A nitrogen-containing heterocyclic compound and its application

Abstract

The present invention discloses a nitrogen-containing heterocyclic compound and its application. The present invention specifically discloses a nitrogen-containing heterocyclic compound as shown in Formula I or Formula II and a pharmaceutically acceptable salt or solvate thereof. The nitrogen-containing heterocyclic compound of the present invention has good inhibitory activity against KRAS-G12D.

Description

[0001] The present invention claims priority to PCT / CN2021 / 141878 filed on December 28, 2021, the contents of which are incorporated herein in their entirety. Technical Field

[0002] The invention relates to a nitrogen-containing heterocyclic compound and application thereof. Background Art

[0003] RAS oncogene mutations are the most common activating mutations in human cancers, occurring in 30% of human tumors (Nat. Rev. Drug Discovery 2014, 13828-851). Although the RAS gene family includes three subtypes (KRAS, HRAS, and NRAS), 85% of RAS-driven cancers are caused by mutations in KRAS subtypes (J. Cell Sci. 2016121287-1292), and mutations are most common in solid tumors such as lung adenocarcinoma, pancreatic ductal carcinoma, and colorectal cancer. In KRAS mutant tumors, 80% of oncogenic mutations occur within codon 12, with the most common mutations being p.G12D (41%), p.G12V (28%), and p.G12C (14%) (Cancer Research, 2012, 722457-2467). Therefore, inhibition of activated RAS function has been shown to not only lead to reversal of the transformed phenotype, but also to cell death and tumor regression.

[0004] Compounds that inhibit RAS remain in great need and are under intensive investigation. In recent years, many advances have been made in this field, such as SOS inhibitors, and covalent G12C inhibitors. However, G12V and G12D inhibitors are gaining more and more attention. Summary of the invention

[0005] The present invention relates to a nitrogen-containing heterocyclic compound and application thereof. The nitrogen-containing heterocyclic compound of the present invention has good inhibitory activity on KRAS-G12D.

[0006] The present invention provides a nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof or a solvate thereof;

[0007]

[0008] in,

[0009] X 1 CR X1 or N; R X1 is hydrogen or halogen;

[0010] X 3 for CH;

[0011] R 1C6-C 14 Aryl, 5- to 14-membered heteroaryl, substituted by one or more R 1-1 Substituted C6-C 14 Aryl or one or more R 1-2 substituted 5- to 14-membered heteroaryl; 5- to 14-membered heteroaryl ("5- to 14-membered heteroaryl" refers to "5- to 14-membered heteroaryl" or "substituted by one or more R 1-2 The corresponding parts in "substituted 5- to 14-membered heteroaryl", other parts of the present invention are similar), the number of heteroatoms is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from the group consisting of O, S and N;

[0012] R 1-1 and R 1-2 Each is independently halogen, cyano, hydroxyl, C1-C4 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, -N(R N1 )2 or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted by halogen or C1-C3 alkyl;

[0013] R 2 is hydrogen, halogen or C1-C3 alkyl;

[0014] L 1 is a single bond, C1-C4 alkylene, -O- or -N(R N1 )-;

[0015] R 3 is a 3- to 12-membered heterocycloalkyl group, 3-1-1 or -L 2 -R 3-1 substituted 3- to 12-membered heterocycloalkyl;

[0016] L 2 is -O-, -N(methyl)-, C1-C4 alkylene or is replaced by one or more R L2 Substituted C1-C4 alkylene; each R L2 are independently hydroxy or C1-C4 hydroxyalkyl;

[0017] R 3-1 C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 14 Aryl, 5- to 14-membered heteroaryl, -N(R N1 2. One or more R 3-1-1 Substituted C3-C 12 Cycloalkyl, with one or more R 3-1-2 substituted to 12-membered heterocycloalkyl, substituted by one or more R3-1-3 Substituted C6-C 14 Aryl or one or more R 3-1-4 substituted 5- to 14-membered heteroaryl; in the 3- to 12-membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, one or more of the heteroatoms are selected from O, S and N; in the 5- to 14-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, one or more of the heteroatoms are selected from the group consisting of O, S and N; n is independently 0, 1, 2, 3 or 4;

[0018] R 3-1-1 , R 3-1-2 , R 3-1-3 and R 3-1-4 Each is halogen, cyano, oxo, C1-C4 alkyl or -N(R N1 )2;

[0019] R 6 is -CN;

[0020] R 4 is C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 3- to 12-membered nitrogen-containing heterocycloalkyl, 3- to 12-membered nitrogen-containing heterocycloalkenyl, 4-1 Substituted C3-C6 cycloalkyl, one or more R 4-2 Substituted C3-C7 cycloalkenyl, substituted by one or more R 4 -3 substituted 3 to 12-membered nitrogen-containing heterocycloalkyl or one or more R 4-4 Substituted 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0021] R 4-1 , R 4-2 , R 4-3 and R 4-4 Each is independently oxo, hydroxyl, cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C3-C6 cycloalkyl, C1-C3 alkoxy or -N(R N1 )2;

[0022] Each R N1 are independently hydrogen or C1-C3 alkyl.

[0023] In certain embodiments, the nitrogen-containing heterocyclic compound represented by Formula I, its pharmaceutically acceptable salt or solvate thereof has the following definition (hereinafter referred to as "in certain embodiments"):

[0024] R 1 C6-C 14 Aryl, 5- to 14-membered heteroaryl, substituted by one or more R 1-1 Substituted C6-C 14 Aryl or one or more R 1-2 Substituted 5- to 14-membered heteroaryl; in the 5- to 14-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from the group consisting of O, S and N;

[0025] R 1-1 and R 1-2 Each is independently halogen, cyano, hydroxy, C2-C4 alkynyl or C1-C3 alkoxy.

[0026] In certain embodiments, R 1 C6-C 14 Aryl, 5- to 14-membered heteroaryl, substituted by one or more R 1-1 Substituted C6-C 14 Aryl or one or more R 1-2 Substituted 5- to 14-membered heteroaryl; in the 5- to 14-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from the group consisting of O, S and N;

[0027] R 1-1 and R 1-2 Each is independently halogen, cyano, hydroxy, C1-C4 alkyl, C2-C4 alkynyl, C1-C3 haloalkyl or C3-C6 cycloalkyl.

[0028] In certain embodiments, R 2 is hydrogen or halogen.

[0029] In certain embodiments, R 2 It is a halogen.

[0030] In certain embodiments, L 1 It is C1-C4 alkylene, -N(methyl)- or -O-.

[0031] In certain embodiments, L 1 It is C1-C4 alkylene or -O-.

[0032] In certain embodiments, R 1 It is -O-.

[0033] In certain embodiments, R 3 is a 3- to 12-membered heterocycloalkyl group, 3-1-1 or -L 2 -R 3-1 substituted 3- to 12-membered heterocycloalkyl;

[0034] L 2 is -O-, -N(methyl)-, C1-C4 alkylene or is replaced by one or more R L2 Substituted C1-C4 alkylene; each R L2 are independently hydroxy or C1-C4 hydroxyalkyl;

[0035] R 3-1 C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 14 Aryl, 5- to 14-membered heteroaryl, -N(R N1 2. One or more R 3-1-1 Substituted C3-C 12 Cycloalkyl, with one or more R 3-1-2 substituted 3-12 membered heterocycloalkyl, 3-1-3 Substituted C6-C 14 Aryl or one or more R 3-1-4 substituted 5- to 14-membered heteroaryl; in the 3- to 12-membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, one or more of the heteroatoms are selected from O, S and N; in the 5- to 14-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, one or more of the heteroatoms are selected from the group consisting of O, S and N; n is independently 0, 1, 2, 3 or 4;

[0036] R 3-1-1 , R 3-1-2 , R 3-1-3 and R 3-1-4 Each is halogen, cyano, C1-C4 alkyl or -N(R N1 )2.

[0037] In certain embodiments, R 3 is a 3- to 12-membered heterocycloalkyl group, 3-1-1 or -L 2 -R 3-1 substituted 3- to 12-membered heterocycloalkyl;

[0038] L 2 is C1-C4 alkylene or is replaced by one or more R L2 Substituted C1-C4 alkylene; each R L2 are independently hydroxy or C1-C4 hydroxyalkyl;

[0039] R 3-1 C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 14 Aryl, 5- to 14-membered heteroaryl, -N(R N1 2. One or more R3-1-1 Substituted C3-C 12 Cycloalkyl, with one or more R 3-1-2 substituted 3 to 12 membered heterocycloalkyl, substituted by one or more R 3-1-3 Substituted C6-C 14 Aryl or one or more R 3-1-4 substituted 5- to 14-membered heteroaryl; in the 3- to 12-membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, one or more of the heteroatoms are selected from O, S and N; in the 5- to 14-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, one or more of the heteroatoms are selected from the group consisting of O, S and N; n is independently 0, 1, 2, 3 or 4;

[0040] R 3-1-1 , R 3-1-2 , R 3-1-3 and R 3-1-4 Each is halogen, cyano, oxo, C1-C4 alkyl or -N(R N1 )2.

[0041] In certain embodiments, R 3 is a 3- to 12-membered heterocycloalkyl group, 3-1-1 or -L 2 -R 3-1 substituted 3- to 12-membered heterocycloalkyl;

[0042] L 2 is C1-C4 alkylene or is replaced by one or more R L2 Substituted C1-C4 alkylene; each R L2 are independently hydroxy or C1-C4 hydroxyalkyl;

[0043] R 3-1 C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 14 Aryl, 5- to 14-membered heteroaryl, -N(R N1 2. One or more R 3-1-1 Substituted C3-C 12 Cycloalkyl, with one or more R 3-1-2 substituted 3 to 12 membered heterocycloalkyl, substituted by one or more R 3-1-3 Substituted C6-C 14 Aryl or one or more R 3-1-4 substituted 5- to 14-membered heteroaryl; in the 3- to 12-membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, one or more of the heteroatoms are selected from O, S and N; in the 5- to 14-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, one or more of the heteroatoms are selected from the group consisting of O, S and N; n is independently 0, 1, 2, 3 or 4;

[0044] R 3-1-1 , R 3-1-2 , R 3-1-3 and R 3-1-4 Each is halogen, cyano, C1-C4 alkyl or -N(R N1 )2.

[0045] In certain embodiments, R 3 For -L 2 -R 3-1 ;

[0046] L 2 is -O-, -N(methyl)- or C1-C4 alkylene;

[0047] R 3-1 C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, 3-1-1 Substituted C3-C 12 Cycloalkyl or one or more R 3-1-2 Substituted 3- to 12-membered heterocycloalkyl; wherein the number of heteroatoms in the 3- to 12-membered heterocycloalkyl is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from O, S and N;

[0048] R 3-1-1 and R 3-1-2 are each independently halogen or oxo.

[0049] In certain embodiments, R 3 For -L 2 -R 3-1 ;

[0050] L 2 is -O-, -N(methyl)- or C1-C4 alkylene;

[0051] R 3-1 C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, 3-1-1 Substituted C3-C 12 Cycloalkyl or one or more R 3-1-2 Substituted 3- to 12-membered heterocycloalkyl; wherein the number of heteroatoms in the 3- to 12-membered heterocycloalkyl is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from O, S and N;

[0052] R 3-1-1 and R 3-1-2 are each independently halogen.

[0053] In certain embodiments, R 3 For -L 2 -R3-1 ;

[0054] L 2 is C1-C4 alkylene;

[0055] R 3-1 C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, 3-1-1 Substituted C3-C 12 Cycloalkyl or one or more R 3-1-2 Substituted 3- to 12-membered heterocycloalkyl; wherein the number of heteroatoms in the 3- to 12-membered heterocycloalkyl is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from O, S and N;

[0056] R 3-1-1 and R 3-1-2 are each independently halogen or oxo.

[0057] In certain embodiments, R 3 For -L 2 -R 3-1 ;

[0058] L 2 is C1-C4 alkylene;

[0059] R 3-1 C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, 3-1-1 Substituted C3-C 12 Cycloalkyl or one or more R 3-1-2 Substituted 3- to 12-membered heterocycloalkyl; wherein the number of heteroatoms in the 3- to 12-membered heterocycloalkyl is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from O, S and N;

[0060] R 3-1-1 and R 3-1-2 are each independently halogen.

[0061] In certain embodiments, R 4 is a 3- to 12-membered nitrogen-containing heterocyclic alkyl group or is replaced by one or more R 4-3 A substituted 3- to 12-membered nitrogen-containing heterocycloalkyl group; wherein the number of heteroatoms in the 3- to 12-membered nitrogen-containing heterocycloalkyl group is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from O, S and N;

[0062] Each R 4-3 are independently C1-C3 cyanoalkyl or -N(R N1 )2;

[0063] Each R N1 are independently hydrogen or C1-C3 alkyl.

[0064] In certain embodiments, R 4 For 1 R 4-1 Substituted C4-C7 cycloalkyl; R 4-1 -N(R N1 )2; Each R N1 are independently hydrogen or C1-C3 alkyl.

[0065] In certain embodiments, R 4 In the above, the C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 3- to 12-membered nitrogen-containing heterocycloalkyl and 3- to 12-membered nitrogen-containing heterocycloalkenyl are bridged rings.

[0066] In certain embodiments, R 4 The following conditions are met:

[0067]

[0068] Among them, Z 1 is independently CH, C or N;

[0069] e is independently 0, 1, 2, 3 or 4;

[0070] R Z1 are independently oxo, hydroxyl, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, -N(RN1)2, -CO2RN1, -CO2N(RN1)2 or 5- to 6-membered heteroaryl; in the 5- to 6-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0071] Each R N1 are independently hydrogen or C1-C3 alkyl;

[0072] R Z2 It is hydrogen or methyl.

[0073] In certain embodiments, the "NH" on the ring does not overlap with R Z1 connect.

[0074] In certain embodiments, R 4 for

[0075] Among them, Z 1 is independently CH, C or N;

[0076] Ring A is a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0077] Ring B is a C3-C7 cycloalkyl, a C3-C7 cycloalkenyl, a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0078] e is independently 0, 1, 2, 3 or 4;

[0079] R Z1 are independently oxo, hydroxyl, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, -N(RN1)2, -CO2RN1, -CO2N(RN1)2 or 5- to 6-membered heteroaryl; in the 5- to 6-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0080] Each R N1 are independently hydrogen or C1-C3 alkyl;

[0081] R Z2 It is hydrogen or methyl.

[0082] In certain embodiments, R 4 Attached via carbon or nitrogen atoms

[0083] R 4 is a 3- to 12-membered nitrogen-containing heterocycloalkyl group or a 3- to 12-membered nitrogen-containing heterocycloalkenyl group; 4-3 substituted 3 to 12-membered nitrogen-containing heterocycloalkyl or one or more R 4-4 substituted 3- to 12-membered nitrogen-containing heterocycloalkenyl;

[0084] R 4 The 3- to 12-membered nitrogen-containing heterocycloalkyl group has an "NH" which is not adjacent to R 4-3 connect;

[0085] R 4 The 3- to 12-membered nitrogen-containing heterocycloalkyl group has an "NH" which is not adjacent to R 4-4 connect.

[0086] In certain embodiments, R 4 Attached via carbon or nitrogen atoms

[0087] R 4 For one or more R 4-1 Substituted C3-C6 cycloalkyl, one or more R 4-2 Substituted C3-C7 cycloalkenyl, substituted by one or more R 4-3 substituted 3 to 12-membered nitrogen-containing heterocycloalkyl or one or more R 4-4 substituted 3- to 12-membered nitrogen-containing heterocycloalkenyl;

[0088] R 4-1 One of them is NH2 or N(methyl); R 4-2 One of them is NH2 or N(methyl); R 4-3 One of them is NH2 or N(methyl); R 4-3 One of them is NH2 or N(methyl).

[0089] In certain embodiments:

[0090] X 1 CR X1 or N; R X1 is hydrogen or halogen;

[0091] X 3 for CH;

[0092] R 1 C6-C 14 Aryl, 5- to 14-membered heteroaryl, substituted by one or more R 1-1 Substituted C6-C 14 Aryl or one or more R 1-2 Substituted 5- to 14-membered heteroaryl; in the 5- to 14-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from the group consisting of O, S and N;

[0093] R 1-1 and R 1-2 Each is independently halogen, cyano, hydroxy, C2-C4 alkynyl or C1-C3 alkoxy;

[0094] R 2 is a halogen;

[0095] L 1 is C1-C4 alkylene, -N(methyl)- or -O-;

[0096] R 3 For -L 2 -R 3-1 ;

[0097] L 2 is -O-, -N(methyl)- or C1-C4 alkylene;

[0098] R 3-1 C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, 3-1-1 Substituted C3-C 12 Cycloalkyl or one or more R 3-1-2 Substituted 3- to 12-membered heterocycloalkyl; wherein the number of heteroatoms in the 3- to 12-membered heterocycloalkyl is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from O, S and N;

[0099] R 3-1-1 and R 3-1-2 are each independently halogen or oxo;

[0100] R 6 is -CN;

[0101] R 4 is a 3- to 12-membered nitrogen-containing heterocyclic alkyl group or is replaced by one or more R 4-3 A substituted 3- to 12-membered nitrogen-containing heterocycloalkyl group; wherein the number of heteroatoms in the 3- to 12-membered nitrogen-containing heterocycloalkyl group is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from O, S and N;

[0102] Each R 4-3 are independently C1-C3 cyanoalkyl or -N(R N1 )2;

[0103] Each R N1 are independently hydrogen or C1-C3 alkyl.

[0104] In certain embodiments:

[0105] X 1 for CH;

[0106] X 3 for CH;

[0107] R 1 C6-C 14 Aryl, 5- to 14-membered heteroaryl, substituted by one or more R 1-1 Substituted C6-C 14 Aryl or one or more R 1-2 Substituted 5- to 14-membered heteroaryl; in the 5- to 14-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from the group consisting of O, S and N;

[0108] R 1-1 and R1-2 Each is independently halogen, cyano, hydroxyl, C1-C4 alkyl, C2-C4 alkynyl, C1-C3 haloalkyl or C3-C6 cycloalkyl;

[0109] R 2 is a halogen;

[0110] L 1 for -O-;

[0111] R 3 For -L 2 -R 3-1 ;

[0112] L 2 is C1-C4 alkylene;

[0113] R 3-1 is a 3- to 12-membered heterocycloalkyl group or is replaced by one or more R 3-1-2 Substituted 3- to 12-membered heterocycloalkyl; wherein the number of heteroatoms in the 3- to 12-membered heterocycloalkyl is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from O, S and N;

[0114] R 3-1-2 Each is independently halogen or C1-C4 alkyl;

[0115] R 6 is -CN;

[0116] R 4 is a 3- to 12-membered nitrogen-containing heterocyclic alkyl group or is replaced by one or more R 4-3 A substituted 3- to 12-membered nitrogen-containing heterocycloalkyl group; wherein the number of heteroatoms in the 3- to 12-membered nitrogen-containing heterocycloalkyl group is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from O, S and N;

[0117] Each R 4-3 are independently C1-C3 alkyl or -N(R N1 )2;

[0118] Each R N1 are independently hydrogen or C1-C3 alkyl.

[0119] In certain embodiments, R 2 is hydrogen or halogen;

[0120] R 4 Attached via carbon or nitrogen atoms

[0121] In certain embodiments:

[0122] for

[0123] Where n is 1, 2, 3 or 4, each R 1-1 are independently halogen, cyano, ethynyl or C1-C4 alkyl;

[0124] R 4 Attached via carbon or nitrogen atoms

[0125] In certain embodiments:

[0126] for

[0127] Where m is 1, 2, 3 or 4, R 3-1-2 are each independently oxo, halogen or cyano;

[0128] R 4-1 , R 4-2 , R 4-3 and R 4-4 are each independently oxo, halogen or cyano;

[0129] R 4 Attached via carbon or nitrogen atoms

[0130] In certain embodiments:

[0131] for

[0132] Among them, R 4 Attached via carbon or nitrogen atoms

[0133] In certain embodiments:

[0134] for

[0135] Among them, R 4 Attached via carbon or nitrogen atoms

[0136] In certain embodiments:

[0137] for

[0138] Wherein, p is 0, 1, 2 or 3, q ​​is 0, 1, 2 or 3;

[0139] R 4 Attached via carbon or nitrogen atoms

[0140] In certain embodiments:

[0141] for

[0142] in,

[0143] R 4 For 1 R 4-1 Substituted C4-C7 cycloalkyl; R 4-1 -N(R N1 )2; Each R N1 are independently hydrogen or C1-C3 alkyl;

[0144] R 4 Attached via carbon or nitrogen atoms

[0145] In certain embodiments:

[0146] for

[0147] Among them, Z 1 is independently CH, C or N;

[0148] Ring A is a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0149] Ring B is a C3-C7 cycloalkyl, a C3-C7 cycloalkenyl, a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0150] e is independently 0, 1, 2, 3 or 4;

[0151] R Z1 are independently oxo, hydroxyl, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, -N(RN1)2, -CO2RN1, -CO2N(RN1)2 or 5- to 6-membered heteroaryl; in the 5- to 6-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0152] Each R N1are independently hydrogen or C1-C3 alkyl;

[0153] R Z2 It is hydrogen or methyl.

[0154] In certain embodiments:

[0155] for

[0156] Among them, Z 1 is independently CH, C or N;

[0157] Ring A is a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0158] Ring B is a C3-C7 cycloalkyl, a C3-C7 cycloalkenyl, a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0159] e is independently 0, 1, 2, 3 or 4;

[0160] R Z1 are independently oxo, hydroxy, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, -N(R N1 2. -CO2R N1 、-CO2N(R N1 ) 2 or 5 to 6 membered heteroaryl; in the 5 to 6 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0161] Each R N1 are independently hydrogen or C1-C3 alkyl;

[0162] R Z2 It is hydrogen or methyl.

[0163] In certain embodiments:

[0164]

[0165] for

[0166] Where n is 1, 2, 3 or 4, each R 1-1 are independently halogen, cyano, ethynyl or C1-C4 alkyl;

[0167] Z 1 is independently CH, C or N;

[0168] Ring A is a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0169] Ring B is a C3-C7 cycloalkyl, a C3-C7 cycloalkenyl, a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0170] e is independently 0, 1, 2, 3 or 4;

[0171] R Z1 are independently oxo, hydroxy, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, -N(R N1 2. -CO2R N1 、-CO2N(R N1 ) 2 or 5 to 6 membered heteroaryl; in the 5 to 6 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0172] Each R N1 are independently hydrogen or C1-C3 alkyl;

[0173] R Z2 It is hydrogen or methyl.

[0174] In certain embodiments:

[0175]

[0176] for

[0177] Where n is 1, 2, 3 or 4, each R 1-1are independently halogen, cyano, ethynyl or C1-C4 alkyl;

[0178] Z 1 is independently CH, C or N;

[0179] Ring A is a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0180] Ring B is a C3-C7 cycloalkyl, a C3-C7 cycloalkenyl, a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0181] e is independently 0, 1, 2, 3 or 4;

[0182] R Z1 are independently oxo, hydroxy, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, -N(R N1 2. -CO2R N1 、-CO2N(R N1 ) 2 or 5 to 6 membered heteroaryl; in the 5 to 6 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0183] Each R N1 are independently hydrogen or C1-C3 alkyl;

[0184] R Z2 It is hydrogen or methyl.

[0185] In certain embodiments, R X1 In the formula (a), halogen is F, Cl, Br or I.

[0186] In certain embodiments, R X1 In the formula, halogen is F.

[0187] In certain embodiments, R 1 Medium, C6-C 14 Aryl is C6-C 10 Aryl.

[0188] In certain embodiments, R1 Medium, C6-C 14 Aryl is monocyclic or bicyclic.

[0189] In certain embodiments, R 1 Medium, C6-C 14 Each ring of the aryl group is aromatic.

[0190] In certain embodiments, R 1 Medium, C6-C 14 Aryl is phenyl, 1-naphthyl, 2-naphthyl or

[0191] In certain embodiments, R 1 In the above, the 5- to 14-membered heteroaryl group is a 9- to 10-membered heteroaryl group.

[0192] In certain embodiments, R 1 In the above, the 5- to 14-membered heteroaryl group is a monocyclic or bicyclic ring.

[0193] In certain embodiments, R 1 In the above, each ring of the 5- to 14-membered heteroaryl group is aromatic.

[0194] In certain embodiments, R 1 In the 5- to 14-membered heteroaryl group, the number of heteroatoms is 1 or 2.

[0195] In certain embodiments, R 1 In the 5- to 14-membered heteroaryl group, the heteroatom is N.

[0196] In certain embodiments, R 1 In the above, the 5- to 14-membered heteroaryl group is pyridyl, indolyl, quinolyl, isoquinolyl, benzothienyl or benzothiazolyl.

[0197] In certain embodiments, in R 1 In the case of a 5- to 14-membered heteroaryl group,

[0198] In certain embodiments, R 1-1 and R 1-2 In the formula (a), halogen is F, Cl, Br or I.

[0199] In certain embodiments, R 1-1 and R 1-2 In the formula (a), halogen is F or Cl.

[0200] In certain embodiments, R 1-1 and R 1-2 In the formula, halogen is F.

[0201] In certain embodiments, R1-1 and R 1-2 In the above, the C1-C4 alkyl group is a methyl group, an ethyl group, a propyl group or an isopropyl group.

[0202] In certain embodiments, R 1-1 and R 1-2 In the above, the C1-C4 alkyl group is a methyl group or an ethyl group.

[0203] In certain embodiments, R 1-1 and R 1-2 In the above, the C1-C4 alkyl group is a methyl group.

[0204] In certain embodiments, R 1-1 and R 1-2 In the above, -S-C1-C3 alkyl is -S-methyl, -S-ethyl, -S-propyl or -S-isopropyl.

[0205] In certain embodiments, R 1-1 and R 1-2 In the above, -S-C1-C3 alkyl is -S-methyl.

[0206] In certain embodiments, R 1-1 and R 1-2 In the above, the C2-C4 alkynyl group is an ethynyl group.

[0207] In certain embodiments, R 1-1 and R 1-2 In the above, C1-C3 haloalkyl is -CF3.

[0208] In certain embodiments, R 1-1 and R 1-2 In the above, -O-C1-C3 haloalkyl is -O-CF3.

[0209] In certain embodiments, R 1-1 and R 1-2 In the above, the C1-C3 alkoxy group is a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.

[0210] In certain embodiments, R 1-1 and R 1-2 In the above, the C1-C3 alkoxy group is a methoxy group.

[0211] In certain embodiments, R 1-1 and R 1-2 In the above, the C3-C6 cycloalkyl group is a cyclopropyl group, a cyclopentyl group or a cyclohexyl group.

[0212] In certain embodiments, R 1-1 and R 1-2 In the above, the C3-C6 cycloalkyl group is a cyclopropyl group.

[0213] In certain embodiments, R 1 for

[0214]

[0215] In certain embodiments, R 1 for

[0216]

[0217] In certain embodiments, R 2 In the formula (a), halogen is F, Cl, Br or I.

[0218] In certain embodiments, R 2 In the formula, halogen is F.

[0219] In certain embodiments, in R 2 In the above, the C1-C3 alkyl group is a methyl group, an ethyl group, a propyl group or an isopropyl group.

[0220] In certain embodiments, L 1 In the above, the C1-C4 alkylene group is a methylene group, an ethylene group, a propylene group or a butylene group.

[0221] In certain embodiments, R 3 In the above, the 3- to 12-membered heterocycloalkyl group is a 3- to 6-membered heterocycloalkyl group.

[0222] In certain embodiments, R 3 In the above, the 3- to 12-membered heterocycloalkyl group is a 4-membered heterocycloalkyl group.

[0223] In certain embodiments, R 3 In the above, the 3- to 12-membered heterocycloalkyl group is a monocyclic or bicyclic ring.

[0224] In certain embodiments, R 3 In the above, the 3- to 12-membered heterocycloalkyl is a monocyclic, spirocyclic or bridged ring.

[0225] In certain embodiments, R 3 In the 3- to 12-membered heterocycloalkyl group, the number of heteroatoms is 1 or 2.

[0226] In certain embodiments, R 3 In the 3- to 12-membered heterocycloalkyl group, the heteroatom is N.

[0227] In certain embodiments, R 3 In the above, the 3- to 12-membered heterocycloalkyl group is azetidinyl group.

[0228] In certain embodiments, R 3In the above, the 3- to 12-membered heterocycloalkyl group is 1-azetidinyl group.

