CN110563656A - Pyrimidine small molecule compound and application thereof in preparing anti-mycobacteria drugs - Google Patents
Pyrimidine small molecule compound and application thereof in preparing anti-mycobacteria drugs Download PDFInfo
- Publication number
- CN110563656A CN110563656A CN201810574690.XA CN201810574690A CN110563656A CN 110563656 A CN110563656 A CN 110563656A CN 201810574690 A CN201810574690 A CN 201810574690A CN 110563656 A CN110563656 A CN 110563656A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- methyl
- isopropoxy
- chloro
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The invention provides a pyrimidine compound, the chemical structure of which is shown as formula I, wherein X, Y, R1,R2,R3Is as defined in the description and claims. Meanwhile, the invention also provides application of the compound in resisting mycobacteria. The compound provided by the invention has better anti-tuberculosis branchHas antibacterial activity, and can be used for preparing antituberculosis drugs.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a 2, 4-pyrimidinediamine antitubercular compound as well as a preparation method and application thereof.
Background
Tuberculosis is a serious infectious disease caused by Mycobacterium tuberculosis (m.tb). According to the evaluation of WHO, about 1040 million new tuberculosis patients and 167 million tuberculosis deaths worldwide have become one of the main diseases died due to infectious diseases in 2016.
At present, the drugs for treating pulmonary tuberculosis mainly comprise isoniazid, rifampicin, streptomycin, ethambutol and the like, but the drugs have toxic and side effects of liver injury and the like, and the treatment period is as long as more than six months, which brings great difficulty to the prevention and treatment of tuberculosis. In recent years, the emergence of drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) has brought about greater difficulties in the treatment of tuberculosis. Therefore, the search for antituberculosis drugs with definite curative effect, little side effect and no drug resistance through various ways becomes an important target of vast pharmaceutical workers.
In a word, the research and development of antituberculosis drugs with new structures and new action mechanisms makes the development of safer, more efficient and less toxic tuberculosis treatment schemes urgent.
Disclosure of Invention
The invention aims to provide a pyrimidine compound with a novel structure and application thereof in preparing anti-mycobacteria medicaments.
In a first aspect of the invention, there is provided a compound of formula I, a pharmacologically acceptable salt or a stereoisomer thereof,
Wherein R is1None or H, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6A cycloalkyl group; r2Is H, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6a cycloalkyl group;
X, Y are each independently C, N or O;
R3Is a substituted OR unsubstituted 5-to 10-membered aromatic ring containing 0, 1, 2 OR 3 heteroatoms selected from N, O OR S, -OR5、-SR5、-NR4R5、-NHR5or-NH (C)1-C6Alkane) R5(ii) a Wherein R is4Is C1-C6An alkyl group; r5Is substituted or unsubstituted C3-C10Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthalene, substituted or unsubstituted 5-to 10-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from N, O or S; or R4And R5And the attached N together form a substituted or unsubstituted 9-10 membered fused ring containing 1, 2 or 3 heteroatoms selected from N, O or S;
wherein the substituent can be positioned at each position of the ring and can be mono-substituted or multi-substituted, and the substituent is selected from the following groups: halogen, hydroxy, cyano, amino, carboxyl, amido, ester, isopropyl sulfone, C1-C6Alkyl, halogen-substituted lower alkyl, C1-C6An alkoxy group.
When the pyrimidine compounds are applied as antimycobacterial drugs, the more preferable compounds are: in the general formula I, R1None or H, C1-C6Alkyl radical, C3-C6A cycloalkyl group;
R2Is H, C1-C6Alkyl radical, C3-C6A cycloalkyl group;
R3is-HNR5、-NH(C1-C6Alkane) R5OrWherein R is5Is substituted or unsubstituted C3-C10Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 5-to 10-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from N, O or S; the substituent can be positioned at each position of the ring, can be mono-substituted or multi-substituted, and is selected from the following group: halogen, hydroxy, cyano, amino, carboxyl, amido, ester, isopropyl sulfone, C1-C6Alkyl, halogen-substituted lower alkyl, C1-C6An alkoxy group;
X is C or N; y is N or O.
When the above pyrimidine compound is used as an antimycobacterial agent, more preferable compounds are: in the general formula I
R1None or H, methyl; r2Is isopropyl;
R3is-HNR5、-NH(C1-C6Alkane) R5OrWherein R is5Is C3-C10Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted thienyl, substituted or unsubstituted quinolyl; the substituent can be positioned at each position of the ring, can be mono-substituted or multi-substituted, and is selected from the following group: halogen, hydroxy, cyano, carboxy, amido, isopropyl sulfone, trifluoromethyl, methoxy;
X is C or N; y is N or O.
Some preferred compounds of the invention are described in Table 1:
5a 5-chloro-N2- (2-isopropoxy-5-methyl-4- (4-methylpiperazin-1-yl) phenyl) -N4- (2- (sulfonylisopropyl) phenyl) pyrimidine-2, 4-diamine,
5b 5-chloro-N2- (2-isopropoxy-5-methyl-4-morpholinylphenyl) -N4- (2- (sulfonylisopropyl) phenyl) pyrimidine-2, 4-diamine,
5c 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperazin-1-yl) phenyl) -N4- (2- (sulfonylisopropyl) phenyl) pyrimidine-2, 4-diamine,
5d 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (naphthalen-1-yl) pyrimidine-2, 4-diamines,
5e 4- (2- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) ethyl) phenol,
5f N4- (3, 5-bis (trifluoromethyl) phenyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5g of 4- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) benzamide,
5h (R) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (1-phenylethyl) pyrimidine-2, 4-diamine,
5i 4- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenol,
5j N4-benzyl-5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5k 4- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenol,
5l 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4-phenethylpyrimidine-2, 4-diamine,
5m 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (4-methoxyphenylethyl) pyrimidine-2, 4-diamine,
5n N4- (4-bromophenylethyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5o 5-chloro-N4- (4-fluorophenethyl) -N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5p 5-chloro-N4-cyclohexyl-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5q 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (naphthalen-2-yl) pyrimidine-2, 4-diamines,
5r N4- ((3s,5s,7s) -adamantan-1-yl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine
5s 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2- (thien-2-yl) ethyl) pyrimidine-2, 4-diamine,
5t N4- ([1,1' -Biphenyl)]-3-yl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamines,
5u N4- (3-bromo-4-methoxyphenyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5v N4- (4-bromo-2-isopropoxy-5-methylphenyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5w 5-chloro-N4-cyclopropyl-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5x 5-chloro-N4- (4', 6-dimethoxy- [1,1' -biphenyl)]-3-yl) -N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine
5Y 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2-methyl-1- (naphthalen-2-yl) propyl-2-yl) pyrimidine-2, 4-diamines
5z 5-chloro-N4- (3, 4-hydroquinin-1-yl) -N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidin-2-amine.
