen substituted or unsubstituted 6-to 10-membered aryl;
R 15 selected from substituted or unsubstitutedSubstituted C1-C8 alkyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted C2-C8 alkenyl;
R 15 wherein the substituent of the substituted C1-C8 alkyl is selected from halogen, C2-C6 alkenyl, 3-8 membered cycloalkyl, and 6-10 membered aryl substituted or unsubstituted by halogen;
R 15 wherein the substituent of the substituted 3-to 8-membered cycloalkyl is selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, 3-to 8-membered cycloalkyl, and halogen substituted or unsubstituted 6-to 10-membered aryl;
R 15 wherein, the substituent of the substituted C2-C8 alkenyl is selected from halogen, 3-8 membered cycloalkyl, and 6-10 membered aryl substituted or unsubstituted by halogen;
R 13 、R 14 independently selected from halogen, hydroxyl, C1-C8 alkyl, C1-C8 alkoxy, or R 13 And R 14 The ring formation is 3-8 membered epoxy group.
2. The compound of claim 1, wherein R is 1 Selected from H, F.
3. The compound of claim 1 or 2,
R 3 ～R 12 independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl; r 3 ～R 12 Wherein the 3-to 6-membered cycloalkyl group contains 0 to 1 hetero atom(s) N, S, O; r 3 ～R 12 Wherein the substituent of the substituted C1-C6 alkyl is selected from halogen, C2-C4 alkenyl, 3-6 membered cycloalkyl, and 6-10 membered aryl substituted or unsubstituted by halogen; r 3 ～R 12 Wherein the substituent of the substituted 3-to 6-membered cycloalkyl is selected from halogen, C1-C4 alkyl, C2-C4 alkenyl, 3-to 6-membered cycloalkyl, and halogen substituted or unsubstituted 6-to 10-membered aryl;
preferably, R 3 ～R 12 Independently selected from H, substituted or unsubstituted C1-C4 alkyl, and substituted or unsubstituted 5-6 membered cycloalkyl; r 3 ～R 12 In the 5-to 6-membered ringThe alkyl group contains 0 to 1 hetero atom, and the hetero atom is N, S, O; r 3 ～R 12 Wherein the substituent of the substituted C1-C4 alkyl group is selected from F, C2 alkenyl, cyclopropyl, fluoro-substituted or unsubstituted 6-membered aryl; r 3 ～R 12 Wherein the substituent of the substituted 5-to 6-membered cycloalkyl is selected from F, C1-C4 alkyl, C2 alkenyl, cyclopropyl, and fluorine substituted or unsubstituted 6-to 10-membered aryl.
4. The compound of claim 1 or 2,
R 15 selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, and substituted or unsubstituted C2-C6 alkenyl; r is 15 Wherein the substituent of the substituted C1-C6 alkyl is selected from halogen, C2-C4 alkenyl, 3-6 membered cycloalkyl, and 6-10 membered aryl substituted or unsubstituted by halogen; r 15 Wherein the substituent of the substituted 3-to 6-membered cycloalkyl is selected from halogen, C1-C4 alkyl, C2-C4 alkenyl, 3-to 6-membered cycloalkyl, and halogen substituted or unsubstituted 6-to 10-membered aryl; r is 15 Wherein, the substituent of the substituted C2-C6 alkenyl is selected from halogen, 3-6 membered cycloalkyl, and 6-10 membered aryl substituted or unsubstituted by halogen;
preferably, R 15 Selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, and substituted or unsubstituted C2-C4 alkenyl; r 15 Wherein the substituent of the substituted C1-C4 alkyl is selected from F, C2 alkenyl, 3-6 membered cycloalkyl, and fluorine substituted or unsubstituted 6 membered aryl; r 15 Wherein the substituent of the substituted 3-6 membered cycloalkyl is selected from F, C1-C4 alkyl, C2 alkenyl, 3-6 membered cycloalkyl, and 6 membered aryl substituted or unsubstituted by fluorine; r 15 Wherein the substituent of the substituted C2-C6 alkenyl is selected from halogen, 3-6 membered cycloalkyl and fluorine substituted or unsubstituted 6 membered aryl.
5. The compound of claim 1 or 2,
R 13 、R 14 independently selected from halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy,or R 13 And R 14 Ring formation is 3-6-membered epoxy group;
preferably, R 13 、R 14 Independently selected from halogen, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, or R 13 And R 14 Ring formation is 5-6-membered epoxy group;
more preferably, R 13 、R 14 Independently selected from F, hydroxy, methyl, methoxy, or R 13 And R 14 Form a ring 5-membered epoxy group.
6. The compound of claim 1 or 2,
R 2 is selected from
Figure FDA0003680695010000021
Figure FDA0003680695010000022
Figure FDA0003680695010000031
7. The compound of any one of claims 1 to 6, of the formula:
Figure FDA0003680695010000032
Figure FDA0003680695010000041
Figure FDA0003680695010000051
8. a pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient, in combination with pharmaceutically acceptable auxiliary ingredients.
9. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 8 for the preparation of an RIPK2 inhibitor.
10. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for the treatment of an autoimmune disease and/or an allergic disorder.
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