[0229] In certain embodiments, L 2 In the above, the C1-C4 alkylene group is a methylene group, an ethylene group, a propylene group or a butylene group.

[0230] In certain embodiments, R 3-1 The bond to L2 is through a carbon atom or a nitrogen atom.

[0231] In certain embodiments, R 3-1 Medium, C3-C 12 The cycloalkyl group is a C3-C8 cycloalkyl group.

[0232] In certain embodiments, R 3-1 Medium, C3-C 12 The cycloalkyl group is a C5-C8 cycloalkyl group.

[0233] In certain embodiments, R 3-1 Medium, C3-C 12 The cycloalkyl group is a monocyclic or bicyclic ring.

[0234] In certain embodiments, R 3-1 Medium, C3-C 12 The cycloalkyl group is a monocyclic ring, a spirocyclic ring or a bridged ring.

[0235] In certain embodiments, R 3-1 Medium, C3-C 12 The cycloalkyl group is cyclopentyl or octahydropentalene.

[0236] In certain embodiments, R 3-1 In the above, the 3- to 12-membered heterocycloalkyl group is a 5- to 10-membered heterocycloalkyl group.

[0237] In certain embodiments, R 3-1 In the above, the 3- to 12-membered heterocycloalkyl group is a 5- to 8-membered heterocycloalkyl group.

[0238] In certain embodiments, R 3-1 In the above, the 3- to 12-membered heterocycloalkyl group is a monocyclic or bicyclic ring.

[0239] In certain embodiments, R 3-1 In the above, the 3- to 12-membered heterocycloalkyl is a monocyclic, spirocyclic or bridged ring.

[0240] In certain embodiments, R 3-1 In the 3- to 12-membered heterocycloalkyl group, the number of heteroatoms is 1 or 2.

[0241] In certain embodiments, R 3-1 In the 3- to 12-membered heterocycloalkyl group, the heteroatom is N.

[0242] In certain embodiments, R 3-1 In the above, the 3- to 12-membered heterocycloalkyl group is a 5- to 6-membered monocyclic heterocycloalkyl group.

[0243] In certain embodiments, R 3-1 In the above, the 3- to 12-membered heterocycloalkyl group is a 7- to 10-membered bridged heterocycloalkyl group.

[0244] In certain embodiments, R 3-1 In the above, the 3- to 12-membered heterocycloalkyl group is tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl or tetrahydro-1H-pyrrolazin-7a(5H)-yl.

[0245] In certain embodiments, R 3-1 wherein the 3- to 12-membered heterocycloalkyl group is tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl or

[0246] In certain embodiments, R 3-1 In the above, the 5- to 14-membered heteroaryl group is a 5- to 6-membered heteroaryl group.

[0247] In certain embodiments, R 3-1 In the above, the 5- to 14-membered heteroaryl group is a monocyclic or bicyclic ring.

[0248] In certain embodiments, R 3-1 In the 5- to 14-membered heteroaryl group, the number of heteroatoms is 1 or 2.

[0249] In certain embodiments, R 3-1 In the 5- to 14-membered heteroaryl group, the heteroatom is N.

[0250] In certain embodiments, R 3-1 In the above, the 5- to 14-membered heteroaryl is pyrazolyl.

[0251] In certain embodiments, R 3-1-1 , R 3-1-2 , R 3-1-3 and R 3-1-4 In the formula (a), halogen is F, Cl, Br or I.

[0252] In certain embodiments, R 3-1-1 , R 3-1-2 , R 3-1-3 and R 3-1-4 In the formula, halogen is F.

[0253] In certain embodiments, R 3-1-1 , R 3-1-2 , R 3-1-3 and R 3-1-4 In the above, the C1-C4 alkyl group is a methyl group, an ethyl group, a propyl group or an isopropyl group.

[0254] In certain embodiments, R 3-1-1 , R 3-1-2 , R 3-1-3 and R 3-1-4 In the above, the C1-C4 alkyl group is a methyl group.

[0255] In certain embodiments, -L 1 -R 3 for

[0256]

[0257] In certain embodiments, -L 1 -R 3 for

[0258] In certain embodiments, R 4 Attached via carbon or nitrogen atoms

[0259] In certain embodiments, R 4 In the above, the C3-C7 cycloalkyl group is a monocyclic or bicyclic ring.

[0260] In certain embodiments, R 4 In the above, the C3-C7 cycloalkyl group is a monocyclic ring, a spirocyclic ring or a bridged ring.

[0261] In certain embodiments, R 4 In the formula (C3-C7), the C3-C7 cycloalkyl group is Cyclopropyl, cyclopentyl or cyclohexyl.

[0262] In certain embodiments, R 4 In the above, the C3-C7 cycloalkyl group is a cyclopentyl group.

[0263] In certain embodiments, R 4 In the 4-1 The substituted C3-C7 cycloalkyl group is

[0264] In certain embodiments, R 4 In the above, the C3-C7 cycloalkenyl group is a monocyclic or bicyclic ring.

[0265] In certain embodiments, R 4 In the above, the C3-C7 cycloalkenyl group is a monocyclic ring, a spirocyclic ring or a bridged ring.

[0266] In certain embodiments, R 4 In the above, the C3-C7 cycloalkenyl group is a cyclopropenyl group, a cyclopentenyl group or a cyclohexenyl group.

[0267] In certain embodiments, R 4 In the above, the C3-C7 cycloalkenyl group is a cyclopentenyl group.

[0268] In certain embodiments, R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a 5- to 9-membered nitrogen-containing heterocycloalkyl group.

[0269] In certain embodiments, R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a 5- to 8-membered nitrogen-containing heterocycloalkyl group.

[0270] In certain embodiments, R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a monocyclic or bicyclic ring.

[0271] In certain embodiments, R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a monocyclic ring, a spirocyclic ring or a bridged ring.

[0272] In certain embodiments, R 4 In the above, the number of heteroatoms in the 3- to 12-membered nitrogen-containing heterocycloalkyl group is 1 or 2.

[0273] In certain embodiments, R 4 In the above, the heteroatom in the 3- to 12-membered nitrogen-containing heterocycloalkyl group is N.

[0274] In certain embodiments, R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a 5- to 7-membered nitrogen-containing heterocycloalkyl group.

[0275] In certain embodiments, in R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a 6- to 8-membered nitrogen-containing bridged heterocycloalkyl group.

[0276] In certain embodiments, in R 4 wherein the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a 7- to 9-membered nitrogen-containing spirocyclic heterocycloalkyl group.

[0277] In certain embodiments, in R 4 wherein the 3- to 12-membered nitrogen-containing heterocyclic alkyl group is tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,

[0278] In certain embodiments, in R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is a 5- to 9-membered nitrogen-containing heterocycloalkenyl group.

[0279] In certain embodiments, in R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is a 5- to 6-membered nitrogen-containing heterocycloalkenyl group.

[0280] In certain embodiments, in R4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is a monocyclic or bicyclic ring.

[0281] In certain embodiments, in R 4 In the above, the 3- to 12-membered nitrogen-containing heterocyclic alkenyl group is a monocyclic ring, a spirocyclic ring or a bridged ring.

[0282] In certain embodiments, in R 4 In the above, the 3- to 12-membered nitrogen-containing heterocyclic alkenyl group is a monocyclic ring.

[0283] In certain embodiments, in R 4 In the 3- to 12-membered nitrogen-containing heterocycloalkenyl group, the number of heteroatoms is 1 or 2.

[0284] In certain embodiments, in R 4 In the above, the number of heteroatoms in the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is 1.

[0285] In certain embodiments, in R 4 In the 3- to 12-membered nitrogen-containing heterocycloalkenyl group, the number of heteroatoms is N.

[0286] In certain embodiments, in R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is a 5- to 7-membered nitrogen-containing monocyclic heterocycloalkenyl group.

[0287] In certain embodiments, in R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is a 6- to 8-membered nitrogen-containing bridged heterocycloalkenyl group.

[0288] In certain embodiments, in R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is a 7- to 9-membered nitrogen-containing spirocyclic heterocycloalkenyl group.

[0289] In certain embodiments, in R 4 wherein the 3 to 12-membered nitrogen-containing heterocyclic alkenyl group is

[0290] In certain embodiments, in R 4-1 , R 4-2 , R 4-3 and R 4-4 In the formula (a), halogen is F, Cl, Br or I.

[0291] In certain embodiments, in R 4-1 , R 4-2 , R 4-3 and R 4-4 In the formula, halogen is F.

[0292] In certain embodiments, R 4-1 , R 4-2 , R 4-3 and R4-4 In the above, the C1-C3 alkyl group is a methyl group, an ethyl group, a propyl group or an isopropyl group.

[0293] In certain embodiments, R 4-1 , R 4-2 , R 4-3 and R 4-4 In the above, the C1-C3 alkyl group is a methyl group.

[0294] In certain embodiments, R 4-1 , R 4-2 , R 4-3 and R 4-4 In the above, C1-C3 cyanoalkyl is cyanomethyl.

[0295] In certain embodiments, R 4-1 , R 4-2 , R 4-3 and R 4-4 In the above, the C3-C6 cycloalkyl group is a cyclopropyl group, a cyclopentyl group or a cyclohexyl group.

[0296] In certain embodiments, R 4-1 , R 4-2 , R 4-3 and R 4-4 In the above, the C3-C6 cycloalkyl group is a cyclopropyl group.

[0297] In certain embodiments, R 4-1 , R 4-2 , R 4-3 and R 4-4 In the above, the C1-C3 alkoxy group is a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.

[0298] In certain embodiments, R 4-1 , R 4-2 , R 4-3 and R 4-4 In the above, the C1-C3 alkyl group is a methoxy group.

[0299] In certain embodiments, in R N1 In the above, the C1-C3 alkyl group is a methyl group, an ethyl group, a propyl group or an isopropyl group.

[0300] In certain embodiments, R N1 In the above, the C1-C3 alkyl group is a methyl group.

[0301] In certain embodiments, the "NH" on Ring A does not overlap with R Z1 connect.

[0302] In certain embodiments, in Ring B, the C3-C7 cycloalkyl group is monocyclic or bicyclic.

[0303] In certain embodiments, in Ring B, the C3-C7 cycloalkyl group is a monocyclic ring, a spirocyclic ring, or a bridged ring.

[0304] In certain embodiments, in Ring B, the C3-C7 cycloalkyl group is Cyclopropyl, cyclopentyl or cyclohexyl.

[0305] In certain embodiments, in Ring B, the C3-C7 cycloalkyl is cyclopentyl.

[0306] In certain embodiments, in Ring B, the C3-C7 cycloalkenyl is monocyclic or bicyclic.

[0307] In certain embodiments, in Ring B, the C3-C7 cycloalkenyl is a monocyclic, spirocyclic, or bridged ring.

[0308] In certain embodiments, in Ring B, the C3-C7 cycloalkenyl group is cyclopropenyl, cyclopentenyl, or cyclohexenyl.

[0309] In certain embodiments, R 4 In the above, the C3-C7 cycloalkenyl group is a cyclopentenyl group.

[0310] In certain embodiments, in Ring A and Ring B, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a 5- to 9-membered nitrogen-containing heterocycloalkyl group.

[0311] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a 5- to 8-membered nitrogen-containing heterocycloalkyl group.

[0312] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a monocyclic or bicyclic ring.

[0313] In certain embodiments, in Ring A and Ring B, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a monocyclic ring, a spirocyclic ring, or a bridged ring.

[0314] In certain embodiments, in Ring A and Ring B, the number of heteroatoms of the 3- to 12-membered nitrogen-containing heterocycloalkyl group is 1 or 2.

[0315] In certain embodiments, in Ring A and Ring B, the number of heteroatoms in the 3- to 12-membered nitrogen-containing heterocycloalkyl group is N.

[0316] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkyl is a 5- to 7-membered nitrogen-containing monocyclic heterocycloalkyl.

[0317] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkyl is a 6- to 8-membered nitrogen-containing bridged heterocycloalkyl.

[0318] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkyl is a 7- to 9-membered nitrogen-containing spirocyclic heterocycloalkyl.

[0319] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,

[0320] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is a 5- to 9-membered nitrogen-containing heterocycloalkenyl group.

[0321] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkenyl is a 5- to 6-membered nitrogen-containing heterocycloalkenyl.

[0322] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkenyl is a monocyclic or bicyclic ring.

[0323] In certain embodiments, in Ring A and Ring B, the 3- to 12-membered nitrogen-containing heterocycloalkenyl is a monocyclic ring, a spirocyclic ring, or a bridged ring.

[0324] In certain embodiments, in Ring A and Ring B, the 3- to 12-membered nitrogen-containing heterocycloalkenyl is a monocyclic ring.

[0325] In certain embodiments, in Ring A and Ring B, the number of heteroatoms of the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is 1 or 2.

[0326] In certain embodiments, in Ring A and Ring B, the number of heteroatoms in the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is 1.

[0327] In certain embodiments, in Ring A and Ring B, the number of heteroatoms in the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is N.

[0328] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkenyl is a 5- to 7-membered nitrogen-containing monocyclic heterocycloalkenyl.

[0329] In certain embodiments, in Ring A and Ring B, the 3- to 12-membered nitrogen-containing heterocycloalkenyl is a 6- to 8-membered nitrogen-containing bridged heterocycloalkenyl.

[0330] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkenyl is a 7- to 9-membered nitrogen-containing spirocyclic heterocycloalkenyl.

[0331] In certain embodiments, in Ring A and Ring B, the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is

[0332] In certain embodiments, in R Z1 In the formula (a), halogen is F, Cl, Br or I.

[0333] In certain embodiments, in R Z1 In the formula, halogen is F.

[0334] In certain embodiments, in R Z1 In the above, the C1-C3 alkyl group is a methyl group, an ethyl group, a propyl group or an isopropyl group.

[0335] In certain embodiments, R Z1 In the above, the C1-C3 alkyl group is a methyl group.

[0336] In certain embodiments, R Z1 In the above, C1-C3 cyanoalkyl is cyanomethyl.

[0337] In certain embodiments, R Z1 In the above, the C3-C6 cycloalkyl group is a cyclopropyl group, a cyclopentyl group or a cyclohexyl group.

[0338] In certain embodiments, R Z1 In the above, the C3-C6 cycloalkyl group is a cyclopropyl group.

[0339] In certain embodiments, R Z1 In the above, the C1-C3 alkoxy group is a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.

[0340] In certain embodiments, R Z1 In the above, the C1-C3 alkoxy group is a methoxy group.

[0341] In certain embodiments, in R N1 In the above, the C1-C3 alkyl group is a methyl group, an ethyl group, a propyl group or an isopropyl group.

[0342] In certain embodiments, R N1 In the above, the C1-C3 alkyl group is a methyl group.

[0343] In certain embodiments, R 4 for

[0344]

[0345] In certain embodiments, R 4 for

[0346]

[0347] In certain embodiments, the "plurality" in the above definition is independently 2, 3, 4 or 5.

[0348] In certain embodiments, the nitrogen-containing heterocyclic compound represented by Formula I is selected from the group consisting of:

[0349]

[0350] The present invention also provides a pharmaceutical composition, comprising a substance X and a pharmaceutically acceptable excipient, wherein the substance X is a nitrogen-containing heterocyclic compound represented by Formula I, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0351] The present invention also provides the use of substance X in the preparation of KRAS-G12D inhibitors;

[0352] The substance X is a nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof or a solvate thereof.

[0353] In certain embodiments, the KRAS-G12D inhibitor is used in vitro or in vivo.

[0354] The present invention also provides the use of substance X in preparing medicines;

[0355] Substance X is a nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, or a solvate thereof;

[0356] This drug is used to treat or prevent KRAS-G12D-related diseases or conditions.

[0357] In certain embodiments, the KRAS-G12D-associated disease or disorder is cancer.

[0358] The present invention also provides the use of substance X in preparing medicines;

[0359] Substance X is a nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, or a solvate thereof;

[0360] This medication is used to treat or prevent cancer.

[0361] The present invention also provides a method for preventing and / or treating a KRAS-G12D-related disease or disorder, comprising administering a therapeutically effective amount of a substance X to a subject in need thereof;

[0362] The substance X is a nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof or a solvate thereof.

[0363] In certain embodiments, the KRAS-G12D-associated disease or disorder is cancer.

[0364] The present invention also provides a method for preventing and / or treating cancer, the method comprising administering a therapeutically effective amount of substance X to a subject in need thereof;

[0365] The substance X is a nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof or a solvate thereof.

[0366] The present invention provides a nitrogen-containing heterocyclic compound represented by formula II, a pharmaceutically acceptable salt thereof or a solvate thereof;

[0367]

[0368] in,

[0369] X 3 CH-R X3 , NH, CR X3 or N; R X3 are independently hydrogen or halogen;

[0370] is a single bond or a double bond;

[0371] R 5 is hydrogen, halogen or C1-C3 alkyl;

[0372] R 1 C6-C 14 Aryl, 5- to 14-membered heteroaryl, substituted by one or more R 1-1 Substituted C6-C 14 Aryl or one or more R 1-2 Substituted 5- to 14-membered heteroaryl; in the 5- to 14-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from the group consisting of O, S and N;

[0373] R 1-1 and R 1-2 Each is independently halogen, cyano, hydroxyl, C1-C4 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, -N(R N1 )2 or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted by halogen or C1-C3 alkyl;

[0374] L 1 is a single bond, C1-C4 alkylene, -O- or -N(R N1 )-;

[0375] R 3 is a 3- to 12-membered heterocycloalkyl group, 3-1-1 or -L 2 -R 3-1 substituted 3- to 12-membered heterocycloalkyl;

[0376] L 2 is -O-, -N(methyl)-, C1-C4 alkylene or is replaced by one or more R L2 Substituted C1-C4 alkylene; each R L2are independently hydroxy or C1-C4 hydroxyalkyl;

[0377] R 3-1 C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 14 Aryl, 5- to 14-membered heteroaryl, -N(R N1 2. One or more R 3-1-1 Substituted C3-C 12 Cycloalkyl, with one or more R 3-1-2 substituted 3 to 12 membered heterocycloalkyl, substituted by one or more R 3-1-3 Substituted C6-C 14 Aryl or one or more R 3-1-4 substituted 5- to 14-membered heteroaryl; in the 3- to 12-membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, one or more of the heteroatoms are selected from O, S and N; in the 5- to 14-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, one or more of the heteroatoms are selected from the group consisting of O, S and N; n is independently 0, 1, 2, 3 or 4;

[0378] R 3-1-1 , R 3-1-2 , R 3-1-3 and R 3-1-4 Each is halogen, cyano, oxo, C1-C4 alkyl or -N(R N1 )2;

[0379] X 2 CR X2 or N; R X2 is hydrogen, cyano or halogen;

[0380] R 4 is C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 3- to 12-membered nitrogen-containing heterocycloalkyl, 3- to 12-membered nitrogen-containing heterocycloalkenyl, 4-1 Substituted C3-C6 cycloalkyl, one or more R 4-2 Substituted C3-C7 cycloalkenyl, substituted by one or more R 4 -3 substituted 3 to 12-membered nitrogen-containing heterocycloalkyl or one or more R 4-4 Substituted 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0381] R 4-1 , R 4-2 , R4-3 and R 4-4 Each is independently oxo, hydroxyl, cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C3-C6 cycloalkyl, C1-C3 alkoxy or -N(R N1 )2;

[0382] Each R N1 are independently hydrogen or C1-C3 alkyl.

[0383] In certain embodiments, the nitrogen-containing heterocyclic compound represented by Formula II, its pharmaceutically acceptable salt or solvate thereof has the following definition (hereinafter referred to as "in certain embodiments"):

[0384] In certain embodiments, X 3 For CH2.

[0385] In certain embodiments, For a single key.

[0386] In certain embodiments, R 5 It is methyl or ethyl.

[0387] In certain embodiments, R 5 For hydrogen.

[0388] In certain embodiments, R 1 C6-C 14 Aryl, 5- to 14-membered heteroaryl, substituted by one or more R 1-1 Substituted C6-C 14 Aryl or one or more R 1-2 Substituted 5- to 14-membered heteroaryl; in the 5- to 14-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from the group consisting of O, S and N;

[0389] R 1-1 and R 1-2 Each is independently halogen, cyano, hydroxy, C2-C4 alkynyl or C1-C3 alkoxy.

[0390] In certain embodiments, L 1 It is C1-C4 alkylene, -N(methyl)- or -O-.

[0391] In certain embodiments, L 1 It is C1-C4 alkylene or -O-.

[0392] In certain embodiments, R 1 It is -O-.

[0393] In certain embodiments, R 3is a 3- to 12-membered heterocycloalkyl group, 3-1-1 or -L 2 -R 3-1 substituted 3- to 12-membered heterocycloalkyl;

[0394] L 2 is -O-, -N(methyl)-, C1-C4 alkylene or is replaced by one or more R L2 Substituted C1-C4 alkylene; each R L2 are independently hydroxy or C1-C4 hydroxyalkyl;

[0395] R 3-1 C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 14 Aryl, 5- to 14-membered heteroaryl, -N(R N1 2. One or more R 3-1-1 Substituted C3-C 12 Cycloalkyl, with one or more R 3-1-2 substituted 3 to 12 membered heterocycloalkyl, substituted by one or more R 3-1-3 Substituted C6-C 14 Aryl or one or more R 3-1-4 substituted 5- to 14-membered heteroaryl; in the 3- to 12-membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, one or more of the heteroatoms are selected from O, S and N; in the 5- to 14-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, one or more of the heteroatoms are selected from the group consisting of O, S and N; n is independently 0, 1, 2, 3 or 4;

[0396] R 3-1-1 , R 3-1-2 , R 3-1-3 and R 3-1-4 Each is halogen, cyano, C1-C4 alkyl or -N(R N1 )2.

[0397] In certain embodiments, R 3 is a 3- to 12-membered heterocycloalkyl group, 3-1-1 or -L 2 -R 3-1 substituted 3- to 12-membered heterocycloalkyl;

[0398] L 2 is C1-C4 alkylene or is replaced by one or more R L2 Substituted C1-C4 alkylene; each R L2 are independently hydroxy or C1-C4 hydroxyalkyl;

[0399] R 3-1 C3-C 12Cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 14 Aryl, 5- to 14-membered heteroaryl, -N(R N1 2. One or more R 3-1-1 Substituted C3-C 12 Cycloalkyl, with one or more R 3-1-2 substituted 3 to 12 membered heterocycloalkyl, substituted by one or more R 3-1-3 Substituted C6-C 14 Aryl or one or more R 3-1-4 substituted 5- to 14-membered heteroaryl; in the 3- to 12-membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, one or more of the heteroatoms are selected from O, S and N; in the 5- to 14-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, one or more of the heteroatoms are selected from the group consisting of O, S and N; n is independently 0, 1, 2, 3 or 4;

[0400] R 3-1-1 , R 3-1-2 , R 3-1-3 and R 3-1-4 Each is halogen, cyano, oxo, C1-C4 alkyl or -N(R N1 )2.

[0401] In certain embodiments, R 3 is a 3- to 12-membered heterocycloalkyl group, 3-1-1 or -L 2 -R 3-1 substituted 3- to 12-membered heterocycloalkyl;

[0402] L 2 is C1-C4 alkylene or is replaced by one or more R L2 Substituted C1-C4 alkylene; each R L2 are independently hydroxy or C1-C4 hydroxyalkyl;

[0403] R 3-1 C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 14 Aryl, 5- to 14-membered heteroaryl, -N(R N1 2. One or more R 3-1-1 Substituted C3-C 12 Cycloalkyl, with one or more R 3-1-2 substituted 3 to 12 membered heterocycloalkyl, substituted by one or more R 3-1-3 Substituted C6-C 14 Aryl or one or more R 3-1-4substituted 5- to 14-membered heteroaryl; in the 3- to 12-membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, one or more of the heteroatoms are selected from O, S and N; in the 5- to 14-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, one or more of the heteroatoms are selected from the group consisting of O, S and N; n is independently 0, 1, 2, 3 or 4;

[0404] R 3-1-1 , R 3-1-2 , R 3-1-3 and R 3-1-4 Each is halogen, cyano, C1-C4 alkyl or -N(R N1 )2.

[0405] In certain embodiments, R 3 For -L 2 -R 3-1 ;

[0406] L 2 is -O-, -N(methyl)- or C1-C4 alkylene;

[0407] R 3-1 C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, 3-1-1 Substituted C3-C 12 Cycloalkyl or one or more R 3-1-2 Substituted 3- to 12-membered heterocycloalkyl; wherein the number of heteroatoms in the 3- to 12-membered heterocycloalkyl is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from O, S and N;

[0408] R 3-1-1 and R 3-1-2 are each independently halogen or oxo.

[0409] In certain embodiments, R 3 For -L 2 -R 3-1 ;

[0410] L 2 is -O-, -N(methyl)- or C1-C4 alkylene;

[0411] R 3-1 C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, 3-1-1 Substituted C3-C 12 Cycloalkyl or one or more R 3-1-2 Substituted 3- to 12-membered heterocycloalkyl; wherein the number of heteroatoms in the 3- to 12-membered heterocycloalkyl is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from O, S and N;

[0412] R 3-1-1 and R 3-1-2 are each independently halogen.

[0413] In certain embodiments, R 3 For -L 2 -R 3-1 ;

[0414] L 2 is C1-C4 alkylene;

[0415] R 3-1 C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, 3-1-1 Substituted C3-C 12 Cycloalkyl or one or more R 3-1-2 Substituted 3- to 12-membered heterocycloalkyl; wherein the number of heteroatoms in the 3- to 12-membered heterocycloalkyl is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from O, S and N;

[0416] R 3-1-1 and R 3-1-2 are each independently halogen or oxo.

[0417] In certain embodiments, R 3 For -L 2 -R 3-1 ;

[0418] L 2 is C1-C4 alkylene;

[0419] R 3-1 C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, 3-1-1 Substituted C3-C 12 Cycloalkyl or one or more R 3-1-2 Substituted 3- to 12-membered heterocycloalkyl; wherein the number of heteroatoms in the 3- to 12-membered heterocycloalkyl is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from O, S and N;

[0420] R 3-1-1 and R 3-1-2 are each independently halogen.

[0421] In certain embodiments, X 2 is N.

[0422] In certain embodiments, R 4 is a 3- to 12-membered nitrogen-containing heterocyclic alkyl group or is replaced by one or more R 4-3A substituted 3- to 12-membered nitrogen-containing heterocycloalkyl group; wherein the number of heteroatoms in the 3- to 12-membered nitrogen-containing heterocycloalkyl group is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from O, S and N;

[0423] Each R 4-3 are independently C1-C3 cyanoalkyl or -N(R N1 )2;

[0424] Each R N1 are independently hydrogen or C1-C3 alkyl.

[0425] In certain embodiments, R 4 For 1 R 4-1 Substituted C4-C7 cycloalkyl; R 4-1 -N(R N1 )2; Each R N1 are independently hydrogen or C1-C3 alkyl.

[0426] In certain embodiments, R 4 In the above, the C3-C7 cycloalkyl, C3-C7 cycloalkenyl, 3- to 12-membered nitrogen-containing heterocycloalkyl and 3- to 12-membered nitrogen-containing heterocycloalkenyl are bridged rings.

[0427] In certain embodiments, R 4 The following conditions are met:

[0428]

[0429] Among them, Z 1 is independently CH, C or N;

[0430] e is independently 0, 1, 2, 3 or 4;

[0431] R Z1 are independently oxo, hydroxyl, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, -N(RN1)2, -CO2RN1, -CO2N(RN1)2 or 5- to 6-membered heteroaryl; in the 5- to 6-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0432] Each R N1 are independently hydrogen or C1-C3 alkyl;

[0433] R Z2 It is hydrogen or methyl.

[0434] In certain embodiments, the "NH" on the ring does not overlap with R Z1 connect.

[0435] In certain embodiments, R 4 for

[0436] Among them, Z 1 is independently CH, C or N;

[0437] Ring A is a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0438] Ring B is a C3-C7 cycloalkyl, a C3-C7 cycloalkenyl, a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0439] e is independently 0, 1, 2, 3 or 4;

[0440] R Z1 are independently oxo, hydroxyl, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, -N(RN1)2, -CO2RN1, -CO2N(RN1)2 or 5- to 6-membered heteroaryl; in the 5- to 6-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0441] Each R N1 are independently hydrogen or C1-C3 alkyl;

[0442] R Z2 It is hydrogen or methyl.

[0443] In certain embodiments, R 4 Attached via carbon or nitrogen atoms

[0444] R 4 is a 3- to 12-membered nitrogen-containing heterocycloalkyl group or a 3- to 12-membered nitrogen-containing heterocycloalkenyl group; 4-3 substituted 3 to 12-membered nitrogen-containing heterocycloalkyl or one or more R 4-4 substituted 3- to 12-membered nitrogen-containing heterocycloalkenyl;

[0445] R 4The 3- to 12-membered nitrogen-containing heterocycloalkyl group has an "NH" which is not adjacent to R 4-3 connect;

[0446] R 4 The 3- to 12-membered nitrogen-containing heterocycloalkyl group has an "NH" which is not adjacent to R 4-4 connect.

[0447] In certain embodiments, R 4 Attached via carbon or nitrogen atoms

[0448] R 4 For one or more R 4-1 Substituted C3-C6 cycloalkyl, one or more R 4-2 Substituted C3-C7 cycloalkenyl, substituted by one or more R 4-3 substituted 3 to 12-membered nitrogen-containing heterocycloalkyl or one or more R 4-4 substituted 3- to 12-membered nitrogen-containing heterocycloalkenyl;

[0449] R 4-1 One of them is NH2 or N(methyl); R 4-2 One of them is NH2 or N(methyl); R 4-3 One of them is NH2 or N(methyl); R 4-3 One of them is NH2 or N(methyl).

[0450] In certain embodiments, R 4 Attached via carbon or nitrogen atoms

[0451] In certain embodiments:

[0452] X 3 is CH2;

[0453] is a single bond;

[0454] R 5 is hydrogen;

[0455] R 1 C6-C 14 Aryl, 5- to 14-membered heteroaryl, substituted by one or more R 1-1 Substituted C6-C 14 Aryl or one or more R 1-2 Substituted 5- to 14-membered heteroaryl; in the 5- to 14-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from the group consisting of O, S and N;

[0456] R 1-1 and R 1-2Each is independently halogen, cyano, hydroxy, C2-C4 alkynyl or C1-C3 alkoxy;

[0457] L 1 is C1-C4 alkylene, -N(methyl)- or -O-;

[0458] R 3 For -L 2 -R 3-1 ;

[0459] L 2 is -O-, -N(methyl)- or C1-C4 alkylene;

[0460] R 3-1 C3-C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, 3-1-1 Substituted C3-C 12 Cycloalkyl or one or more R 3-1-2 Substituted 3- to 12-membered heterocycloalkyl; wherein the number of heteroatoms in the 3- to 12-membered heterocycloalkyl is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from O, S and N;

[0461] R 3-1-1 and R 3-1-2 are each independently halogen or oxo;

[0462] X 2 is N;

[0463] R 4 is a 3- to 12-membered nitrogen-containing heterocyclic alkyl group or is replaced by one or more R 4-3 A substituted 3- to 12-membered nitrogen-containing heterocycloalkyl group; wherein the number of heteroatoms in the 3- to 12-membered nitrogen-containing heterocycloalkyl group is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from O, S and N;

[0464] Each R 4-3 are independently C1-C3 cyanoalkyl or -N(R N1 )2;

[0465] Each R N1 are independently hydrogen or C1-C3 alkyl.

[0466] In certain embodiments:

[0467] X 3 CH-R X3 ; R X3 is a halogen;

[0468] is a single bond;

[0469] R 5 is hydrogen;

[0470] R 1 C6-C 14 Aryl, 5- to 14-membered heteroaryl, substituted by one or more R 1-1 Substituted C6-C 14 Aryl or one or more R 1-2 Substituted 5- to 14-membered heteroaryl; in the 5- to 14-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from the group consisting of O, S and N;

[0471] R 1-1 and R 1-2 Each is independently halogen, cyano, hydroxyl, C1-C4 alkyl, C2-C4 alkynyl, C1-C3 haloalkyl, C1-C3 alkoxy or C3-C6 cycloalkyl;

[0472] L 1 for -O-;

[0473] R 3 For -L 2 -R 3-1 ;

[0474] L 2 is C1-C4 alkylene;

[0475] R 3-1 For one or more R 3-1-2 substituted 3 to 12 membered heterocycloalkyl, substituted by one or more R 3-1-3 Substituted C6-C 14 Aryl or one or more R 3-1-4 substituted 5- to 14-membered heteroaryl; in the 3- to 12-membered heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, one or more of the heteroatoms are selected from O, S and N; in the 5- to 14-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, one or more of the heteroatoms are selected from the group consisting of O, S and N; n is independently 0, 1, 2, 3 or 4;

[0476] R 3-1-2 and R 3-1-4 Each is halogen or C1-C4 alkyl;

[0477] X 2 is N;

[0478] R 4 is a 3- to 12-membered nitrogen-containing heterocyclic alkyl group or is replaced by one or more R 4-3 A substituted 3- to 12-membered nitrogen-containing heterocycloalkyl group; wherein the number of heteroatoms in the 3- to 12-membered nitrogen-containing heterocycloalkyl group is 1, 2, 3 or 4, and one or more of the heteroatoms are selected from O, S and N;

[0479] R 4-3 Each is independently hydroxy, C1-C3 alkyl or C1-C3 cyanoalkyl.

[0480] In certain embodiments:

[0481] for

[0482] Where n is 1, 2, 3 or 4, each R 1-1 are independently halogen, cyano, ethynyl or C1-C4 alkyl;

[0483] R 4 Attached via carbon or nitrogen atoms

[0484] R 5 It is halogen or C1-C3 alkyl.

[0485] In certain embodiments:

[0486] for

[0487] Where n is 1, 2, 3 or 4, each R 1-1 are independently halogen, cyano, ethynyl or C1-C4 alkyl;

[0488] R 4 Attached via carbon or nitrogen atoms

[0489] R 5 It is halogen or C1-C3 alkyl.

[0490] In certain embodiments:

[0491] for

[0492] Where n is 1, 2, 3 or 4, each R 1-1 are independently halogen, cyano, ethynyl or C1-C4 alkyl;

[0493] R 4 Attached via carbon or nitrogen atoms

[0494] R 5 It is halogen or C1-C3 alkyl.

[0495] In certain embodiments:

[0496] for

[0497] Where n is 1, 2, 3 or 4, each R 1-1 are independently halogen, cyano, ethynyl or C1-C4 alkyl;

[0498] R 4 Attached via carbon or nitrogen atoms

[0499] R 5 It is halogen or C1-C3 alkyl.

[0500] In certain embodiments:

[0501] for

[0502] Where n is 1, 2, 3 or 4, each R 1-1 are independently halogen, cyano, ethynyl or C1-C4 alkyl;

[0503] R 4 Attached via carbon or nitrogen atoms

[0504] R 5 It is halogen or C1-C3 alkyl.

[0505] In certain embodiments:

[0506] for

[0507] Where n is 1, 2, 3 or 4, each R 1-1 are independently halogen, cyano, ethynyl or C1-C4 alkyl;

[0508] R 4 Attached via carbon or nitrogen atoms

[0509] R 5 It is halogen or C1-C3 alkyl.

[0510] In certain embodiments:

[0511] for

[0512] Where n is 1, 2, 3 or 4, each R 1-1 are independently halogen, cyano, ethynyl or C1-C4 alkyl;

[0513] R 4 Attached via carbon or nitrogen atoms

[0514] R5 It is halogen or C1-C3 alkyl.

[0515] In certain embodiments:

[0516] for

[0517] Where n is 1, 2, 3 or 4, each R 1-1 are independently halogen, cyano, ethynyl or C1-C4 alkyl;

[0518] R 4 Attached via carbon or nitrogen atoms

[0519] R 5 It is halogen or C1-C3 alkyl.

[0520] In certain embodiments:

[0521] for

[0522] Where n is 1, 2, 3 or 4, each R 1-1 are independently halogen, cyano, ethynyl or C1-C4 alkyl;

[0523] R 4 Attached via carbon or nitrogen atoms

[0524] R 5 It is halogen or C1-C3 alkyl.

[0525] In certain embodiments:

[0526] for

[0527] Where n is 1, 2, 3 or 4, each R 1-1 are independently halogen, cyano, ethynyl or C1-C4 alkyl;

[0528] R 4 Attached via carbon or nitrogen atoms

[0529] R 5 It is halogen or C1-C3 alkyl.

[0530] In certain embodiments:

[0531] for

[0532] Among them, R 4Attached via carbon or nitrogen atoms

[0533] In certain embodiments:

[0534] for

[0535] Wherein, p is 0, 1, 2 or 3, q ​​is 0, 1, 2 or 3;

[0536] R 4 Attached via carbon or nitrogen atoms

[0537] In certain embodiments:

[0538] for

[0539] in,

[0540] R 4 For 1 R 4-1 Substituted C4-C7 cycloalkyl; R 4-1 -N(R N1 )2; Each R N1 are independently hydrogen or C1-C3 alkyl;

[0541] R 4 Attached via carbon or nitrogen atoms

[0542] In certain embodiments:

[0543] for

[0544] Wherein, p is 0, 1, 2 or 3, q ​​is 0, 1, 2 or 3;

[0545] R 4 Attached via carbon or nitrogen atoms

[0546] In certain embodiments:

[0547] for

[0548] in,

[0549] R 4 For 1 R 4-1 Substituted C4-C7 cycloalkyl; R 4-1 -N(R N1 )2; Each R N1 are independently hydrogen or C1-C3 alkyl;

[0550] R 4 Attached via carbon or nitrogen atoms

[0551] In certain embodiments:

[0552] for

[0553] Among them, Z 1 is independently CH, C or N;

[0554] Ring A is a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0555] Ring B is a C3-C7 cycloalkyl, a C3-C7 cycloalkenyl, a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0556] e is independently 0, 1, 2, 3 or 4;

[0557] R Z1 are independently oxo, hydroxyl, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, -N(RN1)2, -CO2RN1, -CO2N(RN1)2 or 5- to 6-membered heteroaryl; in the 5- to 6-membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0558] Each R N1 are independently hydrogen or C1-C3 alkyl;

[0559] R Z2 It is hydrogen or methyl.

[0560] In certain embodiments:

[0561] for

[0562] Among them, Z 1is independently CH, C or N;

[0563] Ring A is a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0564] Ring B is a C3-C7 cycloalkyl, a C3-C7 cycloalkenyl, a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0565] e is independently 0, 1, 2, 3 or 4;

[0566] R Z1 are independently oxo, hydroxy, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, -N(R N1 2. -CO2R N1 、-CO2N(R N1 ) 2 or 5 to 6 membered heteroaryl; in the 5 to 6 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0567] Each R N1 are independently hydrogen or C1-C3 alkyl;

[0568] R Z2 It is hydrogen or methyl.

[0569] In certain embodiments:

[0570] for

[0571] in, is a single bond;

[0572] n is 1, 2, 3 or 4, each R 1-1 are independently halogen, cyano, ethynyl or C1-C4 alkyl;

[0573] Z 1 is independently CH, C or N;

[0574] Ring A is a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0575] Ring B is a C3-C7 cycloalkyl, a C3-C7 cycloalkenyl, a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0576] e is independently 0, 1, 2, 3 or 4;

[0577] R Z1 are independently oxo, hydroxy, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, -N(R N1 2. -CO2R N1 、-CO2N(R N1 ) 2 or 5 to 6 membered heteroaryl; in the 5 to 6 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0578] Each R N1 are independently hydrogen or C1-C3 alkyl;

[0579] R Z2 It is hydrogen or methyl.

[0580] In certain embodiments:

[0581] for

[0582]

[0583] Where n is 1, 2, 3 or 4, each R 1-1 are independently halogen, cyano, ethynyl or C1-C4 alkyl;

[0584] Z 1 is independently CH, C or N;

[0585] Ring A is a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0586] Ring B is a C3-C7 cycloalkyl, a C3-C7 cycloalkenyl, a 3- to 12-membered nitrogen-containing heterocycloalkyl or a 3- to 12-membered nitrogen-containing heterocycloalkenyl; in the 3- to 12-membered nitrogen-containing heterocycloalkyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N; in the 3- to 12-membered nitrogen-containing heterocycloalkenyl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0587] e is independently 0, 1, 2, 3 or 4;

[0588] R Z1 are independently oxo, hydroxy, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, C3-C6 cycloalkyl, -N(R N1 2. -CO2R N1 、-CO2N(R N1 ) 2 or 5 to 6 membered heteroaryl; in the 5 to 6 membered heteroaryl, the number of heteroatoms is 1, 2, 3 or 4, and the heteroatoms are selected from one or more of O, S and N;

[0589] Each R N1 are independently hydrogen or C1-C3 alkyl;

[0590] R Z2 It is hydrogen or methyl.

[0591] In certain embodiments, R X3 In the formula (a), halogen is F, Cl, Br or I.

[0592] In certain embodiments, R X3 In the formula, halogen is F.

[0593] In certain embodiments, R 5 In the formula (a), halogen is F, Cl, Br or I.

[0594] In certain embodiments, R 5 In the formula, halogen is F.

[0595] In certain embodiments, R 5 In the above, the C1-C3 alkyl group is a methyl group, an ethyl group, a propyl group or an isopropyl group.

[0596] In certain embodiments, R5 In the above, the C1-C3 alkyl group is a methyl group or an ethyl group.

[0597] In certain embodiments, R 5 In the above, the C1-C3 alkyl group is a methyl group.

[0598] In certain embodiments, R 1 Medium, C6-C 14 Aryl is C6-C 10 Aryl.

[0599] In certain embodiments, R 1 Medium, C6-C 14 Aryl is monocyclic or bicyclic.

[0600] In certain embodiments, R 1 Medium, C6-C 14 Each ring of the aryl group is aromatic.

[0601] In certain embodiments, R 1 Medium, C6-C 14 Aryl is phenyl, 1-naphthyl, 2-naphthyl or

[0602] In certain embodiments, R 1 In the above, the 5- to 14-membered heteroaryl group is a 9- to 10-membered heteroaryl group.

[0603] In certain embodiments, R 1 In the above, the 5- to 14-membered heteroaryl group is a monocyclic or bicyclic ring.

[0604] In certain embodiments, R 1 In the above, each ring of the 5- to 14-membered heteroaryl group is aromatic.

[0605] In certain embodiments, R 1 In the 5- to 14-membered heteroaryl group, the number of heteroatoms is 1 or 2.

[0606] In certain embodiments, R 1 In the 5- to 14-membered heteroaryl group, the heteroatom is N.

[0607] In certain embodiments, R 1 In the above, the 5- to 14-membered heteroaryl group is pyridyl, indolyl, quinolyl, isoquinolyl, benzothienyl or benzothiazolyl.

[0608] In certain embodiments, in R 1 In the case of a 5- to 14-membered heteroaryl group,

[0609] In certain embodiments, R 1-1 and R1-2 In the formula (a), halogen is F, Cl, Br or I.

[0610] In certain embodiments, R 1-1 and R 1-2 In the formula (a), halogen is F or Cl.

[0611] In certain embodiments, R 1-1 and R 1-2 In the formula, halogen is F.

[0612] In certain embodiments, R 1-1 and R 1-2 In the above, the C1-C4 alkyl group is a methyl group, an ethyl group, a propyl group or an isopropyl group.

[0613] In certain embodiments, R 1-1 and R 1-2 In the above, the C1-C4 alkyl group is a methyl group or an ethyl group.

[0614] In certain embodiments, R 1-1 and R 1-2 In the above, the C1-C4 alkyl group is a methyl group.

[0615] In certain embodiments, R 1-1 and R 1-2 In the above, -S-C1-C3 alkyl is -S-methyl, -S-ethyl, -S-propyl or -S-isopropyl.

[0616] In certain embodiments, R 1-1 and R 1-2 In the above, -S-C1-C3 alkyl is -S-methyl.

[0617] In certain embodiments, R 1-1 and R 1-2 In the above, the C2-C4 alkynyl group is an ethynyl group.

[0618] In certain embodiments, R 1-1 and R 1-2 In the above, C1-C3 haloalkyl is -CF3.

[0619] In certain embodiments, R 1-1 and R 1-2 In the above, -O-C1-C3 haloalkyl is -O-CF3.

[0620] In certain embodiments, R 1-1 and R 1-2 In the above, the C1-C3 alkoxy group is a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.

[0621] In certain embodiments, R 1-1 and R 1-2In the above, the C1-C3 alkoxy group is a methoxy group.

[0622] In certain embodiments, R 1-1 and R 1-2 In the above, the C3-C6 cycloalkyl group is a cyclopropyl group, a cyclopentyl group or a cyclohexyl group.

[0623] In certain embodiments, R 1-1 and R 1-2 In the above, the C3-C6 cycloalkyl group is a cyclopropyl group.

[0624] In certain embodiments, R 1 for

[0625] In certain embodiments, R 1 for

[0626] In certain embodiments, L 1 In the above, the C1-C4 alkylene group is a methylene group, an ethylene group, a propylene group or a butylene group.

[0627] In certain embodiments, R 3 In the above, the 3- to 12-membered heterocycloalkyl group is a 3- to 6-membered heterocycloalkyl group.

[0628] In certain embodiments, R 3 In the above, the 3- to 12-membered heterocycloalkyl group is a 4-membered heterocycloalkyl group.

[0629] In certain embodiments, R 3 In the above, the 3- to 12-membered heterocycloalkyl group is a monocyclic or bicyclic ring.

[0630] In certain embodiments, R 3 In the above, the 3- to 12-membered heterocycloalkyl is a monocyclic, spirocyclic or bridged ring.

[0631] In certain embodiments, R 3 In the 3- to 12-membered heterocycloalkyl group, the number of heteroatoms is 1 or 2.

[0632] In certain embodiments, R 3 In the 3- to 12-membered heterocycloalkyl group, the heteroatom is N.

[0633] In certain embodiments, R 3 In the above, the 3- to 12-membered heterocycloalkyl group is azetidinyl group.

[0634] In certain embodiments, R 3 In the above, the 3- to 12-membered heterocycloalkyl group is 1-azetidinyl group.

[0635] In certain embodiments, L2 In the above, the C1-C4 alkylene group is a methylene group, an ethylene group, a propylene group or a butylene group.

[0636] In certain embodiments, R 3-1 The bond to L2 is through a carbon atom or a nitrogen atom.

[0637] In certain embodiments, R 3-1 Medium, C3-C 12 The cycloalkyl group is a C3-C8 cycloalkyl group.

[0638] In certain embodiments, R 3-1 Medium, C3-C 12 The cycloalkyl group is a C5-C8 cycloalkyl group.

[0639] In certain embodiments, R 3-1 Medium, C3-C 12 The cycloalkyl group is a monocyclic or bicyclic ring.

[0640] In certain embodiments, R 3-1 Medium, C3-C 12 The cycloalkyl group is a monocyclic ring, a spirocyclic ring or a bridged ring.

[0641] In certain embodiments, R 3-1 Medium, C3-C 12 The cycloalkyl group is cyclopentyl or octahydropentalene.

[0642] In certain embodiments, R 3-1 In the above, the 3- to 12-membered heterocycloalkyl group is a 5- to 10-membered heterocycloalkyl group.

[0643] In certain embodiments, R 3-1 In the above, the 3- to 12-membered heterocycloalkyl group is a 5- to 8-membered heterocycloalkyl group.

[0644] In certain embodiments, R 3-1 In the above, the 3- to 12-membered heterocycloalkyl group is a monocyclic or bicyclic ring.

[0645] In certain embodiments, R 3-1 In the above, the 3- to 12-membered heterocycloalkyl is a monocyclic, spirocyclic or bridged ring.

[0646] In certain embodiments, R 3-1 In the 3- to 12-membered heterocycloalkyl group, the number of heteroatoms is 1 or 2.

[0647] In certain embodiments, R 3-1 In the 3- to 12-membered heterocycloalkyl group, the heteroatom is N.

[0648] In certain embodiments, R 3-1 In the above, the 3- to 12-membered heterocycloalkyl group is a 5- to 6-membered monocyclic heterocycloalkyl group.

[0649] In certain embodiments, R 3-1 In the above, the 3- to 12-membered heterocycloalkyl group is a 7- to 10-membered bridged heterocycloalkyl group.

[0650] In certain embodiments, R 3-1 In the above, the 3- to 12-membered heterocycloalkyl group is tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl or tetrahydro-1H-pyrrolazin-7a(5H)-yl.

[0651] In certain embodiments, R 3-1 wherein the 3- to 12-membered heterocycloalkyl group is tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl or

[0652] In certain embodiments, R 3-1 In the above, the 5- to 14-membered heteroaryl group is a 5- to 6-membered heteroaryl group.

[0653] In certain embodiments, R 3-1 In the above, the 5- to 14-membered heteroaryl group is a monocyclic or bicyclic ring.

[0654] In certain embodiments, R 3-1 In the 5- to 14-membered heteroaryl group, the number of heteroatoms is 1 or 2.

[0655] In certain embodiments, R 3-1 In the above, the 5- to 14-membered heteroaryl is pyrazolyl.

[0656] In certain embodiments, R 3-1 In the 5- to 14-membered heteroaryl group, the heteroatom is N.

[0657] In certain embodiments, R 3-1-1 , R 3-1-2 , R 3-1-3 and R 3-1-4 In the formula (a), halogen is F, Cl, Br or I.

[0658] In certain embodiments, R 3-1-1 , R 3-1-2 , R 3-1-3 and R 3-1-4 In the formula, halogen is F.

[0659] In certain embodiments, R 3-1-1 , R 3-1-2 , R 3-1-3 and R 3-1-4 In the above, the C1-C4 alkyl group is a methyl group, an ethyl group, a propyl group or an isopropyl group.

[0660] In certain embodiments, R 3-1-1 , R 3-1-2 , R 3-1-3and R 3-1-4 In the above, the C1-C4 alkyl group is a methyl group.

[0661] In certain embodiments, -L 1 -R 3 for

[0662] In certain embodiments, -L 1 -R 3 for

[0663]

[0664] In certain embodiments, R X2 In the formula (a), halogen is F, Cl, Br or I.

[0665] In certain embodiments, R X2 In the formula, halogen is F.

[0666] In certain embodiments, R 4 Attached via carbon or nitrogen atoms In certain embodiments, R 4 In the above, the C3-C7 cycloalkyl group is a monocyclic or bicyclic ring.

[0667] In certain embodiments, R 4 In the above, the C3-C7 cycloalkyl group is a monocyclic ring, a spirocyclic ring or a bridged ring.

[0668] In certain embodiments, R 4 In the formula (C3-C7), the C3-C7 cycloalkyl group is Cyclopropyl, cyclopentyl or cyclohexyl.

[0669] In certain embodiments, R 4 In the above, the C3-C7 cycloalkyl group is a cyclopentyl group.

[0670] In certain embodiments, R 4 In the 4-1 The substituted C3-C7 cycloalkyl group is

[0671] In certain embodiments, in R4, C3-C7 cycloalkenyl is monocyclic or bicyclic.

[0672] In certain embodiments, R 4 In the above, the C3-C7 cycloalkenyl group is a monocyclic ring, a spirocyclic ring or a bridged ring.

[0673] In certain embodiments, R 4 In the above, the C3-C7 cycloalkenyl group is a cyclopropenyl group, a cyclopentenyl group or a cyclohexenyl group.

[0674] In certain embodiments, R 4 In the above, the C3-C7 cycloalkenyl group is a cyclopentenyl group.

[0675] In certain embodiments, R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a 5- to 8-membered nitrogen-containing heterocycloalkyl group.

[0676] In certain embodiments, R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a 5- to 8-membered nitrogen-containing heterocycloalkyl group.

[0677] In certain embodiments, R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a monocyclic or bicyclic ring.

[0678] In certain embodiments, R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a monocyclic ring, a spirocyclic ring or a bridged ring.

[0679] In certain embodiments, R 4 In the above, the number of heteroatoms in the 3- to 12-membered nitrogen-containing heterocycloalkyl group is 1 or 2.

[0680] In certain embodiments, R 4 In the above, the heteroatom in the 3- to 12-membered nitrogen-containing heterocycloalkyl group is N.

[0681] In certain embodiments, R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a 5- to 7-membered nitrogen-containing monocyclic heterocycloalkyl group.

[0682] In certain embodiments, in R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a 6- to 8-membered nitrogen-containing bridged heterocycloalkyl group.

[0683] In certain embodiments, in R 4 wherein the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a 7- to 9-membered nitrogen-containing spirocyclic heterocycloalkyl group.

[0684] In certain embodiments, in R 4 wherein the 3- to 12-membered nitrogen-containing heterocyclic alkyl group is tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,

[0685] In certain embodiments, in R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is a 5- to 9-membered nitrogen-containing heterocycloalkenyl group.

[0686] In certain embodiments, in R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is a 5- to 6-membered nitrogen-containing heterocycloalkenyl group.

[0687] In certain embodiments, in R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is a monocyclic or bicyclic ring.

[0688] In certain embodiments, in R 4 In the above, the 3- to 12-membered nitrogen-containing heterocyclic alkenyl group is a monocyclic ring, a spirocyclic ring or a bridged ring.

[0689] In certain embodiments, in R 4 In the above, the 3- to 12-membered nitrogen-containing heterocyclic alkenyl group is a monocyclic ring.

[0690] In certain embodiments, in R 4 In the 3- to 12-membered nitrogen-containing heterocycloalkenyl group, the number of heteroatoms is 1 or 2.

[0691] In certain embodiments, in R 4 In the above, the number of heteroatoms in the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is 1.

[0692] In certain embodiments, in R 4 In the 3- to 12-membered nitrogen-containing heterocycloalkenyl group, the number of heteroatoms is N.

[0693] In certain embodiments, in R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is a 5- to 7-membered nitrogen-containing monocyclic heterocycloalkenyl group.

[0694] In certain embodiments, in R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is a 6- to 8-membered nitrogen-containing bridged heterocycloalkenyl group.

[0695] In certain embodiments, in R 4 In the above, the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is a 7- to 9-membered nitrogen-containing spirocyclic heterocycloalkenyl group.

[0696] In certain embodiments, in R 4 wherein the 3 to 12-membered nitrogen-containing heterocyclic alkenyl group is

[0697] In certain embodiments, in R 4-1 , R 4-2 , R 4-3 and R 4-4 In the formula (a), halogen is F, Cl, Br or I.

[0698] In certain embodiments, in R 4-1 , R 4-2 , R 4-3 and R 4-4 In the formula, halogen is F.

[0699] In certain embodiments, R 4-1 , R 4-2 , R4-3 and R 4-4 In the above, the C1-C3 alkyl group is a methyl group, an ethyl group, a propyl group or an isopropyl group.

[0700] In certain embodiments, R 4-1 , R 4-2 , R 4-3 and R 4-4 In the above, the C1-C3 alkyl group is a methyl group.

[0701] In certain embodiments, R 4-1 , R 4-2 , R 4-3 and R 4-4 In the above, C1-C3 cyanoalkyl is cyanomethyl.

[0702] In certain embodiments, R 4-1 , R 4-2 , R 4-3 and R 4-4 In the above, the C3-C6 cycloalkyl group is a cyclopropyl group, a cyclopentyl group or a cyclohexyl group.

[0703] In certain embodiments, R 4-1 , R 4-2 , R 4-3 and R 4-4 In the above, the C3-C6 cycloalkyl group is a cyclopropyl group.

[0704] In certain embodiments, R 4-1 , R 4-2 , R 4-3 and R 4-4 In the above, the C1-C3 alkoxy group is a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.

[0705] In certain embodiments, R 4-1 , R 4-2 , R 4-3 and R 4-4 In the above, the C1-C3 alkyl group is a methoxy group.

[0706] In certain embodiments, in R N1 In the above, the C1-C3 alkyl group is a methyl group, an ethyl group, a propyl group or an isopropyl group.

[0707] In certain embodiments, R N1 In the above, the C1-C3 alkyl group is a methyl group.

[0708] In certain embodiments, the "NH" on Ring A does not overlap with R Z1 connect.

[0709] In certain embodiments, in Ring B, the C3-C7 cycloalkyl group is monocyclic or bicyclic.

[0710] In certain embodiments, in Ring B, the C3-C7 cycloalkyl group is a monocyclic ring, a spirocyclic ring, or a bridged ring.

[0711] In certain embodiments, in Ring B, the C3-C7 cycloalkyl group is Cyclopropyl, cyclopentyl or cyclohexyl.

[0712] In certain embodiments, in Ring B, the C3-C7 cycloalkyl is cyclopentyl.

[0713] In certain embodiments, in Ring B, the C3-C7 cycloalkenyl is monocyclic or bicyclic.

