CN117683051A

CN117683051A - Tetraheterocyclic compound, preparation method thereof, intermediate thereof and application thereof

Info

Publication number: CN117683051A
Application number: CN202311162433.2A
Authority: CN
Inventors: 罗会兵; 屈粒
Original assignee: Shanghai Allist Medicine Polytron Technologies Inc
Current assignee: Shanghai Allist Medicine Polytron Technologies Inc
Priority date: 2022-09-09
Filing date: 2023-09-08
Publication date: 2024-03-12

Abstract

The invention disclosesA tetraheterocyclic compound, a preparation method, an intermediate and application thereof are provided. The invention provides a tetraheterocyclic compound shown in a formula I, a stereoisomer or a pharmaceutically acceptable salt thereof. The compounds of the invention have inhibitory activity against proliferation of one or more of cells Ba/F3 KRAS G12C, ba/F3 KRAS G12D, ba/F3 KRAS G12V, ba/F3 KRAS G12A, ba/F3 KRAS G12R, ba/F3 KRAS G12S, ba/F3 KRAS G13C, ba/F3 KRAS G13D, ba/F3 KRAS Q61H, ba/F3 KRAS Q61K, ba/F3 KRAS Q61R, H358, asPC-1, capan-1, H727, A549, HCT116, H460, MKN-1 and PSN-1, and are expected to treat and/or prevent a variety of diseases mediated by KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61H, KRAS Q61K and KRAS 61R.

Description

Tetraheterocyclic compound, preparation method thereof, intermediate thereof and application thereof

Technical Field

The invention relates to a tetraheterocyclic compound, a preparation method thereof, an intermediate thereof and application thereof.

Background

The RAS protein is a Guanine Trinucleotide Phosphate (GTP) binding protein with molecular weight of 21kDa, which is positioned on cell membrane and consists of 188 or 189 amino acids. The active state of RAS proteins has an effect on cell growth, differentiation, cytoskeleton, protein trafficking and secretion, etc., and its activity is regulated by binding to GTP or Guanine Dinucleotide Phosphate (GDP). When RAS proteins bind to GDP, they are in an "inactive" state; when stimulated by an upstream specific cell growth factor, guanine nucleotide exchange factor (GEF) catalyzes the release of GDP from RAS proteins, binds to GTP, and is in an "activated" state. RAS proteins that bind to GTP activate downstream proteins, activating downstream signaling pathways. RAS proteins themselves have weak gtpase activity, capable of hydrolyzing GTP to GDP, thereby effecting conversion from an activated state to an inactivated state. During this hydrolysis, there is also a need for the involvement of the GTPase Activating Protein (GAP), which interacts with the RAS protein and greatly promotes its ability to hydrolyze GTP to GDP. Any mutation in the RAS protein that affects its own gtpase activity or its ability to interact with GAP or hydrolyze GTP to GDP will result in the RAS protein being in a prolonged activated state, which continues to signal downstream protein growth, resulting in continued growth and differentiation of cells, ultimately possibly leading to cancer. Three members of the RAS gene family: KRAS, NRAS, and HRAS.

KRAS mutations are the most common oncogenic driver, present in a variety of tumors: lung adenocarcinoma (32%), colorectal carcinoma (41%), pancreatic carcinoma (86%). KRAS mutations are most frequently seen in the G12 mutation at codon 12, e.g., in KRAS mutated lung adenocarcinoma, colorectal carcinoma and pancreatic carcinoma, G12 mutations account for 85%, 68% and 91%, respectively; the G12 mutation comprises G12C, G12D, G12V, G R mutant forms and the like. Of the KRAS G12 mutated lung adenocarcinoma, colorectal cancer, pancreatic cancer patients, KRAS G12D mutated patients account for 17%, 45%, respectively, and KRAS G12V mutated patients account for 23%, 30%, 35%, respectively (see, e.g., moore, A.R.et al Nat Rev Drug discovery 19,533 (2020)).

Only inhibitors targeting KRAS G12C mutations are currently marketed, i.e. inhibitors targeting KRAS G12D mutations are about to enter clinical studies, whereas patient populations benefiting from KRAS G12C inhibitors represent only a small fraction of KRAS variant-bearing populations, more than 85% of KRAS mutant cancers still lack effective treatment (see Marco, h.h.et al cancer discover 12,924 (2022)), and patients still need therapies targeting other KRAS variants (e.g. G12V, G12R, G12A).

Pan-KRAS inhibitors can inhibit a variety of KRAS mutants, have the potential to treat a wider patient population, and have a great unmet clinical need.