Preferred compound structures in Table 1
。
Further, the present invention provides the compound of the above formula i or a pharmacologically acceptable salt thereof, wherein the pharmacologically acceptable salt (pharmaceutically acceptable salt) is an inorganic acid salt or an organic acid salt.
The inorganic acid refers to hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid or nitric acid and the like;
The organic acid is p-toluenesulfonic acid, acetic acid, tartaric acid, p-toluenesulfonic acid, oxalic acid, fumaric acid, etc.
The preferred pharmaceutically acceptable salts of the present invention are the hydrochloride or the p-toluenesulfonate salt.
In a second aspect of the invention, there is provided a process for the preparation of a compound of formula I as hereinbefore defined, by reacting a compound of formula II or a salt thereof with a compound of formula III to give a compound of formula I;
Wherein R is1,R2,R3,R4X, Y and n are as defined above.
In a third aspect of the invention, the application of the aminopyrimidine compound or the pharmacologically acceptable salt thereof in preparing anti-tuberculosis drugs is provided.
The invention selects mycobacterium tuberculosis H37Ra as a screening strain to carry out in vivo and in vitro experiments, and the results show that: the compound of the invention has better activity of resisting mycobacterium tuberculosis in vivo and in vitro, has the characteristic of low toxicity, and can be used for preparing anti-tuberculosis drugs.
The invention relates to application of a compound shown in formula I or a pharmacologically acceptable salt thereof in preparing antituberculosis drugs, wherein the antituberculosis drugs are pharmaceutical compositions prepared from the compound shown in formula I or the pharmacologically acceptable salt thereof as an active ingredient and conventional pharmaceutical carriers.
The pharmaceutical composition can be tablets, dispersible tablets, sustained-release agents, capsules and granules.
the compound or the pharmacologically acceptable salt thereof of the present invention provides a novel drug for anti-tuberculosis treatment.
Detailed Description
The present invention will now be described in detail with reference to examples, but the practice of the present invention is not limited thereto.
The reagents and starting materials used in the present invention are commercially available or can be prepared according to literature procedures. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or under conditions recommended by the manufacturers.
Example 1: 5-chloro-N2- (2-isopropoxy-5-methyl-4- (4-methylpiperazin-1-yl) phenyl) -N4- (2- (Sulfonylisopropyl) phenyl) pyrimidine-2, 4-diamine (5a)
step one, 1- (5-isopropoxy-2-methyl-4-nitrophenyl) -4-methylpiperazine (2) is prepared.
In a 50mL three-necked flask were added 2.0mmol of 1-bromo-5-isopropoxy-2-methyl-4-nitrobenzene (1), 6.0mmol of cesium carbonate, 0.8mmol of Xantphos reaction substrate, 20.0mL of dioxane, 3.0mmol of N-methylpiperazine, 0.4mmol of Pd (AcO)2And after N2 is replaced for 20min, reacting overnight under the condition of 110 ℃ under the protection of N2, cooling to room temperature after the reaction is finished, filtering, spin-drying, performing flash column chromatography to obtain a crude product, and directly putting the crude product into the next reaction.
Step two, 2-isopropoxy-5-methyl-4- (4-methylpiperazin-1-yl) aniline (3) is prepared.
Dissolving 2.0mmol of the crude product 1- (5-isopropoxy-2-methyl-4-nitrophenyl) -4-methylpiperazine obtained in the last step and 10mmol of iron powder in 16ml of mixed solvent of ethanol/water (5:1), heating and refluxing for reaction for 3h, cooling to room temperature, performing suction filtration on kieselguhr, spin-drying, performing flash column chromatography to obtain the crude product, and directly putting the crude product into the next step for reaction.
Step three preparation of 5-chloro-N2- (2-isopropoxy-5-methyl-4- (4-methylpiperazin-1-yl) phenyl) -N4- (2- (sulfonylisopropyl) phenyl) pyrimidine-2, 4-diamine (5 a).
To the sealed tube was added 0.30mmol of crude 2-isopropoxy-5-methyl-4- (4-methylpiperazin-1-yl) aniline, 0.36mmol of 4, 5-dichloro-N- (2- (sulfonylisopropyl) phenyl) pyrimidin-2-amine (4),3.0ml of isopropanol, 250. mu.L of concentrated hydrochloric acid, and the mixture was sealed and reacted at 85 ℃ overnight. Cooled to room temperature and saturated NaHCO was added3Extraction with dichloromethane, spin-drying, column chromatography gave the product (69.5mg, yield 33.68%).
1H NMR(400MHz,DMSO-d6)δ11.20(s,1H),10.14(s,1H),9.35(s,1H),8.51(s, 1H),8.08(d,J＝7.2Hz,1H),7.94(dd,J＝8.0,1.6Hz,1H),7.76(dd,J＝12.0,4.0Hz, 1H),7.57(t,J＝7.2Hz,1H),7.33(s,1H),6.71(s,1H),4.68–4.58(m,3H),3.56– 3.38(m,3H),3.24–3.01(m,6H),2.81(d,J＝4.6Hz,3H),1.96(s,3H),1.26(t,J＝ 12.0Hz,6H),1.14(dd,J＝14.0,6..0Hz,6H).13C NMR(101MHz,DMSO-d6)δ 158.40,155.72,155.25,155.17,138.57,135.34,133.48,131.37,124.64,124.18, 123.94,122.18,114.11,104.61,72.03,54.86,53.22(2C),48.56(2C),25.96,22.13 (2C),17.57,15.22(2C).HRMS for C28H37ClN6O3S calcd,572.2336；found,573.2411 (M+H+)。
Example 2: 5-chloro-N2- (2-isopropoxy-5-methyl-4-morpholinylphenyl) -N4- (2- (Sulfonylisopropyl) phenyl) pyrimidine-2, 4-diamine (5b)
The synthesis was as in example 1.
1H NMR(400MHz,CDCl3)δ9.51(s,1H),8.57(d,J＝8.0Hz,1H),8.14(s,1H), 8.01(s,1H),7.93(dd,J＝8.0,4.0Hz,1H),7.68–7.57(m,1H),7.49(s,1H),7.30– 7.22(m,1H),6.65(s,1H),4.54(dt,J＝12.0,8.0Hz,1H),3.91–3.78(m,4H),3.36– 3.15(m,1H),2.94–2.81(m,4H),2.15(s,3H),1.38(d,J＝4.0Hz,6H),1.32(d,J＝ 8.0Hz,6H).13C NMR(101MHz,DMSO-d6)δ157.24,155.42,45.72,145.10,138.44, 134.64,131.28,124.96,124.69,123.68,123.19,121.61,105.66,105.60,71.85,67.47 (2C),55.49,52.56(2C),22.26(2C),17.37,15.37(2C).HRMS for C27H34ClN5O4S calcd,559.2020；found,560.2098(M+H+)。
Example 3: 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperazin-1-yl) phenyl) -N4- (2- (Sulfonylisopropyl) phenyl) pyrimidine-2, 4-diamine (5c)
Synthesis of intermediate 3 from starting Material 1 the synthesis procedure was as in example 1, Steps 1-2.