[0714] In certain embodiments, in Ring B, the C3-C7 cycloalkenyl is a monocyclic, spirocyclic, or bridged ring.

[0715] In certain embodiments, in Ring B, the C3-C7 cycloalkenyl group is cyclopropenyl, cyclopentenyl, or cyclohexenyl.

[0716] In certain embodiments, in Ring B, the C3-C7 cycloalkenyl is cyclopentenyl.

[0717] In certain embodiments, in Ring A and Ring B, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a 5- to 9-membered nitrogen-containing heterocycloalkyl group.

[0718] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a 5- to 8-membered nitrogen-containing heterocycloalkyl group.

[0719] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a monocyclic or bicyclic ring.

[0720] In certain embodiments, in Ring A and Ring B, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a monocyclic ring, a spirocyclic ring, or a bridged ring.

[0721] In certain embodiments, in Ring A and Ring B, the number of heteroatoms of the 3- to 12-membered nitrogen-containing heterocycloalkyl group is 1 or 2.

[0722] In certain embodiments, in Ring A and Ring B, the number of heteroatoms in the 3- to 12-membered nitrogen-containing heterocycloalkyl group is N.

[0723] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is a 5- to 7-membered nitrogen-containing monocyclic heterocycloalkyl group.

[0724] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkyl is a 6- to 8-membered nitrogen-containing bridged heterocycloalkyl.

[0725] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkyl is a 7- to 9-membered nitrogen-containing spirocyclic heterocycloalkyl.

[0726] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkyl group is tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,

[0727] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is a 5- to 9-membered nitrogen-containing heterocycloalkenyl group.

[0728] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkenyl is a 5- to 6-membered nitrogen-containing heterocycloalkenyl.

[0729] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkenyl is a monocyclic or bicyclic ring.

[0730] In certain embodiments, in Ring A and Ring B, the 3- to 12-membered nitrogen-containing heterocycloalkenyl is a monocyclic ring, a spirocyclic ring, or a bridged ring.

[0731] In certain embodiments, in Ring A and Ring B, the 3- to 12-membered nitrogen-containing heterocycloalkenyl is a monocyclic ring.

[0732] In certain embodiments, in Ring A and Ring B, the number of heteroatoms of the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is 1 or 2.

[0733] In certain embodiments, in Ring A and Ring B, the number of heteroatoms in the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is 1.

[0734] In certain embodiments, in Ring A and Ring B, the number of heteroatoms in the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is N.

[0735] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkenyl is a 5- to 7-membered nitrogen-containing monocyclic heterocycloalkenyl.

[0736] In certain embodiments, in Ring A and Ring B, the 3- to 12-membered nitrogen-containing heterocycloalkenyl is a 6- to 8-membered nitrogen-containing bridged heterocycloalkenyl.

[0737] In certain embodiments, in the A ring and the B ring, the 3- to 12-membered nitrogen-containing heterocycloalkenyl is a 7- to 9-membered nitrogen-containing spirocyclic heterocycloalkenyl.

[0738] In certain embodiments, in Ring A and Ring B, the 3- to 12-membered nitrogen-containing heterocycloalkenyl group is

[0739] In certain embodiments, R Z1 In the formula (a), halogen is F, Cl, Br or I.

[0740] In certain embodiments, R Z1 In the formula, halogen is F.

[0741] In certain embodiments, in R Z1 In the above, the C1-C3 alkyl group is a methyl group, an ethyl group, a propyl group or an isopropyl group.

[0742] In certain embodiments, R Z1 In the above, the C1-C3 alkyl group is a methyl group.

[0743] In certain embodiments, R Z1 In the above, C1-C3 cyanoalkyl is cyanomethyl.

[0744] In certain embodiments, R Z1 In the above, the C3-C6 cycloalkyl group is a cyclopropyl group, a cyclopentyl group or a cyclohexyl group.

[0745] In certain embodiments, R Z1 In the above, the C3-C6 cycloalkyl group is a cyclopropyl group.

[0746] In certain embodiments, R Z1 In the above, the C1-C3 alkoxy group is a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.

[0747] In certain embodiments, R Z1 In the above, the C1-C3 alkoxy group is a methoxy group.

[0748] In certain embodiments, in R N1 In the above, the C1-C3 alkyl group is a methyl group, an ethyl group, a propyl group or an isopropyl group.

[0749] In certain embodiments, R N1 In the above, the C1-C3 alkyl group is a methyl group.

[0750] In certain embodiments, R 4 for

[0751] In certain embodiments, R 4 for

[0752] In certain embodiments, the "plurality" in the above definition is independently 2, 3, 4 or 5.

[0753] In certain embodiments, the nitrogen-containing heterocyclic compound represented by Formula II is selected from the group consisting of:

[0754]

[0755]

[0756] The present invention also provides a pharmaceutical composition, comprising a substance Y and a pharmaceutically acceptable excipient, wherein the substance Y is a nitrogen-containing heterocyclic compound represented by formula II, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0757] The present invention also provides the use of substance Y in the preparation of KRAS-G12D inhibitors;

[0758] Substance Y is a nitrogen-containing heterocyclic compound represented by formula II, a pharmaceutically acceptable salt thereof or a solvate thereof.

[0759] In certain embodiments, the KRAS-G12D inhibitor is used in vitro or in vivo.

[0760] The present invention also provides the use of substance Y in preparing medicine;

[0761] Substance Y is a nitrogen-containing heterocyclic compound represented by formula II, a pharmaceutically acceptable salt thereof, or a solvate thereof;

[0762] This drug is used to treat or prevent KRAS-G12D-related diseases or conditions.

[0763] In certain embodiments, the KRAS-G12D-associated disease or disorder is cancer.

[0764] The present invention also provides the use of substance Y in preparing medicine;

[0765] Substance Y is a nitrogen-containing heterocyclic compound represented by formula II, a pharmaceutically acceptable salt thereof, or a solvate thereof;

[0766] This medication is used to treat or prevent cancer.

[0767] The present invention also provides a method for preventing and / or treating a KRAS-G12D-related disease or disorder, comprising administering a therapeutically effective amount of substance Y to a subject in need thereof;

[0768] Substance Y is a nitrogen-containing heterocyclic compound represented by formula II, a pharmaceutically acceptable salt thereof or a solvate thereof.

[0769] In certain embodiments, the KRAS-G12D-associated disease or disorder is cancer.

[0770] The present invention also provides a method for preventing and / or treating cancer, the method comprising administering a therapeutically effective amount of substance Y to a subject in need thereof;

[0771] Substance Y is a nitrogen-containing heterocyclic compound represented by formula II, a pharmaceutically acceptable salt thereof or a solvate thereof.

[0772] The following terms used herein are intended to have the following meanings. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0773] The term "pharmaceutically acceptable salt" refers to a salt or zwitterionic form of a compound. The salt of a compound can be prepared during the final isolation and purification of the compound, or prepared separately by reacting the compound with a suitable acid. The pharmaceutically acceptable salt of a compound can be an acid addition salt formed with a pharmaceutically acceptable acid. Examples of acids that can be used to form pharmaceutically acceptable salts include inorganic acids (e.g., nitric acid, boric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid) and organic acids (e.g., oxalic acid, maleic acid, succinic acid, and citric acid). Non-limiting examples of salts of the compounds include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogenphosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthenate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, edisylate, benzenesulfonate, and p-toluenesulfonate. In addition, available amino groups present in the compounds can be quaternized with the chlorides, bromides and iodides of methyl, ethyl, propyl, butyl; dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; the chlorides, bromides and iodides of decyl, lauryl, myristyl and steryl; and benzyl bromide and phenethyl bromide.

[0774] The term "solvate" refers to a combination, physical combination and / or solvation of a compound of the invention with a solvent molecule, such as a disolvate, a monosolvate or a hemisolvate, wherein the ratio of solvent molecules to the compound of the invention is about 2:1, about 1:1 or about 1:2, respectively. This physical combination involves varying degrees of ionic and covalent bonds, including hydrogen bonds. In some cases, the solvate can be separated, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid. Therefore, "solvate" encompasses solution phases and separable solvates. The compound may exist in the form of a solvate formed with a pharmaceutically acceptable solvent (e.g., water, methanol, ethanol, etc.). In some embodiments, the solvate is a hydrate. "Hydrate" is a specific subgroup of a solvate whose solvent molecule is water. Solvates can generally function as pharmacological equivalents. The preparation of solvates is well known in the art. A typical, non-limiting method for preparing a solvate is to dissolve the compound in a desired solvent (organic solvent, water or a mixture thereof) at a temperature of 20° C. to above about 25° C., then cool the solution at a rate sufficient to form crystals, and isolate the crystals by known methods (e.g., filtration). Analytical techniques such as infrared spectroscopy can be used to confirm the presence of solvent in the solvate crystals.

[0775] When describing the invention (especially in the claims), the use of the terms "a", "an", "the" and similar referents are to be construed to cover both the singular and the plural, unless otherwise indicated.

[0776] The terms "C1-C6 alkyl", "C1-C4 alkyl" and "C1-C3 alkyl" refer to straight and branched aliphatic groups having 1-6 carbon atoms, 1-4 carbon atoms or 1-3 carbon atoms, respectively. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

[0777] The terms "C1-C3 haloalkyl" and "C1-C4 haloalkyl" refer to products in which one or more hydrogens in a C1-C3 alkyl chain or a C1-C4 alkyl chain as defined herein are replaced by halogen. Examples include trifluoromethyl, difluoromethyl and fluoromethyl.

[0778] The term "C1-C4 alkylene" refers to a C1-C4 alkyl group as defined above, which is located between two other chemical groups and is used to connect the two other chemical groups. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene and butylene.

[0779] The terms "C1-C3 alkoxy" and "C1-C4 alkoxy" refer to -OC1-C3 alkyl and -OC1-C4 alkyl, respectively, wherein the alkyl portion is as defined above.

[0780] The terms "C1-C3 hydroxyalkyl" and "C1-C4 hydroxyalkyl" refer to -C1-C3 alkylene-OH and -C1-C4 alkylene-OH, respectively.

[0781] The term "C2-C4hydroxyalkynyl" refers to -C2-C4alkynylene-OH.

[0782] The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group having 3 to 12 carbons, for example, 3 to 8 carbons, and as a further example, a saturated cyclic hydrocarbon group having 3 to 6 carbons. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl. The term "cycloalkyl" can be a monocyclic, bicyclic, spirocyclic or bridged ring system, for example, bicyclo[1.1.1]pentyl.

[0783] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group having 3 to 12 carbons, for example, 3 to 8 carbons, and as a further example, a partially unsaturated cyclic hydrocarbon group having 3 to 6 carbons. The term "cycloalkenyl" does not include aromatic rings. The term "cycloalkenyl" can be a monocyclic, bicyclic, spirocyclic or bridged ring system.

[0784] The term "heterocycloalkyl" is a cyclic structure having 3 to 12 atoms (e.g., 4 to 8 atoms), wherein one or more atoms are selected from the group consisting of N, O and S, and the remaining ring atoms are carbon. Heterocycloalkyl can be a monocyclic, bicyclic, spiral ring or bridged ring system. Heterocycloalkyl is saturated. Examples of heterocyclic groups include, but are not limited to, epoxy, azetidinyl, aziridine, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, imidazolidinyl.

[0785] The term "heterocycloalkenyl" group is a cyclic structure having 3 to 12 atoms (e.g., 4 to 8 atoms), wherein one or more atoms are selected from the group consisting of N, O and S, and the remaining ring atoms are carbon. The heterocycloalkenyl group can be a monocyclic, bicyclic, spirocyclic or bridged ring system. The heterocycloalkenyl group is partially unsaturated and does not contain aromatic rings.

[0786] The term "aryl" refers to a C6-C 14 As an example, the aryl group can be C6-C 10 Aryl. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl. "Aryl" also refers to a bicyclic or tricyclic ring system, wherein one or both rings of the aromatic ring system, respectively, may be saturated or partially saturated.

[0787] The term "heteroaryl" refers to a group having 5 to 14 ring atoms (preferably 5, 6, 9 or 10 ring atoms); its ring arrangement has 6, 10 or 14n shared electrons; in addition to carbon atoms, it also has one to four heteroatoms selected from the group consisting of N, O and S. Examples of heteroaryl include benzimidazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl. "Heteroaryl" also refers to a bicyclic or tricyclic system, in which one or two rings in the aromatic ring system can be saturated or partially saturated.

[0788] The term "KRAS-G12D inhibitor" refers to a compound that is capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRAS-G12D.

[0789] The term "KRAS-G12D-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or involving KRAS-G12D. A non-limiting example of a KRAS-G12D-associated disease or disorder is a KRAS-G12D-associated cancer.

[0790] The term "prevention" refers to a method of preventing the occurrence of a disease or condition and / or its associated symptoms or preventing a subject from developing a disease. As used herein, "prevention" also includes delaying the occurrence of a disease and / or its associated symptoms and reducing the risk of a subject developing a disease. The term "prevention" may include "prophylactic treatment", which refers to reducing the likelihood of a disease or condition recurring, or a previously controlled disease or condition recurring, in a subject who does not have the disease or condition but is at risk of contracting the disease or condition, or who is susceptible to the disease.

[0791] The term "treat" refers to eliminating, reducing or ameliorating a disease or condition and / or symptoms associated therewith. Although treatment of a disease or condition does not require complete elimination of the disease, condition or symptoms associated therewith, this is not excluded. The term "treat" and synonyms refer to administering a therapeutically effective amount of a compound to a subject in need of treatment. Treatment can be symptomatic, such as suppressing symptoms. It can be effective in the short term, can be carried out in the medium term, or can be a long-term treatment, such as maintenance therapy.

[0792] The term "subject" refers to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates or humans. Preferred subjects are humans.

[0793] The term "therapeutically effective amount" of a substance refers to an amount sufficient to cure, alleviate or partially prevent the clinical manifestations of a particular disease or disorder and its complications. The amount effective for a particular therapeutic purpose will depend on the severity of the disease or injury and the weight and general state of the subject. It should be understood that the determination of appropriate dosages can be achieved by using routine experiments, constructing a numerical matrix and testing different points in the matrix, all of which are within the ordinary skills of a trained physician or clinical scientist.

[0794] The above-mentioned preferred conditions can be combined in any way without violating the common knowledge in the art to obtain better embodiments of the present invention.

[0795] The positive improvement effect of the present invention is that the nitrogen-containing heterocyclic compounds of the present invention have better inhibitory activity against KRAS. DETAILED DESCRIPTION

[0796] The present invention is further illustrated by the following examples, but the present invention is not limited thereto.

[0797] abbreviation

[0798] Some abbreviations are listed below.

[0799] MethanolMeOH

[0800] Tetrahydrofuran (THF)

[0801] Dichloromethane DCM

[0802] Petroleum ether: PE

[0803] Ethyl acetate: EtOAc(EA)

[0804] Acetonitrile ACN

[0805] Isopropyl alcohol: IPA

[0806] Triethylamine: TEA

[0807] Trifluoroacetic acid: TFA

[0808] Sodium hydroxide: NaOH

[0809] Nitrogen: N2

[0810] Thin layer chromatography: TLC

[0811] High Performance Liquid Chromatography: HPLC

[0812] N,N-Diisopropylethylamine: DIPEA

[0813] N,N-Dimethylformamide: DMF

[0814] p-Toluenesulfonyl chloride TsCl

[0815] 1,1'-Bis(diphenylphosphino)ferrocene dppf

[0816] Triisopropylsilyl TIPS

[0817] Pinacol borate: BPin

[0818] Normal temperature RT

[0819] Hours: hrs

[0820] Representative method for preparative HPLC: (flow rates and gradients may vary)

[0821] An exemplary method for preparative HPLC is provided below.

[0822] Method A: NH4HCO3:

[0823] (Chromatographic column: Gilson2-Xbrige C18 19*150mm, 5μm; mobile phase: acetonitrile in water (0.1% NH4HCO3) ratio from 20% to 60%, flow rate: 15ml / min).

[0824] Method B: TFA:

[0825] (Chromatographic column: waters-Xbrige C18 10*190mm, 5μm; mobile phase: acetonitrile in water (0.1% TFA) ratio from 15% to 40%, flow rate: 15ml / min)

[0826] Method C: HCOOH:

[0827] (Chromatographic column: waters-Xbrige C18 10*190mm, 5μm; mobile phase: acetonitrile in water (0.1% formic acid) ratio from 15% to 40%, flow rate: 15ml / min)

[0828] Method D: NH4HCO3:

[0829] (Chromatographic column: Waters-Xbrige C18 19*150mm, 5μm; mobile phase: acetonitrile in water (0.1% NH4HCO3) ratio from 40% to 60%, flow rate: 20ml / min).

[0830] Method E: NH4HCO3:

[0831] (Chromatographic column: Waters-Xbrige C18 19*150mm, 5μm; mobile phase: acetonitrile in water (0.1% NH4HCO3) ratio from 20% to 45%, flow rate: 20ml / min).

[0832] Method F: HCOOH:

[0833] (Chromatographic column: waters-SunFire C18 19*150mm, 5μm; mobile phase: acetonitrile in water (0.1% formic acid) ratio from 20% to 60%, flow rate: 20ml / min).

[0834] Representative methods for analytical HPLC

[0835] Method 1: The analysis was performed on an Agilent 1200series HPLC-6120MS. UHPLC long gradient: acetonitrile in water (containing 0.02% NH4OAc) from 5% to 95%, run time 6.5 minutes, flow rate 1.5 mL / min. Waters Xbridged C18 column (18.5 microns, 4.6*50 mm) was used, temperature was 40°C.

[0836] Method 2: The analysis was performed on an Agilent 1200series HPLC-6120MS. UHPLC long gradient: acetonitrile in water (containing 0.1% trifluoroacetic acid) from 5% to 95%, run time 6.5 minutes, flow rate 1.5 mL / min. Waters Xbridged C18 column (18.5 microns, 4.6*50 mm) was used, temperature was 40°C.

[0837] Method 3: The analysis was performed on an Agilent 1260series HPLC-6120MS. UHPLC long gradient: acetonitrile in water (containing 0.02% NH4OAc) from 5% to 95%, run time 6.5 minutes, flow rate 2mL / min. A diamonsil Plus C18 column (18.5 microns, 4.6*30mm) was used, and the temperature was 40°C.

[0838] Method 4: The analysis was performed on an Agilent 1260 series HPLC-6125MS. HPLC long gradient: acetonitrile in water (0.1% formic acid) from 5% to 95%, run time 6.0 minutes, flow rate 0.9 mL / min. Agilent InfinityLab Poroshell 120SB-C18 column (2.7 micron, 3.0*100 mm) was used, and the temperature was 30°C.

[0839] Method 5: The analysis was performed on an Agilent 1260 series HPLC-6125MS. HPLC long gradient: acetonitrile in water (0.1% formic acid) from 50% to 100%, run time 8.0 minutes, flow rate 0.9 mL / min. Agilent InfinityLab Poroshell 120SB-C18 column (2.7 micron, 3.0*100 mm) was used, and the temperature was 30°C.

[0840] Example 1

[0841]

[0842] Step 1 7-Bromo-8-fluoro-1H-benzo[d][1,3]oxazine-2 4-dione (1b)

[0843] A solution of 2-amino-4-bromo-3-fluorobenzoic acid (10 g, 42.73 mmol) (14 g, 47.18 mmol) was added to THF (80 mL) and stirred at 75° C. for 4 hours at room temperature. After cooling to RT, the reaction mixture was filtered and the filter cake was dried to obtain compound 1b (9.5 g, yield 86%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ12.16(s,1H), 7.72-7.69(m,1H), 7.57-7.52(m,1H).

[0844] Step 2 7-Bromo-8-fluoro-2,4-dihydroxyquinoline-3-carbonitrile (1c)

[0845] A solution of 1b (10 g, 38.5 mmol), TEA (15.6 g, 153.8 mmol) and ethyl 2-cyanoacetate (6.54 g, 57.8 mmol) was added to DMF (80 mL) and stirred at 90 °C for 16 hours. After cooling to RT, the reaction mixture was diluted with HO2 (30 mL) and acidified with 1N HCl to adjust pH = 2. The formed solid was filtered and the filtered cake was dried to obtain compound 1c (10.9 g, yield given) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ11.12(s,1H), 7.69-7.66(m,1H), 7.39-7.34(m,1H).

[0846] Step 3 7-Bromo-2-4-dichloro-8-fluoroquinoline-3-carbonitrile (1d)

[0847] A mixture of 1c (2.5 g, 8.83 mmol) in POCl3 (48 mL) and ACN (8 mL) was stirred at 90 ° C for 3 hours. The reaction mixture was cooled and concentrated. The residue was poured into DCM / Et3N (40 mL / 4 mL). Washed with ice water (30 mL) and extracted with ethyl acetate (20 mL*2). The separated organic layer was dried over NaS2O, filtered and concentrated. The residue was purified by column chromatography (PE / EA=10 / 1) to give 1d (770 mg, yield 27%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ 8.17 (dd, J = 6.0, 8.8 Hz, 1H), 8.08 (dd, J = 1.2, 8.8 Hz, 1H).

[0848] Step 4: tert-butyl 3-(7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl)-3,8-diazo[3.2.1]octane-8-carboxylate (1e)

[0849] A mixture of 1d (500 mg, 1.56 mmol), tert-butyl 3,8-diazocyclo[3.2.1]octane-8-carboxylate (398 mg, 1.88 mmol) and TEA (316 mg, 3.13 mmol) was stirred in DCM (10 mL) at RT for 3 hours. The suspension was filtered and the filter cake was dried to give compound 1e (440 mg, yield 57%) as a white solid. LCMS (Method 3): t= R 1.83min,m / z(m+H)= + 495.2.

[0850] Step 5 3-(7-bromo-3-cyano-8-fluoro-2-((2R,7aS)-2-fluorohexahydro-1h-pyrrolidine-7a(5H)-yl)methoxyquinolin-4-yl)-3,8-diazobicyclooctane-8-carboxylate (1f)

[0851] A mixture of 1e (150 mg, 0.30 mmol), (2R,7aS)-2-fluorohexahydro-1h-pyrolizin-7a(5H)-yl)methanol (96 mg, 0.60 mmol) and anhydrous KCO (832 mg3, 0.60 mmol) in DMF (1 mL) was stirred at 80 ° C for 5 hours. After cooling to RT, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL*2). The combined organic phases were concentrated to dryness to give compound 1f (78 mg, 0.12 mmol) as a yellow solid. LCMS (Method III): t = 1.88 R min,m / z(m+H)=618. + 7.

[0852] Step 6 3-(3-cyano-8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-((2R,7aS)-2-fluorohexahydro-1h-pyrrolidine-7a(5H)-yl)methoxyquinolin-4-yl)-3,8-diazobicyclooctane-8-carboxylate (1 g)

[0853] 1f (78 mg, 0.13 mmol), 1i (36 mg, 0.13 mmol), K2CO3 (35 mg, 0.25 mmol) and Pd(dppf)Cl2 (18.6 mg, 0.025 mmol) were mixed in 1,4-dioxane / HO2 (1 mL / 0.2 mL) and stirred at 100 °C for 4 hours without atmosphere. The reaction mixture was cooled and concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH=10 / 1) to obtain 1 g (42 mg, yield 48%) of yellow solid. 1 H NMR (400MHz, DMSO-d6): δ10.23(s,1H), 8.02(d,J=8.8Hz,1H), 7.66(d,J=8.0Hz,1H), 7.57-7.54( m,1H), 7.49-7.46(m,1H), 7.41-7.39(m,1H), 7.33(t,J=2.0Hz,1H), 7.03-6.96(m,1H), 5.37-5.2 4(m,1H), 4.28-4.22(m,3H), 4.15-4.13(m,1H), 3.85-3.65(m,2H), 3.49-3.46(m,2H), 3.19-3.02 (m,3H), 2.84-2.82(m,3H), 2.33-2.20(m,3H), 2.11-1.98(m,3H), 1.46(s,9H), 1.23-1.17(m,4H).

[0854] Step 7 5-Fluoro-4-(4,4,5,5-tetramethyl-13-dioxaborolane-2-yl)naphthalen-2-ol

[0855] 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (764 mg, 3.01 mmol), 4-bromo-5-fluoronaphthalen-2-ol (290 mg, 1.20 mmol, WO2021 / 41671, paragraph 01040), KOAc (230 mg, 2.35 mmol) and Pd(dppf)Cl 2.DCM (88 mg, 0.11 mmol) was mixed in dry dioxane (2 mL) and stirred at 90°C for 2 hours without atmosphere. The reaction mixture was cooled and concentrated under vacuum. Purification by silica gel column chromatography (PE / EA=1 / 5) gave compound 1i (210 mg, yield 61%) as butter. LCMS (Method 3): t R =1.67min,m / z(mh) - =287.2.

[0856] Step 8 4-(3,8-diazoheterocyclo[3.2.1]octan-3-yl)-8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1h-pyrrolidine-7a(5H)-yl)methoxy)quinoline-3-carbonitrile (1)

[0857] Take 1 g (40 mg, 0.057 mmol) of TFA / DCM (0.1 mL / 0.3 mL) and stir at RT for 2 hours. The reaction mixture was concentrated and the residue was purified by pre-treatment HPLC (Method C) to obtain compound 1 (10 mg, yield 27%) as a white solid. LCMS (Method 2): t R =2.77min,m / z(m+H) + =600.3. 1 H NMR (400MHz, DMSO-d6): δ10.28 (brs, 1H), 7.96 (d, J = 8.0Hz, 1H), 7.42-7.37 (m, 1H) ,7.45-7.43(m,1H),7.34-7.33(m,1H),7.03-7.02(m,1H),6.98-6.96(m,1H),5.37- 5.24(m,1H), 4.24-4.22(m,1H), 4.16-4.14(m,1H), 3.85-3.80(m,4H), 3.60-3.56( m,2H), 3.37-3.20(m,3H), 3.10-3.01(m,1H), 2.24-2.22(m,2H), 2.10-1.80(m,8H). Example 2

[0858]

[0859] Step 1 (S)-tert-Butyl (1-(7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl)pyrrolidin-3-yl)carbamate (2a)

[0860] Compound 2a (248 mg, yield 67%) was synthesized using 1d (250 mg, 0.78 mmol) and (S)-tert-butylpyrrolidine-3-carbamate (175 mg, 0.94 mmol) as raw materials using a preparation process similar to that of compound 1. 1 H NMR (400MHz, DMSO-d6): δ8.05 (d, J = 8.8Hz, 1H), 7.72-7.68 (m, 1H), 7.29 (s, 1H), 4.31-4.27 (m, 1H), 4.23-4.41(m,3H), 3.79-3.77(m,1H), 2.16-2.12(m,1H), 1.99-1.97(m,1H), 1.45(s,9H).

[0861] Step 2 Tert-butyl((S)-1-(7-bromo-3-cyano-8-fluoro-2-((2R,7aS)-2-fluorohexahydro-1h-pyrrolin-7a(5H)-yl)methoxy)quinolin-4-yl)pyrrolidin-3-yl)carbon (2b)

[0862] A solution of tert-butyl compound 2a (75 mg, 0.16 mmol) of LiHMDS (0.64 mL, 0.64 mmol, 1 M in THF) and ((2R,7aS)-2-fluorohexahydro-1h-pyrrolizin-7a(5H)-yl)methanol (51 mg, 0.32 mmol) was added to THF (1 mL) (0°C). The mixture was stirred at 50°C for 2 days and at 70°C for 4 hours. The reaction mixture was concentrated and the residue was purified by pre-tlc (PE / EA=2 / 1) to give compound 2b (15 mg, yield 16%) as a yellow solid. LCMS (Method 3): t=1.78 min, m / z (m+H)=592.3.

[0863] Step 3: tert-Butyl ((S)-1-(3-cyano-8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-((2R,7aS)-2-fluorohexahydro-1h-pyrrolin-7a(5H)-yl)methoxy)quinolin-4-yl)pyrrolin-3-yl)carbamate (2c)

[0864] Compound 2c (10 mg crude) was synthesized from 2b (15 mg, 0.025 mmol) and 1i (8 mg, 0.025 mmol) using a similar preparation process to compound 1. LCMS (Method 3): t R =1.52min,m / z(m+H) + =674.3.

