CN114456165A

CN114456165A - Nitrogen-containing fused ring derivative regulator, preparation method and application thereof

Info

Publication number: CN114456165A
Application number: CN202210134470.1A
Authority: CN
Inventors: 苏熠东; 陈晓坡; 汪军; 毛枭峰
Original assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansoh Biomedical Co Ltd
Current assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansoh Biomedical Co Ltd
Priority date: 2022-02-14
Filing date: 2022-02-14
Publication date: 2022-05-10

Abstract

The invention relates to a nitrogenous heterocyclic derivative regulator, a preparation method and application thereof. In particular, the invention relates to compounds of the formula (I)The compound, a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as an SOS1 inhibitor in treating diseases or symptoms such as leukemia, neuroblastoma, melanoma, breast cancer, lung cancer, colon cancer and the like, wherein each substituent in the general formula (I) is defined as the same as in the specification.

Description

Nitrogen-containing fused ring derivative regulator, preparation method and application thereof

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a nitrogenous heterocyclic derivative inhibitor, and a preparation method and application thereof.

Background

The ras (rat sarcoma) protein family is encoded by the protooncogenes HRAS, NRAS and KRAS and is divided into 4 proteins HRAS, NRAS, KRAS4A and KRAS 4B. RAS proteins play an important role in a variety of processes in cells. RAS has two main states in the body: an inactivated state bound to GDP (guanine diphosphate) and an activated state bound to GTP (guanine triphosphate), which are regulated by two types of proteins, a guanosine nucleotidic exchange factor (GEF) that promotes release of GDP from RAS proteins, such that GTP binding activates RAS, a GTPase Activating Protein (GAP) that activates GTPase activity of RAS proteins, hydrolyzes GTP bound to RAS proteins to GDP, and inactivates RAS. RAS proteins in an activated state activate downstream CRAF, PI3K/AKT/mTOR, RalGDS pathways, thereby affecting various functions of cells such as survival, proliferation, metabolism, activity, angiogenesis, etc., RAS mutations inhibit endogenous and GAP-induced gtpase activity, increase RAS-GTP in an activated state, leading to sustained activation of downstream pathways, and then initiating cancer.

RAS mutations are present in many types of cancer, with mutation rates averaging 25% in human cancers, with KRAS mutations predominantly occurring in pancreatic (95%), colorectal (45%) and lung (35%).

SOS1(Son of Sevenless 1) is an important class of guanylate exchange proteins, which interact with growth factor receptor binding protein 2(Grb2) to form SOS1/Grb2 complexes, which are recruited after upstream receptor tyrosine kinase RTKs such as EGFR, HER2, FGFR, ROS, ALK, etc. activate phosphorylation and bind through SH2 domain, and the RTK/Grb2/SOS1 complex positions SOS1 to bind to non-activated GDP-RAS located at the plasma membrane, promoting the exchange of GDP with GTP, thereby activating RAS. The SOS1 protein has two binding sites with the RAS family proteins, one is a catalytic site, and binds with the RAS family proteins in the GDP-bound state to promote the exchange of guanylic acid to make them into the RAS proteins in the GTP-bound state, and the other is an allosteric site, and the binding with the RAS family proteins in the GTP-bound state promotes the further increase of the catalytic function of SOS 1. Inhibition of SOS1 blocks binding of SOS1 to KRAS, thereby blocking KRAS protein in an inactive state.

Although there is a great clinical demand for KRAS mutated tumors, direct targeting of RAS is a great difficulty due to the structural characteristics of RAS proteins, so far, no drug directly targeting KRAS is available on the market, a compound targeting KRAS G12C mutation has recently made a great breakthrough, AMG510 of ann company and MRTX-849 of Mirati company both perform clinical phase I, and early clinical results show good curative effects. The SOS1 inhibitor provides a new treatment method for various KRAS protein mutant cancers, the inhibitor also gains more and more attention, and various companies at home and abroad carry out research and development of the target, wherein the Boringer Vargham company has faster progress, the dominant compound BI-1701963 has entered the clinical stage I, the preclinical dominant compound BI-3406 also shows better in-vivo and in-vitro activity data, but the activity still has a space for improving.

In conclusion, the SOS1 inhibitor can be used for treating all KRAS mutant tumors, and the SOS1 inhibitor with good activity and high safety has great treatment potential and wide clinical application prospect.

Disclosure of Invention

The invention aims to provide a compound shown in a general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound shown in the general formula (I) has the following structure:

wherein, the first and the second end of the pipe are connected with each other,

ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, which may optionally be further substituted;

l is selected from the group consisting of a bond, - (CH)₂)_n1-、-(CH₂)_n1C(O)-、-(CH₂)_n1O-、-(CH₂)_n1S-、-(CH₂)_n1NR_aa-、-(CH₂)_n1C(O)NR_aa-、-C(O)NR_aa(CH₂)_n1-、-(CH₂)_n1NR_aaC(O)-、-(CH₂)_n1S(O)_m1-、-(CH₂)_n1S(O)_m1NR_aa-or- (CH)₂)_n1NR_aaS(O)_m1-；

R_aaSelected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally may be further substituted;

R¹selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;

R²and R^2’Each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;

R³selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkylHaloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, endocycloalkyl, - (CH)₂)_n2R_AA、-(CH₂)_n2OR_AA、-(CH₂)_n2C(O)OR_AA、-(CH₂)_n2OR_AA、-(CH₂)_n2SR_AA、-(CH₂)_n2NR_AAC(O)(CH₂)_n3R_BB、-(CH₂)_n2NR_AAC(O)OR_BB、-(CH₂)_n2NR_AAC(O)NR_BBR_CC、-(CH₂)_n2NR_AAR_BB、-NR_AA(CH₂)_n2R_BB、-(CH₂)_n2C(O)NR_AA(CH₂)_n3R_BB、-(CH₂)_n2C(O)R_AA、-OC(R_AAR_BB)_p(CH₂)_n2R_CC、-(CH₂)_n2S(O)_m2R_AA、-(CH₂)_n2NR_AAS(O)_m2R_BB、-CH＝CH(CH₂)_n2R_AA、-CH＝CH(CH₂)_n2NR_AAR_BB、-CH＝CH(CH₂)_n2NR_AAC(O)R_BBor-CH ═ CH (CH)₂)_n2NR_AAC(O)NR_BBR_CCSaid amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, bridged cycloalkyl and bridged heterocyclyl, optionally further substituted with hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, - (CH)₂)_nR_a1、-(CH₂)_nOR_a1、-(CH₂)_nC(O)OR_a1、-(CH₂)_nOR_a1-(CH₂)_nNR_a1C(O)R_b1Or- (CH)₂)_nNR_a1R_b1Is substituted with one or more substituents of (1);

R_AA、R_BBand R_CCEach independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;

or, R_AA、R_BBAnd R_CCAny two of which are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups, optionally may be further substituted;

R_a1and R_b1Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, or alkynyl;

R^aselected from the group consisting of hydrogen, deuterium, halogen, oxo, thioxo, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;

or R^aAnd R³Or two R which may or may not be adjacent^a(ii) linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, said cycloalkyl, heterocyclyl, aryl and heteroaryl groups optionally being further substituted;

R^bselected from hydrogen,Deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;

or, R²And R^bOr two R which may or may not be adjacent^b(ii) linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, said cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally being further substituted;

R^cselected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)₂)_n4R_A1、-(CH₂)_n4OR_A1、-(CH₂)_n4C(O)OR_A1、-(CH₂)_n4OR_A1、-(CH₂)_n4SR_A1、-(CH₂)_n4NR_A1C(O)(CH₂)_n5R_B1、-(CH₂)_n4NR_A1C(O)OR_B1、-(CH₂)_n4NR_A1C(O)NR_B1R_C1、-(CH₂)_n4NR_A1R_B1、-NR_A1(CH₂)_n4R_B1、-(CH₂)_n4C(O)NR_A1(CH₂)_n5R_B1、-(CH₂)_n4C(O)R_A1、-OC(R_A1R_B1)_p1(CH₂)_n4R_C1、-(CH₂)_n4S(O)_m3R_A1、-(CH₂)_n4NR_A1S(O)_m3R_B1、-CH＝CH(CH₂)_n4R_A1、-CH＝CH(CH₂)_n4NR_A1R_B1、-CH＝CH(CH₂)_n4NR_A1C(O)R_B1or-CH ═ CH (CH)₂)_n4NR_A1C(O)NR_B1R_C1Said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally may be further substituted;

or, R^bAnd R^cOr two adjacent or non-adjacent R^c(ii) linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, said cycloalkyl, heterocyclyl, aryl and heteroaryl groups optionally being further substituted;

R_A1、R_B1and R_C1Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;

or, R_A1、R_B1And R_C1Any two of which are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups, optionally may be further substituted;

x is an integer of 0-3;

y is an integer of 0 to 2;

z is an integer of 0 to 5;

n, n 1-n 5 are integers of 0-5;

p or p1 is an integer of 0-5; and is provided with

m 1-m 3 are integers of 0-3.

