Fused pyrimidine derivatives and uses thereof

Abstract

This invention relates to a novel class of fused pyrimidine compounds of general formula I, or their stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, as well as methods for their preparation and applications, wherein R1, R2, A, Y, L, and n have the meanings given in the specification. This invention also relates to the use of such compounds, their pharmaceutically acceptable salts, solvates, or prodrugs thereof in the preparation of medicaments for treating diseases caused by abnormally high ATR expression, particularly in the preparation of medicaments for treating and / or preventing hyperproliferative diseases, including but not limited to gastric cancer, liver cancer, colorectal cancer, ovarian cancer, and pancreatic cancer.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to a fused pyrimidine derivative and its applications. Background Technology

[0002] Ataxia-telangiectasia mutations and Rad3-associated kinase (ATR) are serine / threonine protein kinases that, along with ATM and DNA-PK, form part of the DNA damage response (DDR), coordinating cellular responses to DNA damage, stress, and cell cycle perturbations. ATR is crucial for the survival of replicating cells that respond to the accumulation of single-strand breaks (SSBs) in DNA (such as stalled replication forks) and massive DNA damage (such as damage caused by chemotherapy drugs and ultraviolet radiation). The sensitivity of tumor cells to chemotherapy drugs has been shown to be mediated by the genetic regulation of ATR activity.

[0003] ATR kinases are responsible for initiating cellular responses to and repair of genomic instability. Upon sensing DNA damage and replication fork pressure, they are rapidly activated, directly phosphorylating over 1000 important intracellular substrates (including proteins encoded by the tumor suppressor gene p53 and cell cycle regulatory proteins), globally regulating genomic stability. Cancer cells typically exhibit high levels of oncogene-induced replication stress and are more dependent on ATR kinases. ATR kinase inhibitors can interfere with DNA repair, causing errors in cancer cell DNA that cannot be repaired, ultimately promoting tumor cell apoptosis. Studies have shown upregulated ATR expression in various tumor tissues, such as liver cancer, gastric cancer, ovarian cancer, and pancreatic cancer, and patients with high ATR levels often have low survival rates. Therefore, ATR is an important target for cancer therapy, and ATR inhibitors are also important anti-tumor drugs.

[0004] Compounds currently in preclinical and clinical research stages include Ceralasertib (AZD-6738), Berzosertib (VX-970, M6620), BAY1895344, and M4344. Among these, AZD-6738 and VX-970 are currently in Phase II clinical trials, while BAY-1895344 and M4344 are in Phase I. Although some ATR inhibitors have been reported, none are yet on the market. There is still a pressing need for new ATR inhibitors, especially those with high activity and other superior properties.

[0005] Summary of the Invention

[0006] The purpose of this invention is to provide a novel fused pyrimidine derivative and its application.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] A fused pyrimidine derivative, wherein the derivative is a compound of general formula I and its stereoisomers, a pharmaceutically acceptable salt, a solvate, or a prodrug.

[0009]

[0010] Ⅰ

[0011] in,

[0012] R1 and R2 together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least 1-4 heteroatoms, wherein the heterocyclic group is optionally substituted by 1-3 identical or different R3s, and optionally substituted by 1-2 oxygens;

[0013] R3 is H, cyano, halogen, (C1-C6) alkyl, halo(C1-C6) alkyl, (C1-C6) alkoxy, (haloC1-C6) alkoxy, carboxyl, (C1-C6) alkoxyformyl, unsubstituted or carbamoyl group substituted with 1-2 (C1-C6) alkyl groups.

[0014] A is a 4-10 membered heterocyclic group, (C6-C10) aryl group, or 5-10 membered heteroaryl group that is unsubstituted or substituted by 1-3 identical or different R4 groups;

[0015] n is 1, 2, or 3;

[0016] Y is -C(O)-, -S(O)2-, -S(O)-, -C(S)-, -CH2-, -C(O)CH2-, -CH2C(O)-;

[0017] L represents an unsubstituted (C1-C6) alkyl, (C1-C6) alkoxy, (C2-C6) alkenyl, (C3-C6) cycloalkyl, or (C6-C6) alkyl group, substituted with 1-3 identical or different R7 groups. 10 )Aryl, 5-10 heteroaryl, -NR5R6;

[0018] R5 and R6 may be the same or different, and are independently selected from hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, 4-10 membered heterocyclic groups, (C6-C6)cycloalkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl, (C4-C6)cycloalkyl, (C3 ... 10 )Aryl, 5-10 heteroaryl;

[0019] Alternatively, R5 and R6 together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least 1-4 heteroatoms, wherein the heterocyclic group is optionally replaced by 1-2 oxygen atoms;

[0020] R4 and R7 are halogens, hydroxyl groups, nitro groups, cyano groups, carboxyl groups, (C1-C6)alkyl groups, (C1-C6)alkoxy groups, halo(C1-C6)alkyl groups, halo(C1-C6)alkoxy groups, (C1-C6)alkylacyl groups, (C1-C6)alkoxyformyl groups, (C1-C6)alkylamide groups, (C1-C6)alkylsulfinyl groups, (C1-C6)alkylsulfonyl groups, (C1-C3)alkyldioxy groups, unsubstituted or amino groups substituted with 1-2 (C1-C6)alkyl groups, and unsubstituted or carbamoyl groups substituted with 1-2 (C1-C6)alkyl groups.

[0021] The aforementioned aryl group is phenyl or naphthyl; the heteroaryl group is an unsaturated cyclic system containing one or more heteroatoms, either monocyclic or polycyclic, wherein the cyclic system is aromatic and is imidazole, pyrazol, pyridinyl, indolyl, azaindolyl, benzimidazolyl, benzopyrazolyl, indolone, isoyindolone, pyrazolyl, furanyl, thiophene, pyrrole, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzoxazolyl; the heterocyclic group is a saturated or partially saturated cyclic system containing one or more heteroatoms, either monocyclic, polycyclic, bridged, or spirocyclic, wherein the cyclic system is pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, indololinyl, or thiazolyl.

[0022] Preferably, the derivative is a compound of general formula I and its stereoisomers, a pharmaceutically acceptable salt, a solvate, or a prodrug thereof.

[0023] in,

[0024] R1 and R2 together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least 1-3 heteroatoms, wherein the heterocyclic group is optionally substituted by 1-2 identical or different R3s or substituted by 1-2 oxygens;

[0025] R3 is H, cyano, halogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkyl, halo(C1-C4)alkoxy, carboxyl, (C1-C4)alkoxyformyl, unsubstituted or substituted with 1-2 (C1-C4)alkyl amino groups, or unsubstituted or substituted with 1-2 (C1-C4)alkyl carbamoyl groups.

[0026] A is an unsubstituted or substituted 4-10 membered heterocyclic group (C6-C) with 1-2 identical or different R4 groups. 10 )Aryl, 5-10 heteroaryl;

[0027] n is 1 or 2;

[0028] Y is -C(O)-, -S(O)2-, -C(O)CH2-, -CH2C(O)-;

[0029] L represents an unsubstituted (C1-C4) alkyl, (C1-C4) alkoxy, (C2-C4) alkenyl, (C3-C6) cycloalkyl, or (C6-C4) alkyl group, substituted with 1-3 identical or different R7 groups. 10 )Aryl, 5-10 heteroaryl, -NR5R6;

[0030] R5 and R6 may be the same or different, and are independently selected from hydrogen, (C1-C4)alkyl, (C3-C4)cycloalkyl, 4-10 membered heterocyclic groups, (C6-C4)cycloalkyl, (C3-C4)cycloalkyl, (C5-C6 ... 10 )Aryl, 5-6 membered heteroaryl;

[0031] Alternatively, R5 and R6 together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least 1-4 heteroatoms, wherein the heterocyclic group is optionally replaced by 1-2 oxygen atoms;

[0032] R4 and R7 are halogens, hydroxyl groups, nitro groups, cyano groups, carboxyl groups, (C1-C4)alkyl groups, (C1-C4)alkoxy groups, halo(C1-C4)alkyl groups, halo(C1-C4)alkoxy groups, (C1-C4)alkylformyl groups, (C1-C4)alkylamide groups, (C1-C4)alkylsulfinyl groups, (C1-C4)alkylsulfonyl groups, (C1-C3)alkyldioxy groups, unsubstituted or amino groups substituted with 1-2 (C1-C4)alkyl groups, and unsubstituted or carbamoyl groups substituted with 1-2 (C1-C4)alkyl groups.