[0865] Step 4 4-((S)-3-aminopyrrolidin-1-yl)-8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1h-pyrrolidine-7a(5H)-yl)methoxy)quinoline-3-carbonitrile (2)

[0866] Compound 2 (3.2 mg, 40% yield) was synthesized using 2c (10 mg, 0.015 mmol) as the starting material using a similar preparation process to compound 1. LCMS (Method 2): t R =3.35min,m / z(m+H) + =574.3. 1 H NMR (400MHz, CD3OD): δ8.15(d,J=8.8Hz,1H), 7.60(d,J=8.8Hz,1H), 7.43-7 .37(m,2H), 7.29(d,J=2.0Hz,1H), 7.03(d,J=2.0Hz,1H), 6.93-6.87(m,1H), 5.58-5.45(m,1H), 4.67-4.42(m,5H), 4.35-4.30(m,1H), 4.13-4.10(m,1H), 4.00-3.85(m,1H), 3.75-3.68(m,3H), 2.53-2.45(m,2H), 2.36-2.11(m,6H).

[0867] Example 3

[0868]

[0869] Step 1: tert-Butyl 4-(7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl)piperazine-1-carboxylate (3a)

[0870] Compound 3a (275 mg, yield 75%) was synthesized using 1d (250 mg, 0.78 mmol) and tert-butylpiperazine-1-carboxylate (186 mg, 1.0 mmol) as raw materials using a preparation process similar to that of compound 1. 1 H NMR (400MHz, DMSO-d6): δ7.52-7.44(m,2H), 3.72-3.69(m,4H), 3.67-3.60(m,4H), 1.44(s,9H).

[0871] Step 2 4-(7-Bromo-3-cyano-8-fluoro-2-((2R,7aS)-2-fluorohexahydro-1h-pyrrolidine-7a(5H)-yl)methoxyquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl (3b)

[0872] Compound 3b (68 mg, yield 45%) was synthesized using 3a (120 mg, 0.25 mmol) and (2R,7aS)-2-fluorohexahydro-1h-pyrrolizine-7a(5H)-acyl)methanol (61 mg, 0.38 mmol) as raw materials using a similar preparation process to compound 1. LCMS (Method 3): t = 1.53 R min,m / z(m+H)=592.2 + .

[0873] Step 3: tert-Butyl 4-(3-cyano-8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-((2R,7aS)-2-fluorohexahydro-1h-pyrrolidine-7a(5H)-yl)methoxyquinolin-4-yl)piperazine-1-carboxylate (3c)

[0874] Compound 3c (73 mg crude) was synthesized from 3b (65 mg, 0.11 mmol) and 1i (32 mg, 0.11 mmol) using a similar preparation process to compound 1. LCMS (Method 3): t R =1.83min,m / z(m+H) + =674.4.

[0875] Step 4 8-Fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-((2R,7aS)-2-fluorohexahydro-1h-pyrrolidine-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)quinoline-3-carbonitrile (3)

[0876] Compound 3 (15.7 mg, yield 25%) was synthesized using 3c (73 mg crude product, 0.11 mmol) as the starting material using a similar preparation process to compound 1. LCMS (Method 2): t R =2.53min,m / z(m+H) + =574.2. 1H NMR (400MHz, DMSO-d6): δ8.19(s,1H), 7.83(d,J=8.4Hz,1H), 7.66(d,J=8.0Hz,1H), 7.48- 7.40(m,2H), 7.33(d,J=2.0Hz,1H), 7.02(d,J=2.0Hz,1H), 6.99-6.96(m,1H), 5.38(s,0.5 H), 5.24 (s, 0.5H), 4.23 (d, J = 2.4Hz, 1H), 4.21 (d, J = 2.4Hz, 1H), 3.68-3.66 (m, 4H), 3.24- 3.20(m,1H), 3.10-3.05(m,7H), 2.85-2.83(m,1H), 2.11-2.01(m,3H), 1.85-1.82(m,3H).

[0877] Example 4

[0878]

[0879] The first step: (S)-tert-butyl (5-(7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl)-5-azaspiro[2.4]hept-7-yl)carbamate (4a)

[0880] Compound 4a (116 mg, yield 42%) was synthesized using a similar preparation method to compound 1, using 1d (177 mg, 0.55 mmol) and (S)-tert-butyl 5-azaspiro[2.4]hept-7-ylcarbamate (123 mg, 0.56 mmol) as raw materials. 1 LCMS(Method3):t R =1.42min,m / z(M+H) + =495.2.

[0881] Step 2: tert-Butyl ((S)-5-(7-bromo-3-cyano-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinolin-4-yl)-5-azaspiro[2.4]hept-7-yl)carbamate (4b)

[0882] To a mixture of 4a (120 mg, 0.24 mmol) and ((2R, 7aS)-2-fluorohexahydro-1H-pyrrolidin-7a (5H) -yl) methanol (58 mg, 0.36 mmol) in DMF (1 ml) was added NaH (19 mg, 0.48 mmol, 60%, dispersed in mineral oil) and stirred at 0 ° C for 30 minutes. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL * 3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound 4b (25 mg, 17% yield) as a white solid. LCMS (Method 3): t R =1.50min,m / z(M+H) + =618.9.

[0883] Step 3: tert-butyl ((S)-5-(3-cyano-8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinolin-4-yl)-5-azaspiro[2.4]hept-7-yl)carbamate (4c)

[0884] Using a similar preparation method to compound 1, 4b (25 mg, 0.04 mmol) and 1i (13 mg, 0.04 mmol) were used as starting materials to synthesize compound 4c (10 mg crude product). LCMS (Method 3): t R =0.29min,m / z(M+H) + =700.7.

[0885] Step 4: 4-((S)-7-amino-5-azaspiro[2.4]hept-5-yl)-8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinoline-3-carbonitrile (4)

[0886] Using a similar preparation method to compound 1, compound 4 (6.0 mg, 70% yield) was synthesized using 4c (10 mg, 0.014 mmol) as the starting material. LCMS (Method 2): t R =3.44min,m / z(M+H) + =600.3. 1H NMR (400MHz, CD3OD): δ8.45 (br s,1H),8.13(d,J=8.8Hz,1H),7.56(d,J=8.0Hz,1H),7.41-7.35(m,2H),7.27(d,J=2.0Hz,1H) ,7.00(d,J=2.0Hz,1H),6.86(dd,J=8.0,13.2Hz,1H),5.58(s,0.5H),5.45(s,0.5H),4.84-4. 25(m,3H),4.23(d,J=11.6Hz,1H),3.93-3.72(m,4H),3.65-3.60(m,1H),3.36-3.30(m,1H),2 .56-2.46(m,2H),2.38-2.11(m,4H),1.37-1.36(m,1H),1.14-1.11(m,1H),0.96-0.88(m,3H).

[0887] Example 5

[0888]

[0889] Step 1 (S)-tert-butyl (5-(7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl)-5-azacyclo[2.4]heptane-7-yl)carbamate (5a)

[0890] Compound 5a (116 mg, 42% yield) was synthesized from 1d (177 mg, 0.55 mmol) and (S)-tert-butyl 5-azacyclo[2.4]heptane-7-carbamate (123 mg, 0.56 mmol) using a similar preparation process to compound 1. 1 MS (method 3): t = 1. R 42min, m / z(m+H)=49 + 5.2.

[0891] Step 2: tert-Butyl ((R)-5-(7-bromo-3-cyano-8-fluoro-2-((2R,7aS)-2-fluorohexahydro-1h-pyrrolin-7a(5H)-yl)methoxy)quinolin-4-yl)-5-azacyclo[2.4]heptane-7-yl)carbamate (5b)

[0892] Compound 5b (60 mg, 65% yield) was synthesized using 5a (75 mg, 0.15 mmol) and (2R,7aS)-2-fluorohexahydro-1h-pyrroline-7a(5H)-yl)methanol (36 mg, 0.23 mmol) as raw materials using a similar preparation process to compound 4. LCMS (Method 3): t = 0.50 Rmin,m / z(m+H)=618. + 7.

[0893] Step 3: tert-Butyl ((R)-5-(3-cyano-8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-((2R,7aS)-2-fluorohexahydro-1h-pyrrolidine-7a(5H)-yl)methoxy)quinolin-4-yl)-5-azacyclo[2.4]heptane-7-yl)carbamate (5c)

[0894] Compound 5c (25 mg crude) was synthesized using 5b (50 mg, 0.08 mmol) and 1i (23 mg, 0.08 mmol) as starting materials using a similar preparation process to compound 1. LCMS (Method 3): t R =0.82min,m / z(m+H) + =700.7.

[0895] Step 4 4-((R)-7-amino-5-azacyclo[2.4]heptane-5-yl)-8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1h-pyrrolidine-7a(5H)-yl)methoxy)quinoline-3-carbonitrile (5)

[0896] Compound 5 (7.3 mg, yield 34%) was synthesized using 5c ​​(25 mg, 0.036 mmol) as the starting material using a similar preparation process to compound 1. LCMS (Method 2): t R =3.67min,m / z(m+H) + =600.3, 1 H NMR (400MHz, dm6sod): δ8.15(s,1H), 8.10(dd,J=4.4,8.8Hz,1H), 7.65(d,J=8.0Hz ,1H), 7.43-7.41(m,1H), 7.33-7.32(m,2H), 7.00-6.96(m,1H), 5.38(s,0.5H), 5.04 -4.01(m,1H), 4.62-4.53(m,2H), 4.19-4.12(m,2H), 3.26-3.03(m,3H), 2.51-2.49( m,1H), 2.49-1.96(m,3H), 1.90-1.83(m,3H), 1.00-0.98(m,1H), 0.82-0.78(m,3H).

[0897] Example 6

[0898]

[0899] The first step: tert-butyl 4-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinolin-4-yl)piperazine-1-carboxylate (6b)

[0900] Compound 6b (160 mg, crude) was synthesized using a procedure similar to the sixth step of the preparation method of compound 1, using 3b (120 mg, 0.20 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (114 mg, 0.22 mmol) as starting materials. LCMS (Method 3): t R =1.24min,m / z(M+H) + =898.4

[0901] Step 2 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)quinoline-3-carbonitrile (6c)

[0902] To a solution of 6b (140 mg, crude) in dioxane (1 mL) was added HCl / dioxane (1 mL, 6 M) at 0°C. After stirring at room temperature for 1 hour, the reaction solution was filtered and the filter cake was purified by reverse phase chromatography to give compound 6c (75 mg crude). LCMS (Method 3): t R =1.17min,m / z(M+H) + =754.7.

[0903] Step 3: 7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)quinoline-3-carbonitrile (6)

[0904] To a solution of 6c (75 mg crude) in DMF (1 ml) was added CsF (79 mg, 0.52 mmol) at 0°C. After stirring at room temperature for 5 hours, the reaction solution was concentrated and the residue was purified by preparative HPLC (Method C) to give compound 6 (13 mg, 22% yield) as a green solid. LCMS (Method 1): t R =3.49min,m / z(M+H) + =598.2.1 H NMR (400 MHz, DMSO-d6): δ8.23 (s, 2H), 7.97 (dd, J=8.8, 1.2 Hz, 1H), 7.78-7.76 (m, 1H), 7.49-7.43 (m, 1H), 7.37 (s, 2H), 7.09 (s, 1H), 5.39 (s, 0.5H), 5.25 (s, 0.5H), 4.24-4.20 (m, 1H), 4.15-4.13 (m, 1H), 3.84-3.83 (m, 1H), 3.74-3.55 (m, 4H), 3.24-3.12 (m, 7H), 2.86-2.84 (m, 1H), 2.20-2.02 (m, 3H), 1.85-1.79 (m, 3H). Example 7

[0905]

[0906] Step 1: tert-Butyl 2,4-dichloro-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (7b)

[0907] After stirring NaIO4 (10.00 g, 46.31 mmol) in HO2 (85 mL) and ethyl acetate (85 mL), 2,4-dichloro-5,8-dihydropyridine [3,4-d] pyrimidine-7 (6H) -carboxylic acid 7a tert-butyl (5.00 g, 16.44 mmol) was added. After 5 minutes, RuCl (0.51 g, 2.463 mmol) was added, and the final reaction mixture was covered and stirred loosely at room temperature for 5 hours. The organic layer was then separated and the aqueous layer was extracted with ethyl acetate (30 mL * 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous NaSO and filtered for 2.4 hours. The filtrate was concentrated in vacuo to obtain a residue, which was purified by silica gel column (PE / EA 20:1 to 6:1) to obtain the title compound 7b (3.42 g, yield 65%) as a light yellow solid. LC-MS (Method IV): t = 3.62 min, m / z (m-boc R +H) + =218.0.

[0908] Step 2: tert-Butyl 4-(4-(phenoxy)carbonyl)piperazin-1-yl)-2-chloro-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (7c)

[0909] DIPEA (0.8 mL, 4.59 mmol) was added to a DCM (10 mL) solution of 2,4-dichloro-8-oxo-5,8-dihydropyridine [3,4-d] tert-butylpyrimidine-7 (6H) -carboxylic acid 7b (1.00 g, 3.14 mmol) and benzylpiperazine-1-carboxylic acid (0.70 g, 3.18 mmol) and stirred at room temperature for 1 hr. The reaction solution was then washed with water (10 mL) and brine (10 mL). The organic layer was separated and concentrated under vacuum to obtain a residue, which was recrystallized with ethyl acetate to obtain the pure product 7c (1.12 g, yield 71%) as a white solid. LC-MS (Method 4): t = R 4.55min,m / z(m+H)= + 502.3.

[0910] Step 3 4-(2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy-8-oxo-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (7d)

[0911] (2R,7aS)-2-fluorotetrahydro-1h-pyrrolizin-7a(5H)-yl)methanol (250 mg, 1.57 mmol) was stirred in THF (11 mL), and NaH (56 mg, 1.4 mmol, 60% mineral oil) was added at room temperature. After stirring for 0.5 hr, tert-butyl 4-(4-(phenoxy)carbonyl)piperazine-1-yl)-2-chloro-8-oxo-5,8-dihydropyridine[3,4-d]-7(6H)-carboxylic acid 7c (245 mg, 0.49 mmol) was added. The resulting mixture was stirred at room temperature for 1 hr. The reaction solution was then quenched with MeOH and filtered. The filtrate was concentrated in vacuo to obtain a residue, which was purified by pre-HPLC (Method D) to obtain 7d (56 mg, 21% yield) as a white solid. LC-MS (Method IV): t=3.04 min, m / z (m + R +H)=525.3.

[0912] Step 4 4-(2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy-7-(2-methoxy)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (7e)

[0913] In dioxane (5 mL), KPO (6243 mg, 0.292 mmol), CuI (28 mg, 0.147 mmol) and N,N-dimethylethane-1, 24-(2-((2R,7aS)-2-fluorotetrahydro-1h-pyrroline-7a(5H)-acyl)-8-oxo-5,6,7,8-tetrahydropyridine-4-yl)-piperazine-1-carboxylic acid 7d (56 mg, 0.107 mmol) and 1-iodo-2-methylpyrrolidine (13.3 mg, 0.151 mmol) were added. 1 The resulting mixture was stirred at 110°C under N for 16 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by pre-thin layer chromatography (DCM / MeOH / NH4OH=10 / 1 / 0.05) to give 7e (32 mg, yield 47%) as a light yellow solid. LC-MS (Method IV): t=3.71 min, m / z (m+H) + R =631.4.

[0914] Step 5 2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy)-7-(2-methoxyphenyl)-4-(piperazin-1-yl)-6,7-dihydropyrido[3,4-d]pyrimidine-8(5H)-1(7)

[0915] 4-(2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy-7-(2-methoxyphenyl)-8-oxo-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid 7e (32 mg, 0.051 mmol) was dissolved in aqueous solution (6N, 1 mL). The resulting mixture was stirred at 90°C for 1 hour. After cooling to room temperature, the reaction solution was concentrated in vacuo to obtain a residue, which was purified by pre-HPLC (E method) to obtain the final product 7 (9 mg, yield 36%) as a white solid. 1 H NMR (400 MHz, CD3OD): δ7. + 41(t R , J = 8.6 Hz, 1H), 7.33 ( 1 dd,J=8.0Hz,2.0Hz,1H), 7.18(dd,J=8.4Hz,1.2Hz,1H), 7.08-7.04(m,1H), 5.50-5.35(m,1H), 4.47(q,J=12.4Hz,2H), 3.89( s,3H), 3.81-3.72(m,6H), 3.31-3.23(m,2H), 3.16(t,J=5.2Hz,4H), 3.11-3.08(m,2H), 2.49-2.40(m,2H), 2.24-2.16(m,2H).

[0916] Example 8

[0917]

[0918] Step 1: tert-Butyl 4-(8-(benzyloxy)carbonyl)-3,8-diazo[3.2.1]octan-3-yl)-2-chloro-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (8a)

[0919] DIPEA (0.2 mL, 1.15 mmol) was added to DCM (3 mL) to obtain a solution of tert-butyl 2,4-dichloro-8-oxo-5,8-dihydropyridine [3,4-d] pyrimidine-7 (6H) -carboxylate 7b (645 mg, 2.03 mmol) and 3,8-diazobicyclo [3.2.1] octane-8-carboxylate (500 mg, 2.03 mmol). The resulting reaction solution was stirred at room temperature for 1 hr. The reaction solution was then washed with water (3 ml) and brine (3 ml). The organic layer was separated and concentrated under vacuum to obtain a residue, which was further purified on a silica gel column (PE / EA from 20:1 to 5:1) to obtain the title compound 8a (789 mg, yield 74%) as a white solid. LC-MS (Method 4): t = R 4.66min,m / z(m+H)= + 528.3.

[0920] Step 2 3-(2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolin-7a(5H)-yl)methoxy-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate (8b)

[0921] Tert-butyl 4-(8-(phenoxy)carbonyl)-3,8-diazoheterocyclo[3.2.1]octan-3-yl)-2-chloro-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid 8a (20 mg, 0.038 mmol) and ((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methanol (12 mg, 0.075 mmol) were dissolved in dioxane (1 mL), and t-BuONa (7.6 mg, 0.079 mmol) was added in one portion. The resulting mixture was irradiated at 140°C for 3 hours in a microwave. The reaction solution was then centrifuged to remove the solid. The clear solution was separated and concentrated under reduced pressure to give a residue, which was purified by pre-HPLC (Method D) to give 8b (3 mg, yield 14%) as a white solid. LC-MS (method 4): t = 3.10 min + R,m / z(m+H)=551.4.

[0922] Step 3 3-(2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolin-7a(5H)-yl)methoxy-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate (8c)

[0923] In dioxane (2 mL), KPO (3943 mg, 0.184 mmol), CuI (16 mg, 0.084 mmol) and N,N-dimethylethane-1, 2 2-diamine (12.6 mg 0.143 mmol), forming 3-(2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolin-7a(5H)-yl)methoxy-8-oxo-5,6,7,8-tetrahydropyridine-3,4-d pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane- 1 A stirred solution of 8-carboxylic acid 8b (40 mg, 0.073 mmol) and 1-bromo-8-chloronaphthalene (36 mg, 0.149 mmol). The resulting mixture was stirred at 110°C under N for 16 h. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by pre-HPLC (F method) to obtain 8c (7 mg, yield 14%) as a light yellow solid. LC-MS (Method IV): t = 4.38 min, m / z (m+H R + )=711.4.

[0924] Step 4 4-(3,8-diazoheterocyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy)-6,7-dihydropyrido[3,4-d]pyrimidine-8(5H)-1(8)

[0925] 3-(2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy-8-oxo-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylic acid 8c (7 mg, 0.010 mmol) was dissolved in aqueous solution (6N, 1 mL) and stirred at 90°C for 1 h. The reaction solution was evaporated under vacuum to obtain a residue, which was purified by pre-HPLC (Method E) to obtain the final product 8 (2.5 mg, yield 44%) as a white solid. LC-MS (Method 4): t = 2.47 min, m R / z(m+H)=577.4H nucleus +Magnetic resonance (400MHz 1 , CD3OD): δ8.03(dd,J=7.6Hz,2.0Hz,1H), 7.95(dd,J=8.4Hz,1H), 7.66-7.6 0(m,3H), 7.46(t,J=8.0Hz,1H), 5.32(d,J=53.6Hz,1H), 4.36-4.26(m,2H), 4.20(d,J=13.2Hz,1H), 4.09-3.89(m,3H), 3.72(s,2H), 3.53-3.35(m,4H), 3.25-3.08(m,2H), 2.43-2.28(m,2H), 2.21-2.04(m,2H), 1.98-1.85(m,5H).

[0926] Example 9

[0927]

[0928] Step 1: tert-Butyl (S)-4-(4-(tert-butylcarbonyl)-3-(cyanoethyl)piperazin-1-yl)-2-chloro-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (9a)

[0929] DIPEA (0.3 mL, 1.72 mmol), 2,4-dichloro-8-oxo-5,8-dihydropyridine-7(6H)-carboxylic acid 7b (500 mg, 1.571 mmol) and tert-butyl (S)-2-(cyanoethyl)piperazine-1-carboxylate (397 mg, 1.762 mmol) of 3,4-d-pyrimidine-7(6H)-carboxylic acid 397 mg, 1.762 mmol) were added to the DCM (10 mL) solution and stirred at room temperature for 1 hr. The reaction solution was then washed with water (10 mL) and brine (10 mL). The organic layer was separated and concentrated under vacuum to obtain a residue, which was recrystallized with ethyl acetate to obtain the pure product 9a (677 mg, yield 85%) as a white solid. LC-MS (Method IV): t = 4.02 min + R ,m / z(m+H)=507.3.

[0930] Step 2 Tert-butyl (S)-2-(cyanoethyl)-4-(2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolin-7a(5H)-yl)methoxy-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (9b)

[0931] A mixture of (2R,7aS)-2-fluorotetrahydro-1h-pyrroline-7a(5H)-yl)methanol (12.6 mg, 0.079 mmol) was added to dioxane (1 mL) with tert-butyl (S)-4-(4-(tert-butyloxycarbonyl)-3-(cyanoethyl)piperazin-1-yl)-2-chloro-8-oxo-5,8-dihydropyridine[3,4-d]-7(6H)-carboxylic acid 9a (20 mg, 0.038 mmol) and t-BuONa (8.0 mg, 0.083 mmol), and microwave irradiated at 140°C for 3 hours. The reaction solution was centrifuged to remove the solid, and the clear solution was concentrated under reduced pressure to obtain a residue, which was purified by pre-HPLC (Method D) to obtain 9b (2.5 mg, yield 12%) as a white solid. LC-MS (Method 4): t=2.61 min, m / z (m+H)=530.3. R +

[0932] Step 3 Tert-butyl (S)-4-(7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanoethyl)piperazine-1-carboxylate (9c)

[0933] A stirred solution of KPO (25 mg, 0.118 mmol), CuI (10 mg, 0.052 mmol) and N,N-dimethylethane-1-2-diamine (8.2 mg, 0.093 mmol) was added to a dioxane (2 mL) solution of (S)-2-((2R,7aS)-2-fluorotetrahydro-1h-pyrroline-7a(5H)-acyl)methoxy-8-oxo-5,6,7,8-tetrahydropyridine-4-acyl)piperazine-1-carboxylic acid 9b (253 mg, 0.047 mmol) and 1- ... in sequence. 1 Bromo-8-chloro-3-(methoxy 2 The resulting mixture was stirred at 110°C under N for 16 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo to obtain a residue, which was purified by pre-HPLC (Method F) to obtain 9c (7 mg, yield 20%) as a light yellow solid. LC-MS (Method IV): t = 3.99 min, m / z (m + H + R )=750.3.

[0934] Step 4 2-(4-(7-(8-chloro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy)-8-oxo-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (9)

[0935] (S)-4-(7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy)-8-oxo-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-4-yl)-2-(cyanoethyl)piperazine-1-carboxylic acid 9c (7 mg, 0.009 mmol) was added to MeOH (1 mL) with an aqueous solution (1N, 0.1 mL) and stirred at 65° C. for 16 hours. The reaction solution was then evaporated under vacuum to obtain a residue, which was purified by pre-HPLC (E method) to obtain the final product 9 (3 mg, yield 53%) as a white solid. LC-MS (Method 4): t=2.13 min, m / z ( R m+H)=606.3H NMR(400 + MHz,CD3OD 1 ): δ7.47(t,J=8.8Hz,2H), 7.15-7.21(m,4H), 7.11(d,J=2.4Hz,1H), 7.07(d,J=2.8Hz,1H), 6.95(bs,1H), 6.87 (bs, 1H), 5.32 and 5.28 (d, J = 54Hz, 2H), 4.38 (t, J = 10.8Hz, 2H), 4.12 and 4.06 (d, J = 11.2Hz, 2H), 4.02 (d, J = 12.8Hz, 2H), 3.82(dd,J=11.6Hz,22Hz,4H), 3.60-3.68(m,4H), 3.36-3.42(m,4H), 2.86-3.01(m,13H), 2.60-2.75(dd, J=6Hz, 16.8Hz, 2H), 2.39 (dd, J=6.8Hz, 16.8Hz, 2H), 2.24-2.29 (m, 2H), 2.07-2.20 (m, 4H), 1.93-1.97 (m, 4h).

[0936] Example 10

[0937]

[0938] Step 1 3-(7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolin-7a(5H)-yl)methoxy-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate (10a)

[0939] In a dioxane ring (2 mL), KPO (333 mg, 0.155 mmol), CuI (11 mg, 0.058 mmol) and N,N-dimethylethane-1-2-diamine (8.2 mg, 0.093 mmol) were added in sequence to form 3-(2-((2R,7aS)-2-fluorotetrahydro-1h-pyrroline-7a(5H)-acyl)methoxyphenyl-8-oxo-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidine 2 pyridine-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylic acid 8b (31 mg4, 0.056 mmol) and 3-bromo-8-chloro-3-(methyl 1 The resulting mixture was stirred at 110°C under N for 16 h. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated to dryness under vacuum. The residue was purified by pre-HPLC (E method) to give 10a (6.4 mg, 15% yield) as a light yellow solid. LC-MS (Method IV): t = 4.27 min, m / z (m+ R + H)=771.3.

[0940] Step 2 4-(3,8-diazoheterocyclo[3.2.1]octan-3-yl)-7-(8-chloro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy)-6,7-dihydropyrido[3,4-d]pyrimidine-8(5H)-1(10)

[0941] 3-(7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy-8-oxo-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylic acid 10a (6.4 mg, 0.008 mmol) was dissolved in aqueous solution (4N, 1 mL). The mixture was stirred at 90° C. for 0.5 h. The reaction solution was then evaporated under vacuum to obtain a residue, which was purified by pre-HPLC (Method F) to obtain the final product 10 (4.2 mg, yield 85%) as a red solid. LC-MS (Method 4): t R =2.06min, m / z(m+H)=593.2. 1 HNMR (400MHz 1 , CD3OD): δ8.38(brs,1H), 7.71(d,J=7.6Hz,1H), 7.35-7.18(m,4H), 5.47(d,J=51.6Hz,1H), 4.65(s,2H), 4.4 7(d,J=12.8Hz,2H), 4.34(d,J=13.6Hz,2H), 4.21(s,2H), 4.08-3.61(m,7H), 3.35(m,2H), 2.37-2.01(m,10H).

[0942] Embodiment 11

[0943]

[0944] Step 1: tert-Butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazo[3.2.1]octane-8-carboxylate (11b)

[0945] At -40 ° C, 2,4,7-trichloro-8-fluoropyridinium [4,3-d] pyrimidine (607 mg, 2.40 mmol WO2021 / 41671, paragraph 0277) and DIPEA (2.05 g, 15.86 mmol) were added to a DCM (10 mL) solution, and tert-butyl 3,8-diazobicyclo [3.2.1] octane-8-carboxylate (510 mg, 2.40 mmol) was added. After stirring at this temperature for 0.5 hours, the reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL * 2). The combined organic layer was washed with brine (30 mL), dried over NaS2O, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EA = 3: 1) to give compound 11b (370 mg, yield 36%) as a yellow solid. LCMS (method 3): t = 1.74 Rmin,m / z(m+H)=428. + 1.

[0946] Step 2 3-(7-chloro-8-fluoro-2-((2R,7aS)-2-fluorohexahydro-1h-pyrrolin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate (11c)

[0947] Compound 11b (300 mg, 0.70 mmol), (2R, 7aS)-2-fluorohexahydro-1h-pyrroline-7a(5H)-yl)methanol (223 mg, 1.40 mmol) and DIPEA (271 mg, 2.10 mmol) were mixed in dioxane (1 mL) and stirred at 80°C for 6 hours. The reaction mixture was cooled and concentrated under vacuum. The residue was purified by reverse chromatography (0-50% ACN / HO2, 0.1% TFA) to give compound 11c (240 mg, yield 62%) as a yellow solid. LCMS (Method 3): t = 1.55 min + R ,m / z(m+H)=551.2.