The synthesis steps of the intermediate 4 are as follows:
Dissolving the intermediate 3(0.4mmol) in dichloromethane, adding 2.0mmol TFA under stirring, reacting for 4h under stirring at room temperature, and after the reaction is finished, drying the organic solvent to obtain a crude product which is directly put into the next reaction.
The synthesis of final product 5c from intermediate 4 was performed as in step 3 of example 1.
1H NMR(400MHz,CDCl3)δ9.53(s,2H),8.54(d,J＝8.0Hz,1H),8.16(s,1H),8.05 (s,1H),7.93(dd,J＝8.0,4.0Hz,1H),7.80(d,J＝8.0Hz,1H),7.65–7.57(m,1H), 7.54(s,1H),7.30–7.21(m,1H),6.65(s,1H),4.53(dt,J＝12.0,8.0Hz,1H),3.43 (s,4H),3.26(dt,J＝12.0,8.0Hz,1H),3.18(d,J＝4.0Hz,4H),2.11(s,1H),1.36(d,J ＝8.0Hz,6H),1.32(d,J＝8.0Hz,6H).13C NMR(101MHz,DMSO-d6)δ158.59, 155.85,155.31,146.68,138.54,135.27,131.41,128.57,125.97,125.62,125.31, 124.88,124.19,124.02,106.64,104.64,71.46,55.31,49.26(2C),44.09(2C),22.36 (2C),17.40,15.32(2C).HRMS for C27H35ClN6O3S calcd,558.2180；found,559.2259 (M+H+)。
Example 4: 4- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenol (5d)
。
Step one, preparing 4- ((2, 5-dichloropyrimidin-4-yl) amino) phenol (3).
3.6mmol of 2,4, 5-trichloropyrimidine, 3.0mmol of 2-aminophenol and 3.0mmol of EIPEA are dissolved in isopropanol, and the mixture is refluxed for 5 hours, cooled to room temperature, a large amount of solid is separated out, filtered under reduced pressure and dried in vacuum to obtain white solid (618.4mg, yield 80.5%).
1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.38(d,J＝4.0Hz,4H),7.34–7.27(m, 1H),5.45–5.32(m,1H),1.62(d,J＝8.0Hz,3H).13C NMR(101MHz,DMSO-d6)δ 157.95,157.56,155.59,155.20,128.95(2C),126.18(2C),115.56(2C),113.62. HRMS for C10H7Cl2N3O calcd,254.9966；found,277.9868(M+Na+)。
Step two, 4- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenol (5d) is prepared.
0.39mmol of 2, 5-dichloro-N- (naphthalen-1-yl) pyrimidin-4-amine, 0.30mmol of 4, 5-dichloro-N- (2- (sulfonylisopropyl) phenyl) pyrimidin-2-amine (4),3.0ml of isopropanol, 250. mu.L of concentrated hydrochloric acid were added to a sealed tube, sealed and reacted at 85 ℃ overnight. Cooled to room temperature and saturated NaHCO was added3Extraction with dichloromethane, spin-drying, column chromatography to give the product (83.3mg, 59.3% yield).
1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),9.68(s,1H),9.27(s,1H),9.10(d,J ＝9.2Hz,1H),8.96(d,J＝9.9Hz,1H),8.42(s,1H),7.50(s,1H),7.27(d,J＝8.7Hz, 2H),6.81(d,J＝9.0Hz,3H),4.56(dt,J＝12.0,6.0Hz,1H),3.33(d,J＝12.0Hz,2H), 3.00(dt,J＝24.0,12.0Hz,3H),2.03(s,3H),1.90(dd,J＝24.0,12.0Hz,2H),1.77(d, J＝12.0Hz,2H),1.28(d,J＝6.0Hz,6H).13C NMR(101MHz,DMSO-d6)δ158.14, 158.08,153.73,144.89,139.96,136.58,128.68(2C),128.54,127.41(2C),127.19, 127.13,121.38,111.72,104.15,71.74,44.14(2C),35.31,29.30(2C),22.40(2C), 18.84.HRMS forC25H30ClN5O2calcd,467.2088；found,468.2162(M+H+)。
Example 5: 4- (2- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) ethyl) phenol (5e)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.91(s,1H),7.44(s,1H),7.26(t,J＝5.7Hz,1H),6.99(d,J＝8.4Hz,2H),6.80(s,1H),6.67(d,J＝8.4Hz,2H),4.58(dt,J ＝12.1,6.0Hz,1H),3.64–3.50(m,2H),3.05(d,J＝11.5Hz,2H),2.76(dd,J＝16.0, 6.0Hz,2H),2.64(dd,J＝20.0,10.0Hz,2H),2.12(s,3H),1.64–1.48(m,4H),1.29 (d,J＝6.0Hz,6H).13C NMR(101MHz,DMSO-d6)δ158.25,157.94,156.14,153.49, 144.88,138.46,129.90(2C),129.79,128.15,126.80,121.32,115.58(2C),111.93, 104.06,71.48,47.17,42.97,38.50,34.47,33.75,22.43(2C),19.07.HRMS for C27H34ClN5O2calcd,495.2401；found,496.2477(M+H+)。
Example 6: n is a radical of4- (3, 5-bis (trifluoromethyl) phenyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine (5f)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),8.45(s,2H),8.29(s,1H),7.85–7.67 (m,3H),7.50(d,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,1H),6.76(s,1H),4.53(dt,J＝ 12.0,6.0Hz,1H),3.15–2.90(m,3H),2.29(s,2H),2.09(s,3H),1.81(s,4H),1.25(d, J＝6.0Hz,6H).13C NMR(101MHz,DMSO-d6)δ157.76,156.06,155.90,146.04, 145.72,141.45,138.19,137.41,130.97,130.65,127.96,127.37,125.12,122.40, 111.85,105.25,71.56,44.33(2C),35.31,29.35,22.24(2C),21.24,18.84.HRMS for C27H28ClF6N5O calcd,587.1887；found,588.1962(M+H+)。