In a further preferred embodiment of the invention, the ring A is selected from C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroAn aryl group;

preferably C_3-12Cycloalkyl, 3-10 membered heterocyclyl, C_6-10Aryl or 5-12 membered heteroaryl;

more preferably C_3-8Cycloalkyl, 3-8 membered heterocyclyl containing 1-4N, O or S atoms, C_6-12Aryl or 5-12 membered heteroaryl containing 1-4N, O or S atoms;

further preferred is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxypropyl, epoxybutyl, epoxypentyl, epoxyhexyl, aziridinyl, azetidinyl, aziridinyl, azacyclopentyl, azacyclohexyl, thienyl, piperazinyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyridonyl or furyl.

In a further preferred embodiment of the invention, L is selected from the group consisting of a bond, - (CH)₂)_n1-、-C(O)NR_aa(CH₂)_n1-, or- (CH)₂)_n1C (O) -; preferably a bond, -C (O) NH (CH)₂)_n1-or- (CH)₂)_n1C (O) -; more preferably a bond, -C (O) NH (CH)₂)_n1-or-c (o) -; and is

n1 is an integer of 0 to 5.

In a further preferred embodiment of the invention, R is¹Selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, C_1-6Alkyl radical, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_3-12Alkoxy, haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl;

preferably hydrogen, deuterium, halogen, amino, hydroxy, halogen, C_1-3Alkyl radical, C_1-3Alkoxy or C_1-3A haloalkyl group;

further preferred is hydrogen, deuterium, halogen, amino, hydroxyl, halogen, methyl, ethyl or isopropyl.

In a further preferred embodiment of the invention, R is²And R^2’Each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyanoHydroxy, C_1-6Alkyl radical, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_3-12Alkoxy, haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl;

In a further preferred embodiment of the invention, R is³Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_3-12Alkoxy radical, C_3-12Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl, 5-14 membered heteroaryl, 5-20 membered bridged cycloalkyl, 5-14 membered bridged heterocyclyl, - (CH)₂)_n2R_AA、-(CH₂)_n2OR_AA、-(CH₂)_n2C(O)OR_AA、-(CH₂)_n2OR_AA、-(CH₂)_n2SR_AA、-(CH₂)_n2NR_AAC(O)(CH₂)_n3R_BB、-(CH₂)_n2NR_AAC(O)OR_BB、-(CH₂)_n2NR_AAC(O)NR_BBR_CC、-(CH₂)_n2NR_AAR_BB、-NR_AA(CH₂)_n2R_BB、-(CH₂)_n2C(O)NR_AA(CH₂)_n3R_BB、-(CH₂)_n2C(O)R_AA、-OC(R_AAR_BB)_p(CH₂)_n2R_CC、-(CH₂)_n2S(O)_m2R_AA、-(CH₂)_n2NR_AAS(O)_m2R_BB、-CH＝CH(CH₂)_n2R_AA、-CH＝CH(CH₂)_n2NR_AAR_BB、-CH＝CH(CH₂)_n2NR_AAC(O)R_BBor-CH ═ CH (CH)₂)_n2NR_AAC(O)NR_BBR_CCSaid amino group, C_1-6Alkyl radical, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_3-12Alkoxy radical, C_3-12Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl, 5-14 membered heteroaryl, 5-20 membered bridged cycloalkyl and 5-14 membered bridged heterocyclyl, optionally further substituted with hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Hydroxyalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, - (CH)₂)_nR_a1、-(CH₂)_nOR_a1、-(CH₂)_nC(O)OR_a1、-(CH₂)_nOR_a1、-(CH₂)_nNR_a1C(O)R_b1Or- (CH)₂)_nNR_a1R_b1Is substituted with one or more substituents of (1);

said R is³Preferably C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Hydroxyalkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_6-12Aryl, 5-12 membered heteroaryl, 6-10 membered bridged cycloalkyl, 6-10 membered bridged heterocyclyl, - (CH)₂)_n2R_AA、-(CH₂)_n2OR_AA、-(CH₂)_n2C(O)OR_AA、-(CH₂)_n2OR_AA、-(CH₂)_n2SR_AA、-(CH₂)_n2NR_AAR_BB、-NR_AA(CH₂)_n2R_BB、-(CH₂)_n2S(O)_m2R_AA(ii) a Said C is_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Hydroxyalkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_6-12Aryl, 5-12 membered heteroaryl, 6-10 membered bridged cycloalkyl, 6-10 membered bridged heterocyclyl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy, - (CH)₂)_nR_a1、-(CH₂)_nNR_a1C(O)R_b1Or- (CH)₂)_nNR_a1R_b1Is substituted with one or more substituents of (1);

R_AA、R_BBand R_CCEach independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, said amino, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl, 5-14 membered heteroaryl, substituted with one or more substituents;

or, R_AA、R_BBAnd R_CCAny two links forming C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, said C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl, cyano-substituted C_1-6Alkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl;

or, R_a1And R_b1Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_3-10Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl, 5-14 membered heteroaryl; the amino group and C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_3-10Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl, 5-14 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl, 5-14 membered heteroaryl, substituted with one or more substituents;

R_a1and R_b1Link formation C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, said C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical、C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl, cyano-substituted C_1-6Alkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl;

n2 is an integer from 0 to 3;

m2 is an integer of 0 to 2; and is

n is an integer of 0 to 3.

In a further preferred embodiment of the invention, R is^aSelected from hydrogen, deuterium, halogen, oxo, amino, nitro, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_2-6Alkenyl or C_2-6An alkynyl group;

preferably hydrogen, halogen, oxo, cyano, hydroxy, C_1-3Alkyl radical, C_1-3Deuterated alkyl, C_1-3Haloalkyl, C_1-3Hydroxyalkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_2-4Alkenyl or C_2-4An alkynyl group;

more preferably hydrogen, oxo, cyano, hydroxy, methyl, ethyl, isopropyl, butyl, isobutyl or tert-butyl.

In a further preferred embodiment of the present invention, said R is^bSelected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl; the amino group and C_1-6Alkyl radical, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl, 5-14 membered heteroaryl, substituted with one or more substituents;

or, R²And R^bOr two R which may or may not be adjacent^bLink formation C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, said C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl, 5-14 membered heteroaryl.

