pyrido[4,3-d]pyrimidines

Abstract

A class of KRAS inhibitor compounds of formula (II) or a pharmaceutically acceptable salt thereof.

Description

[0001] This invention claims the following priority:

[0002] CN202110179648.X, application date: February 9, 2021;

[0003] CN202110247910.X, application date: March 6, 2021;

[0004] CN202110395038.3, application date: April 13, 2021;

[0005] CN202110485807.9, application date: April 30, 2021;

[0006] CN202110982415.3, application date: August 25, 2021;

[0007] CN202111658642.7, application date: December 30, 2021. Technical Field

[0008] This invention relates to a class of pyridine[4,3-d]pyrimidine compounds, specifically to compounds of formula (II) or pharmaceutically acceptable salts thereof. Background Technology

[0009] Cancers caused by mutations in the RAS family, including NRAS, HRAS, and KRAS, account for nearly a quarter of all human cancers, making them among the most common cancer-related gene mutations. They cover almost all cancer types and cause one million deaths globally each year. KRAS is the most common oncogene (85% of all RAS mutations), present in 90% of pancreatic cancers, 30-40% of colon cancers, and 15-20% of lung cancers (mostly non-small cell lung cancer). Depending on the specific mutation present, G12C, G12D, and G12R are the most common KRAS mutations among patients. Other common mutations include G12A, G12S, and G12V.

[0010] RAS (Rat Sarcoma) family proteins are widely expressed in various eukaryotes, exhibiting two forms: a GDP (guanosine diphosphate)-binding form in an inactive state and a GTP (guanosine triphosphate)-binding form in an activated state. RAS proteins regulate multiple downstream pathways, including RAF-MEK-ERK and PI3K / Akt / mTOR, by switching between these two forms, thereby influencing cell growth and differentiation, as well as tumorigenesis and development.

[0011] Because mutant KRAS has a high affinity for guanosine triphosphate (GTP) and is difficult to target due to its small catalytic site and smooth protein surface, the development of small molecule inhibitors has always been challenging, creating the "untreatable" legend of KRAS. However, with Mirati's breakthrough in non-covalent inhibitors of KRAS G12D, tumors with KRAS G12D mutations are gradually entering the field of precision medicine. Summary of the Invention

[0012] This invention provides compounds of formula (II) or pharmaceutically acceptable salts thereof.

[0013]

[0014] in,

[0015] Ring A is selected from The Choose 1, 2, or 3 Rs a replace;

[0016] T1 is selected from CH, CH2, N, and NR5;

[0017] T2, T3, and T4 are independently selected from CH, CH2, N, and NH, respectively;

[0018] m, n, p, and x are each independently selected from 0, 1, or 2;

[0019] r, v, and w are each independently selected from 1 or 2;

[0020] s and u are each independently selected from 1, 2, or 3;

[0021] q is selected from 1 or 3;

[0022] R1 is selected from phenyl, benzothiophene, and naphthyl, wherein the phenyl, benzothiophene, and naphthyl groups are optionally surrounded by 1, 2, 3, 4, or 5 R1 groups. b replace;

[0023] R2 is selected from H, F, Cl, CN, NH2, CH3, OCH3 and CF3;

[0024] R3 is selected from F, and R4 is selected from H;

[0025] Or R3 is selected from H, and R4 is selected from H.

[0026] R5 is selected from H, -C(O)-(OCH(CH3)OC(O)). t -C 1-4 Alkyl group, -C(O)-(OCH(CH3)OC(O)) t -C 9-13Alkyl group, -C(O)-(OCH(CH3)OC(O)) t -C 1-4 Alkylamino and -C(O)-(OCH(CH3)OC(O)) t -C 1-3 Alkyl-COOM, the C 1-4 The alkyl group may be optionally substituted with one NH2 ion;

[0027] Each R a Each of the following is independently selected from F, Cl, Br, I, and CH3;

[0028] Each R b Each of the following is independently selected from F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, cyclopropyl and -O-cyclopropyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, cyclopropyl and -O-cyclopropyl groups are optionally substituted with 1, 2 or 3 R groups, and the OH group is optionally substituted with 1 R'.

[0029] Each R is independently selected from F, Cl, Br, and I;

[0030] R' is selected from -(CH2O) y -(CH2CH2O) z -C(O)-C 1-4 Alkyl group, -(CH2O) y -(CH2CH2O) z -C(O)-C 9-13 Alkyl group, -(CH2O) y -(CH2CH2O) z -C(O)-C 1-4 Alkylamino, -(CH2O) y -(CH2CH2O) z -C(O)-C 1-3 Alkyl groups -COOM, -(CH2O) y -(CH2CH2O) z -P(=O)(OH)(OM), -(CH2O) y -(CH2CH2O) z -P(=O)(OM)2 and The C 1-4 The alkyl group may be optionally substituted with one NH2 ion;

[0031] M is independently selected from Na and K;

[0032] y is 0 or 1;

[0033] z is 0 or 1;

[0034] t is 0 or 1.

[0035] In some embodiments of the present invention, R5 is selected from H, -C(O)-CH2NH2, -C(O)-OCH(CH3)OC(O)-CH2CH3 and -C(O)-OCH(CH3)OC(O)-CH(CH3)2, and other variables are as defined in the present invention.

[0036] In some embodiments of the present invention, ring A is selected from... The Choose 1, 2, or 3 Rs a Replacement, other variables as defined in this invention.

[0037] In some embodiments of the present invention, ring A is selected from... Other variables are as defined in this invention.

[0038] In some embodiments of the present invention, R' is selected from -(CH2O). y -(CH2CH2O) z -C(O)-CH3、-(CH2O) y -(CH2CH2O) z -C(O)-CH(CH3)2、-(CH2O) y -(CH2CH2O) z -C(O)-C(CH3)3、-(CH2O) y -(CH2CH2O) z -C(O)-CH(NH2)CH(CH3)2、-(CH2O) y -(CH2CH2O) z -C(O)-(CH2) 10 CH3、-(CH2O) y -(CH2CH2O) z -C(O)-N(CH3)2、-(CH2O) y -(CH2CH2O) z -C(O)-CH2CH2-COONa、-(CH2O) y -(CH2CH2O) z -P(=O)(ONa)2 and Other variables are as defined in this invention.

[0039] In some embodiments of the present invention, the respective R b The radicals are independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, -C≡CH, cyclopropyl, and -O-cyclopropyl, respectively. The CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, -C≡CH, cyclopropyl, and -O-cyclopropyl radicals are optionally substituted by 1, 2, or 3 R radicals, and the OH radical is optionally substituted by 1 R' radical. Other variables are as defined in this invention.

[0040] In some embodiments of the present invention, the respective R b The groups are independently selected from F, Cl, OH, NH2, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -C≡CH, cyclopropyl, -O-cyclopropyl, and -O-(CH2O). y -(CH2CH2O) z -C(O)-CH3, -O-(CH2O) y -(CH2CH2O) z -C(O)-CH(CH3)2、-O-(CH2O) y -(CH2CH2O) z -C(O)-C(CH3)3、-O-(CH2O) y -(CH2CH2O) z -C(O)-CH(NH2)CH(CH3)2、-O-(CH2O) y -(CH2CH2O) z -C(O)-(CH2) 10 CH3、-O-(CH2O) y -(CH2CH2O) z -C(O)-N(CH3)2、-O-(CH2O) y -(CH2CH2O) z -C(O)-CH2CH2-COONa, -O-(CH2O) y -(CH2CH2O) z -P(=O)(ONa)2 and Other variables are as defined in this invention.

[0041] In some embodiments of the present invention, R1 is selected from... Other variables are as defined in this invention.

[0042] In some embodiments of the present invention, R1 is selected from... Other variables are as defined in this invention.

[0043] In some embodiments of the present invention, R1 is selected from...

[0044] In some embodiments of the present invention, R2 is selected from F, and other variables are as defined in the present invention.

[0045] This invention provides compounds of formula (II) or pharmaceutically acceptable salts thereof.

[0046]

[0047] in,

[0048] Ring A is selected from The Choose 1, 2, or 3 Rs a replace;

[0049] T1 is selected from CH, CH2, N, and NR5;

[0050] T2, T3, and T4 are independently selected from CH, CH2, N, and NH, respectively;

[0051] m, n, p, and x are each independently selected from 0, 1, or 2;

[0052] r, v, and w are each independently selected from 1 or 2;

[0053] s and u are each independently selected from 1, 2, or 3;

[0054] q is selected from 1 or 3;

[0055] R1 is selected from phenyl, benzothiophene, and naphthyl, wherein the phenyl, benzothiophene, and naphthyl groups are optionally surrounded by 1, 2, 3, 4, or 5 R1 groups. b replace;

[0056] R2 is selected from H, F, Cl, CN, NH2, CH3, OCH3 and CF3;

[0057] R3 is selected from F, and R4 is selected from H;

[0058] Or R3 is selected from H, and R4 is selected from H.

[0059] R5 is selected from H, -C(O)-(OCH(CH3)OC(O)). t -C 1-4Alkyl group, -C(O)-(OCH(CH3)OC(O)) t -C 9-13 Alkyl group, -C(O)-(OCH(CH3)OC(O)) t -C 1-4 Alkylamino and -C(O)-(OCH(CH3)OC(O)) t -C 1-3 Alkyl-COOM, the C 1-4 The alkyl group may be optionally substituted with one NH2 ion;

[0060] Each R a Each of the following is independently selected from F, Cl, Br, I, and CH3;

[0061] Each R b Each of the following is independently selected from F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, cyclopropyl and -O-cyclopropyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, cyclopropyl and -O-cyclopropyl groups are optionally substituted with 1, 2, 3, 4 or 5 R groups, and the OH group is optionally substituted with 1 R' group;

[0062] Each R is independently selected from F, Cl, Br, I, cyclopropyl and CF3;

[0063] R' is selected from -(CH2O) y -(CH2CH2O) z -C(O)-C 1-4 Alkyl group, -(CH2O) y -(CH2CH2O) z -C(O)-C 9-13 Alkyl group, -(CH2O) y -(CH2CH2O) z -C(O)-C 1-4 Alkylamino, -(CH2O) y -(CH2CH2O) z -C(O)-C 1-3 Alkyl groups -COOM, -(CH2O) y -(CH2CH2O) z -P(=O)(OH)(OM), -(CH2O) y -(CH2CH2O) z -P(=O)(OM)2 and The C1-4 The alkyl group may be optionally substituted with one NH2 ion;

[0064] M is independently selected from Na and K;

[0065] y is 0 or 1;

[0066] z is 0 or 1;

[0067] t is 0 or 1.

[0068] This invention provides compounds of formula (II) or pharmaceutically acceptable salts thereof.

[0069]

[0070] in,

[0071] Ring A is selected from The Choose 1, 2, or 3 Rs a replace;

[0072] T1 is selected from CH, CH2, N, and NR5;

[0073] T2, T3, and T4 are independently selected from CH, CH2, N, and NH, respectively;

[0074] m, n, p, and x are each independently selected from 0, 1, or 2;

[0075] r, v, and w are each independently selected from 1 or 2;

[0076] s and u are each independently selected from 1, 2, or 3;

[0077] q is selected from 1 or 3;

[0078] R1 is selected from phenyl and naphthyl groups, wherein the phenyl and naphthyl groups are optionally surrounded by 1, 2, 3, 4, or 5 R groups. b replace;

[0079] R2 is selected from H, F, Cl, CN, NH2, CH3, OCH3 and CF3;

[0080] R3 is selected from F, and R4 is selected from H;

[0081] Or R3 is selected from H, and R4 is selected from H.

[0082] R5 is selected from H, -C(O)-(OCH(CH3)OC(O)). t -C 1-4 Alkyl group, -C(O)-(OCH(CH3)OC(O)) t -C 9-13 Alkyl group, -C(O)-(OCH(CH3)OC(O))t -C 1-4 Alkylamino and -C(O)-(OCH(CH3)OC(O)) t -C 1-3 Alkyl-COOM, the C 1-4 The alkyl group may be optionally substituted with one NH2 ion;

[0083] Each R a Each of the following is independently selected from F, Cl, Br, I, and CH3;

[0084] Each R b Each of the following is independently selected from F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 alkenyl and C 2-4 alkynyl group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 alkenyl and C 2-4 The alkynyl group may be optionally substituted by 1, 2 or 3 R groups, and the OH group may be optionally substituted by 1 R' group;

[0085] Each R is independently selected from F, Cl, Br, and I;

[0086] R' is selected from -(CH2O) y -(CH2CH2O) z -C(O)-C 1-4 Alkyl group, -(CH2O) y -(CH2CH2O) z -C(O)-C 9-13 Alkyl group, -(CH2O) y -(CH2CH2O) z -C(O)-C 1-4 Alkylamino, -(CH2O) y -(CH2CH2O) z -C(O)-C 1-3 Alkyl groups -COOM, -(CH2O) y -(CH2CH2O) z -P(=O)(OH)(OM), -(CH2O) y -(CH2CH2O) z -P(=O)(OM)2 and The C 1-4 The alkyl group may be optionally substituted with one NH2 ion;

[0087] M is independently selected from Na and K;

[0088] y is 0 or 1;

[0089] z is 0 or 1;

[0090] t is 0 or 1.

