Method for preparing nitrogen-containing polycyclic fused ring compound, and intermediate and use of compound

A preparation method M1A for a compound of formula I, wherein the preparation method comprises reacting a compound of formula XX with Rk—C(O)—H to give the compound of formula I:

• wherein,
• X1, X2, X3, and X4 are identical or different, and are each independently selected from CR1 or N;
• each R1 is identical or different, and is independently selected from H, halogen, CN, OH, and the following groups unsubstituted or optionally substituted with one, two or more Ra:
• C1-40 alkyl, C3-40 cycloalkyl, C1-40 alkyloxy, C3-40 cycloalkyloxy, NR2R3, —C(O)R4, —OCR5, —S(O)2R6, and OS(O)2R7;
• D and E are identical or different, and are each independently selected from H, halogen, CN, OH, —O—R21, and the following groups unsubstituted or optionally substituted with one, two or more Rc:
• C1-40 alkyl, C3-40 cycloalkyl, C6-20 aryl, 5- to 20-membered heteroaryl, 3- to 20-membered heterocyclyl, and NR2R3, provided that at least one of D and E is selected from —O—R21;
• R21 is selected from the following groups unsubstituted or optionally substituted with one, two or more Rd:
• C1-40 alkyl, C3-40 cycloalkyl, C6-20 aryl, 5- to 20-membered heteroaryl, and 3- to 20-membered heterocyclyl;
• G is selected from the following groups unsubstituted or optionally substituted with one, two or more Re:
• C3-40 cycloalkyl, C3-40 cycloalkenyl, C6-20 aryl, 5- to 20-membered heteroaryl, 3- to 20-membered heterocyclyl, C3-40 cycloalkyloxy, C3-40 cycloalkenyloxy, C6-20 aryloxy, 5- to 20-membered heteroaryloxy, and 3- to 20-membered heterocyclyloxy;
• Rk is selected from the following groups unsubstituted or optionally substituted with one, two or more Rg:
• C1-40 alkyl, C3-40 cycloalkyl, C3-40 cycloalkenyl, C6-20 aryl, 5- to 20-membered heteroaryl, and 3- to 20-membered heterocyclyl;
• each R2 is identical or different, and is independently selected from H, C1-40 alkyl, C3-40 cycloalkyl, C6-20 aryl, 5- to 20-membered heteroaryl, 3- to 20-membered heterocyclyl, —C(O)R4, and —S(O)2R6;
• each R3 is identical or different, and is independently selected from H, C1-40 alkyl, C3-40 cycloalkyl, C6-20 aryl, 5- to 20-membered heteroaryl, 3- to 20-membered heterocyclyl, —C(O)R4, and —S(O)2R6;
• or, R2 and R3, together with the N atom connected thereto, form 5- to 20-membered heteroaryl or 3- to 20-membered heterocyclyl;
• each R4 is identical or different, and is independently selected from H, C1-40 alkyl, C3-40 cycloalkyl, C6-20 aryl, 5- to 20-membered heteroaryl, 3- to 20-membered heterocyclyl, C1-40 alkyloxy, C3-40 cycloalkyloxy, C6-20 aryloxy, 5- to 20-membered heteroaryloxy, 3- to 20-membered heterocyclyloxy, and NR2R3;
• each R5 is identical or different, and is independently selected from H, C1-40 alkyl, C3-40 cycloalkyl, C6-20 aryl, 5- to 20-membered heteroaryl, 3- to 20-membered heterocyclyl, C1-40 alkylcarbonyl, C3-40 cycloalkylcarbonyl, C6-20 arylcarbonyl, 5- to 20-membered heteroarylcarbonyl, and 3- to 20-membered heterocyclylcarbonyl;
• each R6 is identical or different, and is independently selected from H, C1-40 alkyl, C2-40 alkenyl, C2-40 alkynyl, C3-40 cycloalkyl, C6-20 aryl, 5- to 20-membered heteroaryl, 3- to 20-membered heterocyclyl, C1-40 alkyloxy, C3-40 cycloalkyloxy, C6-20 aryloxy, 5- to 20-membered heteroaryloxy, 3- to 20-membered heterocyclyloxy, and NR2R3;
• each R7 is identical or different, and is independently selected from H, C1-40 alkyl, C3-40 cycloalkyl, C6-20 aryl, 5- to 20-membered heteroaryl, and 3- to 20-membered heterocyclyl;
• each Ra, Rc, Rd and Re are identical or different, and are independently selected from halogen, CN, OH, SH, oxo (═O), NO2, and the following groups unsubstituted or optionally substituted with one, two or more Rg:
• C1-40 alkyl, C2-40 alkenyl, C2-40 alkynyl, C3-40 cycloalkyl, C6-20 aryl, 5- to 20-membered heteroaryl, 3- to 20-membered heterocyclyl, C1-40 alkyloxy, C3-40 cycloalkyloxy, C6-20 aryloxy, 5- to 20-membered heteroaryloxy, and 3- to 20-membered heterocyclyloxy;
• each Rg is identical or different, and is independently selected from halogen, CN, OH, SH, oxo (═O), NO2, and the following groups unsubstituted or optionally substituted with one, two or more Rh:
• C1-40 alkyl, C2-40 alkenyl, C2-40 alkynyl, C3-40 cycloalkyl, C3-40 cycloalkenyl, C3-40 cycloalkynyl, C6-20 aryl, 5- to 20-membered heteroaryl, 3- to 20-membered heterocyclyl, C1-40 alkyloxy, C2-40 alkenyloxy, C2-40 alkynyloxy, C3-40 cycloalkyloxy, C3-40 cycloalkenyloxy, C3-40 cycloalkynyloxy, C6-20 aryloxy, 5- to 20-membered heteroaryloxy, and 3- to 20-membered heterocyclyloxy;