Example 7: 4- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) benzamide (5g)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.16(s,1H),7.91(s,1H),7.85(d,J＝ 8.7Hz,2H),7.80(s,1H),7.71(d,J＝8.0Hz,2H),7.66(s,1H),7.25(s,1H),6.79(s, 1H),4.51(dt,J＝12.0,6.0Hz,1H),3.32(s,2H),3.08–2.89(m,3H),2.08(s,3H), 2.01–1.85(m,2H),1.80(d,J＝12.0Hz,2H),1.27(d,J＝6.0Hz,6H).13C NMR (101MHz,DMSO-d6)δ167.76,158.16,156.16,155.67,146.13,141.96,137.64, 129.41,128.45(2C),128.04,127.34,123.04,122.16(2C),111.89,104.53,71.59, 44.17(2C),35.29,29.34(2C),22.42(2C),18.78.HRMS for C26H31ClN6O2calcd, 494.2197；found,495.2273(M+H+)。
example 8: (R) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (1-phenylethyl) pyrimidine-2, 4-diamine (5h)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),7.93(d,J＝9.4Hz,1H),7.40(dd,J＝ 14.6,6.2Hz,3H),7.29(t,J＝7.5Hz,2H),7.20(t,J＝7.3Hz,1H),6.78(d,J＝16.8 Hz,1H),5.36(p,J＝7.0Hz,1H),4.51(tt,J＝12.0,6.2Hz,1H),3.00(dd,J＝23.8, 12.0Hz,3H),2.23(s,2H),1.84(dd,J＝35.5,12.2Hz,3H),1.54(dd,J＝18.2,7.3Hz, 2H),1.27(dd,J＝5.9,1.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ158.06,157.30, 153.87,136.61,128.66(2C),128.59,127.23,127.12,126.60(2C),121.62,111.74, 104.15,71.76,50.00,44.21(2C),35.28,29.34,22.55,22.42(2C),22.38(2C),19.05. HRMS for C27H34ClN5O calcd,479.2452；found,480.1165(M+H+)。
Example 9: 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (Naphthalen-1-yl) pyrimidine-2, 4-diamine (5i)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ9.27(s,1H),8.84(s,2H),8.13(s,1H),8.00(d,J＝ 7.2Hz,1H),7.93(d,J＝7.6Hz,1H),7.86(d,J＝7.6Hz,1H),7.65–7.44(m,4H), 7.36(s,1H),7.12(s,1H),6.60(s,1H),4.52–4.37(m,1H),3.28(d,J＝11.6Hz,2H), 2.93(t,J＝11.6Hz,2H),2.78(s,1H),1.75(d,J＝12.0Hz,2H),1.65(d,J＝12.4Hz, 2H),1.59(s,3H),1.22(d,J＝5.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ158.52 (s),157.79(s),154.96(s),144.10(s),135.83(s),135.06(s),134.52(s),130.71(s), 128.67(s),128.18(s),127.33(s),127.09(s),126.68(s),126.60(s),126.30(s), 125.71(s),123.83(s),120.16(s),111.11(s),104.02(s),71.62(s),44.17(s),35.14(s), 29.25(s),22.32(s),18.48(s).HRMS forC29H32ClN5O calcd,501.2295；found, 502.2367(M+H+)。
Example 10: n is a radical of4-benzyl-5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine (5j)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ8.90(s,2H),7.94(d,J＝120Hz,2H),7.87(t,J＝ 6.0Hz,1H),7.44(s,1H),7.30(s,4H),7.22(d,J＝6.0Hz,1H),6.74(s,1H),4.55(d, J＝4.0Hz),4.50(dt,J＝12.0,8.0Hz,1H)3.27(s,2H),3.09–2.82(m,3H),2.06(s, 3H),1.86(dd,J＝20.0,8.0Hz,2H),1.76(d,J＝12.0Hz,2H),1.27(d,J＝6.0Hz, 6H).13C NMR(101MHz,DMSO-d6)δ158.19,156.70,151.30,146.46,142.11, 128.59,127.98,127.51,127.08(2C),125.95,125.28,115.79(2C),111.93,104.44, 71.97,44.05(2C),35.34,29.08,25.96,22.18(2C),18.71.HRMS for C26H32ClN5O calcd,465.2295；found,466.2373(M+H+)。
Example 11: 4- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenol (5k)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),8.10(s,1H),7.93(d,J＝8.0Hz,1H), 7.72(s,1H),7.63(s,1H),6.94(dt,J＝16.0,8.0Hz,2H),6.78(s,1H),6.74(t,J＝8.0 Hz,1H),4.53(dt,J＝12.0,6.0Hz,2H),3.05(d,J＝12.0Hz,2H),2.67(dt,J＝20.0, 12.0Hz,3H),2.11(s,3H),1.68–1.42(m,4H),1.25(d,J＝6.0Hz,6H).13C NMR (101MHz,DMSO-d6)δ158.49,155.87,154.46,149.56,146.08,139.28,127.58, 126.99,126.89,124.80,123.07,122.59,118.85,115.48,112.00,104.39,71.35,46.18, 38.21,33.28,22.41(2C),18.83.HRMS for C25H30ClN5O2calcd,467.2088；found, 468.2163(M+H+)。
Example 12: 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4-phenethylpyrimidine-2, 4-diamine (5l)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.93(s,1H),7.49(s,1H),7.37(t,J＝ 5.6Hz,1H),7.31-7.27(m,2H),7.23-7.19(m,3H),6.81(s,1H),4.58(dt,J＝12.0, 6.0Hz,1H),3.71–3.60(m,1H),3.11(d,J＝12.0Hz,1H),2.96–2.85(m,1H),2.81 –2.64(m,2H),2.12(s,2H),1.71–1.57(m,2H),1.30(d,J＝6.0Hz,6H).13C NMR (101MHz,DMSO-d6)δ158.21,157.97,153.85,144.90,139.81,137.39,129.05(2C), 128.78(2C),128.46,127.04,126.60,121.35,111.81,104.16,71.61,45.53(2C), 42.61,36.77,35.27,31.38(2C),22.42(2C),19.05.HRMS for C27H34ClN5O calcd, 479.2452；found,480.2527(M+H+)。