In a further preferred embodiment of the invention, R is^cSelected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl, 5-14 membered heteroaryl, - (CH)₂)_n4R_A1、-(CH₂)_n4OR_A1、-(CH₂)_n4C(O)OR_A1、-(CH₂)_n4OR_A1、-(CH₂)_n4SR_A1、-(CH₂)_n4NR_A1C(O)NR_B1R_C1、-(CH₂)_n4NR_A1R_B1、-NR_A1(CH₂)_n4R_B1、-(CH₂)_n4C(O)R_A1、-OC(R_A1R_B1)_p1(CH₂)_n4R_C1、-(CH₂)_n4S(O)_m3R_A1、-(CH₂)_n4NR_A1S(O)_m3R_B1、-CH＝CH(CH₂)_n4R_A1、-CH＝CH(CH₂)_n4NR_A1R_B1、-CH＝CH(CH₂)_n4NR_A1C(O)R_B1or-CH ═ CH (CH)₂)_n4NR_A1C(O)NR_B1R_C1Said amino group, C_1-6Alkyl radical, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl, 5-14 membered heteroaryl;

or, said R^bAnd R^cOr two adjacent or non-adjacent R^cLink formation C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, said C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Alkyl halidesBase, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl, 5-14 membered heteroaryl;

the R is^cPreferably hydrogen, halogen, amino, hydroxy, cyano, C_1-3Alkyl radical, C_1-3Deuterated alkyl, C_1-3Haloalkyl, C_1-3Hydroxyalkyl radical, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_2-4Alkenyl radical, C_2-4Alkynyl, - (CH)₂)_n4NR_A1R_B1Or- (CH)₂)_n4OR_A1；

Said R is^cMore preferably hydrogen, halogen, amino, hydroxy, -cyano, -CH₂NR_A1R_B1or-CH₂OR_A1；

Said R is_A1、R_B1And R_C1Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Deuterated alkyl or C_1-6A haloalkyl group; more preferably hydrogen, methyl, ethyl, n-propyl, isopropyl or n-butyl.

In a further preferred embodiment of the present invention, the compound of the general formula (I) is further represented by the formula (IIa) or the formula (IIa)

In a further preferred embodiment of the present invention, the compound of formula (I) is further represented by formula (III)

R⁴selected from hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxy, C_1-6Alkyl radical, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_2-6Alkenyl or C_2-6An alkynyl group;

preferably hydrogen, cyano, nitro, hydroxy, methyl, ethyl, isopropyl, butyl, isobutyl or tert-butyl;

R^3aselected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_6-10Aryl, 5-10 membered heteroaryl, 5-10 membered bridged cycloalkyl, 5-10 membered bridged heterocyclyl, - (CH)₂)_n6R_A2、-(CH₂)_n6OR_A2、-(CH₂)_n6C(O)OR_A2、-(CH₂)_n6OR_A2、-(CH₂)_n6SR_A2、-(CH₂)_n6NR_A2R_B2、-NR_A2(CH₂)_n6R_B2、-(CH₂)_n6S(O)_m4R_A2(ii) a Said C is_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_6-10Aryl, 5-10 membered heteroaryl, 5-10 membered bridged cycloalkyl, 5-10 membered bridged heterocyclyl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy, - (CH)₂)_n7R_a2、-(CH₂)_n7NR_a2C(O)R_b2Or- (CH)₂)_n7NR_a2R_b2Is substituted with one or more substituents of (1);

preferably C_3-10Cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered bridged cycloalkyl or 5-10 membered bridged heterocyclyl, said C_3-10Cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered bridged cycloalkyl and 5-10 membered bridged heterocyclyl, optionally further substituted by hydrogen, hydroxy, halogen, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy, -NR_a2C(O)R_b2or-CH₂NR_a2R_b2Is substituted with one or more substituents of (1);

R_A2、R_B2、R_a2and R_b2Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl or C_1-3Alkoxy, said amino, C_1-3Alkyl radical, C_1-3Haloalkyl and C_1-3Alkoxy, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl or C_1-3Substituted with one or more substituents of alkoxy;

n6 and n7 are integers of 0-5; and is

m4 is an integer of 0 to 3.

In a further preferred embodiment of the present invention, the compound of formula (I) is further represented by formula (IV)

Wherein the content of the first and second substances,

R^3bselected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_6-10Aryl, 5-to 10-membered heteroaryl, - (CH)₂)_n8R_A3、-(CH₂)_n8OR_A3、-(CH₂)_n8C(O)OR_A3、-(CH₂)_n8OR_A3、-(CH₂)_n8SR_A3、-(CH₂)_n8NR_A3R_B3、-NR_A3(CH₂)_n8R_B3、-(CH₂)_n6S(O)_m5R_A3(ii) a The amino group, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_6-10Aryl, 5-10 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy, - (CH)₂)_n9R_a3、-(CH₂)_n9NR_a3C(O)R_b3Or- (CH)₂)_n9NR_a3R_b3Is substituted with one or more substituents of (1);

the R is^3bPreferably C_3-10Cycloalkyl, 3-10 membered heterocyclyl or- (CH)₂)_n8NR_A3R_B3Said C is_3-10Cycloalkyl or 3-10 membered heterocyclyl, optionally further substituted by hydrogen, hydroxy, halogen, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy, -NR_a3C(O)R_b3or-CH₂NR_a3R_b3Is substituted with one or more substituents of (1);

R_A3、R_B3、R_a3and R_b3Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl or C_1-3Alkoxy, said amino, C_1-3Alkyl radical, C_1-3Haloalkyl and C_1-3Alkoxy, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, C_1-3Alkyl radical, C_1-3Haloalkyl or C_1-3Substituted with one or more substituents of alkoxy;

n8 and n9 are integers of 0-5; and is

m5 is an integer of 0 to 3.

In a further preferred embodiment of the present invention, the compound of formula (I) is further represented by formula (IVa) or formula (IVb)

In a further preferred embodiment of the invention, the compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

the invention also provides a pharmaceutical composition, which comprises an effective dose of the compounds shown in the general formulas and stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

The invention also provides a preferable scheme, and relates to the application of the compounds with the general formulas, the stereoisomers thereof or the pharmaceutically acceptable salts thereof, or the pharmaceutical composition in preparing the drugs of the SOS1 inhibitor and the RAS family protein and/or RACl inhibitor.

The invention also provides a preferable scheme, and relates to application of the compounds with the general formulas, stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition in preparing medicaments for preventing or/and treating diseases or symptoms such as membrane adenocarcinoma, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, cancer of the wing, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, sarcoma and the like.

The compounds and compositions of the invention are useful in methods of treating diseases or disorders such as membranous adenocarcinoma, lung carcinoma, colorectal carcinoma, cholangiocarcinoma, multiple myeloma, melanoma, uterine carcinoma, endometrial carcinoma, thyroid carcinoma, acute myelogenous leukemia, bulgur carcinoma, urothelial carcinoma, gastric carcinoma, cervical carcinoma, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal carcinoma, chronic lymphocytic leukemia, hepatocellular carcinoma, breast carcinoma, ovarian carcinoma, prostate carcinoma, glioblastoma, renal carcinoma, and sarcoma.

In some embodiments, the invention provides a method of treating a cancer disorder comprising administering a compound or composition of the invention to a patient having a cancer disorder.

In some embodiments, neurofibromatosis type I (NFl), Noonan Syndrome (NS), noonan syndrome with multiple plaques (NSML), capillary malformation arteriovenous malformation syndrome (CMAVM), Costello Syndrome (CS), cardio-facial skin syndrome (CFC), lekes syndrome, and hereditary dental root fibromatosis are treated by the compounds or compositions of the present invention.

Detailed description of the invention

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.

The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means-CH₂-, "ethylene" means- (CH)₂)₂-, "propylene" means- (CH)₂)₃-, "butylene" means- (CH)₂)₄-and the like. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms and the monocycloalkyl group being selected from the group consisting of 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms, and further preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 5 to 14, more preferably 6 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

and the like.

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)_m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 8 ring atoms; further preferred is a 3-8 membered heterocyclic group containing 1-3 hetero atoms, optionally substituted with 1-2 oxygen atoms, nitrogen atoms, sulfur atoms, oxo groups, including a nitrogen-containing monocyclic heterocyclic group, a nitrogen-containing spiro heterocyclic group, or a nitrogen-containing fused heterocyclic group.

Non-limiting examples of monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azeptyl, 1, 4-diazepanyl, pyranyl, tetrahydropyranyl and the like, with azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, azeptyl and piperazinyl being preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring. The term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (R) ((R))O)_m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 5 to 14, more preferably 6 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

and so on.

The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.