Disclosure of Invention

The invention aims to solve the technical problem that the Pan-KRAS inhibitor in the prior art has a single structure, and provides a tetraheterocycle compound, a preparation method thereof, an intermediate thereof and application thereof. The compounds of the invention have inhibitory activity against proliferation of one or more of cells Ba/F3KRAS G12C, ba/F3KRAS G12D, ba/F3KRAS G12V, ba/F3KRAS G12A, ba/F3KRAS G12R, ba/F3KRAS G12S, ba/F3KRAS G13C, ba/F3KRAS G13D, ba/F3KRAS Q61H, ba/F3KRAS Q61K, ba/F3KRAS Q61R, H358, asPC-1, capan-1, H727, A549, HCT116, H460, MKN-1 and PSN-1, and are expected to treat and/or prevent a variety of diseases mediated by one or more of KRAS G12C, KRAS G12V, KRAS G12A, KRAS G12R, KRAS G13C, KRAS G13D, KRAS Q61H, KRAS Q61K and KRAS 61R.

The invention solves the technical problems through the following technical proposal.

The invention provides a tetraheterocyclic compound shown in a formula I, a stereoisomer or a pharmaceutically acceptable salt thereof,

wherein,

X ¹ is-CR ⁵ -or-N-;

Y ¹ is-O-, -S-, -NR ⁶ -、-S(O) ₂ -、-SO-、-C(＝O)-、-NR ⁶ C(＝O)-、-(CR ⁷ R ⁷ ) _p1 -, -C (=O) O-or-

C(＝O)NR ⁶ -；

Y ² Is- (CR) ⁷ R ⁷ ) _p2 -、-NR ⁶ -、-C(＝O)(CR ⁷ R ⁷ ) _p3 -、-O(CR ⁷ R ⁷ ) _p4 -or-NR ⁶ (CR ⁷ R ⁷ ) _p5 -；

Alternatively, Y ² The ring carbon atoms or ring nitrogen atoms in (a) together with their adjacent ring atoms form a double bond;

p1, p2, p3, p4 and p5 are each independently 0, 1, 2 or 3;

each R ¹ Each independently is deuterium, halogen, -CN, -OH, oxo (= O), -N (R) ⁶ ) ₂ 、-C(＝O)N(R ⁶ ) ₂ 、C ₁ -C ₆ Alkyl, substituted by one or more R ^1a Substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, substituted by one or more R ^1b Substituted C ₁ -C ₆ alkyl-O-, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, substituted by one or more R ^1c Substituted C ₂ -C ₆ Alkenyl, substituted by one or more R ^1d Substituted C ₂ -C ₆ Alkynyl, -C (=o) H, -CO ₂ R ⁵ 5-10 membered heteroaryl; when the substituents are plural, the same or different;

alternatively, two R's on the same ring carbon atom ¹ Forming a 4-10 membered heterocyclyl, a 5-10 membered heteroaryl, a 3-7 membered cycloalkyl, substituted with one or more R ^1d Substituted 4-10 membered heterocyclyl, substituted with one or more R ^1e Substituted 5-10 membered heteroaryl or substituted with one or more R ^1f Substituted 3-7 membered cycloalkyl; when the substituents are plural, the same or different;

alternatively, two R's on adjacent ring carbon atoms ¹ Condensed into 4-10 membered heterocyclyl, 5-10 membered heteroaryl, 3-7 membered cycloalkyl, substituted with one or more R ^1g Substituted 4-10 membered heterocyclyl, substituted with one or more R ^1h Substituted 5-10 membered heteroaryl or substituted with one or more R ¹ⁱ Substituted 3-7 membered cycloalkyl; when the substituents are plural, the same or different;

n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;

Each R ^1a 、R ^1b 、R ^1c 、R ^1d 、R ^1e 、R ^1f 、R ^1g 、R ^1h And R is ¹ⁱ Each independently is deuterium, -CN, halogen, -OH, oxo (=o), C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-or-N (R) ⁶ ) ₂ ；

L is-O- (CR) ⁷ R ⁷ ) _n1 -、-S-(CR ⁷ R ⁷ ) _n2 -、-N(R ⁶ )-(CR ⁷ R ⁷ ) _n3 -、-SO-(CR ⁷ R ⁷ ) _n4 -or-SO ₂ -(CR ⁷ R ⁷ ) _n5 -；

n1, n2, n4, n5 and n6 are each independently 0, 1,2 or 3; (when 0, represents a bond);

n3 is 1,2 or 3;

