CN116554165A - Tetrahydropyridopyrimidine derivatives and their use - Google Patents

Tetrahydropyridopyrimidine derivatives and their use Download PDF

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CN116554165A
CN116554165A CN202210107126.3A CN202210107126A CN116554165A CN 116554165 A CN116554165 A CN 116554165A CN 202210107126 A CN202210107126 A CN 202210107126A CN 116554165 A CN116554165 A CN 116554165A
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杨胜勇
李琳丽
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Sichuan University
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Sichuan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention belongs to the field of chemical medicines, and provides tetrahydropyridopyrimidine derivatives. The invention provides a novel small molecular compound taking tetrahydropyridopyrimidine as a framework, the derivative shows good anti-tumor activity on enzymes, cells and animals, can be used as an ATR kinase inhibitor for treating cancers, particularly has good anti-cancer effect on colorectal cancer and mantle cell lymphoma, and provides a new choice for treating the diseases.

Description

Tetrahydropyridopyrimidine derivatives and their use
Technical Field
The invention relates to a tetrahydropyridopyrimidine derivative and application thereof, belonging to the field of chemical medicines.
Background
Ataxia telangiectasia and Rad 3-related (ATR) are atypical serine/threonine protein kinases that play a key role in DNA replication stress responses. ATR and ataxia telangiectasia mutated kinase (ATM) and DNA-dependent protein kinase (DNA-PK) both belong to the phosphatidylinositol 3 kinase-like kinase (PIKK) family, an important component of the DNA Damage Response (DDR); DDR has evolved to recognize, signal and promote repair of damaged DNA.
Unlike ATR's response to DNA replication stress, ATM and DNA-PK react primarily to DNA double strand breaks. Typically, DDR networks coordinate the recognition, signaling and repair of damaged DNA, thereby ensuring genomic stability. Numerous studies have shown that tumor cells with ATM mutations or loss of function, or with other DDR defects that promote replicative stress, are generally more dependent on ATR survival. Based on the principle of synthetic lethality, this provides the possibility of killing cancer cells with ATR inhibitors while retaining normal non-cancer cells.
Therefore, developing ATR kinase inhibitors for use in the treatment of related cancers has significant application value.
Disclosure of Invention
The invention develops a novel tetrahydropyridopyrimidine derivative ATR inhibitor and a preparation method thereof, which show good anti-tumor activity on enzymes, cells and animals and can be used for preparing ATR inhibitor medicines.
The invention firstly provides a compound shown as a formula I or pharmaceutically acceptable salt thereof:
R 1 selected from the group consisting ofR 4 、R 5 Independently selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted C1-C8 alkenyl, substituted or unsubstituted 6-10 membered aryl; r is R 1 Wherein the substituent of the substituted C1-C8 alkyl and substituted C1-C8 alkenyl is selected from halogen, C1-C8 acyl, C1-C8 alkoxy and cyano, and the substituent of the substituted 3-10 membered cycloalkyl and substituted 6-10 membered aryl is selected from C1-C8 alkyl, halogen, C1-C8 acyl, C1-C8 alkoxy and cyano;
R 2 、R 3 independently selected from H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 3-10 membered azacycloalkyl, and R 2 、R 3 Not simultaneously H, or R 2 、R 3 The N is connected to form a substituted or unsubstituted 4-10 membered heterocycloalkyl, 1-2N are contained in the 3-10 membered azacycloalkyl, 0-2 hetero atoms are contained in the 4-10 membered heterocycloalkyl besides the N shown in the formula I, and the hetero atoms are N, O or S; r is R 2 、R 3 Wherein the substituent of the substituted C1-C8 alkyl is selected from C1-C8 alkoxycarbonyl, amino and sulfo; the substituent groups of the substituted 4-10 membered azacycloalkyl and the substituted 4-10 membered heterocycloalkyl are selected from C1-C8 alkyl, C1-C8 alkoxycarbonyl, amino and sulfo;
R 4 is indolyl.
Wherein, in the above-mentioned compounds, R 4 Is that
Wherein, in the above-mentioned compounds, R 4 、R 5 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 6-10 membered aryl, and,n＝0～3；R 4 、R 5 Wherein the substituent of the substituted C1-C6 alkyl is selected from halogen, C1-C6 acyl, C1-C6 alkoxy and cyano, and the substituent of the substituted 6-10 membered aryl is selected from C1-C6 alkyl, halogen, C1-C6 acyl, C1-C6 alkoxy and cyano; r is R 6 Selected from H, halogen, cyano, halogen substituted or unsubstituted C1-C6 alkyl; r is R 7 Selected from H, halogen, C1-C6 alkyl; r is R 8 Selected from H, C-C6 alkyl; r is R 9 Selected from H, C-C6 alkyl and C1-C6 alkoxy.
Preferably, in the above compound, R 4 、R 5 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 6 membered aryl,n＝0～3；R 4 、R 5 Wherein the substituent of the substituted C1-C6 alkyl is selected from halogen, C1-C4 acyl, C1-C4 alkoxy and cyano, and the substituent of the substituted 6-10 membered aryl is selected from C1-C4 alkyl, halogen, C1-C4 acyl, C1-C4 alkoxy and cyano; r is R 6 Selected from H, halogen, cyano, halogen substituted or unsubstituted C1-C4 alkyl; r is R 7 Selected from H, halogen, C1-C4 alkyl; r is R 8 Selected from H, C-C4 alkyl; r is R 9 Selected from H, C-C4 alkyl and C1-C4 alkoxy.
More preferably, in the above compound, R 4 、R 5 Independently selected from substituted or unsubstituted C1-C6 alkyl, phenyl, n＝0～3；R 4 、R 5 Wherein the substituent of the substituted C1-C6 alkyl is selected from F, cl and C1-C4 acyl; r is R 6 Selected from H, F, cyano, unsubstituted C1-C4 alkyl, trifluoromethyl; r is R 7 Selected from H, F, C-C4 alkyl; r is R 8 Selected from H, C-C4 alkyl; r is R 9 Selected from H, C-C4 alkyl and C1-C4 alkoxy.
Still preferably, in the above compound, R 4 Selected from substituted or unsubstituted C1-C6 alkyl, phenyl, n＝0～3；R 4 Wherein the substituent of the substituted C1-C6 alkyl is selected from F, cl and C1-C4 acyl; r is R 6 Selected from H, F, cyano, unsubstituted C1-C4 alkyl, trifluoromethyl; r is R 7 Selected from H, F, C-C4 alkyl; r is R 8 Selected from H, C-C4 alkyl; r is R 9 Selected from H, C-C4 alkyl, C1-C4 alkaneAn oxy group; r is R 5 Is a C1-C4 alkyl group substituted or unsubstituted by fluorine.
Most preferably, in the above compound, R 4 Selected from methyl, difluoromethyl, trifluoromethyl, acetylmethyl, isopropyl, tert-butyl, isobutyl, and,Vinyl group,/->Phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, < >>R 5 Selected from trifluoromethyl and methyl.
Wherein, in the above-mentioned compounds, R 2 、R 3 Independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3-8 membered azacycloalkyl, and R 2 、R 3 And the N is not H at the same time, and the 3-8 membered azacycloalkyl contains 1-2N; r is R 2 、R 3 Wherein the substituent of the substituted C1-C6 alkyl is selected from C1-C6 alkoxycarbonyl, -NHR 10 、-SO 2 R 11 The method comprises the steps of carrying out a first treatment on the surface of the The substituent of the substituted 3-8 membered azacycloalkyl is selected from C1-C6 alkyl, C1-C6 alkoxycarbonyl and NHR 12 、-SO 2 R 13 ；R 10 、R 12 Independently selected from H, C to C6 alkyl; r is R 11 、R 13 Independently selected from C1-C6 alkyl groups.
Preferably, in the above compound, R 2 、R 3 Independently selected from H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 5-6 membered azacycloalkyl, and R 2 、R 3 And the N is not H at the same time, and 1N is contained in the 5-6 membered azacycloalkyl; r is R 2 、R 3 Wherein the substituent of the substituted C1-C4 alkyl is selected from C1-C4 alkoxycarbonyl, -NHR 10 、-SO 2 R 11 The method comprises the steps of carrying out a first treatment on the surface of the The substituent of the substituted 5-6 membered azacycloalkyl is selected from C1-C4 alkyl, C1-C4 alkoxycarbonyl and NHR 12 、-SO 2 R 13 ；R 10 、R 12 Independently selected from H, C to C4 alkyl; r is R 11 、R 13 Independently selected from C1-C4 alkyl groups.
More preferably, in the above compound, R 2 、R 3 Independently selected from H, C C1-C4 alkoxycarbonyl substituted or unsubstituted C1-C4 alkyl, unsubstituted 5-6 membered azacycloalkyl, and R 2 、R 3 And the N is not H at the same time, and the 5-to 6-membered azacycloalkyl contains 1N.
Most preferably, in the above compound, R 2 、R 3 Independently selected from H, methyl,
The invention also provides a compound with a structure shown in a formula II or pharmaceutically acceptable salt thereof:
the nitrogen heterocycle A is selected from substituted or unsubstituted 5-8 membered heterocycloalkyl, wherein the 5-8 membered heterocycloalkyl contains 0-1 hetero atom besides N shown in a formula II, and the hetero atom is N, O or S; the substituent of the substituted 5-8 membered heterocycloalkyl is selected from C1-C6 alkyl, C1-C6 alkoxycarbonyl and NHR 14 、-SO 2 R 15 ；R 14 Selected from H, C-C6 alkyl; r is R 15 From C1-C6 alkyl.