[0091] In some embodiments of the present invention, R5 is selected from H, -C(O)-CH2NH2, -C(O)-OCH(CH3)OC(O)-CH2CH3, and other variables are as defined in the present invention.

[0092] In some embodiments of the present invention, ring A is selected from... The Choose 1, 2, or 3 Rs a Replacement, other variables as defined in this invention.

[0093] In some embodiments of the present invention, ring A is selected from... Other variables are as defined in this invention.

[0094] In some embodiments of the present invention, R' is selected from -(CH2O). y -(CH2CH2O) z -C(O)-CH3、-(CH2O) y -(CH2CH2O) z -C(O)-CH(CH3)2、-(CH2O) y -(CH2CH2O) z -C(O)-C(CH3)3、-(CH2O) y -(CH2CH2O) z -C(O)-CH(NH2)CH(CH3)2、-(CH2O) y -(CH2CH2O) z -C(O)-(CH2) 10 CH3、-(CH2O) y -(CH2CH2O) z -C(O)-N(CH3)2、-(CH2O) y -(CH2CH2O) z -C(O)-CH2CH2-COONa、-(CH2O) y -(CH2CH2O) z -P(=O)(ONa)2 and Other variables are as defined in this invention.

[0095] In some embodiments of the present invention, the respective R bThe radicals are independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, -C≡CH, cyclopropyl, and -O-cyclopropyl, respectively. The CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, -C≡CH, cyclopropyl, and -O-cyclopropyl radicals are optionally substituted by 1, 2, 3, 4, or 5 R radicals, and the OH radical is optionally substituted by 1 R'. Other variables are as defined in this invention.

[0096] In some embodiments of the present invention, the respective R b The components are independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2 and -C≡CH, respectively. The CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2 and -C≡CH are optionally replaced by 1, 2 or 3 Rs, and the OH is optionally replaced by 1 R'. Other variables are as defined in this invention.

[0097] In some embodiments of the present invention, the respective R b The groups are independently selected from F, Cl, OH, NH2, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -C≡CH, cyclopropyl, -O-cyclopropyl, and others. -O-(CH2O) y -(CH2CH2O) z -C(O)-CH3, -O-(CH2O) y -(CH2CH2O) z -C(O)-CH(CH3)2、-O-(CH2O) y -(CH2CH2O) z -C(O)-C(CH3)3、-O-(CH2O) y -(CH2CH2O) z -C(O)-CH(NH2)CH(CH3)2、-O-(CH2O) y -(CH2CH2O) z -C(O)-(CH2) 10 CH3、-O-(CH2O) y -(CH2CH2O) z -C(O)-N(CH3)2、-O-(CH2O) y -(CH2CH2O) z-C(O)-CH2CH2-COONa, -O-(CH2O) y -(CH2CH2O) z -P(=O)(ONa)2 and Other variables are as defined in this invention.

[0098] In some embodiments of the present invention, the respective R b The components are independently selected from F, OH, NH2, CH3, CF3, CH2CH3, -C≡CH, and -O-(CH2O). y -(CH2CH2O) z -C(O)-CH3, -O-(CH2O) y -(CH2CH2O) z -C(O)-CH(CH3)2、-O-(CH2O) y -(CH2CH2O) z -C(O)-C(CH3)3、-O-(CH2O) y -(CH2CH2O) z -C(O)-CH(NH2)CH(CH3)2、-O-(CH2O) y -(CH2CH2O) z -C(O)-(CH2) 10 CH3、-O-(CH2O) y -(CH2CH2O) z -C(O)-N(CH3)2、-O-(CH2O) y -(CH2CH2O) z -C(O)-CH2CH2-COONa, -O-(CH2O) y -(CH2CH2O) z -P(=O)(ONa)2 and Other variables are as defined in this invention.

[0099] In some embodiments of the present invention, R1 is selected from... Other variables are as defined in this invention.

[0100] In some embodiments of the present invention, R1 is selected from... Other variables are as defined in this invention.

[0101] In some embodiments of the present invention, R1 is selected from...

[0102] In some embodiments of the present invention, R2 is selected from F, and other variables are as defined in the present invention.

[0103] This invention provides compounds of formula (II) or pharmaceutically acceptable salts thereof.

[0104]

[0105] in,

[0106] Ring A is selected from The Choose 1, 2, or 3 Rs a replace;

[0107] T1, T2, T3, and T4 are independently selected from CH, CH2, N, and NH, respectively;

[0108] m, n, p, and x are each independently selected from 0, 1, or 2;

[0109] r, v, and w are each independently selected from 1 or 2;

[0110] s and u are each independently selected from 1, 2, or 3;

[0111] q is selected from 1 or 3;

[0112] R1 is selected from phenyl and naphthyl groups, wherein the phenyl and naphthyl groups are optionally surrounded by 1, 2, 3, 4, or 5 R groups. b replace;

[0113] R2 is selected from H, F, Cl, CN, NH2, CH3, OCH3 and CF3;

[0114] R3 is selected from F, and R4 is selected from H;

[0115] Or R3 is selected from H, and R4 is selected from H.

[0116] Each R a Each of the following is independently selected from F, Cl, Br, I, and CH3;

[0117] Each R b Each of the following is independently selected from F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 alkenyl and C 2-4 alkynyl group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 alkenyl and C 2-4 The alkynyl group may be optionally substituted by 1, 2 or 3 R groups;

[0118] Each R is independently selected from F, Cl, Br, and I.

[0119] This invention provides compounds of formula (II) or pharmaceutically acceptable salts thereof.

[0120]

[0121] in,

[0122] Ring A is selected from The Choose 1, 2, or 3 Rs a replace;

[0123] T1, T2, T3, and T4 are independently selected from CH, CH2, N, and NH, respectively;

[0124] m, n, p, and x are each independently selected from 0, 1, or 2;

[0125] r, v, and w are each independently selected from 1 or 2;

[0126] s and u are each independently selected from 1, 2, or 3;

[0127] q is selected from 1 or 3;

[0128] R1 is selected from phenyl and naphthyl groups, wherein the phenyl and naphthyl groups are optionally surrounded by 1, 2, 3, 4, or 5 R groups. b replace;

[0129] R2 is selected from H, F, Cl, CN, NH2, CH3, OCH3 and CF3;

[0130] R3 is selected from F, and R4 is selected from H;

[0131] Or R3 is selected from H, and R4 is selected from H.

[0132] Each R a Each of the following is independently selected from F, Cl, Br, I, and CH3;

[0133] Each R b Each of the following is independently selected from F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 alkenyl and C 2-4 alkynyl group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 alkenyl and C 2-4 The alkynyl group may be optionally substituted by 1, 2 or 3 R groups;

[0134] Each R is independently selected from F, Cl, Br, and I.

[0135] In some embodiments of the present invention, ring A is selected from... The Choose 1, 2, or 3 Rs a Replacement, other variables as defined in this invention.

[0136] In some embodiments of the present invention, ring A is selected from... Other variables are as defined in this invention.

[0137] In some embodiments of the present invention, ring A is selected from... Other variables are as defined in this invention.

[0138] In some embodiments of the present invention, the respective R b The variables are independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, and -C≡CH, respectively. The CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, and -C≡CH are optionally replaced by 1, 2, or 3 Rs. Other variables are as defined in this invention.

[0139] In some embodiments of the present invention, the respective R b The variables are independently selected from F, OH, NH2, CH3, CF3, CH2CH3 and -C≡CH, respectively, and other variables are as defined in this invention.

[0140] In some embodiments of the present invention, R1 is selected from... Other variables are as defined in this invention.

[0141] In some embodiments of the present invention, R1 is selected from... Other variables are as defined in this invention.

[0142] In some embodiments of the present invention, R2 is selected from F, and other variables are as defined in the present invention.

[0143] This invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0144]

[0145] in,

[0146] Ring A is selected from The Choose 1, 2, or 3 Rs a replace;

[0147] T1, T2, T3, and T4 are each independently selected from CH and N;

[0148] m, n, p, and x are each independently selected from 0, 1, or 2;

[0149] r, v, and w are each independently selected from 1 or 2;

[0150] q, s, and u are each independently selected from 1, 2, or 3;

[0151] R1 is selected from phenyl and naphthyl groups, wherein the phenyl and naphthyl groups are optionally surrounded by 1, 2, 3, 4, or 5 R groups. b replace;

[0152] R2 is selected from H, F, Cl, CN, NH2, CH3, OCH3 and CF3;

[0153] Each R a Each of the following is independently selected from F, Cl, Br, I, and CH3;

[0154] Each R b The components are independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CF3 and OCH3, respectively.

[0155] In some embodiments of the present invention, ring A is selected from... The Choose 1, 2, or 3 Rs a Replacement, other variables as defined in this invention.

[0156] In some embodiments of the present invention, ring A is selected from... Other variables are as defined in this invention.

[0157] In some embodiments of the present invention, R1 is selected from... Other variables are as defined in this invention.

[0158] In some embodiments of the present invention, R2 is selected from F, and other variables are as defined in the present invention.

[0159] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is selected from...

[0160]

[0161] Wherein, R1, R2, R3, R4 and R5 are as defined in this invention.

[0162] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is selected from...

[0163]

[0164] R1, R2 and R5 are as defined in this invention.

[0165] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is selected from...

[0166]

[0167] in,

[0168] Each R b1 R b2 R b3 R b4 R b5 R b6 R b7 R b8 and R b9 Each of the following is independently selected from F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, cyclopropyl and -O-cyclopropyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 The alkynyl, cyclopropyl and -O-cyclopropyl groups are optionally substituted with 1, 2, 3, 4 or 5 R groups, and the OH group is optionally substituted with 1 R' group;

[0169] Each R is independently selected from F, Cl, Br, I, cyclopropyl and CF3; R2, R5 and R' are as defined in this invention.

[0170] In some embodiments of the present invention, the respective R b1 R b2 R b3 R b4 R b5 R b6 R b7 and R b8 The radicals are independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, -C≡CH, cyclopropyl, and -O-cyclopropyl, respectively. The CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, -C≡CH, cyclopropyl, and -O-cyclopropyl radicals are optionally substituted by 1, 2, 3, 4, or 5 R radicals, and the OH radical is optionally substituted by 1 R'. Other variables are as defined in this invention.

[0171] In some embodiments of the present invention, the respective R b1 R b2 R b3 R b4 R b5 R b6 R b7 and R b8 The groups are independently selected from F, Cl, OH, NH2, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -C≡CH, cyclopropyl, -O-cyclopropyl, and others. -O-(CH2O) y -(CH2CH2O) z -C(O)-CH3, -O-(CH2O) y -(CH2CH2O) z -C(O)-CH(CH3)2、-O-(CH2O) y -(CH2CH2O) z -C(O)-C(CH3)3、-O-(CH2O) y -(CH2CH2O) z -C(O)-CH(NH2)CH(CH3)2、-O-(CH2O) y -(CH2CH2O) z -C(O)-(CH2) 10 CH3、-O-(CH2O) y -(CH2CH2O) z -C(O)-N(CH3)2、-O-(CH2O) y -(CH2CH2O) z - C(O)-CH2CH2-COONa, -O-(CH2O) y -(CH2CH2O) z -P(=O)(ONa)2 and Other variables are as defined in this invention.

[0172] Some solutions in this invention are derived from arbitrary combinations of the above variables.

[0173] The present invention also provides compounds of the following formula or pharmaceutically acceptable salts thereof, wherein the compounds are selected from...

[0174]

[0175]

[0176] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is selected from...

[0177]

[0178]

[0179]

[0180]

[0181] The present invention also provides the said compound or a pharmaceutically acceptable salt thereof for the preparation of a treatment for KRAS. G12D Application of compounds in mutated solid tumors.

[0182] The present invention also provides the following synthesis methods:

[0183] Method 1:

[0184]

[0185] Method 2:

[0186]

[0187] Technical effect

[0188] The compound of this invention and KRAS G12D The protein has good binding ability and can significantly inhibit KRAS. G12D Enzyme, GP2D p-ERK, and the compounds of this invention against KRAS G12D The mutated cells exhibit good cell proliferation inhibitory activity and excellent tumor suppression effect. Furthermore, the compounds of this invention possess favorable pharmacokinetic characteristics.

[0189] Related definitions

[0190] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0191] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0192] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0193] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both.

[0194] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0195] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0196] The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0197] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents can be arbitrary on a chemically feasible basis.

[0198] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0199] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0200] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0201] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linker group L is -MW-. In this case, -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form a ring. Alternatively, rings A and B can be connected in the opposite direction to the left-to-right reading order to form a ring. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0202] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Straight dashed key or wavy line For example, a straight solid line bond in -OCH3 indicates that the oxygen atom in that group is connected to other groups; The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the nitrogen atom in the group; The wavy lines in the text indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2 of the phenyl group. This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... Even if H atoms are drawn on -N- in these four connection methods, Still includes In this type of linkage, when a chemical bond is attached, the number of hydrogen atoms at that site is reduced by one, resulting in a monovalent piperidinyl group.

[0203] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key Or straight dashed key

[0204] Unless otherwise specified, the term "C" 9-13 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 9 to 13 carbon atoms. The C 9-13 Alkyl groups include C 9-12 C 9-11 C 9-10 C9, C 10 C 11 C 12 and C 13 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 9-1Examples of 3-alkyl groups include, but are not limited to, -(CH2)9- and -(CH2). 10 -wait.

[0205] Unless otherwise specified, the term "C" 1-4 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1-4 Alkyl groups include C 1-2 C 1-3 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), etc.

[0206] Unless otherwise specified, the term "C" 1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0207] Unless otherwise specified, the term "C" 1-4 "Alkylamino" refers to alkyl groups containing 1 to 4 carbon atoms that are attached to the rest of the molecule via an amino group. The C 1-4 Alkylamino groups include C 1-3 C 1-2 C 2-4 C4, C3, and C2 alkylamino groups, etc. C 1-4 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, etc.

[0208] Unless otherwise specified, the term "C" 1-3 "Alkoxy" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 C 2-3 C3 and C2 alkoxy groups, etc. 1-3Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0209] Unless otherwise specified, "C 2-4 "Alkenyl" is used to denote a hydrocarbon group consisting of 2 to 4 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon double bond. The carbon-carbon double bond can be located at any position within the group. The C... 2-4 Alkenes include C 2-3 C4, C3, and C2 alkenyl groups, etc.; the C 2-4 Alkenes can be monovalent, divalent, or polyvalent. C 2-4 Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, and butadienyl.

[0210] Unless otherwise specified, "C 2-4 "Alkyne" is used to denote a straight-chain or branched hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon triple bond, which can be located at any position within the group. 2-4 Alkyne groups include C 2-3 C4, C3, and C2 alkynyl groups, etc. They can be monovalent, divalent, or polyvalent. 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, etc.

[0211] Unless otherwise specified, C n-n+m Or C n -C n+m This includes any specific case with n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It also includes any range from n to n+m, such as C 1-12 Including C 1-3 C 1-6 C 1-9 C 3-6 C 3-9 C 3-12 C 6-9 C 6-12 and C 9-12 Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

[0212] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0213] The structures of the compounds of this invention can be confirmed by conventional methods well known to those skilled in the art. If this invention relates to the absolute configuration of a compound, that absolute configuration can be confirmed by conventional techniques in the art. For example, single-crystal X-ray diffraction (SXRD) is used, where the cultured single crystal is used to collect diffraction intensity data using a Bruker D8 venture diffractometer with CuKα radiation as the light source. The scanning method is as follows: After scanning and collecting relevant data, the crystal structure can be further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0214] The solvents used in this invention are commercially available. The following abbreviations are used in this invention: DIEA represents N,N-diisopropylethylamine; Tf₂O represents trifluoromethanesulfonic anhydride; Xantphos represents 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene); Cs₂CO₃ represents cesium carbonate; Pd₂(dba)₃ represents tris(dibenzylacetone)dipalladium; Pd(dppf)Cl₂ represents [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride; K₃PO₄ represents phosphorus. Potassium iodide; CsF represents cesium fluoride; NaNO2 represents sodium nitrite; KI represents potassium iodide; Pd(dppf)Cl2.CH2Cl2 represents [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex; RuPhosPdG2 represents chloro(2-dicyclohexylphosphino-2′,6′-di-isopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II).

[0215] Compounds are named according to conventional naming principles in the field or using Software naming conventions are used; commercially available compounds use supplier catalog names. Attached Figure Description

[0216] Figure 1 Compound A and KRAS G12D Diagram of protein binding patterns;

[0217] Figure 2 Compound B and KRAS G12D A diagram illustrating the protein binding pattern. Detailed Implementation

[0218] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope thereof.

[0219] Calculation Example 1:

[0220]

[0221] The molecular docking process is performed using Maestro ( Glide SP in version 2017-2 [1] The process was performed using the default options. The crystal structure PDB for KRAS_G12C (6UT0) was selected from the PDB database. Cys12 was simulated to Asp12, and after energy optimization, it was used as a docking template. Maestro was used to prepare the protein. [2] The protein preparation wizard module adds hydrogen atoms and uses an OPLS3 force field. For ligand preparation, LigPrep is used to generate the three-dimensional structure of the molecule, and energy minimization is performed. [3] The confgen module was used to sample the conformation of small molecules. A molecule with a side length of [missing information] was generated using the 6UT0 ligand as the centroid. A cubic docking grid was constructed. A reference compound was placed during molecular docking. The interaction types between the protein receptor and ligand were analyzed, and then, based on the calculated docking scrore and binding mode, a reasonable docking conformation was selected and saved, such as... Figure 1 and Figure 2 As shown.

[0222] [1] Glide, LLC, New York, NY, 2017.

[0223] [2] Maestro, LLC, New York, NY, 2017.

[0224] [3]LigPrep, LLC, New York, NY, 2017.

[0225] Conclusion: The compound of this invention has good binding with KRAS G12D.

[0226] Example 1

[0227]

[0228] Step 1: Preparation of intermediates 1-2

[0229] Compound 1-1 (350 mg, 1.39 mmol) was dissolved in anhydrous dichloromethane (3 mL) at -40 °C. Diisopropylethylamine (537.52 mg, 4.16 mmol, 724.42 μL) was added, and the reaction mixture was stirred at this temperature for 0.5 hours. Compound 1-1A (294.31 mg, 1.39 mmol) was then added, and the reaction mixture was slowly heated to 20 °C and stirred for another 0.5 hours. The organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1–4:1) to give compound 1-2. MS m / z = 427.8 [M+1] + .

[0230] Step 2: Preparation of intermediates 1-3

[0231] Compounds 1-2 (270 mg, 630.42 μmol) and 1-2A (150.54 mg, 945.63 μmol) were dissolved in acetonitrile (5 mL), and diisopropylethylamine (244.43 mg, 1.89 mmol, 329.41 μL) was added. The reaction mixture was heated to 80 °C and stirred for 16 hours. The organic solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1 to dichloromethane: methanol = 20:1) to give compounds 1-3. MS m / z = 551.0 [M+1] + .

[0232] Step 3: Preparation of intermediates 1-4

[0233] Under nitrogen protection, compounds 1-3 (180 mg, 326.66 μmol) and 1-3A (200.91 mg, 392.00 μmol) were dissolved in 1,4-dioxane (10 mL) and water (1.5 mL). Sodium carbonate (86.56 mg, 816.66 μmol) and Pd(dppf)Cl2.CH2Cl2 (26.68 mg, 32.67 μmol) were added. The reaction mixture was heated to 100 °C and stirred for 15 hours. After cooling, the mixture was filtered, and extracted with 20 mL of water and ethyl acetate (30 mL * 2). The combined organic phases were washed with saturated brine, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1 to 1:4) to obtain compound 1-4. MS m / z = 901.3 [M+1] + .

[0234] Step 4: Preparation of intermediates 1-5

[0235] Compounds 1-4 (260 mg, 288.52 μmol) were dissolved in anhydrous tetrahydrofuran (5 mL), and tetrabutylamine fluoride (80.62 mg, 865.57 μmol) was added. The reaction mixture was heated to 60 °C and stirred for 19 hours. The organic solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1) to give compounds 1-5. MS m / z = 745.1 [M+1] + .

[0236] Step 5: Preparation of Compound 1

[0237] Compounds 1-5 (50 mg, 67.13 μmol) were dissolved in acetonitrile (3 mL), and a 1,4-dioxane solution of hydrogen chloride (4 M, 671.32 μL) was added. The reaction mixture was stirred at 20 °C for 0.5 hours. After filtration, the crude product was washed with 3 mL of acetonitrile to obtain the hydrochloride salt of compound 1. 1 H NMR (400MHz, CD3OD): δ9.25 (s, 1H), 7.94-7.90 (m, 1H), 7.45-7.35 (m, 2H), 7.28 (d, J=2.4Hz, 1H), 5.68-5.54 (m, 1H), 5.47-5.43(m, 2H), 4.10-3.89(m, 3H), 3.80-3.76(m, 2H), 3.56-3.48(m, 4H), 2.78-2.57(m, 3H), 2.53-2.21(m, 9H).MS m / z=601.3[M+1] + .

[0238] Example 2

[0239]

[0240]

[0241] Step 1: Preparation of intermediate 1-1B-2

[0242] Intermediate 1-1B-1 (120 g, 709 mmol) was dissolved in tert-butanol (1200 mL) and water (1200 mL), followed by the sequential addition of potassium osmium tetroxide dihydrate (10.4 g, 28.3 mmol) and N-methylmorpholine oxide (249 g, 2.13 mol). The reaction mixture was stirred at 45 °C for 16 hours. The mixture was concentrated under reduced pressure to remove excess solvent, extracted with ethyl acetate (500 mL x 2), and washed with saturated sulfurous acid solution (1000 mL). The combined organic layers were washed with saturated brine (500 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1, petroleum ether / ethyl acetate = 0:1) to give 1-1B-2. 1 H NMR (400MHz, CDCl3) δ4.23 (t, J=3.6Hz, 2H), 3.55-3.58 (m, 2H), 3.35-3.32 (m, 2H), 2.87-2.83 (m, 2H), 1.45 (s, 9H).

[0243] Step 2: Preparation of intermediate 1-1B-3

[0244] Intermediate 1-1B-2 (107 g, 526 mmol) was dissolved in dichloromethane (1700 mL) and cooled to 0 °C. Iodobenzene diacetate (254 g, 789 mmol) was then added. The reaction mixture was transferred to 25 °C and stirred for 3 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (500 mL), followed by the addition of dichloromethane (100 mL) and stirring for 0.5 hours. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Methyl tert-butyl ether (200 mL) was added at 25 °C and stirred for 10 minutes. The mixture was then filtered and concentrated under reduced pressure to obtain the crude intermediate 1-1B-3.

[0245] Step 3: Preparation of intermediate 1-1B-4

[0246] Intermediate 1-1B-3 (200 g) was dissolved in tetrahydrofuran (600 mL) and cooled to -78 °C. Ethyl magnesium bromide (1 M, 1.79 L) was then added to the reaction system. The reaction system was subsequently raised to 25 °C and stirred for 16 hours. The reaction system was quenched at 10 °C with saturated ammonium chloride solution (1000 mL) and extracted with ethyl acetate (500 mL). The organic phase was washed with saturated brine (500 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1, petroleum ether:ethyl acetate = 2:1) to obtain intermediate 1-1B-4. 1H NMR (400MHz, CDCl3) δ5.82-5.89 (m, 2H), 5.32 (t, J=11.6Hz, 2H), 5.16-5.19 (m, 2H), 4.45 (s, 2H), 3.60-3.70 (m, 1H), 3.37 (s, 2H), 3.25 (s, 1H), 2.95 (d, J=8.8Hz, 1H), 1.48 (s, 9H).