• each Rh is identical or different, and is independently selected from halogen, CN, OH, SH, oxo (═O), NO2, and the following groups unsubstituted or optionally substituted with one, two or more Rg:
• C1-40 alkyl, C2-40 alkenyl, C2-40 alkynyl, C3-40 cycloalkyl, C3-40 cycloalkenyl, C3-40 cycloalkynyl, C6-20 aryl, 5- to 20-membered heteroaryl, 3- to 20-membered heterocyclyl, C1-40 alkyloxy, C2-40 alkenyloxy, C2-40 alkynyloxy, C3-40 cycloalkyloxy, C3-40 cycloalkenyloxy, C3-40 cycloalkynyloxy, C6-20 aryloxy, 5- to 20-membered heteroaryloxy, and 3- to 20-membered heterocyclyloxy;
• or, where the C3-40 cycloalkyl, C3-40 cycloalkenyl, C3-40 cycloalkynyl or 3- to 20-membered heterocyclyl described above is substituted with two or more substituents at different positions, any two of the substituents may also, together with the atom connected thereto, form a bridged ring, wherein the bridge atoms other than the bridgehead atoms in the bridged ring may comprise 1, 2, 3, 4, or 5 divalent groups selected from CH2, O, and NH;
• or, where one atom (such as carbon atom) is substituted with two or more substituents, two of the substituents may also, together with the shared atom connected thereto, form a cyclic group such as C3-40 cycloalkyl, C3-40 cycloalkenyl, C3-40 cycloalkynyl, 3- to 20-membered heterocyclyl, or the like;
• preferably,
• X1, X2, X3, and X4 are identical or different, and are each independently selected from CR1 or N;
• for example, at least one of X1, X2, X3, and X4 is N, e.g., one, two or three of X1, X2, X3, and X4 are N;
• each R1 is identical or different, and is independently selected from H, halogen, CN, OH, and the following groups unsubstituted or optionally substituted with one, two or more Ra:
• C1-6 alkyl, C3-10 cycloalkyl, C1-6 alkyloxy, and C3-10 cycloalkyloxy, for example, selected from the following group unsubstituted or optionally substituted with 1, 2 or 3 Ra:
• C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, or C3-6 cycloalkyloxy;
• D and E are identical or different, and are each independently selected from H, halogen, CN, NH2, C1-6 alkyl, or —O—R21, provided that at least one of D and E is selected from —O—R21;
• preferably, at least one of D and E is selected from the following group:
• preferably, R2 is selected from C1-6 alkyl unsubstituted or optionally substituted with one, two or more Rd;
• preferably, each Ra, Rc and Rd are identical or different, and are independently selected from halogen, CN, OH, and the following groups unsubstituted or optionally substituted with one, two or more Rg:
• C1-6 alkyl, C1-6 alkyloxy, C3-10 cycloalkyl, and C3-10 cycloalkyloxy;
• preferably, each Rg is identical or different, and is independently selected from halogen or C3-10 cycloalkyl;
• preferably, G is selected from C3-10 cycloalkyl, C6-14 aryl, 5- to 14-membered heteroaryl, and 3- to 10-membered heterocyclyl, for example, 6- to 7-membered heterocyclyl having a monocyclic, bicyclic or bridged ring structure containing 1, 2 or 3 heteroatoms independently selected from N, O, and S;
• preferably, Rk is selected from the following groups unsubstituted or optionally substituted with one, two or more Rg:
• C3-10 cycloalkyl, C6-14 aryl, 5- to 14-membered heteroaryl, and 3- to 10-membered heterocyclyl, wherein the heteroaryl may be pyridinyl, for example, selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, and pyridin-6-yl;
• the aryl may be phenyl;
• preferably, X1, X2, X3, and X4 are identical or different, and are each independently selected from CH or N;
• for example, at least one of X1, X2, X3, and X4 is N, e.g., one, two or three of X1, X2, X3, and X4 are N;
• preferably, R1 is H;
• preferably, E is H;
• preferably, D is selected from the following groups:
• halogen, BnO—, H, —CN, —NH2, —OCH3, and the following groups:
• preferably, G is selected from
• preferably, Rk is selected from pyridinyl or phenyl unsubstituted or optionally substituted with one, two or more R9, wherein where one, two or more R9 substituents are present, the R9 may be a substituent at position 1, 2, 3, 4, 5 or 6 of the pyridinyl or phenyl, as long as it does not affect the connection of Rk to group G via methylene;
• preferably, Rk in the compound of formula I may, together with methylene, form a group selected from the following:
• or Rk in the compound of formula I may be selected from group
• substituted with 1, 2, 3 or 4 groups selected from C1-6 alkyl and C1-6 alkyloxy;
• preferably, the starting material, reaction product or intermediate is not separated or purified using chromatography such as column chromatography;
• and/or
• the reaction is carried out without using hydrogen as a hydrogenation or reduction reagent, and without using hydrogen by means of catalytic hydrogenation.