[0033] More preferably, the derivative is a compound of general formula I and its stereoisomers, a pharmaceutically acceptable salt, a solvate, or a prodrug thereof.

[0034] in,

[0035] R1 and R2 together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least 1-2 heteroatoms, wherein the heterocyclic group is optionally substituted by 1-2 identical or different R3s or substituted by 1-2 oxygens;

[0036] R3 is H, cyano, halogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkyl, halo(C1-C4)alkoxy, carboxyl, (C1-C4)alkoxyformyl, unsubstituted or substituted with 1-2 (C1-C4)alkyl amino groups, or unsubstituted or substituted with 1-2 (C1-C4)alkyl carbamoyl groups.

[0037] A is an unsubstituted or substituted 4-10 membered heterocyclic group (C6-C) with 1-2 identical or different R4 groups. 10 )Aryl, 5-10 heteroaryl;

[0038] n is 1 or 2;

[0039] Y is -C(O)-, -S(O)2-, -C(O)CH2-, -CH2C(O)-;

[0040] L represents unsubstituted (C1-C4) alkyl, (C3-C6) cycloalkyl, phenyl, 5-10 heteroaryl, or -NR5R6 substituted with 1-3 identical or different R7 groups;

[0041] R4 and R7 are halogens, hydroxyl groups, nitro groups, cyano groups, carboxyl groups, (C1-C4)alkyl groups, (C1-C4)alkoxy groups, halo(C1-C4)alkyl groups, halo(C1-C4)alkoxy groups, (C1-C4)alkylformyl groups, (C1-C4)alkylamide groups, (C1-C4)alkylsulfinyl groups, (C1-C4)alkylsulfonyl groups, (C1-C3)alkyldioxy groups, unsubstituted or amino groups substituted with 1-2 (C1-C4)alkyl groups, and unsubstituted or carbamoyl groups substituted with 1-2 (C1-C4)alkyl groups.

[0042] Further preferably, the derivative is a compound of general formula I and its stereoisomers, a pharmaceutically acceptable salt, a solvate, or a prodrug thereof.

[0043] in,

[0044] R1 and R2 together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least 1-2 heteroatoms, wherein the heterocyclic group is optionally substituted by 1-2 identical or different R3s or substituted by 1-2 oxygens;

[0045] R3 is H, cyano, halogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkyl, halo(C1-C4)alkoxy, carboxyl, (C1-C4)alkoxyformyl, unsubstituted or substituted with 1-2 (C1-C4)alkyl amino groups, or unsubstituted or substituted with 1-2 (C1-C4)alkyl carbamoyl groups.

[0046] A is an unsubstituted or substituted 4-10 membered heterocyclic group (C6-C) with 1-2 identical or different R4 groups. 10 )Aryl, 5-10 heteroaryl;

[0047] n is 1 or 2;

[0048] Y is -C(O)-, -S(O)2-, -C(O)CH2-, -CH2C(O)-;

[0049] L is (C1-C4) alkyl, (C3-C6) cycloalkyl, phenyl, 5-10 heteroaryl, and the aforementioned L may be optionally substituted by 1-3 identical or different R7s;

[0050] R4 and R7 are halogens, hydroxyl groups, nitro groups, cyano groups, carboxyl groups, (C1-C4)alkyl groups, (C1-C4)alkoxy groups, halo(C1-C4)alkyl groups, halo(C1-C4)alkoxy groups, (C1-C4)alkylformyl groups, (C1-C4)alkylamide groups, (C1-C4)alkylsulfinyl groups, (C1-C4)alkylsulfonyl groups, (C1-C3)alkyldioxy groups, unsubstituted or amino groups substituted with 1-2 (C1-C4)alkyl groups, and unsubstituted or carbamoyl groups substituted with 1-2 (C1-C4)alkyl groups.

[0051] More preferably, the derivative is a compound of general formula I and its stereoisomers, a pharmaceutically acceptable salt, a solvate, or a prodrug thereof.

[0052] in,

[0053] R1 and R2, together with the nitrogen atoms they are attached to, form the following structure:

[0054] , , , , , , , , , , ;

[0055] A is an unsubstituted or substituted 4-10 membered heterocyclic group (C6-C) with 1-2 identical or different R4 groups. 10 )Aryl, 5-10 heteroaryl;

[0056] n is 1 or 2;

[0057] Y is -C(O)-;

[0058] L is (C1-C4) alkyl, (C3-C6) cycloalkyl, phenyl, 5-10 heteroaryl, and the aforementioned L may be optionally substituted by 1-3 identical or different R7s;

[0059] R4 and R7 are halogens, hydroxyl groups, nitro groups, cyano groups, carboxyl groups, (C1-C4)alkyl groups, (C1-C4)alkoxy groups, halo(C1-C4)alkyl groups, halo(C1-C4)alkoxy groups, (C1-C4)alkylformyl groups, (C1-C4)alkylamide groups, (C1-C4)alkylsulfinyl groups, (C1-C4)alkylsulfonyl groups, (C1-C3)alkyldioxy groups, unsubstituted or amino groups substituted with 1-2 (C1-C4)alkyl groups, and unsubstituted or carbamoyl groups substituted with 1-2 (C1-C4)alkyl groups.

[0060] More preferably, compounds of general formula I and their stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof,

[0061] in,

[0062] R1 and R2, together with the nitrogen atoms they are attached to, form the following structure:

[0063] , , , , , , , , , , ;

[0064] A is , , , , , , , , , , , , , , And A can be arbitrarily replaced by 1-3 identical or different R4s.

[0065] n is 1 or 2;

[0066] Y is -C(O)-;

[0067] L is (C1-C4) alkyl, (C3-C6) cycloalkyl, phenyl, 5-10 heteroaryl, and the aforementioned L may be optionally substituted by 1-3 identical or different R7s;

[0068] R4 and R7 are halogens, hydroxyl groups, nitro groups, cyano groups, carboxyl groups, (C1-C4)alkyl groups, (C1-C4)alkoxy groups, halo(C1-C4)alkyl groups, halo(C1-C4)alkoxy groups, (C1-C4)alkylformyl groups, (C1-C4)alkylamide groups, (C1-C4)alkylsulfinyl groups, (C1-C4)alkylsulfonyl groups, (C1-C3)alkyldioxy groups, unsubstituted or amino groups substituted with 1-2 (C1-C4)alkyl groups, and unsubstituted or carbamoyl groups substituted with 1-2 (C1-C4)alkyl groups.

[0069] Further preferred options include compounds of general formula I and their stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0070] R1 and R2 together with the nitrogen atoms they are attached to form , , , ;

[0071] n is 1 or 2;

[0072] Y is -C(O)-;

[0073] L represents unsubstituted (C1-C4) alkyl, (C3-C6) cycloalkyl, phenyl, thienyl, pyrroleyl, pyrazolyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, quinolinyl, isoquinolinyl, indolyl, benzothiazolyl, and benzoxazolyl.

[0074] A is , , , , , , , , , , , , , , And A can be arbitrarily replaced by 1-3 identical or different R4s.

[0075] R4 and R7 are halogens, hydroxyl groups, nitro groups, cyano groups, carboxyl groups, (C1-C4)alkyl groups, (C1-C4)alkoxy groups, halo(C1-C4)alkyl groups, halo(C1-C4)alkoxy groups, (C1-C4)alkylformyl groups, (C1-C4)alkylamide groups, (C1-C4)alkylsulfinyl groups, (C1-C4)alkylsulfonyl groups, (C1-C3)alkyldioxy groups, unsubstituted or amino groups substituted with 1-2 (C1-C4)alkyl groups, and unsubstituted or carbamoyl groups substituted with 1-2 (C1-C4)alkyl groups.

[0076] The present invention particularly prefers compounds of general formula I and their stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, such as the compounds obtained in Examples 1-80 below.

[0077] The present invention most particularly prefers compounds of general formula I and their stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof.

[0078] ( R )-7,7-dimethyl-2-(1 H -indol-4-yl)-6-methanesulfonyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0079] ( R )-7,7-dimethyl-2-(1 H -indol-4-yl)-6-acetyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0080] ( R )-7,7-dimethyl-2-(1 H -indol-4-yl)-6-isopropionyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0081] ( R )-7,7-dimethyl-2-(1 H -indol-4-yl)-6-cyclopropylformyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0082] ( R )-7,7-dimethyl-2-(1 H-indol-4-yl)-6-propionyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0083] ( R )-7,7-dimethyl-2-(1 H -indol-4-yl)-6-methanesulfonyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0084] ( R )-7,7-dimethyl-2-(1 H -indol-4-yl)-6-cyclobutylformyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0085] ( R )-7,7-dimethyl-2-(1 H -indol-4-yl)-6-(3-methoxybenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0086] ( R )-7,7-dimethyl-2-(1 H -indol-4-yl)-6-(4-methoxybenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0087] ( R )-7,7-dimethyl-2-(1 H -indol-4-yl)-6-(3,4-dimethoxybenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0088] ( R )-7,7-dimethyl-2-(1 H -Indol-4-yl)-6-(1,3-benzodioxacyclopenten-5-formyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0089] ( R )-7,7-dimethyl-2-(1 H -indol-4-yl)-6-(2,3-dihydrobenzo[ b [1,4]dioxin-6-formyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0090] ( R )-7,7-dimethyl-2-(1 H -Indol-4-yl)-6-(4-methylsulfonylbenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0091] ( R )-7,7-dimethyl-2-(1 H -Indol-4-yl)-6-(3-methylsulfonylbenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0092] ( R )-7,7-dimethyl-2-(1 H -indol-4-yl)-6-(4-difluoromethoxybenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0093] ( R )-7,7-dimethyl-2-(1 H -indol-4-yl)-6-(4-acetylbenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0094] ( R )-7,7-dimethyl-2-(1 H -indol-4-yl)-6-(3-acetylbenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0095] ( R )-8,8-dimethyl-2-(1 H-indol-4-yl)-7-methylsulfonyl-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-] d Pyrimidine;

[0096] ( R )-8,8-dimethyl-2-(1 H -indol-4-yl)-7-isopropylformyl-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-] d Pyrimidine;

[0097] ( R )-8,8-dimethyl-2-(1 H -indol-4-yl)-7-propionyl-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-] d Pyrimidine;

[0098] ( R )-8,8-dimethyl-2-(1 H -indol-4-yl)-7-benzoyl-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-] d Pyrimidine;

[0099] ( R )-8,8-dimethyl-2-(1 H -indol-4-yl)-7-(2-acryloyl)-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-] d Pyrimidine;

[0100] ( R )-8,8-dimethyl-2-(1 H -indol-4-yl)-7-(3-fluorobenzoyl)-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-] d Pyrimidine;

[0101] ( R )-8,8-dimethyl-2-(1 H -indol-4-yl)-7-(3,4-dimethoxybenzoyl)-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-] d Pyrimidine;

[0102] ( R )-7,7-dimethyl-2-(1 H -7-azaindol-4-yl)-6-methanesulfonyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5H -pyrrolo[3,4- d Pyrimidine;

[0103] ( R )-7,7-dimethyl-2-(1 H -7-azaindol-4-yl)-6-cyclopropylformyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0104] ( R )-7,7-dimethyl-2-(1 H -7-azaindol-4-yl)-6-benzoyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0105] ( R )-7,7-dimethyl-2-(1 H -7-azaindol-4-yl)-6-(3-methylsulfonylbenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0106] ( R )-7,7-dimethyl-2-(7-methyl-1 H -Indol-4-yl)-6-(3-methylsulfonylbenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0107] ( R )-7,7-dimethyl-2-(7-methyl-1 H -Indol-4-yl)-6-(4-methylsulfonylbenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0108] ( R )-7,7-dimethyl-2-(3 a 7 a -dihydro-1 H -benzo[ d [Imidazol-1-yl)-6-(3-methylsulfonylbenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5] H -pyrrolo[3,4-d Pyrimidine;

[0109] ( R )-7,7-dimethyl-2-(3 a 7 a -dihydro-1 H -benzo[ d [Imidazol-1-yl)-6-(4-methylsulfonylbenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5] H -pyrrolo[3,4- d Pyrimidine;

[0110] ( R )-7,7-dimethyl-2-(1 H -Indazol-4-yl)-6-(4-methylsulfonylbenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine;

[0111] ( R )-7,7-dimethyl-2-(1 H -Indol-3-yl)-6-(4-methylsulfonylbenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine.

[0112] Pharmaceutically acceptable salts of compounds of general formula I are salts formed with acids selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid, and aspartic acid.

[0113] The present invention also includes prodrugs derived from the present invention. The prodrugs derived from the present invention are derivatives of general formula (I), which may have weak or no activity on their own, but are converted into the corresponding biologically active form under physiological conditions (e.g., through metabolism, solvation or other means) after administration.

[0114] In the above-mentioned substituents, "halogen" refers to fluorine, chlorine, or bromine; "alkyl" refers to a straight-chain or branched alkyl group; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl group; "alkoxy" refers to a straight-chain or branched alkoxy group; "alkenyl" refers to a straight-chain or branched alkenyl group; "alkynyl" refers to a straight-chain or branched alkynyl group; "aryl" refers to an unsubstituted or substituted phenyl or naphthyl group; and "heteroaryl" refers to a cyclic system containing one or more monocyclic or polycyclic heteroatoms selected from N, O, and S, wherein the cyclic system is aromatic, such as imidazolyl or pyridine. The terms "saturated or partially saturated heterocyclic groups" refer to cyclic systems containing one or more heteroatoms selected from N, O, and S, such as pyrrolidinyl, indolyl, azaindolyl, benzimidazolyl, benzopyrazoleyl, indoloneyl, isoindoloneyl, pyrazolyl, furanyl, thiophenyl, pyrrolidinyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzoxazolyl, etc.; "saturated or partially saturated heterocyclic groups" refer to cyclic systems containing one or more heteroatoms selected from N, O, and S, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolylyl, indololinyl, imidazolyl, and thiazolyl.

[0115] A pharmaceutical composition comprising a compound of formula I and its stereoisomers, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, mixed with a pharmaceutically acceptable carrier.

[0116] The use of a compound, a pharmaceutical composition, or a compound of general formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, or a composition containing a compound of general formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, in the preparation of a medicament for the treatment and / or prevention of ATR-mediated diseases.

[0117] The preparation of drugs for the treatment and / or prevention of ATR-mediated diseases includes, but is not limited to, osteosarcoma, glioblastoma, lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, and brain cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, biliary tract cancer, bladder cancer, colorectal cancer, breast cancer, ovarian cancer, multiple myeloma, skin cancer, melanoma, leukemia, or kidney cancer.

[0118] The present invention also includes prodrugs derived from the present invention. The prodrugs derived from the present invention are derivatives of general formula (I), which may have weak or no activity on their own, but are converted into the corresponding biologically active form under physiological conditions (e.g., through metabolism, solvation or other means) after administration.

[0119] The present invention also includes pharmaceutical compositions comprising compounds of general formula I and their pharmaceutically acceptable salts and / or solvates as active ingredients and pharmaceutically acceptable carriers; the compounds of the present invention may also be used in combination with other active ingredients, provided that they do not produce other adverse effects, such as allergic reactions.

[0120] The carriers used in the pharmaceutical compositions of this invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, colorants, flavoring agents, etc., for oral formulations; pH adjusters, osmotic pressure adjusters, solubilizers, stabilizers, etc., for injectable formulations; and matrices, diluents, lubricants, preservatives, etc., for topical formulations. The pharmaceutical formulations can be administered orally, parenterally (e.g., intravenously, subcutaneously, intraperitoneally), or topically (e.g., through the eyes, nose, sublingually, skin, etc.). If certain drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0121] The precise amount of the compounds of this invention used to treat cancer, particularly diseases caused by ATR abnormalities, will vary from person to person, depending on the type of patient, age and general condition, severity of the disease being treated, the specific compound used, and the route of administration, such as the route and frequency of administration. Those skilled in the art can determine the appropriate effective amount using only conventional experimental methods.

[0122] The dosage of the compound can range from about 0.1 to 160 mg / kg body weight per day, preferably 1 to 60 mg / kg body weight per day. It is understood that the dosage may vary depending on the patient's needs, the nature of the ATR abnormality being treated, and the specific compound used. Furthermore, it is understood that the initial dose may be increased beyond the upper limit to rapidly achieve the desired blood level, or the initial dose may be lower than the optimal value, and the daily dose may be gradually increased during treatment, depending on the specific circumstances. If necessary, the daily dose may also be divided into multiple doses, for example, 2-4 times daily.

[0123] Mammals refer to humans or animals.

[0124] The amount of the active ingredient, i.e., the compound according to the invention, in the pharmaceutical composition and its unit dosage form can vary, depending on the specific application, the potency of the specific compound, and the required concentration. Generally, the content of the active ingredient will be between 0.5% and 90% based on the total weight of the composition.

[0125] In combination therapy, the compounds of the present invention and other compounds may be administered simultaneously or at intervals. When administered simultaneously, the compounds of the present invention and other compounds may be combined in a single pharmaceutical composition or in separate compositions.

[0126] The examples and preparation methods provided below further illustrate and demonstrate the compounds of the present invention and their preparation methods. It should be understood that the scope of the following examples and preparation methods does not limit the scope of the present invention in any way.

[0127] The following synthetic routes describe the preparation of the general formula I derivatives of this invention. All starting materials were prepared by the methods described in these synthetic routes, by methods well known to those skilled in the art of organic chemistry, or are commercially available. All final compounds of this invention were prepared by the methods described in these synthetic routes or by similar methods well known to those skilled in the art of organic chemistry. All variable factors used in these synthetic routes are defined below.

[0128] According to the general formula I compound of the present invention, in routes one to four, the following compounds are examples, and the definitions of substituents R1, R2, Y, and L are as described above.

[0129] In Route 1, 2-aminoisobutyric acid is used as the starting material. After esterification, intermediate 1 is obtained. Intermediate 1 is substituted with ethyl 3-bromopropionate to obtain intermediate 2. Intermediate 2 is nucleophilically substituted with benzyl bromo to obtain intermediate 3. Intermediate 3 is condensed with Claisen ester under the action of sodium ethoxide to obtain intermediate 4. Intermediate 4 is then cyclized with urea at high temperature to obtain intermediate 5. After chlorination, intermediate 5 is obtained. Intermediate 6 is nucleophilically substituted with R1R2 substituted amine to obtain intermediate 7. Intermediate 7 is coupled with borate esters of different substitutions via Suzuki coupling and then debenzylated to obtain intermediate 9. Intermediate 9 is reacted with alkyl or aromatic halides, alkyl or aromatic acyl chlorides, and alkyl or aromatic sulfonyl chlorides to obtain Ii.

[0130]

[0131] Synthesis of compound Ii via route 1

[0132] In Route 2, 4-aminobutyric acid is used as the starting material. After esterification, intermediate 10 is obtained. Intermediate 10 is substituted with ethyl 2-bromoisobutyrate to obtain intermediate 11. Then, it is nucleophilically substituted with benzyl bromo to obtain intermediate 12. Intermediate 12 is condensed with Claisen ester in the presence of sodium ethoxide to obtain intermediate 13. Then, it is cyclized with urea in the presence of sodium methoxide to obtain intermediate 14. Intermediate 14 is chlorinated to obtain intermediate 15. Intermediate 15 is nucleophilically substituted with an R1R2-substituted amine to obtain intermediate 16. Intermediate 16 is coupled with borate esters of different substitutions via Suzuki coupling to obtain intermediate 17. Intermediate 17 is debenzylated in the presence of palladium hydroxide / carbon to obtain intermediate 18. Then, it is reacted with alkyl or aromatic halides, alkyl or aromatic chlorines, and alkyl or aromatic sulfonyl chlorides to obtain I-ii.

[0133]

[0134] Synthesis of compound I-ii in route two

[0135] In Route 2, intermediate 19 is debenzylated under the action of chloroformate-1-chloroethyl ester to obtain intermediate 20. Intermediate 20 reacts with different substituted aliphatic or aromatic acyl chlorides and different substituted aliphatic or aromatic sulfonyl chlorides to obtain intermediate 21. Intermediate 20 reacts with different substituted borate esters to obtain I-iii.

[0136]

[0137] Synthesis of compounds I-iii via route three

[0138] In Route 4, intermediate 22 is obtained by Suzuki coupling with 19 as raw material. Intermediate 22 is debenzylated under the action of palladium hydroxide / carbon to obtain intermediate 23. Intermediate 23 reacts with different substituted active esters to obtain I-iv.

[0139]

[0140] Synthesis of compounds I-iv in route four

[0141] The compounds of this invention containing fused pyrimidine skeletons have novel structures and excellent properties, and the obtained compounds can be used as ATR inhibitors. In vitro kinase activity screening shows that the compounds involved in this invention have significant inhibitory activity against ATR. Detailed Implementation

[0142] The following examples depict methods for preparing some of the compounds. It should be understood that the following methods, as well as other methods known to those skilled in the art, are applicable to the preparation of all compounds described herein. The examples are intended to illustrate, but not limit, the scope of the invention. The proton NMR spectra of the compounds were determined using a Bruker ARX-600, and mass spectrometry was performed using a Waters ACQUITY triple quadrupole liquid chromatography-mass spectrometry system; all reagents used were analytical grade or chemically pure.

[0143] Example 1 ( R )-7,7-dimethyl-2-(1 H -indol-4-yl)-6-methanesulfonyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine

[0144] 1.1 Synthesis of ethyl 2-amino-2-methylpropionate hydrochloride (1)

[0145] Under ice bath conditions, 40 g (488.9 mmol) of 2-amino-2-methylpropionic acid was added to 400 mL of anhydrous ethanol. Then, 69.1 g (580 mmol) of thionyl chloride was added dropwise to the reaction solution. After the addition was complete, the reaction solution was heated to 80 °C and reacted for 10 h. After the reaction was complete, the reaction solution was concentrated to give 65 g of a white solid, with a yield of 97%. No further purification was required, and it was used directly in the next reaction. MS (ESI) m / z: 132.0 [M+H] + .

[0146] 1.2 Synthesis of ethyl 3-(2,2-dimethyl-3-ethoxy-3-oxo)-aminopropionate (2)

[0147] At room temperature, 25 g (149 mmol) of ethyl 2-amino-2-methylpropionate hydrochloride, 32.38 g (178.9 mmol) of ethyl 3-bromopropionate, 96 g (695.6 mmol) of DIPEA, and 24 g (144.5 mmol) of KI were added sequentially to acetonitrile. After the addition was complete, the reaction mixture was reacted at 80 °C for 96 h. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to obtain 22 g of a brown oily substance, with a yield of 65%. No further purification was required, and it was used directly in the next step.

[0148] 1.3 Synthesis of ethyl 3-(1-benzyl-2,2-dimethyl-3-ethoxy-3-oxo)-aminopropionate (3)

[0149] Under ice bath conditions, 34 g (147.0 mmol) of intermediate 2 was added to 20 mL of DMF. 3.6 g (150 mmol) of NaH was slowly added to the reaction solution, maintaining the temperature at 0–3 °C and stirring for 30 min. Then, 30 g (175.4 mmol) of benzyl bromide was slowly added dropwise. After the addition was complete, the reaction mixture was allowed to react at room temperature for 24 h. After the reaction was complete, the reaction solution was poured into water and extracted with EtOAc (50 mL × 3). The organic layer was washed with 120 mL of saturated brine, dried, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to give 23.6 g of a colorless oil, with a yield of 50%. MS (ESI) m / z: 322.2 [M+H]+.

[0150] 1.4 Synthesis of 1-benzyl-2,2-dimethyl-4-carboxylic acid ethyl ester-3-oxopyrrolidine (4)

[0151] At room temperature, 20 g (62.2 mmol) of intermediate 3 and 8.5 g (126 mmol) of sodium ethoxide were sequentially added to 130 mL of dry toluene, and the mixture was heated to 85 °C and reacted for 8 h. After the reaction was complete, the reaction solution was concentrated, and the residue was poured into water and extracted with DCM (50 mL × 3). The organic layer was washed with 120 mL of saturated brine, dried, filtered, and concentrated under vacuum to give 10.27 g of a brown oily substance, with a yield of 60%. No further purification was required, and it was used directly in the next step. MS (ESI) m / z: 276.2 [M+H] + .

[0152] 1,5-6-Benzyl-7,7-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d ]Pyrimidine-2,4(3 H Synthesis of )-dione ( (5)

[0153] 20 g (72.6 mmol) of intermediate 4 and 17.46 g (290.7 mmol) of urea were added sequentially to the flask, and the reaction was carried out at 180 °C for 8 h. After the reaction was complete, the reaction solution was allowed to cool slightly, and 50 mL of water was added. The mixture was filtered, and the filter cake was dried to give 13.2 g of a pale yellow solid, with a yield of 67%. MS (ESI) m / z: 269.9 [MH] - .