Wherein, in the above compound, the nitrogen heterocyclic ring A is selected fromX is selected from O, NR 20 、CHR 21 、SO 2 ；R 16 、R 17 、R 19 Independently selected from H, C-C4 alkyl, C1-C4 alkoxycarbonyl, -NHR 14 、-SO 2 R 15 ；R 14 Selected from H, C-C4 alkyl; r is R 15 From C1-C4 alkyl; r is R 18 、R 20 、R 21 Independently selected fromH. C1-C4 alkoxycarbonyl, -SO 2 R 22 ；R 22 Selected from C1-C4 alkyl.
Preferably, in the above compound, the nitrogen heterocycle A is selected fromR 17 is-NHR 14 ；R 23 、R 24 、R 25 、R 26 Independently selected from H, C-C4 alkyl, C1-C4 alkoxycarbonyl, -NHR 14 ；R 14 Selected from H, C-C4 alkyl; r is R 27 is-SO 2 R 15 ；R 15 From C1-C4 alkyl.
Most preferably, in the above compound, the nitrogen heterocycle A is selected from
Wherein, in the above-mentioned compounds,is->Is->Is thatIs->Is->Is->
The invention also provides specific compounds with the following structural formulas:
the invention also provides a pharmaceutical composition which is prepared from the compound or pharmaceutically acceptable salt thereof serving as an active ingredient and pharmaceutically acceptable auxiliary ingredients.
The invention also provides application of the compound or pharmaceutically acceptable salt thereof and the pharmaceutical composition in preparing an ATR kinase inhibitor.
The invention also provides application of the compound or pharmaceutically acceptable salt thereof in preparing a medicament for treating cancer; preferably, the cancer is colorectal cancer or mantle cell lymphoma.
The application also provides a preparation method of the compound, which comprises the following steps:
the synthesis route I is as follows:
synthetic reagents and reaction conditions for compound 5-X in synthetic scheme one: a. r is R 4 Palladium tetraphenyl phosphine, potassium carbonate, 1, 4-dioxane/water (V: v=50/1), 95 ℃ for 12h; b. substituted or unsubstituted cyclic amine, DIPEA, DMSO,130 ℃,8h; c. dioxane hydrochloride solution (4M), DCM; d. r is R 1 Acid chloride, TEA, DCM; or R is 1 Acid of (C), HATU, TEA, DCM.
The synthesis route II is as follows:
synthetic reagents and reaction conditions for compound 5-X in scheme two: r is R 3 Palladium tetraphenyl phosphine, potassium carbonate, 1, 4-dioxane/water (V: v=50/1), 95 ℃ for 12h; c. 1, 4-dioxane solution (4M), DCM; d. r is R 1 Acid of (C), HATU, TEA, DCM, or R 1 Acid chloride, TEA, DCM; e. different amines, DIPEA, DMSO,130℃for 8h (note: protected amine requires further removal of protecting groups).
The beneficial effects are that:
the invention provides a novel small molecular compound taking tetrahydropyridopyrimidine as a framework, and the derivative can be used as an ATR kinase inhibitor for treating cancers, and has good anticancer effects on colorectal cancer and mantle cell lymphoma.
Drawings
FIG. 1 shows the antitumor effect of compounds 5-30 on mantle cell lymphoma cell Granta-519.
Detailed Description
The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Target molecule synthesis example 1:
preparation of intermediate 4- (1- (tert-butoxycarbonyl) -1H-indol-3-yl) -2-chloro-5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylic acid tert-butyl ester 2:
the starting materials, tert-butyl 2, 4-dichloro-5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylate 1 (21.37 mmol,1.0 eq) and (1- (tert-butoxycarbonyl) -1H-indol-3-yl) boronic acid (25.64 mmol,1.2 eq) were weighed into 213mL dioxane/water (v/v=50:1), followed by potassium carbonate (42.74 mmol,2 eq) and tetrakis (triphenylphosphine) palladium (3.21 mmol), 0.15 eq). The reaction was completed by TLC under nitrogen protection at 95 ℃ for 12 h. Post-treatment: the system was directly added with 400 mesh crude silica gel, concentrated and stirred, and prep-CC separation (PE: ea=3:1) was performed to give product 2 as a white solid in 60% yield.
Preparation of intermediate 4- (1- (tert-butoxycarbonyl) -1H-indol-3-yl) -2-morpholino-5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylic acid tert-butyl ester 3:
a100 mL round bottom flask was taken and 4- (1- (tert-butoxycarbonyl) -1H-indol-3-yl) -2-chloro-5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylic acid tert-butyl ester 2 (4.74 mmol) and morpholine (23.71 mmol,5 eq) were dissolved in 47 mL DMSO and DIPEA (23.71 mmol,5 eq) was added. Under the protection of argon, the temperature is gradually increased to 130 ℃, the reaction is carried out for 5 hours, and the reaction is monitored by a TLC (thin layer chromatography) plate. Post-treatment: after cooling the reaction to room temperature, 400 mesh crude silica gel was stirred and prep-CC (PE: ea=3:1) was isolated as a white solid product 3 in 67% yield.
Preparation of intermediate 4- (4- (1H-indol-3-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-2-yl) morpholine 4:
a100 mL round bottom flask was charged with 4- (1- (tert-butoxycarbonyl) -1H-indol-3-yl) -2-morpholino-5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylic acid tert-butyl ester 3 (4.29 mmol), dissolved in 5mL DCM and then slowly added with 4mol/L dioxane hydrochloride solution 5mL. The reaction was allowed to proceed overnight at room temperature and monitored by TLC plates for completion. Post-treatment: the reaction solution was directly concentrated under reduced pressure and dried to obtain hydrochloride as a white solid powder, which was directly used in the next step.
Final product 4- (4- (1H-indol-3-yl) -7-R 1 -5,6,7, 8-tetrahydropyrido [3,4-d ]]Preparation of pyrimidin-2-yl) morpholine 5-X:
the method comprises the following steps: a25 mL round bottom flask was taken, 4- (4- (1H-indol-3-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-2-yl) morpholine 4 (149.07 umol) was dissolved in 4mL DCM, the corresponding anhydride or acid chloride (163.98 umol) was added, the flask was placed in an ice-water bath and triethylamine (223.61 mmol) was added and the reaction was allowed to proceed for 5H, and completion was monitored by TLC plate. Post-treatment: the reaction solution was concentrated and isolated by prep-CC (PE: ea=2:1-0:1) to give the product 5-X in 60-95% yield.
The second method is as follows: a25 mL round bottom flask was taken and 4- (4- (1H-indol-3-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-2-yl) morpholine 4 (149.07 umol) and the corresponding acid (149.07 umol) were dissolved in 4mL DCM and HATU (223.61 mmol) and triethylamine (298.14 mmol) were added. The reaction was allowed to react at room temperature for two hours and was monitored by TLC plates for completion. Post-treatment: the reaction solution was concentrated and isolated by prep-CC (PE: ea=2:1-0:1) to give the product 5-X in 60-95% yield.
