CN115073451A

CN115073451A - KRAS G12D Preparation and application of mutant protein inhibitor

Info

Publication number: CN115073451A
Application number: CN202110277549.5A
Authority: CN
Inventors: 梁永宏
Original assignee: Yaoya Technology Shanghai Co ltd
Current assignee: Yaoya Technology Shanghai Co ltd
Priority date: 2021-03-15
Filing date: 2021-03-15
Publication date: 2022-09-20

Abstract

The present invention relates to KRAS ^G12D The invention provides an inhibitor and application thereof, in particular to a compound shown as a formula (I), wherein each substituent is defined as the specification. It also relates to the composition of the inhibitor and its application. The compound of the invention has good activity of inhibiting tumor growth. And has good safety.

Description

KRAS G12D Preparation and application of mutant protein inhibitor

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a novel Bruton's tyrosine kinase inhibitor, and a preparation method and application thereof.

Background

The present invention relates generally to novel compounds, methods for their preparation and their use as KRAS ^G12D Use of an inhibitor (e.g. for the treatment of cancer).

RAS represents a group of closely related 189 amino acid (molecular weight 21kDa) monomeric globular proteins that are associated with the plasma membrane and bind GDP or GTPoRAS as molecular switches. When the RAS contains a bound GDP, it is in a quiescent or off state and is in an "inactive state". In response to exposure of cells to certain growth-promoting stimuli, RAS is induced to convert its bound GDP to GTP. Upon binding to GTP, RAS is "turned on" and is able to interact with and activate other proteins (their "downstream targets"). The RAS protein itself has a very low intrinsic capacity to hydrolyze GTP back to GDP, leaving itself in an off state. Shutting down RAS requires an extrinsic protein called GTPase Activating Proteins (GAPs) that interact with RAS and greatly accelerate conversion of GTP to GDP. Any mutation in RAS that affects its ability to interact with GAPs or convert GTP back to GDP will result in an extended activation time of the protein, resulting in an extended cellular signal that allows it to continue to grow and divide. Because these signals lead to cell growth and division, hyperactive RAS signals may ultimately lead to cancer.

Structurally, the RAS protein contains a G domain responsible for the enzymatic activity of RAS-ornithopterin nuclear-back-acid binding and hydrolysis (GTPase reaction). It also contains a C-terminal extension called CAAX box, can be post-translationally modified, and is responsible for targeting proteins to the membrane. The G domain is about 21-25kDa in size and comprises a phosphate binding ring (P-ring). The P-loop is the pocket for nucleic acids to bind in proteins, a rigid part of the domain with conserved amino acid residues ((glycine 12, threonine 26 and lysine 16)) that is critical for nucleic acid binding and hydrolysis. The G domain also contains the so-called Switch I (residues 30-40) and Switch II (residues 60-76) regions, both of which are dynamic parts of the protein, which are commonly referred to as "spring-loaded" mechanisms because they are capable of switching between resting and loaded states. The key interaction is the hydrogen bond formed by threonine 35 and glycine 60, with the Y-phosphate of GTP, which maintains the Switch1 and Switch2 regions in their active conformations, respectively. After hydrolysis of GTP and release of phosphate, the two relax into the inactive GDP conformation.

The most well-known members of the RAS subfamily are HRAS, KRAS and NRAS, primarily because of their association with various types of cancer. Mutations in any of the three major isoforms of RAS (HRAS, NRAS or KRAS) genes are most common in human tumorigenesis. It was found that about 30% of human tumors carry RAS gene mutations o notably, KRAS mutations were detected in 25-30% of tumors. In contrast, the rate of oncogenic mutations that occur in NRAS and HRAS family members is much lower (8% and 3%, respectively). The most common KRAS mutations were found at residues G12 and G13 and at residue Q61 of the P loop. G12C and G12D are frequent mutations of the KRAS gene (glycine 12 to cysteine, glycine 12 to aspartic acid).

As leading edge target, KRAS ^G12C And KRAS ^G12D Mutant proteins have received much attention. Wherein, KRAS ^G12C Many inhibitors are in the clinic, such as: AMG-510 from Andin (WO2018217651A1) and MRTX-849 from Mirati pharmaceuticals (WO2019099524A 1). However, KRAS ^G12D The mutant protein has no corresponding targeted drug at present. Recently, KRAS candidates developed by Mirati pharmaceutical company ^G12D The inhibitor MRTX-1133(WO2021041671A1) is in preclinical stage. The present invention fulfills this need and provides other related advantages.

Disclosure of Invention

A compound having the general formula (I), a stereoisomer, a pharmaceutically acceptable salt, a polymorph, or an isomer thereof, wherein the compound having the general formula (I) has the following structure:

wherein the content of the first and second substances,

each L ₁ Independently at each occurrence, is selected from absent, (CR) ₃ R ₄ ) _i 、C(C＝O)、O、NR ₃ S, S (═ O) or S (═ O) ₂ ；

Each R ₁ Independently at each occurrence, is selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, each heteroaryl independently at each occurrence, comprising 1,2,3, or 4 heteroatoms selected from N, 0, or S; each R ₁ Optionally at each occurrence independently by 1,2,3, 4, 5 or 6R ₂₀ Substituted or unsubstituted;

each R ₂₀ Independently at each occurrence, selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkylene- (halogen) _1-3 、C _1-6 Heteroalkyl, -CN, -OR ₆ 、-C _1-6 Alkylene- (OR) ₆ ) _1-3 、-O-C _1-6 Alkylene- (halogen) _1-3 、-SR ₆ 、-S-C _1-6 Alkylene- (halogen) _1-3 、-NR ₆ R ₇ -C1-6 alkylene-NR ₆ R ₇ 、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ 、-S(O) ₂ NR ₆ R ₇ or-C _3-6 A carbocyclic group; each R ₁₂ Independently optionally substituted by 1,2,3, 4, 5 or 6 substituents selected from deuterium, halogen, -C _1-6 Alkyl, -C _1-6 Alkoxy, oxo, -OR ₆ 、-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ or-S (O) ₂ NR ₆ R ₇ Substituted or unsubstituted;

each L ₂ Independently at each occurrence, selected from O, NH, CO or S;

each ring A is C _3-10 Carbocyclic ring of

May be attached to the same carbon atom or to different atoms of said ring A;

each R ₂ is-OR ₆ 、-NR ₆ R ₇ 、-SR ₆ 、-S(＝O)R ₆ 、-S(＝O) ₂ R ₆ 5-10 membered heteroaryl or 3-10 membered heterocyclyl, each heterocyclyl and heteroaryl independently containing at each occurrence 1,2,3 or 4 substituents selected from N, O, S, S ═ O or S (═ O) ₂ Each R3 is independently at each occurrence optionally substituted with 1,2,3, 4, 5, or 6R ₁₉ Substituted or unsubstituted;

each R ₃ And R ₄ Independently at each occurrence, selected from deuterium, hydrogen, halogen, -C _1-6 Alkyl, -C _2-6 Alkenyl, -C _2-6 Alkynyl, oxo, -OR ₆ 、-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ or-S (O) ₂ NR ₆ R ₇ or-C _3-10 Carbocyclyl, each heterocyclyl and heteroaryl independently comprise, at each occurrence, 1,2,3 or 4 substituents selected from N, 0, S, S ═ 0 or S (═ O) ₂ A heteroatom of (a); each R ₃ And R ₄ Optionally substituted at each occurrence with 1,2,3, 4, 5 or 6 substituents selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkoxy, oxo, -OR ₆ 、-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ or-S (O) ₂ NR ₆ R ₇ Substituted or unsubstituted;

each R ₅ Independently at each occurrence, selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkylene- (halogen) _1-3 、C _1-6 Heteroalkyl, -CN, -OR ₆ 、-C _1-6 Alkylene- (OR) ₆ ) _1-3 、-O-C _1-6 Alkylene- (halogen) _1-3 、-SR ₆ 、-S-C _1-6 Alkylene- (halogen) _1-3 、-NR ₆ R ₇ 、-C _1-6 alkylene-NR ₆ R ₇ 、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ 、-S(O) ₂ NR ₆ R ₇ or-C _3-6 Carbocyclyl, each heterocyclyl and heteroaryl independently containing, at each occurrence, 1,2,3 or 4 substituents selected from the group consisting of N, O, S, S ═ O or S (═ O) ₂ A heteroatom of (a); each R ₃ And R ₄ Optionally substituted at each occurrence with 1,2,3, 4, 5 or 6 substituents selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkoxy, oxo, -OR ₆ 、-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ or-S (O) ₂ NR ₆ R ₇ Substituted or unsubstituted;

each R ₆ And R ₇ Independently at each occurrence, is selected from hydrogen or-C1-6 alkyl, each R ₆ And R ₇ Independently optionally substituted by 1,2,3, 4, 5 or 6R ₁₉ Substituted or unsubstituted; or R ₇ And R ₇ Together with the N atom to which they are commonly attached form a 3-10 membered heterocyclic ring, which 3-10 membered heterocyclic ring may further comprise 1,2,3 or 4 heteroatoms selected from N, O, S, S (═ O) or S (═ O)2, and which 3-10 membered heterocyclic ring is independently optionally substituted with 1,2,3, 4, 5 or 6R atoms ₁₉ Substituted or unsubstituted;

each R ₁₉ Independently at each occurrence, selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkylene- (halogen) _1-3 、C _1-6 Heteroalkyl, -CN, -OR ₆ 、-C _1-6 Alkylene- (OR) ₆ ) _1-3 、-O-C _1-6 Alkylene- (halogen) _1-3 、-SR ₆ 、-S-C _1-6 Alkylene- (halogen) _1-3 、-NR ₆ R ₇ 、-C _1-6 alkylene-NR ₆ R ₇ 、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ 、-S(O) ₂ NR ₆ R ₇ or-C _3-6 A carbocyclic group;

s is selected from 0, 1,2,3, 4, 5 or 6;

p is selected from 0, 1,2,3, 4, 5 or 6;

q is selected from 0, 1,2,3, 4, 5 or 6.

Y is absent or C is selected _3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spiro cyclic group, 5-12 membered spiro heterocyclic group, aromatic group or heteroaromatic group, wherein said cycloalkyl, heterocycloalkyl, spiro cyclic group, fused heterocyclic group, spiro heterocyclic group, aromatic group or heteroaromatic group is optionally substituted with one or more G ¹ Substituted;

G ¹ and G ² Each independently selected from deuterium, cyano, halogen, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl or 3-to 8-membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, -OR ₁₁ 、-OC(O)NR ₁₁ R ₁₂ 、-C(O)OR ₁₁ 、-C(O)NR ₁₁ R ₁₂ 、-C(O)R ₁₁ 、-NR ₁₁ R ₁₂ 、-NR ₁₁ C(O)R ₁₂ 、-NR ₁₁ C(O)NR ₁₂ R ₁₃ 、-S(O) _m R ₁₁ or-NR ₁₁ S(O) _m R ₁₂ Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1 or more of deuterium, cyano, halogen, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, -OR ₁₄ 、-OC(O)NR ₁₄ R ₁₅ 、-C(O)OR ₁₄ 、-C(O)NR ₁₄ R ₁₅ 、-C(O)R ₁₄ 、-NR ₁₄ R ₁₅ 、-NR ₁₄ C(O)R ₁₅ 、-NR ₁₄ C(O)NR ₁₅ R ₁₆ 、-S(O) _m R ₁₄ or-NR ₁₄ S(O) _n R ₁₅ Substituted with the substituent(s); r is ⁸ 、R ⁹ 、R ¹¹ 、R ¹² 、R ¹³ 、R ¹⁴ And R ¹⁵ Each independently selected from hydrogen, deuterium, cyano, halogen, C _1-6 Alkyl radical, C _3-8 Cycloalkyl or 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl or phenyl;

and m is 1 or 2.

In some embodiments, each R is ₁ Independently at each occurrence, is selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, each heteroaryl independently at each occurrence, comprising 1,2,3, or 4 heteroatoms selected from N, 0, or S; each R ₁ Optionally at each occurrence independently by 1,2,3, 4, 5 or 6R ₂₀ Substituted or unsubstituted;

in some embodiments, eachR is ₁ Independently at each occurrence is selected from phenyl, naphthyl, pyridyl, indolyl, indazolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, each R ₁ Independently at each occurrence is optionally substituted or unsubstituted with 1,2,3, 4, 5 or 6R 12; each R ₁ Optionally at each occurrence independently by 1,2,3, 4, 5 or 6R ₂₀ Substituted or unsubstituted;

in some embodiments, each R is ₁ Selected from:

in some embodiments, each R is ₁ Optionally at each occurrence independently by 1,2,3, 4, 5 or 6R ₂₀ Substituted or unsubstituted;

in some embodiments, each R is ₂₀ Independently at each occurrence, selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkylene- (halogen) _1-3 、C _1-6 Heteroalkyl, -CN, -OR ₆ 、-C _1-6 Alkylene- (OR) ₆ ) _1-3 、-O-C _1-6 Alkylene- (halogen) _1-3 、-SR ₆ 、-S-C _1-6 Alkylene- (halogen) _1-3 、-NR ₆ R ₇ -C1-6 alkylene-NR ₆ R ₇ 、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ 、-S(O) ₂ NR ₆ R ₇ or-C _3-6 A carbocyclic group; each R ₁₂ Independently optionally substituted by 1,2,3, 4, 5 or 6 substituents selected from deuterium, halogen, -C _1-6 Alkyl, -C _1-6 Alkoxy, oxo, -OR ₆ 、-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ or-S (O) ₂ NR ₆ R ₇ Substituted or unsubstituted;

in some embodiments, each R is ₂₀ R in (1) ₆ And R ₇ Independently at each occurrence, selected from hydrogen, deuterium or-C _1-3 An alkyl group;