[0154] 1,6-Benzyl-2,4-dichloro-7,7-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine (6)

[0155] Under ice bath conditions, 10 g (36.9 mmol) of intermediate 5 was slowly added to 150 mL of POCl3, and refluxed overnight under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was poured into ice water, the pH was adjusted to 8-9, and the mixture was extracted with dichloromethane (30 mL × 3). The organic layers were combined, washed with 30 mL of saturated brine, dried, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to give 4.5 g of a pale yellow solid, with a yield of 40%.

[0156] 1.7 ( R )-7,7-dimethyl-2-chloro-4-(3-methylmorpholin-4-yl)-6-benzyl-5,7-dihydro-6 H -pyrrolo[3,4- d Synthesis of pyrimidine (7)

[0157] At room temperature, 5 g (16.2 mmol) of intermediate 6 and 1.8 g (17.8 mmol) of intermediate 6 were added sequentially.R 3-Methylmorpholine and 6.29 g (48.6 mmol) of DIPEA were added sequentially to 10 mL of DMF, and the reaction was carried out at 50 °C for 8 h. After the reaction was complete, the reaction solution was cooled to room temperature, poured into 10 mL of water, and extracted with ethyl acetate (20 mL × 3). The organic phase was concentrated to give a pale yellow oil, which was purified by column chromatography to give 4.2 g of a pale yellow solid, with a yield of 70%. MS (ESI), m / z: 373.1 [M+H] + .

[0158] 1.8 ( R )-7,7-dimethyl-2-(1 H -indol-4-yl)-4-(3-methylmorpholin-4-yl]-6-benzyl-5,7-dihydro-6 H -pyrrolo[3,4- d Synthesis of pyrimidine (8)

[0159] At room temperature, 2.24 g (6 mmol) of intermediate 7 and 2.19 g (9 mmol) of 4-indoleboronic acid pinacol ester were added sequentially to 15 mL of anhydrous ethanol, and the mixture was degassed three times. Then, 0.21 g (0.3 mmol) of bis(triphenylphosphine)palladium dichloride was added, and the mixture was degassed three times. Finally, 5 mL (3.8 g, 17.9 mmol) of potassium phosphate aqueous solution was added at 70 °C. After the addition was complete, the mixture was reacted at 75 °C for 16 h. After the reaction was complete, the organic phase was concentrated, and 10 mL of water was added to the residue. The mixture was extracted with dichloromethane (10 mL × 3), and the organic phase was concentrated. The residue was purified by column chromatography to give 2.1 g of an off-white solid, with a yield of 78%. MS (ESI), m / z: 454.1 [M+H] + 452.0 [MH] - .

[0160] 1.9 ( R )-7,7-dimethyl-2-(1 H -indol-4-yl)-4-(3-methylmorpholin-4-yl)-5,7-dihydro-6 H -pyrrole[3,4- d Synthesis of pyrimidine (9)

[0161] At room temperature, 1.5 g (3.3 mmol) of intermediate 8 and 0.75 g of palladium hydroxide / carbon were sequentially added to 20 mL of anhydrous ethanol. The reaction was carried out at 60 °C for 24 h under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered through a diatomaceous earth filter, and the filtrate was concentrated to give 0.99 g of a grayish-white solid, with a yield of 80%. MS (ESI), m / z: 364.0 [M+H] + 362.1 [MH] - .

[0162] 1.10 ( R )-7,7-dimethyl-2-(1 H -indol-4-yl)-6-methanesulfonyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H Synthesis of pyrrolo[3,4-d]pyrimidine (Compound of Example 1)

[0163] At room temperature, 0.08 g (0.2 mmol) of intermediate 9 and 0.04 g (0.3 mmol) of triethylamine were added sequentially to 3 mL of dry dichloromethane. Then, 0.042 g (0.3 mmol) of methanesulfonyl chloride was slowly added dropwise to the reaction mixture under ice bath conditions. After the addition was complete, the reaction mixture was allowed to react at room temperature for 2 h. After the reaction was complete, 5 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phase was concentrated and purified by column chromatography to obtain a white solid in 60% yield.

[0164] Following the synthesis method of Example 1, compounds of Examples 2 to 20 were synthesized using alkyl or aromatic acyl chlorides. The structures, melting points, MS, and other parameters of Examples 1 to 20 are described. 1 H-NMR data are shown in Table 1.

[0165] Table 1 Examples 1 to 20

[0166]

[0167]

[0168]

[0169]

[0170]

[0171] Example 21 ( R )-8,8-dimethyl-2-(1 H -indol-4-yl)-7-methylsulfonyl-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-] d Pyrimidine

[0172] 21.1 Synthesis of ethyl 4-aminobutyrate hydrochloride

[0173] Under ice bath conditions, 40 g (488.9 mmol) of 4-aminobutyric acid was added to 400 mL of anhydrous ethanol, followed by the slow addition of 80 g (672.4 mmol) of thionyl chloride. After the addition was complete, the reaction mixture was reacted at 80 °C for 15 h. Upon completion of the reaction, the reaction solution was concentrated to give 68 g of a white solid, with a yield of 95%. No further purification was required, and the solid was used directly in the next reaction. MS (ESI) m / z: 132.1 [M+H] + .

[0174] 21.2 Synthesis of ethyl 4-(2,2-dimethyl-3-ethoxy-3-oxo)aminobutyrate

[0175] At room temperature, 18.14 g (118.1 mmol) of ethyl 4-aminobutyrate hydrochloride, 27.62 g (141.6 mmol) of ethyl 2-bromo-2-methylpropionate, 65 g (470.3 mmol) of potassium carbonate, and 19.5 g (117.5 mmol) of potassium iodide were added sequentially to 50 mL of DMF and reacted at 100 °C for 72 h. The reaction solution was cooled to room temperature, and a large amount of white solid precipitated. The insoluble matter was removed by filtration; no further purification was required, and the solid was used directly in the next step. MS (ESI) m / z: 246.1 [M+H] + .

[0176] 21.3 Synthesis of ethyl 4-(1-benzyl-2,2-dimethyl-3-ethoxy-3-oxo)aminobutyrate

[0177] Under ice bath conditions, 27.3 g (125.6 mmol) of ethyl 4-(2,2-dimethyl-3-ethoxy-3-oxo)aminobutyrate was added to 20 mL of DMF. 3.6 g (150 mmol) of NaH was slowly added to the reaction solution, and the temperature was maintained at 0–3 °C. The mixture was stirred for 30 min, and then 24 g (140.3 mmol) of benzyl bromide was slowly added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 24 h. After the reaction was complete, the reaction solution was poured into 50 mL of water and extracted with EtOAc (60 mL × 3). The organic layer was washed with saturated brine (2 × 20 mL), dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography to give 23.5 g of a colorless oil, with a yield of 50%. MS (ESI) m / z: 322.2 [M+H] + .

[0178] 21.4 Synthesis of 1-benzyl-2,2-dimethyl-4-carboxylic acid ethyl ester-3-oxoperididine

[0179] At room temperature, 20 g (59.6 mmol) of ethyl 4-(1-benzyl-2,2-dimethyl-3-ethoxy-3-oxo)aminobutyrate and 7.69 g (113 mmol) of sodium ethoxide were added sequentially to 130 mL of dry toluene, and the mixture was heated to 85 °C. After the reaction was complete, 30 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (3 × 40 mL). The organic layers were combined, washed with saturated brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give 11.53 g of a brown oily substance, with a yield of 74%. No further purification was required, and the substance was used directly in the next reaction.

[0180] 21.5 7-Benzyl-8,8-dimethyl-5,6,7,8-tetrahydropyrido[3,4- d ]Pyrimidine-2,4(1 H ,3 H Synthesis of )-dione

[0181] Under ice bath conditions, 3.4 g (147.8 mmol) of finely chopped metallic sodium was added to 140 mL of anhydrous ethanol and stirred. After the sodium was completely consumed, 13.5 g (224.7 mmol) of urea and 14.7 g (56.2 mmol) of 1-benzyl-2,2-dimethyl-4-carboxylic acid ethyl ester-3-oxoperididine were added to the reaction mixture, and the mixture was heated under reflux for 24 h. After the reaction was complete, the reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was poured into ice water. The pH was adjusted to 6-7 with acetic acid under ice bath conditions. The mixture was filtered, and the filter cake was washed with ice water. The filter cake was the product, which was dried to give 9.6 g of a brown solid, with a yield of 60%. MS (ESI) m / z: 286.1 [M+H] + .