[0247] Step 4: Preparation of intermediate 1-1B-5

[0248] Intermediate 1-1B-4 (80.0 g, 310 mmol) was dissolved in dichloromethane (1000 mL). The reaction mixture was then transferred to 0 °C and DBU (23.6 g, 155 mmol) and 2,2,2-trichloroacetonitrile (269 g, 1.87 mol) were added. The reaction mixture was then transferred to 25 °C and stirred for 16 hours. The mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (500 mL x 2), washed with water (100 mL x 2), washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1, petroleum ether:ethyl acetate = 5:1) to obtain intermediate 1-1B-5. 1 HNMR (400MHz, CDCl3) δ8.37 (s, 2H), 5.81-5.87 (m, 2H), 5.45 (s, 2H), 5.39-5.43 (m, 2H), 5.25-5.30 (m, 2H), 3.61-3.81 (m, 4H), 1.48 (s, 9H).

[0249] Step 5: Preparation of intermediate 1-1B-6

[0250] Intermediate 1-1B-5A (32.1 g, 238 mmol) was dissolved in DCE (850 mL), followed by the addition of 1,5-cyclooctadiene iridium chloride dimer (12.3 g, 18.3 mmol). The reaction system was cooled to 0 °C, and then intermediate 1-1B-5 (100 g, 183.1 mmol) was dissolved in DCE (1.00 L) and transferred to the above reaction system. The reaction was heated to 25 °C and stirred for 16 hours. Excess solvent was removed by concentration under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1, petroleum ether / ethyl acetate = 10:1) to obtain intermediate 1-1B-6. 1H NMR (400MHz, CDCl3) δ7.52-7.55 (m, 2H), 7.30 (t, J=7.2Hz, 2H), 7.22 (t, J=7.2Hz, 1H), 5.94-6.03 (m, 2H), 5.10 (t, J=19.2Hz, 2H), 4.99 (d, J=10.4Hz, 2H), 3.51-3.61 (m, 4H), 3.33 (t, J=13.6Hz, 2H), 1.48 (s, 15H).

[0251] Step 6: Preparation of intermediate 1-1B-7

[0252] 1-1B-6 (36.0 g, 50.4 mmol) was dissolved in toluene (900 mL), followed by the addition of a second-generation Grubbs catalyst (2.14 g, 2.52 mmol). The reaction mixture was heated to 125 °C and stirred for 16 hours. The mixture was filtered, the filter cake was discarded, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1, petroleum ether / ethyl acetate = 10:1) to give intermediate 1-1B-7. MS: m / z = 329.2, [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.60 (t, J=1.2Hz, 2H), 7.31 (t, J=7.2Hz, 2H), 7.22 (s, 1H), 5.96 (t, J=9.2Hz, 2H), 3.60-3.65(m, 2H), 3.46-3.53(m, 2H), 3.09-3.14(m, 2H), 1.42(s, 9H), 1.25(d, J=6.0Hz, 6H).

[0253] Step 7: Preparation of intermediate 1-1B-8

[0254] Intermediate 1-1B-7 (26.8 g, 81.6 mmol) was dissolved in methanol (201 mL), followed by the addition of HCl / MeOH (4 M, 67.3 mL). The reaction mixture was stirred at 35 °C for 16 hours. The pH of the reaction mixture was adjusted to 12, and the mixture was extracted with ethyl acetate (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-1B-8. MS: m / z = 229.2, [M+1] + . 1HNMR (400MHz, CDCl3) δ7.62 (t, J=7.2Hz, 2H), 7.31 (t, J=7.6Hz, 2H), 7.21 (s, 1H ), 6.01(s, 2H), 3.42(s, 2H), 2.89-2.93(m, 2H), 2.30-2.34(m, 2H), 1.23(s, 6H).

[0255] Step 8: Preparation of intermediate 1-1B-9

[0256] Intermediate 1-1B-8 (18.6 g, 79.4 mmol) was dissolved in THF (190 mL), followed by the addition of fluorenyl chloroformate (20.5 g, 79.4 mmol) and sodium carbonate (25.2 g, 238.2 mmol). The mixture was stirred at 0 °C for 1 hour. Extraction was performed with ethyl acetate (50.0 mL x 2) and washing with water (200.0 mL). The organic phases were combined, washed with saturated brine (150.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate 1-1B-9. MS: m / z = 451.3, [M+1] + . 1 H NMR (400MHz, CDCl3) δ7.76 (d, J=13.6Hz, 2H), 7.54-7.61 (m, 4H), 7.24-7.40 (m, 7H), 5.93-6.01 (m, 2H), 4.34 -4.40 (m, 2H), 4.21 (s, 1H), 3.70 (t, J=2Hz, 2H), 3.55-3.59 (m, 2H), 3.15-3.23 (m, 2H), 1.27 (d, J=2.4Hz, 6H).

[0257] Step 9: Preparation of intermediate 1-1B-10

[0258] Intermediate 1-1B-9 (9.52 g, 21.1 mmol) was dissolved in trifluoroacetic acid (192 mL) and heated to 75 °C with stirring for 16 hours. Water (20.0 mL) was added, and the pH was adjusted to 9. Dichloromethane (20.0 mL) was added for extraction. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was slurried at 25 °C with n-heptane (6 mL) for 2 hours to give trifluoroacetate of 1-1B-10. MS: m / z = 333.1, [M+1] + . 1H NMR (400MHz, CDCl3) δ7.77 (d, J=7.6Hz, 2H), 7.56 (d, J=7.2Hz, 2H), 7.41 (t, J=7.6Hz, 2H), 7.33 (t, J=6Hz, 2H), 6.18-6.27 (m, 2H), 4.38-4.42 (m, 2H), 4.23 (s, 1H), 3.88 (d, J=2.0Hz, 2H), 3.82 (d, J=2.4Hz, 1H), 3.72 (d, J=2.0Hz, 1H), 3.21-3.60 (m, 2H).

[0259] Step 10: Preparation of intermediate 1-1B-11

[0260] The trifluoroacetate of intermediate 1-1B-10 (1.00 g, 2.92 mmol) was dissolved in tetrahydrofuran (10.0 mL), followed by the sequential addition of di-tert-butyl dicarbonate (764 mg, 3.50 mmol) and triethylamine (885 mg, 8.75 mmol) and stirring at 25 °C for 1 hour. Extraction was performed with ethyl acetate (10.0 mL x 2) and water (10.0 mL). The organic phases were combined, washed with saturated brine (15.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1, petroleum ether:ethyl acetate = 3:1) to give intermediate 1-1B-11. MS: m / z = 433.2, [M+1] + .

[0261] Step 11: Preparation of intermediate 1-1B

[0262] Intermediate 1-1B-11 (5.69 g, 12.59 mmol) was dissolved in ethanol (60.0 mL), followed by the addition of dimethylamine (34.4 g, 251.8 mmol). The reaction mixture was stirred at 25 °C for 3 hours. The mixture was directly concentrated under reduced pressure, and the residue was extracted with ethyl acetate (40.0 mL) and 10% citric acid (40.0 mL). The pH of the aqueous phase was adjusted to 9, filtered, and extracted again with ethyl acetate (40.0 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate 1-1B. MS: m / z = 211.2, [M+1] + . 1 H NMR (400MHz, CDCl3) δ6.22 (d, J=10Hz, 2H), 4.40 (d, J=38.8Hz, 2H), 2.89-3.01 (m, 2H), 2.40 (d, J=13.2Hz, 2H), 1.49 (s, 9H).

[0263] Step 12: Preparation of intermediate 2-1

[0264] Intermediate 1-1 (900 mg, 3.56 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0 °C. Then, N,N-diisopropylethylamine (1.38 g, 10.69 mmol) and 1-1B (749.60 mg, 3.56 mmol) were added sequentially, and the reaction was carried out at 0 °C for 1 hour. The crude product 2-1 was then directly concentrated under reduced pressure. MS: m / z = 426.0, [M+1] + .

[0265] Step 13: Preparation of intermediate 2-2

[0266] Intermediate 2-1 (220 mg, 516.10 μmol) and 1-2A were dissolved in acetonitrile (10 mL), followed by the addition of N,N-diisopropylethylamine (200.10 mg, 1.55 mmol). The reaction mixture was heated to 80 °C and stirred for 16 hours. The reaction solution was concentrated under reduced pressure to remove most of the solvent, then extracted with ethyl acetate (10 mL) and water (5 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by silica gel column chromatography (PE / EA = 1 / 1 to DCM / MeOH = 20 / 1) to obtain intermediate 2-2. MS: m / z = 549.1, [M+1] + .

[0267] Step 14: Preparation of intermediates 2-3

[0268] Intermediates 2-2 (120 mg, 218.57 μmol) and 2-2A (70.85 mg, 262.29 μmol) were dissolved in a mixed solution of dioxane (5 mL) and water (0.6 mL). Then, sodium carbonate (69.50 mg, 655.72 μmol) and Pd(dppf)Cl2.CH2Cl2 (17.85 mg, 21.86 μmol, 0.1 ea) were added. The mixture was purged three times with nitrogen, and the reaction was carried out at 100 °C for 5 hours. Solid impurities were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (DCM / MeOH = 20 / 1) to obtain intermediate 2-3. MS: m / z = 657.1, [M+1] + .

[0269] Step 15: Preparation of Compound 2

[0270] Intermediate 2-3 was dissolved in dichloromethane (5 mL), followed by the addition of trifluoroacetic acid (2 mL). The reaction mixture was stirred at 20 °C for 0.5 hours. The trifluoroacetic acid was removed by vacuum concentration to obtain the crude product, which was then separated by prep-HPLC (HPLC: column: Ultimate C18 150*40mm*5μm; mobile phase: [H2O(0.05% HCl)-ACN]; ACN%: 1%-30%, 10 min) to obtain the hydrochloride salt of compound 2 (45 mg, 80.85 μmol). MS: m / z = 557.1 [M+H + ]. 1 H NMR (400MHz, CD3OD) δppm9.38 (s, 1H), 7.85-7.83 (m, 1H), 7.60-7.58 (m, 1H), 7.51 (t, J=7.53Hz, 1H), 7.31 -7.45(m, 3H), 6.44(s, 2H), 5.53-5.72(m, 1H), 5.06-5.02(m, 2H), 4.82(s, 2H), 4.77-4.74(m, 2H), 4.26(br d, J=13.80Hz, 2H), 3.85-4.11(m, 3H), 3.42-3.55(m, 2H), 2.58-2.84(m, 2H), 2.18-2.55(m, 4H).

[0271] Example 3

[0272]

[0273] Step 1: Preparation of intermediate 3-1

[0274] Intermediates 2-2 (500 mg, 0.91 mmol) and 2-2B (308 mg, 0.91 mmol) were dissolved in a mixed solution of dioxane (15 mL) and water (1.2 mL), followed by the addition of sodium carbonate (286 mg, 2.7 mmol). Under nitrogen protection, [1,1-bis(diphenylphosphine)ferrocene]palladium dichloromethane (73 mg, 0.09 mmol) was added, and the mixture was purged three times with nitrogen. The reaction was carried out at 85 °C for 5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (DCM / MeOH = 20 / 1) to obtain intermediate 3-1. MS: m / z = 724.3, [M+1] + .

[0275] Step 15: Preparation of Compound 3

[0276] Intermediate 3-1 (487 mg, 0.67 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of trifluoroacetic acid (3 mL). The reaction mixture was stirred at 20 °C for 1 hour. The trifluoroacetic acid was removed by vacuum concentration to obtain the crude product, which was then separated by preparative HPLC (column: Ultimate C18 150*40 mm*5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile %: 1%-30%, 10 min) to obtain the hydrochloride salt of compound 3 (212 mg, 0.366 mmol). 1 H NMR (400MHz, CD3OD) δ9.16 (s, 1H), 6.94 (s, 1H), 6.74 (s, 1H), 6.31 (s, 2H), 5.58 (d, J=51.9Hz, 1H), 4.66-4.59(m, 3H), 4.11-4.07(m, 2H), 3.94-3.80(m, 3H), 3.38-3.35(m, 2H), 2.68-1.96(m, 11H), 1.76-1.71(m, 2H). MS: m / z=580.2, [M+1] +

[0277] Example 4

[0278]

[0279] Step 1: Synthesis of intermediate 4-1

[0280] 1-1 (3 g, 11.88 mmol) and dichloromethane (30 mL) were added to a pre-dried reaction flask. The reaction solution was cooled to -40 °C. 1-1B-8 (1.90 g, 8.32 mmol) and N,N-diisopropylethylamine (7.68 g, 59.42 mmol) were added sequentially to the reaction solution. The reaction solution was stirred at -40 °C for 0.5 hours. After the reaction was complete, 50 mL of dichloromethane and 50 mL of water were added to the reaction solution. Extraction was performed, and the liquid was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 100:1 to 0:1) to obtain 4-1. MS m / z: 444.1 [M+1] + .