in some embodiments, each R is ₂₀ Independently at each occurrence is selected from-deuterium, -F, -Cl, -Br, oxo, methyl, ethyl, propyl, isopropyl, -CH ₂ F、-CHF ₂ 、-CF ₃ 、-CH ₂ CH ₂ F、-CH ₂ CHF ₂ 、-CH ₂ CF ₃ 、-CH ₂ CH ₂ CH ₂ F、-CH ₂ CH ₂ CH ₂ F ₂ 、-CH ₂ CH ₂ CF ₃ 、-CH ₂ OCH3、-CH ₂ CH ₂ OCH ₃ 、-CH ₂ CH ₂ CH ₂ OCH ₃ 、-CN，-OH，-OCH ₃ 、-OCH ₂ CH ₃ 、-OCH ₂ CH ₂ CH ₃ 、-OCH(CH ₃ ) ₂ 、-CH ₂ OH，-CH ₂ CH ₂ OH，-CH ₂ CH ₂ CH ₂ OH，-OCH ₂ F、-OCHF ₂ 、-OCF ₃ 、-OOOF、-OCH ₂ CHF ₂ 、-OCH ₂ CF ₃ 、-OCH ₂ CH ₂ CH ₂ F、-OCH ₂ CH ₂ CHF ₂ 、-OCH ₂ CH ₂ CF ₃ 、-SH、-SCH ₃ 、-SCH ₂ CH ₃ 、-SCH(CH ₃ ) ₂ 、-SOF、-SCHF ₂ 、-SCF ₃ 、-SCH ₂ CH ₂ F、-SCH ₂ CH ₂ F ₂ 、-SCH ₂ CF ₃ 、-SCH ₂ CH ₂ CH ₂ F、-SCH ₂ CH ₂ CHF ₂ 、-SCH ₂ CH ₂ CF ₃ 、-NH ₂ 、-NHCH ₃ 、-NHCH ₂ CH ₃ 、-NHCH ₂ CH ₂ CH ₃ 、-NHCH(CH ₃ ) ₂ 、-N(CH ₃ ) ₂ 、-N(CH3)CH ₂ CH ₃ 、-N(O)CH ₂ CH ₂ CH ₃ 、-N(CH3)CH(CH ₃ ) ₂ 、-CH2NH ₂ 、-CH ₂ CH ₂ NH ₂ 、-CH ₂ CH ₂ CH ₂ NH ₂ 、-CH ₂ N(CH ₃ ) ₂ 、-CH ₂ CH ₂ N(CH ₃ ) ₂ 、-CH ₂ CH ₂ CH ₂ N(CH ₃ ) ₂ 、-C(＝O)CH ₃ 、-C(＝O)OCH ₃ 、-C(＝O)OCH ₂ CH ₃ 、-C(＝O)OCH ₂ CH ₂ CH ₃ 、-OC(＝O)CH ₃ 、-C(＝O)NH ₂ 、-C(＝O)NH(CH ₃ )、-C(＝O)N(CH ₃ ) ₂ 、-NHC(＝O)CH ₃ 、-N(CH3)C(＝O)CH ₃ 、-S(O) ₂ NH ₂ 、-S(O)2NH(CH ₃ )、-S(O) ₂ N(CH ₃ ) ₂ 3-, 4-, 5-or 6-membered carbocyclyl; each R ₂₀ Independently optionally substituted with 1,2,3, 4, 5 or 6 substituents selected from-deuterium, -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH ₂ 、-NHCH ₃ 、_N(CH ₃ )2、-CN、-C(＝O)CH ₃ 、_C(＝O)OO、-OC(＝O)O、-C(＝O)NH ₂ 、-C(＝O)NH(CH ₃ )、-C(＝O)N(CH ₃ )2、-NHC(＝O)CH ₃ 、-N(CH ₃ )C(＝O)CH ₃ 、-S(O) ₂ NH ₂ 、-S(O) ₂ NH(CH ₃ ) or-S (O) ₂ N(CH ₃ )2 is substituted or unsubstituted;

in some embodiments, each R is ₁ Selected from:

in some embodiments, each ring a is a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring, or a 6-membered carbocyclic ring, and

may be attached to the same carbon atom or to different atoms of said ring A; each R ₂ Independently at each occurrence is selected from-NR ₆ R ₇ Or 3-6 membered heterocyclyl, each heterocyclyl independently at each occurrence containing 1 heteroatom selected from N, each R ₂ Optionally at each occurrence independently by 1,2,3, 4, 5 or 6R ₂₀ Substituted or unsubstituted;

in some embodiments, each R is independently selected from R, and R ₂ R in (1) ₆ And R ₇ Independently at each occurrence is selected from hydrogen, deuterium, methyl, ethyl, propyl or isopropyl; or

R ₂ R in (1) ₆ And R ₇ Together with the N atom to which they are commonly attached form a 3-6 membered heterocyclic ring, said 3-6 membered heterocyclic ring may further comprise 1 heteroatom selected from N, and said 3-6 membered heterocyclic ring is independently optionally substituted with 1,2,3, 4, 5 or 6R ₂₀ Substituted or unsubstituted;

in some embodiments, each R is ₂ Independently at each occurrence is selected from-NH ₂ 、-N(CH ₃ ) ₂ 、-N(CH ₃ )(CH ₂ CH ₃ )、-N(CH ₂ CH ₃ ) ₂ 、

Each R ₂ Independently optionally substituted by 1,2,3, 4, 5 or 6R ₂₀ Substituted or unsubstituted;

in some embodiments, each R is ₂₀ Independently at each occurrence is selected from deuterium,Halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkylene- (halogen) _1-3 、C _1-6 Heteroalkyl, -CN, -OR ₆ 、-C _1-6 Alkylene- (OR) ₆ ) _1-3 、-O-C _1-6 Alkylene- (halogen) _1-3 、-SR ₆ 、-S-C _1-6 Alkylene- (halogen) _1-3 、-NR ₆ R ₇ -C1-6 alkylene-NR ₆ R ₇ 、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ 、-S(O) ₂ NR ₆ R ₇ or-C _3-6 A carbocyclic group; each R ₁₂ Independently optionally substituted by 1,2,3, 4, 5 or 6 substituents selected from deuterium, halogen, -C _1-6 Alkyl, -C _1-6 Alkoxy, oxo, -OR ₆ 、-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ or-S (O) ₂ NR ₆ R ₇ Substituted or unsubstituted;

in some embodiments, each R is ₃ And R ₄ Independently at each occurrence, selected from deuterium, hydrogen, halogen, -C _1-6 Alkyl, -C _2-6 Alkenyl, -C _2-6 Alkynyl, oxo, -OR ₆ 、-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ or-S (O) ₂ NR ₆ R ₇ or-C _3-10 Carbocyclyl, each heterocyclyl and heteroaryl independently comprise, at each occurrence, 1,2,3 or 4 substituents selected from N, 0, S, S ═ 0 or S (═ O) ₂ A heteroatom of (c); each R ₃ And R ₄ Optionally substituted at each occurrence with 1,2,3, 4, 5 or 6 substituents selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkoxy, oxo, -OR ₆ 、-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ or-S (O) ₂ NR ₆ R ₇ Substituted or unsubstituted;

in some embodiments, each R is ₃ And R ₄ R in (1) ₆ And R ₇ Independently at each occurrence, selected from hydrogen, deuterium or-C _1-3 An alkyl group;

in some embodiments, each R is ₃ And R ₄ Independently at each occurrence is selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, isopropenyl, ethynyl, propynyl, oxo, -OH, -OCH ₃ 、-OCH ₂ CH ₃ 、-OCH ₂ CH ₂ CH ₃ 、-OCH(CH ₃ ) ₂ 、-NH ₂ 、-NHCH ₃ 、-NHCH ₂ CH ₃ 、-NHCH ₂ CH ₂ CH ₃ 、-NHCH(CH ₃ )2、-N(CH ₃ ) ₂ 、-N(CH ₃ )CH ₂ CH ₃ 、-N(CH ₃ )CH ₂ CH ₂ CH ₃ 、-N(CH ₃ )CH(CH ₃ ) ₂ 、-CN、-C(＝O)CH ₃ 、-C(＝O)OCH ₃ 、-OC(＝O)CH ₃ 、-C(＝O)NH ₂ 、-C(＝O)NH(CH ₃ )、-C(＝O)N(CH ₃ ) ₂ 、-NHC(＝O)CH ₃ 、-N(CH3)C(＝O)CH ₃ 、-S(O) ₂ NH ₂ 、-S(O) ₂ NH(CH ₃ )、-S(O) ₂ N(CH ₃ ) ₂ 3-, 4-, 5-or 6-membered carbocyclyl; each R5 or R6 is independently optionally substituted by 1,2,3, 4, 5 or 6 groups selected from-F, -Cl, -Br, oxo, methyl, ethyl, propyl, isopropyl, -OH, OCH ₃ 、-OCH ₂ CH ₃ 、-OCH ₂ CH ₂ CH ₃ 、-OCH(CH ₃ ) ₂ 、-NH ₂ 、-N(CH ₃ ) ₂ 、-CN、-C(＝O)CH ₃ 、-OC(＝O)CH ₃ 、-C(＝O)NH ₂ 、-C(＝O)NH(CH ₃ )、-C(＝O)N(CH ₃ ) ₂ 、-NHC(＝O)CH ₃ 、-N(CH3)C(＝O)CH ₃ 、-S(O) ₂ NH ₂ 、-S(O) ₂ NH(CH ₃ )、-S(O) ₂ N(CH ₃ ) ₂ Substituted or unsubstituted.

In some embodiments, each R is ₅ Independently at each occurrence is selected from deuterium, -F, -Cl, -Br, -C _1-3 Alkyl, -C _1-3 Alkylene- (halogen) _1-3 、C _1-3 Heteroalkyl, -C _2-3 Alkenyl, -C _2-3 Alkynyl, -CN, -OR ₆ 、-C _1-6 Alkylene- (OR) ₆ ) _1-3 、-O-C _1-6 Alkylene- (halogen) _1-3 、-SR ₆ 、-S-C _1-6 Alkylene- (halogen) _1-3 、-NR ₆ R ₇ 、-C _1-6 alkylene-NR ₆ R ₇ 、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ 、-S(O) ₂ NR ₆ R ₇ or-C _3-6 Carbocyclyl, each heterocyclyl and heteroaryl independently containing, at each occurrence, 1,2,3 or 4 substituents selected from the group consisting of N, O, S, S ═ O or S (═ O) ₂ A heteroatom of (a); each R ₃ And R ₄ Optionally substituted at each occurrence with 1,2,3 or 4, 5 or 6 substituents selected from deuterium, -F, -Cl, -Br, oxo, -C _1-6 Alkyl, -C _1-6 Alkoxy, oxo, -OR ₆ 、-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ or-S (O) ₂ NR ₆ R ₇ Substituted or unsubstituted;

in some embodiments, each R is ₅ R in (1) ₆ And R ₇ Independently at each occurrence, selected from hydrogen, deuterium or-C _1-3 Alkyl, or

R ₅ R in (1) ₆ And R ₇ Together with the N atom to which they are commonly attached form a 3-6 membered heterocyclic ring, said 3-6 membered heterocyclic ring may further comprise 1 heteroatom selected from N, and said 3-6 membered heterocyclic ring is independently optionally substituted with 1,2,3, 4 heteroatoms selected from N, O or S;

in some embodiments, each R is ₅ Independently at each occurrence, is selected from deuterium, -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, isopropenyl, ethynyl, propynyl, -methylene- (halogen) 1-3, -ethylene- (halogen) _1-3 -propylene- (halogen) _1-3 Hetero-methyl, hetero-ethyl, hetero-propyl, ethenyl, propenyl, ethynyl, propynyl, oxo, -OR ₆ -methylene- (OR) ₆ ) _1-3 -ethylene- (OR) ₆ ) _1-3 -propylene- (OR) ₆ ) _1-3 -O-methylene- (halogen) _1-3 -O-ethylene- (halogen) _1-3 -O-propylene- (halogen) _1-3 、-NR ₆ R ₇ -methylene-NR ₆ R ₇ -ethylene-NR 6R7, -propylene-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ -S (o)2NR6R7, phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl, 8-membered heteroaryl, 10-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl, each heterocyclyl and heteroaryl independently at each occurrence comprising 1,2,3, or 4 heteroatoms selected from N, O or S; each R7 is independently optionally substituted at each occurrence with 1,2,3, 4, 5 OR 6 substituents selected from-F, -C1, -Br, oxo, methyl, ethyl, propyl, isopropyl, -OR ₆ 、-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₆ or-S (O) ₂ NR ₆ R ₇ Substituted with the substituent(s);

in some embodiments, each R is ₅ R in (1) ₆ And R ₇ Independently at each occurrence is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl; or

Each R ₅ R in (1) ₆ And R ₇ Together with the N atom to which they are jointly attached form

In some embodiments, each R is ₅ Independently at each occurrence, is selected from deuterium, -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, -CH ₂ F、-CHF ₂ 、-CF ₃ 、-CH ₂ CH ₂ F、-CH ₂ CHF ₂ 、-CH ₂ CF ₃ 、-CH ₂ CH ₂ CH ₂ F、-CH ₂ CH ₂ CH ₂ F ₂ 、-CH ₂ CH ₂ CF ₃ 、-CH ₂ OCH3、-CH ₂ CH ₂ OCH ₃ 、-CH ₂ CH ₂ CH ₂ OCH ₃ 、-CN，-OH，-OCH ₃ 、-OCH ₂ CH ₃ 、-OCH ₂ CH ₂ CH ₃ 、-OCH(CH ₃ ) ₂ 、-CH ₂ OH，-CH ₂ CH ₂ OH，-CH ₂ CH ₂ CH ₂ OH，-OCH ₂ F、-OCHF ₂ 、-OCF ₃ 、-OOOF、-OCH ₂ CHF ₂ 、-OCH ₂ CF ₃ 、-OCH ₂ CH ₂ CH ₂ F、-OCH ₂ CH ₂ CHF ₂ 、-OCH ₂ CH ₂ CF ₃ 、-SH、-SCH ₃ 、-SCH ₂ CH ₃ 、-SCH(CH ₃ ) ₂ 、-SOF、-SCHF ₂ 、-SCF ₃ 、-SCH ₂ CH ₂ F、-SCH ₂ CH ₂ F ₂ 、-SCH ₂ CF ₃ 、-SCH ₂ CH ₂ CH ₂ F、-SCH ₂ CH ₂ CHF ₂ 、-SCH ₂ CH ₂ CF ₃ 、-NH ₂ 、-NHCH ₃ 、-NHCH ₂ CH ₃ 、-NHCH ₂ CH ₂ CH ₃ 、-NHCH(CH ₃ ) ₂ 、-N(CH ₃ ) ₂ 、-N(CH3)CH ₂ CH ₃ 、-N(O)CH ₂ CH ₂ CH ₃ 、-N(CH3)CH(CH ₃ ) ₂ 、-CH2NH ₂ 、-CH ₂ CH ₂ NH ₂ 、-CH ₂ CH ₂ CH ₂ NH ₂ 、-CH ₂ N(CH ₃ ) ₂ 、-CH ₂ CH ₂ N(CH ₃ ) ₂ 、-CH ₂ CH ₂ CH ₂ N(CH ₃ ) ₂ 、-C(＝O)CH ₃ 、-C(＝O)OCH ₃ 、-C(＝O)OCH ₂ CH ₃ 、-C(＝O)OCH ₂ CH ₂ CH ₃ 、-OC(＝O)CH ₃ 、-C(＝O)NH ₂ 、-C(＝O)NH(CH ₃ )、-C(＝O)N(CH ₃ ) ₂ 、-NHC(＝O)CH ₃ 、-N(CH3)C(＝O)CH ₃ 、-S(O) ₂ NH ₂ 、-S(O)2NH(CH ₃ )、-S(O) ₂ N(CH ₃ ) ₂ 3-, 4-, 5-or 6-membered carbocyclyl; each R ₂₀ Independently optionally substituted with 1,2,3, 4, 5 or 6 substituents selected from-deuterium, -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH ₂ 、-NHCH ₃ 、_N(CH ₃ )2、-CN、-C(＝O)CH ₃ 、_C(＝O)OO、-OC(＝O)O、-C(＝O)NH ₂ 、-C(＝O)NH(CH ₃ )、-C(＝O)N(CH ₃ )2、-NHC(＝O)CH ₃ 、-N(CH ₃ )C(＝O)CH ₃ 、-S(O) ₂ NH ₂ 、-S(O) ₂ NH(CH ₃ ) or-S (O) ₂ N(CH ₃ )2 is substituted or unsubstituted;

in some embodiments of the present invention, the substrate is,

selected from the following structures:

in some embodiments, the compound of formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

in another aspect, the invention also provides a pharmaceutical composition, which comprises the compound shown in the formula (I) or pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.

In another aspect, the present invention relates to a method of treating a disease associated with KRAS G12D in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In another aspect, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a medicament for preventing or treating a disease associated with KRAS G12D.

In another aspect, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a KRAS G12D-related disease.