[0948] Step 3 3-(8-Fluoro-2-((2R,7aS)-2-fluorohexahydro-1h-pyrrolin-7a(5H)-yl)methoxy-7-phenylpyrido[4,3-d]pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate (11d) tert-butyl

[0949] Compound 11d (32 mg crude) was synthesized using 11c (30 mg, 0.05 mmol) and phenylboronic acid (13 mg, 0.1 mmol) as starting materials using a similar preparation process to that of compound 1 in step 6. LCMS (Method 3): t R =1.60min,m / z(m+H) + =593.3.

[0950] Step 4 4-((1R,5S)-3,8-diazo[3.2.1]octan-3-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy)-7-phenylpyrido[4,3-d]pyrimidine (11)

[0951] Compound 11 (18.5 mg, yield 68%) was synthesized using a similar preparation process to compound 1, using 11d (32 mg crude) as the starting material. Compound 11 was purified by pre-HPLC (C method), LCMS (method 2): t R =2.69min,m / z(m+H)+ =493.2. 1 HNMR (400MHz, DMSO-d6): δ9.17 (s, 1H), 8.03 (d, J = 7.6Hz, 2H), 7.59-7.52 (m, 3H), 5.38 (s, 0.5H), 5.24 (s, 0.5H), 4.58 (d, J = 12.8Hz, 2H) , 4.20-4.17(m,1H), 4.11-4.05(m,4H), 3.85-3.75(m,3H), 3.19-3.07(m,3H), 2.87-2.85(m,1H), 2.16-2.03(m,3H), 1.85-1.80(m,6H).

[0952] Example 12

[0953]

[0954] Step 1 Tert-butyl (1R, 5S)-3-(6-fluoro-7-(8-fluoro-3-(2-(trimethylsilyl)ethoxy)methoxy)naphthalen-1-yl)-2-((2R, 7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)yl)methoxy)pyridin[2,3-d]pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate (12a)

[0955] Compound 12a (21 mg, yield 32%) was prepared from compound 1 and 11c (45 mg, 0.08 mmol) and (2-(((5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy)methoxy)ethyl)trimethylsilane (41 mg, 0.098 mmol, WO2021 / 41671, paragraph 01283) as starting materials. LCMS (Method 3): t R =2.32min,m / z(m+H) + =808.0.

[0956] Step 2 4-(4-((1R,5S)-3,8-diazo[3.2.1]octan-3-yl)-6-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidin-7-yl)-5-fluoronaphthalen-2-ol (12)

[0957] Compound 12 (4.5 mg, yield 28%) was synthesized by a similar preparation method to compound 1 in the last step with 12a (21 mg, 0.02 mmol) as the starting material. LCMS (method 3): t R =2.38min,m / z(m+H)+ =577.3. 1 H NMR (400MHz, DMSO-d6): δ10.16 (br s,1H), 8.26(d,J=10.8Hz,1H), 7.63(d,J=8.4Hz,1H), 7.42-7.37(m,1H), 7.29(d,J=2 .0Hz,1H), 6.95(dd,J=12.4,7.6Hz,1H), 5.37(s,0.5H), 5.29(s,0.5H), 4.33(d,J=13. 2Hz,2H), 4.28(d,J=10.8Hz,1H), 4.23(d,J=10.4Hz,2H), 3.96(s,2H), 3.67(d,J=13. 6Hz,2H), 3.17-3.01(m,3H), 2.88-2.83(m,1H), 2.18-2.00(m,3H), 1.84-1.77(m,7H).

[0958] Embodiment 13

[0959]

[0960] Step 1 Benzyl (1R, 2R, 4S)-7-azabicyclo[2.2.1]heptane-2-carbamate hydrochloride (13b)

[0961] (1R,2R,4S)-tert-butyl 2-((phenoxy)carbonyl)amino-7-azacyclo[2.2.1]heptane-7-carboxylate (160 mg, 0.46 mmol, WO2004 / 74292, Page 7) was dissolved in hydrochloric acid / ethyl acetate (2 ml, 2M) and stirred at RT for 2 hours. The mixture was concentrated to dryness to give compound 13b (130 mg, yield given). LCMS (Method 3): t=1.15 R min,m / z(m+H)=247.0 + .

[0962] Step 2 Benzyl ((1R, 2R, 4S)-7-(7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl)-7-azacyclo[2.2.1]heptane-2-yl)carbamate (13c)

[0963] Compound 13b (230 mg, 0.81 mmol) in DCM (5 mL) was added to a solution of DIPEA (420 mg, 3.25 mmol) in DCM (5 mL) at 0°C. Stir at RT for 10 hours. Dilute with DCM (20 mL) and wash with HO2 (10 mL). The separated organic layer was dried over NaS2O and filtered. The filtrate was concentrated to dryness. Purification by silica gel column chromatography (PE / EA=3 / 1) gave compound 13c (235 mg, yield 55%) as a yellow solid. LCMS (Method III): t=1.89 R min,m / z(m+H)=529. + 8.

[0964] Step 3 Benzyl ((1R, 2R, 4S)-7-(7-bromo-3-cyano-8-fluoro-2-((2R, 7aS)-2-fluorohexahydro-1h-pyrrolin-7a(5H)-yl)methoxy)quinolin-4-yl)-7-azacyclo[2.2.1]heptane-2-yl)carbamate (13d)

[0965] Compound 13d (220 mg, yield 74%) was synthesized using 13c (240 mg, 0.45 mmol) and (2R,7aS)-2-fluorohexahydro-1h-pyrroline-7a(5H)-yl)methanol (87 mg, 0.55 mmol) as raw materials using a similar preparation process to compound 4 in the second step. LCMS (Method 3): t = 0.95 R min,m / z(m+H)=652.7 + .

[0966] Step 4 Benzyl ((1R, 2R, 4S)-7-(3-cyano-8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-((2R, 7aS)-2-fluorohexahydro-1h-pyrrolin-7a(5H)-yl)methoxy)quinolin-4-yl)-7-azacyclo[2.2.1]heptane-2-yl)carbamate (13e)

[0967] Compound 13e (35 mg, yield 92%) was synthesized using 13d (50 mg, 0.077 mmol) and 1i (15 mg, 0.052 mmol) as starting materials using a similar preparation process to that of compound 1 in step 6. LCMS (Method 3): t R =1.01min,m / z(m+H) + =734.7.

[0968] Step 5: 4-((1R,2R,4S)-2-amino-7-azacyclo[2.2.1]heptane-7-yl)-8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1h-pyrrolin-7-yl)methoxy)quinoline-3-carbonitrile (13)

[0969] To a solution of 13e (35 mg, 0.048 mmol) in CHCl3 (2 mL) was added iodotrimethylsilane (19 mg, 0.095 mmol). After stirring at RT for 3 h, the reaction was quenched with 1-hydrochloric acid (0.5 mL) and extracted with EA (5 mL*2). The combined organic layers were concentrated and purified by column chromatography (DCM / MeOH=10 / 1) to obtain a crude product. The crude product was purified by pre-thin layer chromatography (DCM / MeOH=10 / 1) to obtain compound 13 (3 mg, yield 10%) as a white solid. LCMS (Method 3): t R =0.65min,m / z(m+H) + =60 1 0.7H NMR (400MHz, DMSO-d6): δ8.24-8.22(m,2H), 7.67(d,J=8.0Hz,1H), 7.49-7.43( m,2H), 7.34(s,1H), 7.03-6.97(m,2H), 5.69(s,1H), 5.54(s,0.5H), 5.07(s,1H) ,5.00(s,1H),3.97-3.77(m,3H),3.17-3.10(m,2H),2.89-2.80(m,2H),2.09-1 .97(m,5H), 1.86-1.83(m,5H), 1.69-1.65(m,1H), 1.44(dd,J=12.8,4.8Hz,1H).

[0970] Embodiment 14

[0971]

[0972] Step 1 2,4-Dichloro-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one (14a)

[0973] 4-HCl / dioxane (25 mL) was added to a solution of 7b (5 g, 15.72 mmol) in dioxane (25 mL). The reaction mixture was stirred at room temperature for 4 h, and then the reaction solution was concentrated under vacuum to give the crude product 14a (3.5 g, yield given) as an off-white solid, which was used directly in the next step without further purification. LC-MS (Method 4)t R =2.35min,m / z(m+H) +=218.0.

[0974] Step 2: tert-Butyl 3-(2-chloro-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazo[3.2.1]octane-8-carboxylate (14b)

[0975] DIEA (6.1 g, 47.16 mmol) was added to a solution of 14a (3.5 g, 15.72 mmol) and DMSO (20 mL) to obtain tert-butyl 3,8-diazoheterocyclo[3.2.1]octane-8-carboxylate (4.0 g, 18.87 mmol). The reaction solution was stirred at 60°C for 1 h, water (50 mL) was added, and extracted with EA (35 mL*3). The combined organic layers were washed with water (50 mL) and brine (50 mL) and concentrated under vacuum to obtain a residue, which was further purified by flash chromatography on silica gel (DCM / MeOH from 100 / 1 to 20 / 1) to obtain the title compound 14b (4.5 g, two-step yield 73%) as a brown solid.

[0976] Step 3: tert-Butyl 3-(2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolin-7a(5H)-yl)methoxy-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate (14c)

[0977] In a solution of 14b (4.5 g, 11.45 mmol), (2R,7aS)-2-fluorotetrahydro-1h-pyrroline-7a(5H)-yl)methanol (5.4 g, 34.35 mmol) and 4 Molecular sieves (4.5 g) were added to DMSO (50 mL) with DIEA (4.43 g, 34.35 mmol). The resulting mixture was stirred at 140 ° C in a sealed tube for 48 h. The mixture was filtered and diluted with water (100 mL). EA extraction (50 mL * 3). The combined organic layers were washed with water (75 mL) and brine (75 mL) and concentrated under vacuum to obtain a residue, which was further purified by flash chromatography on silica gel (DCM / EtOH from 20 / 1 to 5 / 1) to obtain the title compound 14c (4.0 g, yield 67%) as a brown solid. LC-MS (Method 4) t = 2.91 R min,m / z(m+H)=517. + 3.

[0978] Step 4 1-Bromo-3-chloro-2-cyclopropyl-5-(methoxymethoxy)benzene (14e)

[0979] In DCM (5mL), bromo(methoxy)methane (151mg, 1.21mmol) was added to stir a solution of 14d (150mg, 0.606mmol) and DIEA (235mg, 1.82mmol). The resulting mixture was stirred at 20°C for 16 hours. The reaction solution was then washed with water (3mL) and brine (3mL). The organic layer was separated and concentrated under vacuum to obtain a residue, which was further purified by flash chromatography on silica gel (PE / EA from 1 / 0 to 50 / 1) to obtain the title compound 14e (110mg, 62% yield) as a yellow liquid.

[0980] Step 5 (3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)boronic acid (14f)

[0981] A solution of 14e (100 mg, 0.34 mmol) and triisopropyl borate (96.8 mg, 0.514 mmol, 0.12 mL) in THF (2 mL) was added with n-butyl lithium (2.4 M, 0.16 mL) at -78 ° C, stirred at -78 ° C for 2 h, and the reaction solution was quenched with 1N HCl aq (1 mL) at -78 ° C, then stirred at 20 ° C for 1 h, and the mixture was extracted with EA (2 mL * 3). The combined organic layer was washed with water (3 ml) and brine (3 ml), separated and concentrated under vacuum to obtain a residue, which was further purified on Prep-TLC (PE / EA = 2 / 1) to obtain the title compound 14f (38 mg, yield 43%) as a yellow solid.

[0982] Step 6 Tert-butyl 3-(7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)yl)methoxy-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate (14 g)

[0983] A solution of 14c (20 mg, 0.039 mmol), 14f (20 mg, 0.078 mmol) and Cu2(TMEDA)2(OH)2Cl2 (9.0 mg, 0.019 mmol) in DCM (1 mL) was stirred at 20°C for 18 h. The reaction solution was concentrated under vacuum to obtain a residue, which was further purified on Prep-TLC (PE / EA=2 / 1) to obtain the title compound 14g (6 mg, 21% yield) as a yellow solid. LC-MS (Method 4) t R =4.32min,m / z(m+H) + =727.5.

[0984] Step 7 4-(3,8-diazoheterocyclo[3.2.1]octan-3-yl)-7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy)-6,7-dihydropyrido[3,4-d]pyrimidine-8(5H)-1(14)

[0985] Take 14g (6mg, 0.008mmol) of 4N HCl / dioxane (0.5mL) solution, stir at 20℃ for 2 hours, then evaporate the reaction solution in vacuo to obtain a residue, which is purified by Prep-HPLC (Method E) to obtain compound 14 (2.5mg, yield 44%) as a white solid. LC-MS (Method IV) t R =2.79min,m / z(m+H) + =583.3. 1 H NMR (400MHz, CD3OD) δ6.86(s,1H), 6.67(s,1H), 5.58-5.44(m,1H), 4.54-4.44(m,2H), 4.22(s,2H), 3.92-3.65(m,8H), 3.48-3.36(m,1H) ), 3.24-3.14(m,2H), 2.74-2.52(m,2H), 2.48-2.26(m,3H), 2.23-2.00(m,6H), 1.72-1.54(m,2H), 1.02-0.85(m,2H), 0.59-0.42(m,2H).

[0986] Embodiment 15

[0987]

[0988] The first step: (3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)boronic acid (15a)

[0989] To a solution of triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (2.0 g, 4.04 mmol) in CHCl3 / MeOH (1 / 1, 50 ml) at room temperature, 2-(2-hydroxyethylamino)ethanol (4.68 g, 44.49 mmol) was added. The reaction solution was then stirred at 70°C for 48 hours. The reaction solution was diluted with water (100 mL), extracted with DCM (50 mL×3), washed with brine (50 mL), dried over Na2SO4, concentrated and purified by flash chromatography (PE / EA from 20 / 1 to 3 / 1) to give compound 15a (1.45 g, yield 87%) as an off-white solid. LCMS (Method 5)t R =5.79min,m / z(M+H) + =413.2. 1 H NMR (400MHz, CDCl3) δ7.73(d,J=8.4Hz,1H),7.67(d,J=7.2Hz,1H),7.41-7.37(m,3H),5.29(s,2H),4.52(s,2H),3.51(s,3H),1.26-1.18(m,21H).

[0990] Step 2: Tert-butyl 3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl))naphthalen-1-yl)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (15b)

[0991] A mixture of 14c (20 mg, 0.039 mmol), 15a (32 mg, 0.078 mmol), Cu2(TMEDA)2(OH)2Cl2 (9 mg, 0.019 mmol) in DCM (1 mL) was stirred at 25°C under an oxygen atmosphere for 72 hours. The reaction solution was diluted with H2O (10 mL), extracted with DCM (10 mL×3), washed with brine (15 mL), dried over Na2SO4, and concentrated to give a crude compound 15b (15 mg, 44% yield) as a yellow solid. LCMS (Method 5) R =5.03min,m / z(M+H) + =883.7.

[0992] Step 3: Tert-butyl 3-(7-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (15c)

[0993] To a solution of 15b (15 mg, 0.017 mmol) in THF (0.5 mL) was added TBAF (0.017 mL, 0.017 mmol, 1 M in THF) at room temperature. The reaction solution was then stirred at room temperature for 30 minutes. The reaction solution was diluted with water (10 mL), extracted with EtOAc (10 mL×3), washed with brine (10 mL), dried over Na2SO4, concentrated and purified by preparative HPLC (Method F) to give compound 15c (6 mg, 49% yield) as a yellow solid. LCMS (Method 4)t R =4.16min,m / z(M+H) + =727.5.

[0994] Step 4: 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one (15A and 15B)

[0995] To a solution of 15c (4 mg, 0.005 mmol) in ACN (0.5 mL) was added HCl / dioxane (4 M, 0.5 mL) at 0 ° C, and the reaction solution was stirred at 10 ° C for 1 hour. The reaction solution was concentrated in vacuo. The residue was diluted with DMF (1 mL) and the pH was adjusted to 8 with saturated NaHCO3 aqueous solution. The reaction solution was filtered and concentrated. The residue was purified by preparative HPLC (method F) to give compounds 15A (0.3 mg, 9% yield) and 15B (1.2 mg, 37% yield), all of which were off-white solids.

[0996] 15A: 1H NMR (400MHz, CD3OD) δ7.78(d,J=8.4Hz,1H),7.55(d,J=6.8Hz,1H),7.38(t,J=7.2Hz,1H),7.26(d,J=2.4Hz,1H) ,7.21(d,J=2.4Hz,1H),5.46-5.33(m,1H),4.55-4.52(m,2H),4.47-4.43(m,1H),4.38-4.34(m,1H),4.23-4.17 (m,1H),4.09-4.03(m,1H),3.96-3.93(m,3H),3.79-3.76(m,1H),3.73-3.59(m,3H),3.56(s,1H),3.53-3.51(m ,1H),3.36-3.32(1H),3.22-3.19(m,1H),2.48-2.31(m,3H),2.25-2.17(m,3H),2.08-1.95(m,4H).LCMS(Method 4)t R =2.67min,m / z(M+H) + =583.4.

[0997] According to the co-crystal of k-Ras-G12D and a similar compound (PDB: 7RPZ) in J. Med. Chem. 2022, 65, 3123-3133, the active isomer was identified as 15A.

[0998] 15B: 1 H NMR (400MHz, CD3OD) δ7.79(d,J=8.4Hz,1H),7.56(d,J=6.8Hz,1H),7.39(t,J=7.2Hz,1H),7.26(d,J=2 .4Hz,1H),7.21(d,J=2.4Hz,1H),5.44-5.30(m,1H),4.49-4.42(m,2H),4.39-4.36(m,1H),4.21-4.17 (m,1H),4.12-4.09(m,1H),3.97-3.92(m,4H),3.80-3.68(m,2H),3.61(s,1H),3.59-3.55(m,3H),3.4 2-3.39(1H),3.25-3.24(m,1H),2.48-2.40(m,1H),2.21-2.17(m,4H),2.06-1.97(m,5H).LCMS(Method 4)t R =2.71min,m / z(M+H) + =583.4.

[0999] Example 16

[1000]

[1001] The first step: 2-(4,5-dibromonaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (16b)

[1002] The reaction mixture of 16a (2.0 g, 6.99 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (229 mg, 0.35 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (113 mg, 0.42 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborane (2.69 g, 20.98 mmol) in THF (30 mL) was stirred at 60° C. under N2 atmosphere for 16 hours. The reaction mixture was concentrated in vacuo to give the crude product 16b (3.0 g, 7.28 mmol, yield is given) as a brown oil.

[1003] Step 2: 4,5-Dibromonaphthalene-2-ol (16c)

[1004] To a solution of 16b (2.88 g, 6.99 mmol) in water (30 mL) and THF (30 mL) was added AcOH (30 mL) and hydrogen peroxide (4.76 g, 139.83 mmol, 4.32 mL) at 10 ° C. The reaction solution was then stirred at 10 ° C for 1 hour. The reaction solution was quenched with saturated NaHSO3 solution (40 mL) and extracted with EtOAc (40 mL), washed with brine (40 mL), dried over Na2SO4, concentrated and purified by flash chromatography (PE / EA from 10 / 1 to 3 / 1) to give compound 16c (800 mg, yield 38%) as an off-white solid. LCMS (Method 4)t R =2.44min,m / z(MH) - =298.8.

[1005] Step 3: 1,8-dibromo-3-(methoxymethoxy)naphthalene (16d)

[1006] To a solution of 16c (800 mg, 2.65 mmol) in DCM (10 mL) was added DIEA (1.03 g, 7.95 mmol) and bromo(methoxy)methane (497 mg, 3.97 mmol) at 0°C. The reaction solution was then stirred at 10°C for 30 minutes. The reaction solution was diluted with water (30 mL), extracted with DCM (30 mL x 3), washed with brine (30 mL) and concentrated to give the crude product 16d (800 mg, 87% yield) as a light yellow solid.

[1007] Step 4: 8-Bromo-6-(methoxymethoxy)-1-naphthalenecarbonitrile (16e)

[1008] CuCN (52 mg, 0.57 mmol) was added to a solution of 16d (200 mg, 0.57 mmol) in DMF (7 mL). The reaction solution was stirred at 100 ° C. under microwave for 30 minutes. The reaction solution was filtered and purified by preparative HPLC (method E) to give compound 16e (50 mg, 30% yield) and white solid 8-bromo-3-(methoxymethoxy)naphthalene-1-carbonitrile (55 mg, 33% yield). 1 HNMR (400MHz, CDCl3) δ7.96-7.91(m,2H),7.69(d,J=2.4Hz,1H),7.47(t,J=7.2Hz,1H),7.42(d,J=2.4Hz,1H),5.28(s,2H),3.50(s,3H).LCMS(Method 4)t R =4.41min,m / z(M+H) + =292.0.

[1009] Step 5: Tert-butyl 3-(7-(8-cyano-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (16f)

[1010] A mixture of 14c (20 mg, 0.039 mmol), 16e (23 mg, 0.04 mmol), Cs2CO3 (32 mg, 0.09 mmol) and XantPhos Pd G3 (7 mg, 0.008 mmol) in dioxane (0.5 mL) was stirred at 110° C. under nitrogen atmosphere for 24 hours. The reaction solution was diluted with water (10 mL), extracted with EA (10 mL×3), washed with brine (15 mL), dried over Na2SO4 and concentrated to give crude compound 16f (18 mg, 64% yield) as a yellow solid. LCMS (Method 4) R =3.95min,m / z(M+H) + =728.5.

[1011] Step 6: 8-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-6-hydroxy-1-naphthalenecarbonitrile (16)

[1012] To a solution of 16f (15 mg, 0.021 mmol) in ACN (0.5 mL) was added HCl / dioxane (4 M, 0.5 mL), and the reaction was stirred at room temperature for 2 h. The reaction was concentrated and purified by preparative HPLC (Method F) to afford compound 16 (4.0 mg, 33% yield) as a light yellow solid. 1 HNMR (400MHz, CD3OD) δ8.08(d,J=8.4Hz,1H),7.83(d,J=6.8Hz,1H),7.54(t,J=6.8Hz,1H),7.34- 7.32(m,2H),5.45-5.33(m,1H),4.56-4.52(m,1H),4.47-4.43(m,1H),4.29-4.25(m,1H),4.13-4. 03(m,2H),4.00-3.99(m,1H),3.95-3.71(m,2H),3.70-3.39(m,6H),3.28-3.24(m,1H),3.13-3.09 (m,1H),2.47-2.41(m,2H),2.36-2.33(m,1H),2.24-2.15(m,3H),2.02-1.99(m,4H).LCMS(Method 4)t R =2.44min,m / z(M+H) + =584.4.

[1013] Embodiment 17

[1014]

[1015] Step 1 Tert-butyl 3-(7-(5-chloro-6-methyl-1-(tetrahydro-2h-pyran-2-yl)-1-indazol-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1h-pyrrolin-7a(5H)-yl)methoxy-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate (17b))

[1016] A mixture of 14c (20 mg, 0.039 mmol), 17a (26 mg, 0.077 mmol), Cs2CO3 (25 mg, 0.077 mmol) and XantPhos Pd G3 (4 mg, 0.004 mmol) in dioxane (1 mL) was stirred at 110°C overnight. The mixture was filtered through a celestite pad and purified by Prep-TLC (DCM / MeOH=15 / 1) to give compound 17b (30 mg, yield given) as a light yellow solid. LC-MS (Method 4) t=4.09 R min,m / z(m+H)=765.5 + .

[1017] Step 2 4-(3,8-diazoheterocyclo[3.2.1]octan-3-yl)-7-(5-chloro-6-methyl-1h-indazol-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1h-pyridin-7a(5H)-yl)methoxy)-6,7-dihydropyrido[3,4-d]pyrimidine-8(5H)-monocarboxylic acid (17A and 17B)

[1018] A solution of 17b (30 mg, 0.039 mmol) in ACN (0.5 mL) was added to hydrochloric acid (0.5 mL, 4 M dioxane) in an ice bath and then stirred at room temperature for 2 hours. The mixture was concentrated and purified by preparative HPLC (Method F) to obtain compounds 17A (5.6 mg, 25% yield) and 17B (6.0 mg, 26%), both of which were light yellow solids.

[1019] 17A: LC-MS (Method 4) R =2.54min,m / z(m+H) + =581.4. 1 H NMR (400MHz, DMSO-d6) δ8.07(s,1H), 7.59(s,1H), 5.36-5.22(m,1H), 4.07-3.94(m,5H), 3.83-3.81(m,2H), 3.7 5-3.71(m,2H), 3.37-3.32(m,2H), 3.14-3.03(m,6H), 2.88-2.84(m,1H), 2.14-2.06(m,2H), 2.00-1.78(m,9H).

[1020] 17B: LC-MS (Method 4) R =2.57min,m / z(m+H) + =581.4. 1H NMR (400MHz, DMSO-d6) δ8.07(s,1H), 7.59(s,1H), 5.35-5.21(m,1H), 4.04-3.96(m,5H), 3.82-3.80(m,2H), 3.76-3.70(m ,2H), 3.376-3.32(m,2H), 3.15-3.03(m,6H), 2.84-2.82(m,1H), 2.13-2.05(m,2H), 2.04-1.98(m,1H), 1.86-1.74(m,8H).

[1021] Embodiment 18

[1022]

[1023] Step 1: 2-(3-Bromo-5-chloro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18b)

[1024] To a solution of 18a (5.00 g, 19.3 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.93 g, 38.5 mmol) in THF (60 mL) was added dtbbpy (621 mg, 2.31 mmol) and [Ir(OMe)(cod)]2 (1.28 g, 1.93 mmol) under nitrogen atmosphere, and the reaction was stirred at 60 ° C for 2 hours. The reaction was concentrated to give compound 18b (12.2 g, crude), which was used in the next step without further purification. LC-MS (Method 4)t R =3.52min,m / z(M+H) + =385.0.

[1025] Step 2 3-Bromo-5-chloro-4-(trifluoromethyl)phenol (18c)

[1026] To a solution of 18b (12.0 g, 31.1 mmol) in THF (100 mL) and water (50 mL) was added AcOH (74.8 g, 1250 mmol) and H2O2 (70.6 g, 623 mmol, 30% purity in water) at 10°C. The reaction solution was stirred at 10°C for 2 hours. Water (200 mL) and EtOAc (200 mL) were added to the reaction solution. The organic layer was separated, washed with saturated Na2S2O3 solution (200 mL×2), then washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by silica gel flash chromatography (PE / EA from 10 / 1 to 1 / 4) to obtain compound 18c (5.10 g, two-step yield 82%). LC-MS (Method 4)tR =2.86min,m / z(M+H) + =275.0.

[1027] Step 3: 1-Bromo-3-chloro-5-(methoxymethoxy)-2-(trifluoromethyl)benzene (18d)

[1028] To a solution of 18c (500 mg, 1.83 mmol) in DCM (10 mL) at 25°C was added TEA (369 mg, 3.66 mmol) and bromo(methoxy)methane (226 mg, 1.83 mmol). The reaction was stirred at 25°C for 2 hours, concentrated and purified by silica gel flash chromatography (PE / EA from 10 / 1 to 1 / 3) to give compound 18d (400 mg, 68% yield) as a yellow solid. LC-MS (Method 4) R =4.45min,m / z(M+H) + =319.0.

[1029] Step 4: Tert-butyl 3-(7-(3-chloro-5-(methoxymethoxy)-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (18e)

[1030] Xantphos Pd G3 (8 mg, 0.009 mmol) and Cs2CO3 (58.0 mg, 0.18 mmol) were added to a solution of 18d (60 mg, 0.18 mmol) and 14c (49 mg, 0.09 mmol) in dioxane (1 mL) at 25 °C. The reaction solution was stirred at 100 °C under a nitrogen atmosphere for 15 hours. The reaction solution was diluted with water (10 mL), extracted with EA (20 mL×3), washed with brine (20 mL), dried over Na2SO4, concentrated and purified by silica gel flash chromatography (DCM / MeOH from 100 / 1 to 10 / 1) to give compound 18e (21 mg, 16% yield) as a yellow solid. LC-MS (Method 4)t R =3.54min,m / z(M+H) + =755.3.