[0281] Step 2: Synthesis of intermediate 4-2

[0282] In a pre-dried reaction flask, 4-1 (2.2 g, 4.95 mmol), 1-2A (1.58 g, 9.90 mmol), N,N-diisopropylethylamine (1.92 g, 14.85 mmol, 2.59 mL), and 1,4-dioxane (20 mL) were stirred at 95 °C for 12 hours. After the reaction was complete, the reaction solution was directly evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 100:1 to 0:1) to obtain 4-2. MS m / z: 567.3 [M+1] + .

[0283] Step 3: Synthesis of intermediate 4-3

[0284] In a pre-dried reaction flask, 4-2A (1.48 g, 4.23 mmol), 4-2 (2 g, 3.53 mmol), cesium carbonate (2.87 g, 8.82 mmol), 1,4-dioxane (20 mL), and water (2 mL) were added. Under nitrogen protection, [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane (288.02 mg, 352.69 μmol) was added to the reaction solution, and the reaction solution was stirred at 80 °C for 3 hours. After the reaction was complete, 30 mL of ethyl acetate and 30 mL of water were added to the reaction solution, and the mixture was extracted. The liquid was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether:ethyl acetate = 100:1 to 0:1) to obtain 4-3. MS m / z: 755.3 [M+1] + .

[0285] Step 4: Synthesis of intermediate 4-4

[0286] 4-3 (2 g, 2.65 mmol) and trifluoroacetic acid (12.08 g, 105.99 mmol) were added to a pre-dried reaction flask, and the reaction mixture was stirred at 65 °C for 0.5 h. The reaction mixture was cooled to room temperature, and 50 mL of water and 100 mL of ethyl acetate were added. The pH was adjusted to 7 with the addition of solid sodium carbonate. Extraction was performed, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: A (acetonitrile) and B (water, containing 10 mM ammonium bicarbonate); gradient: B%: 30%-60%, 8 min) to obtain compound 4-4. MS m / z: 593.2 [M+1] + .

[0287] Step 5: Synthesis of intermediates 4-5

[0288] In a pre-dried reaction flask, 4-4 (1 g, 1.69 mmol), dichloromethane (20 mL), N,N-diisopropylethylamine (654.30 mg, 5.06 mmol), and di-tert-butyl carbonate anhydride (405.13 mg, 1.86 mmol) were added. The reaction mixture was stirred at 20 °C for 3 hours. TLC (DCM:MeOH = 15:1) showed that the starting material was completely consumed and new spots were formed. 20 mL of dichloromethane and 20 mL of water were added to the reaction mixture, and extraction was performed. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was subjected to column chromatography (mobile phase: dichloromethane:methanol = 100:1 to 0:1). Product 4-5 was obtained. MS m / z: 693.4 [M+1] + .

[0289] Step 6: Synthesis of intermediates 4-6

[0290] Add 4-5 (0.2 g, 288.72 μmol), dichloromethane (5 mL), and N,N-diisopropylethylamine (149.26 mg, 1.15 mmol) to a pre-dried reaction flask. Add trifluoromethanesulfonic anhydride (122.19 mg, 433.09 μmol) to the reaction solution at 0 °C and stir for 1 hour. After the reaction is complete, add 10 mL of dichloromethane and 10 g of ice water to the reaction solution, extract, separate, dry the organic phase with anhydrous sodium sulfate, filter, and evaporate to dryness to obtain crude intermediate 4-6. The crude product is used directly in the next step. MS m / z: 825.2 [M+1] + ...

[0291] Step 7: Synthesis of intermediates 4-7

[0292] In a pre-dried reaction flask, 4-6 (0.22 g, 266.74 μmol), diphenylimine (96.69 mg, 533.49 μmol), toluene (5 mL), cesium carbonate (260.73 mg, 800.23 μmol), and 4,5-bis(diphenylphosphine-99-dimethyloxaxanthracene) (30.87 mg, 53.35 μmol) were added. Under nitrogen protection, tris(dibenzylacetone)dipalladium (24.43 mg, 26.67 μmol) was added, and the reaction mixture was stirred at 100 °C for 12 hours. The reaction mixture was directly evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 100:1 to 0:1) to obtain 4-7. MS m / z: 856.2 [M+1] + .

[0293] Step 8: Synthesis of Compound 4

[0294] Compound 4 was added to a pre-dried reaction flask containing 4-7 (0.2 g, 233.67 μmol), ethyl acetate (1 mL), and hydrogen chloride / ethyl acetate (4 M, 20.00 mL). The reaction mixture was stirred at 20 °C for 0.5 h. The reaction mixture was directly evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: A (acetonitrile) and B (water, containing 10 mM ammonium bicarbonate); gradient: B%: 30%-50%, 8 min) to obtain compound 4. 1 H NMR (400MHz, CD3OD) δ = 9.10 (s, 1H), 7.75-7.55 (m, 1H), 7.53-7.47 (m, 1H), 7.38-7.2 5(m, 1H), 7.20-7.14(m, 2H), 6.33(s, 2H), 5.45-5.38(m, 1H), 5.32-5.18(m, 1H), 4.58 -4.47(m, 1H), 4.35-4.20(m, 2H), 4.15-4.00(m, 2H), 3.98-3.78(m, 2H), 3.27-3.22(m , 1H), 3.12-3.01(m, 1H), 2.43-2.13(m, 3H), 1.91-1.73(m, 3H), 2.09-1.89(m, 3H).MS m / z: 592.3[M+1] + .

[0295] Example 5

[0296]

[0297] Step 1: Synthesis of intermediate 5-1

[0298] Add 2-2 (0.3 g, 546.44 μmol), methanol (5 mL), and hydrogen chloride / methanol (4 M, 1.37 mL) to a pre-dried reaction flask. Stir the reaction mixture at 0 °C for 1 hour. After the reaction is complete, evaporate the reaction mixture directly to dryness to obtain the crude product. Add 10 mL of water and 10 mL of ethyl acetate to the crude product, adjust the pH to 8 with sodium bicarbonate solid, extract, separate the layers, collect the organic phase, and evaporate to dryness to obtain 5-1. MS m / z: 449.2 [M+1] + .

[0299] Step 2: Synthesis of intermediate 5-2

[0300] In a pre-dried reaction flask, 5-1 (0.21 g, 467.81 μmol), dichloromethane (10 mL), and triethylamine (142.01 mg, 1.40 mmol) were added. A solution of ethyl 1-(((4-nitrophenoxy)carbonyl)oxy)isobutyrate (166.88 mg, 561.38 μmol) in dichloromethane (3 mL) was added to the reaction mixture. The reaction mixture was stirred at 20 °C for 12 hours. Then, 20 mL of dichloromethane and 20 mL of water were added to the reaction mixture, followed by extraction. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by column chromatography (mobile phase: petroleum ether:ethyl acetate = 100:1 to 0:1) to obtain compound 5-2. MS m / z: 607.2 [M+1] + .

[0301] Step 3: Synthesis of intermediate 5-3

[0302] In a pre-dried reaction flask, 4-2A (89.99 mg, 256.98 μmol), 5-2 (0.13 g, 214.15 μmol), potassium phosphate (90.91 mg, 428.30 μmol), tetrahydrofuran (1 mL), and water (0.25 mL) were added. Under nitrogen protection, [(bis(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)palladium(II) chloride (14.32 mg, 21.42 μmol)] was added to the reaction solution. The reaction solution was stirred at 80 °C for 3 hours. After the reaction was complete, 5 mL of ethyl acetate and 5 mL of water were added to the reaction solution, and the mixture was extracted. The liquid was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by column chromatography (mobile phase: petroleum ether:ethyl acetate = 100:1 to 0:1) to obtain 5-3. MS m / z: 795.3 [M+1] + .

[0303] Step 4: Synthesis of Compound 5

[0304] Compound 5-3 (0.07 g, 88.07 μmol) and hydrogen chloride / ethyl acetate (4 M, 21.00 mL) were added to a pre-dried reaction flask, and the reaction mixture was stirred at 0 °C for 1 hour. 3 g of ice water was added to the reaction mixture, followed by the addition of solid sodium bicarbonate. The pH was adjusted to 8, and 5 mL of ethyl acetate was added. The mixture was extracted, separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: A (acetonitrile) and B (water containing 10 mM ammonium bicarbonate); gradient: B%: 30%-60%, 8 min) to obtain compound 5. 1H NMR (400MHz, CDCl3) δ = 9.14 (s, 1H), 7.79-7.73 (m, 1H), 7.64-7.54 (m, 1H), 7.43-7.39 (m, 1H) ), 7.27-7.23(m, 1H), 6.81-6.75(m, 1H), 6.36-6.25(m, 2H), 5.37-5.20(m, 1H), 4.85-4.70( m, 2H), 4.63-4.43 (m, 2H), 4.16-4.00 (m, 2H), 3.90-3.60 (m, 2H), 3.16-3.00 (m, 3H), 2.88-2 .75(m, 1H), 2.20-1.97(m, 3H), 1.91-1.73(m, 3H), 1.57-1.45(m, 3H), 1.16-1.05(m, 6H).MS m / z: 751.3[M+1] + .

[0305] Examples 6 and 7

[0306]

[0307] Step 1: Synthesis of intermediate 7-1

[0308] In a pre-dried reaction flask, 2-2C (0.23 g, 418.93 μmol), 2-2 (279.13 mg, 544.62 μmol), 1,4-dioxane (4 mL) / water (0.5 mL), and sodium carbonate (111.01 mg, 1.05 mmol) were added. Under nitrogen protection, [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane (34.21 mg, 41.89 μmol) was added, and the reaction mixture was stirred at 100 °C for 3 hours. 10 mL of ethyl acetate and 5 mL of water were added to the reaction mixture, and the mixture was extracted. The liquid was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was subjected to column chromatography (mobile phase: petroleum ether:ethyl acetate = 100:1 to 0:1) to give 7-1. MS m / z: 899.4 [M+1] + .

[0309] Step 2: Synthesis of intermediate 7-2

[0310] 7-1 (0.23 g, 255.80 μmol), tetrahydrofuran (5 mL), and tetramethylammonium fluoride (71.48 mg, 767.41 μmol) were added to a pre-dried reaction flask. The reaction mixture was stirred at 60 °C for 15 hours. The reaction mixture was directly evaporated to dryness to obtain the crude product. The crude product was subjected to column chromatography (mobile phase: petroleum ether: ethyl acetate = 100:1 to 0:1) to give 7-2. MS m / z: 743.5 [M+1] + .

[0311] Step 3: Synthesis of Compound 6

[0312] 7-2 (40 mg, 53.85 μmol), ethyl acetate (1 mL), and hydrogen chloride / ethyl acetate (4 M, 2 mL) were added to a pre-dried reaction flask. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was directly evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography (HPLC) (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: A (acetonitrile) and B (water containing 10 mM formic acid); gradient: B%: 1%-40%, 8 min) to obtain the formate salt of compound 6. 1 H NMR (400MHz, CD3OD) δ = 9.11 (s, 1H), 8.47 (s, 1H), 7.92-7.87 (m, 1H), 7.41-7.32 (m, 2 H), 7.23-7.21(m, 1H), 6.41-6.32(m, 2H), 5.56-5.38(m, 1H), 4.70-4.58(m, 2H), 4.56 -4.43(m, 2H), 4.25-4.17(m, 2H), 3.98-3.86(m, 2H), 3.80-3.55(m, 3H), 3.40-3.35(m , 1H), 2.63-2.37(m, 2H), 2.35-2.28(m, 1H), 2.27-2.15(m, 2H), 2.13-2.00(m, 1H).MS m / z: 599.9[M+1] + .

[0313] Step 4: Synthesis of intermediate 7-4

[0314] Ethyl 1-(((4-nitrophenoxy)carbonyl)oxy)isobutyrate (32.77 mg, 110.25 μmol), dichloromethane (1 mL), compound 6 (33 mg, 55.13 μmol), and N,N-diisopropylethylamine (21.37 mg, 165.38 μmol) were added to a pre-dried reaction flask. The reaction mixture was stirred at 20 °C for 12 hours. 10 mL of water and 10 mL of dichloromethane were added to the reaction mixture, and the mixture was extracted. The extract was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by high-performance liquid chromatography (HPLC) (column: Waters Xbridge BEH C18100*30 mm*10 μm; mobile phase: A (acetonitrile) and B (water, containing 10 mM ammonium bicarbonate); gradient: B%: 55%-85%, 8 min) to obtain 7-4. MS m / z: 915.4 [M+1] + .