Certain chemical terms

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

Has the following meanings and is used herein in the manner of _x-y "denotes a range of numbers of carbon atoms wherein x and y are both integers, e.g. C _3-8 Cycloalkyl denotes cycloalkyl having 3 to 8 carbon atoms, i.e. cycloalkyl having 3, 4, 5,6,7 or 8 carbon atoms. It is also understood that "C" is _3-8 "also includes any subrange therein, e.g. C _3-7 、C _3-6 、C _4-7 、C _4-6 、C _5-6 And the like.

"alkyl" refers to a straight or branched chain hydrocarbyl group containing 1 to 20 carbon atoms, for example 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples of alkyl groups 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, and 2-ethylbutyl. The alkyl group may be substituted or unsubstituted.

"alkenyl" refers to a straight or branched chain hydrocarbyl group containing at least one carbon-carbon double bond and typically 2 to 20 carbon atoms, e.g., 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1, 4-pentadienyl, and 1, 4-butadienyl. The alkenyl group may be substituted or unsubstituted.

"alkynyl" refers to a straight or branched chain hydrocarbyl group containing at least one carbon-carbon triple bond and typically 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl. The alkynyl group may be substituted or unsubstituted.

"cycloalkyl" refers to a saturated cyclic hydrocarbyl substituent containing from 3 to 14 carbon ring atoms. Cycloalkyl groups may be monocyclic, typically containing from 3 to 7 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups may alternatively be bi-or tricyclic fused together, such as decahydronaphthyl, which may be substituted or unsubstituted.

"Heterocyclyl", "heterocycloalkyl", "heterocycle" means a stable 3-to 18-membered monovalent non-aromatic ring comprising 2 to 12 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specified, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused, spiro or bridged ring systems, the nitrogen, carbon or sulfur of the heterocyclyl group may optionally be oxidized, the nitrogen atom may optionally be quaternized, and the heterocyclyl group may be partially or fully saturated. The heterocyclic group may be attached to the rest of the molecule through a single bond via a carbon or heteroatom in the ring. The heterocyclic group containing fused rings may contain one or more aromatic or heteroaromatic rings, provided that the atoms on the non-aromatic ring are attached to the rest of the molecule. For purposes of this application, a heterocyclyl group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, indolinyl, dioxolanyl, 1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidinonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl and the like.

"Spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group with one atom (called the spiro atom) shared between monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O) _m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated electronic system, preferably 6 to 14, more preferably 7 to 10. The spirocycloalkyl group is classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro group. Non-limiting examples of spiroheterocyclyl radicals include:

"fused heterocyclyl" means a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) _m (wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

"aryl" or "aryl" refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 membered, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.

"heteroaryl" or "heteroaryl" refers to a 5-16 membered ring system containing 1-15 carbon atoms, preferably 1-10 carbon atoms, 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, at least one aromatic ring. Unless otherwise specified, a heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may contain fused or bridged ring systems, provided that the point of attachment to the rest of the molecule is an aromatic ring atom, on which nitrogen, carbon, and sulfur atoms may be selectively oxidized, and which may optionally be quaternized. For the purposes of the present invention, heteroaryl groups are preferably stable 4-11 membered monocyclic aromatic rings containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-8 membered monocyclic aromatic rings containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl groups include acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzodioxinyl, benzodioxolyl, benzofuranonyl, benzofuranyl, benzonaphthofuranyl, benzopyranonyl, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, furanyl, imidazolyl, indazolyl, indolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quininyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, and the like. In the present application, heteroaryl is preferably 5-8 membered heteroaryl comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably pyridyl, pyrimidinyl, thiazolyl. The heteroaryl group may be substituted or unsubstituted.

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

"hydroxy" means-OH, and "amino" means-NH ₂ "amido" means-NHCO-, "cyano" means-CN, "nitro" means-CN, "isocyano" means-NC, and "trifluoromethyl" means-CF ₃ 。

The term "heteroatom" or "hetero", as used herein alone or as part of another ingredient, refers to atoms other than carbon and hydrogen, and is independently selected from, but not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, and in embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different.

The terms "fused" or "fused ring" as used herein, alone or in combination, refer to a cyclic structure in which two or more rings share one or more bonds.

The term "spiro" or "spirocyclic" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.

"optionally" 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 occur-for example, "heterocyclic group optionally substituted with alkyl" means that alkyl may but need not be present, and that the description includes instances where the heterocyclic group is substituted with alkyl and instances where the heterocyclic group is not substituted with alkyl.

"substituted" means that one or more atoms, preferably 5, more preferably 1 to 3 atoms, in the group are independently substituted with a corresponding number of substituents. It goes without saying that the skilled person in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort, when the substituents are in their possible chemical positions. For example, having a free amine or hydroxyl group may be unstable in combination with a carbon atom having an unsaturated (e.g., olefinic) bond. Such substituents include, but are not limited to, hydroxy, amine, halogen, cyano, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl groups, and the like.

"pharmaceutical composition" refers to a composition containing one or more compounds described herein, or a pharmaceutically acceptable salt or prodrug thereof, and other ingredients such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote administration to the organism, facilitate absorption of the active ingredient and further exert biological activity.

"isomers" refer to compounds having the same molecular formula but differing in the nature or order of their bonding of atoms or the spatial arrangement of their atoms, referred to as "isomers", and isomers differing in the spatial arrangement of their atoms, referred to as "stereoisomers". Stereoisomers include optical isomers, geometric isomers and conformational isomers. The compounds of the present invention may exist in the form of optical isomers. Depending on the configuration of the substituents around the chiral carbon atom, these optical isomers are either in the "R" or "S" configuration. Optical isomers, including enantiomers and diastereomers, and methods of preparing and separating optical isomers are known in the art.

Geometric isomers may also exist for the compounds of the present invention. The present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as either the Z or E configuration, substituents around cycloalkyl or heterocyclic rings are designated as either the cis or trans configuration.

The compounds of the invention may also exhibit tautomerism, such as keto-enol tautomerism.

It is to be understood that the present invention includes any tautomeric or stereoisomeric form and mixtures thereof, and is not to be limited solely to any one tautomeric or stereoisomeric form employed in the nomenclature or chemical structure of the compounds.

"isotopes" are all isotopes of atoms occurring in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as but not limited to ² H、 ³ H、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and ³⁶ and (4) Cl. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using appropriate isotopically-labeled reagents in place of non-isotopically-labeled reagents. Such compounds have a variety of potential uses, for example, as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.

By "prodrug" is meant that the compounds of the present invention can be administered in the form of a prodrug. Prodrugs refer to derivatives that are converted to the biologically active compounds of the present invention under physiological conditions in vivo, e.g., by oxidation, reduction, hydrolysis, and the like, each of which utilizes or proceeds without the participation of an enzyme. Examples of prodrugs are the following compounds: compounds in which the amine group in the compounds of the invention is acylated, alkylated or phosphorylated, e.g. eicosanoylamino, propylaminoylamino, pivaloyloxymethylamino, or in which the hydroxyl group is acylated, alkylated, phosphorylated or converted to a borate, e.g. acetoxy, palmitoyloxy, pivaloyloxy, succinoyloxy, fumaroyloxy, propylaminoyloxy, or in which the carboxyl group is esterified or amidated, or in which the sulfhydryl group forms a disulfide bridge with a carrier molecule, e.g. a peptide, which selectively delivers a drug to the target and/or to the cytosol of a cell, can be prepared from the compounds of the invention according to well-known methods.

"pharmaceutically acceptable salt" or "pharmaceutically acceptable" refers to those made from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. Where the compounds of the invention contain one or more acidic or basic groups, the invention also includes their corresponding pharmaceutically acceptable salts. Thus, the compounds of the invention containing acidic groups can be present in the form of salts and can be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium, potassium, calcium, magnesium or salts with amines or organic amines, such as primary, secondary, tertiary, cyclic amines, and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purines, piperazine, piperidine, choline, caffeine, and the like, with particularly preferred organic bases being isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The compounds of the invention containing basic groups can be present in the form of salts and can be used according to the invention in the form of their addition to inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compounds of the invention contain both acidic and basic groups in the molecule, the invention also includes inner salts or betaine salts in addition to the salt forms mentioned. The salts are obtained by conventional methods known to the person skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants or by anion exchange or cation exchange with other salts.

Thus, when reference is made in this application to "a compound", "a compound of the invention" or "a compound of the invention", all said compound forms are included, such as prodrugs, stable isotopic derivatives, pharmaceutically acceptable salts, isomers, meso-forms, racemates, enantiomers, diastereomers and mixtures thereof.

In this context, the term "tumor" includes both benign tumors and malignant tumors (e.g., cancers).

The term "cancer" as used herein includes various malignancies in which Bruton's tyrosine kinase is involved, including, but not limited to, non-small cell lung cancer, esophageal cancer, melanoma, striated muscle garnet, cell carcinoma, multiple myeloma, breast cancer ovarian cancer, endometrial cancer, cervical cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer and liver cancer (e.g., hepatocellular carcinoma), more specifically liver cancer, gastric cancer and bladder cancer.

The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein, refer to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is clinically necessary to provide a significant remission effect of the condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.

The term "polymorph" or "polymorph" as used herein means that the compounds of the present invention have multiple crystal lattice forms, some of the compounds of the present invention may have more than one crystal form, and the present invention encompasses all polymorphic forms or mixtures thereof.

Intermediate compounds of the present invention and polymorphs thereof are also within the scope of the present invention.

Crystallization often results in a solvate of a compound of the present invention, and the term "solvate" as used herein refers to an association of one or more molecules of a compound of the present invention and one or more molecules of a solvent.

The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent may be used. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like, as well as corresponding solvated forms. The compounds of the invention may be true solvates, but in other cases the compounds of the invention may also be present only occasionally as water or as a mixture of water with some other solvent the compounds of the invention may be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.

As used herein, the term "acceptable" in reference to a formulation, composition or ingredient means that there is no lasting deleterious effect on the overall health of the subject being treated.

The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.

"pharmaceutically acceptable carriers" include, but are not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonizing agents, solvents, or emulsifiers that have been approved by the relevant governmental authorities for use in humans and domestic animals.

As used herein, the term "subject", "patient", "subject" or "individual" refers to an individual suffering from a disease, disorder or condition, and the like, including mammals and non-mammals, examples of which include, but are not limited to, any member of the class mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment related to the methods and compositions provided herein, the mammal is a human.

The term "treatment" as used herein refers to the treatment of a disease condition associated with a mammal, particularly a human, and includes

(i) Preventing the development of a disease or condition in a mammal, particularly a mammal that has been previously exposed to the disease or condition but has not been diagnosed with the disease or condition;

(ii) inhibiting the disease or disorder, i.e., controlling its development;

(iii) relieving the disease or condition, i.e., slowing the regression of the disease or condition;

(iv) relieving symptoms caused by the disease or disorder.

The terms "disease" and "condition" as used herein may be used interchangeably and may have different meanings, as certain specific diseases or conditions have no known causative agent (and therefore the cause of the disease is unknown) and therefore are not to be considered as diseases but only as unwanted conditions or syndromes, some more or less specific symptoms of which have been confirmed by clinical researchers.

The terms "administering," "administration," "administering," and the like as used herein refer to methods that are capable of delivering a compound or composition to a desired site for biological action. Including, but not limited to, oral, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

Detailed description of the invention

The invention also provides a method for preparing the compound. The preparation of the compounds of the general formula (I) according to the invention can be carried out by the following exemplary methods and examples, which should not be construed as limiting the scope of the invention in any way. The compounds of the invention can also be synthesized using synthetic techniques known to those skilled in the art, or a combination of methods known in the art and those described herein. The product of each step is obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatography, and the like. The starting materials and chemical reagents required for the synthesis can be routinely synthesized or purchased according to the literature (reaxys).

Unless otherwise indicated, temperatures are in degrees celsius. Reagents were purchased from commercial suppliers such as Chemblocks Inc, Astatech Inc or mclin, and these reagents were used directly without further purification unless otherwise stated.

Unless otherwise stated, the following reactions are carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or gas, or using a drying tube; glassware was dried and/or heat dried.

Unless otherwise stated, column chromatography purification was performed using 200-300 mesh silica gel from Qingdao oceanic plants; preparation of thin-layer chromatography silica gel precast slab (HSGF254) produced by Nicotiana chemical industry research institute; MS was measured using a Therno LCD flash model (ESI) liquid chromatography-mass spectrometer.

Nuclear magnetic data (1H NMR) Using a Bruker Avance-400MHz or Varian Oxford-400Hz nuclear magnetic spectrometer, the nuclear magnetic data was performed using CDCl as the solvent ₃ 、CD ₃ OD、D ₂ O, DMS-d6, based on tetramethylsilane (0.000ppm) or based on residual solvent (CDCl) ₃ :7.26ppm；CD ₃ OD:3.31ppm；D ₂ 4.79ppm of O; d6-DMSO:2.50ppm) when indicating the diversity of the peak shapes, the following abbreviations represent the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). If the coupling constant is given, it is given in Hertz (Hz).

Preparation of intermediates

Preparation of 3- (dimethylamino) cyclobutane-1-ol

HCHO (6mL) and HCOOH (6mL) were mixed with 3-aminocyclobutanol (600mg, 6.89mmol) at room temperature and heated at reflux for 3 h. Reduced distillation gave the crude product, which was dissolved in methanol (40mL) and treated with Dowex 50WX4 (form H) resin for 30 min. The resin was then filtered and washed with methanol (2 × 20 mL). Then, 7.0M NH was used ₃ The resin was eluted in MeOH (200mL) and evaporated to afford 3- (dimethylamino) cyclobutanol as a pale yellow sticky mass (221mg, 28% yield, two steps).

LC/MS(ESI):m/z＝116[M+H] ⁺ .

Preparation of 1- (dimethylaminomethyl) cyclopropane-1-methanol

HCHO (6mL) and HCOOH (6mL) were combined with 3-aminocyclobutanol (600mg, 6.89mmol) at room temperature and heated at reflux for 3 h. Reduced evaporation gave the crude product, which was dissolved in methanol (40mL) and treated with Dowex 50WX4 (form H) resin for 30 minutes. The resin was then filtered and washed with methanol (2 × 20 mL). Then, 7.0M NH was used ₃ Elution of the resin in MeOH (200mL) reduced the evaporation to afford 1- (dimethylaminomethyl) cyclopropane-1-methanol (270mg, 35% yield, two steps).

LC/MS(ESI):m/z＝130[M+H] ⁺ .

Preparation of 1- (1-pyrrolidinylmethyl) cyclopropane-1-methanol

A solution of oxalyl chloride (12.5mL, 2M) in methylene chloride was added to a solution of methyl cyclopropane-1, 1-dicarboxylate (2.90g, 20mmol) in methylene chloride (50mL) with stirring while cooling in an ice/water bath, followed by addition of DMF (100. mu.l) and stirring for about 2 hours. At room temperature, a pale yellow solution was obtained. The solution was concentrated to a yellow semi-solid. The yellow semi-solid was dissolved (20mL of THF under ice/water cooling with stirring) then pyrrolidine (6mL, 71mmol) was added slowly and stirred for about 60min, ethyl acetate (150mL) was added, the organic phase was washed with water (2X75mL) and saturated aqueous sodium chloride (75mL) the organic phase was dried over anhydrous magnesium sulphate and concentrated to give a yellow brown oil methyl 1- (pyrrolidine-1-acyl) -cyclopropanecarboxylate (2.0g, 50%).

Lithium aluminum tetrahydroborate THF solution (20mL, 1M) was slowly added to 25mL THF in methyl 1- (pyrrolidine-1-acyl) -cyclopropanecarboxylate (2.0g, 10mmol) under nitrogen blanket and ice/water bath, then warmed to room temperature and the resulting solution was stirred for 3 hours. The solution was cooled in an ice/water bath and sodium sulfate decahydrate (4.9g, 15mmol) was added portionwise to give a white suspension. Diethyl ether (25mL) was added and the suspension was stirred for about 18 hours. At room temperature. The resulting suspension was filtered through celite and the solid was washed with diethyl ether (2 × 50 mL). The combined filtrates were concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether: 1:20 to 1:1) to give 1- (pyrrolidin-1-ylmethyl) cyclopropyl-1-methanol (1.15g, 64%) as a yellow oily compound.

LC/MS(ESI):m/z＝156[M+H] ⁺ .

Preparation of (R) -1- (3-fluoropyrrolidine-1-methyl) cyclopropane-1-methanol

A solution of oxalyl chloride (12.5mL, 2M) in methylene chloride was added to a solution of methyl cyclopropane-1, 1-dicarboxylate (2.90g, 20mmol) in methylene chloride (50mL) with stirring while cooling in an ice/water bath, followed by addition of DMF (100. mu.l) and stirring for about 2 hours. At room temperature, a pale yellow solution was obtained. The solution was concentrated to a yellow semi-solid. The yellow semi-solid was dissolved in (20mL of hf) with ice/water cooling stirring, then (R) -3-fluoropyrrolidine (3.16g, 40mmol) was slowly added and stirred for about 60min, ethyl acetate (150mL) was added, the organic phase was washed with water (2x75mL) and saturated aqueous sodium chloride (75mL), the organic phase was dried over anhydrous magnesium sulfate and concentrated to give a yellow brown oil methyl (R) -1- (3-fluoropyrrolidine-1-acyl) -cyclopropanecarboxylate (2.06g, 48%).

Lithium aluminum hydride THF solution (20mL, 1M) was slowly added to a solution of 25mL THF in (R) -methyl 1- (3-fluoropyrrolidin-1-acyl) -cyclopropanecarboxylate (2.0g, 9.3mmol) under nitrogen and ice/water bath, then warmed to room temperature and the resulting solution was stirred for 3 hours. The solution was cooled in an ice/water bath and sodium sulfate decahydrate (4.9g, 15mmol) was added portionwise to give a white suspension. Diethyl ether (25mL) was added and the suspension was stirred for about 18 hours. At room temperature. The resulting suspension was filtered through celite and the solid was washed with diethyl ether (2 × 50 mL). The filtrates were combined and concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether: 1:20 to 1:1) to give (R) -1- (3-fluoropyrrolidin-1-ylmethyl) cyclopropyl-1-methanol (0.93g, 58%) as a yellow oily compound.

LC/MS(ESI):m/z＝174[M+H] ⁺ .

Preparation of 1- (1-azetidinylmethyl) cyclopropane-1-methanol

A solution of oxalyl chloride (12.5mL, 2M) in methylene chloride was added to a solution of methyl cyclopropane-1, 1-dicarboxylate (2.90g, 20mmol) in methylene chloride (50mL) with stirring while cooling in an ice/water bath, followed by addition of DMF (100. mu.l) and stirring for about 2 hours. At room temperature, a pale yellow solution was obtained. The solution was concentrated to a yellow semi-solid. The yellow semisolid was dissolved in THF (20mL) with ice/water cooling stirring, then azetidine (6mL, 88mmol) was added slowly and stirred for about 60 min. Ethyl acetate (150mL) was added and the organic phase was washed with water (2 × 75mL) and saturated aqueous sodium chloride (75 mL). The organic phase was dried over anhydrous magnesium sulfate and concentrated to give methyl 1- (azetidine-1-acyl) -cyclopropanecarboxylate (1.9g, 52%) as a yellow-brown oil.

Lithium alanate THF solution (20mL, 1M) was slowly added to 25mL THF in 1- (pyrrolidine-1-acyl) -cyclopropanecarboxylic acid methyl ester (1.8g, 9.8mmol) under nitrogen blanket and ice/water bath, then warmed to room temperature and the resulting solution was stirred for 3 hours. The solution was cooled in an ice/water bath and sodium sulfate decahydrate (4.9g, 15mmol) was added portionwise to give a white suspension. Diethyl ether (25mL) was added and the suspension was stirred for about 18 hours. At room temperature. The resulting suspension was filtered through celite and the solid was washed with diethyl ether (2 × 50 mL). The combined filtrates were concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether: 1:20 to 1:1) to give 1- (azetidin-1-ylmethyl) cyclopropyl-1-methanol (0.95g, 69%) as a yellow oily compound.

LC/MS(ESI):m/z＝142[M+H] ⁺ .

Preparation of (S) -1-cyclopropylpyrrolidine-2-methanol

Under the protection of nitrogen, (S) -pyrrolidin-2-yl-methanol (5.0g 50mmol), tert-butyldiphenylchlorosilane (16.3g 59mmol) and imidazole (8.5g 125mmol) were dissolved in 100mLDMF, reacted at 20 ℃ for 4 hours until the conversion of the raw materials reached 100%, quenched with water, the diluted solution was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and subjected to silica gel column chromatography purification (eluent: ethyl acetate: petroleum ether ═ 1:20 to 1:1), and S) -2- (((tert-butyldiphenylsilyl) oxy) methyl) pyrrolidine as a yellow oily compound (11.8g, 70%).

(S) -2- ((((tert-butyldiphenylsilyl) oxy) methyl) pyrrolidine (3g, 8.84mmol) and cyclopropylboronic acid (3.17g, 36.9mmol) were dissolved in 40mL of DCE, and Na was added ₂ CO ₃ (1.95g，18.4mmol)、Cu(OAc) ₂ (1.67g, 9.19mmol) and 2- (2-pyridyl) pyridine (1.44g, 9.22 mmol). The reaction was stirred at 70 ℃ under a 15psi oxygen sparge for 2h, then filtered, and the filtrate was diluted with 40mL of water and then extracted with ethyl acetate (2X50 mL). The combined organic layers were washed with 80mL of saturated brine and anhydrous Na ₂ SO ₄ Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate, 10:1 to 4:1) to give (S) -2- ((((tert-butyldiphenylsilyl) oxy) methyl) -l-cyclopropylpyrrolidine as a pale yellow oil (1.3g, 38%).

CsF (1.75g, 1.5mmol) was added to a solution of (S) -2- ((((tert-butyldiphenylsilyl) oxy) methyl) -l-cyclopropylpyrrolidine (1.5g, 3.95mmol) in DMF (15mL), stirred at 50 ℃ for 20H, then the reaction mixture was cooled to room temperature and quenched with H ₂ O (20mL) was diluted and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with 80mL of saturated brine and anhydrous Na ₂ SO ₄ Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate, 10:1 to 1:1) to give (S) - (1-cyclopropylpyrrolidine-2-methanol (345mg, 62% yield) as a pale yellow oil.

LC/MS(ESI):m/z＝142[M+H] ⁺ .

Preparation of (2S,4R) -1-cyclopropylpyrrolidine-2-methanol

According to the synthesis method of (S) -1-cyclopropyl pyrrolidine-2-methanol:

under the protection of nitrogen, (2S,4R) -4-fluoro-L-prolinol hydrochloride (5.95g 50mmol), tert-butyldiphenylchlorosilane (16.3g 59mmol) and imidazole (17g 250mmol) are dissolved in 100mL DMF, and after reaction at 20 ℃ for 4 hours until the conversion of the raw material reaches 100%, the reaction is quenched with water, the diluted solution is extracted with ethyl acetate, the organic phases are combined, dried with anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether ═ 1: 20-1: 1), yellow oily compound (2S,4R) -4-fluoro-2- ((((tert-butyldiphenylsilyl) oxy) methyl) pyrrolidine (11.9g, 67%).

(2S,4R) -4-fluoro-2- (((((tert-butyldiphenylsilyl) oxy) methyl) pyrrolidine (3.16g, 8.84mmol) and cyclopropylboronic acid (3.17g, 36.9mmol) were dissolved in 40mL of DCE, and Na was added ₂ CO ₃ (1.95g，18.4mmol)、Cu(OAc) ₂ (1.67g, 9.19mmol) and 2- (2-pyridyl) pyridine (1.44g, 9.22 mmol). The reaction was stirred at 70 ℃ under a 15psi oxygen sparge for 2h, then filtered, and the filtrate was diluted with 40mL of water and then extracted with ethyl acetate (2X50 mL). The combined organic layers were washed with 80mL of saturated brine and anhydrous Na ₂ SO ₄ Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate, 10:1 to 4:1) to give (2S,4R) -4-fluoro-2- (((((tert-butyldiphenylsilyl) oxy) methyl) -l-cyclopropylpyrrolidine as a pale yellow oil (1.2g, 34%).

CsF (1.75g, 1.5mmol) was added to a solution of (2S,4R) -4-fluoro-2- ((((tert-butyldiphenylsilyl) oxy) methyl) -l-cyclopropylpyrrolidine (1.57g, 3.95mmol) in DMF (15mL), stirred at 50 ℃ for 20H, then the reaction mixture was cooled to room temperature and taken up with H ₂ O (20mL) was diluted and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with 80mL of saturated brine and anhydrous Na ₂ SO ₄ Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate)Ester, 10:1 to 1:1) to give (2S,4R) -4-fluoro- (1-cyclopropylpyrrolidine-2-methanol (352mg, 56% yield) as a pale yellow oil.

LC/MS(ESI):m/z＝160[M+H] ⁺ .

Preparation of 1, 4-dimethylpiperazine-2-methanol

To a solution of compound 1, 4-dimethylpiperazine-2-carboxylic acid (1.9g, 0.012mol) in tetrahydrofuran (20mL) was added BH dropwise ₃ THF complex (24mL, 0.024mol), at 0 ℃ and at N ₂ Under an atmosphere. The mixture was then warmed to room temperature and heated to reflux for 2-3 hours. The mixture was quenched with methanol (10mL) at 0 ℃ and the resulting solution was concentrated in vacuo. The residue was redissolved in MeOH (20mL) and the solution was refluxed for 3 to 4 hours. The solvent was then removed to give the crude product (1.0 g). The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc 10:1 to 1:1) to give the compound 1, 4-dimethylpiperazine-2-methanol as a pale yellow oil (0.68g, 39%).

LC/MS(ESI):m/z＝145[M+H] ⁺ .

Preparation of 8-fluoronaphthalene boronic acid

At 0 deg.C, 48% HBF ₄ (100mL) to 8-bromo-1-naphthylamine (10g, 45.2mmol) in 100mL THF, followed by addition of NaNO ₂ (4.9g, 135.8mmol) in 20mL of water. The reaction was stirred at 0 ℃ for 1h, then NaBF ₄ (24.9g, 226 mmol). The mixture was warmed to room temperature and filtered. The solid was washed with diethyl ether and dried under high vacuum overnight to give the diazonium salt as a green solid, which was suspended in xylene (50mL) and refluxed for 1 h. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give 8-bromo-1-fluoronaphthalene (4.6g, 45%).

8-bromo-1-fluoronaphthalene (2.79g, 0.0124mol) was dissolved in anhydrous tetrahydrofuran (20.0mL), triisopropyl borate (2.68g, 0.0142mol) was added, the mixture was cooled to-78 ℃, n-butyllithium (0.95g, 0.0149mol) was added, and the mixture was stirred for reaction for 0.5h, and then returned to room temperature. Adding saturated ammonium chloride aqueous solution to extract and kill the reaction. The pH was adjusted to a strongly acidic pH, and extraction was performed with ethyl acetate (20.0 ml. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled under reduced pressure. Slurried with n-hexane and filtered to give 8-fluoronaphthalene-1-boronic acid (1.98g, 84%).

LC/MS(ESI):m/z＝191[M+H] ⁺ .

Preparation of 3- (2- (trimethylsilyl) ethoxymethoxy) -8-fluoronaphthaleneboronic acid pinacol ester

According to the documents Journal of the American Chemical Society,1976, vol.98, #11, p.3237-3242 and KR 102121583:

to Br ₂ (5.2g, 32.5mmol) in AcOH (15mL) solution 5-fluoronaphthylamine (2.4g, 15mmol) in AcOH (10mL) was added and the reaction stirred at 70 ℃ for 1 h. The reaction mixture was cooled at room temperature and filtered. The filter cake was washed with 15mL of lacoh, then 20% aqueous NaOH (30mL) was added. The mixture was stirred for 20 minutes and filtered. The solid was isolated by washing with 20mL of water and dried under vacuum to afford 2, 4-dibromo-8-fluoronaphthalen-1-amine (4.45g, 93% yield) as a gray solid. LC/MS (ESI) 320[ M + H ]] ⁺ 。

2, 4-dibromo-8-fluoronaphthalen-1-amine (3.84g, 12mmol) was dissolved in 65 mM ACOH and cooled to 0 ℃. Then 11mL of propionic acid was added and stirred. Then, 1.2g of sodium nitrite was added and stirred for 30 minutes. Then the reaction solution was poured into ice water at 0 ℃. Filtering the obtained solid and further adding to the filtrate and stirring to generate yellow precipitate, filtering and drying the obtained precipitate to obtain intermediate 6-fluoro-5-bromobenzo [1,2-d ]][1,2,3]Oxadiazole (1.35g, 42% yield). LC/MS (ESI) M/z 268[ M + H ]] ⁺ 。

Under the protection of nitrogen, 6-fluoro-5-bromonaphtho [1,2-d ] is reacted][1,2,3]Oxa-diOxazole (1.34g, 5mmol) was dissolved in 25mL of LEtOH, then 0.57g of sodium borohydride was added and the reaction stirred for 12 hours. Then, 28mL of hydrochloric acid solution was added dropwise and stirred for 1 hour. At the end of the reaction, 10% aqueous NaOH was added for neutralization. After completion of neutralization, extraction was performed with dichloromethane, and the organic layer was concentrated. Flash column purification afforded 5-fluoro-4-bromo-2-naphthol (0.92 g, 76%). LC/MS (ESI) 242[ M + H ] M/z] ⁺ 。

5-fluoro-4-bromo-2-naphthol (0.91g, 3.78mmol) was dissolved in 10mL of tetrahydrofuran. Subsequently, 60% NaH (1.35g, 5.67mmol) was added in portions with stirring at 0 ℃. Then, SEMCl (5.6g, 5.67mmol) was added. The resulting solution was stirred at 25 ℃ overnight and then 10ml of water was added to quench the reaction. The resulting solution was extracted with 2 × 10mL ethyl acetate and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give crude 1-bromo-3- (2- (trimethylsilyl) ethoxymethoxy) -8-fluoronaphthalene (1.35g, 96%). LC/MS (ESI) M/z 272[ M + H ═] ⁺ 。

Under the protection of nitrogen, adding [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (240mg,0.3mmol) and potassium acetate (726mg,7.38mmol) were added to a solution of 1-bromo-3- (2- (trimethylsilyl) ethoxymethoxy) -8-fluoronaphthalene (816mg, 3mmol) and bis (pinacolato) diboron (980mg, 3.9 mmol) in 60mL of DMF and the reaction stirred at 90 ℃ for 5 h. The mixture was then diluted with water (100ml) and extracted with ethyl acetate (100ml), the organic phase was dried with anhydrous, filtered and the filtrate was concentrated to give the crude product. The crude product was purified by column chromatography to give a white solid (905mg, 72% yield). LC/MS (ESI): M/z 419.2[ M + H] ⁺ 。

Preparation of 3- (2- (trimethylsilyl) ethoxymethoxy) -8-chloronaphthalene boronic acid pinacol ester

According to the synthesis method of 3- (2- (trimethylsilyl) ethoxymethoxy) -8-fluoronaphthalene boronic acid pinacol ester:

to Br ₂ (5.2g, 32.5mmol) was dissolved in AcOH (15mL) and 5-chloronaphthylamine (2)65g, 15mmol) in AcOH (10mL) and the reaction stirred at 70 ℃ for 1 hour. The reaction mixture was cooled at room temperature and filtered. The filter cake was washed with 15mL of lacoh, then 20% aqueous NaOH (30mL) was added. The mixture was stirred for 20 minutes and filtered. The isolated solid was washed with 20mL of water and dried under vacuum to provide 2, 4-dibromo-8-chloronaphthalen-1-amine (4.83g, 96% yield) as a gray solid. LC/MS (ESI) 336[ M + H ]] ⁺ 。

2, 4-dibromo-8-chloronaphthalen-1-amine (4.03g, 12mmol) was dissolved in 65 mM ACOH and cooled to 0 ℃. Then 11mL of propionic acid was added and stirred. Then, 1.2g of sodium nitrite was added and stirred for 30 minutes. Then the reaction solution was poured into ice water at 0 ℃. Filtering the obtained solid and further adding to the filtrate and stirring to generate yellow precipitate, filtering and drying the obtained precipitate to obtain intermediate 6-chloro-5-bromobenzo [1,2-d ]][1,2,3]Oxadiazole (1.50g, 44% yield). LC/MS (ESI) 284[ M + H ]] ⁺ 。

Under the protection of nitrogen, 6-chloro-5-bromonaphtho [1,2-d ] is reacted][1,2,3]Oxadiazole (1.42g, 5mmol) was dissolved in 25mLEtOH and 0.57g sodium borohydride was added and the reaction stirred for 12 h. Then, 28mL of hydrochloric acid solution was added dropwise and stirred for 1 hour. At the end of the reaction, 10% aqueous NaOH was added for neutralization. After completion of neutralization, extraction was performed with dichloromethane, and the organic layer was concentrated. Flash column purification yielded 5-chloro-4-bromo-2-naphthol (1.02 g, 79%). LC/MS (ESI) M/z 259[ M + H ═ M] ⁺ 。

5-chloro-4-bromo-2-naphthol (0.973g, 3.78mmol) was dissolved in 10mL of tetrahydrofuran. Subsequently, 60% NaH (1.35g, 5.67mmol) was added in portions with stirring at 0 ℃. Then, SEMCl (5.6g, 5.67mmol) was added. The resulting solution was stirred at 25 ℃ overnight and then 10ml of water was added to quench the reaction. The resulting solution was extracted with 2 × 10mL ethyl acetate and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give crude 1-bromo-3- (2- (trimethylsilyl) ethoxymethoxy) -8-chloronaphthalene (1.39 g, 95%). LC/MS (ESI) M/z 388[ M + H ]] ⁺ 。

Under the protection of nitrogen, adding [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (240mg,0.3mmol) and vinegarPotassium (726mg,7.38mmol) was added to a solution of 1-bromo-3- (2- (trimethylsilyl) ethoxymethoxy) -8-fluoronaphthalene (1.16mg, 3mmol) and bis-pinacolato diboron (980mg, 3.9 mmol) in 60mL of DMF and the reaction stirred at 90 ℃ for 5 h. The mixture was then diluted with water (100ml) and extracted with ethyl acetate (100ml), the organic phase was dried with anhydrous, filtered and the filtrate was concentrated to give the crude product. The crude product was purified by column chromatography to give a white solid (992mg, 76% yield). LC/MS (ESI) M/z 436[ M + H ]] ⁺ 。

Example 1

Preparation of 7- (2-fluoro-6-hydroxyphenyl) -6-fluoro-4- (((R) 4-acryloyl- (R) -2-methylpiperazin) -1-yl) -2- (2-dimethylaminoethylamino) pyrido [2,3-d ] pyrimidine (Compound 1)

The first step is as follows: preparation of N-carbamyl fluorochloro nicotinamide

Fluorochloronicotinamide 1a (20.90.1mol) was dissolved in 200mL of anhydrous tetrahydrofuran, oxalyl chloride (14g, 0.11mol) was added dropwise at 0 ℃, and the mixture was heated to 65 ℃ and stirred for 2 hours. After cooling to 0 ℃, triethylamine (50mL) and ammonia (110mL) were added and the mixture was stirred at room temperature for 2 hours, after the reaction was completed. Concentration under reduced pressure, extraction with ethyl acetate three times, combination of organic layers, drying over anhydrous sodium sulfate, concentration under reduced pressure, and then slurrying with ethyl acetate/petroleum ether (1/5) gave the desired product, N-carbamyl fluoronicotinamide 1b (15.8g, 62%).

LC/MS(ESI):m/z＝253[M+H] ⁺ .

The second step is that: preparation of 6-fluoro-7-chloropyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione

Reacting N-ammoniaDissolving benzoylfluoronicotinamide (9.1g, 36mmol) in THF (200mL), adding KHMDS (72.0mL, 1M THF solution, 72mmol) dropwise in ice water bath under nitrogen protection, gradually heating to room temperature, stirring for 1 hr, adding saturated NH ₄ Aqueous Cl was quenched and extracted with ethyl acetate (3 × 150 mL). Combining organic layers, drying by anhydrous sodium sulfate, concentrating to obtain a crude product, and pulping by using ethanol to obtain a target product 6-fluoro-7-chloropyrido [2,3-d]Pyrimidine-2, 4(1H,3H) -dione 1c (6.67g, 86%).

LC/MS(ESI):m/z＝217[M+H] ⁺ .

The third step: preparation of 7- (2-fluoro-6-methoxyphenyl) -6-fluoro-pyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione

After 6-fluoro-7-chloropyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione 1c (2.17g, 0.01mol), 6-methoxy-2-fluorobenzeneboronic acid (1.7g, 0.01mol), tris (dibenzylideneacetone) dipalladium (0.8g, 0.88mmol), cesium carbonate, 1, 4-dioxane (100mL) and water (20mL) were mixed, they were heated to 120 ℃ under reflux and reacted for 16 hours with stirring. The reaction was cooled to room temperature and stirred overnight to give a pale yellow precipitate. The reaction mixture was diluted with water (2mL) and the solid was collected by filtration. The crude product was slurried with methanol (10mL) to give 7- (2-fluoro-6-methoxyphenyl) -6-fluoro-pyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione 1d (2.17g, 72%) as a beige solid, which was then used without further purification for the next reaction.

LC/MS(ESI):m/z＝306[M+H] ⁺ .

The fourth step: preparation of 7- (2-fluoro-6-methoxyphenyl) -6-fluoro-2, 4-dichloropyrido [2,3-d ] pyrimidine

Reacting 7- (2-fluoro-6-methoxyphenyl) -6-fluoro-pyrido [2,3-d]Pyrimidine-2, 4(1H,3H) -dione (1.83g 6mmol) in POCl ₃ (30mL), a small amount of N, N-dimethylaniline was added, and the mixture was heated under reflux with stirring to react 1And 0 h. Then pouring into ice water for quenching, filtering to obtain a solid product, washing with water, and drying to obtain a crude yellow solid 7- (2-fluoro-6-methoxyphenyl) -6-fluoro-2, 4-dichloropyrido [2,3-d ]]Pyrimidine 1f (1.51g, 74%) was used for the next reaction without further purification.

LC/MS(ESI):m/z＝343[M+H] ⁺ .

The fifth step: preparation of 7- (2-fluoro-6-methoxyphenyl) -6-fluoro-4- (((R) -4-boc-2-methylpiperazin) -1-yl) -2-chloropyrido [2,3-d ] pyrimidine

7- (2-fluoro-6-methoxyphenyl) -6-fluoro-2, 4-dichloropyrido [2,3-d ] pyrimidine (1.37g, 4mmol), (R) -4-Boc- (R) -2-methylpiperazine (0.88g, 4.4mmol), potassium carbonate (0.88g, 6.4mmol) and a catalytic amount of potassium iodide and DMF (80mL) were mixed, heated to 120 ℃ and stirred for 4 hours. Cooled to room temperature and evaporated under reduced pressure to give 7- (2-fluoro-6-methoxyphenyl) -6-fluoro-4- (((R) -4-boc-2-methylpiperazin) -1-yl) -2-chloropyrido [2,3-d ] pyrimidine as a yellow solid (1 g, 1.34g, 68%),

LC/MS(ESI):m/z＝507[M+H] ⁺ 。

and a sixth step: preparation of 7- (2-fluoro-6-methoxyphenyl) -6-fluoro-4- (((R) -4-boc-2-methylpiperazin) -1-yl) -2- (2-dimethylaminoethylamino) pyrido [2,3-d ] pyrimidine

7- (2-fluoro-6-methoxyphenyl) -6-fluoro-4- (((R) -4-boc-2-methylpiperazine) -1-yl) -2-chloropyrido [2,3-d ] pyrimidine (152mg, 0.3mmol), N-dimethylethylenediamine (29mg, 0.33mmol), potassium carbonate (62mg, 0.45mmol) in catalytic amount and DMF (10mL) were mixed, heated to 120 ℃ and stirred for 4 hours. Cooled to room temperature, evaporated under reduced pressure and subjected to column chromatography to give 7- (2-fluoro-6-methoxyphenyl) -6-fluoro-4- (((R) -4-boc-2-methylpiperazin) -1-yl) -2- (2-dimethylaminoethylamino) pyrido [2,3-d ] pyrimidine as a yellow solid (109mg, 65%).

LC/MS(ESI):m/z＝558.3[M+H] ⁺ 。

The seventh step: preparation of 7- (2-fluoro-6-hydroxyphenyl) -6-fluoro-4- (((R) -2-methylpiperazino) -1-yl) -2- (2-dimethylaminoethylamino) pyrido [2,3-d ] pyrimidine

7- (2-fluoro-6-methoxyphenyl) -6-fluoro-4- (((R) -4-boc-2-methylpiperazin) -1-yl) -2- (2-dimethylaminoethylamino) pyrido [2,3-d ] pyrimidine 1h (100mg,0.18mmol) was dissolved in 10mL of DCM, BBr (0.8mL) was added at-78 deg.C, and the reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water and extracted with DCM (2 × 15mL), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give the desired product 7- (2-fluoro-6-hydroxyphenyl) -6-fluoro-4- (((R) -2-methylpiperazin) -1-yl) -2- (2-dimethylaminoethylamino) pyrido [2,3-d ] pyrimidine 1 as a yellow solid (62mg, 78%).

LC/MS(ESI):m/z＝444.2[M+H] ⁺ 。

¹ H NMR(500MHz,CD ₃ OD)δ8.51(d,1H),7.39-7.35(m,1H),6.87-6.80(m,3H),6.21-6.14(m,1H),5.43(dd,1H),4.78(broad s,1H),4.40-3.96(m,4H),3.75-3.45(m,4H),3.15-2.95(m,2H),2.64(s,6H),1.30(s,3H)；LC/MS(ESI):m/z＝498.2[M+H] ⁺ .

Examples 2-24 preparation of reference Compound 1 and preparation of the corresponding intermediates

Example 25

Preparation of 7- (2-fluoro-6-methoxyphenyl) -6-fluoro-4- ((R) -2-methylpiperazin) -1-yl) -2- (2-dimethylaminoethylamino) pyridine [2,3-d ] pyrimidine (Compound 25)

The first step is as follows: preparation of 6-fluoro-2, 4, 7-trichloropyrido [2,3-d ] pyrimidine

Reacting 7-chloro-6-fluoro-pyrido [2,3-d]Pyrimidine-2, 4(1H,3H) -dione 1c (18.3g 85mmol) in POCl ₃ To (200mL) was added 10mL of N-dimethylaniline, and the mixture was stirred under reflux for 10 hours. Then pouring into ice water for quenching, filtering to obtain a solid product, washing with water, and drying to obtain a crude yellow solid 6-fluoro-2, 4, 7-trichloropyrido [2,3-d ]]Pyrimidine 25a (18.0g, 84%) was used for the next reaction without further purification.

LC/MS(ESI):m/z＝253[M+H] ⁺ .

The second step is that: preparation of 6-fluoro-2, 7-dichloro-4- (((R) 4-boc-2-methylpiperazin) -1-yl) -pyrido [2,3-d ] pyrimidine

6-fluoro-2, 4, 7-trichloropyrido [2,3-d ] pyrimidine 25a (12.6g, 50mmol), (R) -4-Boc-2-methylpiperazine (11g, 55mmol), potassium carbonate (10.35g, 75mmol) and a catalytic amount of potassium iodide in DMF (300mL) were mixed, heated to 120 ℃ and stirred for 4 hours. Cooled to room temperature and evaporated under reduced pressure to give 6-fluoro-2, 7-dichloro-4- (((R) 4-boc-2-methylpiperazin) -1-yl) -pyrido [2,3-d ] pyrimidine 25b as a yellow solid (16.2g, 78%),

LC/MS(ESI):m/z＝417[M+H] ⁺ 。

the third step: preparation of 6-fluoro-7-chloro-4- (((R) 4-boc-2-methylpiperazin) -1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [2,3-d ] pyrimidine

6-fluoro-2, 7-dichloro-4- (((R)4-boc- (R) -2-methylpiperazine) -1-yl) -pyrido [2,3-d ] pyrimidine (12.51g, 30mmol), N-methyl-L-prolinol (3.9g, 33mmol), potassium carbonate (6.2mg, 45mmol) and a catalytic amount of potassium iodide were mixed with DMF (100mL), heated to 120 ℃ and stirred for 4 hours. Cooled to room temperature, evaporated under reduced pressure and subjected to column chromatography to give 6-fluoro-7-chloro-4- (((R) 4-boc-2-methylpiperazin) -1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [2,3-d ] pyrimidine 25c as a yellow solid (10.24g, 69%).

LC/MS(ESI):m/z＝496[M+H] ⁺ 。

The fourth step: preparation of 7- (2-fluoro-6-methoxyphenyl) -6-fluoro-4- (((R) 4-boc-2-methylpiperazin) -1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [2,3-d ] pyrimidine

After 6-fluoro-7-chloro-4- (((R) 4-boc-2-methylpiperazin) -1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [2,3-d ] pyrimidine 1c (496mg, 1mmol), 6-methoxy-2-fluorobenzeneboronic acid (170g, 1mmol), tris (dibenzylideneacetone) dipalladium (0.08g, 0.088mmol), cesium carbonate, 1, 4-dioxane (10mL) and water (2mL) were mixed, it was heated to 120 ℃ under reflux, and the reaction was stirred for 16 hours. The reaction was cooled to room temperature and stirred overnight to give a pale yellow precipitate. The reaction mixture was diluted with water (2mL) and the solid was collected by filtration. The crude product was slurried with methanol (10mL) then the next reaction was carried out without further purification to give 7- (2-fluoro-6-methoxyphenyl) -6-fluoro-4- (((R) 4-boc-2-methylpiperazin) -1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridine [2,3-d ] opyrimidine 25d (397mg, 68%) as a beige solid.

