Pyrimido[5,4-b]indolizine or pyrimido[5,4-b]pyrrolizine compound, preparation method and use thereof

A method for preparing a 5-aryl-pyrimidoindolizine or 5-aryl-pyrimidopyrrolizine compound, the preparation method comprising:

• Scheme 1a:
• 4-amino-pyrrolo[2,3-d]pyrimidine, Compound 1 as a starting material is iodo-substituted with N-iodosuccinimide (NIS) on 5-position to give Compound 2,
• Fragment 3 is incorporated into Compound 2 through Mitsunobu reaction to give compound 4,
• Compound 4 is coupled with a substituted phenylboronic acid or borate to give Compound 6,
• Bromine is introduced at 6-position of Compound 6 by N-bromosuccinimide (NBS) to give Compound 7,
• Compound 7 reacts with 9-boronbicyclo[3.3.1]nonane (9-BBN) in anhydrous tetrahydrofuran (THF), then forms a six-membered ring through a self-Suzuki-Miyaura coupling in the presence of [1,1′-bis(diphenylphosphinyl)ferrocene]palladium dichloride (PdCl2(dppf)), and is deprotected to give Compound 8 with a core of tetrahydrogenpyrido[5,4-b]indole,
• Compound 8 condensates with a carboxylic acid or a sulfonic acid to give Compound 9,
• or
• Scheme 1b:
• Compound 7 forms a five-membered cyclic compound through an intramolecular Heck reaction in the presence of PdCl2(dppf), and is deprotected to give Compound 10, which condensates with a substituted carboxylic acid to give Compound 11,
• or
• Scheme 1c:
• Compound 10 is hydrogenated in the presence of a catalyst to give Compound 12, Compound 12 condensates with an acid to give Compound 13;
• or
• Compound 8 condensates with a N-Boc protected amino acid 14, and is deprotected to give Compound 15,
• Compound 15 condensates with a substituted carboxylic acid to give Compound 16;
• or
• Scheme 3a:
• Compound 4 is coupled with a substituted phenylboronic acid or borate 17 to give Compound 18,
• Bromine is incorporated at 6-position of Compound 18 by NBS to give brominated Compound 19,
• Compound 19 reacts with 9-BBN in anhydrous THF, forms a six-membered ring through a self-Suzuki-Miyaura coupling in the presence of PdCl2(dppf), and then is hydrolyzed in the presence of lithium hydroxide to give Compound 20,
• Compound 20 condensates with a substituted alkylamine to give Compound 21,
• Compound 21 is deprotected and condensates with a carboxylic acid to give Compound 22,
• or
• Scheme 3b:
• Compound 20 condensates with an arylamine to give Compound 23,
• Compound 23 is deprotected and condensates with a carboxylic acid to give Compound 24;
• or
• Brominated compound 19 forms a five-membered cyclic compound through an intramolecular Heck reaction in the presence of PdCl2(dppf), and treated with LiOH to give a carboxylic acid 25,
• the carboxylic acid 25 condensates with an arylamine to give an amide 26,
• the amide 26 is hydrogenated in the presence of a catalyst to give Compound 27,
• Compound 27 is deprotected with CF3COOH to remove Boc-protection, and condensates with a carboxylic acid to give Compound 28,
• wherein the above schemes,
• R2 is hydrogen or substituted or unsubstituted C1-C3 alkyl, wherein the substituent in R2 is halogen or C1-C3 alkoxy;
• Ar is substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-20 membered heteroaryl containing one or more heteroatoms selected from the group consisting of O, N and S, wherein the substituent in Ar is halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl or trifluoromethoxy;
• R3 and R4 may be independently hydrogen or C1-C3 alkyl, or R3, R4 and the carbon atom attached thereto form C3-C5 cycloalkyl;
• n is 0, 1 or 2;
• T is
• R5, R6 and R7 may be independently selected from the group consisting of hydrogen, cyano, halogen, and substituted or unsubstituted C1-C20 alkyl, preferably are independently selected from the group consisting of hydrogen, cyano, halogen, and substituted or unsubstituted C1-C10 alkyl, more preferably are independently selected from the group consisting of hydrogen, cyano, halogen, and substituted or unsubstituted C1-C5 alkyl;
• the substituent in R5, R6 or R7 is dimethylamino, C1-C10 alkoxy, or 3 to 10 membered heterocyclyl containing one or more heteroatoms selected from the group consisting of O, N and S;
• preferably dimethylamino, C1-C6 alkoxy, or 3 to 10 membered heterocyclyl containing one or more heteroatoms selected from the group consisting of O, N and S;
• more preferably dimethylamino, C1-C5 alkoxy, or 3 to 6 membered heterocyclyl containing 1 to 3 heteroatoms selected from the group consisting of O, N and S;
• and
• R8 is selected from the group consisting of hydrogen and C1-C10 alkyl, preferably selected from the group consisting of hydrogen and C1-C5 alkyl, more preferably selected from the group consisting of hydrogen and C1-C3 alkyl.