Example molecules and nuclear magnetic data:
final product 1- (4- (1H-indol-3-yl) -2-morpholino-5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -2, 2-difluoroethane-1-one (5-1) was a white solid in 78% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.76(s,1H),8.28(t,J＝8.0Hz,1H),7.92(d,J＝26.1Hz,1H),7.48(d,J＝7.8Hz,1H),7.17(dt,J＝20.3,7.0Hz,2H),6.88(td,J＝52.7,14.0Hz,1H),4.62(s,1H),4.55(s,1H),3.74(d,J＝17.0Hz,10H),2.97(t,J＝5.1Hz,1H),2.91(t,J＝5.3Hz,1H)。
Final product 1- (4- (1H-indol-3-yl) -2-morpholino-5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) ethan-1-one (5-2) was a white solid in 82% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.77(d,J＝9.3Hz,1H),8.28(d,J＝5.1Hz,1H),7.92(d,J＝7.5Hz,1H),7.48(d,J＝7.6Hz,1H),7.16(dt,J＝20.6,7.1Hz,3H),4.51(d,J＝18.9Hz,2H),3.87–3.54(m,12H),2.95(s,1H),2.83(s,1H),2.13(d,J＝8.0Hz,3H). 13 CNMR(101MHz,DMSO-d 6 )δ169.05,162.40,160.14,136.64,129.96,129.74,126.87,122.52,122.20,120.85,113.08,112.23,66.56,50.54,46.86,44.74,44.18,26.96,22.16,21.58。
Final product 1- (4- (1H-indol-3-yl) -2-morpholino-5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) prop-2-en-1-one (5-3) was an off-white solid in 72% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.74(s,1H),8.28(d,J＝6.8Hz,1H),7.93(d,J＝12.1Hz,1H),7.47(d,J＝7.9Hz,1H),7.16(dt,J＝20.5,7.0Hz,2H),6.93(dt,J＝17.1,8.5Hz,1H),6.26–6.11(m,1H),5.75(t,J＝10.7Hz,1H),4.62(d,J＝32.7Hz,2H),3.74(d,J＝15.9Hz,10H),2.91(d,J＝21.0Hz,2H)。
Final product 1- (4- (1H-indol-3-yl) -2-morpholino-5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -2-methylpropan-1-one (5-4) was an off-white solid with 75% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.74(s,1H),8.28(d,J＝7.0Hz,1H),7.95(s,1H),7.47(d,J＝7.7Hz,1H),7.16(dt,J＝20.5,7.0Hz,2H),4.54(d,J＝40.2Hz,2H),3.73(d,J＝13.3Hz,10H),3.06–2.90(m,2H),2.83(s,1H),1.06(dd,J＝17.1,6.5Hz,H)。
End product (4- (1H-indol-3-yl) -2-morpholino-5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) (cyclopropyl) methanone (5-5) was an off-white solid in 80% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.74(s,1H),8.29(s,1H),7.94(d,J＝2.5Hz,1H),7.48(d,J＝7.8Hz,1H),7.16(dt,J＝20.3,7.0Hz,2H),4.77(s,1H),4.51(s,1H),3.91(s,1H),3.73(d,J＝16.4Hz,11H),2.97(s,1H),2.84(s,1H),2.09(s,1H),0.77(d,J＝8.0Hz,7H)。
Final product 1- (4- (1H-indol-3-yl) -2-morpholino-5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -2, 2-dimethylpropane-1-one (5-6) was an off-white solid in 78% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.74(s,1H),8.31(d,J＝7.8Hz,1H),7.97(d,J＝2.8Hz,1H),7.48(d,J＝7.9Hz,1H),7.16(dt,J＝20.0,6.9Hz,2H),4.55(s,2H),3.81(t,J＝5.3Hz,2H),3.73(d,J＝9.6Hz,8H),2.90(t,J＝5.0Hz,2H),2.51(s,1H),1.27(s,9H)。
End product (4- (1H-indol-3-yl) -2-morpholino-5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) (phenyl) methanone (5-7) was an off-white solid in 70% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.74(s,1H),8.29(d,J＝7.7Hz,1H),7.97(s,1H),7.60–7.44(m,6H),7.16(dt,J＝20.0,7.0Hz,2H),4.65(s,1H),4.45(s,1H),3.97–3.44(m,10H),2.95(s,2H)。
End product 4- (4- (1H-indol-3-yl) -7- (methylsulfonyl) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidin-2-yl) morpholine (5-8) as pale yellowThe solid was found to be 74% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.91(s,1H),8.30(d,J＝7.7Hz,1H),7.99(s,1H),7.49(d,J＝7.8Hz,1H),7.16(dt,J＝19.8,7.0Hz,2H),4.24(s,2H),3.73(d,J＝10.9Hz,8H),3.40(d,J＝16.0Hz,2H),3.01(s,5H)。
End product 4- (4- (1H-indol-3-yl) -7- ((trifluoromethyl) sulfonyl) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidin-2-yl) morpholine (5-9) was a pale yellow solid in 83% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.80(s,1H),8.27(d,J＝7.8Hz,1H),7.99(d,J＝2.8Hz,1H),7.48(d,J＝7.9Hz,1H),7.17(dt,J＝19.5,6.9Hz,2H),4.53(s,2H),3.74(dt,J＝17.3,10.1Hz,19H),3.03(s,2H)。
Final product (R) -4- (4- (1H-indol-4-yl) -7-trifluoroacetyl-5, 6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidin-2-yl) -3-methylmorpholine (5-10) as an off-white solid in 75% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.29(s,1H),7.51(d,J＝7.9Hz,1H),7.41(s,1H),7.18(t,J＝7.6Hz,1H),7.10(d,J＝7.0Hz,1H),6.37(s,1H),4.66(td,J＝18.0,7.4Hz,3H),4.26(d,J＝12.7Hz,1H),3.90(d,J＝11.2Hz,1H),3.72(dd,J＝18.4,9.5Hz,3H),3.57(d,J＝10.7Hz,1H),3.42(t,J＝11.6Hz,1H),3.16(t,J＝12.2Hz,1H),2.72–2.56(m,2H),1.21(d,J＝6.7Hz,3H)。
Final product (R) -4- (4- (1H-indol-4-yl) -7-acetyl-5, 6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidin-2-yl) -3-methylmorpholine (5-11) as a white solid in 70% yield. 1 H NMR(400MHz,Chloroform-d)δ8.59(s,1H),7.47(d,J＝7.9Hz,1H),7.26(s,1H),7.16(d,J＝7.0Hz,1H),6.52(s,1H),4.80(d,J＝16.6Hz,1H),4.60(s,1H),4.40(d,J＝13.3Hz,1H),3.97(d,J＝6.8Hz,1H),3.73(t,J＝18.7Hz,3H),3.66–3.51(m,3H),3.37–3.21(m,1H),2.65(t,J＝18.9Hz,2H),2.20(d,J＝28.9Hz,3H),1.33(d,J＝6.7Hz,3H)。
Final product (R) -4- (4- (1H-indol-4-yl) -7-methanesulfonyl-5, 6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidin-2-yl) -3-methylmorpholine (5-12) as a white solid in 70% yield. 1 H NMR(400MHz,Chloroform-d)δ8.45(s,1H),7.48(d,J＝8.0Hz,1H),7.24(s,1H),7.16(d,J＝7.2Hz,1H),6.49(s,1H),4.84–4.71(m,1H),4.43(d,J＝15.9Hz,2H),3.93(dd,J＝27.3,10.8Hz,2H),3.78–3.67(m,3H),3.56(s,1H),3.46(dd,J＝11.7,5.6Hz,1H),3.34(dd,J＝21.1,14.5Hz,3H),2.89(s,3H),1.33(d,J＝6.7Hz,3H)。
Final product (R) -4- (4- (1H-indol-3-yl) -7-trifluoroacetyl-5, 6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidin-2-yl) -3-methylmorpholine (5-13) as an off-white solid in 78% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.75(s,1H),8.29(dd,J＝7.4,3.6Hz,1H),7.96(dd,J＝7.7,2.9Hz,1H),7.49(d,J＝8.3Hz,1H),7.17(dt,J＝20.6,7.8Hz,2H),4.76–4.67(m,1H),4.66–4.59(m,1H),4.30(d,J＝16.9Hz,1H),4.00–3.92(m,1H),3.91–3.79(m,2H),3.76(d,J＝13.0Hz,1H),3.63(dd,J＝12.7,3.4Hz,1H),3.48(t,J＝10.3Hz,1H),3.42–3.36(m,1H),3.27–3.17(m,1H),3.05–2.94(m,2H),1.26(d,J＝6.8Hz,3H)。
Final product (R) -4- (4- (1H-indol-3-yl) -7-difluoroacetyl-5, 6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidin-2-yl) -3-methylmorpholine (5-14) as an off-white solid in 72% yield. 1 H NMR(400MHz,Chloroform-d)δ8.48(s,1H),8.29(d,J＝7.9Hz,1H),7.56(s,1H),7.45(d,J＝8.1Hz,1H),7.29(dd,J＝13.8,5.1Hz,2H),6.20(td,J＝53.7,52.9,9.3Hz,1H),4.87–4.80(m,1H),4.77–4.66(m,2H),4.65–4.59(m,1H),4.47–4.41(m,1H),4.01(dd,J＝11.2,2.3Hz,1H),3.87–3.82(m,1H),3.77(dd,J＝10.6,3.7Hz,1H),3.60(td,J＝11.6,3.0Hz,1H),3.39–3.33(m,1H),3.32–3.27(m,1H),3.00–2.92(m,2H),1.29–1.24(m,4H)。