[1031] Step 5: 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one (18)

[1032] A solution of 18e (21 mg, 0.28 mmol) in HCl / dioxane (2 mL, 4 M) was stirred at 25 °C for 2 h. The reaction solution was concentrated and purified by preparative HPLC (Method E) to give compound 18 (2.5 mg, 15% yield) as an off-white solid. LC-MS (Method 4) R =2.83min,m / z(M+H) + =611.3. 1 H NMR(400MHz,CD3OD)δ7.10(s,1H),6.87(s,1H),5.69-5.51(m,1H),4.85-4.41(m,4H),4.28 -4.18(m,2H),4.07-3.70(m,8H),3.46-3.37(m,1H),3.29-3.19(m,1H),2.81-2.20(m,10H).

[1033] Embodiment 19

[1034]

[1035] Step 1 4-Bromo-5-chloro-1-1-difluoronaphthalen-2(1h)——(b)19

[1036] 19a (508 mg, 1.97 mmol) and selected flour (1.388 g, 3.92 mmol) were added to MeCN (8 mL), stirred at room temperature for 2 hours, quenched with water (10 mL), and extracted with EA (15 mL*3). The combined organic layers were washed with brine (15 mL), dried over anhydrous NaS2O, and concentrated under vacuum to give the crude product 19b (438 mg, yield 76%) as a brown oil. LC-MS (Method 4) t = 3.69 R min,m / z(m+H)=292.9 + .

[1037] Step 2 4-Bromo-5-chloro-1-fluoronaphthalen-2-ol(c)19

[1038] Under nitrogen atmosphere, a solution of 19b (438 mg, 1.49 mmol) in toluene (2.5 mL) was added dropwise to a solution of NaS2O2 (4859 mg, 4.93 mmol) in HO2 (4 mL) and i-PrOH (4 mL). The resulting reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated in vacuo to obtain a residue, which was purified by flash chromatography on silica gel (PE / EA=5 / 1) to obtain compound 19c (276 mg, yield 67%) as a red solid. LC-MS (Method 4) t=5. R 41min, m / z(m+H)=27 + 4.9.

[1039] Step 3 (4-Bromo-5-chloro-1-fluoro-2)-methoxymethoxynaphthalene (d) 19

[1040] 19c (276 mg, 1.00 mmol) and DIEA (0.25 mL, 1.43 mmol) were mixed in DCM (8 mL), bromo(methoxy)methane (112 mg, 0.89 mmol) was added, and the mixture was stirred at room temperature for 2 h. Then the solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel (PE / EA=5 / 1) to give compound 19d (233 mg, 73% yield) as a red solid. 1 . h NMR (400MHz, CDCl3) δ 8.05-8.01 (m, 1H), 7.87 (d, J = 8.0Hz, 1H), 7.60-7.57 (m, 1H), 7.42-7.36 (m, 1H), 5.29 (s), 2H), 3.56 (s, 3H).

[1041] Step 4 Tert-butyl 3-(7-(8-chloro-4-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)yl)methoxy-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate (19e)

[1042] XantPhos Pd G3 (4 mg, 0.004 mmol) and CsCO2 (253 mg, 0.077 mmol) were added and 19d (20 mg, 0.064 mmol) and 14c (20 mg, 0.039 mmol) were stirred in anhydrous 1,4-dioxane (1 mL). The resulting mixture was stirred at 110 °C for 16 h under nitrogen atmosphere. After cooling to rt, the mixture was filtered and the filtrate was concentrated in vacuo to give the crude product 19e (10 mg, yield 34%) as palm oil. LC-MS (Method 4) t = 3.R 87min, m / z(m+H)=75 + 5.4.

[1043] Step 5 4-(3,8-diazacyclo[3.2.1]octan-3-yl)-7-(8-chloro-4-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy)-6,7-dihydropyrido[3,4-d]pyrimidine-8(5H)-1(19)

[1044] A solution of 19e (10 mg, 0.013 mmol) in MeOH (1 ml) and concentrated hydrochloric acid (0.05 mL) were stirred at 65°C for 16 h. After cooling to room temperature, the reaction solution was concentrated and the residue was purified by preparative HPLC (E method) to obtain compound 19 (4.6 mg, yield 57%) as a white solid. LC-MS (Method 4) t R =3.56min,m / z(m+H) + =611.3. 1 H NMR (400MHz, CD3OD) δ8.52 (s, 1H), 7.98 (s, 1H), 7.44 (d, J = 4.8Hz, 2H), 7.34 (s, 1H), 5.43-5.30 (m, 1H), 4.44-4.34 (m, 2H), 4.26-4.23 ( m,1H), 4.06-4.02(m,2H), 3.91(s,3H), 3.56-3.45(m,4H), 3.23-3.17(m,2H), 2.44-2.35(m,2H), 2.23-2.14(m,4H), 1.99-1.96(m,6H).

[1045] Embodiment 20

[1046]

[1047] Step 1: tert-butyl 4-(8-(tert-butylcarbonyl)-3,8-diazo[3.2.1]octan-3-yl)-2-chloro-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (20a)

[1048] To a solution of 7b (500 mg, 1.57 mmol) in DCM (10 mL) was added tert-butyl 3,8-diazo[3.2.1]octane-8-carboxylate (334 mg, 1.57 mmol) and DIEA (405 mg, 3.14 mmol). The reaction mixture was stirred at room temperature for 2 h, concentrated and flash chromatographed on silica gel (PE / EA ratio of 10 / 1 to 1 / 1) to give compound 20a (500 mg, yield 65%) as a yellow solid. LC-MS (Method IV) t = 4.15 R min,m / z(m+H)=494.3 + .

[1049] Step 2: tert-Butyl 3-(2-(1-(tert-butylcarbonyl)-4-methylpiperidin-4-yl)methoxy-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazo[3.2.1]octane-8-carboxylate (20b)

[1050] To a solution of 20a (205 mg, 0.41 mmol) and tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (124 mg, 0.54 mmol) was added in anhydrous 1,4-dioxane (20 mL), t-BuONa (80 mg, 0.83 mmol) was added, and the reaction mixture was stirred at 140°C for 3 h. After cooling to rt, the solid was filtered and the filtrate was concentrated to obtain a residue, which was purified by preparative HPLC (C18 column, MeCN / HO (0.5% 2NH4HCO3), 5％-35％ , 30min) to obtain compound 20a (43mg, yield 18%) as a white solid. LC-MS (Method 4) t = 4.04min, m + R / z(m+H)=587.5.

[1051] Step 3 Tert-butyl 3-(7-(8-bromo-3-(methoxymethoxy)naphthalen-1-yl)-2-((1-(tert-butyloxy)-4-methylpiperidin-4-yl)methoxy-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate (20c)

[1052] XantPhos Pd G3 (6.5 mg, 0.0068 mmol) and CsCO2 (483 mg, 0.15 mmol) were added to a stirred solution of 20b (43 mg, 0.073 mmol) and 16d (51 mg, 0.15 mmol) in anhydrous 1,4-dioxane (2 mL). The resulting mixture was stirred at 110 ° C for 16 h under a nitrogen atmosphere. After cooling to rt, the mixture was filtered and the filtrate was concentrated in vacuo to obtain compound 20c (30 mg, yield 48%) as a brown solid. LC-MS (Method 5) t = 6.50 min + R ,m / z(m+H)=851.5.

[1053] Step 4 4-(3,8-diazacyclo[3.2.1]octan-3-yl)-7-(8-bromo-3-hydroxynaphthalen-1-yl)-2-((4-methylpiperidin-4-yl)methoxy)-6,7-dihydropyrido[3,4-d]pyrimidine-8(5H)-1(20d)

[1054] A solution of 20c (30 mg, 0.035 mmol) in MeOH (1 ml) and concentrated hydrochloric acid (0.05 mL) were stirred at 65°C for 16 h. After cooling to room temperature, the reaction solution was concentrated and the residue was purified by preparative HPLC (E method) to obtain compound 20d (6.5 mg, yield 31%) as a white solid. LC-MS (Method 4) t R =2.29min,m / z(m+H) + =607.3.

[1055] Step 5 4-(3,8-diazacyclo[3.2.1]octan-3-yl)-7-(3-hydroxy-8-(triisopropylsilyl)ethyl)naphthalen-1-yl)-2-((4-methylpiperidin-4-yl)methoxy)-6,7-dihydropyrido[3,4-d]pyrimidine-8(5H)-1(20e)

[1056] 20d (6.5 mg, 0.01 mmol) and ethyltriisopropylsilane (39.0 mg, 0.21 mmol) solution were added to anhydrous DMA (1 mL), CuI (1.0 mg, 0.052 mmol), Pd(PPh3)2Cl2 (1.2 mg, 0.0017 mmol) and DIEA (0.018 mL, 0.10 mmol) respectively. The resulting mixture was stirred at 100 ° C under nitrogen atmosphere for 5 h, then cooled to room temperature and filtered. The filtrate was purified by preparative high performance liquid chromatography (E method) to obtain compound 20e (3.5 mg, yield 46%) as a white solid. LC-MS (Method 4) t R =3.23min,m / z(m+H)+ =709.5.

[1057] Step 6 4-(3,8-diazacyclo[3.2.1]octan-3-yl)-7-(8-ethyl-3-hydroxynaphthalen-1-yl)-2-((4-methylpiperidin-4-yl)methoxy)-6,7-dihydropyrido[3,4-d]pyrimidine-8(5H)-1(20)

[1058] TBAF (0.02 mL, 0.02 mmol, 1 M in THF) was added to a solution of 20e (3.5 mg, 0.005 mmol) in THF (1 mL) at 0°C, and the mixture was stirred at 0°C for 1 h. The solvent was removed and purified by preparative HPLC (E method) to obtain compound 20 (2.1 mg, 79% yield) as a white solid. LC-MS (Method 4) t R =1.55min,m / z(m+H) + =553.4. 1 H NMR (400MHz, CD3OD) δ7.78 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 4.31-4.15 (m, 4H), 4.40 -3.86(m,5H), 3.56(s,1H), 3.53-3.48(m,1H), 3.38-3.32(m,3H), 3.22-3.16(m,3H), 2.14-1.93(m,6H), 1.66-1.63(m,2H), 1.18(s,3H).

[1059] Embodiment 21

[1060]

[1061] Step 1 7-Bromo-2-chloro-4-((3s,5s)3,5-dimethylpiperazin-1-yl)8-fluoroquinoline-3-carbonitrile(21)

[1062] (2S,6S)-2,6-dimethylpiperazine (140 mg, 0.75 mmol) was added to a mixture of 1d (200 mg, 0.63 mmol) and DIEA (404 mg, 3.13 mmol) in DCM (2 mL) at 0°C. The reaction was stirred at room temperature for 3 hours. The solid formed was filtered, washed with DCM (5 mL) and dried under vacuum to give 21a (184 mg, 74% yield) as a yellow solid. LC-MS (Method 3) t = 1.11R min,m / z(m+H)=397.1 + .

[1063] Step 2 7-Bromo-4-((3S,5S)-3,5-dimethylpiperazin-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxyquinoline-3-carbonitrile (21b)

[1064] LiHMDS (5.55 mL, 5.55 mmol, 1 M in THF) was added to a solution of 21a (184 mg, 0.46 mmol) and ((2R,7aS)-2-fluorotetrahydro-1h-pyrrolizin-7a(5H)-yl)methanol (110 mg, 0.69 mmol) in anhydrous THF (1 mL) at 0°C. The reaction was stirred at 30°C for 64 h. After cooling to room temperature, the reaction mixture was diluted with ice water (5 mL) and extracted with DCM (10 mL*2). The combined organic layers were concentrated and purified by flash chromatography on silica gel (DCM / MeOH=20 / 1) to give 21b (90 mg, 37% yield) as a brown solid. HNMR ( 1 400MHz, DMSO-d6) δ7.73(d,J=9.2Hz,1H), 7.65(dd,J=9.2,6.4Hz,1H), 5.31(m,0.5H), 4.24-4.09(m,2H), 3.75(m,2H), 3.40-3.3 6(m,2H), 3.18-3.09(m,4H), 3.07-3.02(m,1H), 2.84-2.83(m,1H), 2.19-1.98(m,4H), 1.86-1.79(m,3H), 1.07(d,J=6.4Hz,6H).

[1065] Step 3 4-((3S,5S)-3,5-dimethylpiperazin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)yl)methoxy)quinoline-3-carbonitrile (21c)

[1066] 21b (50 mg, 0.096 mmol), (2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboronic acid-2-yl)naphthalen-1-yl)ethyl)triisopropylsilane (59 mg, 0.16 mmol), cataCXium(R)APd G3 (14 mg, 0.019 mmol) and K3PO4 (41 mg, 0.19 mmol) were stirred in THF (0.5 mL) and HO2 (0.1 mL) at 60 ° C in a sealed tube without air for 20 h. The reaction mixture was cooled, concentrated, and purified by flash chromatography on silica gel (DCM / MeOH=20 / 1) to give 21c (60 mg, yield 76%) as a brown solid. LC-MS (Method 3) t=0.77 min, m / z (m+H) + =826.8.

[1067] Step 4 4-((3S,5S)-3,5-dimethylpiperazin-1-yl)-8-fluoro-7-(7-fluoro-3-hydroxy-8-(triisopropylsilyl)ethyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)yl)methoxy)quinoline-3-carbonitrile hydrochloride (21d)

[1068] A solution of 21c (60 mg, 0.072 mmol) in HCl / EtOAc (1.5 mL, 2 M) was stirred at room temperature for 0.5 h. The reaction mixture was concentrated to 21d (58 mg, yield given) as an off-white solid. LC-MS (Method 3) t R =0.67min,m / z(m+H) + =782.1.

[1069] Step 5 4-((3S,5S)-3,5-dimethylpiperazin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy)quinoline-3-carbonitrile (21)

[1070] A solution of 21d (58 mg, 0.074 mmol) and CsF (135 mg, 0.89 mmol) was added to DMF (1 mL) and stirred at 40 °C for 4 hours. The reaction mixture was filtered and the filtrate was purified by prepare-hplc (Method A) to give 21 (25 mg, 54% yield) as a yellow solid. LC-MS (Method 1) t R =3.44min,m / z(m+H) + =626. 11H NMR (400MHz, DMSO-d6) δ10.12 (s, 1H), 7.96 (dd, J = 8.8, 5.6Hz, 1H), 7.83-7.7 8(m,1H), 7.48-7.43(m,2H), 7.09-7.07(m,1H), 5.37(s,0.5H), 5.24(s,0.5H) , 4.23-4.07(m,2H), 3.88-3.76(m,3H), 3.43-3.40(m,2H), 3.27-2.98(m,6H) , 2.86-2.80(m,3H), 2.24-2.00(m,3H), 1.85-1.79(m,3H), 1.14-1.11(m,6H).

[1071] Embodiment 22

[1072]

[1073] The first step (R)-4-(7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (22a)

[1074] To a solution of 1d (150 mg, 0.47 mmol) in DCM (2 mL) at 0°C, DIEA (182 mg, 1.41 mmol) and (R)-tert-butyl 3-methylpiperazine-1-carboxylate (113 mg, 0.56 mmol) were added. After stirring at 30°C for 12 hours, the reaction solution was concentrated. The residue was purified by flash chromatography on silica gel (PE / EA=3 / 1) to give 22a (350 mg, 89% yield) as a yellow solid. LC-MS (Method 3) R =1.79min,m / z(M+H) + =483.0.

[1075] Step 2 Tert-butyl (R)-4-(7-bromo-3-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinolin-4-yl)-3-methylpiperazine-1-carboxylate (22b)

[1076] To a solution of 22a (100 mg, 0.21 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (50 mg, 0.32 mmol) in anhydrous THF (1 mL) was added LiHMDS (1.2 mL, 1.2 mmol, 1 M in THF) at 0°C. After stirring at 30°C overnight, the reaction solution was concentrated and the residue was purified by silica gel flash chromatography (PE / EA=2 / 1) to give 22b (115 mg, 91% yield) as a yellow oil. LC-MS (Method 3) R =2.00min,m / z(M+H) + =606.2.

[1077] Step 3 (R)-tert-butyl 4-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)quinolin-4-yl)-3-methylpiperazine-1-carboxylate (22c)

[1078] To a solution of 22b (50 mg, 0.82 mmol), cataCXium(R)APd G3 (12 mg, 0.016 mmol) and K3PO4 (53 mg, 0.25 mmol) in THF / water (5 / 1, 0.6 mL) was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (63 mg, 0.12 mmol) under nitrogen atmosphere. After stirring at 60° C. for 3 hours under nitrogen atmosphere, the reaction solution was concentrated and the residue was purified by silica gel flash chromatography (PE / EA=2 / 1) to give 22c (60 mg, 80% yield) as a yellow oil. LC-MS (Method 3) R =1.20min,m / z(M+H) + =912.8.

[1079] Step 4: 8-Fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-4-((R)-2-methylpiperazin-1-yl)quinoline-3-carbonitrile hydrochloride (22d)

[1080] To a solution of 22c (60 mg, 0.07 mmol) in EtOAc (1 mL) was added HCl / EtOAc (1 mL, 2 M) at 0°C. The reaction was stirred at room temperature for 1 hour. The solid was filtered and dried to afford 22d (45 mg, 85% yield) as a yellow solid. LC-MS (Method 3) R =1.21min,m / z(M+H) + =768.3.

[1081] Step 5: 7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((R)-2-methylpiperazin-1-yl)quinoline-3-carbonitrile (22)

[1082] A mixture of 22d (45 mg, 0.056 mmol) and CsF (58 mg, 0.88 mmol) in DMF (0.5 mL) was stirred at 40 °C for 3 h. The reaction solution was filtered and the filtrate was purified by preparative HPLC (Method A) to give 22 (18 mg, 53% yield) as a yellow solid. LC-MS (Method 2) R =2.89min,3.12min,m / z(M+H) + =612.3. 1 H NMR(400MHz,DMSO-d6)δ10.12(s,1H),7.97(dd,J=9.2,6.0Hz,1H),7.90-7.86(m,1H),7 .48-7.44(m,1H),7.42-7.37(m,2H),7.09(dd,J=8.4,2.4Hz,1H),5.38(s,0.5H),5.26( s,0.5H),4.21-4.17(m,2H),4.08-4.06(m,1H),3.82-3.75(m,2H),3.11-3.10(m,5H),2 .92-2.73(m,4H),2.21-2.12(m,1H),2.08-2.02(m,3H),1.84(s,3H),1.24-1.16(m,3H).

[1083] Embodiment 23

[1084]

[1085] Step 1 Tert-butyl (S)-4-(7-(8-bromo-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2-(cyanoethyl)piperazine-1-carboxylate (23a)

[1086] XantPhos Pd G3 (6.5 mg, 0.0068 mmol) and CsCO2 (303 mg, 0.092 mmol) were added and 9b (23 mg, 0.043 mmol) and 16d (33 mg, 0.095 mmol) were stirred in anhydrous 1,4-dioxane (1 mL) solution. The resulting mixture was stirred at 110 °C under nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo to obtain a residue, which was purified by prepare-hplc (method E) to obtain compound 23a (7 mg, yield 21%) as a white solid. LC-MS (method IV) t = 4.17 min, m R + / z(m+H)=794.3.

[1087] Step 2 2-((S)-4-(7-(8-bromo-3-hydroxynaphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolin-7a(5H)-yl)methoxy-8-oxo-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (23b)

[1088] A solution of 23a (7 mg, 0.009 mmol) in MeOH (1 ml) and conc. HCl (0.05 mL) was stirred at 65 °C for 16 h. After cooling to room temperature, the reaction solution was concentrated and the residue was purified by preparative HPLC (E method) to give compound 23b (4 mg, yield 70%) as a white solid. LC-MS (Method 4) t R =1.14min,m / z(m+H) + =650.2.

[1089] Step 3: (2)-(4-(2-(((2r,7)2-fluorotetrahydro-1h-pyrrolizin-7a(5h)-yl)methoxy)7-(3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (23c)

[1090] 23b (2.4 mg, 0.004 mmol) and acetylene triisopropylsilane (6.7 mg, 0.037 mmol) solution were added to anhydrous DMA (1 mL), CuI (1.0 mg, 0.0052 mmol), Pd(PPh3)2Cl2 (1.2 mg, 0.0017 mmol) and DIEA (0.007 mL, 0.04 mmol) respectively. The resulting mixture was stirred at 100 ° C under nitrogen atmosphere for 5 h, then cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by preparative HPLC by E method to obtain a mixture compound 23c (2 mg, yield 72%) as a white solid. LC-MS (Method 4) t R =3.50min,m / z(m+H) + =752.5.

[1091] Step 4 2-((S)-4-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1h-pyrrolin-7a(5H)-yl)methoxy)-8-oxo-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (23)

[1092] TBAF (0.004 mL, 1 M in THF, 0.004 mmol) was added to a solution of 23c (2.0 mg, 0.0026 mmol) in THF (1 mL) at 0°C, and the reaction was stirred at 0°C for 1 h, then the solvent was removed and purified by preparative HPLC (Method F) to obtain compound 23 (1.3 mg, 82% yield) as a white solid. NMR (400 MHz, CDCl3) R δ7.65 (d, J=8.0 Hz, 1H) + , 7.39(d,J=7.2Hz,1H), 7.28(t,J=7.2Hz,1H), 7.19(d,J=2.4Hz,1H), 7.07( d,J=2.4Hz,1H), 5.35-5.22(m,1H), 4.43-4.36(m,1H), 4.14-4.01(m,1H), 3. 1 88-3.79(m,2H), 3.71-3.61(m,3H), 3.43-3.33(m,2H), 3.29-3.13(m,3H), 3.02-2.83 (m,4H), 2.76-2.62(m,2H), 2.53-2.28(m,3H), 2.21-2.07(m,2H), 2.03-1.86(m,3H).

[1093] Embodiment 24

[1094]

[1095] Step 1 (8-Fluoro-3-(methoxymethoxy)naphthalen-1-yl)boronic acid (24b)

[1096] HCOONH4 (114 mg, 1.81 mmol) in HO2 (1.5 mL) was added to a solution of 24a (150 mg, 4.52 mmol) in acetone (1.5 mL), and then NaIO (4390 mg, 1.81 mmol) was added. After isothermal stirring for 16 h, the reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL*3). After the organic layer was concentrated, the residue was purified by flash chromatography on silica gel with PE / EA = 2 / 1 to obtain 24b (62 mg, yield 55%) as a yellow solid. LC-MS (Method 3) t = 1. R 06min,m / z(m+H)=25 + 1.2.

[1097] Step 2: tert-Butyl 2-chloro-4-(3-hydroxy-3-methylpiperidin-1-yl)-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (24c)

[1098] 3-Methylpiperidin-3-ol hydrochloride (500 mg, 3.30 mmol), 7b (1.00 g, 3.14 mmol) and TEA (1.27 g, 12.57 mmol) were mixed in DCM (0.5 mL), stirred at 20 °C for 16 h, concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (PE / EA = 10 / 1) to give 24c (850 mg, yield 68%) as a yellow solid. LC-MS (Method 3) t R =1.06min,m / z(m+H) + =397.0.

[1099] Step 3 2-Chloro-4-(3-hydroxy-3-methylpiperidin-1-yl)-6,7-dihydropyrido[3,4-d]pyrimidine-8(5H)-12,2,2-trifluoroacetate (24d)

[1100] A solution of 24c (550 mg, 1.39 mmol) was added to TFA / DCM (5 mL, v / v = 3 / 1) and stirred at 25°C for 4 hours. The solvent was removed by pumping N2, and the residue was lyophilized with water (10 mL) to give 24d (450 mg, yield 79%) as a yellow solid. LC-MS (Method 3) t R =0.97min,m / z(m+H) + =297.2.

[1101] Step 4 2-((2R,7aS)-2-fluorohexahydro-1h-pyrrolin-7a-yl)methoxy-4-(3-hydroxy-3-methylpiperidin-1-yl)-6,7-dihydropyrido[3,4-d]pyrimidine-8(5H)-1(24e)

[1102] A solution of 24d (400 mg, 1.35 mmol) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrolizin-8-yl]methanol (429 mg, 2.70 mmol) in LiHMDS (4 mL, 1 M in THF) was stirred at 70 °C overnight. After cooling to room temperature, the mixture was quenched with 1 mL of water. Purification by preparative HPLC (Method A) gave 24e (96 mg, yield 17%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.18 (s, 1H), 5.30 (s, 0.5H), 5.19 (s, 0.5H), 4.34 (s, 1H), 3.97 (d, J = 10.0Hz, 1H), 3.87 (d, J = 10.0Hz, 1H) , 3.65-3.62(m,1H), 3.25-2.89(m,7H), 2.76-2.69(m,2H), 2.57-2.50(m,1H), 2.15-1.68(m,8H), 1.63-1.44(m,3H), 1.08(s,3H).

[1103] Step 5 7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2R,7aS)-2-fluorohexahydro-1h-pyrrolidine-7a-yl)methoxy)-4-(3-hydroxy-3-methylpiperidin-1-yl)-6,7-dihydropyrido[3,4-d]pyrimidine-8(5H)-1(24f)

[1104] 24e (85 mg, 0.20 mmol), 24b (56 mg, 0.22 mmol) and Cu2(TMEDA)(OH)2Cl2 (47 mg, 0.10 mmol) were mixed in DCM (0.5 mL) and stirred at room temperature overnight under 0 atmosphere. The mixture was diluted with DCM (6 mL), washed with water (4 mL) and brine (4 mL). The separated organic layer was concentrated and the residue was purified by Prep-TLC (DCM / MeOH=10 / 1) to give 24f (17 mg, yield 13%) as a yellow solid. LC-MS (Method 3) t R =1.58min,m / z(m+H) + =624.4.

[1105] Step 6 7-(8-Fluoro-3-hydroxynaphthalen-1-yl)-2-((2R,7aS)-2-fluorohexahydro-1h-pyrrolin-7a-yl)methoxy)-4-(3-hydroxy-3-methylpiperidin-1-yl)-6,7-dihydropyrido[3,4-d]pyrimidine-8(5H)-1(24)

[1106] At 0°C, hydrochloric acid / EtOAc (3 mL, 2 M) was added to a solution of 24f (15 mg, 0.024 mmol) in EtOAc (1 mL). After stirring at room temperature for 2 h, the reaction mixture was concentrated. Purification by preparative HPLC (Method A) gave compound 24 (4.7 mg, yield 34%) as a white solid. LC-MS (Method 1) t R =2.76min,m / z(m+H) + =5 1 83.HNMR (400MHz, dm6sod) δ10.23 (s, 1H), 7.62 (d, J = 8.0Hz, 1H), 7.42-7.37 (m, 1H), 7.24 (d ,J=2.0Hz,1H), 7.13(d,J=2.0Hz,1H), 7.05-6.99(m,1H), 5.33(s,0.5H), 5.20(s,0.5H), 4. 56-4.49(m,1H), 4.01(d,J=10.0Hz,1H), 3.91(d,J=10.4Hz,1H), 3.72-3.66(m,4H), 3.25-2 .79(m,8H), 2.16-1.95(m,4H), 1.93-1.71(m,3H), 1.63-1.44(m,3H), 1.12(d,J=4.8Hz,3H).

[1107] Embodiment 25

[1108]

[1109] Step 1 6-(8-(tert-butylcarbonyl)-3,8-diazo[3.2.1]octan-3-yl)-5-(2-(tert-butylcarbonyl)amino)ethyl)-2-(2-(1-methyl-1h-imidazol-2-yl)ethoxy)pyrimidine-4-carboxylic acid (25a)

[1110] 2-(1-methyl-1h-imidazol-2-yl)ethylene glycol (192 mg, 2.02 mmol) and t-BuONa (144 mg, 1.5 mmol) were added to the dioxane (9 mL) solution, and the mass of the solution was 20a (500 mg, 1.01 mmol). Stir at 90 ° C for 3 h, dilute with HO (25 mL), extract with EA (20 mL*3), wash with brine (20 mL), dry with NaSO2, concentrate on silica gel (DCM / MeOH from 100 / 1 to 10 / 1) and purify to obtain compound 25a (200 mg, yield 33%) as a white solid. LC-MS (method four) t = 1.89 min, m / z (m+H) + =602.4.