LC/MS(ESI):m/z＝585.3[M+H] ⁺ .

The fifth step: preparation of 7- (2-fluoro-6-methoxyphenyl) -6-fluoro-4- (((R) -2-methylpiperazin) -1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrido [2,3-d ] pyrimidine

To a reaction flask was added the intermediate 7- (2-fluoro-6-methoxyphenyl) -6-fluoro-4- (((R)4-boc- (R) -2-methylpiperazin) -1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridine [2,3-d ] pyrimidine (292mg,0.5mmol), 2ml of ethyl acetate, 4ml of 1, 4-dioxane solution of 1NHCl in the previous step. After stirring at room temperature for 2 hours, the reaction solution was neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. To give 7- (2-fluoro-6-methoxyphenyl) -6-fluoro-4- (((R) -2-methylpiperazin) -1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridine [2,3-d ] pyrimidine 25(183mg, 76% yield) which was used directly in the next step.

LC/MS(ESI):m/z＝485.2[M+H] ⁺ 。

EXAMPLES 26-44 preparation of reference Compound 25 and preparation of corresponding intermediates

Example 53

Preparation of 7- (3-hydroxy-8-chloronaphthyl) -6-fluoro-4- (3, 6-diazabicyclo [3.1.1] heptan-6-yl) -2- (((2R,7aS) -2-fluorotetrahydro-1H-pyri-zine cyclo-7 a (5H) -yl) methoxy) pyridine [2,3-d ] pyrimidine (Compound 57)

Preparation of 7-chloro-6-fluoro-4- (6-boc-3, 6-diazabicyclo [3.1.1] heptan-6-yl) -2-chloropyridine [2,3-d ] pyrimidine

6-fluoro-2, 4, 7-trichloropyrido [2,3-d ] pyrimidine 25a (2.52g, 10mmol), 6-boc-3, 6-diazabicyclo [3.1.1] heptane (2.18g, 11mmol), potassium carbonate (2.07g, 15mmol) and a catalytic amount of potassium iodide in DMF (60mL) were combined, heated to 120 ℃ and stirred for 4 hours. Cooled to room temperature and evaporated under reduced pressure to give 7-chloro-6-fluoro-4- (6-boc-3, 6-diazabicyclo [3.1.1] heptan-6-yl) -2-chloropyridine [2,3-d ] pyrimidine 53a (3.81g, 74%) as a yellow solid,

LC/MS(ESI):m/z＝515[M+H] ⁺ 。

preparation of 7-chloro-6-fluoro-4- (6-boc-3, 6-diazabicyclo [3.1.1] heptan-6-yl) -2- (((2R,7aS) -2-fluorotetrahydro-1H-pyri-ridin-cyclo-7 a (5H) -yl) methoxy) pyridine [2,3-d ] pyrimidine

6-fluoro-2, 7-dichloro-4- (((R)4-boc- (R) -2-methylpiperazine) -1-yl) -pyrido [2,3-d ] pyrimidine (250mg, 1mmol), (2R,8S) -2-fluoro-1, 2,3,5,6, 7-hexahydropyrrol-azin-7-yl ] methanol (148mg, 1.1mmol), potassium carbonate (0.12mg, 1.4mmol) a catalytic amount of potassium iodide and DMF (8mL) were mixed, heated to 120 ℃ and stirred for 4 hours. Cooled to room temperature, evaporated under reduced pressure and chromatographed to give 7-chloro-6-fluoro-4- (6-boc-3, 6-diazabicyclo [3.1.1] heptan-6-yl) -2- (((2R,7aS) -2-fluorotetrahydro-1H-pyrazino-ring-7 a (5H) -yl) methoxy) pyridine [2,3-d ] pyrimidine 53b (0.387g, 72%) aS a yellow solid.

LC/MS(ESI):m/z＝538.2[M+H] ⁺ 。

Preparation of 7- (3- (2- (trimethylsilyl) ethoxymethoxy) -8-chloronaphthyl) -6-fluoro-4- (6-boc-3, 6-diazabicyclo [3.1.1] heptan-6-yl) -2- (((2R,7aS) -2-fluorotetrahydro-1H-pyrazin-cyclo-7 a (5H) -yl) methoxy) pyrido [2,3-d ] pyrimidine

After 7-chloro-6-fluoro-4- (6-boc-3, 6-diazabicyclo [3.1.1] heptan-6-yl) -2- (((2R,7aS) -2-fluorotetrahydro-1H-pyrazino-ring-7 a (5H) -yl) methoxy) pyridine [2,3-d ] pyrimidine 53c (107mg, 0.2mmol), 3- (2- (trimethylsilyl) ethoxymethoxy) -8-chloronaphthalene boronic acid pinacol ester (87mg, 0.2mmol), tris (dibenzylideneacetone) dipalladium (20mg, 0.022mmol), cesium carbonate, 1, 4-dioxane (5mL) and water (1mL) were mixed, followed by heating to 120 ℃ under reflux and stirring for reaction for 16 hours. The reaction was cooled to room temperature and stirred overnight to give a pale yellow precipitate. The reaction mixture was diluted with water (2mL) and the solid was collected by filtration. The crude product was slurried with methanol (10mL) to give 7- (3- (2- (trimethylsilyl) ethoxymethoxy) -8-chloronaphthyl) -6-fluoro-4- (6-boc-3, 6-diazabicyclo [3.1.1] heptan-6-yl) -2- (((2R,7aS) -2-fluorotetrahydro-1H-pyridinylcyclo-7 a (5H) -yl) methoxy) pyridino [2,3-d ] pyrimidine aS a beige solid (94mg, 58% yield), which was subjected to the next reaction without further purification.

LC/MS(ESI):m/z＝809.3[M+H] ⁺ .

Preparation of 7- (3-hydroxy-8-chloronaphthyl) -6-fluoro-4- (3, 6-diazabicyclo [3.1.1] heptan-6-yl) -2- (((2R,7aS) -2-fluorotetrahydro-1H-pyri-zine cyclo-7 a (5H) -yl) methoxy) pyridine [2,3-d ] pyrimidine

The intermediate 7- (3- (2- (trimethylsilyl) ethoxymethoxy) -8-chloronaphthyl) -6-fluoro-4- (6-boc-3, 6-diazabicyclo [ 3.1.1) obtained in the last step]Heptane-6-yl) -2- (((2R,7aS) -2-fluorotetrahydro-1H-pyrinnin cyclo-7 a (5H) -yl) methoxy) pyridine [2,3-d]Pyrimidine (81mg, 0.1mmol) in CF ₃ COOH (3mL), stirred at room temperature for 2h, then concentrated under reduced pressure, the residue was dissolved with 10mL methanol, then K was added ₂ CO ₃ Adjusting to neutral pH>8, then concentrated under reduced pressure by filtration and purified by preparative HPLC to give compound 53(32mg, yield 56%, this is the final step yield, the same below) as a pale yellow solid.

LC/MS(ESI):m/z＝579.2[M+H] ⁺ .

Example 57

Preparation of 7- (3-hydroxy-8-fluoronaphthyl) -6-fluoro-4- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- (((2R,7aS) -2-fluorotetrahydro-1H-pyri-ridin-ring-7 a (5H) -yl) methoxy) -1, 8-naphthyridine (Compound 57)

The first step is as follows: preparation of 2- (3- (2- (trimethylsilyl) ethoxymethoxy) -8-fluoronaphthyl) -3-fluoro-6-aminopyridine

6-amino-2-bromo-3-fluoropyridine (95mg, 0.5mmol), 3- (2- (trimethylsilyl) ethoxymethoxy) -8-fluoronaphthaleneboronic acid pinacol ester (209mg, 0.5mmol), tris (dibenzylideneacetone) dipalladium (40mg, 0.044mmol), cesium carbonate, 1, 4-dioxane (5mL) and water (1mL) were mixed, then heated to 120 ℃ under reflux, and the reaction was stirred for 16 hours. The reaction was cooled to room temperature and stirred overnight to give a pale yellow precipitate. The reaction mixture was diluted with water (1mL) and the solid was collected by filtration and then dried to give 2- (3- (2- (trimethylsilyl) ethoxymethoxy) -8-fluoronaphthyl) -3-fluoro-6-aminopyridine (153mg, 76%) as a beige solid, which was used for the next reaction without further purification.

LC/MS(ESI):m/z＝403.2[M+H] ⁺ .

The second step is that: preparation of 7- (3- (2- (trimethylsilyl) ethoxymethoxy) -8-fluoronaphthyl) -6-fluoro-2, 4-dihydroxy-1, 8-naphthyridine

2- (3- (2- (trimethylsilyl) ethoxymethoxy) -8-fluoronaphthyl) -3-fluoro-6-aminopyridine (121mg, 0.3mmol) and diethyl malonate (55.1g, 0.33mmol) were suspended in diphenyl ether (5mL) and the reaction was heated at 150 ℃ for 0,5 hours, whereupon the reaction became a homogeneous solution. The reaction was then refluxed for 2 hours, then cooled to room temperature, poured into water (300mL) and extracted with ethyl acetate (10 mL). The organic phase was over anhydrous MgSO ₄ Drying, filtering and concentrating. The residue was heated at 220 ℃ under reduced pressure for 2 hours, and the mixture solidified. The reaction was cooled to room temperature and slurried with ethanol to give 7- (3- (2- (trimethylsilyl) ethoxymethoxy) -8-fluoronaphthyl) -6-fluoro-2, 4-dihydroxy-1, 8-naphthyridine as a yellow solid (96mg, 68%).

LC/MS(ESI):m/z＝471.2[M+H] ⁺

The third step: preparation of 7- (8-fluoronaphthyl) -6-fluoro-2, 4-dichloro-1, 8-naphthyridine

7- (3- (2- (trimethylsilyl) ethoxymethoxy) -8-fluoronaphthyl) -6-fluoro-2, 4-dihydroxy-1, 8-naphthyridine (95mg 0.2mmol) was dissolved in POCl ₃ (2mL) and 5mL of toluene, a small amount of N, N-dimethylaniline was added, and the mixture was stirred under reflux with heating for 10 hours. Then quenched into ice water, filtered to obtain a solid product, washed with water, and dried to obtain a crude yellow solid of 7- (8-fluoronaphthyl) -6-fluoro-2, 4-dichloro-1, 8-naphthyridine (67mg, 87%) which was then subjected to the next reaction without further purification.

LC/MS(ESI):m/z＝378[M+H] ⁺ .

The fourth step: preparation of 7- (3-hydroxy-8-fluoronaphthyl) -6-fluoro-4-chloro-2- (((2R,7aS) -2-fluorotetrahydro-1H-pyri-din-o-7 a (5H) -yl) methoxy) -1, 8-naphthyridine

7- (3-hydroxy-8-fluoronaphthyl) -6-fluoro-2, 4-dichloro-1, 8-naphthyridine (66mg, 0.175mmol), (2R,8S) -2-fluoro-1, 2,3,5,6, 7-hexahydro-pyrrol-zin-7-yl ] methanol (31mg, 0.193mmol), potassium carbonate (48mg, 0.35mmol), a catalytic amount of potassium iodide and DMF (8mL) were mixed, heated to 120 ℃ and stirred for 4 hours. Cooled to room temperature and evaporated under reduced pressure to give 7- (3-hydroxy-8-fluoronaphthyl) -6-fluoro-4-chloro-2- (((2R,7aS) -2-fluorotetrahydro-1H-pirtine cyclo-7 a (5H) -yl) methoxy) -1, 8-naphthyridine aS a yellow solid (68mg, 78%),

LC/MS(ESI):m/z＝501.2[M+H] ⁺ 。

the fifth step: preparation of 7- (3-hydroxy-8-fluoronaphthyl) -6-fluoro-4- (8-boc-3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- (((2R,7aS) -2-fluorotetrahydro-1H-pyrazin-cyclo-7 a (5H) -yl) methoxy) -1, 8-naphthyridine

8-boc-3, 8-diazabicyclo [3.2.1] octane (31.8mg, 0.15mmol), 7- (3-hydroxy-8-fluoronaphthyl) -6-fluoro-4-chloro-2- (((2R,7aS) -2-fluorotetrahydro-1H-pyridon-cyclo-7 a (5H) -yl) methoxy) -1, 8-naphthyridine (67mg, 0.134mmol), cesium carbonate (87mg, 0.268mmol) and BINAP (4mg, 0.0067mmol) were dissolved in 1.4-dioxane (2mL) and the mixture was degassed by bubbling nitrogen for 5 min. To the reaction mass was added tris (dibenzylideneacetone) dipalladium (10mg, 0.01mmol) and the reaction mixture was stirred under reflux for 24 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (5mL), washed with water (2mL), washed with brine (1mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave a crude product aS a brown solid, which was then subjected to preparative HPLC to give 7- (3-hydroxy-8-fluoronaphthyl) -6-fluoro-4- (8-boc-3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- (((2R,7aS) -2-fluorotetrahydro-1H-pyrazin-cyclo-7 a (5H) -yl) methoxy) -1, 8-naphthyridine (74mg, 82%).

LC/MS(ESI):m/z＝676.3[M+H] ⁺ .

And a sixth step: preparation of 7- (3-hydroxy-8-fluoronaphthyl) -6-fluoro-4- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- (((2R,7aS) -2-fluorotetrahydro-1H-pyri-ridin-cyclo-7 a (5H) -yl) methoxy) -1, 8-naphthyridine

7- (3-hydroxy-8-fluoronaphthyl) -6-fluoro-4- (8-boc-3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- (((2R,7aS) -2-fluorotetrahydro-1H-pyrazin-cyclo-7 a (5H) -yl) methoxy) -1, 8-naphthyridine (72mg,0.1mmol), 1ml ethyl acetate, 1ml 1N HCl in 1, 4-dioxane were added. After stirring at room temperature for 2 hours, the reaction solution was neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. Preparative HPLC then gave 7- (8-fluoronaphthyl) -6-fluoro-4- (((R) -2-methylpiperazin) -1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyridine [2,3-d ] pyrimidine 57(50mg, 87% yield).

LC/MS(ESI):m/z＝576.2[M+H] ⁺ .

Example 58 biological Activity assay

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

First, KRAS-G2C/SOS1 binding assay

1. Experimental methods

A) The Tagged-His Tag G12D protein, Tag1-SOS protein were diluted with diluent according to the ratio of 1: 100, and diluting the anti-Tag1-Tb ³⁺ Antibodies and anti-Tag2-XL665 were tested in the detection buffer according to the following protocol 1: 100 or 1: 25, dilution was carried out.

B) The test compound was diluted with a diluent starting at 10000mM concentration, 4-fold gradient, for a total of 6 concentration gradients, to 10 Xstock solution.

C) In a 96-well plate, 4uL Tagged-His Tag G12D protein, 4uL Tag1-SOS protein, 2u1 diluent (positive control) or a compound to be detected (10 x mother liquor with different concentrations) are added into each well in sequence, 10u1 is totally added, and after incubation for 15 minutes at room temperature, 5uL anti-Tagl-Tb mixed in advance is added ³⁺ And 5uL anti-Tag2-xL665, after sealing the plates, incubated at room temperature for 2 hours and the HTRF signal was read using a TECAN INFINITEF NANO + microplate reader.