Final product (R) -4- (4- (1H-indol-3-yl) -7-methanesulfonyl-5, 6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidin-2-yl) -3-methylmorpholine (5-15) as a pale yellow solid in 74% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.72(s,1H),8.31(dd,J＝7.4,3.6Hz,1H),7.94(dd,J＝7.7,2.9Hz,1H),7.48(d,J＝8.3Hz,1H),7.14(dt,J＝20.6,7.8Hz,2H),4.74–4.67(m,1H),4.68–4.59(m,1H),4.40(d,J＝16.9Hz,1H),4.00–3.92(m,1H),3.91–3.79(m,2H),3.76(d,J＝13.0Hz,1H),3.63(dd,J＝12.7,3.4Hz,1H),3.48(t,J＝10.3Hz,1H),3.42–3.36(m,1H),3.27–3.17(m,1H),3.08(s,5H)，3.05–2.94(m,2H),1.26(d,J＝6.8Hz,3H)。
Final product (R) -1- (4- (1H-indol-3-yl) -2- (3-methylmorpholino) -5, 8-dihydropyrido [3,4-d ]]Pyrimidine-7 (6H) -yl) butane-1, 3-dione (5-16) was an off-white solid in 63% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.67(s,1H),8.31(d,J＝7.9Hz,1H),7.90(d,J＝2.6Hz,1H),7.47(d,J＝8.0Hz,1H),7.14(dt,J＝23.1,6.9Hz,2H),4.68(d,J＝4.6Hz,1H),4.27(d,J＝13.3Hz,1H),3.94(d,J＝11.4Hz,1H),3.74(d,J＝6.2Hz,3H),3.64–3.59(m,1H),3.52–3.44(m,6H),3.17(t,J＝11.1Hz,1H),2.96(h,J＝6.7Hz,2H),2.81–2.71(m,2H),1.23(d,J＝6.6Hz,3H)。
Final product (R) -4- (4- (1H-indol-3-yl) -7-ethoxyacryloyl-5, 6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidin-2-yl) -3-methylmorpholine (5-17) as an off-white solid in 65% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.73(s,1H),8.30(d,J＝7.7Hz,1H),7.92(d,J＝2.2Hz,1H),7.48(dd,J＝9.7,7.2Hz,2H),7.16(dt,J＝21.3,6.9Hz,2H),6.00(t,J＝11.1Hz,1H),4.76–4.69(m,1H),4.57(q,J＝23.7,20.7Hz,2H),4.31(d,J＝12.5Hz,1H),3.98(p,J＝7.3Hz,3H),3.76(td,J＝17.2,7.0Hz,3H),3.63(dd,J＝11.2,2.6Hz,1H),3.47(td,J＝11.8,2.5Hz,1H),3.21(td,J＝13.0,3.1Hz,1H),2.88(s,2H),1.26(d,J＝8.4Hz,6H)。
Final product (R) -4- (4- (1H-indol-3-yl) -7-isopropyl-5, 6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidin-2-yl) -3-methylmorpholine (5-18) as an off-white solid in 72% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.74(s,1H),8.30(d,J＝6.8Hz,1H),7.95(s,1H),7.48(d,J＝7.6Hz,1H),7.16(dt,J＝21.0,7.1Hz,2H),4.71(s,1H),4.59(s,1H),4.55–4.41(m,1H),4.30(d,J＝12.5Hz,1H),3.96(d,J＝10.8Hz,1H),3.76(d,J＝10.5Hz,2H),3.66(dd,J＝24.8,8.9Hz,2H),3.47(t,J＝10.8Hz,1H),3.28–3.13(m,1H),3.04–2.79(m,3H),1.28–1.22(m,3H),1.06(dd,J＝16.6,6.2Hz,6H)。
Final product (R) -1- (4- (1H-indol-3-yl) -2- (3-methylmorpholino) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -2-methylpropan-2-en-1-one (5-19) as a white solid in 80% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.75(s,1H),8.32(d,J＝7.7Hz,1H),7.97(s,1H),7.49(d,J＝7.8Hz,1H),7.17(dt,J＝20.5,7.1Hz,1H),5.30(s,1H),5.15(s,1H),4.77–4.66(m,2H),4.58(d,J＝16.8Hz,1H),4.30(d,J＝13.0Hz,1H),3.95(d,J＝9.1Hz,1H),3.76-3.61(m,3H),3.47(t,J＝10.8Hz,1H),3.37(t,J＝10.8Hz,1H),3.21(t,J＝12.6Hz,1H),3.3-2.91(m,2H),1.93(s,3H),1.26(d,J＝6.6Hz,3H)。
Final product (R) -1- (4- (1H-indol-3-yl) -2- (3-methylmorpholino) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -2-fluoro-2-methylpropan-1-one (5-20) was a white solid with 73% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.75(s,1H),8.32(d,J＝7.7Hz,1H),7.97(s,1H),7.49(d,J＝7.8Hz,1H),7.17(dt,J＝20.5,7.1Hz,1H),4.87–4.70(m,2H),4.62-4.46(m,1H),4.30(d,J＝13.0Hz,1H),3.96-3.70(m,4H),3.66-3.60(m,1H),3.46(t,J＝10.8Hz,1H),3.21(t,J＝12.6Hz,1H),3.03-2.91(m,2H),δ1.61(d,J＝21.3Hz,6H),1.26(d,J＝5.3Hz,3H)。
Final product (R) - (4- (1H-indol-3-yl) -2- (3-methylmorpholino) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) (1-fluorocyclopropyl methanone (5-21) was a white solid in 83% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.74(s,1H),8.31(d,J＝7.8Hz,1H),7.95(s,1H),7.49(d,J＝8.0Hz,1H),7.17(dt,J＝20.5,6.9Hz,2H),4.72(d,J＝4.6Hz,2H),4.51(m,1H),4.31(d,J＝12.3Hz,1H),4.02-3.72(m,4H),3.63(dd,J＝11.3,2.7Hz,1H),3.47(t,J＝11.7Hz,1H),3.30–3.15(m,1H),3.05-2.95(d,2H),1.40–1.17(m,7H)。
End product 1- (4- (1H-indol-3-yl) -2- ((R) -3-methylmorpholino) -5, 8-dihydropyrido [3, 4-d)]Pyrimidin-7 (6H) -yl) -2-methylbutan-1-one (5-22) was an off-white solid in 64% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.75(s,1H),8.32(t,J＝7.4Hz,1H),7.95(d,J＝4.8Hz,1H),7.50(d,J＝7.2Hz,1H),7.17(dt,J＝20.4,7.0Hz,2H),4.72(s,1H),4.52(dd,J＝42.0,18.9Hz,2H),4.31(d,J＝11.9Hz,1H),3.95(d,J＝11.0Hz,1H),3.86–3.58(m,4H),3.47(t,J＝11.3Hz,1H),3.28–3.15(m,1H),2.93(s,1H),2.81(dd,J＝13.3,6.5Hz,2H),1.63(dt,J＝12.8,6.4Hz,1H),1.40–1.31(m,1H),1.25(q,J＝8.2,6.9Hz,3H),1.04(dd,J＝18.3,7.3Hz,3H),0.84(dt,J＝12.2,7.1Hz,3H)。
Final product (R) - (4- (1H-indol-3-yl) -2- (3-methylmorpholino) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) (cyclobutyl) methanone (5-23) was an off-white solid in 78% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.73(s,1H),8.29(d,J＝7.0Hz,1H),7.92(d,J＝11.4Hz,1H),7.49(d,J＝7.9Hz,1H),7.16(dt,J＝20.8,7.0Hz,2H),4.76–4.64(m,1H),4.57–4.37(m,2H),4.30(d,J＝13.4Hz,1H),3.95(d,J＝11.1Hz,1H),3.75(d,J＝11.0Hz,1H),3.69–3.41(m,4H),3.26–3.13(m,1H),2.98–2.76(m,2H),2.31–2.07(m,4H),2.00–1.87(m,1H),1.85-1.74(m,1H),1.25(d,J＝6.5Hz,6H)。
Final product (R) - (4- (1H-indol-3-yl) -2- (3-methylmorpholino) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) (cyclopentyl) methanone (5-24) was an off-white solid in 83% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.74(s,1H),8.30(d,J＝7.1Hz,1H),7.94(s,1H),7.49(d,J＝7.8Hz,1H),7.16(dt,J＝21.0,7.0Hz,2H),4.76–4.67(m,1H),4.50(dd,J＝42.9,18.8Hz,2H),4.35–4.26(m,1H),3.95(d,J＝11.0Hz,1H),3.84–3.57(m,4H),3.47(t,J＝11.5Hz,1H),3.20(td,J＝14.9,12.3,5.6Hz,1H),3.10(p,J＝7.4Hz,1H),2.99–2.87(m,1H),2.83(s,1H),1.89–1.48(m,8H),1.25(d,J＝6.5Hz,3H)。
Final product (R) - (4- (1H-indol-3-yl) -2- (3-methylmorpholino) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) (cyclohexyl) methanone (5-25) was an off-white solid in 75% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.74(s,1H),8.29(d,J＝7.2Hz,1H),7.95(s,1H),7.48(d,J＝7.8Hz,1H),7.16(dt,J＝21.4,7.0Hz,2H),4.71(s,1H),4.60–4.38(m,2H),4.29(d,J＝12.0Hz,1H),3.96(d,J＝11.0Hz,1H),3.81–3.57(m,3H),3.47(t,J＝11.6Hz,1H),3.36(t,J＝11.6Hz,1H),3.23–3.16(m,1H),2.96–2.80(m,2H),2.71(t,J＝8.4Hz,1H),1.71(dd,J＝21.4,8.1Hz,5H),1.32(dt,J＝47.1,8.6Hz,8H)。
Final product (R) -1- (4- (1H-indol-3-yl) -2- (3-methylmorpholino) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -2, 2-dimethylpropane-1-one (5-26) was an off-white solid in 65% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.73(s,1H),8.32(d,J＝7.8Hz,1H),7.97(d,J＝2.6Hz,1H),7.48(d,J＝7.9Hz,1H),7.16(dt,J＝21.2,7.1Hz,2H),4.71(d,J＝6.4Hz,1H),4.55(q,J＝18.2Hz,2H),4.30(d,J＝12.7Hz,1H),3.96(d,J＝11.1Hz,1H),3.90–3.82(m,1H),3.76(d,J＝11.5Hz,2H),3.63(d,J＝11.2Hz,1H),3.47(t,J＝11.7Hz,1H),3.20(t,J＝12.8Hz,1H),2.90(d,J＝4.9Hz,2H),1.26(d,J＝10.3Hz,12H)。