R ² is-COOH, C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, -NHC (=nh) NH ₂ 、-C(O)N(R ⁶ ) ₂ 、-(CH ₂ OR ⁶ )(CH ₂ ) _n6 OR ⁶ 、-NR ⁶ C(＝O)-C ₆ -C ₁₀ Aryl, -C (=o) O-C ₁ -C ₆ Alkyl, substituted by one or more R ^2a Substituted 3-7 membered cycloalkyl, substituted with one or more R ^2b Substituted 3-7 membered cycloalkenyl, substituted with one or more R ^2c Substituted 4-10 membered heterocyclyl, substituted with one or more R ^2d Substituted C ₆ -C ₁₀ Aryl or by one or more R ^2e Substituted 5-10 membered heteroaryl; when the substituents are plural, the same or different;

each R ^2a 、R ^2b 、R ^2c 、R ^2d And R is ^2e Each independently is halogen, -OH, deuterium, -CN, -C (=O) H, C ₁ -C ₄ Alkyl, C ₂ -C ₄ Alkenyl, C ₂ -C ₄ Alkynyl, substituted by one or more R ^2-a Substituted C ₁ -C ₄ Alkyl, C ₁ -C ₄ alkyl-O-, substituted by one or more R ^2-b Substituted C ₁ -C ₄ alkyl-O-, -N (R) ⁶ ) ₂ 、(C _l -C ₄ Alkyl) -C (=o) -, oxo (=o), -SO ₂ F、(C _l -C ₄ Alkyl) -SO ₂ -、(C _l -C ₄ Alkyl) -O- (C _l -C ₄ Alkyl) -O-, -CH ₂ OC(＝O)N(R ⁶ ) ₂ 、(C _l -C ₄ Alkyl) -O-C (=o) -NHCH ₂ -、-CH ₂ NHC(＝O)N(R ⁶ ) ₂ 、(C _l -C ₄ Alkyl) -C (=o) NHCH ₂ -, (pyrazolyl) -CH ₂ -、(C _l -C ₄ Alkyl) -SO ₂ -NHCH ₂ -, (4-10 membered heterocyclyl) -C (=o) -OCH ₂ -、(R ⁶ ) ₂ N-C(＝O)-O-、(C _l -C ₄ Alkyl) -O- (C _l -C ₄ Alkyl) -NH-C (=o) -O-, phenyl-C (=o) NH-, phenyl- (C) _l -C ₄ Alkyl) -NH-C (=o) -O-, (4-10 membered heterocyclyl) -C (=o) -O-, or (4-10 membered heterocyclyl) -CH ₂ -; the phenyl-C (=O) NH-and phenyl- (C) _l -C ₄ Alkyl) -NH-C (=o) -O-phenyl optionally substituted with-C (=o) H, halogen, -CN or-OH; the (4-10 membered heterocyclic) -C (=O) -OCH ₂ -, (4-10 membered heterocyclyl) -C (=o) -O-, and (4-10 membered heteroalkyl) -CH ₂ -the 4-10 membered heterocyclyl in is optionally substituted with =o; when the substituents are plural, the same or different;

each R ^2-a And R is ^2-b Each independently deuterium, -CN, halogen or-OH;

R ³ is C ₆ -C ₁₀ Aryl, substituted by one or more R ^3a Substituted C ₆ -C ₁₀ Aryl, 5-to 10-membered heteroaryl, or substituted with one or more R ^3b Substituted 5-10 membered heteroaryl; when the substituents are plural, the same or different;

each R ^3a And R is ^3b Each independently is deuterium, halogen, -OH, -CN, C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ alkyl-S-, substituted by one or more R ^3-a Substituted C ₁ -C ₆ Alkyl, substituted by one or more R ^3-b Substituted C ₁ -C ₆ alkyl-O-, substituted by one or more R ^3-c Substituted C ₁ -C ₆ alkyl-S-, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, substituted by one or more R ^3-d Substituted C ₂ -C ₆ Alkenyl, substituted by one or more R ^3-e Substituted C ₂ -C ₆ Alkynyl, -N (R) ⁶ ) ₂ 、-(CH ₂ )-C(＝O)N(R ⁶ ) ₂ 3-7 membered cycloalkyl, substituted with one or more R ^3-f Substituted 3-7 membered cycloalkyl or triazolyl; when the substituents are plural, the same or different;

each R ^3-a 、R ^3-b 、R ^3-c 、R ^3-d 、R ^3-e And R is ^3-f Each independently is deuterium, halogen, -CN, -OH, C ₁ -C ₄ Alkyl, C ₁ -C ₄ alkyl-O-or 3-7 membered cycloalkyl;