[0182] 21.6 7-Benzyl-2,4-dichloro-8,8-dimethyl-5,6,7,8-tetrahydropyrido[3,4- d Synthesis of pyrimidines

[0183] Under ice bath conditions, 10 g (35.1 mmol) of 7-benzyl-8,8-dimethyl-5,6,7,8-tetrahydropyrido[3,4- d ]Pyrimidine-2,4(1 H ,3 HThe diketone was slowly added to 200 mL of POCl3 and refluxed overnight under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was poured into ice water, the pH was adjusted to 8-9, and the mixture was extracted with dichloromethane (40 mL × 3). The organic layers were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was purified by column chromatography to give 7.8 g of a pale yellow solid, with a yield of 70%. MS (ESI) m / z: 322.1 [M+H] + .

[0184] 21.7 ( R )-8,8-dimethyl-2-chloro-4-(3-methylmorpholin-4-yl)-7-benzyl-5,6,7,8-tetrahydropyrido[3,4- d Synthesis of pyrimidines

[0185] At room temperature, 1.93 g (6 mmol) of 7-benzyl-2,4-dichloro-8,8-dimethyl-5,6,7,8-tetrahydropyrido[3,4- d 0.67 g (6.6 mmol) of pyrimidine was added to the DMF solution. R 3-Methylmorpholine and 2.3 g (17.8 mmol) DIPEA. The reaction mixture was stirred at 50 °C for 5 h. After the reaction was complete, the reaction solution was cooled to room temperature, and the residue was poured into ice water. It was extracted with ethyl acetate (10 mL × 3), the organic layers were combined, washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was purified by column chromatography to give 1.58 g of a pale yellow solid, with a yield of 68%. MS (ESI), m / z: 373.1 [M+H] + ; 1 H NMR (600 MHz, DMSO- d 6) d 7.39 (d, J = 7.1 Hz, 2H), 7.33(t, J = 7.6 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 4.08 (q, J = 6.4 Hz, 1H), 3.80 (dd, J = 11.3, 1.8 Hz, 1H), 3.71 (d, J = 14.1 Hz, 1H), 3.62 (d, J= 14.1 Hz, 1H), 3.59 –3.56 (m, 2H), 3.55 (s, 1H), 3.47 (td, J = 11.5, 2.6 Hz, 1H), 3.34 (dd, J = 11.2,2.6 Hz, 1H), 2.50 – 2.47 (m, 2H), 2.46 – 2.43 (m, 2H), 1.43 (d, J = 14.3 Hz, 6H), 1.21 (d, J = 6.7 Hz, 3H).

[0186] 21.8 ( R )-8,8-dimethyl-2-(1 H -indol-4-yl)-4-(3-methylmorpholin-4-yl)-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-] d Synthesis of pyrimidines

[0187] At room temperature, 1.7 g (4.3 mmol) was added sequentially. R )-8,8-dimethyl-2-chloro-4-(3-methylmorpholin-4-yl)-7-benzyl-5,6,7,8-tetrahydropyrido[3,4- d Pyrimidine and 1.6 g (6.5 mmol) of 4-indoleboronic acid pinacol ester were added to 15 mL of anhydrous ethanol and degassed three times. Then, 0.15 g (0.2 mmol) of bis(triphenylphosphine)palladium dichloride was added, and the mixture was degassed three times. Finally, 5 mL (2.8 g, 13.2 mmol) of potassium phosphate aqueous solution was added at 70 °C. After the addition was complete, the mixture was reacted at 75 °C for 16 h. The organic phase was concentrated, and 5 mL of water was added to the residue. The mixture was extracted with dichloromethane (20 mL × 3), and the organic phase was concentrated. The residue was purified by column chromatography to give 1.4 g of an off-white solid, with a yield of 79%. Mp: 124.6-128.7 °C; 1 H NMR (600 MHz, DMSO- d 6) d 11.24 (s, 1H), 8.14 (d, J = 7.4 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.45 (dd, J = 10.8, 5.5 Hz, 4H), 7.35 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.3 Hz, 1H), 7.20 (t,J = 7.7 Hz, 1H), 4.05(d, J = 6.3 Hz, 1H), 3.86 (dd, J = 12.3, 7.3 Hz, 2H), 3.71 (dd, J = 10.9, 2.0 Hz, 1H), 3.63 (dd, J = 13.3, 8.1 Hz, 2H), 3.58 (d, J = 11.7 Hz, 1H), 3.52 (d, J = 13.3Hz, 1H), 3.46 (dd, J = 17.4, 6.6 Hz, 1H), 2.61 – 2.53 (m, 4H), 1.64 (s, 3H), 1.58 (s, 3H), 1.23 (d, J = 6.5 Hz, 3H).

[0188] 21.9 ( R )-8,8-dimethyl-2-(1 H Synthesis of (-indol-4-yl)-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

[0189] At room temperature, 1.5g (3.2 mmol) R )-8,8-dimethyl-2-(1 H -indol-4-yl)-4-(3-methylmorpholin-4-yl)-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-] d Pyrimidine and 0.15 g palladium hydroxide / carbon were sequentially added to 20 mL of anhydrous ethanol. The reaction was carried out at 60 °C for 24 h under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered through a diatomaceous earth filter, and the filtrate was concentrated to give 0.84 g of a grayish-white solid, with a yield of 70%. Mp: 99.7-102.9 °C; MS (ESI), m / z: 378.3 [M+H] + ; 1 H NMR (600MHz, DMSO- d 6 ) d 11.25 (s, 1H), 8.15 – 8.06 (m, 1H), 7.51 (dd, J = 7.3, 4.6 Hz, 1H), 7.45 (d, J= 1.9 Hz, 1H), 7.41 (s, 1H), 7.24 – 7.14 (m, 1H), 4.03 (d, J =2.1 Hz, 1H), 3.89 (d, J = 10.5 Hz, 1H), 3.75 (d, J = 10.9 Hz, 1H), 3.62 (d, J =11.1 Hz, 2H), 3.46 (d, J = 2.1 Hz, 1H), 3.01 – 2.91 (m, 2H), 2.76 (s, 2H), 2.65(d, J = 3.0 Hz, 2H), 1.52 (dd, J = 15.4, 3.7 Hz, 6H), 1.23 (d, J = 5.6 Hz, 3H).

[0190] 21.10 ( R )-8,8-dimethyl-2-(1 H -indol-4-yl)-7-methylsulfonyl-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-] d Synthesis of pyrimidine (Example 21)

[0191] At room temperature, 0.08 g (0.2 mmol) ( R )-8,8-dimethyl-2-(1 H -indol-4-yl)-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-] d Pyrimidine and 0.04 g (0.3 mmol) triethylamine were added sequentially to 3 mL of dry dichloromethane. Under ice bath conditions, 0.042 g (0.3 mmol) methanesulfonyl chloride was slowly added dropwise to the reaction solution. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 h. After the reaction was complete, 5 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was concentrated and purified by column chromatography to give 0.05 g of a white solid, with a yield of 60%.

[0192] Following the synthesis method of Example 21, compounds of Examples 22-43 were synthesized using alkyl or aromatic acyl chlorides. The structures, chemical names, melting points, and MS data of Examples 21-43 are described below. 1 H-NMR data are shown in Table 2.

[0193] Table 2 Examples 21 to 43

[0194]

[0195]

[0196]

[0197]

[0198]

[0199] Example 44 ( R )-8,8-dimethyl-2-(1 H -indol-4-yl)-7-(2-dimethylaminoacetyl)-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-] d Pyrimidine

[0200] 44.1 ( R )-8,8-dimethyl-2-(1 H -indol-4-yl)-7-(2-chloroacetyl)-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-] d Synthesis of pyrimidines

[0201] At room temperature, 0.2 g (0.5 mmol) ( R )-8,8-dimethyl-2-(1 H -indol-4-yl)-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-] d Pyrimidine and 0.11 g (1.1 mmol) triethylamine were added sequentially to 3 mL of dry dichloromethane. Under ice bath conditions, 0.120 g (1.1 mmol) chloroacetyl chloride was slowly added dropwise to the reaction mixture. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 h. After the reaction was complete, 5 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phase was concentrated and purified by column chromatography to give 0.19 g of a gray solid, with a yield of 66%.