Final product (R) -1- (4- (1H-indol-3-yl) -2- (3-methylmorpholino) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -3-chloro-2, 2-dimethylpropane-1-one (5-27) was an off-white solid in 68% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.74(s,1H),8.33(d,J＝7.7Hz,1H),7.96(s,1H),7.49(d,J＝8.0Hz,1H),7.17(dt,J＝21.1,6.9Hz,2H),4.76–4.64(m,1H),4.55(q,J＝18.2Hz,2H),4.31(d,J＝12.6Hz,1H),3.99–3.72(m,6H),3.63(d,J＝13.4Hz,1H),3.47(t,J＝10.5Hz,1H),3.21(t,J＝12.8Hz,1H),3.01-2.84(m,2H),1.37(s,6H),1.26(d,J＝6.7Hz,3H)。
Final product (R) -1- (4- (1H-indol-3-yl) -2- (3-methylmorpholino) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -2, 2-dimethylbutan-1-one (5-28) was an off-white solid in 68% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.76(s,1H),8.32(d,J＝7.6Hz,1H),7.96(s,1H),7.48(d,J＝7.8Hz,1H),7.16(dt,J＝21.2,6.9Hz,2H),4.75–4.64(m,1H),4.55(q,J＝18.3Hz,2H),4.30(d,J＝12.9Hz,1H),3.95(d,J＝9.5Hz,1H),3.87(d,J＝13.2Hz,1H),3.76(d,J＝10.5Hz,1H),3.63(d,J＝10.2Hz,1H),3.47(t,J＝11.0Hz,1H),3.41–3.37(t,J＝11.0Hz,1H),3.20(t,J＝12.3Hz,1H),3.02–2.80(m,2H),1.66(d,J＝7.2Hz,2H),1.37–1.15(m,9H),0.81(t,J＝7.0Hz,3H)。
Final product (R) - (4- (1H-indol-3-yl) -2- (3-methylmorpholino) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) (1-methylcyclopropyl) methanone (5-29) was an off-white solid in 75% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.75(s,1H),8.31(d,J＝7.7Hz,1H),7.97(s,1H),7.48(d,J＝8.0Hz,1H),7.16(dt,J＝21.3,6.9Hz,3H),4.71-4.70(m,1H),4.65-4.465(m,1H),4.30(d,J＝12.5Hz,1H),3.95(d,J＝10.9Hz,1H),3.91-3.81(m,1H),3.76(d,J＝11.2Hz,2H),3.63(d,J＝11.1Hz,1H),3.47(t,J＝12.7Hz,1H),3.40(d,J＝7.0Hz,1H),3.20(t,J＝14.4Hz,1H),2.93(m,2H),1.31(s,3H),1.25(d,J＝6.6Hz,3H),0.88(s,2H),0.61(s,2H)。
Final product (R) - (4- (1H-indol-3-yl) -2- (3-methylmorpholino) -5, 8-dihydropyrido [3 ],4-d]Pyrimidin-7 (6H) -yl) (1- (trifluoromethyl) cyclopropyl) methanone (5-30) was an off-white solid in 64% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.77(s,1H),8.31(d,J＝7.8Hz,1H),7.95(s,1H),7.49(d,J＝7.9Hz,1H),7.17(dt,J＝20.9,7.1Hz,2H),4.76–4.45(m,3H),4.30(d,J＝12.7Hz,1H),4.02–3.71(m,4H),3.63(d,J＝11.2Hz,1H),3.53–3.32(m,1H),3.21(t,J＝12.8Hz,1H),3.06–2.84(m,2H),1.26(q,J＝15.4,11.6Hz,7H)。
Final product (R) -1- (4- (1H-indol-3-yl) -2- (3-methylmorpholino) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) -3, 3-trifluoro-2, 2-dimethylpropane-1-one (5-31) was an off-white solid in 77% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.76(s,1H),8.33(d,J＝7.7Hz,1H),7.97(s,1H),7.49(d,J＝7.9Hz,1H),7.17(dt,J＝20.6,7.0Hz,2H),4.77–4.67(m,1H),4.57(q,J＝18.2Hz,2H),4.31(d,J＝12.6Hz,1H),4.05–3.84(m,2H),3.84–3.74(m,2H),3.69–3.59(m,1H),3.53–3.43(m,1H),3.21(t,J＝14.3Hz,1H),3.04–2.87(m,2H),1.56(s,6H),1.26(d,J＝6.6Hz,3H)。
Final product (R) - (4- (1H-indol-3-yl) -2- (3-methylmorpholino) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) (2, 3-tetramethylcyclopropyl) methanone (5-32) was a white solid in 72% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.73(s,1H),8.31(d,J＝5.6Hz,1H),7.95(d,J＝2.7Hz,1H),7.48(t,J＝7.5Hz,1H),7.16(dt,J＝21.1,7.0Hz,2H),4.71(d,J＝6.4Hz,1H),4.56(s,1H),4.53–4.39(m,1H),4.30(d,J＝13.0Hz,1H),3.96(d,J＝10.8Hz,1H),3.76(d,J＝9.1Hz,2H),3.63(d,J＝10.4Hz,2H),3.48(t,J＝13.1Hz,1H),3.21(t,J＝12.6Hz,1H),3.02–2.90(m,1H),2.81(s,1H),1.25(d,J＝5.0Hz,3H),1.19(d,J＝9.9Hz,6H),1.13(d,J＝3.5Hz,3H),1.05(d,J＝20.5Hz,3H)。
The final product (4- (1H-indol-3-yl) -2- ((R) -3-methylmorpholino) -5, 8-dihydropyrido [3,4-d ] pyrimidin-7 (6H) -yl) (2, 2-difluoro-1-methylcyclopropyl) methanone (5-33) was a white solid in 79% yield. 1H NMR (400 mhz, dmso-d 6) δ11.88 (s, 1H), 8.31 (d, j=7.8 hz, 1H), 7.97 (d, j=7.5 hz, 1H), 7.49 (t, j=8.0 hz, 1H), 7.16 (dt, j=21.4, 7.2hz, 2H), 4.74-4.67 (m, 1H), 4.60 (dt, j=20.7, 9.6hz, 1H), 4.52-4.39 (m, 1H), 4.35-4.26 (m, 1H), 3.96 (d, j=10.5 hz, 1H), 3.76 (d, j=11.2 hz, 1H), 3.66-3.42 (m, 4H), 3.19 (dd, j=23.8, 11.2hz, 2H), 2.93-2.83 (m, 1H), 1.52-4.39 (m, 1H), 4.35-4.26 (d, 1H), 3.76 (d=10.5 hz, 1H), 3.76 (d, j=11.2 hz, 1H).
Final product (R) -1- (4- (1H-indol-3-yl) -2- (3-methylmorpholino) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidine-7-carbonyl) cyclopropane-1-carbonitrile (5-34) was a white solid in 64% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.92(s,1H),8.29(d,J＝7.8Hz,1H),7.91(s,1H),7.50(d,J＝7.9Hz,1H),7.16(dt,J＝21.3,7.3Hz,2H),4.71(d,J＝7.0Hz,2H),4.66–4.45(m,1H),4.31(d,J＝13.0Hz,1H),4.11–3.89(m,2H),3.76(d,J＝11.2Hz,1H),3.63(dd,J＝11.2,2.7Hz,1H),3.52–3.41(m,2H),3.21(q,J＝9.8,7.8Hz,1H),3.12–2.85(m,2H),1.70–1.56(m,4H),1.26(d,J＝6.7Hz,3H)。
End product (4- (1H-indol-3-yl) -2- ((R) -3-methylmorpholino) -5, 8-dihydropyrido [3, 4-d)]Pyrimidin-7 (6H) -yl) (adamantan-1-yl) methanone (5-35) was an off-white solid in 84% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.72(s,1H),8.33(d,J＝7.8Hz,1H),7.98(s,1H),7.49(d,J＝8.0Hz,1H),7.16(dt,J＝21.4,6.8Hz,2H),4.75–4.64(m,1H),4.56(q,J＝18.3Hz,2H),4.30(d,J＝12.3Hz,1H),4.00–3.89(m,2H),3.83–3.78(m,1H),3.76(d,J＝11.2Hz,1H),3.63(d,J＝13.7Hz,1H),3.47(t,J＝11.6Hz,1H),3.20(t,J＝12.8Hz,1H),3.01-2.84(m,2H),1.98(d,J＝6.3Hz,9H),1.71(s,6H),1.25(d,J＝6.7Hz,3H)。
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Final product (S) - (4- (1H-indol-3-yl) -2- (3-methylmorpholino) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) (1- (trifluoromethyl) cyclopropyl) methanone (5-36) was a pale yellow solid in 35% yield. 1 H NMR(400MHz,DMSO-d 6 )δ12.25(s,1H),8.31(d,J＝7.7Hz,1H),8.12(d,J＝2.5Hz,1H),7.52(d,J＝7.7Hz,1H),7.20(dt,J＝15.5,6.8Hz,2H),4.89–4.70(m,2H),4.39(d,J＝13.0Hz,1H),3.98(d,J＝11.0Hz,1H),3.90(s,1H),3.78(d,J＝11.4Hz,1H),3.65(d,J＝13.6Hz,1H),3.50(t,J＝11.5Hz,1H),3.33(d,J＝15.8Hz,1H),2.96(s,2H),1.31(d,J＝6.7Hz,3H)。
End product (4- (1H-indol-3-yl) -2-morpholino-5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) (1- (trifluoromethyl) cyclopropyl) methanone (5-37) was an off-white solid in 32% yield. 1 H NMR(400MHz,DMSO-d 6 )δ12.18(s,1H),8.30(d,J＝7.6Hz,1H),8.10(d,J＝2.7Hz,1H),7.52(d,J＝7.7Hz,1H),7.20(dt,J＝15.7,6.8Hz,2H),4.70(s,2H),3.74(d,J＝4.4Hz,10H),2.96(s,2H),1.37(d,J＝4.0Hz,2H),1.32(s,2H)。
Final product (S) - (2- (3-aminopiperidin-1-yl) -4- (1H-indol-3-yl) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) (1- (trifluoromethyl) cyclopropyl) methanone (5-38) was an off-white solid in 38% yield. 1 H NMR(400MHz,DMSO-d 6 )δ12.06(s,1H),8.42(s,2H),8.29(d,J＝6.8Hz,1H),8.04(d,J＝2.4Hz,1H),7.51(d,J＝8.2Hz,1H),7.25–7.15(m,2H),4.65–4.60(m,2H),4.37(d,J＝13.3Hz,1H),3.86(s,2H),3.44–3.32(m,1H),3.31–3.17(m,2H),2.95(s,2H),2.08(s,1H),1.87(d,J＝12.7Hz,1H),1.72(q,J＝9.3Hz,1H),1.64–1.50(m,1H),1.43–1.25(m,4H)。