R ^4b is H, deuterium, -N (R) ⁶ ) ₂ Halogen, -OH, C ₁ -C ₆ Alkyl, -CN, halo C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, deuterated C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl or C ₂ -C ₆ Alkynyl;

R ⁵ is hydrogen, halogen, -CN, C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ alkyl-S-, 5-10 membered heteroaryl, substituted with one or more R ^5a Substituted C ₁ -C ₆ Alkyl, substituted by one or more R ^5b Substituted C ₁ -C ₆ alkyl-O-, substituted by one or more R ^5c Substituted C ₁ -C ₆ alkyl-S-or by one or more R ^5d Substituted 5-10 membered heteroaryl; when the substituents are plural, the same or different;

each R ^5a 、R ^5b 、R ^5c And R is ^5d Each independently is deuterium, halogen, -CN, -OH, C ₁ -C ₄ Alkyl, C ₁ -C ₄ alkyl-O-or 3-7 membered cycloalkyl;

each R ⁶ Each independently is hydrogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, deuterated C ₁ -C ₆ Alkyl or 5-10 membered heteroaryl;

each R ⁷ Each independently is hydrogen, halogen, -CN, C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, deuterated C ₁ -C ₆ Alkyl or 5-10 membered heteroaryl;

or two R on a ring atom ⁷ Together with the ring atom to which it is attached, form oxo (=o), 3-7 membered cycloalkyl or 3-7 membered heterocyclyl;

The 5-10 membered heteroaryl, 4-10 membered heterocyclyl, 3-7 membered heterocyclyl, substituted with one or more R ^1d Substituted 4"4-10 membered heterocyclyl", in a 10 membered heterocyclyl, is substituted with one or more R ^1e "5-10 membered heteroaryl" in substituted 5-10 membered heteroaryl, substituted with one or more R ^1g "4-10 membered heterocyclyl", in substituted 4-10 membered heterocyclyl, is substituted with one or more R ^1h "5-10 membered heteroaryl" in substituted 5-10 membered heteroaryl, substituted with one or more R ^2c "4-10 membered heterocyclyl", in substituted 4-10 membered heterocyclyl, is substituted with one or more R ^2e "5-10 membered heteroaryl", (4-10 membered heterocyclyl) -C (=o) -OCH in substituted 5-10 membered heteroaryl ₂ "4-10 membered heterocyclyl" in (4-10 membered heterocyclyl) -C (=o) -O-in "4-10 membered heterocyclyl", (4-10 membered heterocyclyl) -CH ₂ "4-10 membered heterocyclyl", in "one or more R ^3b "5-10 membered heteroaryl" in a substituted 5-10 membered heteroaryl and substituted with one or more R ^5d The hetero atom in the '5-10 membered heteroaryl' in the substituted 5-10 membered heteroaryl is independently selected from one or more of N, O and S, and the number of the hetero atom is independently 1, 2 or 3.

In one embodiment, certain groups in the tetraheterocyclic compound shown in formula I, the stereoisomer thereof or the pharmaceutically acceptable salt thereof have the following definitions, and the non-mentioned groups are defined as in any one embodiment of the invention (hereinafter referred to as "in one embodiment"): y is Y ¹ In said formula (I), said-NR ⁶ In C (=O) -, carbonyl and Y ² Are connected.

In one embodiment, Y ¹ In the-C (=O) O-, oxygen and Y ² Are connected.

In one embodiment, Y ¹ In the formula, the-C (=O) NR ⁶ In-nitrogen and Y ² Are connected.

In one embodiment, Y ² In the formula (I), the formula (I) is that the formula (I) ⁷ R ⁷ ) _p3 in-C, carbonyl and Y ¹ Are connected.

In one embodiment, Y ² In said formula (I), said-NR ⁶ (CR ⁷ R ⁷ ) _p5 In-nitrogen and Y ¹ Are connected.

In one embodiment, Y ² Wherein the formula is-O%CR ⁷ R ⁷ ) _p4 In-oxygen and Y ¹ Are connected.

In one embodiment, when R ¹ When halogen, the halogen is independently F, cl, br or I, such as fluorine.

In one embodiment, when R ¹ Is C ₁ -C ₆ Alkyl, substituted by one or more R ^1a Substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, substituted by one or more R ^1b Substituted C ₁ -C ₆ alkyl-O-, wherein C ₁ -C ₆ Alkyl is independently C _1-4 Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also, for example, methyl.