Example 13: 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (4-methoxyphenylethyl) pyrimidine-2, 4-diamine (5m)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.91(s,1H),7.46(s,1H),7.31(t,J＝ 5.6Hz,1H),7.10(d,J＝8.4Hz,2H),6.83(d,J＝8.8Hz,2H),6.79(s,1H),4.56(dt, J＝12.0,6.0Hz,1H),3.71(s,3H),3.59(dd,J＝14.8,6.0Hz,2H),3.10(d,J＝11.6 Hz,2H),2.87–2.78(m,2H),2.78–2.65(m,3H),2.12(s,3H),1.60(d,J＝13.5Hz, 4H),1.29(d,J＝6.0Hz,6H).13C NMR(101MHz,DMSO-d6)δ158.23,158.16, 157.96,153.47,144.88,137.88,131.67,129.98(2C),128.32,126.92,121.34,114.19 (2C),111.86,104.12,71.54,55.43(2C),46.25,42.82,37.64,34.38(2C),32.54,22.40 (2C),19.05.HRMS for C28H36ClN5O2calcd,509.2558；found,510.2676(M+H+)。
Example 14: n is a radical of4- (4-bromophenylethyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine (5n)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ9.62(s,1H),9.17(d,J＝28.0Hz,2H),8.96(s,1H), 8.35(s,1H),7.73(s,1H),7.43(d,J＝8.0Hz,2H),7.10(d,J＝8.0Hz,2H),6.88(s, 1H),4.65–4.47(m,1H),3.66(d,J＝6.0Hz,2H),3.34(d,J＝8.0Hz,2H),3.02(s, 3H),2.88(t,J＝4.0Hz,2H),2.15(s,3H),1.97(d,J＝12.0Hz,2H),1.79(d,J＝16.0 Hz,2H),1.30(d,J＝4.0Hz,6H).13C NMR(101MHz,DMSO)δ158.75,151.49, 140.75,138.54,131.63(2C),131.34(2C),127.41,125.20,125.01,124.96,124.87, 119.90,112.38,104.39,71.93,44.07(2C),43.05,35.38,33.74,29.15(2C),22.24 (2C),18.82。
Example 15: 5-chloro-N4- (4-fluorophenethyl) -N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine (5o)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ9.55(s,1H),9.23(d,J＝16.0Hz,2H),8.91(s,1H), 8.34(s,1H),7.76(s,1H),7.17(dd,J＝8.0,6.0Hz,2H),7.08(t,J＝8.0Hz,2H),6.89 (s,1H),4.65–4.51(m,1H),3.66(dd,J＝16.0,8.0Hz,2H),3.34(d,J＝12.0Hz,2H), 3.12–2.95(m,3H),2.89(t,J＝8.0Hz,2H),2.15(s,3H),2.06–1.88(m,2H),1.79(d, J＝12.0Hz,2H),1.30(d,J＝8.0Hz,6H).13C NMR(101MHz,DMSO-d6)δ162.60, 160.20,158.74,151.38,140.53,135.21,130.89(2C),130.81,127.40,124.78,115.61 (2C),115.40,112.40,104.38,71.94,44.05,43.40,35.37,33.55,29.13,22.21(2C), 18.80.HRMS for C27H33ClFN5O calcd,497.2358；found,498.2439(M+H+)。
example 16: 5-chloro-N4-cyclohexyl-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine (5p)
the synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),9.24(d,J＝28.0Hz,2H),8.51(d,J＝ 4.0Hz,1H),8.35(s,1H),7.79(s,1H),6.91(s,1H),4.66–4.54(m,1H),3.99(d,J＝ 8.0Hz,1H),3.33(d,J＝8.0Hz,2H),3.01(d,J＝12.0Hz,3H),2.30(s,3H),2.08– 1.89(m,2H),1.81(s,5H),1.62(t,J＝12.0Hz,1H),1.52(dd,J＝20.0,12.0Hz,2H), 1.30(t,J＝4.0Hz,6H),1.27–1.17(m,4H).13C NMR(101MHz,DMSO-d6)δ 157.79,151.27,127.14,112.25,104.19,71.91,56.48,51.87,44.06(2C),35.44,31.56 (2C),29.10(2C),25.60(2C),22.21(2C),19.12.HRMS for C25H36ClN5O calcd, 457.2608；found,458.2685(M+H+)。
Example 17: 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl)-N4- (Naphthalen-2-yl) pyrimidine-2, 4-diamine (5q)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),9.57(s,1H),9.26(d,J＝16.0Hz, 2H),8.56(s,1H),8.08(s,1H),7.96(d,J＝8.0Hz,2H),7.78(d,J＝4.0Hz,1H),7.69 (d,J＝8.0Hz,1H),7.54(d,J＝3.6Hz,2H),7.37(s,1H),6.81(s,1H),4.67–4.42(m, 1H),3.29(d,J＝12.0Hz,2H),2.96(d,J＝8.0Hz,2H),2.86(t,J＝12.0Hz,1H),1.92 (d,J＝12.0Hz,2H),1.67(d,J＝12.0Hz,2H),1.54(s,3H),1.27(d,J＝4.0Hz,6H).13C NMR(101MHz,DMSO-d6)δ158.37,151.78,134.87,133.40,132.00,128.85, 123.01,112.10,104.68,71.96,43.97(2C),35.24,29.01(2C),22.18(2C),18.09. HRMS for C29H32ClN5O calcd,501.2295；found,502.2376(M+H+)。
example 18: n is a radical of4- ((3s,5s,7s) -adamantan-1-yl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine (5r)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),9.27(s,2H),8.28(s,1H),7.18(s,1H), 6.99(s,1H),6.88(s,1H),4.55–4.40(m,1H),3.33(d,J＝12.0Hz,2H),3.03(s,3H), 2.23(s,3H),2.10–1.97(m,2H),1.95(s,5H),1.90(s,3H),1.77(d,J＝12.0Hz,2H), 1.51(d,J＝12.0Hz,3H),1.36(d,J＝8.0Hz,3H),1.32–1.26(m,1H),1.23(d,J＝ 8.0Hz,6H).13C NMR(101MHz,DMSO-d6)δ158.10,151.97,150.42,142.63, 140.97,129.44,127.64,124.14,113.04,104.39,71.65,56.48,54.97(2C),44.04(2C), 35.89(3C),35.49,29.25(3C),28.99,22.32(3C),18.48.HRMS for C29H40ClN5O calcd,509.2921；found,510.2997(M+H+)。
Example 19: 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2- (thiophen-2-yl) ethyl) pyrimidine-2, 4-diamine (5s)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),9.38–9.09(m,1H),9.02(s,1H),8.37 (s,1H),7.71(s,1H),7.43–7.30(m,1H),6.95(dd,J＝5.0,3.4Hz,1H),6.88(s,1H), 6.82(d,J＝2.8Hz,1H),4.58(dt,J＝12.0,6.0Hz,1H),3.71(dd,J＝13.6,6.9Hz, 1H),3.33(d,J＝11.8Hz,1H),3.13(t,J＝7.4Hz,1H),3.09–2.93(m,1H),2.15(s, 1H),1.97(dd,J＝23.8,11.3Hz,1H),1.78(d,J＝12.6Hz,1H),1.29(d,J＝6.0Hz, 1H).13C NMR(101MHz,DMSO-d6)δ158.82,151.42,140.85,140.66,127.53, 127.46,125.79,124.81,112.43,104.45,71.89,45.89(2C),44.09,35.41,29.09(2C), 22.22(2C),18.77,8.90.HRMS for C25H32ClN5OS calcd；485.2016,found,486.2093 (M+H+)。
Example 20: n is a radical of4- ([1,1' -Biphenyl)]-3-yl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine (5t)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),9.48(s,1H),9.27(d,J＝24.0 Hz,2H),8.54(s,1H),7.82(s,1H),7.68–7.54(m,4H),7.51(s,2H),7.40(d,J＝4.0 Hz,2H),7.36(d,J＝4.0Hz,1H),6.80(s,1H),4.56(s,1H),3.28(d,J＝9.8Hz,2H), 3.05–2.75(m,2H),1.90(d,J＝11.6Hz,1H),1.84(s,2H),1.65(d,J＝12.2Hz,2H), 1.29(d,J＝5.3Hz,4H).13C NMR(101MHz,DMSO-d6)δ158.23,141.06,139.79, 137.86,129.81,129.39(2C),128.18,127.33,127.01(2C),125.36,124.90,124.41, 123.91,123.55,112.01,104.71,71.94,43.98,35.30,28.99,22.18(2C),18.62.HRMS for C31H34ClN5O calcd,527.2452；found,528.2530(M+H+)。
Example 21: n is a radical of4- (3-bromo-4-methoxyphenyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine (5u)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),9.50(s,1H),9.34–9.09(m,2H), 8.52(s,1H),7.73(d,J＝2.0Hz,1H),7.51(dd,J＝8.0,2.0Hz,1H),7.45(s,1H), 7.18(d,J＝8.0Hz,1H),6.83(s,1H),4.58(dt,J＝12.0,6.0Hz,1H),3.88(s,3H), 3.31(d,J＝12.0Hz,2H),3.10–3.01(m,3H),1.90(d,J＝12.0Hz,2H),1.74(d,J＝ 12.0Hz,2H),1.29(d,J＝6.0Hz,6H).13C NMR(101MHz,DMSO-d6)δ162.59, 160.19,158.73,151.30,140.75,140.41,135.20,135.17,130.88,130.80,127.37, 125.00,115.61,115.40,112.41,104.36,71.95,44.03(2C),35.37,33.55,29.10(2C), 22.20(2C),18.82.HRMS for C26H31BrClN5O2calcd,559.1350；found,560.1427(M +H+)。
Example 22: n is a radical of4- (4-bromo-2-isopropoxy-5-methylphenyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine (5v)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO)δ9.66(s,1H),9.36(s,1H),9.21(d,J＝16.0Hz,2H), 8.49(s,1H),7.54(s,1H),7.36(s,2H),6.81(s,1H),4.56(dq,J＝16.0,8.0Hz,2H), 3.31(d,J＝8.0Hz,2H),3.00(dd,J＝20.0,8.0Hz,3H),2.23(s,3H),2.05–1.83(m, 5H),1.74(d,J＝12.0Hz,2H),1.28(d,J＝4.0Hz,6H),1.13(d,J＝4.0Hz,6H). HRMS forC29H37BrClN5O2calcd,601.1819；found,602.1900(M+H+)。
Example 23: 5-chloro-N4-cyclopropyl-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine (5w)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO)δ9.46(s,1H),9.18(d,J＝20.0Hz,2H),8.81(s,1H), 8.34(s,1H),8.12(s,1H),6.88(s,1H),4.61(dt,J＝12.0,6.0Hz,1H),3.33(d,J＝ 12.0Hz,2H),3.10–2.87(m,4H),2.25(s,3H),2.03–1.88(m,2H),1.80(d,J＝12.0 Hz,2H),1.33(d,J＝6.0Hz,6H),0.91–0.75(m,4H)。
Example 24: 5-chloro-N4- (4', 6-dimethoxy- [1,1' -biphenyl)]-3-yl) -N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine (5x)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),9.50(s,1H),9.20(s,2H),8.51(s, 1H),7.53(s,1H),7.44(d,J＝7.8Hz,1H),7.33(d,J＝9.0Hz,3H),7.15(d,J＝8.7 Hz,1H),6.91(d,J＝8.0Hz,2H),6.82(s,1H),4.67–4.45(m,1H),3.79(d,J＝20.0 Hz,6H),3.29(d,J＝10.8Hz,2H),3.07–2.82(m,3H),1.89(s,5H),1.69(d,J＝12.0 Hz,2H),1.30(d,J＝8.0Hz,6H).13C NMR(101MHz,DMSO-d6)δ158.85,158.59, 155.16,150.95,150.93,146.19,141.81,139.81,130.68(2C),129.99,129.84,128.16, 127.33,125.87,125.33,123.11,113.92(2C),112.33,111.99,104.55,72.05,56.32, 55.62,43.98(2C),35.24,29.02(2C),22.14(2C),18.60.HRMS for C33H38ClN5O3 calcd,587.2663；found,588.2745(M+H+)。
Example 25: 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidine)-4-yl) phenyl) -N4- (2-methyl-1- (naphthalen-2-yl) propyl-2-yl) pyrimidine-2, 4-diamine (5Y)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),9.20(s,1H),9.11(s,1H),8.34(s,1H), 7.88(d,J＝8.0Hz,1H),7.81(d,J＝8.0Hz,2H),7.57(s,1H),7.54(s,1H),7.48(s, 2H),7.18(d,J＝8.0Hz,1H),6.97(s,1H),6.90(s,1H),4.61–4.45(m,1H),3.33(d,J ＝12.0Hz,2H),3.23(s,2H),3.04(s,3H),2.25(s,3H),1.97(d,J＝12.0Hz,2H), 1.80(d,J＝12.0Hz,2H),1.39(s,6H),1.26(d,J＝8.0Hz,6H).13C NMR(101MHz, DMSO-d6)δ158.46,135.38,133.29,132.25,129.30,129.12,127.91,127.85,127.73, 127.68,126.53,126.06,113.01,104.80,71.97,57.32,56.49,44.04,35.47(2C),29.16 (2C),26.78(2C),22.31(2C),18.52.HRMS for C33H40ClN5O calcd,557.2921；found, 558.3000(M+H+)。
Example 26: 5-chloro-4- (3, 4-hydroquinin-1-yl) -N- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) piperidin-2-amine (5Z)
The synthesis was as in example 4.