Final product (R) - (2- (3-aminopiperidin-1-yl) -4- (1H-indol-3-yl) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) (1- (trifluoromethyl) cyclopropyl) methanone (5-39) was an off-white solid in 42% yield. 1 H NMR(400MHz,DMSO-d 6 )δ12.21(s,1H),8.54(s,3H),8.35–8.24(m,1H),8.06(d,J＝2.6Hz,1H),7.57–7.46(m,1H),7.20(dt,J＝9.7,5.3Hz,2H),4.86–4.55(m,3H),4.39(d,J＝12.9Hz,1H),3.86(s,3H),3.45–3.33(m,1H),3.33–3.15(m,2H),2.95(s,2H),2.55(s,1H),2.10(d,J＝8.7Hz,1H),1.91–1.82(m,1H),1.80–1.68(m,1H),1.57(q,J＝13.5,12.0Hz,1H),1.35(d,J＝20.9Hz,4H)。
Final product (4- (1H-indol-3-yl) -2- (methyl (pyrrolidin-3-yl) amino) -5, 8-dihydropyrido [3, 4-d)]Pyrimidin-7 (6H) -yl) (1- (trifluoromethyl) cyclopropyl) methanone (5-40) was an off-white solid in 46% yield. 1 H NMR(400MHz,DMSO-d 6 )δ12.02(s,1H),8.41–8.29(m,1H),7.95(d,J＝2.6Hz,1H),7.55–7.45(m,1H),7.27–7.05(m,2H),5.64–5.49(m,1H),4.73–4.47(m,3H),3.85(s,3H),3.18(d,J＝20.3Hz,6H),2.93(s,1H),2.18–2.10(m,1H),2.05–1.93(m,1H),1.39–1.28(m,4H)。
Final product (R) - (4- (1H-indol-3-yl) -2- (3- (methylamino) pyrrolidine)-1-yl) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) (1- (trifluoromethyl) cyclopropyl) methanone (5-41) was an off-white solid in 38% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.97(s,1H),8.49(d,J＝7.8Hz,1H),7.96(d,J＝2.8Hz,1H),7.49(d,J＝7.8Hz,1H),7.16(dt,J＝18.5,6.8Hz,2H),4.58(s,2H),4.00–3.73(m,6H),3.64(d,J＝8.5Hz,1H),2.94(s,2H),2.60(s,3H),2.33(ddt,J＝27.4,12.8,6.6Hz,2H),1.34(d,J＝26.6Hz,4H)。
Final product (S) - (2- (3-aminopyrrolidin-1-yl) -4- (1H-indol-3-yl) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) (1- (trifluoromethyl) cyclopropyl) methanone (42) was an off-white solid in 38% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.93(s,1H),8.50(d,J＝7.9Hz,1H),7.97(s,1H),7.49(d,J＝7.9Hz,1H),7.16(dt,J＝22.4,7.0Hz,2H),4.58(s,2H),3.99–3.63(m,7H),2.94(s,2H),2.34(dq,J＝14.1,7.4Hz,1H),2.17(dd,J＝12.1,6.6Hz,1H),1.35(d,J＝28.0Hz,4H)。
Final product (R) - (4- (1H-indol-3-yl) -2- (methyl (pyrrolidin-3-yl) amino) -5, 8-dihydropyrido [3, 4-d)]Pyrimidin-7 (6H) -yl) (1- (trifluoromethyl) cyclopropyl) methanone (5-43) was an off-white solid in 28% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.76(s,1H),8.36(d,J＝8.1Hz,1H),7.93(s,1H),7.48(d,J＝7.8Hz,1H),7.22–7.11(m,2H),5.46–5.39(m,1H),4.67–4.46(m,3H),3.90–3.78(m,2H),3.08(q,J＝11.7,10.9Hz,4H),2.96–2.79(m,4H),2.03–1.97(m,1H),1.84–1.75(m,1H),1.41–1.28(m,4H)。
End product (2- (1, 1-dioxothiomorpholino) -4- (1H-indol-3-yl)) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) (1- (trifluoromethyl) cyclopropyl) methanone (5-44) was an off-white solid in 48% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.84(s,1H),8.21(d,J＝7.6Hz,1H),7.98(s,1H),7.49(d,J＝7.8Hz,1H),7.17(ddt,J＝14.4,7.4,3.7Hz,2H),4.61(s,2H),4.29(s,4H),3.85(s,3H),3.21(s,3H),2.96(s,2H),2.55(s,2H),1.41–1.28(m,4H)。
The end product (2- (((3 aR,6 aS) -hexahydropyrrolo [3, 4-c)]Pyrrol-2 (1H) -yl) -4- (1H-indol-3-yl) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) (1- (trifluoromethyl) cyclopropyl) methanone (5-45) was an off-white solid in 42% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.85(s,1H),8.48(d,J＝7.7Hz,1H),7.95(s,1H),7.48(d,J＝7.8Hz,1H),7.16(dt,J＝19.0,7.0Hz,2H),4.56(s,2H),3.96–3.73(m,5H),3.49(s,3H),3.13(dd,J＝10.4,6.2Hz,2H),2.93(s,4H),2.81(d,J＝10.9Hz,2H),1.34(d,J＝26.2Hz,4H)。
Final product (4- (1H-indol-3-yl) -7- (1- (trifluoromethyl) cyclopropane-1-carbonyl) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Pyrimidine-2-yl) piperidine-4-carboxylic acid methyl ester (5-46) was an off-white solid in 38% yield. 1 H NMR(400MHz,DMSO-d 6 )δ12.15(s,1H),8.30(d,J＝7.5Hz,1H),8.19–8.11(m,1H),7.53(d,J＝7.8Hz,1H),7.22(dt,J＝14.0,6.4Hz,2H),4.83–4.56(m,4H),3.63(s,3H),3.46(d,J＝9.9Hz,1H),3.25(t,J＝11.5Hz,2H),2.96(s,2H),2.76(t,J＝11.2Hz,1H),2.71(s,1H),1.98(d,J＝12.5Hz,2H),1.69–1.57(m,2H),1.34(dd,J＝25.9,6.5Hz,4H)。
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Final product (2- (((2R, 6S) -2, 6-dimethylmorpholino)) -4- (1H-indol-3-yl) -5, 8-dihydropyrido [3,4-d ]]Pyrimidin-7 (6H) -yl) (1- (trifluoromethyl) cyclopropyl) methanone (5-47) was an off-white solid in 33% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.76(s,1H),8.28(d,J＝7.8Hz,1H),7.95(d,J＝2.6Hz,1H),7.49(d,J＝7.9Hz,1H),7.17(dt,J＝20.4,6.9Hz,2H),4.57(d,J＝12.2Hz,4H),3.85(s,2H),3.62(dd,J＝9.5,4.1Hz,2H),2.92(s,2H),2.55(s,2H),1.41–1.27(m,4H),1.19(d,J＝6.1Hz,6H)。
End product (4- (1H-indol-3-yl) -2- (pyrrolidin-3-ylamino) -5, 8-dihydropyrido [3, 4-d)]Pyrimidin-7 (6H) -yl) (1- (trifluoromethyl) cyclopropyl) methanone (5-48) was an off-white solid in 35% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.85(s,1H),8.52(d,J＝7.8Hz,1H),7.94(s,1H),7.48(d,J＝7.9Hz,1H),7.16(dt,J＝22.3,7.0Hz,2H),4.55(s,2H),3.89–3.58(m,6H),2.92(s,2H),2.11(dt,J＝11.7,6.0Hz,1H),1.78(dt,J＝12.0,6.0Hz,1H),1.43–1.27(m,4H)。
Final product (4- (1H-indol-3-yl) -2- (4- (methylsulfonyl) piperazin-1-yl) -5, 8-dihydropyrido [3, 4-d)]Pyrimidin-7 (6H) -yl) (1- (trifluoromethyl) cyclopropyl) methanone (5-49) was an off-white solid in 43% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.93(s,1H),8.28(d,J＝7.7Hz,1H),7.96(s,1H),7.50(d,J＝7.6Hz,1H),7.24–7.11(m,2H),4.59(s,2H),3.89(d,J＝30.7Hz,6H),3.23(s,4H),2.93(s,2H),2.90(s,3H),1.36(dd,J＝22.3,12.1Hz,4H)。
End product (2- ((3-azabicyclo [ 3.1.0)]Hex-6-yl) amino) -4- (1H-indol-3-yl) -5, 8-dihydropyrido [3,4-d]Pyrimidin-7 (6H) -yl) (1-Trifluoromethyl) cyclopropyl) methanone (5-50) was an off-white solid in 38% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.87(s,1H),8.42(d,J＝7.8Hz,1H),7.94(s,1H),7.48(d,J＝7.8Hz,1H),7.16(dt,J＝21.4,7.3Hz,2H),4.65–4.49(m,2H),3.84(s,2H),3.20(s,4H),2.93(d,J＝6.9Hz,2H),2.03–1.95(m,1H),1.49–1.27(m,6H)。
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The final product methyl N- (4- (1H-indol-3-yl) -7- (1- (trifluoromethyl) cyclopropane-1-carbonyl) -5,6,7, 8-tetrahydropyrido [3,4-d ]]Pyrimidin-2-yl) -methyl N-methylglycinate (5-51) was an off-white solid in 44% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.72(s,1H),8.42(d,J＝7.8Hz,1H),7.94(d,J＝2.6Hz,1H),7.48(d,J＝8.0Hz,1H),7.16(dt,J＝21.2,6.9Hz,2H),4.57(s,2H),3.85(d,J＝11.4Hz,2H),3.43–3.35(m,3H),3.20(s,3H),2.93(s,2H),2.70(s,2H),1.35(d,J＝25.6Hz,4H)。
Note that: the synthesis of the example molecule is selected from either the first or second route synthesis.