"alkylthio-alkyl" means an alkylthio group attached to an alkyl group, wherein alkyl and alkylthio are as defined above.

"alkylaminocarbonyl" refers to (alkyl) -N-C (O) -, wherein alkyl is as defined above.

"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

"haloalkoxy" refers to an alkylthio group substituted with one or more halogens, wherein the alkylthio group is as defined above.

"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

"alkenyl" refers to alkenyl, also known as alkenylene, wherein the alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"hydroxy" means-OH.

"halogen" means fluorine, chlorine, bromine or iodine.

"amino" means-NH₂。

"cyano" means-CN.

"nitro" means-NO₂。

"carbonyl" means-C (O) -.

"carboxy" refers to-C (O) OH.

"THF" refers to tetrahydrofuran.

"EtOAc" refers to ethyl acetate.

"MeOH" refers to methanol.

"DMF" refers to N, N-dimethylformamide.

"DIPEA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

"MeCN" refers to acetonitrile.

"DMA" refers to N, N-dimethylacetamide.

“Et₂O "means diethyl ether.

"DCE" refers to 1,2 dichloroethane.

"DIPEA" refers to N, N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"Cbz-Cl" refers to benzyl chloroformate.

“Pd₂(dba)₃"refers to tris (dibenzylideneacetone) dipalladium.

"Dppf" refers to 1, 1' -bisdiphenylphosphinoferrocene.

"HATU" refers to 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bistrimethylsilyl amide.

"MeLi" refers to methyllithium.

"n-BuLi" refers to n-butyllithium.

“NaBH(OAc)₃"refers to sodium triacetoxyborohydride.

Different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B, C.

All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compound of the embodiment related to the present invention can also be replaced by a deuterium atom.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the heterocyclic group is not substituted with an alkyl group.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.

Detailed Description

The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.

Examples

The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated methanol (CD)₃OD) and deuterated chloroform (CDCl)₃) Internal standard is Tetramethylsilane (TMS).

LC-MS was measured using an Agilent 1200Infinity Series Mass spectrometer. HPLC was measured using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C)₁₈150X 4.6mm column).

The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.

All reactions of the present invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees centigrade (deg.C).

Example 1

4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (3-methyltetrahydrofuran-3-yl) pyrido [4,3-d ] pyrimidin-7 (6H) -one

4- (((R) -1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (3-methyltetrahydrofuran-3-yl) pyrido [4,3-d ] pyrimidin-7 (6H) -one (1A)

4- (((S) -1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (3-methyltetrahydrofuran-3-yl) pyrido [4,3-d ] pyrimidin-7 (6H) -one (1B)

The first step is as follows: 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine

A mixed solution of 4, 6-dichloro-2-methylpyrimidine-5-carbaldehyde (10.0g, 52.36mmol), ethylene glycol (3.2g, 78.53mmol), p-toluenesulfonic acid (894mg, 5.2mmol) and toluene (150mL) was refluxed for 24 hours, the reaction system was cooled to room temperature, the reaction was quenched with water, ethyl acetate (100mL × 3) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was separated by column chromatography (petroleum ether/ethyl acetate ═ 15/1) to give 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine (11.0g, yield: 89%).

¹H NMR(400MHz,CDCl₃)δ6.34(s,1H),4.31(t,J＝6.9Hz,2H),4.09(dd,J＝8.3,5.5Hz,2H),2.70(s,3H).

The second step is that: dimethyl 2- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) malonate

A mixture of 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine (11.0g, 46.81mmol), diethyl malonate (6.2g, 46.81mmol), cesium carbonate (30.4g, 9.62mmol) and dimethyl sulfoxide (150mL) was stirred at 100 ℃ for 16 hours, the reaction system was cooled to room temperature, quenched with water, extracted with ethyl acetate (100mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, dried, and the crude product was separated by column chromatography (petroleum ether/ethyl acetate ═ 2/1) to give dimethyl 2- (6-chloro-5- (1, 3-dioxan-2-yl) -2-methylpyrimidin-4-yl) malonate (12.0g, yield: 78%).

¹H NMR(400MHz,CDCl₃)δ6.11(s,1H),5.35(s,1H),4.20(dd,J＝8.8,5.4Hz,2H),4.03(dd,J＝8.7,5.3Hz,2H),3.77(s,6H),2.71(s,3H).

The third step: methyl 2- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate

A mixture of dimethyl 2- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) malonate (12.0g, 36.36mmol), lithium chloride (6.1g, 145.4mmol) and dimethyl sulfoxide (120mL) was stirred at 100 ℃ for 24 hours, the reaction system was cooled to room temperature, the reaction was quenched with water, extracted with ethyl acetate (100mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, dried, and the crude product was separated by column chromatography (petroleum ether/ethyl acetate ═ 2/1) to give methyl 2- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate (7.0g, yield: 71%).

MS m/z(ESI):273.0[M+H]⁺.

The fourth step: methyl (R) -2- (6- ((1- (5-bromothien-2-yl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate

A mixture of methyl 2- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate (7.0g, 25.74mmol), 1- (5-bromothien-2-yl) ethan-1-amine (6.33g, 30.88mmol), N, N-diisopropylethylamine (6.6g, 51.48mmol) and dimethyl sulfoxide (80mL) was stirred at 100 ℃ for 6 hours, the reaction system was cooled to room temperature, water was added to quench the reaction, ethyl acetate (100 mL. times.3) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was separated by column chromatography (petroleum ether/ethyl acetate. times. 1/1) to give methyl (R) -2- (6- ((1- (5-bromothien-2-yl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate (6.0g, yield: 53%).

MS m/z(ESI):442.0[M+H]⁺.

The fifth step: methyl (R) -2- (6- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -5- (1, 3-dioxan-2-yl) -2-methylpyrimidin-4-yl) acetate

Methyl (R) -2- (6- ((1- (5-bromothien-2-yl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate (5.0g, 11.3mmol) was dissolved in dioxane (80mL) and (2- ((dimethylamino) methyl) phenyl) boronic acid (2.6g, 14.7mmol) and saturated aqueous potassium carbonate (20mL) were added. Pd (dppf) Cl_2.CH₂Cl₂(360mg, 0.464mmol) was added to the reaction under nitrogen. The reaction was stirred at 100 ℃ for 4 hours. Water was added to the reaction solution, and ethyl acetate was added thereto for extraction. The organic phase was dried and then spin dried. The crude product was purified by column chromatography to give methyl (R) -2- (6- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -5- (1, 3-dioxalan-2-yl) -2-methylpyrimidin-4-yl) acetate (4.0g, yield: 70.7%).

MS m/z(ESI):497.2[M+H]⁺

And a sixth step: (R) -2- (6- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetic acid

Methyl (R) -2- (6- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate (500mg, 1.0mmol) was dissolved in DMSO (5mL) and MeCN (2mL) and 5N NaOH (0.3mL) was added. The reaction was stirred at room temperature overnight. To obtain (R) -2- (6- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -5- (1, 3-dioxan-2-yl) -2-methylpyrimidin-4-yl) acetic acid which is directly used for the next reaction.

MS m/z(ESI):483.2[M+H]⁺

The seventh step: 2- (6- (((R) -1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -5- (1, 3-dioxan-2-yl) -2-methylpyrimidin-4-yl) -N- (3-methyltetrahydrofuran-3-yl) acetamide

(R) -2- (6- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetic acid (482mg, 1mmol) was dissolved in DMF (5mL), 3-methyltetrahydrofuran-3-amine (120mg, 1.2mmol), HATU (380mg, 1mmol) and DIEA (400mg, 3mmol) were added. The reaction was stirred at room temperature overnight. Water was added to the reaction mixture, and ethyl acetate was added thereto for extraction. The organic phase was dried and concentrated. The crude product was purified by column chromatography to give 2- (6- (((R) -1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -5- (1, 3-dioxalan-2-yl) -2-methylpyrimidin-4-yl) -N- (3-methyltetrahydrofuran-3-yl) acetamide for direct use in the next reaction.

MS m/z(ESI):566.2[M+H]⁺

Eighth step: 4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (3-methyltetrahydrofuran-3-yl) pyrido [4,3-d ] pyrimidin-7 (6H) -one

2- (6- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) -N- (3-methyltetrahydrofuran-3-yl) acetamide (200mg, 0.35mmol) was dissolved in isopropanol (5mL) and 5N HCl (1mL) was added. The reaction was stirred under sealed conditions at 50 ℃ for 2 hours. NaHCO₃Adding the aqueous solution, adjusting pH to 7-8, and extracting with ethyl acetate. The organic phase was dried and then spin dried. The crude product was subjected to prep-HPLC to give 4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (3-methyltetrahydrofuran-3-yl) pyrido [4, 3-d)]Pyrimidin-7 (6H) -one.

MS m/z(ESI):504.2[M+H]⁺

¹H NMR(400MHz,Methanol-d₄)δ8.85(s,1H),7.50–7.44(m,1H),7.40–7.27(m,3H),7.10(d,J＝3.7Hz,1H),7.05–6.98(m,1H),6.35(s,1H),6.11–6.00(m,1H),4.54–4.44(m,1H),4.07–3.92(m,3H),3.56(s,2H),2.64–2.52(m,2H),2.43(s,3H),2.18(s,6H),1.78(d,J＝7.0Hz,3H),1.69(d,J＝3.3Hz,3H).

The ninth step: 4- (((R) -1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (3-methyltetrahydrofuran-3-yl) pyrido [4,3-d ] pyrimidin-7 (6H) -one (1A) and 4- (((S) -1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (3-methyltetrahydrofuran-3-yl) pyrido [4,3-d ] pyrimidin-7 (6H) -one (1B)

4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (3-methyltetrahydrofuran-3-yl) pyrido [4,3-d ] pyrimidin-7 (6H) -ketone is prepared and resolved by a chiral column to obtain 4- (((R) -1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (3-methyltetrahydrofuran-3-yl) pyrido [4,3-d ] pyrimidin-7 (6H) -ketone (1A) and 4- (((S) -1- (5- (2- ((dimethylamino) methyl) phenyl) thiophene- 2-yl) ethyl) amino) -2-methyl-6- (3-methyltetrahydrofuran-3-yl) pyrido [4,3-d ] pyrimidin-7 (6H) -one (1B).

Example 1A:

MS m/z(ESI):504.2[M+H]⁺

example 1B:

MS m/z(ESI):504.2[M+H]⁺

example 2

4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -6- (1- (fluoromethyl) cyclopropyl) -2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one

Taking 2- (6- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetic acid as a raw material and changing 3-methyltetrahydrofuran-3-amine into 1- (fluoromethyl) cyclopropane-1-amine, the product 4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -6- (1- (fluoromethyl) cyclopropyl) -2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one is obtained in the seventh step to the eighth step of reference example 1.

MS m/z(ESI):492.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ9.03(s,1H),8.93(s,1H),7.39–7.20(m,4H),7.11(s,1H),7.05(s,1H),6.04(s,1H),5.93–5.78(m,1H),4.67–4.43(m,2H),3.20(s,2H),2.25(s,3H),2.10(s,6H),1.63(d,J＝7.0Hz,3H),1.25–1.16(m,4H).

Example 3

4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (1-methylcyclopropyl) pyrido [4,3-d ] pyrimidin-7 (6H) -one

2- (6- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetic acid as starting material and the conversion of 3-methyltetrahydrofuran-3-amine into 1-methylcyclopropan-1-amine reference example 1 the seventh to eighth steps give the product 4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (1-methylcyclopropyl) pyrido [4,3-d ] pyrimidin-7 (6H) -one.

MS m/z(ESI):474.2[M+H]⁺.

¹H NMR(400MHz,Methanol-d₄)δ9.15(s,1H),7.46(d,J＝7.5Hz,1H),7.39–7.20(m,3H),7.09(s,1H),7.05–6.96(m,1H),6.36(s,1H),6.07–5.96(m,1H),3.52(s,2H),2.42(s,3H),2.19–2.05(m,6H),1.77(d,J＝7.0Hz,3H),1.57(s,3H),1.23–1.16(m,2H),1.10–1.03(m,2H).

Example 4

4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (1-methylcyclopropyl) -7-carbonyl-6, 7-dihydropyrido [4,3-d ] pyrimidine-8-carbonitrile

The first step is as follows: 8-bromo-4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (1-methylcyclopropyl) pyrido [4,3-d ] pyrimidin-7 (6H) -one

8-bromo-2-methyl-6- (1-methylcyclopropyl) pyrido [4,3-d ] pyrimidine-4, 7(3H,6H) -dione (500mg, 1.61mmol), potassium phosphate (1.03g, 4.84mmol) and acetonitrile (20mL) were added phosphazene trichloride (729mg, 2.10mmol), followed by stirring at room temperature for 1 hour, then 1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethan-1-amine (504mg, 1.93mmol) was added, stirred at room temperature for 16 hours, water was added to quench the reaction, dichloromethane (30 mL. multidot.3) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, dried, and the crude product was chromatographed to give 8-bromo-4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thia-ne Phen-2-yl) ethyl) amino) -2-methyl-6- (1-methylcyclopropyl) pyrido [4,3-d ] pyrimidin-7 (6H) -one.

MS m/z(ESI):552.0[M+H]⁺

The second step is that: 4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (1-methylcyclopropyl) -7-carbonyl-6, 7-dihydropyrido [4,3-d ] pyrimidine-8-carbonitrile

8-bromo-4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (1-methylcyclopropyl) pyrido [4,3-d]Pyrimidin-7 (6H) -one (200mg, 0.362mmol) was dissolved in anhydrous DMSO (5ml) and zinc cyanide (128mg, 1.09mmol) was added. Under the protection of nitrogen, Pd₂(dba)₃(6.6mg, 0.00724mmol) and dppf (8.0mg, 0.01448mmol) were added thereto. The reaction was carried out under microwave conditions at 150 ℃ for 3 hours. The reaction solution was filtered and purified by prep-HPLC to give 4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (1-methylcyclopropyl) -7-carbonyl-6, 7-dihydropyrido [4, 3-d)]Pyrimidine-8-carbonitrile.

MS m/z(ESI):499.2[M+H]⁺。

Example 5

4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (tetrahydro-2H-pyran-4-yl) pyrido [4,3-d ] pyrimidin-7 (6H) -one

2- (6- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetic acid as starting material and the conversion of 3-methyltetrahydrofuran-3-amine into tetrahydro-2H-pyran-4-amine reference example 1 the seventh to eighth step gives the product 4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (tetrahydro-2H-pyran-4-yl) pyrido [4 ", 3-d ] pyrimidin-7 (6H) -one.

MS m/z(ESI):504.2[M+H]⁺.

¹H NMR(400MHz,Methanol-d₄)δ9.01(s,1H),7.45(d,J＝7.5Hz,1H),7.40–7.23(m,3H),7.10(s,1H),7.06–6.98(m,1H),6.42(s,1H),6.12–5.97(m,1H),5.30–5.17(m,1H),4.15–4.05(m,2H),3.70–3.54(m,2H),3.51(s,2H),2.44(s,3H),2.15(s,6H),2.11–1.98(m,2H),1.97–1.84(m,2H),1.78(d,J＝6.9Hz,3H).

Example 6

4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -6- (3-fluorocyclobutyl) -2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one

Taking 2- (6- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetic acid as a raw material and changing 3-methyltetrahydrofuran-3-amine into 3-fluorocyclobutane-1-amine, the seventh step to the eighth step of reference example 1 obtain the product 4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -6- (3-fluorocyclobutyl) -2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one.

MS m/z(ESI):492.2[M+H]⁺.

¹H NMR(400MHz,Methanol-d₄)δ8.96(s,1H),7.46(d,J＝7.6Hz,1H),7.39–7.23(m,3H),7.10(s,1H),7.02(d,J＝3.6Hz,1H),6.38(s,1H),6.10–5.99(m,1H),5.51–5.41(m,1H),5.38–5.20(m,1H),3.52(s,2H),2.92–2.76(m,4H),2.44(s,3H),2.15(s,6H),1.78(d,J＝7.0Hz,3H).

Example 7

6- (bicyclo [1.1.1] pentan-1-yl) -4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one

Taking 2- (6- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetic acid as a raw material and changing 3-methyltetrahydrofuran-3-amine into bicyclo [1.1.1] pentan-1-amine, the product 6- (bicyclo [1.1.1] pentan-1-yl) -4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one is obtained from the seventh step to the eighth step of reference example 1.

MS m/z(ESI):486.2[M+H]⁺.

Example 8

4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -6- (3-hydroxy-3-methylcyclobutyl) -2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one

Taking 2- (6- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetic acid as a raw material and changing 3-methyltetrahydrofuran-3-amine into 3-amino-1-methylcyclobutan-1-ol, the seventh step to the eighth step of reference example 1 give the product 4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -6- (3-hydroxy-3-methylcyclobutyl) -2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one.

MS m/z(ESI):504.2[M+H]⁺.

Example 9

6- (1-azabicyclo [2.2.1] heptan-4-yl) -4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one

Starting from 2- (6- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetic acid and changing 3-methyltetrahydrofuran-3-amine to 1-azabicyclo [2.2.1] heptan-4-amine reference example 1 the seventh to eighth step gives the product 6- (1- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylpyrido [4 ], 3-d ] pyrimidin-7 (6H) -one.

MS m/z(ESI):515.2[M+H]⁺.

Example 10

6- (1-azabicyclo [2.2.1] heptan-4-yl) -4- ((1- (5- (2- (methoxymethyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one

Starting from methyl 2- (6- ((1- (5-bromothien-2-yl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetate and converting the (2- ((dimethylamino) methyl) phenyl) boronic acid penta to (2- (methoxymethyl) phenyl) boronic acid and the 3-methyltetrahydrofuran-3-amine to 1-azabicyclo [2.2.1] heptan-4-amine reference example 1 from the fifth to eighth step gives the product 6- (1-azabicyclo [2.2.1] heptan-4-yl) -4- ((1- (5- (2- (methoxymethyl) phenyl) thien-2-yl) ethyl) amino) -2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one.

MS m/z(ESI):502.2[M+H]⁺.

Example 11

4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -6- (3-methoxycyclobutyl) -2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one

Taking 2- (6- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetic acid as a raw material and changing 3-methyltetrahydrofuran-3-amine into 3-methoxycyclobutane-1-amine, the product 4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -6- (3-methoxycyclobutyl) -2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one is obtained by the seventh step to the eighth step of reference example 1.

MS m/z(ESI):504.2[M+H]⁺.

¹H NMR(400MHz,Methanol-d₄)δ9.01(s,1H),7.50-7.48(m,1H),7.40-7.29(m,3H),7.10(d,J＝3.1Hz,1H),7.02(s,1H),6.37(s,1H),6.10-6.02(m,1H),4.79–4.69(m,1H),3.91–3.82(m,1H),3.52(s,2H),3.30(s,3H),3.05–2.86(m,2H),2.44(s,3H),2.32–2.24(m,2H),2.15(s,6H),1.79(d,J＝7.0Hz,3H).

Example 12

4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (3-methyloxetan-3-yl) pyrido [4,3-d ] pyrimidin-7 (6H) -one

Taking 2- (6- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetic acid as a raw material and changing 3-methyltetrahydrofuran-3-amine into 3-methyloxetan-ring-3-amine, the product 4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methyl-6- (3-methyloxetan-ring-3-yl) pyrido [4,3-d ] pyrimidin-7 (6H) -one is obtained in the seventh step to the eighth step of reference example 1.

MS m/z(ESI):490.2[M+H]⁺.

Example 13

N- ((3S) -1- (4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidine-6-carbonyl) pyrrolidin-3-yl) acetamide

The first step is as follows: ethyl 4- ((1- (5-bromothien-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidine-6-carboxylate

With ethyl 4-chloro-2-methylthiophene [2,3-d ]]Pyrimidine-6-carboxylic acid ester as raw material ethyl 4- ((1- (5-bromothien-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] product obtained in the fourth step of reference example 1]Pyrimidine-6-carboxylates. MS M/z (ESI) 426.0[ M + H ]]⁺.

The second step is that: ethyl 4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidine-6-carboxylate

Ethyl 4- ((1- (5-bromothien-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidine-6-carboxylate as starting material the product, ethyl 4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thien-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidine-6-carboxylate, obtained in the fifth step of reference example 1.

MS m/z(ESI):481.1[M+H]⁺.

The third step: 4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidine-6-carboxylic acid

4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidine-6-carboxylic acid product 4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidine-6-carboxylic acid, which was obtained in the sixth step of reference example 1, was used as a starting material.

MS m/z(ESI):453.1[M+H]⁺.

The fourth step: n- ((3S) -1- (4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidine-6-carbonyl) pyrrolidin-3-yl) acetamide

4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidine-6-carboxylic acid is used as a raw material, and the product N- ((3S) -1- (4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidine-6-carbonyl) pyrrolidin-3-yl) acetamide is obtained by the seventh step of reference example 1.

MS m/z(ESI):563.2[M+H]⁺.

Example 14

4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -N, 2-trimethylthieno [2,3-d ] pyrimidine-6-carboxamide

4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidine-6-carboxylic acid is used as a raw material, and the product 4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -N, N, 2-trimethylthieno [2,3-d ] pyrimidine-6-carboxamide is obtained by the seventh step of reference example 1.

MS m/z(ESI):480.1[M+H]⁺.

¹H NMR(400MHz,Methanol-d₄)δ8.41(s,1H),7.96(s,1H),7.59(s,1H),7.49–7.46(m,2H),7.14(d,J＝3.2Hz,1H),6.99(s,1H),6.04–5.91(m,1H),4.31(s,2H),3.30-3.05(m,6H),2.60(s,6H),2.54(s,3H),1.77(d,J＝7.0Hz,3H).

Example 15

(4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidin-6-yl) (3-methoxyazetidin-1-yl) methanone

Starting from 4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidine-6-carboxylic acid, the product (4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidin-6-yl) (3-methoxyazetidin-1-yl) methanone obtained in the seventh step of reference example 1.

MS m/z(ESI):522.1[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ8.54(d,J＝8.3Hz,1H),8.26(s,1H),8.07(s,1H),7.45–7.36(m,2H),7.32–7.29(m,1H),7.23–7.15(m,1H),7.10(d,J＝3.7Hz,1H),5.96–5.83(m,1H),4.79–4.63(m,1H),4.38–4.24(m,3H),3.90–3.86(m,1H),3.36(s,2H),3.26(s,3H),2.48(s,3H),2.11(s,6H),1.70(d,J＝6.9Hz,3H).

Example 16

N- (1- (4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidine-6-carbonyl) azetidin-3-yl) acetamide

Starting from 4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidine-6-carboxylic acid, the product N- (1- (4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidine-6-carbonyl) azetidin-3-yl) acetamide was obtained by the seventh step of reference example 1.

MS m/z(ESI):549.2[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ8.62(d,J＝6.7Hz,1H),8.55(d,J＝8.3Hz,1H),8.03(s,1H),7.43(d,J＝6.9Hz,1H),7.38(d,J＝6.9Hz,1H),7.35–7.26(m,2H),7.19(d,J＝3.3Hz,1H),7.09(d,J＝3.7Hz,1H),5.94–5.82(m,1H),4.85–4.72(m,1H),4.60–4.48(m,1H),4.39–4.21(m,2H),4.03–3.86(m,1H),3.36(s,2H),2.48(s,3H),2.11(s,6H),1.84(s,3H),1.70(d,J＝6.9Hz,3H).

Example 17

(4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidin-6-yl) (3-hydroxy-3-methylpyrrolidin-1-yl) methanone

4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidine-6-carboxylic acid was used as a raw material, and the product (4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylthieno [2,3-d ] pyrimidin-6-yl) (3-hydroxy-3-methylpyrrolidin-1-yl) methanone was obtained by the seventh step in reference example 1.

MS m/z(ESI):536.2[M+H]⁺.

Example 18

4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -N- (2-methoxyethyl) -2-methylthieno [2,3-d ] pyrimidine-6-carboxamide

With 4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylthieno [2,3-d]Pyrimidine-6-carboxylic acid as raw material the product obtained in the seventh step of reference example 1,4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -N- (2-methoxyethyl) -2-methylthieno [2,3-d]Pyrimidine-6-carboxamides. MS M/z (ESI) 510.1[ M + H]⁺.

Example 19

6-cyclopropyl-4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one

Starting from 2- (6- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetic acid and replacing 3-methyltetrahydrofuran-3-amine with cyclopropylamine reference example 1 the seventh to eighth step gave the product 6-cyclopropyl-4- ((1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) amino) -2-methylpyrido [4,3-d ] pyrimidin-7 (6H) -one.

MS m/z(ESI):460.2[M+H]⁺.

1H NMR(400MHz,Methanol-d4)δ8.96(s,1H),7.46(d,J＝7.6Hz,1H),7.39–7.22(m,3H),7.09(s,1H),7.01(s,1H),6.40(s,1H),6.07–5.97(m,1H),3.61–3.54(m,1H),3.51(s,2H),2.43(s,3H),2.15(s,6H),1.77(d,J＝7.0Hz,3H),1.24–1.15(m,2H),1.13–1.04(m,2H).

Example 20

6- (3-fluorocyclobutyl) -2-methyl-4- ((1- (5- (2- (pyrrolidin-1-ylmethyl) phenyl) thiophen-2-yl) ethyl) amino) pyrido [4,3-d ] pyrimidin-7 (6H) -one

The first step is as follows: methyl (R) -2- (5- (1, 3-dioxolan-2-yl) -2-methyl-6- ((1- (5- (2- (pyrrolidin-1-ylmethyl) phenyl) thiophen-2-yl) ethyl) amino) pyrimidin-4-yl) acetate

The fifth step of reference example 1 was followed to start with methyl (R) -2- (6- ((1- (5-bromothien-2-yl) ethyl) amino) -5- (1, 3-dioxan-2-yl) -2-methylpyrimidin-4-yl) acetate and to convert (2- ((dimethylamino) methyl) phenyl) boronic acid to (2- (pyrrolidin-1-ylmethyl) phenyl) boronic acid to give the product methyl (R) -2- (5- (1, 3-dioxan-2-yl) -2-methyl-6- ((1- (5- (2- (pyrrolidin-1-ylmethyl) phenyl) thiophen-2-yl) ethyl) amino) pyrimidin-4-yl) acetate.

MS m/z(ESI):523.2[M+H]⁺.

The second step is that: 6- (3-fluorocyclobutyl) -2-methyl-4- ((1- (5- (2- (pyrrolidin-1-ylmethyl) phenyl) thiophen-2-yl) ethyl) amino) pyrido [4,3-d ] pyrimidin-7 (6H) -one

Starting from methyl (R) -2- (5- (1, 3-dioxolan-2-yl) -2-methyl-6- ((1- (5- (2- (pyrrolidin-1-ylmethyl) phenyl) thiophen-2-yl) ethyl) amino) pyrimidin-4-yl) acetate and changing 3-methyltetrahydrofuran-3-amine to 3-fluorocyclobutan-1-amine reference example 1 the sixth to eighth steps give the product 6- (3-fluorocyclobutyl) -2-methyl-4- ((1- (5- (2- (pyrrolidin-1-ylmethyl) phenyl) thiophen-2-yl) ethyl) amino) pyrido [4 ], 3-d ] pyrimidin-7 (6H) -one.

MS m/z(ESI):518.2[M+H]⁺.

¹H NMR(400MHz,Methanol-d4)δ8.96(s,1H),7.50(d,J＝7.4Hz,1H),7.40–7.30(m,3H),7.11(d,J＝3.2Hz,1H),7.03(d,J＝3.3Hz,1H),6.37(s,1H),6.09–5.99(m,1H),5.51–5.39(m,1H),5.38–5.17(m,1H),3.80(s,2H),2.92–2.74(m,4H),2.60–2.53(m,4H),2.42(s,3H),1.79(d,J＝7.0Hz,3H),1.74–1.64(m,4H).

Biological test evaluation

The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.

Test example 1 determination of inhibitory Activity of the Compound of the present invention on activation of KRAS G12C function by SOS1

1.1 purpose of experiment:

measuring the inhibition effect of the compound on the functions of KRAS G12C-GTP activated by SOS1 and KRAS G12C-GDP

1.2 laboratory instruments and reagents:

1.2.1 Instrument:

microplate reader (BioTek Synergy H1);

pipettors (Eppendorf & Rainin);

centrifuge (Eppendorf).

1.2.2 reagents:

KRAS Protein, Human, Recombinant (12Cys, His Tag) Protein was purchased from Beijing Yiqian Shenzhou science Inc., having a cat number of 12259-H07E 2;

SOS1 protein was purchased from Cytoskeleton under the accession number CS-GE 02;

GDP was purchased from Sigma under the accession number G7127-25 MG;

EDA-GTP-Dy647P1 is purchased from Jena Bioscience and has the product number NU-820-647P 1;

MAb Anti-6HIS Eu cryptate Gold from Cisbio under the accession number 61HI2 KLA;

HEPES was purchased from Life Technologies, cat # 15630-;

sodium chloride was purchased from national pharmaceutical group chemical agents limited under the product number 10019318;

magnesium chloride is purchased from Sigma under the trade name of M1028-100 ML;

BSA was purchased from Sigma under the designation B2064-100G;

NP40 from Abcam corporation under cat # ab 142227;

DTT is purchased from Sigma under the trade designation 43816-50 ML;

the 384 well plate was purchased from Greiner, Inc. under the designation 784075.

1.2.3 test compounds:

the compound of the embodiment of the invention is prepared by self.

1.3 Experimental methods:

SOS1 can convert KRAS protein from a non-activated GDP-binding state to an activated GTP-binding state. The experiment is carried out in 384-well plate by TR-FRET method, and the buffer solution used in the experimental system is 10mM HEPES, 150mM NaCl, 5mM MgCl₂1mM DTT, 0.05% BSA, 0.0025% NP 40. 25nM KRAS G12C-GDP protein was mixed with 37.5ng/mL MAb Anti-6HIS Eu cryptate Gold using assay buffer, added to 384 well plates at 2.5. mu.L/well, centrifuged at 1000rpm for 1 minute, and then compound solutions of different concentrations prepared in assay buffer were added to 384 well plates at 2.5. mu.L/well, centrifuged at 1000rpm for 1 minute, mixed and incubated at room temperature for 10 minutes. The wells were filled with 100nM of the mixed solution of EDA-GTP-Dy647P1 and 50nM of SOS1, 2.5. mu.L per well, centrifuged at 1000rpm for 1 min, sealed, and reacted at room temperature for 3 hours, and the plate was read using the time-resolved fluorescence program in BioTek Synergy H1 to detect fluorescence at 665nM and 620 nM.

1.4 Experimental data processing method:

calculating the fluorescence ratio of 665nm/620nm, and fitting the concentration and the fluorescence ratio by using Graphpad Prism software to obtain IC₅₀The values are shown in table 1 below.

1.5 Experimental results:

TABLE 1 IC of inhibition of SOS1 activation of KRAS G12C-GDP to KRAS G12C-GTP function by compounds₅₀Value of

Example numbering	IC₅₀Value (nM)
		1	59
2	40
		3	60
5	75
		6	80
11	77
		19	74
20	91

1.5 conclusion of the experiment:

the above data show that the compounds of the examples of the present invention show good inhibitory activity in the SOS1 activity inhibition assay.

Test example 2 measurement of in vitro inhibitory Effect of the Compound of the present invention on tumor cell proliferation

2.1 purpose of experiment:

the inhibitory effect of the compounds of the present invention on the in vitro proliferative activity of tumor cells was measured.

2.2 laboratory instruments and reagents:

2.2.1 Instrument:

microplate reader (BioTek Synergy H1);

pipettor (Eppendorf & Rainin).

2.2.2 reagents:

mia PaCa-2 was purchased from ATCC;

3D Cell visual Assay available from Promega under the product number G9683;

the sphere micropore plate is purchased from Sigma company, and has the commodity number of CLS 4520;

DMEM medium was purchased from Gibco, Inc. under the accession number 11995065;

FBS is available from Gibco corporation under the product number 10091148;

pancreatin was purchased from Gibco under the cat number 25200056;

PBS was purchased from Gibco, Inc. under the designation 10010023.

2.2.3 test compounds:

the compound of the embodiment of the invention is prepared by self.

2.3 Experimental methods:

the experiment adopts a 3D-CTG method to detect the inhibition effect of the compound on the in vitro proliferation activity of tumor cells.

Culturing Mia PaCa-2 cells (KRAS G12C mutant) to appropriate fusion degree, washing with PBS once, adding pancreatin, re-suspending with complete medium (RPMI 1640 medium containing 10% FBS or DMEM medium), centrifuging at 1000rpm for 5 min, collecting cells, adjusting cell concentration to appropriate cell concentration with complete medium, spreading the cell suspension in 96-well spheroplast plate (180. mu.L per well), adding 37 deg.C, 5% CO, and making into pellet₂Culturing in incubator for about 72 hr, preparing compound solutions with different concentrations by using DMSO and culture medium, setting solvent control, adding compound solution into 96-well plate, 20 μ L per well, placing at 37 deg.C and 5% CO₂And (3) continuously culturing for about 120-192H in the incubator, adding CellTiter-Glo 3D solution, shaking and mixing uniformly, incubating for 30 minutes in a dark place, and reading by using a BioTek Synergy H1 enzyme-labeling instrument.

2.4 Experimental data processing method:

calculating the inhibition rate by using the luminescence signal value, and fitting the concentration and the inhibition rate by using Graphpad Prism software to obtain IC₅₀Values, as shown in table 2.

2.5 Experimental results:

TABLE 2 IC inhibition of tumor cell proliferation activity in vitro by compounds₅₀Value of

2.5 conclusion of the experiment:

the above data show that the compounds of the examples of the present invention show good biological activity in the inhibition assay of tumor cell proliferation activity.

Claims

1. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R_aaSelected from the group consisting of hydrogen, deuterium, halogen, nitro, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, andoptionally, the alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl can be further substituted;

R²and R^2’Each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxy, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted;

R³selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, bridged alkyl, bridged heterocyclyl, - (CH)₂)_n2R_AA、-(CH₂)_n2OR_AA、-(CH₂)_n2C(O)OR_AA、-(CH₂)_n2OR_AA、-(CH₂)_n2SR_AA、-(CH₂)_n2NR_AAC(O)(CH₂)_n3R_BB、-(CH₂)_n2NR_AAC(O)OR_BB、-(CH₂)_n2NR_AAC(O)NR_BBR_CC、-(CH₂)_n2NR_AAR_BB、-NR_AA(CH₂)_n2R_BB、-(CH₂)_n2C(O)NR_AA(CH₂)_n3R_BB、-(CH₂)_n2C(O)R_AA、-OC(R_AAR_BB)_p(CH₂)_n2R_CC、-(CH₂)_n2S(O)_m2R_AA、-(CH₂)_n2NR_AAS(O)_m2R_BB、-CH＝CH(CH₂)_n2R_AA、-CH＝CH(CH₂)_n2NR_AAR_BB、-CH＝CH(CH₂)_n2NR_AAC(O)R_BBor-CH ═ CH (CH)₂)_n2NR_AAC(O)NR_BBR_CCSaid amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, bridged cycloalkyl and bridged heterocyclyl, optionally further substituted with hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, - (CH)₂)_nR_a1、-(CH₂)_nOR_a1、-(CH₂)_nC(O)OR_a1、-(CH₂)_nOR_a1-(CH₂)_nNR_a1C(O)R_b1Or- (CH)₂)_nNR_a1R_b1Is substituted with one or more substituents of (1);

R_AA、R_BBand R_CCEach independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl, and heteroaryloxy, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further comprisingIs substituted;

R^bselected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;

x is an integer of 0-3;

y is an integer of 0 to 2;

z is an integer of 0 to 5;

n and n 1-n 5 are integers of 0-5;

p and p1 are integers of 0-5; and is

m 1-m 3 are integers of 0-2.

2. The compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof according to claim 1, wherein R is^cSelected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl, 5-14 membered heteroaryl, - (CH)₂)_n4R_A1、-(CH₂)_n4OR_A1、-(CH₂)_n4C(O)OR_A1、-(CH₂)_n4OR_A1、-(CH₂)_n4SR_A1、-(CH₂)_n4NR_A1C(O)NR_B1R_C1、-(CH₂)_n4NR_A1R_B1、-NR_A1(CH₂)_n4R_B1、-(CH₂)_n4C(O)R_A1、-OC(R_A1R_B1)_p1(CH₂)_n4R_C1、-(CH₂)_n4S(O)_m3R_A1、-(CH₂)_n4NR_A1S(O)_m3R_B1、-CH＝CH(CH₂)_n4R_A1、-CH＝CH(CH₂)_n4NR_A1R_B1、-CH＝CH(CH₂)_n4NR_A1C(O)R_B1or-CH ═ CH (CH)₂)_n4NR_A1C(O)NR_B1R_C1Said amino group, C_1-6Alkyl radical, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl, 5-14 membered heteroaryl, substituted with one or more substituents;

The R is^cMore preferably hydrogen, halogen, amino, hydroxy, cyano, -CH₂NR_A1R_B1or-CH₂OR_A1；

The R is_A1、R_B1And R_C1Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl; preferably hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C_1-6Alkyl radical, C_1-6Deuterated alkyl or C_1-6A haloalkyl group;

more preferably hydrogen, methyl, ethyl, n-propyl, isopropyl or n-butyl.

3. The compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound of formula (I) is further represented by formula (IIa) or formula (IIa),

4. the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that the compound of formula (I) is further represented by formula (III),

wherein the content of the first and second substances,

n6 and n7 are integers of 0-5; and is

m4 is an integer of 0 to 2.

5. The compound of formula (III), its stereoisomers or pharmaceutically acceptable salts thereof according to claim 4, wherein R is^3aIs selected from C_3-6Cycloalkyl or 5-6 membered heterocyclyl, optionally further substituted by hydrogen, halogen, C_1-3Alkyl radical, C_1-3Haloalkyl and C_1-3Substituted with one or more substituents of alkoxy;

C_3-6cycloalkyl or 5-6 membered heterocyclyl is preferably the following;

6. compound of general formula (I) according to any one of claims 1 to 5, characterized in that it is chosen from the following compounds:

7. a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

8. Use of a compound according to any one of claims 1 to 6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, for the manufacture of a medicament for the treatment of an SOS1 inhibitor and a RAS family protein and/or RACl inhibitor.

9. The compound according to any one of claims 1 to 6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7, for use in the preparation of a medicament for preventing or/and treating diseases or disorders such as membrane adenocarcinoma, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.

10. Use of a compound according to any one of claims 1 to 6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, for the preparation or/and treatment of a RAS-related disease or disorder; preferably for the preparation or/and treatment of KRAS-related diseases or disorders; more preferably for the preparation or/and treatment of a disease or condition mediated by an SOS1 inhibitor; the RAS disease is selected from type I neurofibromatosis, Noonan syndrome accompanied by multiple plaques, capillary malformation arteriovenous malformation syndrome, Costellor syndrome, cardio-facial skin syndrome, Lenges syndrome and hereditary dental root fibromatosis.