2. Results of the experiment

Using the formula ratio of 665nm signal value/620 nm signal value x10 ⁴ The ratio of the love and donor excitation signals was calculated for each single well. Data was processed using Graphpadprism5 software. Calculation of IC by sigmoidal dose-response curve fitting ₅₀ The value is obtained. Wherein "+" denotes IC ₅₀ Less than or equal to 50 nM; "+ +" indicates 50<IC ₅₀ Less than or equal to 500 nM; "+ + + +" indicates 500nM<IC ₅₀ The results are shown in Table 1 below

TABLE 1 inhibition of KRAS-G2C/SOS1 binding Activity IC by Compounds ₅₀ (nm)

Second, tumor cell proliferation inhibition experiment

1. Experimental methods

ATCC CRL-1739 (KRAS) ^G12D Mutation) cell digestion after centrifugation and resuspension the cell density was measured using a Scepter automated cell counter, the cells were diluted to 44,000 cells per ml, and the cell solution adjusted to the density was added to a 96-well plate at 90 μ l per well. Mixing 96-well platePlacing at 37 ℃ and 5% CO ₂ After the cells are cultured for 24 hours in an incubator, the cells with different concentrations of compounds to be tested are added and cultured with the compounds in the presence of 10% fetal calf serum for 72 hours, the Cell Titer-Glo luminescent Cell viability assay kit is used for determining the ATP content to evaluate the Cell growth inhibition, in brief, 30 microliters of Cell Titer-Glo reagent is added into each well, the plate is shaken for 10 minutes to induce Cell lysis, fluorescent signals are recorded by fluoroska assay FL (thermo), and the maximum signal value is obtained from the cells treated by dimethyl sulfoxide for 72 hours. The minimum signal value was obtained from the medium alone (cell number zero), the inhibition% (maximum signal value compound signal value)/(maximum signal value-minimum signal value × 100%), the data were processed using Graphpadprism5 software, the IC was calculated by sigmoidal dose response curve fitting ₅₀ The value is obtained. Wherein "A" represents IC ₅₀ Less than or equal to 50 nM; "B" means 50<IC ₅₀ Less than or equal to 500 nM; "C" means 500<IC ₅₀ Less than or equal to 2000 nM; "D" means 2000<IC ₅₀

2. Results of the experiment

The 1C of each compound in the above experiment was calculated ₅₀ The results are shown in Table 2 below

TABLE 2 inhibitory Activity of Compounds on tumor cell proliferation IC ₅₀ (nm)。

Claims

1. A compound having the general formula (I), a stereoisomer, a pharmaceutically acceptable salt, a polymorph, or an isomer thereof, wherein the compound having the general formula (I) has the following structure:

wherein the content of the first and second substances,

each L ₁ Independently at each occurrence is selected from absent;

each L ₂ Independently at each occurrence, selected from O, NH, CO or S;

each ring A is C _3-10 Carbocyclic ring of

May be attached to the same carbon atom or to different atoms of said ring A;

each R ₂ is-OR ₆ 、-NR ₆ R ₇ 、-SR ₆ 、-S(＝O)R ₆ 、-S(＝O) ₂ R ₆ 5-10 membered heteroaryl or 3-10 membered heterocyclyl, each heterocyclyl and heteroaryl independently containing at each occurrence 1,2,3 or 4 substituents selected from the group consisting of N, O, S, S ═ O or S (═ O) ₂ Each R3 is independently at each occurrence optionally substituted with 1,2,3, 4, 5, or 6R ₁₉ Substituted or unsubstituted;

each R ₃ And R ₄ Independently at each occurrence is selected from deuterium, hydrogen, halogen, -C _1-6 Alkyl, -C _2-6 Alkenyl, -C _2-6 Alkynyl, oxo, -OR ₆ 、-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ or-S (O) ₂ NR ₆ R ₇ or-C _3-10 Carbocyclyl, each heterocyclyl and heteroaryl independently comprise, at each occurrence, 1,2,3 or 4 substituents selected from N, 0, S, S ═ 0 or S (═ O) ₂ A heteroatom of (a); each R ₃ And R ₄ Optionally substituted at each occurrence with 1,2,3, 4, 5 or 6 substituents selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkoxy, oxo, -OR ₆ 、-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ or-S (O) ₂ NR ₆ R ₇ Substituted or unsubstituted;

each R ₅ Independently at each occurrence, selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkylene- (halogen) _1-3 、C _1-6 Heteroalkyl, -CN, -OR ₆ 、-C _1-6 Alkylene- (OR) ₆ ) _1-3 、-O-C _1-6 Alkylene- (halogen) _1-3 、-SR ₆ 、-S-C _1-6 Alkylene- (halogen) _1-3 、-NR ₆ R ₇ 、-C _1-6 alkylene-NR ₆ R ₇ 、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ 、-S(O) ₂ NR ₆ R ₇ or-C _3-6 Carbocyclyl, each heterocyclyl and heteroaryl independently at each occurrence containing 1,2,3 or 4 substituents selected from N, O, S, S ═ O or S (═ O) ₂ A heteroatom of (a); each R ₃ And R ₄ Optionally substituted at each occurrence with 1,2,3, 4, 5 or 6 substituents selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkoxy, oxo, -OR ₆ 、-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ or-S (O) ₂ NR ₆ R ₇ Substituted or unsubstituted;

each R ₆ And R ₇ Independently at each occurrence is selected from hydrogen or-C1-6 alkyl, each R ₆ And R ₇ Independently optionally substituted by 1,2,3, 4, 5 or 6R ₁₉ Substituted or unsubstituted; or R ₇ And R ₇ Together with the N atom to which they are commonly attached form a 3-10 membered heterocyclic ring, which 3-10 membered heterocyclic ring may further comprise 1,2,3 or 4 heteroatoms selected from N, O, S, S (═ O) or S (═ O)2, and which 3-10 membered heterocyclic ring is independently optionally substituted with 1,2,3, 4, 5 or 6R atoms ₁₉ Substituted or unsubstituted;

s is selected from 0, 1,2,3, 4, 5 or 6;

p is selected from 0, 1,2,3, 4, 5 or 6;

q is selected from 0, 1,2,3, 4, 5 or 6.

Y is absent or selected from C _3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spiro cyclic group, 5-12 membered spiro heterocyclic group, aromatic group or heteroaromatic group, wherein said cycloalkyl, heterocycloalkyl, spiro cyclic group, fused heterocyclic group, spiro heterocyclic group, aromatic group or heteroaromatic group is optionally substituted with one or more G ¹ Substituted;

G ¹ and G ² Each independently selected from deuterium, cyano, halogen, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, -OR ₁₁ 、-OC(O)NR ₁₁ R ₁₂ 、-C(O)OR ₁₁ 、-C(O)NR ₁₁ R ₁₂ 、-C(O)R ₁₁ 、-NR ₁₁ R ₁₂ 、-NR ₁₁ C(O)R ₁₂ 、-NR ₁₁ C(O)NR ₁₂ R ₁₃ 、-S(O) _m R ₁₁ or-NR ₁₁ S(O) _m R ₁₂ Wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1 or more of deuterium, cyano, halogen, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-8 Cycloalkyl or 3-8 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, -OR ₁₄ 、-OC(O)NR ₁₄ R ₁₅ 、-C(O)OR ₁₄ 、-C(O)NR ₁₄ R ₁₅ 、-C(O)R ₁₄ 、-NR ₁₄ R ₁₅ 、-NR ₁₄ C(O)R ₁₅ 、-NR ₁₄ C(O)NR ₁₅ R ₁₆ 、-S(O) _m R ₁₄ or-NR ₁₄ S(O) _n R ₁₅ Substituted with the substituent(s);

R ⁸ 、R ⁹ 、R ¹¹ 、R ¹² 、R ¹³ 、R ¹⁴ and R ¹⁵ Each independently selected from hydrogen, deuterium, cyano, halogen、C _1-6 Alkyl radical, C _3-8 Cycloalkyl or 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl or phenyl;

and m is 1 or 2.

2. The compound of claim 1, wherein each R is ₁ Independently at each occurrence, is selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, each heteroaryl independently at each occurrence, comprising 1,2,3, or 4 heteroatoms selected from N, 0, or S; each R ₁ Optionally at each occurrence independently by 1,2,3, 4, 5 or 6R ₂₀ Substituted or unsubstituted;

preferably, each R ₁ Independently at each occurrence is selected from phenyl, naphthyl, pyridyl, indolyl, indazolyl, benzofuranyl, benzothienyl, quinolinyl, isoquinolinyl, each R ₁ Independently at each occurrence is optionally substituted or unsubstituted with 1,2,3, 4, 5 or 6R 12; each R ₁ Optionally at each occurrence independently by 1,2,3, 4, 5 or 6R ₂₀ Substituted or unsubstituted;

more preferably, each R ₁ Selected from the group consisting of:

each R ₁ Optionally at each occurrence independently by 1,2,3, 4, 5 or 6R ₂₀ Substituted or unsubstituted;

preferably, each R ₂₀ Independently at each occurrence, selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkylene- (halogen) _1-3 、C _1-6 Heteroalkyl, -CN, -OR ₆ 、-C _1-6 Alkylene- (OR) ₆ ) _1-3 、-O-C _1-6 Alkylene- (halogen) _1-3 、-SR ₆ 、-S-C _1-6 Alkylene- (halogen) _1-3 、-NR ₆ R ₇ -C1-6 alkylene-NR ₆ R ₇ 、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ 、-S(O) ₂ NR ₆ R ₇ or-C _3-6 A carbocyclic group; each R ₁₂ Independently optionally substituted by 1,2,3, 4, 5 or 6 substituents selected from deuterium, halogen, -C _1-6 Alkyl, -C _1-6 Alkoxy, oxo, -OR ₆ 、-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ or-S (O) ₂ NR ₆ R ₇ Substituted or unsubstituted;

each R ₂₀ R in (1) ₆ And R ₇ Independently at each occurrence, selected from hydrogen, deuterium or-C _1-3 An alkyl group;

more preferably, each R ₂₀ Independently at each occurrence is selected from-deuterium, -F, -Cl, -Br, oxo, methyl, ethyl, propyl, isopropyl, -CH ₂ F、-CHF ₂ 、-CF ₃ 、-CH ₂ CH ₂ F、-CH ₂ CHF ₂ 、-CH ₂ CF ₃ 、-CH ₂ CH ₂ CH ₂ F、-CH ₂ CH ₂ CH ₂ F ₂ 、-CH ₂ CH ₂ CF ₃ 、-CH ₂ OCH3、-CH ₂ CH ₂ OCH ₃ 、-CH ₂ CH ₂ CH ₂ OCH ₃ 、-CN，-OH，-OCH ₃ 、-OCH ₂ CH ₃ 、-OCH ₂ CH ₂ CH ₃ 、-OCH(CH ₃ ) ₂ 、-CH ₂ OH，-CH ₂ CH ₂ OH，-CH ₂ CH ₂ CH ₂ OH，-OCH ₂ F、-OCHF ₂ 、-OCF ₃ 、-OOOF、-OCH ₂ CHF ₂ 、-OCH ₂ CF ₃ 、-OCH ₂ CH ₂ CH ₂ F、-OCH ₂ CH ₂ CHF ₂ 、-OCH ₂ CH ₂ CF ₃ 、-SH、-SCH ₃ 、-SCH ₂ CH ₃ 、-SCH(CH ₃ ) ₂ 、-SOF、-SCHF ₂ 、-SCF ₃ 、-SCH ₂ CH ₂ F、-SCH ₂ CH ₂ F ₂ 、-SCH ₂ CF ₃ 、-SCH ₂ CH ₂ CH ₂ F、-SCH ₂ CH ₂ CHF ₂ 、-SCH ₂ CH ₂ CF ₃ 、-NH ₂ 、-NHCH ₃ 、-NHCH ₂ CH ₃ 、-NHCH ₂ CH ₂ CH ₃ 、-NHCH(CH ₃ ) ₂ 、-N(CH ₃ ) ₂ 、-N(CH3)CH ₂ CH ₃ 、-N(O)CH ₂ CH ₂ CH ₃ 、-N(CH3)CH(CH ₃ ) ₂ 、-CH2NH ₂ 、-CH ₂ CH ₂ NH ₂ 、-CH ₂ CH ₂ CH ₂ NH ₂ 、-CH ₂ N(CH ₃ ) ₂ 、-CH ₂ CH ₂ N(CH ₃ ) ₂ 、-CH ₂ CH ₂ CH ₂ N(CH ₃ ) ₂ 、-C(＝O)CH ₃ 、-C(＝O)OCH ₃ 、-C(＝O)OCH ₂ CH ₃ 、-C(＝O)OCH ₂ CH ₂ CH ₃ 、-OC(＝O)CH ₃ 、-C(＝O)NH ₂ 、-C(＝O)NH(CH ₃ )、-C(＝O)N(CH ₃ ) ₂ 、-NHC(＝O)CH ₃ 、-N(CH3)C(＝O)CH ₃ 、-S(O) ₂ NH ₂ 、-S(O)2NH(CH ₃ )、-S(O) ₂ N(CH ₃ ) ₂ 3-, 4-, 5-or 6-membered carbocyclyl; each R ₂₀ Independently optionally substituted with 1,2,3, 4, 5 or 6 substituents selected from-deuterium, -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH ₂ 、-NHCH ₃ 、_N(CH ₃ )2、-CN、-C(＝O)CH ₃ 、_C(＝O)OO、-OC(＝O)O、-C(＝O)NH ₂ 、-C(＝O)NH(CH ₃ )、-C(＝O)N(CH ₃ )2、-NHC(＝O)CH ₃ 、-N(CH ₃ )C(＝O)CH ₃ 、-S(O) ₂ NH ₂ 、-S(O) ₂ NH(CH ₃ ) or-S (O) ₂ N(CH ₃ )2 is substituted or unsubstituted;

further preferably, each R ₁ Selected from:

3. a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each ring a is a 3-membered, 4-membered, 5-membered, or 6-membered carbocyclic ring

each R ₂ R in (1) ₆ And R ₇ Independently at each occurrence is selected from hydrogen, deuterium, methyl, ethyl, propyl or isopropyl; or

preferably, each R ₂ Independently at each occurrence is selected from-NH ₂ 、-N(CH ₃ ) ₂ 、-N(CH ₃ )(CH ₂ CH ₃ )、-N(CH ₂ CH ₃ ) ₂ 、