[0202] 44.2 ( R )-8,8-dimethyl-2-(1 H -indol-4-yl)-7-(2-dimethylaminoacetyl)-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-] d Synthesis of pyrimidine (Example 44)

[0203] At room temperature, 0.1 g (0.22 mmol) was added sequentially. R )-8,8-dimethyl-2-(1H -indol-4-yl)-7-(2-chloroacetyl)-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-] d Pyrimidine, 0.026 g (0.32 mmol) dimethylamine hydrochloride, and 0.12 g (0.86 mmol) potassium carbonate were added to 3 mL of acetonitrile, and the mixture was reacted at 60 °C for 5 h. After the reaction was complete, the reactants were cooled to room temperature, the reaction solution was concentrated, 5 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phase was concentrated, and purified by column chromatography to give 0.079 g of white solid, with a yield of 79%.

[0204] 44.3 ( R )-8,8-dimethyl-2-(1 H -indol-4-yl)-7-[2-(4-methylpiperazin-1-yl)acetyl]-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-] d Synthesis of pyrimidine (Example 45)

[0205] by N- Methylpiperazine was used as a raw material and synthesized according to the synthesis method in section 44.2. R )-8,8-dimethyl-2-(1 H -indol-4-yl)-7-[2-(4-methylpiperazin-1-yl)acetyl]-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-] d Pyrimidine. Yield 77%.

[0206] Structure, chemical name and melting point, MS of Examples 44-45 1 The H-NMR data are shown in Table 3.

[0207] Table 3 Examples 44-45

[0208]

[0209] It was synthesized from 7-aza-4-indoleborate according to the synthesis method in 1.1.8 of Example 1. R )-7,7-dimethyl-2-(1 H -7-azaindol-4-yl)-4-(3-methylmorpholin-4-yl]-6-benzyl-5,7-dihydro-6 H -pyrrolo[3,4- d ]Pyrimidine or ( R )-8,8-dimethyl-2-(1 H-7-azaindol-4-yl)-4-(3-methylmorpholin-4-yl)-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-] d Pyrimidine. It was then synthesized according to the synthesis method described in 1.1.9 of Example 1. R )-7,7-dimethyl-2-(1 H -7-azaindol-4-yl)-4-(3-methylmorpholin-4-yl)-5,7-dihydro-6 H -pyrrolo[3,4- d ]Pyrimidine or ( R )-8,8-dimethyl-2-(1 H -7-azaindol-4-yl)-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-] d Pyrimidine was then synthesized using alkyl or aromatic acyl chlorides according to the synthetic method in 1.10 of Example 1 to obtain the compounds of Examples 46 to 57. The structures, chemical names, melting points, MS times, and other parameters of Examples 46 to 57 are described below. 1 H-NMR data are shown in Table 4.

[0210] Table 4 Examples 46-57

[0211]

[0212]

[0213]

[0214] Example 58 ( R )-7,7-dimethyl-2-(1 H -Indol-2-one-4-yl)-6-acetyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine

[0215] 58.1 ( R )-7,7-dimethyl-2-chloro-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Synthesis of pyrimidines

[0216] At room temperature, 1g (2.7 mmol) ( R )-7,7-dimethyl-2-chloro-4-(3-methylmorpholin-4-yl)-6-benzyl-5,7-dihydro-6 H -pyrrolo[3,4- dPyrimidine was added to 10 mL of dichloromethane, and 1.5 g (10.5 mmol) of 1-chloroethyl chloroformate was added dropwise under ice bath conditions. After the addition was complete, the mixture was reacted at room temperature for 10 h. The solvent was evaporated to dryness, and 10 mL of methanol was added to the residue. The mixture was then refluxed for 3 h. After the reaction was complete, the solvent was evaporated to dryness, and the pH of the residue was adjusted to 7-8 with 1N NaOH solution. The residue was extracted with dichloromethane (10 mL × 3), dried, filtered, and the filtrate was concentrated to give 0.3 g of a pale yellow oil, with a yield of 40%. MS (ESI) m / z: 283.12 [M+H] + .

[0217] 58.2 ( R )-7,7-dimethyl-2-chloro-6-acetyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Synthesis of pyrimidines

[0218] With propionyl chloride and ( R )-7,7-dimethyl-2-chloro-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Using pyrimidine as a raw material, it was synthesized according to the synthesis method in 1.10 of Example 1. R )-7,7-dimethyl-2-chloro-6-acetyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine.

[0219] 58.3 ( R )-7,7-dimethyl-2-(1 H -Indol-2-one-4-yl)-6-benzoyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Synthesis of pyrimidines

[0220] by( R )-7,7-dimethyl-2-chloro-6-acetyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Using pyrimidine and 4-boronate-indole-2-one as starting materials, it was synthesized according to the synthesis method in 1.8 of Example 1. R )-7,7-dimethyl-2-(1 H -Indol-2-one-4-yl)-6-benzoyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- dPyrimidine. Yield 56%. MS (ESI) m / z: 437.0 [M+H] + .

[0221] by( R )-7,7-dimethyl-2-chloro-6-acetyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Using pyrimidine and substituted boronic esters as raw materials, the compounds of Examples 59 to 65 were synthesized using the synthetic method described in 58.3. R )-7,7-dimethyl-2-chloro-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Using pyrimidine and m-methylsulfonyl benzoyl chloride or p-sulfonyl benzoyl chloride as starting materials, the corresponding intermediates were obtained according to the synthetic method in 57.2, and then reacted with boronic esters or amines with different substitutions as starting materials. The structures, chemical names and MS data of Examples 58 to 75 are shown in Table 5.

[0222] Table 5 Examples 58-75

[0223]

[0224]

[0225]

[0226]

[0227] Using different substituted small molecule amines and intermediate 6 as starting materials, compounds of Examples 76 to 80 were synthesized according to the synthesis method of Example 1. The structures, chemical names, melting points, MS, and other parameters of Examples 76 to 80 are described below. 1 The H-NMR data are shown in Table 6.

[0228] Table 6 Examples 76-80

[0229]

[0230]

[0231] The ATR enzyme activity of the compounds of the present invention was studied, and the results are as follows:

[0232] The fused pyrimidine compounds according to Formula I of the present invention were subjected to in vitro ATR enzyme activity testing by fluorescence analysis. The compounds described below are all fused pyrimidine compounds according to Formula I obtained in the above examples.

[0233] The kinase buffer consisted of 50 mM HEPES (pH 7.5), 0.0015% Brij-35, and 1M MnCl2. The stop buffer consisted of 100 mM HEPES (pH 7.5), 0.015% Brij-35, 0.2% Coating Reagent #3, and 50 mM EDTA. The compound was diluted 1000 / 3 times with 100% dimethyl sulfoxide to the desired maximum inhibitor concentration. 100 μL of dimethyl sulfoxide was added to two empty wells for a compound-free control and an enzyme-free control in the same 96-well plate. This plate was labeled as the source plate. 40 μL of the compound was transferred from the source plate to a new 384-well plate as an intermediate plate, and 60 nL of the compound was transferred to the analysis plate via Echo in 100% dimethyl sulfoxide. Two aliquots of the enzyme solution were prepared, and the kinase was added to the kinase base buffer. The 2-fold enzyme solution was transferred to the analysis plate, and 10 μL of the enzyme solution was added to each well of the 384-well analysis plate. Incubate at room temperature for 10 min. Add FAM-labeled peptide and ATP to kinase base buffer, transfer the peptide solution to an analysis plate, and add 10 μL of peptide solution to each well of a 384-well plate. Once the kinase reaction stops, copy the converted data from the Caliper program; the drug IC50 can be determined using the Bliss method. 50 Value. ATR enzyme IC in some embodiments. 50 Activity data are shown in Table 7.

[0234] Table 7. ATR enzyme ICs from some examples 50 Activity data

[0235]

[0236] The general formula compounds listed in the table above all exhibit good ATR inhibitory activity, with some compounds being comparable to or superior to the positive control drug AZ20.

[0237] Subsequently, in vitro experiments were conducted on the partial fused pyrimidine derivatives of Formula I according to the present invention to inhibit the activity of LOVO cells and HT-29 cells.