[1111] Step 2 5-(2-aminoethyl)-6-(3,8-diazo[3.2.1]octan-3-yl)-2-(2-(1-methyl-1h-imidazol-2-yl)ethoxy)pyrimidine-4-carboxylic acid (25b)

[1112] Hydrochloric acid / dioxane (2 ml, 4 M) was added to a CH3CN (2 ml) solution at a concentration of 25a (200 mg, 0.33 mmol) at 0°C. The reaction mixture was stirred at 0°C for 6 h and concentrated with aq NaC2Os3 olution to adjust pH>7. The organic layer was then concentrated and flash chromatographed on silica gel (DCM / MeOH from 100 / 1 to 7 / 1) to give compound 25b (110 mg, yield 83%) as a yellow solid. LC-MS (Method 4) t=1.58 R min,m / z(m+H)=402.3 + .

[1113] Step 3 4-(3,8-diazacyclo[3.2.1]octan-3-yl)-2-(2-(1-methyl-1h-imidazol-2-yl)ethoxy)-6,7-dihydropyrido[3,4-d]pyrimidine-8(5H)-1(25c)

[1114] HATU (154 mg, 0.40 mmol) and DIEA (103 mg, 0.8 mmol) of 25b (110 mg, 0.27 mmol) were added to a DMF (1 mL) solution at 25°C. The reaction mixture was stirred at 25°C for 4 h, diluted with HO2 (5 mL), extracted with EA (20 mL*3), washed with brine (20 mL), dried over NaS2O, and concentrated and purified on silica gel (DCM / MeOH from 100 / 1 to 10 / 1) to obtain compound 25c (50 mg, yield 48%) as a yellow solid. LC-MS (Method 4) t=2. R81min, m / z(m+H)=38 + 4.3.

[1115] Step 4 3-(2-(2-(1-methyl-1h-imidazol-2-yl)ethoxy)-8-oxo-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate (25d)

[1116] BocO2 (56 mg, 0.26 mmol) and DIEA (26 mg, 0.26 mmol) were added to a THF (1 mL) solution at a concentration of 25c (50 mg, 0.13 mmol) at 25°C. The reaction mixture was stirred at 25°C for 4 h, diluted with HO2 (5 mL), extracted with EA (20 mL*3), washed with brine (20 mL), dried over NaS2O, and concentrated and purified on silica gel (DCM / MeOH from 100 / 1 to 15 / 1) to give compound 25d (60 mg, yield 95%) as a yellow solid. LC-MS (Method IV) t=3. R 81min, m / z(m+H)=48 + 4.3.

[1117] Step 5 3-(7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-2-(2-(1-methyl-1h-imidazol-2-yl)ethoxy)-8-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazobicyclo[3.2.1]octane-8-carboxylate (25e)

[1118] 1-Bromo-8-chloro-3-(methoxymethoxy)naphthalene (56 mg, 0.18 mmol) was dissolved in dioxane (2 mL), XantPhos Pd G3 (11 mg, 0.012 mmol) and CsCO2 (783 mg, 0.24 mmol) were added at 25°C, and 25d (60 mg, 0.12 mmol) was obtained. The reaction mixture was stirred at 100°C for 15 h under Natmosphere2, diluted with HO (5 mL), extracted with EA (20 mL*3), washed with brine (20 mL), dried over NaSO, concentrated and purified by flash chromatography on silica gel (DCM / MeOH from 100 / 1 to 10 / 1) to give compound 25e (25 mg, 30% yield) as a yellow solid.

[1119] LC-MS (Method 4) R =3.36min,m / z(m+H) + =704.3.

[1120] Step 6 4-(3,8-diazacyclo[3.2.1]octan-3-yl)-7-(8-chloro-3-hydroxynaphthalen-1-yl)-2-(2-(1-methyl-1h-imidazol-2-yl)ethoxy)-6,7-dihydropyrido[3,4-d]pyrimidine-8(5H)-1(25)

[1121] Hydrochloric acid / dioxane (1 mL, 1 mL) was added to a solution of 25e (25 mg, 0.035 mmol) in CH3CN (1 mL) at 0°C. The reaction mixture was stirred at 0°C for 5 h and concentrated and purified by preparative HPLC (Method E) to give compound 25 (3.3 mg, yield 17%) as an off-white solid. LC-MS (Method 4) t R =1.05min,m / z(m+H) + =560.3.

[1122] 1H NMR (400MHz, CD3OD) δ8.50 (s, 1H), 7.72-7.65 (m, 1H), 7.32 (s, 1H), 7.31 (d, J = 4.8 Hz,1H), 7.24(d,J=4.8Hz,1H), 7.17(d,J=4.8Hz,1H), 6.98(s,1H), 6.87(s,1H), 4. 68(t,J=7.6Hz,3H), 4.17(d,J=8.4Hz,1H), 4.05-3.90(m,4H), 3.90-3.80(m,1H), 3 .69(d,J=8.4Hz,1H), 3.46(d,J=8.4Hz,1H), 3.22-3.06(m,5H), 2.10-2.01(m,2H).

[1123] Embodiment 26

[1124]

[1125] Step 1 2-Amino-7-bromo-8-fluoro-4-hydroxyquinoline-3-carbonitrile(26)

[1126] A solution of malononitrile (1.40 g, 21.15 mmol) (810 mg, 21.15 mmol, mineral oil purity 60%) was added to anhydrous DMF (30 mL). After stirring at rt for 30 min, 1b (5 g, 19.23 mmol) was added to the solution. After stirring at 60 °C for 30 min, the reaction mixture was diluted with HO2 (150 mL) and acidified with conc. HCl to pH = 1. The resulting mixture was stirred for 1 h and then filtered. The filtrate was concentrated under reduced pressure to give 26a (4 g, yield 74%) as a white solid. LC-MS (Method 3) t = 0. R 34min, m / z(m+H)=28 + 1.7.

[1127] Step 2 2-Amino-7-bromo-4-chloro-8-fluoroquinoline-3-carbonitrile (b) 26

[1128] A solution of 26a (5 g, 17.73 mmol) in POCl3 (8 mL) was stirred at 110°C for 4 h. The reaction mixture was cooled to room temperature, and the solid was collected by filtration and dried to afford 26b (3.8 g, 71% yield) as an off-white solid. 1 h NMR (400MHz, DMSO-d6) δ9.33(brs,2H), 7.72-7.67(m,1H), 7.51-7.47(m,1H).

[1129] Step 3: tert-Butyl 3-(2-amino-7-bromo-3-cyano-8-fluoroquinolin-4-yl)-2,5-dihydro-1h-pyrrole-1-carboxylate (26c)

[1130] Pd(dppf)Cl2 (1.16 g, 1.60 mmol) was added to 1,4-dioxane / HO2 / NMP (35 mL, v / v / v = 5 / 1 / 1) to obtain a solution of tert-butyl 3-(3,4,4,5,5-tetramethyl-1,3,2-dioxaboronic acid-2-yl)-2,5-dihydropyrrole-1-carboxylate (2.12 g, 7.19 mmol) and NaC2O (3.39 g, 31.95 mmol) of 26b (2.4 g, 7.99 mmol). The reaction was degassed with N2 for 3 times and stirred at 40°C overnight. The suspension was filtered and the filtrate was diluted with ethyl acetate (50 mL) and washed with water (15 mL) and brine (15 mL). After the separated organic layer was concentrated, the residue was purified by flash chromatography on silica gel (DCM / EA=15 / 1) to obtain compound 26c (1.69 g, yield 49%) as a red solid. LC-MS (Method 3) t=1. R80min, m / z(m+H)=43 + 3.1.

[1131] Step 4: tert-Butyl 3-(7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl)-2,5-dihydro-1h-pyrrole-1-carboxylate (26d)

[1132] To a solution of 26c (1.4 g, 3.23 mmol) in ACN (20 mL) was added tert-butyl nitrite (666 mg, 6.46 mmol). After stirring at room temperature for 10 minutes, CuCl (640 mg, 6.46 mmol) was added. The reaction was stirred at room temperature overnight, diluted with water (10 mL) and NHHO3· (24 mL). The mixture was extracted with ethyl acetate (15 mL*3) and the combined organic layers were concentrated. Flash chromatography on silica gel (PE / EA=4 / 1) was used to obtain compound 26d (645 mg, yield 44%) as a white solid. H NMR 1 (400MHz, DMSO-d6) δ8.03-8.01(m,1H), 7.95(d,J=9.2Hz,1H), 6.41-6.35(m,1H), 4.47-4.45(m,2H), 4.39(s,2H), 1.47-1.42(m,9H).

[1133] Step 5 7-Bromo-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolin-7a(5H)-yl)methoxy)-4-(1h-pyrrol-3-yl)quinoline-3-carbonitrile (26e)

[1134] LiHMDS (0.82 mL, 0.82 mmol, 1 M in THF) was added to a solution of 26d (93 mg, 0.21 mmol) and ((2R,7aS)-2-fluorotetrahydro-1h-pyrrolizin-7a(5H)-yl)methanol (49 mg, 0.31 mmol) in anhydrous THF (1.5 mL) at 0 °C. The mixture was then stirred at room temperature overnight and quenched with HO (3 ml2). The resulting mixture was extracted with ethyl acetate (5 mL*2). After the combined organic layers were concentrated, the residue was purified by flash chromatography on silica gel (PE / EA=2 / 1) to give compound 26e (25 mg, yield 26%) as a yellow solid. LC-MS (Method 3) t=1.85 min + R ,m / z(m+H)=473.1.

[1135] Step 6 8-Fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy)-4-(1h-pyrrol-3-yl)quinoline-3-carbonitrile (26f)

[1136] 26e (25 mg, 0.053 mmol), 24a (23 mg, 0.069 mmol), K2CO3 (15 mg, 0.11 mmol) and Pd(dppf)Cl2 (8 mg, 0.010 mmol) were mixed in DMSO / 1,4-dioxane / HO2 (0.5 mL / 0.5 mL / 0.1 mL) and stirred at 100 °C under N2 atmosphere for 2 h. The reaction mixture was diluted with ethyl acetate (8 mL) and rinsed with water (3 mL). The organic layer was concentrated and the residue was purified by flash chromatography on silica gel (DCM / MeOH=20 / 1) to give compound 26f (18 mg, yield 57%) as butter. LC-MS (Method 3) t=1.63 min, m / z (m+H) + =599.5.

[1137] Step 7 8-Fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy)-4-(1h-pyrrol-3-yl)quinoline-3-carbonitrile (26)

[1138] HCl / EtOAc (1 mL, 2 M) was added to a solution of 26f (18 mg, 0.030 mmol) in EtOAc (0.5 mL), and the mixture was stirred for 30 min. The reaction mixture was concentrated and purified by preparative HPLC (method a) to obtain compound 26 (4.4 mg, yield 26%) as a white solid. LC-MS (method 2) t R =3.34min,m / z(m+H) + =555.0. 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H), 8.01(d,J=8.4Hz,1H), 7.66(d,J=8.4Hz,1H), 7.54(t,J=8.0Hz,1H), 7.40(m,2H), 7.09(s,1H), 7.05(d,J=2.0H z,1H), 6.99(m,2H), 6.58(s,1H), 5.40-5.24(m,1H), 4.30-4.21(m,2H), 3. 26-3.04(m,3H), 2.87-2.81(m,1H), 2.23-2.01(m,3H), 1.92-1.83(m,3H).

[1139] Embodiment 27

[1140]

[1141] Step 1: tert-Butyl 3-(2-amino-7-bromo-3-cyano-8-fluoroquinolin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (27a)

[1142] 26b (1.37 g, 4.56 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.13 g, 3.65 mmol), NaC2O (33.38 g, 31.91 mmol) and Pd(dppf)Cl2 (662 mg, 0.91 mmol) were mixed in 1,4-dioxane (15 mL), HO2 (3 mL) and NMP (3 mL) and stirred at 35°C under N2 atmosphere for 18 h. After cooling to room temperature, it was diluted with HO (10 mL) and extracted with EtOAc (25 mL*2). The combined organic layers were concentrated. Flash chromatography on silica gel (DCM / EtOAc=30 / 1) was used to obtain compound 27a (980 mg, yield 48%) as a yellow solid. LC-MS (Method 3) t = 1.66 min, m + R / z(m+H)=447.1.

[1143] Step 2: tert-Butyl 3-(7-bromo-2-chloro-3-cyano-8-fluoroquinolin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (27b)

[1144] A mixture of 27a (1.02 g, 2.28 mmol) and tert-butyl nitrite (353 mg, 3.42 mmol) in CuCl (452 ​​mg, 4.56 mmol) was added to ACN (25 mL). After standing and stirring for 18 h, it was diluted with HO2 (15 mL), and NH. 3H2O (5 mL) was allowed to stand, and extracted with EtOAc (30 mL*2). The combined organic layers were concentrated. Compound 27b (482 mg, yield 45%) was purified by silica gel flash chromatography with PE / EA = 10 / 1 as a yellow solid. LC-MS (Method 3) t = 1. R 88min, m / z(m-56+H)=410. + 0.

[1145] Step 3: tert-Butyl (S)-5-(7-bromo-3-cyano-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)quinolin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (27c)

[1146] LiHMDS (0.96 mL, 0.96 mmol, 1.0 M in THF) was added to a THF solution (0°C) of 27b (150 mg, 0.32 mmol) and (S)-(1-methylpyrolidin-2-yl)methanol (74 mg, 0.64 mmol) (4 mL). The mixture was stirred at room temperature for 2 hours and poured into HO2 (5 mL). The mixture was extracted with EtOAc (15 mL*2) and the combined organic layers were concentrated. Flash chromatography on silica gel (PE / EA=2 / 1) gave compound 27c (146 mg, 83% yield) as a yellow solid. LC-MS (Method 3) t=1.85 R min,m / z(m+H)=545.3 + .

[1147] Step 4 Tert-butyl (S)-5-(3-cyano-8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)quinolin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (27d)

[1148] A solution of 27c (135 mg, 0.25 mmol), 24a (99 mg, 0.30 mmol), K2CO3 (102 mg, 0.74 mmol) and Pd(dppf)Cl2 (18 mg, 0.025 mmol) was stirred in 1,4-dioxane (3 mL) and HO2 (1 mL) at 80°C under N2 atmosphere for 2 h. The mixture was concentrated and the residue was purified by flash chromatography on silica gel (DCM / MeOH=20 / 1) to give compound 27d (105 mg, yield 63%) as a yellow solid. LC-MS (Method 3) t=2.12 min, m / z (m+ R + H)=671.5.

[1149] Step 5 ((S)8-fluoro-7)-8-fluoro-3-hydroxynaphthalen-1-yl 2-((1-methylpyrrolidin-2-yl)methoxy)4(1,2,5,6-tetrahydropyridin-3-yl)quinoline-3-carbonitrile(27)

[1150] A solution of 27d (25 mg, 0.037 mmol) in HCl / EtOAc (1 mL, 2.0 M) and EtOAc (0.5 mL) was stirred at room temperature for 1 h. The mixture was concentrated and the residue was purified by preparative HPLC (Method A) to give compound 27 (5 mg, yield 25%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) R δ10.27 (brs, 1H) + ,7.86(d,J= 1 8.4Hz,1H), 7.67(d,J=8.4Hz,1H), 7.64-7.58(m,1H), 7.46-7.40(m,1H) ), 7.35-7.06(m,2H), 7.02-6.97(m,1H), 6.14-6.12(m,1H), 4.53-4.40 (m,2H), 3.53-3.48(m,2H), 3.23-2.90(m,3H), 2.72-2.67(m,1H), 2.43 -2.41(m,3H), 2.33-2.18(m,4H), 2.02-1.95(m,1H), 1.77-1.67(m,3H).

[1151] Embodiment 28

[1152]

[1153] Step 1: tert-Butyl 3-(7-bromo-3-cyano-8-fluoro-2-((2R,7aS)-2-fluorohexahydro-1h-pyrrolin-7a-yl)methoxy)quinolin-4-yl)-2,5-dihydro-1h-pyrrole-1-carboxylate (28a)

[1154] LiHMDS (0.46 mL, 0.46 mmol, 1 M in THF) was added to a solution of (2R, 7aS)-2-fluorotetrahydro-1h-pyrrolizin-7a(5H)-yl)methanol (74 mg, 0.46 mmol) in THF (1.5 mL) at 0°C. After stirring at room temperature for 30 min, the reaction mixture was cooled to 0°C, and 26d (140 mg, 0.31 mmol) was added to the reaction mixture. The reaction was stirred at room temperature for 4 hours and quenched with 5 mL of ice water. The resulting mixture was extracted with EtOAc (8 mL*2) and the combined organic layers were concentrated. The residue was purified by flash chromatography on silica gel (PE / EA=2 / 1) to give compound 28a (130 mg, yield 73%) as a yellow solid. LC-MS (Method 3) t=0.99 R min,m / z(m+H)=575.1 + .

[1155] Step 2 3-(3-cyano-8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1h-pyrrolin-7-yl)methoxyquinolin-4-yl)-2,5-dihydro-1h-pyrrole-1-carboxylate (28b)

[1156] A solution of 28a (110 mg, 0.19 mmol), 24a (70 mg, 0.21 mmol), K2CO3 (53 mg, 0.38 mmol) and Pd(dppf)Cl2 (28 mg, 0.038 mmol) in 1,4-dioxane / HO2 (1 mL / 0.2 mL) was stirred at 60°C under n2 for 4 h, then diluted with EtOAc (10 mL) and washed with HO2 (5 mL). The organic layer was concentrated and the residue was purified by flash chromatography on silica gel (DCM / MeOH=20 / 1) to give compound 28b (91 mg, yield 68%) as butter. LC-MS (Method 3) t=1. R 06min,m / z(m+H)=70 + 1.3.

[1157] Step 3 Tert-butyl 3-(3-cyano-8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-((2R,7aS)-2-fluorohexahydro-1h-pyrrolidine-7-yl)methoxyquinolin-4-yl)pyrrolidine-1-carboxylate (28c)

[1158] A mixture of 28b (91 mg, 0.13 mmol), Pd / C (80 mg, 10% wt wet in 50% water) and Pd(OH)2 (80 mg) in EtOH (2 mL) was stirred overnight under 50 Psi h2, then the mixture was filtered and washed with EtOH (6 mL). The filtrate was concentrated to give 28c (70 mg, 77% yield) as a yellow oil. LC-MS (Method 3) t = 1. R 13min, m / z(m+H)=70 + 3.2.

[1159] Step 4 8-Fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-((2R,7aS)-2-fluorohexahydro-1h-pyrrolin-7-yl)methoxy)-4-(pyrrolidin-3-yl)quinoline-3-carbonitrile hydrochloride (28)

[1160] HCl / EtOAc (0.5 mL, 2 M) was added to a solution of 28c (17 mg, 0.024 mmol) in EtOAc (1 mL) at 0°C. After stirring at room temperature for 2 h, the formed solid was filtered and triturated with ether (2 ml). The solid was filtered and dried to give compound 28 (8.0 mg, 52% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) R δ11.78(s,1H) + ,10.38(s,1H),9. 1 81(s,1H), 9.63(s,1H), 8.27(d,J=9.2Hz,1H), 7.69(m,2H), 7.43(m,1H), 7.37(t,J=2.0Hz,1H), 7.11(t,J=2.0Hz,1H), 7.01-6.97(m,1H), 5.6 9(s,0.5H), 5.56(s,0.5H), 4.81-4.67(m,2H), 4.57-4.59(m,2H), 3.54 -3.43(m,1H), 2.73-2.50(m,4H), 2.27-2.20(m,2H), 2.13-1.91(m,3H).

[1161] Embodiment 29

[1162]

[1163] Step 1 2-Chloro-4-(3,5-dimethyl-1-(tetrahydro-2h-pyran-2-yl)-1h-pyrazol-4-yl)-6,7-dihydropyrano[3,4-d]pyrimidine-8(5H)-1(29a)

[1164] A solution of 14a (300 mg, 1.38 mmol), 3,5-dimethyl-1-(tetrahydro-2h-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole (421 mg, 1.38 mmol), Pd(PPh3) (159 mg4, 0.138 mmol), NaCO (4382 mg3, 4.13 mmol), dioxane (5 mL) and HO (1 mL)2 was stirred at 85 °C for 4 h, the mixture was concentrated, and the residue was purified by flash chromatography on silica gel (DCM / MeOH from 100 / 1 to 20 / 1) to give compound 29a (100 mg, yield 20%) as a yellow solid. LC-MS (Method 4) t = 2.41 min R + ,m / z(m+H)=362.2.

[1165] Step 2 4-(3,5-dimethyl-1-(tetrahydro-2h-pyran-2-yl)-1h-pyrazol-4-yl)-2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolin-7a(5H)-yl)methoxy)-6,7-dihydropyrido[3,4-d]pyrimidine-8(5H)-1(29b)

[1166] To a solution of 29a (80 mg, 0.22 mmol), ((2R,7aS)-2-fluorotetrahydro-1h-pyrrolizin-7a(5H)-yl)methanol (106 mg, 0.66 mmol) was added 4% paraformaldehyde in 1 mL of dioxane. Molecular sieves (80 mg) and DIEA (86 mg, 0.66 mmol). Then stirred at 110°C for 48 h, the mixture was concentrated, and the residue was purified by flash chromatography on silica gel (DCM / MeOH from 50 / 1 to 5 / 1) to obtain compound 29b as a yellow solid. LC-MS (Method 4) t = 3.16 min, m / z (m+H) = + R 485.4.

[1167] Step 3 7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-4-(3,5-dimethyl-1-(tetrahydro-2h-pyran-2-yl)-1h-pyrazol-4-yl)-2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy)-6,7-dihydropyrido[3,4-d]pyrimidine-8(5H)-1(29c)

[1168] A solution of 29b (30 mg, 0.062 mmol), 1-bromo-8-chloro-3-(methoxymethoxy)naphthalene (37 mg, 0.12 mmol), XantPhos Pd G3 (10 mg, 0.012 mmol), CsCO2 (503 mg, 0.155 mmol) and dioxane (1 mL) was stirred at 110°C for 24 h, the mixture was concentrated, and the residue was purified by flash chromatography on silica gel (DCM / MeOH: 50 / 1 to 15 / 1) to obtain compound 29c (10 mg, yield 23%) as a yellow solid. LC-MS (Method 4) t = 2. R 65min, m / z(m+H)=70 + 5.4.

[1169] Step 4 7-(8-Chloro-3-hydroxynaphthalen-1-yl)-4-(3,5-dimethyl-1h-pyrazol-4-yl)-2-((2R,7aS)-2-fluorotetrahydro-1h-pyrrolidine-7a(5H)-yl)methoxy)-6,7-dihydropyrido[3,4-d]pyrimidine-8(5H)-1carboxylic acid (29)

[1170] HCl (0.5 mL, 4 M dioxane) was added to the ACN (0.5 mL) solution, and 29c (10 mg, 0.014 mmol) was added in an ice bath, and then stirred at room temperature for 2 h. The mixture was concentrated, and the residue was purified by preparative HPLC (Method F) to obtain compound 29 (5.6 mg, 68% yield) as a light yellow solid. LC-MS (Method IV) t R =3.08min,m / z(m+H) + =577.4. 1 H NMR (400 MHz, DMSO-d6) δ 7.82--7.78 (m, 1H), 7.39--7.37 (m, 2H), 7.30--7.28 (m, 2H), 5.35--5.21 (s, 1H), 4.11--4.07 (m, 1H), 4.04--4.01 (m, 1H), 3.92--3.88 (m, 2H), 3.11--3.08 (m, 3H), 3.02--2.97 (m, 2H), 2.89--2.80 (m, 1H), 2.20 (s, 6H), 2.17--2.13 (m, 1H), 2.08--1.99 (m, 3H), 1.87--1.73 (m, 2H).

[1171] Table 1

[1172]

[1173]

[1174]

[1175]

[1176]

[1177]

[1178]

[1179]

[1180] KRAS-G12D surface plasmon resonance (SPR) binding assay

[1181] This example illustrates that exemplary compounds of the invention bind to KRAS-G12D protein in an incubation buffer (50 mM

[1182]

[1183] After incubation at 30°C for 1 hour in the presence of Hepes (pH 7.4, 150 mM NaCl, 5 mM MgCl2, 10 mM EDTA and 0.01% Triton X-100), 20 mM MgCl2 (final concentration) was added to terminate GppNHp release, and the release was measured by surface plasmon resonance (SPR) method.

[1184] Prior to testing, the Biacore 8K (GE) instrument was perfused with 1X Running buffer (HBS-P + / 10mM MgCl2 / +0.5mM TCEP 2% DMSO, flow rate: 100μL / mL) before docking to the GE Streptavidin (SA) chip and twice more after docking before starting the fixation step. All immobilized protein mixtures were prepared at 20μg / mL. The steps for biotinylated KRAS-G12D protein fixation are as follows:

[1185] Prior to fixation, the sensor surface was conditioned by three consecutive 1-minute injections of 1M NaCl in 50mM NaOH. Afterwards, 20μg / ml of Biotin-KRAS(G12D) / Biotin-KRAS(G12D)-GppNHp was injected at a rate of 10μL / min for 320 seconds. Washing was performed using 1M NaCl and 50mM NaOH containing 50% isopropanol. All compounds were prepared as 10mM DMSO stock solutions and then serially diluted 3-fold to test their affinity to KRAS-G12D protein. The assay steps are as follows:

[1186] Running Buffer plus containing 10mM MgCl2, 0.5mM TCEP and 2% DMSO was used as the running buffer for binding measurement, and the experiment was performed at 25°C. The compounds were diluted to 6-8 concentrations using the running buffer in a 1:2 serial dilution. The compound solutions with serial concentrations were injected into the channel at a rate of 100μL / min. The association and dissociation times were 40 seconds and 120 seconds, respectively. Two solvent corrections were performed to correct the signal caused by DMSO, and two blank solutions were injected to eliminate the reference signal. At the end of each cycle, 50% DMOS was injected to clean the system.

[1187] Data were analyzed using BIAcore Insight Evaluation Software. After subtracting the reference and zero concentration signals from the sample signals, the binding kinetic parameters were curve fitted using the 1:1 binding model and the steady-state affinity model.

[1188] The results for exemplary compounds are shown in Table 2. ND = Not Determined.

[1189] KRAS-G12D / RAF1 binding assay

[1190] This example illustrates that exemplary compounds of the invention bind to KRAS-G12D protein and can block the interaction between KRAS-G12D and RAF1 protein.

[1191] The ability of the compounds to bind to the KRAS-G12D protein and block the interaction between KRAS-G12D and RAF1 proteins was measured using a homogeneous time-resolved fluorescence (HTRF) detection kit (Cisbio, 63ADK000CB21PEG). Compounds that block the KRAS-G12D / RAF1 interaction will result in a decrease in the HTRF signal.

[1192] All compounds were prepared as 10 mM DMSO stocks and then serially diluted 3-fold to test their activity in blocking the KRAS-G12D:RAF1 interaction. The diluted compounds were incubated with GppNHp-loaded Tag2-KRAS-G12D and Tag1-RAF1 at room temperature for 15 minutes. A mixture of dye-labeled anti-Tag2 antibody and europium-coupled anti-Tag1 antibody was then added. After incubation for 2 hours at 4°C, the plates were read on a Molecular Device (Spectra MAX i3X) plate reader with an HTRF module. Data analysis was performed by GraphPad Prism 9, and IC50 was obtained by a four-parameter fitting method for dose-response curves.

[1193] The results for exemplary compounds are shown in Table 2. ND = Not Determined.

[1194] Table 2 SPR and RAS-RAF1 binding values ​​of illustrative compounds

[1195]

[1196]

[1197] It should be understood that the above description of the preferred embodiments is intended to purely illustrate the principles of the present invention rather than to be exhaustive, and that modifications and variations will be apparent to those skilled in the art, and that the present invention is not intended to be limited except as expressly provided in the following claims.

Claims

1. A nitrogen-containing heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof, in, The nitrogen-containing heterocyclic compound represented by formula II is selected from:

2. A pharmaceutical composition comprising a substance Y and a pharmaceutically acceptable excipient, wherein the substance Y is a nitrogen-containing heterocyclic compound represented by formula II as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

3. Use of a substance Y in the preparation of a KRAS-G12D inhibitor; the substance Y is a nitrogen-containing heterocyclic compound represented by formula II according to claim 1 or a pharmaceutically acceptable salt thereof; The KRAS-G12D inhibitor is used in vitro or in vivo.

4. Use of a substance Y in the preparation of a drug; The substance Y is a nitrogen-containing heterocyclic compound represented by formula II according to claim 1 or a pharmaceutically acceptable salt thereof; The drug is used to treat or prevent KRAS-G12D-related diseases or conditions; The KRAS-G12D-associated disease or disorder is cancer.

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