Each R ₂ Independently optionallyBy 1,2,3, 4, 5 or 6R ₂₀ Substituted or unsubstituted;

more preferably, each R ₂ Independently at each occurrence is selected from-NH ₂ 、-N(CH ₃ ) ₂ 、-N(CH ₃ )(CH ₂ CH ₃ )、-N(CH ₂ CH ₃ ) ₂ 、

preferably, each R ₂₀ Independently at each occurrence is selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkylene- (halogen) _1-3 、C _1-6 Heteroalkyl, -CN, -OR ₆ 、-C _1-6 Alkylene- (OR) ₆ ) _1-3 、-O-C _1-6 Alkylene- (halogen) _1-3 、-SR ₆ 、-S-C _1-6 Alkylene- (halogen) _1-3 、-NR ₆ R ₇ -C1-6 alkylene-NR ₆ R ₇ 、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ 、-S(O) ₂ NR ₆ R ₇ or-C _3-6 A carbocyclic group; each R ₁₂ Independently optionally substituted by 1,2,3, 4, 5 or 6 substituents selected from deuterium, halogen, -C _1-6 Alkyl, -C _1-6 Alkoxy, oxo, -OR ₆ 、-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ or-S (O) ₂ NR ₆ R ₇ Substituted or unsubstituted;

more preferably, each R ₂₀ Independently at each occurrence is selected from-deuterium, -F, -Cl, -Br, oxo, methyl, ethyl, propyl, isopropyl,-CH ₂ F、-CHF ₂ 、-CF ₃ 、-CH ₂ CH ₂ F、-CH ₂ CHF ₂ 、-CH ₂ CF ₃ 、-CH ₂ CH ₂ CH ₂ F、-CH ₂ CH ₂ CH ₂ F ₂ 、-CH ₂ CH ₂ CF ₃ 、-CH ₂ OCH3、-CH ₂ CH ₂ OCH ₃ 、-CH ₂ CH ₂ CH ₂ OCH ₃ 、-CN，-OH，-OCH ₃ 、-OCH ₂ CH ₃ 、-OCH ₂ CH ₂ CH ₃ 、-OCH(CH ₃ ) ₂ 、-CH ₂ OH，-CH ₂ CH ₂ OH，-CH ₂ CH ₂ CH ₂ OH，-OCH ₂ F、-OCHF ₂ 、-OCF ₃ 、-OOOF、-OCH ₂ CHF ₂ 、-OCH ₂ CF ₃ 、-OCH ₂ CH ₂ CH ₂ F、-OCH ₂ CH ₂ CHF ₂ 、-OCH ₂ CH ₂ CF ₃ 、-SH、-SCH ₃ 、-SCH ₂ CH ₃ 、-SCH(CH ₃ ) ₂ 、-SOF、-SCHF ₂ 、-SCF ₃ 、-SCH ₂ CH ₂ F、-SCH ₂ CH ₂ F ₂ 、-SCH ₂ CF ₃ 、-SCH ₂ CH ₂ CH ₂ F、-SCH ₂ CH ₂ CHF ₂ 、-SCH ₂ CH ₂ CF ₃ 、-NH ₂ 、-NHCH ₃ 、-NHCH ₂ CH ₃ 、-NHCH ₂ CH ₂ CH ₃ 、-NHCH(CH ₃ ) ₂ 、-N(CH ₃ ) ₂ 、-N(CH3)CH ₂ CH ₃ 、-N(O)CH ₂ CH ₂ CH ₃ 、-N(CH3)CH(CH ₃ ) ₂ 、-CH2NH ₂ 、-CH ₂ CH ₂ NH ₂ 、-CH ₂ CH ₂ CH ₂ NH ₂ 、-CH ₂ N(CH ₃ ) ₂ 、-CH ₂ CH ₂ N(CH ₃ ) ₂ 、-CH ₂ CH ₂ CH ₂ N(CH ₃ ) ₂ 、-C(＝O)CH ₃ 、-C(＝O)OCH ₃ 、-C(＝O)OCH ₂ CH ₃ 、-C(＝O)OCH ₂ CH ₂ CH ₃ 、-OC(＝O)CH ₃ 、-C(＝O)NH ₂ 、-C(＝O)NH(CH ₃ )、-C(＝O)N(CH ₃ ) ₂ 、-NHC(＝O)CH ₃ 、-N(CH3)C(＝O)CH ₃ 、-S(O) ₂ NH ₂ 、-S(O)2NH(CH ₃ )、-S(O) ₂ N(CH ₃ ) ₂ 3-, 4-, 5-or 6-membered carbocyclyl; each R ₂₀ Independently optionally substituted with 1,2,3, 4, 5 or 6 substituents selected from-deuterium, -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH ₂ 、-NHCH ₃ 、_N(CH ₃ )2、-CN、-C(＝O)CH ₃ 、_C(＝O)OO、-OC(＝O)O、-C(＝O)NH ₂ 、-C(＝O)NH(CH ₃ )、-C(＝O)N(CH ₃ )2、-NHC(＝O)CH ₃ 、-N(CH ₃ )C(＝O)CH ₃ 、-S(O) ₂ NH ₂ 、-S(O) ₂ NH(CH ₃ ) or-S (O) ₂ N(CH ₃ )2, substituted or unsubstituted.

4. A compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each R ₃ And R ₄ Independently at each occurrence, selected from deuterium, hydrogen, halogen, -C _1-6 Alkyl, -C _2-6 Alkenyl, -C _2-6 Alkynyl, oxo, -OR ₆ 、-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ or-S (O) ₂ NR ₆ R ₇ or-C _3-10 Carbocyclyl, each heterocyclyl and heteroaryl independently comprise, at each occurrence, 1,2,3 or 4 substituents selected from N, 0, S, S ═ 0 or S (═ O) ₂ A heteroatom of (a); each R ₃ And R ₄ Optionally substituted at each occurrence with 1,2,3, 4, 5 or 6 substituents selected from deuterium, halogen, oxo, -C _1-6 Alkyl, -C _1-6 Alkoxy, oxo, -OR ₆ 、-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ or-S (O) ₂ NR ₆ R ₇ Substituted or unsubstituted;

each R ₃ And R ₄ R in (1) ₆ And R ₇ Independently at each occurrence, selected from hydrogen, deuterium or-C _1-3 An alkyl group;

preferably, each R ₃ And R ₄ Independently at each occurrence is selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, isopropenyl, ethynyl, propynyl, oxo, -OH, -OCH ₃ 、-OCH ₂ CH ₃ 、-OCH ₂ CH ₂ CH ₃ 、-OCH(CH ₃ ) ₂ 、-NH ₂ 、-NHCH ₃ 、-NHCH ₂ CH ₃ 、-NHCH ₂ CH ₂ CH ₃ 、-NHCH(CH ₃ )2、-N(CH ₃ ) ₂ 、-N(CH ₃ )CH ₂ CH ₃ 、-N(CH ₃ )CH ₂ CH ₂ CH ₃ 、-N(CH ₃ )CH(CH ₃ ) ₂ 、-CN、-C(＝O)CH ₃ 、-C(＝O)OCH ₃ 、-OC(＝O)CH ₃ 、-C(＝O)NH ₂ 、-C(＝O)NH(CH ₃ )、-C(＝O)N(CH ₃ ) ₂ 、-NHC(＝O)CH ₃ 、-N(CH3)C(＝O)CH ₃ 、-S(O) ₂ NH ₂ 、-S(O) ₂ NH(CH ₃ )、-S(O) ₂ N(CH ₃ ) ₂ 3-, 4-, 5-or 6-membered carbocyclyl; each R5 or R6 is independently optionally substituted by 1,2,3, 4, 5 or 6 groups selected from-F, -Cl, -Br, oxo, methyl, ethyl, propyl, isopropyl, -OH, OCH ₃ 、-OCH ₂ CH ₃ 、-OCH ₂ CH ₂ CH ₃ 、-OCH(CH ₃ ) ₂ 、-NH ₂ 、-N(CH ₃ ) ₂ 、-CN、-C(＝O)CH ₃ 、-OC(＝O)CH ₃ 、-C(＝O)NH ₂ 、-C(＝O)NH(CH ₃ )、-C(＝O)N(CH ₃ ) ₂ 、-NHC(＝O)CH ₃ 、-N(CH3)C(＝O)CH ₃ 、-S(O) ₂ NH ₂ 、-S(O) ₂ NH(CH ₃ )、-S(O) ₂ N(CH ₃ ) ₂ Substituted or unsubstituted.

5. A compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein each R ₅ Independently at each occurrence is selected from deuterium, -F, -Cl, -Br, -C _1-3 Alkyl, -C _1-3 Alkylene- (halogen) _1-3 、C _1-3 Heteroalkyl, -C _2-3 Alkenyl, -C _2-3 Alkynyl, -CN, -OR ₆ 、-C _1-6 Alkylene- (OR) ₆ ) _1-3 、-O-C _1-6 Alkylene- (halogen) _1-3 、-SR ₆ 、-S-C _1-6 Alkylene- (halogen) _1-3 、-NR ₆ R ₇ 、-C _1-6 alkylene-NR ₆ R ₇ 、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ 、-S(O) ₂ NR ₆ R ₇ or-C _3-6 Carbocyclyl, each heterocyclyl and heteroaryl independently at each occurrence containing 1,2,3 or 4 substituents selected from N, O, S, S ═ O or S (═ O) ₂ A heteroatom of (a); each R ₃ And R ₄ Optionally substituted at each occurrence with 1,2,3 or 4, 5 or 6 substituents selected from deuterium, -F, -Cl, -Br, oxo, -C _1-6 Alkyl, -C _1-6 Alkoxy, oxo, -OR ₆ 、-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ or-S (O) ₂ NR ₆ R ₇ Substituted or unsubstituted;

each R ₅ R in (1) ₆ And R ₇ Independently at each occurrence, selected from hydrogen, deuterium or-C _1-3 Alkyl, or

R ₅ R in (1) ₆ And R ₇ Together with the N atom to which they are jointly attachedForming a 3-6 membered heterocyclic ring, said 3-6 membered heterocyclic ring may further comprise 1 heteroatom selected from N, and said 3-6 membered heterocyclic ring is independently optionally substituted with 1,2,3, 4 heteroatom selected from N, O or S;

preferably, each R ₅ Independently at each occurrence is selected from deuterium, -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, isopropenyl, ethynyl, propynyl, -methylene- (halogen) 1-3, -ethylene- (halogen) _1-3 -propylene- (halogen) _1-3 Hetero-methyl, hetero-ethyl, hetero-propyl, ethenyl, propenyl, ethynyl, propynyl, oxo, -OR ₆ -methylene- (OR) ₆ ) _1-3 -ethylene- (OR) ₆ ) _1-3 -propylene- (OR) ₆ ) _1-3 -O-methylene- (halogen) _1-3 -O-ethylene- (halogen) _1-3 -O-propylene- (halogen) _1-3 、-NR ₆ R ₇ -methylene-NR ₆ R ₇ -ethylene-NR 6R7, -propylene-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₇ -S (o)2NR6R7, phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl, 8-membered heteroaryl, 10-membered heteroaryl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, or 6-membered carbocyclyl, each heterocyclyl and heteroaryl independently at each occurrence comprising 1,2,3, or 4 heteroatoms selected from N, O or S; each R7 is independently optionally substituted at each occurrence by 1,2,3, 4, 5, OR 6 groups selected from-F, -C1, -Br, oxo, methyl, ethyl, propyl, isopropyl, -OR ₆ 、-NR ₆ R ₇ 、-CN、-C(＝O)R ₆ 、-C(＝O)OR ₆ 、-OC(＝O)R ₆ 、-C(＝O)NR ₆ R ₇ 、-NR ₆ C(＝O)R ₆ or-S (O) ₂ NR ₆ R ₇ Substituted with the substituent(s);

each R ₅ R in (1) ₆ And R ₇ Independently at each occurrence is selected from hydrogen, deuterium, and aAlkyl, ethyl, propyl, isopropyl; or

More preferably, each R ₅ Independently at each occurrence, is selected from deuterium, -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, -CH ₂ F、-CHF ₂ 、-CF ₃ 、-CH ₂ CH ₂ F、-CH ₂ CHF ₂ 、-CH ₂ CF ₃ 、-CH ₂ CH ₂ CH ₂ F、-CH ₂ CH ₂ CH ₂ F ₂ 、-CH ₂ CH ₂ CF ₃ 、-CH ₂ OCH3、-CH ₂ CH ₂ OCH ₃ 、-CH ₂ CH ₂ CH ₂ OCH ₃ 、-CN，-OH，-OCH ₃ 、-OCH ₂ CH ₃ 、-OCH ₂ CH ₂ CH ₃ 、-OCH(CH ₃ ) ₂ 、-CH ₂ OH，-CH ₂ CH ₂ OH，-CH ₂ CH ₂ CH ₂ OH，-OCH ₂ F、-OCHF ₂ 、-OCF ₃ 、-OOOF、-OCH ₂ CHF ₂ 、-OCH ₂ CF ₃ 、-OCH ₂ CH ₂ CH ₂ F、-OCH ₂ CH ₂ CHF ₂ 、-OCH ₂ CH ₂ CF ₃ 、-SH、-SCH ₃ 、-SCH ₂ CH ₃ 、-SCH(CH ₃ ) ₂ 、-SOF、-SCHF ₂ 、-SCF ₃ 、-SCH ₂ CH ₂ F、-SCH ₂ CH ₂ F ₂ 、-SCH ₂ CF ₃ 、-SCH ₂ CH ₂ CH ₂ F、-SCH ₂ CH ₂ CHF ₂ 、-SCH ₂ CH ₂ CF ₃ 、-NH ₂ 、-NHCH ₃ 、-NHCH ₂ CH ₃ 、-NHCH ₂ CH ₂ CH ₃ 、-NHCH(CH ₃ ) ₂ 、-N(CH ₃ ) ₂ 、-N(CH3)CH ₂ CH ₃ 、-N(O)CH ₂ CH ₂ CH ₃ 、-N(CH3)CH(CH ₃ ) ₂ 、-CH2NH ₂ 、-CH ₂ CH ₂ NH ₂ 、-CH ₂ CH ₂ CH ₂ NH ₂ 、-CH ₂ N(CH ₃ ) ₂ 、-CH ₂ CH ₂ N(CH ₃ ) ₂ 、-CH ₂ CH ₂ CH ₂ N(CH ₃ ) ₂ 、-C(＝O)CH ₃ 、-C(＝O)OCH ₃ 、-C(＝O)OCH ₂ CH ₃ 、-C(＝O)OCH ₂ CH ₂ CH ₃ 、-OC(＝O)CH ₃ 、-C(＝O)NH ₂ 、-C(＝O)NH(CH ₃ )、-C(＝O)N(CH ₃ ) ₂ 、-NHC(＝O)CH ₃ 、-N(CH3)C(＝O)CH ₃ 、-S(O) ₂ NH ₂ 、-S(O)2NH(CH ₃ )、-S(O) ₂ N(CH ₃ ) ₂ 3-, 4-, 5-or 6-membered carbocyclyl; each R ₂₀ Independently optionally substituted with 1,2,3, 4, 5 or 6 substituents selected from-deuterium, -F, -Cl, -Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -OH, -NH ₂ 、-NHCH ₃ 、_N(CH ₃ )2、-CN、-C(＝O)CH ₃ 、_C(＝O)OO、-OC(＝O)O、-C(＝O)NH ₂ 、-C(＝O)NH(CH ₃ )、-C(＝O)N(CH ₃ )2、-NHC(＝O)CH ₃ 、-N(CH ₃ )C(＝O)CH ₃ 、-S(O) ₂ NH ₂ 、-S(O) ₂ NH(CH ₃ ) or-S (O) ₂ N(CH ₃ )2, substituted or unsubstituted.

6. A compound of the thermal insulating layer of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,

selected from the following structures:

7. a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to claims 1 to 6, which is selected from:

8. a pharmaceutical composition comprising (1) a compound of claims 1-7; and (2) a pharmaceutically acceptable carrier.

9. Use of a compound according to claims 1-7 for the preparation of a pharmaceutical composition for: (i) preventing and/or treating tumors; (ii) inhibiting or reversing multidrug resistance in tumors to antineoplastic drugs; (iii) inhibition of P-glycoprotein; (iv) the anti-tumor activity of the anti-tumor medicine is enhanced; and/or (v) inhibition of KRAS ^G12D Use of a mutein-related cancer medicament.

Preferably, the cancer is selected from the group consisting of: hematologic cancer, lung cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, oral cancer; the blood cancer is selected from acute myelogenous leukemia or acute lymphocytic leukemia, and the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

10. The use of claim 9, wherein the neoplasm comprises a neoplasm that is multidrug resistant to an antineoplastic drug.