1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),7.89(s,1H),7.82(s,1H),7.16(d,J＝7.2Hz,1H),7.06(t,J＝7.2Hz,1H),7.00–6.91(m,1H),6.80(s,1H),6.76(d,J＝8.0Hz,1H),4.56(dt,J＝12.0,6.0Hz,1H),3.82(t,J＝6.0Hz,2H),3.33(d,J＝12.0 Hz,2H),2.98(dd,J＝23.6,11.2Hz,3H),2.78(t,J＝6.4Hz,2H),2.16(s,3H),2.04 –1.85(m,4H),1.78(d,J＝12.8Hz,2H),1.30(d,J＝6.0Hz,6H).13C NMR(101 MHz,DMSO-d6)δ159.59,158.55,158.27,145.39,140.23,137.29,129.15(2C), 128.00,127.23,126.21,122.89,122.05,120.62,111.66,110.03,71.58,47.57,44.20 (2C),35.38,29.37(2C),26.64,23.68,22.38(2C),19.01.HRMS for C28H34ClN5O calcd,491.2452；found,492.2495(M+H+)。
Example 27: in vitro bacteriostatic experiments of the compounds of the invention.
The in vitro antibacterial activity results of the in vitro antibacterial activity experiments carried out by using the engineering bacteria of mycobacterium tuberculosis H37Ra with self-luminescence are shown in Table 2.
TABLE 2 minimal inhibitory concentration (MIC, μ g/mL) of the target compound against Mycobacterium tuberculosis (H37Ra) in vitro
。
The experimental results show that the compound has better activity against mycobacterium tuberculosis.
While the preferred embodiments of the present invention have been illustrated and described, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (9)
1. A pyrimidine compound or a pharmacologically acceptable salt thereof, wherein the chemical structure of the pyrimidine compound is represented by formula I:
Wherein R is1none or H, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6A cycloalkyl group;
R2is H, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6A cycloalkyl group;
R3Is a substituted OR unsubstituted 5-to 10-membered aromatic ring containing 0, 1, 2 OR 3 heteroatoms selected from N, O OR S, -OR5、-SR5、-NR4R5、-NHR5or-NH (C)1-C6Alkane) R5(ii) a Wherein R is4Is C1-C6An alkyl group; r5Is substituted or unsubstituted C3-C10Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthalene, substituted or unsubstituted 5-to 10-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from N, O or S; or R4and R5and the attached N together form a substituted or unsubstituted 9-10 membered fused ring containing 1, 2 or 3 heteroatoms selected from N, O or S;
Wherein, the substituent can be positioned at each position of the ring and can be mono-substituted or multi-substituted, and the substituent is selected from the following groups: halogen, hydroxy, cyano, amino, carboxyl, amido, ester, isopropyl sulfone, C1-C6Alkyl, halogen-substituted lower alkyl, C1-C6An alkoxy group;
X and Y are each independently C, N or O.
2. A compound of formula I according to claim 1, wherein R is1None or H, C1-C6Alkyl radical, C3-C6A cycloalkyl group;
R2is H, C1-C6Alkyl radical, C3-C6A cycloalkyl group;
R3is-HNR5、-NH(C1-C6Alkane) R5OrWherein R is5Is substituted or unsubstituted C3-C10Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl containing 1, 2 or 3 heteroatoms selected from N, O or SA 5-10 membered aromatic ring; the substituent can be positioned at each position of the ring, can be mono-substituted or multi-substituted, and is selected from the following group: halogen, hydroxy, cyano, amino, carboxyl, amido, ester, isopropyl sulfone, C1-C6Alkyl, halogen-substituted lower alkyl, C1-C6An alkoxy group;
X is C or N; y is N or O.
3. A compound of formula I according to claim 2, wherein R is1None or H, methyl; r2Is isopropyl;
R3is-HNR5、-NH(C1-C6Alkane) R5OrWherein R is5Is C3-C10Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted thienyl, substituted or unsubstituted quinolyl; the substituent can be positioned at each position of the ring, can be mono-substituted or multi-substituted, and is selected from the following group: halogen, hydroxy, cyano, carboxy, amido, isopropyl sulfone, trifluoromethyl, methoxy; x is C or N; y is N or O.
4. A compound of formula i, or a pharmacologically acceptable salt thereof, as claimed in claim 1, wherein said compound of formula i is:
5a 5-chloro-N2- (2-isopropoxy-5-methyl-4- (4-methylpiperazin-1-yl) phenyl) -N4- (2- (sulfonylisopropyl) phenyl) pyrimidine-2, 4-diamine,
5b 5-chloro-N2- (2-isopropoxy-5-methyl-4-morpholinylphenyl) -N4- (2- (sulfonylisopropyl) phenyl) pyrimidine-2, 4-diamine,
5c 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperazin-1-yl) phenyl) -N4- (2- (sulfonylisopropyl) phenyl) pyrimidine-2, 4-diamine,
5d 4- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenol,
5e 4- (2- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) ethyl) phenol,
5f N4- (3, 5-bis (trifluoromethyl) phenyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5g of 4- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) benzamide,
5h (R) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (1-phenylethyl) pyrimidine-2, 4-diamine,
5i 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (naphthalen-1-yl) pyrimidine-2, 4-diamines,
5j N4-benzyl-5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5k 2- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenol,
5l 4-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4-phenethylpyrimidine-2, 4-diamine,
5m 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (4-methoxyphenylethyl) pyrimidine-2, 4-diamine,
5n N4- (4-bromophenylethyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5o 5-chloro-N4- (4-fluorophenethyl) -N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5p 5-chloro-N4-cyclohexyl-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5q 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (naphthalen-2-yl) pyrimidine-2, 4-diamines、
5r N4- ((3s,5s,7s) -adamantan-1-yl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine
5s 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2- (thien-2-yl) ethyl) pyrimidine-2, 4-diamine,
5t N4- ([1,1' -Biphenyl)]-3-yl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5u N4- (3-bromo-4-methoxyphenyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5v N4- (4-bromo-2-isopropoxy-5-methylphenyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5w 5-chloro-N4-cyclopropyl-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5x 5-chloro-N4- (4', 6-dimethoxy- [1,1' -biphenyl)]-3-yl) -N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5y 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2-methyl-1- (naphthalen-2-yl) propyl-2-yl) pyrimidine-2, 4-diamine,
5z 5-chloro-N4- (3, 4-hydroquinin-1-yl) -N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidin-2-amine
。
5. A process for the preparation of a compound of formula i and pharmacologically acceptable salts thereof as claimed in any one of claims 1 to 4, wherein a compound of formula ii or a salt thereof is used as a starting material, which is reacted with a compound of formula iii to give a compound of formula i:
Wherein R is1,R2,R3X, Y are as defined in claims 1-4.
6. Use of a compound of formula i or a pharmacologically acceptable salt thereof as claimed in claims 1 to 4, for the manufacture of a medicament, which is a pharmaceutical composition comprising a compound of formula i or a pharmacologically acceptable salt thereof as an active ingredient in combination with conventional pharmaceutical carriers.
7. Use of a compound of formula i, or a pharmacologically acceptable salt thereof, as claimed in claim 6, in the manufacture of a medicament for the treatment of mycobacterium, wherein the pharmacologically acceptable salt of the compound is an inorganic or organic salt selected from the group consisting essentially of: hydrochloride, sulfate, phosphate, nitrate, hydrobromide, p-toluenesulfonate, acetate, tartrate, oxalate or fumarate.
8. Use of a compound of formula i or a pharmacologically acceptable salt thereof in the manufacture of a medicament for the treatment of mycobacterium as claimed in claim 6, wherein the pharmaceutical composition is in the form of a tablet, a dispersible tablet, a sustained release formulation, a capsule, a granule.
9. The use of a compound of formula i, or a pharmacologically acceptable salt thereof, as claimed in claim 6, in the manufacture of a medicament for the treatment of tuberculosis caused by infection with mycobacterium tuberculosis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810574690.XA CN110563656A (en) | 2018-06-06 | 2018-06-06 | Pyrimidine small molecule compound and application thereof in preparing anti-mycobacteria drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810574690.XA CN110563656A (en) | 2018-06-06 | 2018-06-06 | Pyrimidine small molecule compound and application thereof in preparing anti-mycobacteria drugs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110563656A true CN110563656A (en) | 2019-12-13 |
Family
ID=68772129
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810574690.XA Pending CN110563656A (en) | 2018-06-06 | 2018-06-06 | Pyrimidine small molecule compound and application thereof in preparing anti-mycobacteria drugs |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110563656A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111166750A (en) * | 2018-11-09 | 2020-05-19 | 四川大学 | Novel antibacterial application of 4-fluoro-2-methylindole compound |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101616895A (en) * | 2006-12-08 | 2009-12-30 | Irm责任有限公司 | Compound and composition as kinases inhibitor |
| WO2010049731A1 (en) * | 2008-10-29 | 2010-05-06 | Astrazeneca Ab | Pyrazolo- and imidazopyridinylpyrimidineamines as igf-1r tyrosine kinase inhibitors |
| WO2015081813A1 (en) * | 2013-12-03 | 2015-06-11 | 上海翰森生物医药科技有限公司 | Compound with alk inhibitory activity and preparation and use thereof |
| WO2015180685A1 (en) * | 2014-05-30 | 2015-12-03 | 北京浦润奥生物科技有限责任公司 | Alk kinase inhibitor, and preparation method and use thereof |
| CN107973727A (en) * | 2017-12-11 | 2018-05-01 | 中山大学 | Between disubstituted benzenes phenolic compounds and preparation method thereof and anti-tubercle bacillus application |
| CN108420822A (en) * | 2017-02-15 | 2018-08-21 | 四川大学 | The antibacterial new application of Ceritinib |
-
2018
- 2018-06-06 CN CN201810574690.XA patent/CN110563656A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101616895A (en) * | 2006-12-08 | 2009-12-30 | Irm责任有限公司 | Compound and composition as kinases inhibitor |
| WO2010049731A1 (en) * | 2008-10-29 | 2010-05-06 | Astrazeneca Ab | Pyrazolo- and imidazopyridinylpyrimidineamines as igf-1r tyrosine kinase inhibitors |
| WO2015081813A1 (en) * | 2013-12-03 | 2015-06-11 | 上海翰森生物医药科技有限公司 | Compound with alk inhibitory activity and preparation and use thereof |
| WO2015180685A1 (en) * | 2014-05-30 | 2015-12-03 | 北京浦润奥生物科技有限责任公司 | Alk kinase inhibitor, and preparation method and use thereof |
| CN108420822A (en) * | 2017-02-15 | 2018-08-21 | 四川大学 | The antibacterial new application of Ceritinib |
| CN107973727A (en) * | 2017-12-11 | 2018-05-01 | 中山大学 | Between disubstituted benzenes phenolic compounds and preparation method thereof and anti-tubercle bacillus application |
Non-Patent Citations (1)
| Title |
|---|
| THOMAS H. MARSILJE ET AL.: "Synthesis,Structure-Activity Relationships,and in Vivo Efficacy of the Novel Potent and Selective Anaplastic Lymphoma Kinase(ALK) Inhibitor LDK378 Currently in Phase 1 and Phase 2 Clinical Trials", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111166750A (en) * | 2018-11-09 | 2020-05-19 | 四川大学 | Novel antibacterial application of 4-fluoro-2-methylindole compound |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI532727B (en) | Pyrazinecarboxamide compound | |
| WO2018196677A1 (en) | Fluoroallylamine derivative and use thereof | |
| JP6954567B2 (en) | 2-Substituted Aromatic Ring-Pyrimidine Derivatives and Their Preparation and Medical Use | |
| JP5124471B2 (en) | Substituted bicyclic pyrimidone derivatives | |
| WO2005034870A2 (en) | Amide compounds and ion channel ligands and uses thereof | |
| WO2000075113A1 (en) | Novel heterocyclic carboxamide derivatives | |
| EP3390374A1 (en) | Hydroxyalkylamine- and hydroxycycloalkylamine-substituted diamine-arylsulfonamide compounds with selective activity in voltage-gated sodium channels | |
| KR20130008050A (en) | Method and process for preparation and production of deuterated ω-diphenylurea | |
| JP2004503549A (en) | Bioisosteric benzamide derivatives and their use as apo B-100 secretion inhibitors | |
| EP3722292B1 (en) | Novel pyrimidine derivative having effect of inhibiting cancer cell growth and pharmaceutical composition containing same | |
| JPH06509798A (en) | New pyrazine derivatives, their production and use | |
| KR20150052419A (en) | Biguanide compounds and use thereof | |
| WO2017083756A1 (en) | Heterocyclic compounds for the treatment of disease | |
| JPWO2009041559A1 (en) | Indazole acrylic acid amide compound | |
| CN105008347A (en) | Isoquinolines as potassium ion channel inhibitors | |
| CN113880772B (en) | CDK kinase inhibitors and application thereof | |
| WO2010057418A1 (en) | A phenoxypyrimidine derivative, its preparation method and the use thereof | |
| JP2022528042A (en) | Methods for preparing amide compounds and their use in the pharmaceutical field | |
| JP7007374B2 (en) | Indazole compounds for use in tendon and / or ligament injuries | |
| CN110563656A (en) | Pyrimidine small molecule compound and application thereof in preparing anti-mycobacteria drugs | |
| CA2888369A1 (en) | 6-aminoindole derivatives as trp channel antagonists | |
| KR100571945B1 (en) | 2-?3-[4-2-t-Butyl-6-trifluoromethylpyrimidin-4-ylpiperazin-1-yl]propylmercapto?pyrimidin-4-ol-fumarate | |
| TW201249801A (en) | 3-ureidoisoquinolin-8-yl derivatives | |
| WO2014072903A1 (en) | Novel aminomethyl-phenol derivatives as antimalarial agents | |
| WO2013093458A2 (en) | Antiviral drug derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20191213 |