Evaluation of pharmacological Activity of Compounds
In vitro kinase assay for tetrahydropyridopyrimidine derivatives
In vitro Kinase assays were performed using the Kinase Profiler service provided by Eurofins Inc. A mixture of test compound 5-X and kinase ATR/ATRIP was incubated with 50nM GST-CMyc-p53 and an ATP buffer containing Mg ions to initiate a reaction via Mg/ATP. After 30 minutes incubation at room temperature, the reaction was stopped by adding a stop buffer containing EDTA, followed by the addition of a detection buffer containing a d 2-tagged anti-GST monoclonal antibody and a phosphorylated p53 europam-tagged anti-phosphorylated monoclonal antibody. The reaction plate was placed in an microplate reader and HTRF signal values were calculated using time resolved fluorescence (HTRF) mode according to the formula htrf= (Em 665nm/Em620 nm) ×10000.
Test results: the inhibition of ATR activity by Compound 5-X was measured, and the results are shown in Table 1 (A represents IC 50 <100nM, B500 nM>IC 50 >100nM, C representing 1000nM>IC 50 >500nM, D represents IC 50 >1000nM)。
TABLE 1 kinase Activity data
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Kinase selectivity assay for Compounds 5-30
Table 2 inhibition data for compounds 5-30 on 4 off-target targets
Kinase enzymes IC 50 (μM) Kinase enzymes IC 50 (μM)
AAK1 2.326 PI3K(p110d/p85a) 4.945
mTOR/FKBP12 >10 PI3K(p110a/p85a) >10
In kinase selectivity assay, the present inventionThe invention found that compounds 5-30 at a concentration of 10 μm showed excellent selectivity for only 4 kinase targets of the 412 recombinant human protein kinases tested, greater than 50%, kinase AAK1, PI3K (p 110d/p85 a), PI3K (p 110a/p85 a) and mTOR/FKBP12, respectively. Further testing of IC's for these 4 kinase targets 50 The values, results are shown in Table 2, with kinase activity of compounds 5-30 within 10. Mu.M for only 2 of the targets. In general, compounds 5-30 showed excellent kinase selectivity for 412 recombinant human protein kinases.
In vitro cell experiments of tetrahydropyridopyrimidine derivatives
(1) Cell culture consumable:
cell culture medium: DMEM medium (Gibco Co.), RPMI-1640 (Gibco Co.); fetal bovine serum (FBS, hyclone); penicillin solution and streptomycin solution (Invitrogen Bio Inc.)
And (3) cells: HT-29 (human colorectal adenocarcinoma cells), loVo (human colorectal adenocarcinoma cells), NCI-H23 (human non-small cell lung carcinoma cells), A549 (human lung carcinoma cells), HL60 (human promyelocytic leukemia cells) were all purchased from the American Type Culture Collection (ATCC), mantle cell lymphoma cell Granta519.
Cell culture consumable: pancreatin (Invitrogen biology company); 6-well plates, 24-well plates, 96-well plates, centrifuge tubes, gun tips, etc. (Corning Inc.), 20, 100mm cell culture dishes (WHB Inc.).
(2) Cell culture:
HT-29 and LoVo cells were cultured in DMEM medium (containing 10% fetal bovine serum, 100U/mL penicillin and 100. Mu.g/mL streptomycin); NCI-H23, A549, HL60 cells were cultured in RPMI1640 medium (containing 10% fetal bovine serum, 100U/mL penicillin and 100. Mu.g/mL streptomycin). Simultaneously placing all cells at 37deg.C and 5% CO 2 The culture was performed in a wet cell incubator. In the cell culture process, cells are reasonably passaged by digesting with pancreatin to ensure proper cell density, and all experiments adopt cells in logarithmic growth phase.
(3) MTT assay
A. Solution configuration
5mg/mL MTT solution: MTT powder was dissolved in physiological saline to prepare a 5mg/mL solution, and the solution was filtered through a 0.22 μm filter membrane and stored at 4℃in the absence of light, and used within 1 month.
20% acidic SDS solution: 80g of SDS powder was weighed and ultrapure water was added to 320mL. After ultrasonic treatment until dissolution, 400. Mu.L of concentrated hydrochloric acid was added, and finally, ultrapure water was used to set the volume to 400mL.
B. Adherent cell (HT-29, loVo, A549) treatment
Cells in the logarithmic growth phase were seeded in 96-well plates (3500, 2000 and 3000 cells/well for LoVo, HT-29 and a549 cells, respectively) per 100 μl of each well, a blank group and a cell control group were left, 200 μl of physiological saline for injection was added to the side wells, the well plates were cultured overnight in a cell incubator, 100 μl of medium containing compounds at different concentrations was added to the well plates seeded with cells, and 3 multiplex wells were placed in each group. Incubate in the cell incubator for 72h.
C. Suspension cell (NCI-H23 and HL 60) treatment
After 100. Mu.L of a medium containing compounds of different concentrations was added to an orifice plate inoculated with cells, cells in the logarithmic growth phase were inoculated into 96-well plates at a rate of 100. Mu.L per well (NCI-H23 and HL60 cells were inoculated at 8000 and 10000 cells/well, respectively), 3 compound wells were provided per group, a blank group and a cell control group were left, 200. Mu.L of physiological saline for injection was added to the side wells, and incubated in a cell incubator for 72 hours.
D. Color development
mu.L of 5mg/mL MTT staining solution was added to each well, incubated in a cell incubator for 2-4h, complete staining of the cells was confirmed under a microscope, 50. Mu.L of 20% acid SDS solution was added, and the incubation was continued overnight in the cell incubator. Finally, detecting the absorption light value at 570nm by using a multifunctional enzyme-labeled instrument.
E. Computing IC 50
Cell viability was calculated using absorbance of each well at different concentrations of compound, on the abscissa of compound concentration, and on the ordinate of viability, IC was calculated by fitting using GraphPad Prism 5.0 software 50 . Survival = 100-100% × (control-dosing)/(control-blank).
Lovo cell assay results inhibition of ATR activity by Compound 5-X was determined and the results are shown in Table 3.
TABLE 3 cell Activity of representative tetrahydropyridopyrimidine derivatives LoVo
Cell experiments were performed on compounds with ATR kinase activity within 0.5 μm. MTT assay was performed using the LoVo cell line deficient in ATM. Cell data as shown in Table 3, compounds 5-30 were most potent in inhibiting proliferation of human colorectal cancer LoVo cells, IC 50 0.270. Mu.M; compounds 5-27 times, IC 50 0.330. Mu.M; the proliferation inhibiting effect of other compounds on LoVo cells is mostly 1.0 μm.
In order to find tumor cell lines more sensitive to tetrahydropyridopyrimidines. The invention performs a large number of cell screens, and finds that the series of compounds are sensitive to the Granta519 cell strain of the ATM mutant mantle cell lymphoma cell. By MTT experiments, we tested 8 representative compounds for their ability to inhibit proliferation of mantle cell lymphoma cells Granta519 cells. The test results are shown in Table 4, with compounds 5-30 exhibiting excellent antiproliferative activity in mantle cell lymphoma cells, IC 50 0.089. Mu.M.
TABLE 4 Activity of representative tetrahydropyridopyrimidine derivatives in 519 cells
Compounds of formula (I) 5-26 5-22 5-19 5-28 5-30 5-31 5-33 5-36
Cell IC 50 (μM) 0.308 0.377 0.600 0.300 0.089 0.263 0.708 0.768
To evaluate the in vivo antitumor activity of compounds 5-30, the present invention established a mantle cell lymphoma cell Granta-519 subcutaneous tumor xenograft model using female NOD/SCID mice. 37.5 or 75mg/kg of compound 5-30 is orally taken twice daily (BID), the same volume of solvent is orally taken by the control group, and after 13 days of continuous administration, the mantle cell lymphoma of the control group is found to have a volume exceeding 2000mm 3 The experiment was stopped. Animal results as shown in figure 1, compounds 5-30 slowed tumor growth in a dose dependent manner in all treatment groups. Compared with a blank group, the growth of mantle cell lymphoma can be obviously controlled by orally taking 75mg/kg of compound 5-30 twice daily (BID); the mice of the administration group have no obvious change in weight during the administration period, and the preliminary indication that the compounds 5-30 are nontoxic in the miceThere is a certain safety.

Claims (11)

1. A compound of formula i or a pharmaceutically acceptable salt thereof, characterized in that: the structure is as follows:
R 1 selected from the group consisting ofR 4 、R 5 Independently selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted C1-C8 alkenyl, substituted or unsubstituted 6-10 membered aryl; r is R 1 Wherein the substituent of the substituted C1-C8 alkyl and substituted C1-C8 alkenyl is selected from halogen, C1-C8 acyl, C1-C8 alkoxy and cyano, and the substituent of the substituted 3-10 membered cycloalkyl and substituted 6-10 membered aryl is selected from C1-C8 alkyl, halogen, C1-C8 acyl, C1-C8 alkoxy and cyano;
R 2 、R 3 independently selected from H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 3-10 membered azacycloalkyl, and R 2 、R 3 Not simultaneously H, or R 2 、R 3 The N is connected to form a substituted or unsubstituted 4-10 membered heterocycloalkyl, 1-2N are contained in the 3-10 membered azacycloalkyl, 0-2 hetero atoms are contained in the 4-10 membered heterocycloalkyl besides the N shown in the formula I, and the hetero atoms are N, O or S; r is R 2 、R 3 Wherein the substituent of the substituted C1-C8 alkyl is selected from C1-C8 alkoxycarbonyl, amino and sulfo; the substituent groups of the substituted 4-10 membered azacycloalkyl and the substituted 4-10 membered heterocycloalkyl are selected from C1-C8 alkyl, C1-C8 alkoxycarbonyl, amino and sulfo;
R 4 is indolyl.
2. A compound according to claim 1, characterized in that: r is R 4 Is that
3. A compound according to claim 1 or 2, characterized in that:
R 4 、R 5 independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 6-10 membered aryl, and, n＝0～3；R 4 、R 5 Wherein the substituent of the substituted C1-C6 alkyl is selected from halogen, C1-C6 acyl, C1-C6 alkoxy and cyano, and the substituent of the substituted 6-10 membered aryl is selected from C1-C6 alkyl, halogen, C1-C6 acyl, C1-C6 alkoxy and cyano; r is R 6 Selected from H, halogen, cyano, halogen substituted or unsubstituted C1-C6 alkyl; r is R 7 Selected from H, halogen, C1-C6 alkyl; r is R 8 Selected from H, C-C6 alkyl; r is R 9 Selected from H, C-C6 alkyl, C1-C6 alkoxy;
preferably, R 4 、R 5 Independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 6 membered aryl,n＝0～3；R 4 、R 5 Wherein the substituent of the substituted C1-C6 alkyl is selected from halogen, C1-C4 acyl, C1-C4 alkoxy and cyano, and the substituent of the substituted 6-10 membered aryl is selected from C1-C4 alkyl, halogen, C1-C4 acyl, C1-C4 alkoxy and cyano; r is R 6 Selected from H, halogen, cyano, halogen substituted or unsubstituted C1-C4 alkyl; r is R 7 Selected from H, halogen, C1-C4 alkyl; r is R 8 Selected from H, C-C4 alkyl; r is R 9 Selected from H, C-C4 alkyl, C1-C4 alkoxy;
more preferably, R 4 、R 5 Independently selected from substituted or unsubstituted C1-C6 alkyl, phenyl,n＝0～3；R 4 、R 5 Wherein the substituent of the substituted C1-C6 alkyl is selected from F, cl and C1-C4 acyl; r is R 6 Selected from H, F, cyano, unsubstituted C1-C4 alkyl, trifluoromethyl; r is R 7 Selected from H, F, C-C4 alkyl; r is R 8 Selected from H, C-C4 alkyl; r is R 9 Selected from H, C-C4 alkyl, C1-C4 alkoxy;
still more preferably, R 4 Selected from substituted or unsubstituted C1-C6 alkyl, phenyl,n＝0～3；R 4 Wherein the substituent of the substituted C1-C6 alkyl is selected from F, cl and C1-C4 acyl; r is R 6 Selected from H, F, cyano, unsubstituted C1-C4 alkyl, trifluoromethyl; r is R 7 Selected from H, F, C-C4 alkyl; r is R 8 Selected from H, C-C4 alkyl; r is R 9 Selected from H, C-C4 alkyl, C1-C4 alkoxy; r is R 5 A C1-C4 alkyl group substituted or unsubstituted with fluorine;
most preferably, R 4 Selected from methyl, difluoromethyl, trifluoromethyl, acetylmethyl, isopropyl, tert-butyl, isobutyl, and,Vinyl group,/->Phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, < >>R 5 Selected from trifluoromethyl and methyl.
4. A compound according to any one of claims 1 to 3, characterized in that:
R 2 、R 3 independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3-8 membered azacycloalkyl, and R 2 、R 3 And the N is not H at the same time, and the 3-8 membered azacycloalkyl contains 1-2N; r is R 2 、R 3 Wherein the substituent of the substituted C1-C6 alkyl is selected from C1-C6 alkoxycarbonyl, -NHR 10 、-SO 2 R 11 The method comprises the steps of carrying out a first treatment on the surface of the The substituent of the substituted 3-8 membered azacycloalkyl is selected from C1-C6 alkyl, C1-C6 alkoxycarbonyl and NHR 12 、-SO 2 R 13 ；R 10 、R 12 Independently selected from H, C to C6 alkyl; r is R 11 、R 13 Independently selected from C1-C6 alkyl;
preferably, R 2 、R 3 Independently selected from H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 5-6 membered azacycloalkyl, and R 2 、R 3 And the N is not H at the same time, and 1N is contained in the 5-6 membered azacycloalkyl; r is R 2 、R 3 Wherein the substituent of the substituted C1-C4 alkyl is selected from C1-C4 alkoxycarbonyl, -NHR 10 、-SO 2 R 11 The method comprises the steps of carrying out a first treatment on the surface of the The substituent of the substituted 5-6 membered azacycloalkyl is selected from C1-C4 alkyl, C1-C4 alkoxycarbonyl and NHR 12 、-SO 2 R 13 ；R 10 、R 12 Independently selected from H, C to C4 alkyl; r is R 11 、R 13 Independently selected from C1-C4 alkyl;
more preferably, R 2 、R 3 Independently selected from H, C C1-C4 alkoxycarbonyl substituted or unsubstituted C1-C4 alkyl, unsubstituted 5-6 membered azacycloalkyl, and R 2 、R 3 And the N is not H at the same time, and 1N is contained in the 5-6 membered azacycloalkyl;
most preferably, R 2 、R 3 Independently selected from H, methyl,
5. A compound according to any one of claims 1 to 4, wherein: the structure is shown as formula II:
the nitrogen heterocycle A is selected from substituted or unsubstituted 5-8 membered heterocycloalkyl, wherein the 5-8 membered heterocycloalkyl contains 0-1 hetero atom besides N shown in a formula II, and the hetero atom is N, O or S; the substituent of the substituted 5-8 membered heterocycloalkyl is selected from C1-C6 alkyl, C1-C6 alkoxycarbonyl and NHR 14 、-SO 2 R 15 ；R 14 Selected from H, C-C6 alkyl; r is R 15 From C1-C6 alkyl.
6. A compound according to claim 5, characterized in that:
the nitrogen heterocycle A is selected fromX is selected from O, NR 20 、CHR 21 、SO 2 ；R 16 、R 17 、R 19 Independently selected from H, C-C4 alkyl, C1-C4 alkoxycarbonyl, -NHR 14 、-SO 2 R 15 ；R 14 Selected from H, C-C4 alkyl; r is R 15 From C1-C4 alkyl; r is R 18 、R 20 、R 21 Independently selected from H, C-C4 alkoxycarbonyl, -SO 2 R 22 ；R 22 Selected from C1-C4 alkyl;
preferably, the nitrogen heterocycle A is selected fromR 17 is-NHR 14 ；R 23 、R 24 、R 25 、R 26 Independently selected from H, C-C4 alkyl, C1-C4 alkoxycarbonyl, -NHR 14 ；R 14 Selected from H, C-C4 alkyl; r is R 27 is-SO 2 R 15 ；R 15 From C1-C4 alkyl;
most preferably, the nitrogen heterocycle A is selected from
7. A compound according to claim 6, characterized in that:is-> Is-> Is-> Is-> Is-> Is->
8. A compound according to claims 1 to 7, characterized in that: the structural formula is as follows:
9. a pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable auxiliary ingredient.
10. Use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 9, for the preparation of an ATR kinase inhibitor.
11. Use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 9, in the manufacture of a medicament for the treatment of cancer; preferably, the cancer is colorectal cancer or mantle cell lymphoma.
CN202210107126.3A 2022-01-28 2022-01-28 Tetrahydropyridopyrimidine derivatives and their use Pending CN116554165A (en)

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