[0238] Human colon cancer HT-29 and LOVO cells were purchased from the Shanghai Cell Bank (CAS), Chinese Academy of Sciences. After cell resuscitation and stabilization through 2-3 passages, cells in the logarithmic growth phase were collected, prepared into single-cell suspensions, and counted. The cell concentration was adjusted to the desired level, and 100 μL was added to each well of a 96-well cell culture plate. 100 μL of complete culture medium containing different concentrations of the test compound or positive control compound, or complete culture medium of the control, was added to each well (each concentration was tested in duplicate). After incubation for 72 h, the fluorescence intensity (530 / 590 nm) of each well was detected using the Alamar blue method, and the proliferation rate of each concentration was calculated.

[0239] Proliferation rate = 1 - [(Negative control wells - Test wells) / (Negative control wells - Positive control wells) × 100%]

[0240] The experimental results of some compounds in LOVO cells L and HT-29 are shown in Table 8.

[0241] Table 8 Cell proliferation rate (%) in some examples

[0242]

[0243] Cell activity assays of the compounds showed that some compounds had activity comparable to or superior to the positive control drug AZ20 in LOVO and HT-29 cells.

[0244] Meanwhile, in vitro kinase and cell activity tests showed that the compounds involved in this invention have good ATR enzyme activity and excellent cell activity, with some compounds exhibiting activity superior to the positive control drug AZ20.

Claims

1. A fused pyrimidine derivative, characterized in that: The derivatives are compounds of the general formula I, wherein R1and R2together with the nitrogen atom to which they are attached form ; A is , ; n is 1, 2 or 3; Y is -C(O)-, -S(O)2-; L is (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, phenyl, thienyl, which are unsubstituted or substituted by 1 to 3 identical or different R7; R7 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkylacyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C3)alkylenedioxy; but does not comprise .

2. The fused pyrimidine derivative according to claim 1, characterized by: The derivatives are compounds of the general formula I, wherein R1and R2together with the nitrogen atom to which they are attached form ; A is ; n is 1 or 2; Y is -C(O)-, -S(O)2-; L is (C1-C4)alkyl, (C2-C4)alkenyl, (C3-C6)cycloalkyl, phenyl, thienyl, which are unsubstituted or substituted by 1 to 3 identical or different R7; R7 is halogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkyl, halo(C1-C4)alkoxy, (C1-C4)alkylacyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C3)alkylenedioxy; but does not comprise .

3. The fused pyrimidine derivative according to claim 2, wherein: The derivatives are compounds of the general formula I, L is (C1-C4)alkyl, (C3-C6)cycloalkyl, phenyl, thienyl, which are unsubstituted or substituted by 1 to 3 identical or different R7; R7is halogen, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkyl, halo(C1-C4)alkoxy, (C1-C4)alkylacyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C3)alkylenedioxy; but not including .

4. A fused pyrimidine derivative, characterized in that: The derivatives are as follows, R )-7,7-dimethyl-2-(1 H - indol-4-yl)-6-acetyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H - pyrrolo[3,4- d ]pyrimidine;​ R )-7,7-dimethyl-2-(1 H - indol-4-yl)-6-isopropylcarbonyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H - pyrrolo[3,4- d ]pyrimidine;​ R )-7,7-dimethyl-2-(1 H - indol-4-yl)-6-cyclopropylcarbonyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H - pyrrolo[3,4- d ]pyrimidine;​ R )-7,7-dimethyl-2-(1 H - indol-4-yl)-6-propionyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H - pyrrolo[3,4- d ]pyrimidine;​ ； R )-7,7-dimethyl-2-(1 H - indol-4-yl)-6-cyclobutylcarbonyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H - pyrrolo[3,4- d ]pyrimidine;​ R )-7,7-dimethyl-2-(1 H - indol-4-yl)-6-(3-methoxybenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H - pyrrolo [3, 4- d ]pyrimidine;​ R )-7,7-dimethyl-2-(1 H - indol-4-yl)-6-(4-methoxybenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H - pyrrolo [3, 4- d ]pyrimidine;​ R )-7,7-dimethyl-2-(1 H - indol-4-yl)-6-(3,4-dimethoxybenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H - pyrrolo [3,4- d ]pyrimidine;​ R )-7,7-dimethyl-2-(1 H - indol-4-yl)-6-(1,3-benzodioxol-5-ylcarbonyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H - pyrrolo[3,4- d ]pyrimidine;​ R )-7,7-dimethyl-2-(1 H - indol-4-yl)-6-(2,3-dihydrobenzo[ b ][1,4]dioxane-6-carbonyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H - pyrrolo[3,4- d ]pyrimidine;​ R )-7,7-dimethyl-2-(1 H - indol-4-yl)-6-(4-methylsulfonylbenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H - pyrrolo [3, 4- d ]pyrimidine;​ R )-7,7-dimethyl-2-(1 H - indol-4-yl)-6-(3-methylsulfonylbenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H - pyrrolo [3, 4- d ]pyrimidine;​ R )-7,7-dimethyl-2-(1 H - indol-4-yl)-6-(4-difluoromethoxybenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H - pyrrolo [3, 4- d ]pyrimidine;​ R )-7,7-dimethyl-2-(1 H - indol-4-yl)-6-(4-acetylbenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H - pyrrolo [3, 4- d ]pyrimidine;​ R )-7,7-dimethyl-2-(1 H - indol-4-yl)-6-(3-acetylbenzoyl)-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H - pyrrolo [3, 4- d ]pyrimidine;​ R )-8,8-dimethyl-2-(1 H -indol-4-yl)-7-acetyl-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4- d ]pyrimidine;​ R )-8,8-dimethyl-2-(1 H - indol-4-yl)-7-isopropylcarbonyl-4-(3-methylmorpholin-4-yl)-5,6,7,8- tetrahydropyrido[3,4- d ]pyrimidine;​ R )-8,8-dimethyl-2-(1 H -indol-4-yl)-7-cyclopropylcarbonyl-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4- d ]pyrimidine;​ R )-8,8-dimethyl-2-(1 H -Indol-4-yl)-7-propionyl-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4- d ]pyrimidine;​ R )-8,8-dimethyl-2-(1 H -Indol-4-yl)-7-[2-(thiophen-2-yl)acetyl]-4-(3-methylmorpholin-4-yl)- 5,6,7,8-tetrahydropyrido[3,4- d ]pyrimidine;​ R )-8,8-dimethyl-2-(1 H -Indol-4-yl)-7-benzoyl-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4- d ]pyrimidine;​ R )-8,8-dimethyl-2-(1 H - indol-4-yl)-7-(2-propenoyl)-4-(3-methylmorpholin-4-yl)-5,6,7,8- tetrahydropyrido[3,4- d ]pyrimidine;​ R )-8,8-dimethyl-2-(1 H - indol-4-yl)-7-(3-fluorobenzoyl)-4-(3-methylmorpholin-4-yl)-5,6,7,8- tetrahydropyrido[3,4- d ]pyrimidine;​ R )-8,8-dimethyl-2-(1 H - indol-4-yl)-7-(3-methoxybenzoyl)-4-(3-methylmorpholin-4-yl)-5,6,7,8- tetrahydropyrido[3,4- d ]pyrimidine;​ R )-8,8-dimethyl-2-(1 H -Indol-4-yl)-7-(4-methoxybenzoyl)-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4- d ]pyrimidine;​ R )-8,8-dimethyl-2-(1 H -Indol-4-yl)-7-(3,4-dimethoxybenzoyl)-4-(3-methylmorpholin-4-yl)-5,6,7,8-tetrahydropyrido[3,4- d ]pyrimidine;​ R )-7,7-dimethyl-2-(1 H -7-azaindol-4-yl)-6-methanesulfonyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d ]pyrimidine;​ ( R )-7,7-dimethyl-2-(1 H -7-azaindol-4-yl)-6-benzoyl-4-(3-methylmorpholin-4-yl)-6,7-dihydro-5 H -pyrrolo[3,4- d Pyrimidine.

5. A pharmaceutical composition, which comprises a compound of the general formula I according to any one of claims 1 to 4.

6. The use of a compound according to claim 1 or a pharmaceutical composition according to claim 5 for the preparation of a medicament for the treatment and / or prophylaxis of ATR-mediated diseases.

7. The use according to claim 6, characterized in that: The prophylaxis of ATR-mediated diseases is osteosarcoma, glioblastoma, head and neck cancer, pancreatic cancer, gastric cancer, brain cancer, non-small cell lung cancer, small cell lung cancer, biliary tract cancer, bladder cancer, colorectal cancer, breast cancer, ovarian cancer, multiple myeloma, skin cancer, melanoma, leukemia or renal cancer.

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