[0315] Step 5: Synthesis of Compound 7

[0316] In a pre-dried reaction flask, 7-4 (30 mg, 32.79 μmol), acetonitrile (1 mL), and ammonia (32.83 mg, 327.90 μmol) were added, and the reaction mixture was stirred at 20 °C for 2 hours. Then, 5 mL of dichloromethane and 5 mL of water were added to the reaction mixture, followed by extraction and separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by high-performance liquid chromatography (HPLC) (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: A (acetonitrile) and B (water containing 10 mM ammonium bicarbonate); gradient: B%: 40%-70%, 8 min) to obtain compound 7. 1 H NMR (400MHz, CD3OD) δ = 9.04 (s, 1H), 7.93-7.84 (m, 1H), 7.39-7.30 (m, 2H), 7.22-7.19 (m, 1H), 6. 93-6.85(m, 2H), 6.40-6.26(m, 2H), 5.40-5.25(m, 1H), 4.87-4.78(m, 2H), 4.73-4.53(m, 2H), 4. 35-4.20(m, 2H), 3.96-3.75(m, 2H), 3.40-3.35(m, 1H), 3.29-3.18(m, 3H), 3.09-2.99(m, 1H), 2. 73-2.50(m, 1H), 2.40-2.10(m, 3H), 2.05-1.85(m, 3H), 1.61-1.51(m, 3H), 1.27-1.11(m, 6H).MS m / z: 757.2[M+1] + .

[0317] Example 8

[0318]

[0319] Step 1: Synthesis of Intermediate 8-1

[0320] Intermediate 2-2D (2.3 g, 7.15 mmol), 2-2 (1.96 g, 3.58 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (292.08 mg, 357.66 μmol), and cesium carbonate (3.50 g, 10.73 mmol) were dissolved in a mixed solvent of 1,4-dioxane (15 mL) and water (2 mL). The mixture was purged with nitrogen three times and reacted at 85 °C for 12 hours. After the reaction was complete, 50 mL of ethyl acetate and 10 mL of water were added to the reaction solution, and the mixture was extracted. The liquid was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was subjected to column chromatography (mobile phase: petroleum ether:ethyl acetate = 100:1 to 0:1) to give 8-1. MS m / z: 708.2 [M+1]+

[0321] Step 2: Synthesis of Compound 8

[0322] Intermediate 8-1 (1.3 g, 1.84 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of trifluoroacetic acid (4.62 g, 40.52 mmol), and the reaction was carried out at 25 °C for 1 hour. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, and the mixture was separated by preparative HPLC (column: Ultimate C18 150*40 mm*10 μm; mobile phase: [water (formic acid)-acetonitrile]; B (acetonitrile)%: 5%-35%, 7 min) to obtain the formate salt of compound 8. 1 H NMR (400MHz, CD3OD) δ9.09 (s, 1H), 8.40 (s, 1H), 6.94 (d, J=2.3Hz, 1H), 6.52 (d, J=2.3Hz, 1H), 6.36 (s, 2H), 5.58 (d, J=51.9Hz, 1H), 4.88-4.75 (m, 3H), 4. 66 (s, 2H), 4.55 (s, 2H), 4.16-3.78 (m, 6H), 3.45 (td, J=10.5, 5.7Hz, 1H), 2. 78-2.51(m, 2H), 2.48-2.39(m, 1H), 2.38-2.28(m, 2H), 2.27-2.14(m, 1H).MS m / z: 608.1 [M+1] + .

[0323] Example 9

[0324]

[0325] Step 1: Synthesis of intermediate 9-2

[0326] The starting material 9-1 (2 g, 5.58 mmol) was dissolved in DCM (40 mL), and DIEA (4.33 g, 33.47 mmol) was added under ice bath conditions at 0-10 °C, followed by the dropwise addition of Tf₂O (6.30 g, 22.31 mmol), and the reaction was continued for 1.5 hours. Water (20 mL) was added to the reaction solution and stirred thoroughly. The aqueous phase was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1 to 2:1) to obtain intermediate 9-2.

[0327] Step 2: Synthesis of intermediate 9-3

[0328] Intermediate 9-2 (3 g, 4.82 mmol), 9-2A (1.75 g, 9.64 mmol), Xantphos (557.57 mg, 963.63 μmol), and Cs₂CO₃ (4.71 g, 14.45 mmol) were dissolved in toluene (60 mL), followed by the addition of Pd₂(dba)₃ (441.21 mg, 481.82 μmol). The reaction mixture was reacted at 100 °C for 2 hours under nitrogen protection. The reaction solution was cooled to 25 °C, insoluble matter was filtered off, and the mixture was concentrated to remove most of the toluene. It was diluted with ethyl acetate (30 mL), washed with water (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain intermediate 9-3.

[0329] Step 3: Synthesis of intermediate 9-4

[0330] Intermediate 9-3 (3.1 g, 4.74 mmol), pinacol diboronate (2.41 g, 9.48 mmol), Pd(dppf)Cl2 (693.88 mg, 948.30 μmol), and KOAc (1.40 g, 14.22 mmol) were dissolved in toluene (60 mL) and reacted at 110 °C for 18 hours under nitrogen protection. The reaction solution was cooled to 25 °C, insoluble matter was filtered off, extracted with ethyl acetate (50 mL), washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated into intermediate 9-4 by column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1 to 2:1). MS (ESI) m / z: 468.2 [M+1-Ph2NH] + .

[0331] Step 4: Synthesis of intermediate 9-5

[0332] Intermediate 9-4 (2 g, 3.17 mmol) was dissolved in ethyl acetate (20 mL), and a 2 M, 20 mL solution of ethyl acetate containing hydrogen chloride was added at 25 °C. The mixture was stirred for 0.5 hours. The reaction solution was diluted with ethyl acetate (20 mL), washed with saturated sodium bicarbonate solution (3 x 30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain intermediate 9-5. MS (ESI) m / z: 468.2 [M+1] + .

[0333] Step 5: Synthesis of intermediate 9-6

[0334] Intermediate 9-5 (0.65 g, 1.18 mmol), intermediate 2-2 (830.24 mg, 1.78 mmol), RuPhosPdG2, n-butyldi(1-adamantyl)phosphine (79.16 mg, 118.39 μmol), and K3PO4 (753.95 mg, 3.55 mmol) were dissolved in dioxane (13 mL) and H2O (3 mL). The reaction mixture was reacted at 85 °C for 3 hours under nitrogen protection. The reaction solution was cooled to 25 °C, insoluble matter was filtered off, eluted with ethyl acetate (50 mL), washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (mobile phase: dichloromethane:methanol = 100:1 to 50:1) to obtain intermediate 9-6. MS (ESI) m / z: 854.4 [M+1] + .

[0335] Step 6: Synthesis of intermediate 9-7

[0336] Intermediate 9-6 (50 mg, 58.54 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (385.00 mg, 3.38 mmol) was added at 25 °C. The reaction was continued for 1 hour, and the reaction solution was concentrated to dryness to obtain intermediate 9-7. MS (ESI) m / z: 754.3 [M+1] + .

[0337] Step 7: Synthesis of Compound 9

[0338] Intermediate 9-7 (44 mg, 58.36 μmol) was dissolved in DMF (1 mL), and K2CO3 (80.65 mg, 583.58 μmol) and CsF (44.32 mg, 291.79 μmol) were added at 25 °C. The reaction was continued at 60 °C for 3 hours. The reaction solution was cooled to 25 °C, diluted with ethyl acetate (20 mL), and the aqueous phase was back-extracted with ethyl acetate (20 mL). The organic phases were combined, washed with water (2 x 20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (0.05% NH3H2O)-acetonitrile]; acetonitrile %: 39%-69%, 8 min) to obtain compound 9. MS (ESI) m / z: 598.2 [M+1] + . 1H NMR (400MHz, CD3OD) δ9.02 (s, 1H), 7.74 (dd, J=5.82, 9.07Hz, 1H), 7.24 (t, J=8.94Hz, 1H), 7.19 (d, J=2.25Hz, 1H ), 7.12(d, J=2.13Hz, 1H), 6.27-6.37(m, 2H), 5.22-5.42(m, 1H), 4.47-4.63(m, 2H), 4.16-4.33(m, 2H), 4.05(br s, 2H), 3.77-3.93 (m, 2H), 3.36 (br s, 1H), 3.29 (br d, J=7.88Hz, 2H), 3.23 (br d, J=5.88Hz, 1H), 3.00-3.07 (m, 1H), 2.10-2.40 (m, 3H), 1.83-2.07 (m, 3H).

[0339] Example 10

[0340]

[0341] Step 1: Synthesis of intermediate 10-2

[0342] Intermediate 10⁻¹ (310 g, 1.23 mol) was placed in acetic acid (3000 mL) and cooled to 0 °C. Then, concentrated sulfuric acid (1.21 kg, 12.33 mol) was added, followed by dropwise addition of a 500 mL solution of NaNO₂ (127.59 g, 1.85 mol). The mixture was stirred at 0 °C for 30 min, and then dropwise addition of a 500 mL solution of KI (306.96 g, 1.85 mol). The reaction was carried out at 25 °C for 30 min. 1000 mL of water was added, and the mixture was filtered. The filter cake was washed with water (1500 mL x 3), then with saturated sodium thiosulfate solution (1500 mL x 3), then with water (1500 mL x 3), and finally dried to obtain intermediate 10⁻².

[0343] Step 2: Synthesis of intermediate 10-3

[0344] Intermediate 10⁻² (10 g, 27.60 mmol) and cuprous iodide (15.77 g, 82.79 mmol) were placed in N,N-dimethylformamide (100 mL), followed by the addition of methyl fluorosulfonyl difluoroacetate (21.21 g, 110.39 mmol). The mixture was purged with nitrogen three times and then stirred at 90 °C for 16 hours. After cooling to room temperature, the reaction solution was filtered. The filtrate was added to 100 mL of saturated brine, and the aqueous phase was extracted three times with 100 mL of ethyl acetate. The organic phase was collected, and most of it was removed by rotary evaporation. Approximately 20 mL of the organic phase was washed three times with 20 mL of saturated brine. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 20:1–10:1) to obtain intermediate 10⁻³.

[0345] Step 3: Synthesis of intermediate 10⁻⁴

[0346] Intermediate 10⁻³ (13 g, 44.29 mmol) and iron (9.89 g, 177.14 mmol) were added to ethanol (100 mL) and water (100 mL), followed by ammonium chloride (9.48 g, 177.14 mmol) in water (100 mL). The mixture was stirred at 90 °C for 3 hours. After cooling to room temperature, the mixture was filtered. The ethanol was removed from the filtrate by rotary evaporation, and 50 mL of 2M sodium hydroxide solution was added and stirred for 10 min. The aqueous phase was then extracted three times with 25 mL of ethyl acetate. The organic phase was collected, washed with 25 mL of saturated brine, then washed with 25 mL of water, and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure to obtain the crude product. Intermediate 10⁻⁴ was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 15:1–10:1). MS (ESI) m / z: 274.3 (M+1) + .

[0347] Step 4: Synthesis of intermediate 10-5

[0348] Intermediate 10⁻⁴ (7.5 g, 27.33 mmol), potassium cyclopropyltrifluoroborate (4.85 g, 32.79 mmol), n-butyl-bis(1-adamantyl)phosphine (1.47 g, 4.10 mmol), cesium carbonate (26.71 g, 81.98 mmol), and palladium acetate (613.49 mg, 2.73 mmol) were added to a mixed solvent of toluene (180 mL) and water (18 mL). The mixture was stirred at 80 °C under nitrogen protection for 16 hours. The reaction solution was cooled to room temperature, and 20 mL of water was added. The mixture was separated directly, and the aqueous phase was extracted twice with 20 mL of ethyl acetate. The organic phase was collected and evaporated to dryness to obtain the crude product. Intermediate 10⁻⁵ was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 15:1–10:1). MS (ESI) m / z: 236.0 (M+1) + .

[0349] Step 5: Synthesis of intermediate 10-6

[0350] Intermediate 10⁻⁵ (4.5 g, 19.10 mmol), bis-pinacol boronic acid ester (7.27 g, 28.65 mmol), palladium acetate (428.75 mg, 1.91 mmol), 2-dicyclohexylphosphonium-2,6-dimethoxybiphenyl (1.57 g, 3.82 mmol, 0.2 eq), and potassium acetate (5.62 g, 57.29 mmol, 3 eq) were dissolved in toluene (40 mL) and reacted at 95 °C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature and directly evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 15:1–10:1) to obtain intermediate 10⁻⁶. MS (ESI) m / z: 327.8 (M+1) + .

[0351] Step 6: Synthesis of intermediate 10-7

[0352] Intermediate 10⁻⁶ (419.54 mg, 764.18 μmol), compound 2⁻⁂ (0.5 g, 1.53 mmol), [(di(1-adamantyl)butylphosphino)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (55.65 mg, 76.42 μmol), and potassium phosphate (486.63 mg, 2.29 mmol) were dissolved in water (4 mL) and tetrahydrofuran (20 mL). The reaction mixture was reacted at 80 °C for 16 hours under nitrogen protection. 5 mL of water was added to the reaction mixture, followed by extraction of the aqueous phase three times with 5 mL of ethyl acetate. The organic phase was collected and evaporated to dryness to obtain the crude product. Intermediate 10⁻⁷ was obtained after purification by column chromatography (mobile phase: dichloromethane:methanol = 100:1–50:1). MS (ESI) m / z: 714.3 (M+1) + .

[0353] Step 7: Synthesis of Compound 10

[0354] Intermediate 10-7 (0.3 g, 420.32 μmol) was added to dichloromethane (3 mL), followed by trifluoroacetic acid (924.00 mg, 8.10 mmol, 0.6 mL). The mixture was stirred at 25 °C for 0.5 h. The pH was adjusted to approximately 11 with saturated sodium bicarbonate aqueous solution, and the aqueous phase was extracted three times with 5 mL of dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain the crude product. The crude product was purified by preparative HPLC (column: Boston Green ODS 150*30 mm*5 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile %: 10%-40%, 6 min). Compound 10 was obtained. MS (ESI) m / z: 614.3 (M+1) + . 1 HNMR (400MHz, CD3OD) δppm 9.05 (s, 1H) 8.46 (br s, 1H) 6.54 (s, 1H) 6.38 (d, J = 2.01Hz, 1H) 6.32 (s, 2H) 5.36-5.59 (m, 1H) 4.65 (br s, 2H) 4.52 (q, J = 11.80Hz, 2H) 4.27 (br s, 2H) 3.93 (br s, 2 H) 3.60-3.87 (m, 3H) 3.32-3.40 (m, 1H) 2.03-2.67 (m, 8H) 0.99 (br d, J=8.53Hz, 2H) 0.79 (br s, 2H).

[0355] Example 11

[0356]

[0357] Step 1: Synthesis of intermediate 11-2

[0358] The starting material 11-1 (500 mg, 1.93 mmol) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (3.42 g, 9.65 mmol) were dissolved in acetonitrile (20 mL), and the mixture was heated to 80 °C and reacted for 16 hours. The reaction solution was concentrated to dryness. The crude product was diluted and dissolved in DCM (100 mL), and the insoluble matter was filtered off. The mother liquor was concentrated to obtain intermediate 11-2.

[0359] Step 2: Synthesis of intermediate 11-3

[0360] Intermediate 11-2 (520 mg, 1.88 mmol), bis-pinacolborate (714.96 mg, 2.82 mmol), Pd(dppf)Cl2.CH2Cl2 (153.28 mg, 187.70 μmol), and KOAc (552.63 mg, 5.63 mmol) were dissolved in dioxane (20 mL) and reacted at 80 °C for 7 hours under nitrogen protection. The reaction solution was cooled to 25 °C, filtered to remove insoluble matter, washed with ethyl acetate (50 mL), and concentrated. The crude product was separated into intermediate 11-3 by column chromatography (mobile phase: petroleum ether: ethyl acetate = 20:1 to 10:1). MS (ESI) m / z: 367.1 [M+1] + .

[0361] Step 3: Synthesis of intermediate 11-4

[0362] Intermediate 11-3 (390 mg, 710.37 μmol), intermediate 2-2 (390.14 mg, 1.07 mmol), Pd(dppf)Cl2.CH2Cl2 (58.01 mg, 71.04 μmol), and K3PO4 (452.37 mg, 2.13 mmol) were dissolved in 1,4-dioxane (10 mL) and H2O (2 mL), and reacted at 70 °C for 19 hours under nitrogen protection. The reaction solution was cooled to 25 °C, and insoluble matter was removed by filtration. The crude product was separated by silica gel column chromatography and then by SFC (column: DAICELCHIRALCEL OD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% ammonia, methanol]; methanol %: 45%-45%, 70 min) to obtain intermediate 11-4. MS(ESI) m / z: 711.3 [M+1] + .

[0363] Step 4: Synthesis of Compound 11

[0364] Intermediate 11-4 (18 mg, 25.33 μmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1.54 g, 13.51 mmol) was added at 25 °C. The reaction was continued for 0.5 hours. The reaction solution was concentrated to dryness, and methyl tert-butyl ether (3 x 1 mL) was added and sonicated to form a suspension. The supernatant was removed by centrifugation, and the solid was concentrated to dryness to give compound 11. MS (ESI) m / z: 611.3 [M+1] + . 1HNMR (400MHz, CD3OD) δ9.14 (s, 1H), 7.90 (br dd, J=4.14, 9.16Hz, 1H), 7.46-7.64 (m, 1H), 7.39 (d, J=7.78Hz, 1H), 6.37 (s, 2H), 5.48-5.69 (m, 1H), 4.92-4.99 (m, 2H ), 4.61-4.70(m, 3H), 3.85-4.18(m, 5H), 3.41-3.54(m, 1H), 2.54-2.81(m, 2H), 2.30-2.49(m, 3H), 2.07-2.28(m, 2H).

[0365] Example 12

[0366]

[0367] Step 1: Synthesis of Intermediate 12-2

[0368] Intermediate 12-1 (10.6 g, 45.68 mmol) was dissolved in N,N-dimethylformamide (100 mL), and then potassium tert-butoxide (5.38 g, 47.97 mmol) was added under nitrogen protection. The resulting reaction solution was stirred at 20 °C for 30 minutes, and then ethoxycarbonyl isothiocyanate (6.29 g, 47.97 mmol) was added dropwise. After the addition was complete, the reaction solution was stirred for 1 hour, and then stirred at 100 °C for 1 hour. The reaction solution was poured into 500 mL of water and stirred for 10 minutes. The solid was collected by filtration and dried under vacuum at 45 °C for 2 hours to obtain intermediate 12-2. 1 H-NMR (400MHz, CDCl3) δ: 8.11 (brs, 1H), 7.55-7.51 (m, 1H), 6.96-6.89 (m, 1H), 4.40 (q, J=6.8Hz, 2H), 1.41 (t, J=7.2Hz, 3H).

[0369] Step 2: Synthesis of intermediate 12-3

[0370] Intermediate 12-2 (10.4 g, 30.31 mmol) was added to dimethyl sulfoxide (43.6 mL), followed by sodium hydroxide (5 M, 33.34 mL). The resulting reaction mixture was stirred at 130 °C for 4 hours. The reaction mixture was then slowly poured into 500 mL of water and stirred for 30 minutes, and allowed to stand overnight. The solid was collected by filtration and washed with 100 mL of water. The solid was then collected and dried under vacuum at 45 °C for 4 hours to obtain intermediate 12-3. 1 H-NMR (400MHz, CDCl3) δ: 7.46-7.43 (m, 1H), 6.81 (t, J=8.8Hz, 1H), 5.38 (brs, 2H).

[0371] Step 3: Synthesis of intermediate 12-4

[0372] Intermediate 12-3 (6.0 g, 22.13 mmol) was added to anhydrous ethanol (100 mL), followed by tert-butyloxycarbonyl dianhydride (14.49 g, 66.39 mmol). The resulting reaction solution was stirred in an oil bath at 95 °C for 15 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was dispersed in a mixed solvent (petroleum ether / tert-butylmethyl ether = 20:1, 20 mL) for 10 minutes. The solid was collected by filtration and dried under vacuum at 45 °C for 0.5 hours to obtain intermediate 12-4. 1 H-NMR (400MHz, CDCl3) δ: 7.54-7.51 (m, 1H), 6.92 (t, J=8.8Hz, 1H), 1.60 (s, 9H).

[0373] Step 4: Synthesis of intermediate 12-5

[0374] Intermediate 12-4 (3.2 g, 8.62 mmol) and bis-pinacol boronic acid ester (2.63 g, 10.34 mmol) were added to dioxane (20 mL), followed by potassium acetate (2.54 g, 25.86 mmol) and Pd(dppf)Cl2 (630.74 mg, 862.01 μmol). The resulting reaction solution was completely purged with nitrogen, and then stirred in an oil bath at 105 °C for 15 hours under nitrogen protection. The reaction solution was evaporated to dryness to obtain the crude product. After purification by column chromatography, the crude product was separated by preparative HPLC (column YMC Triart C18 250*50 mm*7 μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile %: 40%-90%, 20 min) to obtain intermediate 12-5. 1 H-NMR (400MHz, CDCl3) δ: 7.91 (br, s, 1H), 7.83-7.79 (m, 1H), 7.03-6.99 (m, 1H), 1.59 (s, 9H), 1.43 (s, 12H).

[0375] Step 5: Synthesis of intermediate 12-6

[0376] Intermediate 12-5 (38.09 mg, 91.07 μmol) and compound 2-2 (50 mg, 91.07 μmol) were dissolved in a mixed solvent of dioxane (2 mL) and water (0.5 mL), followed by nitrogen purging. K3PO4 (57.99 mg, 273.22 μmol) and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1′-biphenyl-2-yl)palladium(II) (6.63 mg, 9.11 μmol) were then added, followed by nitrogen purging, and the reaction was carried out at 60 °C for 10 hours. Insoluble matter was removed by filtration, followed by washing with water (5 mL * 2), extraction with ethyl acetate (20 mL * 2), washing with saturated brine (10 mL), drying on anhydrous sodium sulfate, concentration under reduced pressure to remove organic solvent, and column chromatography to obtain intermediate 12-6. MS (ESI) m / z: 805.5 [M+1] + .

[0377] Step 6: Synthesis of Compound 12

[0378] Intermediate 12-6 (10 mg, 12.42 μmol) was added to a pre-dried reaction flask and dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1.42 mg, 12.42 μmol) was then added, and the reaction mixture was stirred at 20 °C for 12 hours. The organic solvent was removed by concentration under reduced pressure. The crude product was separated by preparative HPLC (column: Phenomenex Luna C18 150*30 mm*5 μm; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; acetonitrile %: 5%-35%, 8 min) to obtain compound 12. MS (ESI) m / z: 605.0 [M+1] + . 1 H NMR (400MHz, CD3OD) δ=9.16 (s, 1H), 7.45 (dd, J=5.1, 8.4Hz, 1H), 7.10 (t, J=8.9Hz, 1H), 6.37 (s, 2H), 5.69-5.51 (m, 1H ), 4.76-4.64(m, 4H), 4.17-3.89(m, 5H), 3.55-3.45(m, 1H), 2.82-2.55(m, 3H), 2.53-2.29(m, 4H), 2.26-2.14(m, 1H).

[0379] Experimental Example 1. KRAS G12D Inhibition activity test

[0380] 1. Experimental objective:

[0381] Using the TR-FRET method, we screened for drugs that can effectively inhibit KRAS. G12D Compounds that bind to GTP.

[0382] 2. Consumables and instruments:

[0383] Table 1 Consumables and Instruments

[0384]

[0385]

[0386] 3. Reagent preparation:

[0387] a. Storage of reagents:

[0388] 1) KRAS nucleotide exchange buffer

[0389] Take 20 mL of 1000 mM HEPES, 20 mL of 500 mM EDTA, 10 mL of 5 M sodium chloride, 100% 0.1 mL of Tween 20, and 949.9 mL of water to prepare a 1 L solution. Sterilize by filtration and store at 4 °C.

[0390] 2) KRAS experimental buffer

[0391] Take 20 mL of 1000 mM HEPES, 10 mL of 1000 mM magnesium chloride, 30 mL of 5 M sodium chloride, 100% 0.05 mL of Tween 20, and 939.95 mL of water to prepare a 1 L solution. Sterilize by filtration and store at 4 °C.

[0392] 3) KRAS / Bodipy GDP / Tb-SA mixture

[0393] Take 9.5 μL of 95 μM KRAS G12D The protein was mixed with 440.5 μL of KRAS nucleotide exchange buffer and incubated at room temperature for 1 hour. Then, it was mixed with 8.4 μL of 17.9 μM Tb-SA, 1.8 μL of 5 mM Bodipy GDP, and 9539.8 μL of KRAS experimental buffer to prepare a 1 L solution. After mixing, the solution was allowed to stand at room temperature for 6 hours and then stored at -80°C.

[0394] b. Experimental reagents:

[0395] 1) KRAS enzyme solution

[0396] Take 73.3 μL of KRAS / Bodipy GDP / Tb-SA mixture and 2126.7 μL of KRAS experimental buffer to prepare a 2200 μL solution.

[0397] 2) SOS / GTP mixture

[0398] Prepare a 2200 μL solution by taking 1.59 μL of 166 μM SOS protein, 198 μL of 100 mM GTP, and 2000.41 μL of KRAS experimental buffer.

[0399] 4. Experimental Procedure:

[0400] 1) The stock solution concentration of the control compound was 1 mM, and the stock solution concentration of the test compound was 10 mM. Transfer 9 μL of the control compound and the test compound to a 384-LDV plate;

[0401] 2) Use Bravo to perform a 10-point 3-fold dilution of the compound on the LDV plate;

[0402] 3) Use ECHO to transfer 9 nL of the compound from the LDV plate to the experimental plate;

[0403] 4) Using the Dragonfly autosampler, add 3 μL of 3 nM Kras / 0.5 nM TB-SA / 30 nM BodipyGDP mixture and 3 μL of Ras buffer to each well of the experimental plate, and centrifuge the experimental plate at 1000 rpm / min for 1 minute.

[0404] 5) The experimental plate was incubated at room temperature for 1 hour;

[0405] 6) Using the Dragonfly autopilot, add 3 μL of 120 nM SOS / 9 mM GTP mixture to each well of the experimental plate, and centrifuge the experimental plate at 1000 rpm / min for 1 minute.

[0406] 7) The experimental plate was incubated at room temperature for 1 hour;

[0407] 8) Use Envision to read the board and record the data;

[0408] 9) Use Excel and XLfit to perform data analysis and calculate the IC50 of the compound to be tested.

[0409] 5. Experimental Results:

[0410] The results are shown in Table 2.

[0411] Table 2. The effects of compounds on KRAS G12D Enzyme-inhibited IC 50 value

[0412] Hydrochloride salt of compound 1 1.8 Hydrochloride salt of compound 2 3.7 Formate of compound 6 0.1

[0413] 6. Experimental Conclusion:

[0414] The compounds of this invention exhibit significant KRAS. G12D Enzyme inhibition.

[0415] Experimental Example 2. GP2D Cell p-ERK Inhibition Test

[0416] 1. Experimental objective:

[0417] Compounds that can effectively inhibit p-ERK in GP2D cells were screened using the HTRF method.

[0418] 2. Experimental Procedure:

[0419] 1) GP2D cells were seeded in clear 96-well cell culture plates, with 80 μL of cell suspension per well, containing 8000 cells per well. The cell culture plates were placed in a CO2 incubator and incubated overnight at 37°C.

[0420] 2) Add 2 μL of the compound to 78 μL of cell culture medium, mix well, then add 20 μL of the compound solution to the corresponding wells of the cell plate, and put the cell plate back into the CO2 incubator to continue incubation for 1 hour;

[0421] 3) After incubation, discard the cell supernatant and add 50 μL of 1X cell lysis buffer to each well, then incubate at room temperature with shaking for 30 minutes;

[0422] 4) Dilute Phospho-ERK1 / 2 Eu Cryptate antibody and Phospho-ERK1 / 2 d2 antibody 20-fold using detection buffer;

[0423] 5) Transfer 16 μL of cell lysate supernatant to each well of a new 384 white microplate, then add 2 μL of Phospho-ERK1 / 2 Eu Cryptate antibody dilution buffer and 2 μL of Phospho-ERK1 / 2 d2 antibody dilution buffer, and incubate at room temperature for at least 4 hours;

[0424] 6) After incubation, use a multi-label analyzer to read HTRF excitation: 320nm, emission: 615nm, 665nm;

[0425] 7) Calculate the IC of the compound to be tested. 50 .

[0426] 3. Experimental Results:

[0427] The results are shown in Table 3.

[0428] Table 3 IC50 of compounds on p-ERK inhibition in GP2D cells 50 value

[0429] Hydrochloride salt of compound 3 8.84 Compound 4 2.50 Formate of compound 8 1.19 Compound 9 0.43

[0430] 4. Experimental conclusions:

[0431] The compounds of this invention exhibit significant GP2D p-ERK inhibitory activity.

[0432] Experiment Example 3. GP2D 3D CTG Experiment

[0433] 1. Experimental objective:

[0434] This experiment aims to verify the inhibitory effect of the compound of the present invention on the proliferation of KRAS G12D mutant GP2D human pancreatic cancer cells.

[0435] 2. Experimental materials:

[0436] Cell lines were cultured in GP2D and DMEM medium. Penicillin / streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera. CellTiter- The 3D Cell Viability Assay reagent was purchased from Promega.

[0437] 3. Experimental methods:

[0438] GP2D cells were seeded in 96-well U-bottom cell culture plates, with 80 μL of cell suspension per well, containing 2000 GP2D cells. The cell culture plates were incubated overnight in a CO2 incubator. The test compound was diluted 5-fold to the 8th concentration using a multipipeline, i.e., from 200 μM to 2.56 nM, and a double-duplicate assay was performed. 78 μL of culture medium was added to the intermediate plate, and then 2 μL of the serially diluted compound was transferred to each well of the intermediate plate according to the corresponding position. After mixing, 20 μL of the compound was transferred to each well of the cell culture plate. The concentration range of the compound transferred to the cell culture plate was 1 μM to 0.0128 nM. The cell culture plates were incubated in a CO2 incubator for 5 days. After the cell culture plates with added compounds had finished incubating, 100 μL of chemiluminescent cell viability assay reagent was added to each well of the cell culture plate, and the plate was incubated at room temperature for 10 minutes to stabilize the luminescence signal. The readings were taken using a multilabel analyzer.

[0439] 4. Data Analysis:

[0440] The original data were converted into inhibition rate using the equation (Sample-Min) / (Max-Min)*100%, IC 50 The value can be obtained by curve fitting using four parameters (obtained in the "log(inhibitor) vs. response--Variable slope" mode of GraphPad Prism).

[0441] 5. Experimental Results:

[0442] The results are shown in Table 4.

[0443] Table 4. IC50 values ​​of compounds against GP2D cell proliferation.

[0444] Formate of compound 8 2.62

[0445] 6. Experimental Conclusion:

[0446] The compounds of this invention exhibit significant anti-proliferative activity in GP2D cells.

[0447] Experimental Example 4. In vivo pharmacokinetic experiment

[0448] 1. Experimental objective:

[0449] This experiment aims to investigate the pharmacokinetic characteristics of the compound of the present invention under oral and intravenous administration in SD mice.

[0450] 2. Experimental Methods:

[0451] The test compound was mixed with a 10% dimethyl sulfoxide / 60% polyethylene glycol 400 / 30% aqueous solution, vortexed and sonicated to prepare a 1 mg / mL clear solution, which was then filtered through a microporous membrane for later use. Male SD mice aged 7 to 10 weeks were selected and administered the candidate compound solution intravenously at a dose of 3 mg / kg. The candidate compound solution was also administered orally at a dose of 30 mg / kg. Whole blood was collected over a certain period to prepare plasma, and drug concentrations were analyzed by LC-MS / MS. Pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight Pharmaceuticals, USA).

[0452] 3. Experimental Results:

[0453] The results are shown in Table 5.

[0454] Table 5. PK properties of the compounds in SD mice.

[0455]

[0456] 4. Experimental conclusions:

[0457] The compounds of this invention exhibit good pharmacokinetic characteristics in mice.

[0458] Experimental Example 5. In vivo pharmacodynamics experiment

[0459] 1. Experimental objective:

[0460] In vivo pharmacodynamic study of a nude mouse model of subcutaneous transplantation of human colorectal cancer GP2D cells into tumors (Balb / c Nude mouse model)

[0461] 2. Experimental Methods:

[0462] Cell culture: Human colorectal cancer GP2D cells were cultured in vitro in a monolayer under the following conditions: DMEM / F12 medium supplemented with 20% fetal bovine serum and 1% penicillin-drug antibiotics, incubated at 37°C in a 5% CO2 incubator. Cells were passaged twice a week using trypsin-EDTA digestion. When cell saturation reached 80%-90% and the desired cell count was achieved, cells were harvested, counted, resuspended in an appropriate amount of PBS, and mixed 1:1 with matrix gel to obtain a cell density of 25 x 10⁶ cells / mL. 6 Cell suspension of cells / mL.

[0463] Cell seeding: 0.2 mL (5 × 10⁻⁶ cells / mL) 6 Mia PaCa-2 cells (with matrix gel, volume ratio 1:1) were subcutaneously inoculated into the right back of each mouse.

[0464] Experimental procedure: The average tumor volume reached 190 mm. 3 At that time, the tumors were randomly divided into groups of 6 animals each, according to their tumor volume. The control group was given a dose of 0 mg / kg, and the test groups were given doses of 30 mg / kg and 100 mg / kg, respectively, with a dose volume of 10 μL / g, administered orally for 22 days, twice a day.

[0465] 3. Tumor measurement and experimental indicators:

[0466] The tumor diameter was measured twice a week using calipers. The formula for calculating tumor volume is: V = 0.5a × b 2 , where a and b represent the long and short diameters of the tumor, respectively.

[0467] The antitumor efficacy of the compounds was evaluated using TGI (%) or relative tumor proliferation rate (T / C) (%). Relative tumor proliferation rate (T / C) (%) = TRTV / CRTV × 100% (TRTV: RTV in the treatment group; CRTV: RTV in the negative control group). Relative tumor volume (RTV) was calculated based on tumor measurements using the formula: RTV = V t / V0, where V0 is the average tumor volume measured at the time of grouped drug administration (i.e., D0), V t The average tumor volume at a given measurement is used; TRTV and CRTV data are taken from the same day.

[0468] TGI (%) reflects the tumor growth inhibition rate. TGI (%) = [(1 - (mean tumor volume at the end of treatment - mean tumor volume at the start of treatment)) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the start of treatment in the solvent control group)] × 100%.

[0469] 4. Experimental Results:

[0470] Table 6. Pharmacodynamic results of compound 8 formate in the mouse GP2D in vivo pharmacodynamic model.

[0471] Number of days of medication 22d TGI 85％

[0472] The formate of compound 8 showed good efficacy in the GP2D mouse in vivo pharmacological model, with a TGI of 85% at an oral dose of 100 mg / kg twice daily.

[0473] 5. Experimental Conclusion:

[0474] The compounds of this invention have excellent tumor-suppressing effects.

Claims

1. The compound of formula (V-2) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (V-2) is, ； in, R1 is selected from phenyl and naphthyl groups, wherein the phenyl and naphthyl groups are optionally surrounded by 1, 2, 3, 4, or 5 R groups. b replace; R2 is F; R3 is F, R4 is H; R5 is H; Each R b Each element is independently selected from F, Cl, OH, NH2, and C. 1-3 Alkyl, C 2-4 alkynyl and cyclopropyl, the C 1-3 Alkyl groups may be optionally substituted with 1, 2, or 3 Rs; R is F; Furthermore, the compound represented by formula (V-2) is not any of the following compounds: , , , , , or .

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R b Each of the following is independently selected from F, Cl, OH, NH2, CH3, CH2CH3, And cyclopropyl, wherein the CH3 and CH2CH3 are optionally substituted with 1, 2 or 3 R.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein each R b Each of the following is independently selected from F, Cl, OH, NH2, CH3, CH2F, CHF2, CF3, CH2CH3, And cyclopropyl.

4. The compound according to claim 1 or 3, or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from , , , , and .

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from , , , , , and .

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from , , , , , , , , , , , , , , and .

7. The compound shown in the following formula or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: , , , , , , , , , and .

8. The compound shown in the following formula or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: , , , , , , , , , , , , and .

9. The compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof in the preparation of a treatment for KRAS G12D Application of compounds in mutated solid tumors.

Images