A preparation method M15 for the compound of formula XV, comprising reacting a compound of formula XIV with an acid to give the compound of formula XV:

• wherein D and E are independently defined as above;
• L10 and PG3 are independently defined as above;
• preferably, the acid may be selected from at least one of organic acids or inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trimethylsilyl trifluoromethanesulfonate, trifluoroacetic acid, phosphorus oxychloride, succinic acid, and ascorbic acid;
• preferably, the molar ratio of the compound of formula XIV to trifluoroacetic acid may be 1:1 to 1:10, for example, 1:4 to 1:6, such as 1:5 to 1:5.5.
• preferably, the preparation method M15 comprises subjecting compound 14 to the following reaction to prepare compound 15:

A preparation method M14 for the compound of formula XIV, comprising reacting a compound of formula IIIA with ethanol to give the compound of formula XIV:

• wherein D is defined as above;
• L10 and PG3 are independently defined as above;
• L3a is selected from a leaving group, for example, halogen, such as chlorine, bromine, or iodine;
• preferably, the preparation method for the compound of formula XIV may be carried out in the presence of a copper(I) catalyst or a copper(I) catalyst with a ligand;
• the copper catalyst may be selected from at least one of copper(I) iodide (CuI), copper(I) bromide (CuBr), and copper(II) acetylacetonate (Cu(acac)2);
• preferably, the ligand may be selected from at least one of N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxamide, 8-hydroxyquinoline, N,N-bis(2,4,6-trimethoxyphenyl)oxamide, N-benzyl-N-(2-methylnaphthalen-1-yl)oxamide, and N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxamide;
• preferably, the molar volume ratio of the compound of formula IIIA to ethanol may be 1 mol:(2-5) L, such as 1 mol:(3-4) L;
• preferably, the molar ratio of the compound of formula IIIA to the copper(I) catalyst may be 1:0.01 to 1:0.2;
• preferably, the molar ratio of the compound of formula IIIA to the base may be 1:1 to 1:10, such as 1:2 to 1:4;
• preferably, the molar ratio of the compound of formula IIIA to the ligand may be 1:0.01 to 1:0.2, such as 1:0.02;
• preferably, the reaction may be carried out at a temperature of not less than 50° C., for example, not less than 70° C., such as 80 to 100° C.;
• preferably, the preparation method M14 comprises subjecting compound 3a to the following reaction to prepare compound 14: