A compound with anti-tumor activity and its uses

Abstract

The present invention provides a class of compounds, or their tautomers, optical isomers, hydrates, solvates, isotope derivatives, prodrugs or pharmaceutically acceptable salts thereof. The compounds designed by the present invention have novel structures, providing a new direction for the development of drugs of the SOS-1 inhibitor class. In vitro enzyme activity inhibition studies show that these compounds have strong inhibitory effects on SOS-1 and can be used as promising compounds for treating diseases mediated by SOS-1 inhibitors. In addition, the present invention has studied a specific synthesis method, which has a simple process, convenient operation and is conducive to large-scale industrial production and application.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and more particularly, to compounds as SOS1 inhibitors, and methods for preparing and using such compounds. Background Art

[0002] There are three genes in the currently known RAS family: KRAS (Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog), and HRAS (Harvey murine sarcoma viral oncogene). RAS family proteins are a class of small GTPases and were the first oncogenes identified in human tumors. RAS family proteins have weak intrinsic GTPase activity and a slow nucleotide exchange rate. Binding of a GTPase-activating protein (GAP), such as NF1, increases the GTPase activity of RAS family proteins.

[0003] Mutations in the RAS enzyme are closely related to tumorigenesis, and the types of RAS mutations vary in different types of tumors. In human tumors, KRAS mutations (such as amino acids G12, G13, Q61, A146) are the most common, accounting for approximately 85%, while NRAS (such as amino acids G12, G13, Q61, A146) and HRAS (such as amino acids G12, G13, Q61) account for 12% and 3%, respectively. Alterations (such as mutations, overexpression, gene amplification) in RAS family proteins have also been described as resistance mechanisms to cancer drugs such as the EGFR antibodies cetuximab and panitumumab, and the EGFR tyrosine kinase inhibitor osimertinib. For oncogenic RAS mutants, GAP activity is weakened or greatly reduced, resulting in permanent activation, which is the basis of oncogenic RAS signaling. Due to the picomolar affinity of GTP for its binding site, the lack of other well-defined pockets, and the interaction of RAS with GEF, GAP, and effectors through an extended and flat protein-protein interaction surface, directly inhibiting RAS has proven to be extremely challenging and difficult to drug. Therefore, there may be new hope in inhibiting the activation of RAS by targeting the upstream guanine nucleotide exchange factor protein SOS.

[0004] There are two human isoforms of SOS, namely SOS1 and SOS2, but most studies have focused on SOS1. Human SOS1 consists of 1333 amino acids (15 kDa) and includes an N-terminal domain, a Dbl homology (DH) domain, a pleckstrin homology (PH) domain, including a Ras exchanger motif (Rem) domain and a Cdc25 domain, and a C-terminal region. Among them, PH, Rem, and Cdc25 are SOS catComponents of the core catalytic domain.

[0005] In the past few decades, the RAS family protein - SOS1 protein interaction has gained increasing recognition. Additionally, recently, research has been conducted to combine rational design and screening platforms to identify small molecule inhibitors of SOS1, i.e., compounds that bind to SOS1 and inhibit protein - protein interactions with RAS family proteins. As described in CN110167928 / CN111372932 and WO2018172250 / WO2019201848, SOS1 inhibitors of quinazolines and their analogs are described.

[0006] Although some small molecule SOS1 inhibitors have been disclosed, no SOS1 inhibitor has been developed and marketed yet. Therefore, it is still urgently necessary to develop new compounds with potential for marketing and better pharmacodynamic and pharmacokinetic results. The present invention designs a series of compounds with a new structure represented by the general formula and finds that compounds with such a structure exhibit excellent effects and functions, which is of positive significance for the development of SOS1 inhibitors. Summary of the Invention

[0007] The object of the present invention is to provide a compound with a completely new structure as an SOS1 inhibitor, a preparation method of the compound, and its use in treating diseases mediated by SOS1.

[0008] In the first aspect of the present invention, there is provided a compound represented by the following formula (I), or a tautomer, stereoisomer, optical isomer, hydrate, solvate, isotope derivative, prodrug or pharmaceutically acceptable salt thereof,

[0009]

[0010] Wherein,

[0011] represents a single bond or a double bond, and are not both double bonds at the same time, and are not both double bonds at the same time;

[0012] When is a single bond, X is selected from C(R A )(R A ), NR A , O, S; when is a double bond, X is selected from CR A , N;

[0013] R A each occurrence is independently selected from hydrogen, C 1-6 alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3 - 10 - membered heterocyclic group, -C(O)-C 1-6 Alkyl, -C(O)-C 3-10 Cycloalkyl, -C(O)-3 - 10 - membered heterocyclic group, -C 1-6 Alkyl - C(O)-C 1-6 Alkyl, -C 1-6 Alkyl C(O)-C 3-10 Cycloalkyl, -C 1-6 Alkyl C(O)-3 - 10 - membered heterocyclic group and 5 - 10 - membered heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3 - 10 - membered heterocyclic group, -C(O)-C 1-6 Alkyl, -C(O)-C 3-10 Cycloalkyl, -C(O)-3 - 10 - membered heterocyclic group, -C 1-6 Alkyl - C(O)-C 1-6 Alkyl, -C 1-6 Alkyl C(O)-C 3-10 Cycloalkyl, -C 1-6 Alkyl C(O)-3 - 10 - membered heterocyclic group and 5 - 10 - membered heteroaryl are each independently optionally substituted by one or more identical or different R a1 Substituted;

[0014] R a1 Each occurrence is independently selected from -OR c 、-NR c R c 、Halogen, -CN, -C(O)R c 、-C(O)OR c 、-C(O)NR c R c 、-S(O) 2 R c 、-S(O) 2 NR c R c 、-NHC(O)R c 、-N(C 1-4 Alkyl)C(O)R c 、Oxo group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3 - 10 - membered heterocyclic group and 5 - 10 - membered heteroaryl, wherein the C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3- to 10-membered heterocyclic group, and 5- to 10-membered heteroaryl are each optionally substituted by one or more identical or different R c substituents;

[0015] R c each occurrence is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3- to 10-membered heterocyclic group, and 5- to 10-membered heteroaryl;

[0016] When is a single bond, Y is selected from C 1-6 alkyl; when is a double bond, Y is selected from O, S;

[0017] When is a single bond, Z is selected from C, N, O, S, and when Z is selected from O, S, R 2 is absent; when is a double bond, Z is selected from C and N, and when Z is selected from N, R 2 is absent;

[0018] When is a double bond, R 1 is O; when is a single bond, R 1 is selected from -O-R B optionally substituted C 2-4 alkyl, C 2-4 alkenyl, C 3-12 carbocyclic group, C 6-10 aryl, 3- to 12-membered heterocyclic group, and 5- to 10-membered heteroaryl;

[0019] wherein, when is a single bond and R 1 is selected from -O-R B then R B is selected from C 1-6 alkyl, C 3-10 cycloalkyl, and 3- to 10-membered heterocyclic group, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, and 3- to 10-membered heterocyclic group are each optionally substituted by one or more identical or different R b1 substituents;

[0020] R b1 each occurrence is independently selected from -ORc1 、 -NR c1 R c1 、 halogen, -CN, -C(O)R c1 、 -C(O)OR c1 、 -C(O)NR c1 R c1 、 -S(O) 2 R c1 、 -S(O) 2 NR c1 R c1 、 -NHC(O)R c1 、 -N(C 1-4 alkyl)C(O)R c1 、 oxo group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3 - 10 - membered heterocyclic group and 5 - 10 - membered heteroaryl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3 - 10 - membered heterocyclic group and 5 - 10 - membered heteroaryl are each optionally substituted by one or more identical or different R c1 substituents;

[0021] R c1 each occurrence is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3 - 10 - membered heterocyclic group and 5 - 10 - membered heteroaryl;

[0022] Or, when is a single bond and R 1 is selected from C 3-12 carbocyclic group, C 6-10 aryl, 3 - 12 - membered heterocyclic group and 5 - 10 - membered heteroaryl, the C 3-12 carbocyclic group, C 6-10 aryl, 3 - 12 - membered heterocyclic group and 5 - 10 - membered heteroaryl are each optionally substituted by one or more identical or different R a2 substituents;

[0023] R a2 each occurrence is independently selected from -OR c2 、 -C 1-4 alkyl - OH, -NR c2 R c2, halogen, -CN, -C(O)R c2 , -C(O)OR c2 , -C 0-4 alkyl C(O)NR c2 R c2 , -OC(O)R c2 , -S(O) 2 R c2 , -S(O) 2 , -S(O) c2 NR c2 , -NHC(O)R c2 , -N(C 1-4 alkyl)C(O)R c2 , -NHC(O)OR c2 , oxo group, divalent substituent =NH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3- to 10-membered heterocyclic group, and 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3- to 10-membered heterocyclic group, and 5- to 10-membered heteroaryl are optionally substituted by one or more identical or different R c2 substituents;

[0024] R c2 each occurrence is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3- to 10-membered heterocyclic group, and 5- to 10-membered heteroaryl;

[0025] or when is a single bond and R 1 is selected from C 2-4 alkyl and C 2-4 alkenyl, the C 2-4 alkyl and C 2-4 alkenyl are optionally substituted by one or more identical or different R b2 substituents;

[0026] R b2 each occurrence is independently selected from -C(O)R c3 , -C(O)OR c3 , -C(O)NR c3 R c3 , -C(O)NHORc3 and -C(O)-N(C 1-4 alkyl)-OR c3 ;

[0027] R c3 each occurrence is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3 - 10 - membered heterocyclic group, and 5 - 10 - membered heteroaryl;

[0028] R 2 is selected from hydrogen, C 1-6 alkyl, -O - C 1-4 alkyl, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl)(C 1-4 alkyl), and halogen;

[0029] R 3 is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, -O - C 1-4 alkyl, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl)(C 1-4 alkyl), and halogen;

[0030] Ring A is selected from C 4-12 cycloalkyl, 4 - 12 - membered heterocyclic group, C 6-10 aryl, 5 - 12 - membered heteroaryl;

[0031] R 4 each occurrence is independently selected from hydrogen, -NH 2 , C 1-4 alkyl, halogen, C 1-4 haloalkyl, -O - C 1-4 alkyl, -O - C 1-4 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5 - 10 - membered heteroaryl, 3 - 6 - membered heterocyclic group, -O - C 3-6 cycloalkyl, -O - C 6-10 aryl, -O - 5 - 10 - membered heteroaryl, -O - 3 - 6 - membered heterocyclic group, -O - CH 2 -C 3-6 cycloalkyl, -O - CH 2 -C 6-10 aryl, -O - CH 2-5-10-membered heteroaryl, -O-CH 2 -3-6-membered heterocyclic group, -CH=CH-C 3-6 cycloalkyl, -CH=CH-C 6-10 aryl, -CH=CH-5-10-membered heteroaryl, -CH=CH-3-6-membered heterocyclic group, -CH=CH-CH 2 -C 3-6 cycloalkyl, -CH=CH-CH 2 -C 6-10 aryl, -CH=CH-CH 2 -5-10-membered heteroaryl, -CH=CH-CH 2 -3-6-membered heterocyclic group, -SO 2 -C 1-4 alkyl, wherein C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10-membered heteroaryl, 3-6-membered heterocyclic group, -O-C 3-6 cycloalkyl, -O-C 6-10 aryl, -O-5-10-membered heteroaryl, -O-3-6-membered heterocyclic group, -O-CH 2 -C 3-6 cycloalkyl, -O-CH 2 -C 6-10 aryl, -O-CH 2 -5-10-membered heteroaryl, -O-CH 2 -3-6-membered heterocyclic group, -CH=CH-C 3-6 cycloalkyl, -CH=CH-C 6-10 aryl, -CH=CH-5-10-membered heteroaryl, -CH=CH-3-6-membered heterocyclic group, -CH=CH-CH 2 -C 3-6 cycloalkyl, -CH=CH-CH 2 -C 6-10 aryl, -CH=CH-CH 2 -5-10-membered heteroaryl, -CH=CH-CH 2 -3-6-membered heterocyclic group, and the group is optionally substituted with one or more identical or different substituents selected from hydroxy, oxo, C 1-6 alkyl, amino, cyano, nitro, halogen, -C 1-4 alkyl-NH 2 、-C 1-4 alkyl-NH-C 1-4 alkyl, -C 1-4 alkyl-N-(C 1-4 alkyl)(C 1-4 alkyl), C 2-6An alkenyl, C 2-6 substituted by a group of alkynyl; where w = 0, 1, 2, 3, 4.

[0032] Unless otherwise specified, the heteroatoms in the above-mentioned heterocycloalkyl, heteroaryl, and heterocyclic groups are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.

[0033] In a preferred embodiment of the present invention, is a double bond, and Y is selected from O, S.

[0034] In a preferred embodiment of the present invention, is a single bond, and X is selected from C(R A )(R A ), NR A , O, S; where R A is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-8 aryl, 3-6 membered heterocyclic group, -C(O)-C 1-6 alkyl, -C(O)-C 4-6 cycloalkyl, -C(O)-3-6 membered heterocyclic group, -C 1-6 alkyl-C(O)C 1-6 alkyl, -C 1-6 alkyl-C(O)-C 4-6 cycloalkyl, -C 1-6 alkyl-C(O)-3-6 membered heterocyclic group and 5-6 membered heteroaryl; where the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-8 aryl, 3-6 membered heterocyclic group, -C(O)-C 1-6 alkyl, -C(O)-C 4-6 cycloalkyl, -C(O)-3-6 membered heterocyclic group, -C 1-6 alkyl-C(O)-C 1-6 alkyl, -C 1-6 alkyl-C(O)-C 4-6 cycloalkyl, -C 1-6 alkyl-C(O)-3-6 membered heterocyclic group and 5-6 membered heteroaryl are optionally substituted by one or more identical or different R a1 .

[0035] More preferably, in the above scheme, each occurrence of R a1 is independently selected from -OR c , -NR cR c 、 halogen, -CN, -C(O)R c 、 -C(O)OR c 、 -C(O)NR c R c 、 -S(O) 2 R c 、 -S(O) 2 NR c R c 、 -NHC(O)R c 、 -N(C 1-4 alkyl)C(O)R c 、 oxo group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 4-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocyclic group and 5-6 membered heteroaryl group, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 4-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocyclic group and 5-6 membered heteroaryl group are optionally substituted by one or more identical or different R c substituents.

[0036] More preferably, in the above scheme, R c each occurrence independently is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 4-6 cycloalkyl, C 6-10 aryl, 4-6 membered heterocyclic group and 5-6 membered heteroaryl group.

[0037] In a further preferred embodiment of the present invention, is a single bond, X is selected from C(R A )(R A ), NR A , O, S; wherein, R A is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 4-6 cycloalkyl, C 6-8 aryl, 3-6 membered heterocyclic group, -C(O)-C 1-6 alkyl, -C(O)-C 4-6 cycloalkyl, -C(O)-3-6 membered heterocyclic group, -C 1-6 alkyl-C(O)C 1-6 alkyl, -C 1-6alkyl-C(O)-C 4-6 cycloalkyl, -C 1-6 alkyl-C(O)-3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 4-6 cycloalkyl, C 6-8 aryl, 3- to 6-membered heterocyclic group, -C(O)-C 1-6 alkyl, -C(O)-C 4-6 cycloalkyl, -C(O)-3- to 6-membered heterocyclic group, -C 1-6 alkyl-C(O)C 1-6 alkyl, -C 1-6 alkyl-C(O)-C 4-6 cycloalkyl, -C 1-6 alkyl-C(O)-3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are optionally substituted with one or more identical or different R a1 substituents.

[0038] More preferably, in the above scheme, R a1 each occurrence is independently selected from -OR c , -NR c R c , halogen, -CN, -C(O)R c , -C(O)OR c , -C(O)NR c R c , -S(O) 2 R c , -S(O) 2 NR c R c , -NHC(O)R c , -N(C 1-4 alkyl)C(O)R c , oxo group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 4-6 cycloalkyl, C 6-10 aryl, 4- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 4-6 cycloalkyl, C 6-10 aryl, 4- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are optionally substituted with one or more identical or different R c substituents.

[0039] More preferably, in the above scheme, Rc Each occurrence is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, cyclobutyl, vinyl, ethynyl, C 4-6 cycloalkyl, C 6 aryl, 5- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl.

[0040] In a further preferred embodiment of the present invention, is a single bond, and X is selected from NR A , R A is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl.

[0041] In a preferred embodiment of the present invention, is a double bond, Z is selected from C and N, and when Z is selected from N, R 2 does not exist; preferably, is a double bond, and Z is selected from C.

[0042] In a preferred embodiment of the present invention, is a single bond, and R 1 is -O-R B ;

[0043] wherein, R B is selected from C 1-6 alkyl, C 3-10 cycloalkyl, and 3- to 10-membered heterocyclic group, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, and 3- to 10-membered heterocyclic group are optionally substituted by one or more identical or different R b1 ;

[0044] R b1 each occurrence is independently selected from -OR c1 , -NR c1 R c1 , halogen, -CN, -C(O)R c1 , -C(O)OR c1 , -C(O)NR c1 R c1 , -S(O) 2 R c1 , -S(O) 2 NR c1 R c1 , -NHC(O)R c1 , -N(C 1-4 alkyl)C(O)R c1 , oxo group, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3- to 10-membered heterocyclic group, and 5- to 10-membered heteroaryl, wherein the C1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3 - 10 - membered heterocyclic group, and 5 - 10 - membered heteroaryl are optionally substituted by one or more identical or different R c1 substituents;

[0045] R c1 each occurrence is independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3 - 10 - membered heterocyclic group, and 5 - 10 - membered heteroaryl.

[0046] In a further preferred embodiment of the present invention, is a single bond, and R 1 is - O - R B ; wherein, R B is selected from C 1-4 alkyl, C 4-6 cycloalkyl, and 4 - 6 - membered heterocyclic group, and the C 1-4 alkyl, C 4-6 cycloalkyl, and 4 - 6 - membered heterocyclic group are optionally substituted by one or more identical or different R b1 substituents; More preferably, R B is selected from methyl, ethyl, n - propyl, isopropyl, n - butyl, isobutyl, C 5-6 cycloalkyl, 5 - 6 - membered heterocyclic group, all optionally substituted by one or more R b1 substituents.

[0047] More preferably, R b1 each occurrence is independently selected from - OR c1 , - NR c1 R c1 , halogen, - CN, - C(O)R c1 , - C(O)OR c1 , - C(O)NR c1 R c1 , - S(O) 2 R c1 , - S(O) 2 , - NR c1 R c1 , - NHC(O)R c1 , - N(C 1-4 alkyl) - C(O)R c1 , oxo group, C 1-4 alkyl.

[0048] Further preferably, R c1 each occurrence is independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C6-10 aryl, 3- to 10-membered heterocyclic group, and 5- to 10-membered heteroaryl; more preferably, R c1 each occurrence is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, cyclobutyl, tert-butyl.

[0049] In a further preferred embodiment of the present invention, is a single bond, and R 1 is -O-R B wherein R B is selected from C 1-4 alkyl, C 1-4 alkyl-OH, -C 1-4 alkyl-C(O)O C 1-4 alkyl, 5- to 6-membered heterocycloalkyl, said 5- to 6-membered heterocycloalkyl being unsubstituted or substituted by a group selected from halogen, C 1-4 alkyl, -C(O)O C 1-4 alkyl, and the heteroatoms of the heterocycloalkyl are independently selected from O, N, or S, and the number of heteroatoms is 1 or 2; more preferably, R B is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH 2 CH 2 OH, -CH 2 C(O)OCH 2 CH 3 、5- to 6-membered heterocycloalkyl, said 5- to 6-membered heterocycloalkyl being unsubstituted or substituted by a group selected from halogen, methyl, Boc, and the heteroatoms of the heterocycloalkyl are independently selected from O, N, or S, and the number of heteroatoms is 1.

[0050] More preferably, is a single bond, and R 1 is -O-R B wherein R B is selected from methyl, ethyl, isopropyl, -CH 2 CH 2 OH, -CH 2 C(O)OCH 2 CH 3 、tetrahydrofuranyl, pyrrolidinyl, piperidinyl, said tetrahydrofuranyl, pyrrolidinyl, piperidinyl being optionally substituted by a group selected from methyl, Boc.

[0051] More preferably, is a single bond, and R 1 is -O-R B wherein R B is selected from methyl, ethyl, isopropyl, -CH 2 CH 2 OH, -CH2 C(O)OCH 2 CH 3 、

[0052] In a preferred embodiment of the present invention, is a single bond, and R 1 is selected from C 3-10 carbocyclic group, C 6-10 aryl group, 3- to 12-membered heterocyclic group, and 5- to 10-membered heteroaryl group, wherein the C 3-10 carbocyclic group, C 6-10 aryl group, 3- to 12-membered heterocyclic group, and 5- to 10-membered heteroaryl group are optionally substituted by one or more identical or different R a2 substituents.

[0053] More preferably, is a single bond, and R 1 is selected from C 4-9 cycloalkyl group, C 4-9 cycloalkenyl group, C 6-10 aryl group, 4- to 10-membered heterocyclic group, and 5- to 10-membered heteroaryl group, and the C 4-9 cycloalkyl group, C 4-9 cycloalkenyl group, C 6-10 aryl group, 4- to 10-membered heterocyclic group, and 5- to 10-membered heteroaryl group are optionally substituted by one or more identical or different R a2 substituents.

[0054] Even more preferably, R 1 is selected from C 4 monocyclic alkyl group, C 5 monocyclic alkyl group, C 6 monocyclic alkyl group, C 7 monocyclic alkyl group, 3-membered / 4-membered spirocycloalkyl group, 4-membered / 3-membered spirocycloalkyl group, 4-membered / 4-membered spirocycloalkyl group, 4-membered / 5-membered spirocycloalkyl group, 5-membered / 4-membered spirocycloalkyl group, 5-membered / 5-membered spirocycloalkyl group, 4-membered / 6-membered spirocycloalkyl group, 6-membered / 4-membered spirocycloalkyl group, 3-membered / 4-membered fused cycloalkyl group, 4-membered / 3-membered fused cycloalkyl group, 4-membered / 4-membered fused cycloalkyl group, 4-membered / 5-membered fused cycloalkyl group, 5-membered / 4-membered fused cycloalkyl group, 5-membered / 5-membered fused cycloalkyl group, 4-membered / 6-membered fused cycloalkyl group, 6-membered / 4-membered fused cycloalkyl group, C 4 monocyclic alkenyl group, C 5 monocyclic alkenyl group, C 6 monocyclic alkenyl group, C 7Monocyclic alkenyl, 3-membered / 4-membered spiroalkenyl, 4-membered / 3-membered spiroalkenyl, 4-membered / 4-membered spiroalkenyl, 4-membered / 5-membered spiroalkenyl, 5-membered / 4-membered spiroalkenyl, 5-membered / 5-membered spiroalkenyl, 4-membered / 6-membered spiroalkenyl, 6-membered / 4-membered spiroalkenyl, 3-membered / 4-membered fused alkenyl, 4-membered / 3-membered fused alkenyl, 4-membered / 4-membered fused alkenyl, 4-membered / 5-membered fused alkenyl, 5-membered / 4-membered fused alkenyl, 5-membered / 5-membered fused alkenyl, 4-membered / 6-membered fused alkenyl, 6-membered / 4-membered fused alkenyl, 4-membered monocyclic heteroaryl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, 7-membered monocyclic heteroaryl, 3-membered / 4-membered spiroheterocyclic, 4-membered / 3-membered spiroheterocyclic, 4-membered / 4-membered spiroheterocyclic, 4-membered / 5-membered spiroheterocyclic, 5-membered / 4-membered spiroheterocyclic, 5-membered / 5-membered spiroheterocyclic, 4-membered / 6-membered spiroheterocyclic, 6-membered / 4-membered spiroheterocyclic, 3-membered / 4-membered fused heterocyclic, 4-membered / 3-membered fused heterocyclic, 4-membered / 4-membered fused heterocyclic, 4-membered / 5-membered fused heterocyclic, 5-membered / 4-membered fused heterocyclic, 5-membered / 5-membered fused heterocyclic, 4-membered / 6-membered fused heterocyclic, 6-membered / 4-membered fused heterocyclic, 5-membered / 6-membered fused heterocyclic, C 6 Groups of aryl, 5-membered heteroaryl, 6-membered heteroaryl, wherein said groups are optionally substituted by one or more identical or different R a2 Substituents.

[0055] More preferably, in the above scheme, R a2 Each occurrence independently is selected from C 1-6 Alkyl, -OR c2 , -NR c2 R c2 , halogen, -CN, -C(O)R c2 , -C(O)OR c2 , -C(O)NR c2 R c2 , -OC(O)R c2 , -S(O) 2 R c2 , -S(O) 2 NR c2 R c2 , -NHC(O)R c2 , -N(C 1-4 Alkyl)C(O)R c2 , -NHC(O)OR c2 , -C 0-4 Alkyl-C(O)NR c2 R c2 , oxo group, divalent substituent =NH.

[0056] More preferably, in the above scheme, R c2 Each occurrence independently is selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C6-10 aryl, 3- to 10-membered heterocyclic group, and 5- to 10-membered heteroaryl; more preferably, R c2 each occurrence independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, C 3-6 cycloalkyl, phenyl, 3- to 6-membered heterocyclic group.

[0057] In a further preferred embodiment of the present invention, is a single bond, and R 1 is selected from 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group, C 6 aryl, 5-membered heteroaryl, 6-membered heteroaryl, and the 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group, C 6 aryl, 5-membered heteroaryl, and 6-membered heteroaryl are unsubstituted or substituted by substituents selected from halogen, -CN, amino, oxo group, C 1-4 alkyl, C 1-4 alkyl-OH, -C(O)NH 2 , -C(O)-C 1-4 alkyl, and the heteroatoms of the heterocyclic group and heteroaryl are independently selected from O, N, or S, and the number of heteroatoms is 1 or 2; more preferably, R 1 is selected from 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group, C 6 aryl, and the 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group, C 6 aryl are unsubstituted or substituted by substituents selected from halogen, oxo group, methyl, ethyl, -CH 2 OH, -C(O)NH 2 , -C(O)CH 3 , and the heteroatoms of the heterocyclic group and heteroaryl are independently selected from O, N, or S, and the number of heteroatoms is 1.

[0058] More preferably, R 1 is selected from phenyl, 6-membered monocyclic heterocyclic group, and the phenyl and 6-membered monocyclic heterocyclic group are optionally substituted by oxo group, methyl, ethyl, -CH 2 OH, -C(O)NH 2 , -C(O)CH 3 , and the heteroatoms of the heterocyclic group and heteroaryl are independently selected from N, and the number of heteroatoms is 1.

[0059] More preferably, R 1 is selected from phenyl,

[0060] In a preferred embodiment of the present invention, when is a single bond and R 1 is selected from C 2-4 alkyl and C 2-4 alkenyl, the C2-4 Alkyl and C 2-4 The alkenyl is optionally substituted by one or more R b2 substituents;

[0061] R b2 Each occurrence is independently selected from -C(O)R c3 、-C(O)OR c3 、-C(O)NR c3 R c3 、-C(O)NHOR c3 and -C(O)N(C 1-4 alkyl)-OR c3 ;

[0062] R c3 Each occurrence is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3- to 10-membered heterocyclic group, and 5- to 10-membered heteroaryl.

[0063] In a preferred embodiment of the present invention, R 2 is selected from hydrogen, C 1-4 alkyl, -O-C 1-4 alkyl, and halogen; more preferably, R 2 is selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -O-CH 3 、-O-CH 2 CH 3 、-O-CH 2 CH 2 CH 3 、-O-CHCH 3 CH 3 、-O-CH 2 CHCH 3 CH 3 、-O-CH 2 CH 2 CH 2 CH 3 ; when Z is selected from O, S, R 2 is absent. Even more preferably, R 2 is selected from hydrogen, methoxy.

[0064] In a preferred embodiment of the present invention, R 3 is selected from hydrogen, C 1-4 alkyl, -O-C 1-4 alkyl, and halogen; more preferably, R 3Selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl. More preferably, R 3 is selected from hydrogen.

[0065] In a preferred embodiment of the present invention, ring A is selected from C 4-8 cycloalkyl, 4-8 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl; more preferably, ring A is selected from C 5-6 cycloalkyl, 5-6 membered heterocyclic group, C 6-10 aryl, 5-6 membered heteroaryl; even more preferably, ring A is selected from phenyl.

[0066] In a preferred embodiment of the present invention, R 4 each occurrence is independently selected from hydrogen, -NH 2 , C 1-4 alkyl, halogen, C 1-4 haloalkyl, -O-C 1-4 alkyl, -O-C 1-4 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclic group, -O-C 3-6 cycloalkyl, -O-C 6-10 aryl, -O-5-10 membered heteroaryl, -O-3-6 membered heterocyclic group, -O-CH 2 -C 3-6 cycloalkyl, -O-CH 2 -C 6-10 aryl, -O-CH 2 -5-10 membered heteroaryl, -O-CH 2 -3-6 membered heterocyclic group, wherein C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclic group, -O-C 3-6 cycloalkyl, -O-C 6-10 aryl, -O-5-10 membered heteroaryl, -O-3-6 membered heterocyclic group, -O-CH 2 -C 3-6 cycloalkyl, -O-CH 2 -C 6-10 aryl, -O-CH 2 -5-10 membered heteroaryl, -O-CH 2 -3-6 membered heterocyclic group, and the groups are optionally substituted with one or more identical or different groups selected from hydroxy, oxo, C 1-6 alkyl, amino, cyano, nitro, halogen, -C 1-4 alkyl-NH 2 , -C 1-4alkyl-NH-C 1-4 alkyl, -C 1-4 alkyl-N-(C 1-4 alkyl)(C 1-4 alkyl), C 2-6 alkenyl, C 2-6 alkynyl groups; where w = 0, 1, 2, 3, 4;

[0067] More preferably, R 4 each occurrence is independently selected from hydrogen, -NH 2 , C 1-4 alkyl, halogen, C 1-4 haloalkyl, -O-C 1-4 alkyl, -O-C 1-4 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclic group, -O-C 3-6 cycloalkyl, -O-C 6-10 aryl, -O-5-10 membered heteroaryl, -O-3-6 membered heterocyclic group, -O-CH 2 -C 3-6 cycloalkyl, -O-CH 2 -C 6-10 aryl, -O-CH 2 -5-10 membered heteroaryl, -O-CH 2 -3-6 membered heterocyclic group, where C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclic group, -O-C 3-6 cycloalkyl, -O-C 6-10 aryl, -O-5-10 membered heteroaryl, -O-3-6 membered heterocyclic group, -O-CH 2 -C 3-6 cycloalkyl, -O-CH 2 -C 6-10 aryl, -O-CH 2 -5-10 membered heteroaryl, -O-CH 2 -3-6 membered heterocyclic group, and the group is optionally substituted by one or more identical or different groups selected from hydroxy, oxo, C 1-6 alkyl, amino, cyano, nitro, halogen, -C 1-4 alkyl-NH 2 , -C 1-4 alkyl-NH-C 1-4 alkyl, -C 1-4 alkyl-N-(C 1-4 alkyl)(C 1-4 alkyl); where w = 0, 1, 2, 3, 4

[0068] More preferably, R 4 each occurrence is independently selected from hydrogen, -NH 2 , methyl, ethyl, n-propyl, isopropyl, F, Cl, Br, CHF 2 , CF 3 , -O-CH 3 , -O-CF 3 , a 3-membered heterocyclic group, a 4-membered heterocyclic group, a 5-membered heterocyclic group, a 6-membered heterocyclic group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 6 aryl, a 5-membered heteroaryl group, a 6-membered heteroaryl group, and the 3-membered heterocyclic group, 4-membered heterocyclic group, 5-membered heterocyclic group, 6-membered heterocyclic group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 6 aryl, 5-membered heteroaryl group, 6-membered heteroaryl group, and the group is optionally substituted by one or more identical or different groups selected from hydroxy, oxo, C 1-6 alkyl, amino, cyano, nitro, halogen, -C 1-4 alkyl-NH 2 , -C 1-4 alkyl-NH-C 1-4 alkyl, -C 1-4 alkyl-N-(C 1-4 alkyl)(C 1-4 alkyl); where w = 0, 1, 2, 3, 4. Even more preferably, R 4 each occurrence is independently selected from hydrogen, -NH 2 , methyl, ethyl, n-propyl, isopropyl, F, Cl, Br, CHF 2 , -CH(CH 3 )F 2 , CF 3 , -O-CH 3 , -O-CF 3 , and w = 1, 2.

[0069] In a preferred embodiment of the present invention, the compound of formula (I), or its tautomer, stereoisomer, optical isomer, hydrate, solvate, isotope derivative, prodrug or its pharmaceutically acceptable salt, wherein the compound of formula (I) has the structure shown in formula (Ia):

[0070]

[0071] Each substituent in formula (Ia) is defined as in formula (I).

[0072] In a preferred embodiment of the present invention, the compound represented by formula (I), or its tautomer, stereoisomer, optical isomer, hydrate, solvate, isotope derivative, prodrug or pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) has a structure selected from those represented by formula (II) to formula (X):

[0073] Wherein,

[0074] The definitions of the substituents in formula (II) to formula (X) are the same as those in formula (I).

[0075] In a preferred embodiment of the present invention, the compound represented by formula (I), or its tautomer, stereoisomer, optical isomer, hydrate, solvate, isotope derivative, prodrug or pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) has a structure selected from that represented by formula (II-1):

[0076]

[0077] The definitions of the substituents in formula (II-1) are the same as those in formula (I).

[0078] Preferably, in formula (II-1), Y is selected from O.

[0079] In a preferred embodiment of the present invention, the compound represented by formula (I), or its tautomer, stereoisomer, optical isomer, hydrate, solvate, isotope derivative, prodrug or pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) further has a structure selected from those represented by formula (IIa) to formula (Xa):

[0080]

[0081] The definitions of the substituents in formula (IIa) to formula (Xa) are the same as those in formula (I).

[0082] In a preferred embodiment of the present invention, the compound represented by formula (I), or its tautomer, stereoisomer, optical isomer, hydrate, solvate, isotope derivative, prodrug or pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) has a structure selected from that represented by formula (IIa-1):

[0083]

[0084] The definitions of the substituents in formula (IIa-1) are the same as those in formula (I).

[0085] Preferably, in formula (IIa-1), Y is selected from O.

[0086] In a preferred embodiment of the present invention, the compound represented by formula (I), or its tautomer, stereoisomer, optical isomer, hydrate, solvate, isotope derivative, prodrug or pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:

[0087]

[0088]

[0089]

[0090] The object of the present invention also includes providing a method for preparing the compound represented by formula (I), or its tautomer, stereoisomer, optical isomer, hydrate, solvate, isotope derivative, prodrug or pharmaceutically acceptable salt thereof.

[0091] The method can be prepared, for example, by using the method shown in the following scheme, and can be connected by a substitution reaction to obtain the target compound.

[0092]

[0093] Or the method can use halogenation and nucleophilic substitution for connection to synthesize the target compound.

[0094]

[0095] The object of the present invention also includes providing an intermediate for preparing the compound represented by formula (I) as described above in the present invention, or its tautomer, stereoisomer, optical isomer, hydrate, solvate, isotope derivative, prodrug or pharmaceutically acceptable salt thereof.

[0096] The present invention also provides a pharmaceutical composition comprising the compound shown in the present invention, or its tautomer, stereoisomer, optical isomer, hydrate, solvate, isotope derivative, prodrug or pharmaceutically acceptable salt thereof.

[0097] The present invention also provides a pharmaceutical composition comprising the compound shown in the present invention, or its tautomer, stereoisomer, optical isomer, hydrate, solvate, isotope derivative, prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0098] The object of the present invention also includes providing the use of the compound shown in the present invention, or its tautomer, stereoisomer, optical isomer, hydrate, solvate, isotope derivative, prodrug or pharmaceutically acceptable salt thereof in the preparation of a drug for preventing and / or treating diseases mediated by SOS1.

[0099] In some embodiments, the SOS1-mediated disease is cancer or tumor, and related diseases.

[0100] The object of the present invention also includes providing the use of the compound shown in the present invention, or its tautomer, stereoisomer, optical isomer, hydrate, solvate, isotope derivative, prodrug or pharmaceutically acceptable salt thereof in the preparation of a drug for preventing and / or treating diseases caused by RAS mutation.

[0101] The object of the present invention also includes providing a method for preventing and / or treating a disease mediated by SOS1, which includes administering to a patient a therapeutically effective dose of the compound shown in the present invention, or its tautomer, stereoisomer, optical isomer, hydrate, solvate, isotope derivative, prodrug or pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention.

[0102] In some embodiments, the SOS1-mediated disease is cancer or tumor, and related diseases.

[0103] The object of the present invention also includes providing a method for preventing and / or treating a disease caused by RAS mutation, which includes administering to a patient a therapeutically effective dose of the compound shown in the present invention, or its tautomer, stereoisomer, optical isomer, hydrate, solvate, isotope derivative, prodrug or pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention.

[0104] The object of the present invention also includes providing the use of the compound shown in the present invention, or its tautomer, stereoisomer, optical isomer, hydrate, solvate, isotope derivative, prodrug or pharmaceutically acceptable salt thereof for non-diagnostic and non-therapeutic inhibition of the activity of guanine nucleotide exchange factors (GEFs) in vitro, wherein the guanine nucleotide exchange factor is selected from SOS1.

[0105] Definition

[0106] Unless otherwise specified, "carbocyclic group" or "carbocycle" refers to a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C 3-14 carbocyclic group"), and having no heteroatoms in the non-aromatic ring system. In some embodiments, the carbocyclic group has 3-12 ring carbon atoms ("C 3-12 carbocyclic group"), or 4-12 ring carbon atoms ("C 4-12 carbocyclic group"), or 3 to 10 ring carbon atoms ("C 3-10 carbocyclic group"). In some embodiments, the carbocyclic group has 3 to 8 ring carbon atoms ("C 3-8carbocyclic group”). In some embodiments, the carbocyclic group has 3 to 7 ring carbon atoms (“C 3-7 carbocyclic group”). In some embodiments, the carbocyclic group has 4 to 6 ring carbon atoms (“C 4-6 carbocyclic group”). In some embodiments, the carbocyclic group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclic group”), or 5 to 7 ring carbon atoms (“C 5-7 carbocyclic group”). Exemplary C 3-6 carbocyclic groups include, but are not limited to, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), etc. Exemplary C 3-8 carbocyclic groups include, but are not limited to, the aforementioned C 3-6 carbocyclic groups and cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptyl (C 7 ), bicyclo[2.2.2]octyl (C 8 ), etc. Exemplary C 3-10 carbocyclic groups include, but are not limited to, the aforementioned C 3-8 carbocyclic groups and cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10) etc. As illustrated in the above examples, in certain embodiments, the carbocyclic group is monocyclic ("monocyclic carbocyclic") or a fused (fused ring group), bridged (bridged ring group) or spiro-fused (spiro ring group) ring system, such as a bicyclic system ("bicyclic carbocyclic") and can be saturated or can be partially unsaturated. "Carbocyclic" also includes a ring system in which the carbocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclic ring, and in such cases, the number of members of the carbocyclic ring system is the number of carbons in the carbocyclic system after fusion. In certain embodiments, each example of the carbocyclic group is independently optionally substituted, for example, unsubstituted (an "unsubstituted carbocyclic") or substituted with one or more substituents (a "substituted carbocyclic"). In certain embodiments, the carbocyclic group is unsubstituted C 3-10 carbocyclic. In certain embodiments, the carbocyclic group is a substituted C 3-10 carbocyclic.

[0107] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, including straight-chain or branched-chain groups containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (i.e., C 1-10 alkyl), more preferably containing 1-8 carbon atoms (C 1-8 alkyl), even more preferably containing 1-6 carbon atoms (i.e., C 1-6 alkyl), for example, "C 1-6 alkyl" means that the group is an alkyl and the number of carbon atoms in the carbon chain is between 1-6 (specifically 1, 2, 3, 4, 5 or 6). Examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0108] Unless otherwise specified, the term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms, which is straight-chain or branched-chain and has at least one double bond. The alkenyl can contain 2-20 carbon atoms, preferably containing 2-10 carbon atoms (i.e., C 2-10 alkenyl), more preferably containing 2-8 carbon atoms (C 2-8 alkenyl), even more preferably containing 2-6 carbon atoms (i.e., C 2-6 alkenyl), 2-5 carbon atoms (i.e., C 2-5 alkenyl), 2-4 carbon atoms (i.e., C 2-4 alkenyl), 2-3 carbon atoms (i.e., C 2-3 alkenyl), 2 carbon atoms (i.e., C 2 alkenyl), for example, "C2-6 "Alkenyl" means that the group is alkenyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl, etc.

[0109] Unless otherwise specified, the term "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl may contain 2 - 20 carbon atoms, preferably 2 - 10 carbon atoms (i.e., C 2-10 alkynyl), more preferably 2 - 8 carbon atoms (C 2-8 alkynyl), still more preferably 2 - 6 carbon atoms (i.e., C 2-6 alkynyl), 2 - 5 carbon atoms (i.e., C 2-5 alkynyl), 2 - 4 carbon atoms (i.e., C 2-4 alkynyl), 2 - 3 carbon atoms (i.e., C 2-3 alkynyl), 2 carbon atoms (i.e., C 2 alkynyl), for example, "C 2-6 alkynyl" means that the group is alkynyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl, etc.

[0110] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, preferably containing 3 - 12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably 3 - 10 carbon atoms (C 3-10 cycloalkyl), still more preferably 3 - 6 carbon atoms (C 3-6 cycloalkyl), 4 - 6 carbon atoms (C 4-6 cycloalkyl), 5 - 6 carbon atoms (C 5-6 cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc.

[0111] Unless otherwise specified, "cycloalkenyl" means consisting of sub-groups of monocyclic hydrocarbon rings, bicyclic hydrocarbon rings, and spiro - hydrocarbon rings. However, the system is unsaturated, i.e., there is at least one C-C double bond but no aromatic system. Preferably contains 3 - 12 carbon atoms (i.e., C 3-12 cycloalkenyl), more preferably 3 - 10 carbon atoms (C 3-10 cycloalkenyl), still more preferably 3 - 6 carbon atoms (C 3-6 cycloalkenyl), 4 - 6 carbon atoms (C 4-6 cycloalkenyl), 5 - 6 carbon atoms (C5-6 cycloalkenyl).

[0112] Unless otherwise specified, the term "alkoxy" means -O-alkyl, where the alkyl is as defined above, i.e., containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, still more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc.

[0113] Unless otherwise specified, the term "halogen" or "halo" means F, Cl, Br, I. The term "haloalkyl" means that one, two, or more hydrogen atoms or all hydrogen atoms in the alkyl as defined above are replaced by halogen. Representative examples of haloalkyl include CCl 3 , CF 3 , CHCl 2 , CH 2 Cl, CH 2 Br, CH 2 I, CH 2 CF 3 CF 2 CF 3 , etc.

[0114] Unless otherwise specified, the term "heterocyclic group" means a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent, which is a non-aromatic structure and contains 3 to 20 ring atoms, where 1, 2, 3, or more ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably, it contains 3 to 14 ring atoms, more preferably 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 4 to 6 ring atoms, or 5 to 6 ring atoms. The heteroatoms are preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, etc. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

[0115] Unless otherwise specified, "heterocycloalkyl" refers to a monocyclic, saturated "heterocyclic group" or "heterocycle" as defined above, with the ring atoms defined as above, i.e., containing 3 to 20 ring atoms ("3-20 membered heterocycloalkyl"), 1 to 4 heteroatoms (1, 2, 3, or 4), preferably 1 to 3 heteroatoms (1, 2, or 3), where the heteroatoms are each independently selected from N, O, or S. Preferably, it contains 3 to 14 ring atoms ("3-14 membered heterocycloalkyl"), more preferably 3 to 10 ring atoms ("3-10 membered heterocycloalkyl"), even more preferably 3 to 8 ring atoms ("3-8 membered heterocycloalkyl"), even more preferably 4 to 7 ring atoms ("4-7 membered heterocycloalkyl"), even more preferably 5 to 10 ring atoms ("5-10 membered heterocycloalkyl"), and even more preferably 5 to 6 ring atoms ("5-6 membered heterocycloalkyl"). In certain embodiments, each instance of heterocycloalkyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocycloalkyl") or substituted with one or more substituents (a "substituted heterocycloalkyl"). Some exemplary "heterocycloalkyls" are given in the "heterocyclic group" or "heterocycle" section above and also include, but are not limited to, aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, oxanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathianyl, oxazolidinyl, dioxolanyl, dithianyl, thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, etc.

[0116] Unless otherwise specified, the term "aryl" refers to a monocyclic, bicyclic, and tricyclic aromatic carbocyclic system containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms, and the term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups can include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, or pyrenyl, etc.

[0117] Unless otherwise specified, the term "heteroaryl" means an aromatic monocyclic or polycyclic ring system containing 5-12 members, or preferably 5-10 members, 5-8 members, and more preferably 5-6 members, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms being independently selected from O, N or S, and the number of heteroatoms being preferably 1, 2 or 3. Examples of heteroaryl include, but are not limited to, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridinyl, benzopyrimidinyl, benzo pyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0118] Unless otherwise specified, the term "pharmaceutically acceptable salt", "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts which are suitable for use in contact with mammalian tissues, particularly human tissues, without excessive toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid with a suitable reagent. For example, a free base function can be reacted with a suitable acid.

[0119] Unless otherwise specified, the term "solvate" or "solvate" means a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. The physical association includes hydrogen bonding. In certain cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be capable of being separated. The solvent molecules in the solvate may exist in a regular arrangement and / or a disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. Solvates encompass solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0120] Unless otherwise specified, the term "isotope derivative" means that the compounds of the present invention may exist in isotopically labeled or enriched forms and contain one or more atoms whose atomic weights or mass numbers are different from those of the atoms found in the largest amounts in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes commonly used for isotope labeling are: hydrogen isotopes, 2 H and 3 H; carbon isotopes: 13 C and 14 C; chlorine isotopes: 35 Cl and 37 Cl; fluorine isotope: 18 F; iodine isotopes: 123 I and 125 I; nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotope 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. In particular, 3 H and 13 C are more widely used because they are easy to label and convenient to detect. The substitution of certain heavy isotopes, such as deuterium ( 2 H), can enhance metabolic stability, extend the half-life, and thus achieve the purpose of reducing the dose and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques in the same way as non-isotope-labeled compounds.

[0121] Unless otherwise specified, the term "stereoisomer" means a compound having the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers, etc. Any mixture of the resulting stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers based on the differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0122] Unless otherwise specified, the term "tautomer" means a structural isomer that can be interconverted through a low energy barrier and has different energies. If tautomerism is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called proton-transfer tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through the reorganization of some bonding electrons.

[0123] Unless otherwise indicated, the structural formulas described in this invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, the R and S configurations containing asymmetric centers, the (Z) and (E) isomers of double bonds, and the (Z) and (E) conformational isomers. Therefore, the individual stereochemical isomers of the compounds of this invention, or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers) are all within the scope of this invention.

[0124] Unless otherwise specified, the term "prodrug" refers to a drug that is converted into the parent drug in vivo. Prodrugs are usually useful because in some cases, they may be more easily administered than the parent drug. For example, they can be bioavailable by oral administration, while the parent cannot. Compared with the parent drug, the solubility of prodrugs in pharmaceutical compositions is also increased. An example of a prodrug, but not limited to this, can be any compound of formula I that is administered as an ester ("prodrug") to facilitate transport across cell membranes, where water solubility is harmful to mobility but beneficial once inside the cell, and is subsequently metabolically hydrolyzed to a carboxylic acid, i.e., the active entity. Another example of a prodrug can be a short peptide (polyamino acid) conjugated to an acid group, where the peptide is metabolized to reveal the active moiety.

[0125] Unless otherwise specified, the terms "optionally substituted", "optionally substituted by...", "optionally... substituted" mean that the hydrogen at the substitutable site of the group is either unsubstituted or substituted by one or more substituents, which are preferably selected from the following substituents: halogen, hydroxy, mercapto, cyano, nitro, amino, azido, oxo, carboxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 aryl or 5-10 membered heteroaryl, wherein the C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 aryl or 5-10 membered heteroaryl may be optionally substituted by substituents selected from halogen, hydroxy, amino, cyano, C 1-6 alkyl or C 1-6substituted by one or more of alkoxy groups, the oxo group refers to a group in which two Hs at the same substitution position are replaced by the same O to form a double bond, and the “=NH” refers to a group in which two Hs at the same substitution position are replaced by the same -NH- to form a double bond.

[0126] The beneficial effects of the present invention are as follows:

[0127] The present invention designs a class of compounds with novel structures, providing a new direction for the development of SOS1 inhibitor drugs. In vitro enzyme inhibition test studies show that these compounds have strong inhibitory effects on SOS1 and can be used as prospective compounds for treating SOS1-mediated diseases. In addition, the present invention studies a specific synthesis method, which has simple process, convenient operation, and is conducive to large-scale industrial production and application. Specific Embodiments

[0128] The following further elaborates the present invention in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to professionals in the field. In addition, any methods and materials similar or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials shown in the text are only for demonstration purposes.

[0129] The compound structure of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS) or / and high performance liquid chromatography (HPLC). The instrument used for NMR measurement is Bruker AVANCE III 600MHz, and the instruments used for LC-MS are LCMS WATERS ACQUITY UPLC H-Class PLUS or / and SQD2; the instruments used for HPLC are WATERSe2695_2998 or / and Agilent 1100.

[0130] The starting materials in the embodiments of the present invention are known and can be purchased on the market, or can be synthesized by adopting or according to methods known in the art.

[0131] I. Preparation Examples

[0132] Preparation Example 1: Synthesis of Intermediate C-6

[0133]

[0134] Synthesis of Intermediate C-6-1

[0135] Methyl 2-amino-4,5-dimethoxybenzoate (10.01 g, 47.39 mmol) was dissolved in tetrahydrofuran (100 mL), and then sodium hydride (5.69 g, 142.25 mmol, 60% by mass) and methyl iodide (10.10 g, 71.16 mmol) were added. The reaction system was reacted at 65 °C for 3 h, and the raw materials were monitored by LCMS and no residue was left. The reaction solution was quenched slowly with water, extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated and purified by column chromatography (n-hexane:ethyl acetate = 30:1 - 15:1) to obtain intermediate C-6-1 (6.40 g, 28.41 mmol, 60%). ESI-MS (m / z): 226.02 [M+H] + 。

[0136] Synthesis of intermediate C-6-2

[0137] Intermediate C-6-1 (6.40 g, 28.41 mmol) was dissolved in glacial acetic acid (30 mL), and then an aqueous solution of potassium cyanate (4.61 g, 56.84 mmol, 12 mL) was added. The reaction system was reacted overnight at room temperature. The next day, the reaction system was reacted at 80 °C for 16 h, and the raw materials were monitored by LCMS and no residue was left. It was filtered, and the filter cake was washed with water to obtain intermediate C-6-2 (4.39 g, 18.58 mmol, 65%). ESI-MS (m / z): 237.02 [M+H] +

[0138] Synthesis of intermediate C-6

[0139] Intermediate C-6-2 (2.10 g, 8.89 mmol) was dissolved in methanesulfonic acid (20 mL), and then DL-methionine (2.00 g, 13.40 mmol) was added. The reaction system was reacted at 90 °C for 8 h, and the raw materials were monitored by LCMS and no residue was left. The reaction solution was quenched with ice water, and the pH was adjusted to 7 - 8 with saturated aqueous sodium hydroxide solution, and the precipitated solid was filtered to obtain intermediate C-6 (1.69 g, 7.61 mmol, 86%). ESI-MS (m / z): 223.01 [M+H] + 。

[0140] Preparation Example 2: Synthesis of intermediate G-3a

[0141]

[0142] Synthesis of intermediate G-1

[0143] Methyl 2-amino-4-methoxybenzoate (500 mg, 2.76 mmol) was dissolved in N,N-dimethylformamide (20 mL). Subsequently, methyl iodide (588 mg, 4.14 mmol) and anhydrous cesium carbonate (1.80 g, 5.52 mmol) were added. The reaction system was reacted at 100 °C for 48 h, and LCMS monitored that there was no remaining raw material. After cooling to room temperature, water (50 mL) was added to the reaction solution, and it was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (methylene chloride:methanol = 80:1 - 30:1) to obtain intermediate G-1 (300 mg, 1.54 mmol, 56%). ESI-MS (m / z): 196.12 [M+H] + 。

[0144] Synthesis of intermediate G-2

[0145] Intermediate G-1 (300 mg, 1.54 mmol) was dissolved in glacial acetic acid (15 mL). Subsequently, an aqueous solution of potassium cyanate (250 mg, 3.08 mmol, 5 mL) was added. The reaction system was reacted at room temperature for 24 h, and then continued to react at 100 °C for 4 h. LCMS monitored that there was no remaining raw material. After cooling to room temperature, water (50 mL) was added to the reaction solution, and a large amount of solid was precipitated. It was filtered and dried to obtain intermediate G-2 (250 mg, 1.21 mmol, 79%). ESI-MS (m / z): 207.10 [M+H] + 。

[0146] Synthesis of intermediate G-3a:

[0147] Intermediate G-2 (250 mg, 1.21 mmol) was dissolved in carbon tetrachloride (20 mL). Subsequently, bromine (233 mg, 1.45 mmol) was added. The reaction system was stirred and reacted at room temperature for 24 h. LCMS monitored that there was no remaining raw material. Water (50 mL) was added to the reaction solution, and it was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (methylene chloride:methanol = 50:1 - 20:1) to obtain intermediate G-3a (300 mg, 1.05 mmol, 87%). ESI-MS (m / z): 284.98 / 286.98 [M+H] + 。Preparation Example 3: Synthesis of intermediate G-3b

[0148]

[0149] Synthesis of intermediate G-3b-1

[0150] Methyl 2-amino-5-methoxybenzoate (0.50 g, 2.76 mmol) was dissolved in tetrahydrofuran (50 mL), and then cesium carbonate (1.80 g, 5.52 mmol) and methyl iodide (0.59 g, 4.14 mmol) were added. The reaction system was reacted at 65 °C for 3 h, and LCMS monitored that there was no remaining raw material. The reaction solution was filtered, the solvent was removed under reduced pressure from the filtrate, and the residue was separated and purified by column chromatography (n-hexane:ethyl acetate = 40:1 - 20:1) to obtain intermediate G-3b-1 (0.21 g, 1.08 mmol, yield 39%). ESI-MS (m / z): 196.08 [M+H] + 。

[0151] Synthesis of Intermediate G-3b

[0152] Intermediate G-3b-1 (0.21 g, 1.08 mmol) was dissolved in glacial acetic acid (10 mL), and then an aqueous solution of potassium cyanate (0.17 g, 2.16 mmol, 2 mL) was added. The reaction system was reacted overnight at room temperature. The next day, the reaction system was reacted at 80 °C for 3 h, and LCMS monitored that there was no remaining raw material. It was filtered, and the filter cake was washed with water to obtain intermediate G-3b (0.16 g, 0.78 mmol, yield 72%). ESI-MS (m / z): 207.11 [M+H] + 。

[0153] Preparation Example 4: Synthesis of Intermediate G-3c

[0154]

[0155] Synthesis of Intermediate G-3c-1

[0156] Methyl 2-amino-4,5-dimethoxybenzoate (500 mg, 2.37 mmol) was dissolved in dichloromethane (20 mL), and then acetaldehyde (115 mg, 2.61 mmol) and sodium cyanoborohydride (962 mg, 4.54 mmol) were added. The whole reaction system was stirred and reacted at room temperature for 48 h. TLC was used to monitor until there was no remaining raw material. Water (50 mL) was added to the reaction solution, and it was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated and purified by column chromatography (n-hexane:ethyl acetate = 20:1 - 4:1) to obtain intermediate G-3c-1 (500 mg, 2.09 mmol, 88%). ESI-MS (m / z): 240.10 [M+H] + 。

[0157] Synthesis of Intermediate G-3c

[0158] Dissolve intermediate G-3c-1 (500 mg, 2.09 mmol) in glacial acetic acid (15 mL), then add an aqueous potassium cyanate solution (339 mg, 4.18 mmol, 5 mL). The entire system is stirred at room temperature for 24 h, and then stirred at 100 °C for 4 h. TLC is used to monitor the reaction until no raw materials remain. Cool the reaction mixture to room temperature, add water (50 mL) to the reaction solution, a large amount of solid precipitates. Filter and dry to obtain intermediate G-3c-1 (300 mg, 1.19 mmol, 57%). ESI-MS (m / z): 251.12 [M+H] + 。

[0159] Preparation Example 5: Synthesis of Intermediate B-7a

[0160]

[0161] Synthesis of Intermediate B-7a-1

[0162] Dissolve 5-nitro-3-(trifluoromethyl)acetophenone (10.00 g, 43.89 mmol) in ethanol (200 mL), then add iron powder (7.20 g, 128.92 mmol) and concentrated hydrochloric acid (50 mL). The system is reacted at 80 °C for 2 h. LCMS monitors until no raw materials remain. Cool and filter, evaporate the solvent under reduced pressure from the filtrate, and purify the residue by column chromatography (dichloromethane:methanol = 50:1 - 20:1) to obtain intermediate B-7a-1 (8.12 g, 39.97 mmol, 91%). ESI-MS (m / z): 204.12 [M+H] + 。

[0163] Synthesis of Intermediate B-7a-2

[0164] Dissolve intermediate B-7a-1 (27.02 g, 133.00 mmol) in tetrahydrofuran (50 mL), then add (R)-(+)-2-methyl-2-propanesulfinamide (24.24 g, 200.00 mmol) and Ti(OEt) 4 (91.02 g, 399.02 mmol). The system is reacted at 80 °C for 2 h. LCMS monitors until no raw materials remain. Quench the reaction mixture with ice water, dissolve the precipitate in ethyl acetate and filter. Evaporate the solvent under reduced pressure from the filtrate, and purify the residue by column chromatography (dichloromethane:methanol = 50:1 - 20:1) to obtain intermediate B-7a-2 (34.65 g, 113.11 mmol, 85%). ESI-MS (m / z): 307.12 [M+H] + 。

[0165] Synthesis of Intermediate B-7a-3

[0166] Intermediate B-7a-2 (34.65 g, 113.11 mmol) was dissolved in tetrahydrofuran (50 mL). At -78 °C, sodium borohydride (6.40 g, 169.18 mmol) was added. The temperature of the reaction system was slowly raised to room temperature, and LCMS was used to monitor that no starting material remained. The reaction solution was quenched with ice water and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride (100 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated and purified by column chromatography (methylene chloride:methanol = 50:1 - 20:1) to obtain intermediate B-7a-3 (28.41 g, 92.13 mmol, 81%). ESI-MS (m / z): 309.10 [M+H] + 。

[0167] Synthesis of Intermediate B-7a

[0168] Intermediate B-7a-3 (28.41 g, 92.13 mmol) was dissolved in hydrochloric acid dioxane solution (50 mL). The system was reacted at room temperature for 2 h, and LCMS was used to monitor that no starting material remained. The solvent was removed under reduced pressure, and intermediate B-7a was obtained in the form of hydrochloride salt and directly used for the next step of the reaction. ESI-MS (m / z): 205.22 [M+H] + 。

[0169] Preparation Example 6: Synthesis of Intermediate B-7b

[0170]

[0171] The synthesis method of intermediate B-7b is the same as that of intermediate B-7a. ESI-MS (m / z): 190.02 [M+H] + 。

[0172] Preparation Example 7: Synthesis of Intermediate B-7e

[0173]

[0174] The synthesis method of intermediate B-7e is the same as that of intermediate B-7a. ESI-MS (m / z): 204.09 [M+H] + 。

[0175] Preparation Example 8: Synthesis of Intermediate B-7g

[0176]

[0177] The synthesis method of intermediate B-7g is the same as that of intermediate B-7a. ESI-MS (m / z): 208.02 [M+H] + 。

[0178] II. Examples

[0179] Example 1

[0180]

[0181] Intermediate G-3b (50 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (15 mL), and then Intermediate B-7a (74 mg, 0.36 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (140 mg, 0.31 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (55 mg, 0.36 mmol) were added. The reaction system was reacted at room temperature for 8 h. LCMS monitored that there was no remaining raw material. Water (30 mL) was added to the reaction solution, and it was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol = 25:1) to obtain Compound 1 (37 mg, 0.094 mmol, 39%). ESI-MS (m / z): 393.13 [M+H] + 。 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.39 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 3.0 Hz, 1H), 7.36 - 7.30 (m, 2H), 6.83 - 6.80 (m, 2H), 6.71 (s, 1H), 5.56 (s, 2H), 5.49 - 5.47 (m, 1H), 3.85 (s, 3H), 3.42 (s, 3H), 1.53 (d, J = 7.2 Hz, 3H).

[0182] Example 2

[0183]

[0184] Intermediate G-3c (40 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (30 mL), then intermediate B-7a (50 mg, 0.24 mmol), 1,8-diazabicycloundec-7-ene (73 mg, 0.48 mmol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (93 mg, 0.21 mmol) were added. The whole system was stirred at room temperature for 24 h, monitored by TLC until no raw materials remained. Water (50 mL) was added to the reaction solution, and it was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated sodium chloride (50 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. It was separated and purified by column chromatography (methylene chloride:methanol = 60:1 - 15:1) to obtain Compound 2 (40 mg, 0.092 mmol, 58%). ESI-MS (m / z): 437.20 [M+H] + 。 1 HNMR (600 MHz, DMSO-d 6 ) δ 8.18 (d, J = 6.0 Hz, 1H), 7.74 (s, 1H), 6.83 - 6.80 (m, 3H), 6.72 (s, 1H), 5.57 (s, 2H), 5.50 - 5.48 (m, 1H), 4.14 (q, J = 6.0 Hz, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 1.53 (d, J = 6.0 Hz, 3H), 1.16 (t, J = 6.0 Hz, 3H).

[0185] Example 3

[0186]

[0187] Synthesis of Intermediate 3-1:

[0188] Intermediate C-6 (100 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (15 mL), then isopropyl iodide (84 mg, 0.50 mmol) and potassium carbonate (124 mg, 0.90 mmol) were added. The system was reacted at 100 °C for 2 h, monitored by LCMS until no raw materials remained. Water (30 mL) was added to the reaction solution, and it was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated sodium chloride (30 mL×2), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was separated and purified by column chromatography (methylene chloride:methanol = 80:1 - 40:1) to obtain Intermediate 3-1 (75 mg, 0.28 mmol, 63%) ESI-MS (m / z): 264.98 [M+H] + 。

[0189] Synthesis of Compound 3:

[0190] Intermediate 3-1 (75 mg, 0.28 mmol) was dissolved in N,N-dimethylformamide (15 mL), then Intermediate B-7b (96 mg, 0.42 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (163 mg, 0.36 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (130 mg, 0.84 mmol) were added. The reaction system was reacted at room temperature for 8 h. LCMS monitored that there was no remaining raw material. Water (30 mL) was added to the reaction solution, and it was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated sodium chloride (30 mL×2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin-layer chromatography (methylene chloride:methanol = 33:1) to obtain Compound 3 (40 mg, 0.092 mmol, 33%). ESI-MS (m / z): 436.14 [M+H] + 。 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.25 (d, J = 12 Hz, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.71 (d, J = 6.0 Hz, 1H), 7.61 - 7.57 (m, 2H), 6.79 (s, 1H), 5.64 - 5.61 (m, 1H), 4.66 - 4.63 (m, 1H), 3.90 (s, 3H), 3.46 (s, 3H), 1.59 (d, J = 6.0 Hz, 3H), 1.33 - 1.24 (m, 6H).

[0191] Example 4

[0192]

[0193] Synthesis of Intermediate 4-1

[0194] N,N-Dimethylformamide (10 mL), C-6 (50 mg, 0.23 mmol), (S)-3-hydroxytetrahydrofuran tosylate (56 mg, 0.23 mmol), and cesium carbonate (90 mg, 0.28 mmol) were successively added to a 50 mL reaction flask. The reaction system was heated to 100 °C and reacted for 2 h. TLC monitored the completion of the reaction. The reaction solution was concentrated to dryness, and the residue was purified by thin-layer chromatography (methylene chloride:methanol = 50:1) to obtain Intermediate 4-1 (30 mg, 0.10 mmol, 45%). ESI-MS (m / z): 293.12 [M+H] + 。

[0195] Synthesis of Compound 4

[0196] In a 50 mL reaction flask, N,N-dimethylformamide (10 mL), intermediate 4-1 (25 mg, 0.086 mmol), intermediate B-7b (29 mg, 0.13 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (53 mg, 0.12 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (41 mg, 0.27 mmol) were successively added, and the mixture was stirred at room temperature overnight. After monitoring the reaction by TLC until completion, the reaction solution was concentrated to dryness, and the residue was purified by thin-layer chromatography (dichloromethane:methanol = 50:1) to obtain compound 4 (5 mg, 0.011 mmol, 13%). ESI-MS (m / z): 464.17 [M+H] + 。 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.24 (d, J = 7.8 Hz, 1H), 7.79 (s, 1H), 7.74 (s, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.62 - 7.58 (m, 2H), 6.82 (s, 1H), 5.65 - 5.62 (m, 1H), 5.10 - 5.08 (m, 1H), 3.95 (s, 3H), 3.92 - 3.89 (m, 2H), 3.86 - 3.84 (m, 1H), 3.82 - 3.78 (m, 1H), 3.46 (s, 3H), 2.25 - 2.19 (m, 1H), 2.00 - 1.98 (m, 1H), 1.60 (d, J = 7.2 Hz, 3H).

[0197] Example 5

[0198]

[0199] Synthesis of Intermediate 5-1

[0200] The synthesis method was the same as that of compound 4-1, except that (R)-3-hydroxy tetrahydrofuran tosylate was used instead of (S)-3-hydroxy tetrahydrofuran tosylate to obtain intermediate 5-1 with a yield of 72%. ESI-MS (m / z): 293.11 [M+H] + 。

[0201] Synthesis of Compound 5

[0202] The synthesis method was the same as that of compound 4, except that intermediate 5-1 was used instead of 4-1 to obtain compound 5 with a yield of 22%. ESI-MS (m / z): 464.20 [M+H] + 。 1 H NMR (600 MHz, DMSO-d 6)δ8.23(d, J = 7.8Hz, 1H), 7.78(s, 1H), 7.74(s, 1H), 7.71(d, J = 7.2Hz, 1H), 7.61 - 7.57(m, 2H), 6.81(s, 1H), 5.65 - 5.60(m, 1H), 5.09 - 5.08(m, 1H), 3.94(s, 3H), 3.91 - 3.87(m, 2H), 3.84 - 3.82(m, 1H), 3.81 - 3.77(m, 1H), 3.45(s, 3H), 2.24 - 2.18(m, 1H), 2.00 - 1.98(m, 1H), 1.58(d, J = 7.2Hz, 3H).

[0203] Example 6

[0204]

[0205] Synthesis of Intermediate 6-1

[0206] The synthesis method was the same as that of Compound 4-1, except that (R)-3-(tosyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester was used instead of (S)-3-hydroxytetrahydrofuran p-toluenesulfonate to obtain Intermediate 6-1 with a yield of 80%. ESI-MS (m / z): 392.17 [M+H] + .

[0207] Synthesis of Compound 6

[0208] The synthesis method was the same as that of Compound 4 to obtain Compound 6 with a yield of 18%. ESI-MS (m / z): 563.24 [M+H] + . 1 HNMR(600MHz, DMSO-d 6 )δ8.24 - 8.23(m, 1H), 7.84(d, J = 9.0Hz, 1H), 7.73(s, 1H), 7.70(d, J = 7.2Hz, 1H), 7.61 - 7.56(m, 2H), 6.82(s, 1H), 5.64 - 5.59(m, 1H), 5.04 - 4.98(m, 1H), 3.93(s, 3H), 3.56 - 3.53(m, 1H), 3.45(s, 3H), 3.43 - 3.39(m, 3H), 2.08 - 2.05(m, 2H), 1.58(d, J = 6.6Hz, 3H), 1.41(d, J = 13.2Hz, 9H).

[0209] Example 7

[0210]

[0211] In a 50 mL reaction flask, dichloromethane (5 mL), compound 6 (120 mg, 0.21 mmol) and trifluoroacetic acid (1 mL) were successively added. The reaction was stirred at room temperature for 2 h. After monitoring the completion of the reaction by TLC, the solvent was removed by concentration under reduced pressure. The residue was dissolved in dichloromethane (30 mL), and the organic phase was washed with saturated sodium bicarbonate solution. After drying over anhydrous sodium sulfate, the solvent was removed to obtain the crude product. The crude product was purified by thin layer chromatography (dichloromethane:methanol = 20:1) to obtain compound 7 (80 mg, 0.17 mmol, 82%). ESI-MS (m / z): 463.19 [M+H] + 。 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.23 (d, J = 7.8 Hz, 1H), 7.84 (s, 1H), 7.74 - 7.71 (m, 2H), 7.62 - 7.57 (m, 2H), 6.84 (s, 1H), 5.65 - 5.60 (m, 1H), 5.10 - 5.09 (m, 1H), 3.95 (s, 3H), 3.51 - 3.49 (m, 1H), 3.48 (s, 3H), 3.44 - 3.41 (m, 1H), 3.40 - 3.35 (m, 2H), 2.18 - 2.15 (m, 2H), 1.91 (s, 1H), 1.60 (d, J = 7.2 Hz, 3H).

[0212] Example 8

[0213]

[0214] In a 50 mL reaction flask, compound 7 (20 mg, 0.043 mmol), formic acid (1 mL) and aqueous formaldehyde solution (2 mL) were successively added. The reaction was stirred at 70 °C for 6 h. After monitoring the completion of the reaction by TLC, the reaction solution was poured into saturated sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and then concentrated under reduced pressure to remove the solvent. The residue was purified by thin layer chromatography (dichloromethane:methanol:triethylamine = 100:3:1) to obtain compound 8 (15 mg, 0.031 mmol, 73%). ESI-MS (m / z): 477.20 [M+H] + 。 1 HNMR (600 MHz, DMSO-d 6)δ8.31(d, J = 7.8 Hz, 1H), 7.83(s, 1H), 7.76(s, 1H), 7.73(d, J = 7.2 Hz, 1H), 7.62 - 7.57(m, 2H), 6.84(s, 1H), 5.67 - 5.62(m, 1H), 5.13 - 5.09(m, 1H), 3.96(s, 3H), 3.46(s, 3H), 3.12 - 3.08(m, 2H), 2.78 - 2.75(m, 2H), 2.50(s, 3H), 2.14 - 2.02(m, 2H), 1.60(d, J = 7.2 Hz, 3H).

[0215] Example 9

[0216]

[0217] Synthesis of Intermediate 9 - 1:

[0218] Dissolve Intermediate C - 6 (150 mg, 0.68 mmol) in N,N - dimethylformamide (15 mL), then add (S)-3-(tosyloxy)pyrrolidine - 1 - carboxylic acid tert - butyl ester (253 mg, 0.75 mmol) and cesium carbonate (264 mg, 0.82 mmol). React the system at 100 °C for 3 h and monitor by LCMS until no raw materials remain. Add water (30 mL) to the reaction solution, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (30 mL × 2), and dry over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure, and purify the residue by column chromatography (dichloromethane:methanol = 50:1 - 25:1) to obtain Intermediate 9 - 1 (105 mg, 0.27 mmol, 40%). ESI - MS (m / z): 392.10 [M + H] + .

[0219] Synthesis of Compound 9:

[0220] The intermediate 9-1 (105 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (15 mL). Then, intermediate B-7b (91 mg, 0.41 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (154 mg, 0.35 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (122 mg, 0.81 mmol) were added. The reaction system was stirred at room temperature for 8 h. When no starting materials were detected by LCMS, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated sodium chloride solution (30 mL×2) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol = 25:1) to obtain compound 9 (88 mg, 0.16 mmol, 59%). ESI-MS (m / z): 563.22 [M+H] + 。 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.27 (m, 1H), 7.83 (s, 1H), 7.75 - 7.66 (m, 2H), 7.61 - 7.53 (m, 2H), 6.82 (s, 1H), 5.62 - 5.61 (m, 1H), 5.03 - 5.00 (m, 1H), 3.93 (s, 3H), 3.54 - 3.43 (m, 4H), 3.41 (s, 3H), 2.09 - 2.05 (m, 2H), 1.56 (d, J = 7.2 Hz, 3H), 1.42 - 1.40 (m, 9H).

[0221] Example 10

[0222]

[0223] Compound 9 (70 mg, 0.12 mmol) was dissolved in dichloromethane (15 mL). Then, trifluoroacetic acid (2 mL) was added. The reaction system was stirred at room temperature for 3 h. When no starting materials were detected by LCMS, the solvent of the reaction mixture was removed under reduced pressure. Water (5 mL) was added to the residue, and the pH was adjusted to 8 - 9 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated sodium chloride solution (10 mL×2) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol = 5:1) to obtain compound 10 (25 mg, 0.054 mmol, 45%). ESI-MS (m / z): 463.13 [M+H] + 。 1 H NMR (600 MHz, DMSO-d 6)δ8.32(d, J = 7.8 Hz, 1H), 7.88(s, 1H), 7.75 - 7.72(m, 2H), 7.61 - 7.58(m, 2H), 6.81(s, 1H), 5.64 - 5.62(m, 1H), 5.03 - 5.02(m, 1H), 3.93(s, 3H), 3.45(s, 3H), 3.25 - 3.11(m, 4H), 2.10 - 2.08(m, 3H), 1.60(d, J = 7.2 Hz, 3H).

[0224] Example 11

[0225]

[0226] Compound 10 (30 mg, 0.065 mmol) was dissolved in formic acid (4 mL), and then aqueous 37% formaldehyde solution (2 mL) was added. The reaction system was reacted at 70 °C for 12 h. LCMS monitored that there was no remaining raw material. The reaction solution was adjusted to pH 7 - 8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (15 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (15 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by thin layer chromatography (methylene chloride:methanol:triethylamine = 100:2.5:1) to obtain compound 11 (18 mg, 0.038 mmol, 58%). ESI-MS (m / z): 477.23 [M + H] + . 1 1H NMR (600 MHz, DMSO-d 6 )δ8.30(d, J = 7.8 Hz, 1H), 7.75 - 7.72(m, 3H), 7.62 - 7.57(m, 2H), 6.81(s, 1H), 5.66 - 5.62(m, 1H), 5.04 - 5.03(m, 1H), 3.94(s, 3H), 3.46(s, 3H), 3.05(m, 1H), 2.84 - 2.80(m, 2H), 2.66(m, 1H), 2.42(s, 3H), 2.40 - 2.34(m, 1H), 1.88 - 1.86(m, 1H), 1.60(d, J = 7.2 Hz, 3H).

[0227] Example 12

[0228]

[0229] Synthesis of Intermediate 12 - 1

[0230] Intermediate C-6 (150 mg, 0.68 mmol) was dissolved in N,N-dimethylformamide (15 mL). Then, tert-butyl 4-(tosyloxy)piperidine-1-carboxylate (264 mg, 0.74 mmol) and potassium carbonate (186 mg, 1.36 mmol) were added. The reaction system was reacted at 100 °C for 3 h, and LCMS monitored that there was no remaining raw material. Water (30 mL) was added to the reaction solution, and it was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated and purified by column chromatography (methylene chloride:methanol = 70:1 - 20:1) to obtain Intermediate 12-1 (120 mg, 0.30 mmol, yield 44%). ESI-MS (m / z): 406.11 [M+H] + 。

[0231] Synthesis of Intermediate 12-2

[0232] Intermediate 12-1 (120 mg, 0.30 mmol) was dissolved in N,N-dimethylformamide (15 mL). Then, Intermediate B-7b (100 mg, 0.45 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (170 mg, 0.39 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (135 mg, 0.90 mmol) were added. The reaction system was reacted at room temperature for 8 h. LCMS monitored that there was no remaining raw material. Water (30 mL) was added to the reaction solution, and it was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated and purified by thin layer chromatography (methylene chloride:methanol = 25:1) to obtain Intermediate 12-2 (70 mg, 0.12 mmol, 41%). ESI-MS (m / z): 577.26 [M+H] + 。

[0233] Synthesis of Intermediate 12-3

[0234] Intermediate 12-2 (35 mg, 0.061 mmol) was dissolved in methylene chloride (15 mL). Then, trifluoroacetic acid (2 mL) was added. The reaction system was reacted at room temperature for 3 h. LCMS monitored that there was no remaining raw material. The solvent of the reaction solution was removed under reduced pressure. Water (5 mL) was added to the residue, and the pH was adjusted to 8 - 9 with saturated aqueous sodium bicarbonate solution. It was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride (10 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated and purified by thin layer chromatography (methylene chloride:methanol = 5:1) to obtain Intermediate 12-3 (23 mg, 0.048 mmol, 79%). ESI-MS (m / z): 477.15 [M+H] + 。

[0235] Synthesis of Compound 12

[0236] Dissolve intermediate 12-3 (23 mg, 0.048 mmol) in formic acid (4 mL), then add aqueous 37% formaldehyde solution (2 mL). The reaction system is reacted at 70 °C for 12 h. LCMS monitors that there is no remaining raw material. The reaction solution is adjusted to pH 7-8 with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate (15 mL × 3). The organic phases are combined, washed with saturated sodium chloride solution (15 mL × 2), and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure, and the residue is purified by thin layer chromatography (methylene chloride:methanol:triethylamine = 100:2.5:1) to obtain compound 12 (10 mg, 0.020 mmol, 42%). ESI-MS (m / z): 491.17 [M+H] + 。 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.34 (d, J = 6.0 Hz, 1H), 7.96 (s, 1H), 7.76 (s, 1H), 7.72 (d, J = 12.0 Hz, 1H), 7.62 - 7.57 (m, 2H), 6.81 (s, 1H), 5.63 - 5.60 (m, 1H), 4.41 - 4.40 (m, 1H), 3.95 (s, 3H), 3.45 (s, 3H), 3.05 - 2.91 (m, 4H), 2.43 (s, 3H), 1.99 - 1.97 (m, 2H), 1.80 - 1.78 (m, 2H), 1.59 (d, J = 6.0 Hz, 3H).

[0237] Example 13

[0238]

[0239] Synthesis of Intermediate 13-1

[0240] Intermediate G-3a (300 mg, 1.05 mmol) was dissolved in N,N-dimethylformamide (30 mL), followed by the addition of intermediate B-7b (239 mg, 1.27 mmol), 1,8-diazabicycloundec-7-ene (484 mg, 3.18 mmol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (610 mg, 1.38 mmol). The whole system was stirred at room temperature for 24 h, monitored by TLC until no raw materials remained. Water (50 mL) was added to the reaction solution, and it was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated sodium chloride (50 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (methylene chloride:methanol = 60:1 - 15:1) to obtain intermediate 13-1 (350 mg, 0.77 mmol, 73%). ESI-MS (m / z): 456.10 [M+H] + .

[0241] Synthesis of Compound 13:

[0242] Intermediate 13-1 (50 mg, 0.11 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by the addition of cesium carbonate (72 mg, 0.22 mmol), 1-methyl-6-oxo-1,6-dihydropyridine-3-boronic acid pinacol ester (40 mg, 0.17 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (4.4 mg, 0.006 mmol). The system was purged with nitrogen three times to make the whole system under a nitrogen atmosphere. The system was refluxed and stirred at 100 °C for 3 h, monitored by TLC until no raw materials remained. Water (50 mL) was added to the reaction solution, and it was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride (50 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. It was separated and purified by column chromatography (methylene chloride:methanol = 50:1 - 20:1) to obtain Compound 13 (27 mg, 0.056 mmol, 51%). ESI-MS (m / z): 485.21 [M+H] + . 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.39 (d, J = 6.0 Hz, 1H), 8.19 (s, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 7.73 (d, J = 6.0 Hz, 1H), 7.63 - 7.58 (m, 3H), 6.83 (s, 1H), 6.48 (d, J = 12 Hz, 1H), 5.63 - 5.59 (m, 1H), 3.95 (s, 3H), 3.52 (s, 3H), 3.49 (s, 3H), 1.58 (d, J = 6.0 Hz, 3H).

[0243] Example 14

[0244]

[0245] Synthesis of Intermediate 14-1:

[0246] Dissolve G-3a (300 mg, 1.05 mmol) in N,N-dimethylformamide (30 mL), then add B-7a (260 mg, 1.27 mmol), 1,8-diazabicycloundec-7-ene (484 mg, 3.18 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (610 mg, 1.38 mmol). Stir the whole system at room temperature for 24 h, monitor the reaction by TLC until no raw materials remain. Add water (50 mL) to the reaction solution, extract with ethyl acetate (30 mL×3), combine the organic phases, wash with saturated sodium chloride (50 mL×2), dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify the residue by column chromatography (methylene chloride:methanol = 60:1 - 15:1) to obtain Intermediate 14-1 (320 mg, 0.68 mmol, 65%). ESI-MS (m / z): 471.10 [M+H] + 。

[0247] Synthesis of Compound 14:

[0248] Dissolve Intermediate 14-1 (52 mg, 0.11 mmol) in dioxane (10 mL) and water (2 mL), then add cesium carbonate (72 mg, 0.22 mmol), 1-methyl-6-oxo-1,6-dihydropyridine-3-boronic acid pinacol ester (40 mg, 0.17 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (4.4 mg, 0.006 mmol). Replace the air with nitrogen three times to make the whole system under a nitrogen atmosphere. Reflux and stir the system at 100 °C for 3 h, monitor the reaction by TLC until no raw materials remain. Add water (100 mL) to the reaction solution, extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated sodium chloride (50 mL×2), dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify by column chromatography (methylene chloride:methanol = 50:1 - 20:1) to obtain Compound 14 (31 mg, 0.062 mmol, 56%). ESI-MS (m / z): 500.21 [M+H] + 。 1 H NMR (600 MHz, DMSO-d 6)δ8.31(d, J = 6.0 Hz, 1H), 8.21(s, 1H), 7.90(s, 1H), 7.63(d, J = 12 Hz, 1H), 6.84 - 6.81(m, 3H), 6.71(s, 1H), 6.49(d, J = 6.0 Hz, 1H), 5.56(s, 2H), 5.50 - 5.45(m, 1H), 3.96(s, 3H), 3.52(s, 3H), 3.50(s, 3H), 1.52(d, J = 6.0 Hz, 3H).

[0249] Example 15

[0250]

[0251] Synthesis of Compound 15:

[0252] Intermediate 13 - 1 (50 mg, 0.11 mmol) was dissolved in dioxane (10 mL) and water (2 mL). Then, cesium carbonate (72 mg, 0.22 mmol), 3 - hydroxymethylphenylboronic acid (21 mg, 0.14 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (4.4 mg, 0.006 mmol) were added. The system was purged with nitrogen three times to make the whole system under a nitrogen atmosphere. The system was refluxed and stirred at 100 °C for 3 h, and the raw materials were monitored by TLC and no residue was left. Water (100 mL) was added to the reaction solution, and it was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (dichloromethane:methanol = 50:1 - 15:1) to obtain Compound 15 (30 mg, 0.062 mmol, 56%). ESI - MS (m / z): 484.22 [M + H] + . 1 H NMR (600 MHz, DMSO - d 6 )δ8.46(d, J = 6.0 Hz, 1H), 8.23(s, 1H), 7.75(s, 1H), 7.72(d, J = 6.0 Hz, 1H), 7.59 - 7.57(m, 2H), 7.44 - 7.40(m, 2H), 7.37 - 7.32(m, 2H), 6.85(s, 1H), 5.63 - 5.59(m, 1H), 5.25(t, J = 6.0 Hz, 1H), 4.58(d, J = 4 Hz, 2H), 3.93(s, 3H), 3.51(s, 3H), 1.57(d, J = 6.0 Hz, 3H).

[0253] Example 16

[0254]

[0255] Dissolve intermediate 13-1 (50 mg, 0.11 mmol) in dioxane (10 mL) and water (2 mL). Then add (4-carbamoylphenyl)boronic acid (27 mg, 0.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (10 mg, 0.01 mmol), and cesium carbonate (107 mg, 0.33 mmol). Replace the atmosphere with nitrogen three times, and react the system at 100 °C for 3 h. Monitor by LCMS until no starting material remains. Evaporate the solvent under reduced pressure. Add water (5 mL) to the residue, and extract with ethyl acetate (10 mL × 3). Combine the organic phases, wash with saturated sodium chloride solution (10 mL × 2), and dry over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure, and purify the residue by thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain compound 16 (25 mg, 0.050 mmol, 46%). ESI-MS (m / z): 497.16 [M+H] + 。 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.47 (d, J = 6.0 Hz, 1H), 8.29 (s, 1H), 8.03 (s, 1H), 7.97 - 7.96 (m, 2H), 7.75 (s, 1H), 7.72 (d, J = 6.0 Hz, 1H), 7.63 - 7.57 (m, 4H), 7.41 (s, 1H), 6.87 (s, 1H), 5.61 - 5.60 (m, 1H), 3.95 (s, 3H), 3.51 (s, 3H), 1.56 (d, J = 6.0 Hz, 3H).

[0256] Example 17

[0257]

[0258] Intermediate 13-1 (50 mg, 0.11 mmol) was dissolved in dioxane (10 mL) and water (2 mL). Then, (3-carbamoylphenyl)boronic acid (27 mg, 0.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (10 mg, 0.01 mmol), and cesium carbonate (107 mg, 0.33 mmol) were added. The system was purged with nitrogen three times and reacted at 100 °C for 3 h. LCMS monitored that no raw materials remained. The solvent was removed under reduced pressure. Water (10 mL) was added to the residue, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride (10 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by thin-layer chromatography (dichloromethane:methanol = 33:1) to obtain compound 17 (30 mg, 0.060 mmol, 55%). ESI-MS (m / z): 497.15 [M+H] + 。 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.47 (d, J = 6.0 Hz, 1H), 8.28 (s, 1H), 8.04 - 8.02 (m, 2H), 7.88 (d, J = 7.2 Hz, 1H), 7.75 (s, 1H), 7.72 (d, J = 6.0 Hz, 1H), 7.65 (d, J = 6.0 Hz, 1H), 7.59 - 7.54 (m, 3H), 7.43 (s, 1H), 6.87 (s, 1H), 5.61 - 5.60 (m, 1H), 3.94 (s, 3H), 3.52 (s, 3H), 1.56 (d, J = 6.0 Hz, 3H).

[0259] Example 18

[0260]

[0261] Synthesis of Intermediate 18-1:

[0262] Intermediate 13-1 (300 mg, 0.66 mmol) was dissolved in dioxane (10 mL) and water (2 mL). Then cesium carbonate (420 mg, 1.29 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (263 mg, 0.85 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (29 mg, 0.04 mmol) were added. The system was purged with nitrogen three times to make the whole system under a nitrogen atmosphere. The system was refluxed and stirred at 100 °C for 3 h, and TLC monitored that there was no remaining raw material. Water (100 mL) was added to the reaction solution, and it was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (methylene chloride:methanol = 50:1 - 20:1) to obtain Intermediate 18-1 (220 mg, 0.39 mmol, 60%). ESI-MS (m / z): 559.31 [M+H] + 。

[0263] Synthesis of Compound 18:

[0264] Intermediate 18-1 (150 mg, 0.27 mmol) was dissolved in 2 M hydrochloric acid / methanol solution (10 mL). The system was stirred overnight at room temperature, and TLC monitored that there was no remaining raw material. The solvent was removed under reduced pressure and directly used for the next step. The concentrated crude product was dissolved in methylene chloride (20 mL) again. Then triethylamine (54 mg, 0.54 mmol) and acetyl chloride (25 mg, 0.32 mmol) were added. The system was stirred at room temperature for 24 h, and TLC monitored that there was no remaining raw material. The solvent was removed under reduced pressure, and it was separated and purified by column chromatography (methylene chloride:methanol = 60:1 - 15:1) to obtain Compound 18 (55 mg, 0.11 mmol, 41%). ESI-MS (m / z): 501.20 [M+H] + 。 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.40 (d, J = 6.0 Hz, 1H), 8.05 (s, 1H), 7.76 (s, 1H), 7.72 (d, J = 6.0 Hz, 1H), 7.61 - 7.57 (m, 2H), 6.75 (s, 1H), 5.87 - 5.85 (m, 1H), 5.61 - 5.59 (m, 1H), 4.16 - 4.10 (m, 2H), 3.94 (s, 3H), 3.66 - 3.61 (m, 2H), 3.46 (s, 3H), 2.08 - 2.06 (m, 2H), 2.30 (s, 3H), 1.57 (d, J = 6.0 Hz, 3H).

[0265] Example 19

[0266]

[0267] Intermediate 18-1 (151 mg, 0.27 mmol) was dissolved in 2 M hydrochloric acid / methanol solution (10 mL). The system was stirred overnight at room temperature, and TLC monitored that there was no remaining raw material. The solvent was removed under reduced pressure and directly used for the next step. The concentrated crude product was dissolved in formic acid (20 mL) again, and then aqueous formaldehyde solution (5 mL) was added. The system was stirred and reacted at 70 °C for 24 h, and TLC monitored that there was no remaining raw material. The solvent was removed under reduced pressure, and the residue was separated and purified by column chromatography (methylene chloride:methanol = 60:1 - 10:1) to obtain Compound 19 (37 mg, 0.078 mmol, 29%). ESI-MS (m / z): 473.25 [M+H] + 。 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.40 (d, J = 7.8 Hz, 1H), 8.04 (s, 1H), 7.75 (s, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.60 - 7.57 (m, 2H), 6.78 (s, 1H), 5.81 - 5.77 (m, 1H), 5.60 - 5.58 (m, 1H), 3.92 (s, 3H), 3.45 (s, 3H), 3.05 - 3.00 (m, 2H), 2.57 - 2.55 (m, 2H), 2.49 - 2.46 (m, 2H), 2.30 (s, 3H), 1.56 (d, J = 7.2 Hz, 3H).

[0268] Example 20

[0269]

[0270] Synthesis of Intermediate 20-1

[0271] Intermediate C-6 (300 mg, 1.35 mmol) was dissolved in N,N-dimethylformamide (30 mL). Then ethyl bromoacetate (336 mg, 2.03 mmol) and potassium carbonate (373 mg, 2.70 mmol) were added. The system was reacted at 100 °C for 2 h, and LCMS monitored that there was no remaining raw material. Water (50 mL) was added to the reaction solution, and it was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated sodium chloride (40 mL × 2), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was separated and purified by column chromatography (methylene chloride:methanol = 70:1 - 50:1) to obtain Intermediate 20-1 (142 mg, 0.46 mmol, 34%). ESI-MS (m / z): 309.07 [M+H] + 。

[0272] Synthesis of Compound 20

[0273] Dissolve intermediate 20-1 (142 mg, 0.46 mmol) in N,N-dimethylformamide (30 mL), then add intermediate B-7b (156 mg, 0.69 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (265 mg, 0.60 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (210 mg, 1.38 mmol), and react the system at room temperature for 8 h. Monitor by LCMS until no starting materials remain. Add water (50 mL) to the reaction solution, extract with ethyl acetate (40 mL×3), combine the organic phases, wash with saturated sodium chloride solution (40 mL×2), and dry over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure, and purify the residue by column chromatography (dichloromethane:methanol = 80:1 - 50:1) to obtain compound 20 (90 mg, 0.19 mmol, 41%). ESI-MS (m / z): 480.18 [M+H] + 。 1 H NMR (600 MHz, DMSO-d 6 ) δ8.25 (d, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.73 (s, 1H), 7.71 (d, J = 6.0 Hz, 1H), 7.61 - 7.59 (m, 2H), 6.83 (s, 1H), 5.64 - 5.59 (m, 1H), 4.84 (s, 2H), 4.20 - 4.19 (m, 2H), 3.96 (s, 3H), 3.46 (s, 3H), 1.58 (d, J = 12.0 Hz, 3H), 1.22 (t, J = 6.0 Hz, 3H).

[0274] Example 21

[0275]

[0276] Dissolve compound 20 (20 mg, 0.042 mmol) in tetrahydrofuran (10 mL), add lithium borohydride (2 mg, 0.092 mmol) under ice bath, and react the system at room temperature for 3 h. Monitor by LCMS until no starting materials remain. Quench the reaction with water, then add water (10 mL), extract with ethyl acetate (10 mL×3), combine the organic phases, wash with saturated sodium chloride solution (10 mL×2), dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure. Purify the residue by thin layer chromatography (dichloromethane:methanol = 50:3) to obtain compound 21 (10 mg, 0.023 mmol, 54%). ESI-MS (m / z): 438.12 [M+H] + 。 1 H NMR (600 MHz, DMSO-d 6)δ8.30(d,J=7.8Hz,1H),7.75-7.72(m,3H),7.61-7.60(m,2H),6.80(s,1H),5.65-5.60(m,1H),4.97(d,J=6.0Hz,1H),4.09-4.07(m,2H),3.94(s,3H),3.80-3.79(m,2H),3.46(s,3H),1.59(d,J=12.0Hz,3H).

[0277] Example 22

[0278]

[0279] Intermediate C-6-2 (70 mg, 0.30 mmol) was dissolved in N,N-dimethylformamide (15 mL). Then intermediate B-7e (107 mg, 0.45 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (170 mg, 0.39 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (135 mg, 0.90 mmol) were added. The reaction system was reacted at room temperature for 8 h. LCMS monitored that there was no remaining raw material. 30 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated sodium chloride (30 mL×2), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by thin layer chromatography (methylene chloride:methanol = 50:1) to obtain compound 22 (40 mg, 0.095 mmol, 32%). ESI-MS (m / z): 422.18 [M+H] + 。 1 1H NMR (600 MHz, DMSO-d 6 )δ8.26(d,J=7.8Hz,1H),7.80(s,1H),7.59(s,1H),7.49-7.45(m,1H),7.28(d,J=6.0Hz,1H),6.80(s,1H),5.78-5.76(m,1H),3.94(s,3H),3.89(s,3H),3.45(s,3H),2.04(t,J=12Hz,3H),1.58(d,J=6.0Hz,3H).

[0280] Example 23

[0281]

[0282] The intermediate C-6-2 (250 mg, 1.06 mmol) was dissolved in N,N-dimethylformamide (30 mL), and then intermediate B-7g (263 mg, 1.27 mmol), 1,8-diazabicycloundec-7-ene (484 mg, 3.18 mmol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (610 mg, 1.38 mmol) were added. The whole system was stirred at room temperature for 24 h, monitored by TLC until no raw materials remained. Water (50 mL) was added to the reaction solution, and it was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated sodium chloride (50 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated and purified by column chromatography (methylene chloride:methanol = 60:1 - 15:1) to obtain compound 23 (302 mg, 0.71 mmol, 67%). ESI-MS (m / z): 426.17 [M+H] + 。 1 HNMR (600 MHz, DMSO-d 6 ) δ 8.28 (d, J = 7.8 Hz, 1H), 7.78 (s, 1H), 7.76 - 7.74 (m, 1H), 7.68 - 7.66 (m, 1H), 7.40 - 7.37 (m, 1H), 6.79 (s, 1H), 5.77 - 5.72 (m, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.44 (s, 3H), 1.58 (d, J = 7.2 Hz, 3H).

[0283] Example 24

[0284]

[0285] Synthesis of Compound 24-1

[0286] The intermediate C-6-2 (50 mg, 0.21 mmol) was dissolved in N,N-dimethylformamide (15 mL), and then intermediate B-7b (72 mg, 0.32 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (124 mg, 0.28 mmol), and 1,8-diazabicycloundec-7-ene (97 mg, 0.64 mmol) were added. The system was reacted at room temperature for 8 h. LCMS monitored until no raw materials remained. Water (30 mL) was added to the reaction solution, and it was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated sodium chloride (30 mL×2), and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by thin-layer chromatography (methylene chloride:methanol = 30:1) to obtain compound 24-1 (30 mg, 0.074 mmol, 35%). ESI-MS (m / z): 408.12 [M+H] + 。1 1H NMR (600 MHz, DMSO-d 6 ) δ 8.26 (d, J = 7.8 Hz, 1H), 7.74 (s, 1H), 7.72 - 7.70 (m, 2H), 7.61 - 7.56 (m, 2H), 6.79 (s, 1H), 5.64 - 5.61 (m, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.45 (s, 3H), 1.59 (d, J = 6.6 Hz, 3H).

[0287] Synthesis of Compound 24

[0288] Dissolve Compound 24-1 (301 mg, 0.74 mmol) in toluene (30 mL), then add Lawesson's reagent (599 mg, 1.48 mmol). The whole system is refluxed and stirred for 3 h, monitored by TLC until no raw materials remain. Add water (50 mL) to the reaction solution, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated sodium chloride (50 mL × 2), dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify by column chromatography (dichloromethane:methanol = 50:1 - 15:1) to obtain Compound 24 (156 mg, 0.37 mmol, 50%). ESI-MS (m / z): 424.10 [M + H] + . 1 1HNMR (600 MHz, DMSO-d 6 ) δ 8.58 (d, J = 7.9 Hz, 1H), 7.78 (s, 1H), 7.76 - 7.74 (m, 2H), 7.63 - 7.59 (m, 1H), 6.97 (s, 1H), 5.80 - 5.76 (m, 1H), 4.07 (s, 3H), 3.96 (s, 3H), 3.90 (s, 3H), 1.63 (d, J = 7.2 Hz, 3H).

[0289] Example 25

[0290]

[0291] Synthesis of Intermediate C-8g

[0292] Dissolve methyl 2-amino-4,5-dimethoxybenzoate (1000 mg, 4.76 mmol) in glacial acetic acid (15 mL), then add an aqueous solution of potassium cyanate (768 mg, 9.48 mmol, 5 mL). The system is reacted overnight at room temperature. The next day, the system is reacted at 80 °C for 16 h, monitored by LCMS until no raw materials remain. Filter, and wash the filter cake with water to obtain Intermediate C-8g (900 mg, 4.05 mmol, 85%). ESI-MS (m / z): 223.06 [M + H]+ 。

[0293] Synthesis of Intermediate 25-1:

[0294] Dissolve Intermediate C-8g (140 mg, 0.63 mmol) in phosphorus oxychloride (20 mL). Stir the whole system at 105 °C for 8 h, and monitor the reaction by TLC until no raw materials remain. Directly remove the solvent in the reaction solution under reduced pressure. The residue is separated and purified by column chromatography (n-hexane:ethyl acetate = 20:1 - 4:1) to obtain Intermediate 25-1 (140 mg, 0.54 mmol, 86%). ESI-MS (m / z): 259.01 [M+H] + 。

[0295] Synthesis of Intermediate 25-2:

[0296] Dissolve Intermediate 25-1 (140 mg, 0.54 mmol) in isopropanol (20 mL). Then add Intermediate B-7b (123 mg, 0.65 mmol) and N,N-diisopropylethylamine (279 mg, 2.16 mmol). Stir the whole system at 105 °C for 48 h, and monitor the reaction by TLC until no raw materials remain. After the reaction is complete, cool the reaction system to room temperature. Add 50 mL of water to the reaction solution to quench the reaction, and then extract with ethyl acetate (30 mL × 3). Combine the organic phases. The organic phase is washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. The residue is separated and purified by column chromatography (methylene chloride:methanol = 60:1 - 20:1) to obtain Intermediate 25-2 (100 mg, 0.24 mmol, yield 45%). ESI-MS (m / z): 412.12 [M+H] + 。

[0297] Synthesis of Compound 25:

[0298] Dissolve Intermediate 25-2 (100 mg, 0.24 mmol) in glacial acetic acid (20 mL). Stir the whole system at 90 °C for 8 h, and monitor the reaction by TLC until no raw materials remain. After the reaction is complete, directly remove the solvent under reduced pressure. The residue is separated and purified by column chromatography (methylene chloride:methanol = 60:1 - 15:1) to obtain Compound 25 (60 mg, 0.15 mmol, yield 63%). ESI-MS (m / z): 394.13 [M+H] + 。 1 HNMR (600 MHz, DMSO-d 6)δ10.51(s,1H),8.26(d,J=6.0Hz,1H),7.75(s,1H),7.73(d,J=6.0Hz,1H),7.68(s,1H),7.63 - 7.58(m,2H),6.67(s,1H),5.65 - 5.61(m,1H),3.84(s,3H),3.81(s,3H),1.60(d,J=6.0Hz,3H).

[0299] III. Bioactivity Assay Experiment:

[0300] 1. K - Ras G12D Binding Analysis with hSOS1

[0301] This assay can be used to examine the potency of a compound to inhibit the protein - protein interaction between SOS1 and KRAS G12D. The binding of GST - KRas bound to anti - GSK - Europium (FRET donor) and His - tagged hSOS1 (FRET acceptor) bound to anti - 6His - XL665 is detected by homogeneous time - resolved fluorescence (HTRF) to determine the inhibitory effect of the compound on K - Ras G12D binding with hSOS1. G12D

[0302] Reagents

[0303] Buffer (5 mM HEPES pH 7.4, 150 mM NaCl, 10 mM EDTA, 1 mM DTT, 0.05% BAS pH 7.0, 0.0025% Igepal and 100 mM KF);

[0304] GST - tagged hK - RasG12D (produced in - house)

[0305] His - tagged hSOS1 (produced in - house)

[0306] Ras Mixture

[0307] Before use, mix GST - hK - RasG12D 10 nM (final concentration) and anti - GSK - Europium 2 nM (final concentration) in the assay buffer and keep at room temperature.

[0308] SOS Mixture

[0309] Before use, mix His - tagged hSOS1 20 nM (final concentration) and anti - 6His - XL665 10 nM (final concentration) in the assay buffer and keep at room temperature.

[0310] ​Dissolve the compound to be tested in DMSO at a concentration 100 times the experimental concentration. Use a Hummingbird liquid handler or an Echo acoustic system to take out 50 nL and transfer it into a black microplate for detection.

[0311] All experimental procedures are completed at 20 °C. In the experiment, 2.5 μL of the Ras mixture is added to all wells on the microplate through a Multidrop dispenser. After pre-incubating for 2 minutes, 2.5 μL of the SOS mixture is added to all wells to be tested except for the edge wells, and 2.5 μL of the compound control solution is added to the edge wells. After incubating for 60 minutes, use the HTRF module of Pheraster (excitation light: 337 nm, emission light 1: 620 nm, emission light 2: 665 nm).

[0312] Result calculation:

[0313] Use a four-parameter logistic model to calculate and analyze the IC 50 value.

[0314] SOS-1 inhibitory activity of the compound:

[0315] Test the representative compounds in the examples according to the above method, and it is found that they inhibit the activity of SOS-1. The compound activity data are shown in the following table. "A" indicates that the compound activity is < 100 nM.

[0316]

[0317]

Claims

1. A compound represented by the formula (Ⅱa-1), its stereoisomers or its pharmaceutically acceptable salts, having the following structure: Wherein, R A selected from hydrogen, methyl, ethyl, n-propyl, isopropyl; R 1 selected from phenyl, R 2 selected from hydrogen, methoxy; R 3 selected from hydrogen; Ring A is selected from phenyl; R 4 Each occurrence is independently selected from Cl, Br, methyl, ethyl, n-propyl, isopropyl, -O-CH 3 , -O-CF 3 , where w = 1, 2; Y is selected from O.

2. A pharmaceutical composition, Characterized in that: It contains the compound, its stereoisomers or its pharmaceutically acceptable salts described in claim 1.

3. Use of the compound, its stereoisomers or its pharmaceutically acceptable salts described in claim 1 or the pharmaceutical composition described in claim 2 in the preparation of a medicament for treating diseases mediated by SOS1.

4. According to the use of claim 3, the disease is cancer or tumor, and related diseases.

5. Use of the compound, its stereoisomers or its pharmaceutically acceptable salts described in claim 1 or the pharmaceutical composition described in claim 2 in the preparation of a medicament for treating diseases caused by RAS mutations.

6. Use of the compound, its stereoisomers or its pharmaceutically acceptable salts described in claim 1 for non-diagnostic and non-therapeutic inhibition of the activity of guanine nucleotide exchange factors (GEFs) in vitro, Wherein, The guanine nucleotide exchange factor is selected from SOS1.

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