In one embodiment, when R ¹ Is C ₂ -C ₆ Alkenyl or by one or more R ^1c Substituted C ₂ -C ₆ Alkenyl group, C therein ₂ -C ₆ Alkenyl groups are independently C ₂ -C ₄ Alkenyl is, for example, ethenyl, propenyl or butenyl.

In one embodiment, when R ¹ Is C ₂ -C ₆ Alkynyl or by one or more R ^1d Substituted C ₂ -C ₆ Alkynyl group, C therein ₂ -C ₆ Alkynyl groups are independently C ₂ -C ₄ Alkynyl is, for example, ethynyl, propynyl or butynyl.

In one embodiment, when R ¹ In the case of a 5-10 membered heteroaryl, the heteroatom in the 5-10 membered heteroaryl is independently selected from one or both of N and O.

In one embodiment, when R ¹ In the case of a 5-10 membered heteroaryl, the number of heteroatoms in the 5-10 membered heteroaryl is independently 1 or 2.

In one embodiment, when R ¹ In the case of a 5-10 membered heteroaryl, the 5-10 membered heteroaryl may independently be a 5-6 membered heteroaryl.

In one embodiment, when two R's are on the same ring carbon atom ¹ Forming a 4-10 membered heterocyclic group or by one or more R ^1d Substituted 4-10 memberedWhen heterocyclic, the hetero atom in the 4-10 membered heterocyclic is independently selected from one or two of N and O.

In one embodiment, when two R's are on the same ring carbon atom ¹ Forming a 4-10 membered heterocyclic group or by one or more R ^1d When the heterocyclic group is substituted, the number of hetero atoms in the 4-10 membered heterocyclic group is independently 1 or 2.

In one embodiment, when two R's are on the same ring carbon atom ¹ Forming a 4-10 membered heterocyclic group or by one or more R ^1d When a 4-10 membered heterocyclic group is substituted, the 4-10 membered heterocyclic group may be independently a 5-6 membered heterocyclic group.

In one embodiment, when two R's are on the same ring carbon atom ¹ Formed by one or more R ^1d Substituted 4-10 membered heterocyclyl, said substituted with one or more R ^1d The substituted 4-10 membered heterocyclic groups may independently be 5-6 membered heterocyclic groups substituted with oxo and/or methyl, e.g

In one embodiment, when two R's are on the same ring carbon atom ¹ Forming a 5-to 10-membered heteroaryl or by one or more R ^1e When the 5-10 membered heteroaryl is substituted, the hetero atom in the 5-10 membered heteroaryl is independently selected from one or two of N and O, and the number of the hetero atom is independently 1 or 2.

In one embodiment, when two R's are on the same ring carbon atom ¹ Forming 3-7 membered cycloalkyl or by one or more R ^1f When substituted, 3-7 membered cycloalkyl, wherein 3-7 membered cycloalkyl is independently 3-6 membered cycloalkyl, is for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In one embodiment, when two R's on adjacent ring carbon atoms ¹ Condensed into 4-10 membered heterocyclic groups or by one or more R ^1g When the 4-10 membered heterocyclic group is substituted, the hetero atom in the 4-10 membered heterocyclic group is independently selected from one or two of N and O.

In a certain schemeWhen two R's on adjacent ring carbon atoms ¹ Condensed into 4-10 membered heterocyclic groups or by one or more R ^1g When the heterocyclic group is substituted, the number of hetero atoms in the 4-10 membered heterocyclic group is independently 1 or 2.

In one embodiment, when two R's on adjacent ring carbon atoms ¹ Condensed into 4-10 membered heterocyclic groups or by one or more R ^1g When a 4-10 membered heterocyclic group is substituted, the 4-10 membered heterocyclic group may independently be a 5-6 membered heterocyclic group.

In one embodiment, when two R's on adjacent ring carbon atoms ¹ Condensed into 5-to 10-membered heteroaryl groups or into one or more R groups ^1h When the 5-10 membered heteroaryl is substituted, the hetero atom in the 5-10 membered heteroaryl is independently selected from one or two of N and O, and the number of the hetero atom is independently 1 or 2.

In one embodiment, when two R's on adjacent ring carbon atoms ¹ Condensed into 3-7 membered cycloalkyl groups or by one or more R ¹ⁱ When substituted, 3-7 membered cycloalkyl, wherein 3-7 membered cycloalkyl is independently 3-6 membered cycloalkyl, is for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In one embodiment, when R ^1a 、R ^1b 、R ^1c 、R ^1d 、R ^1e 、R ^1f 、R ^1g 、R ^1h Or R is ¹ⁱ When halogen, the halogen is independently F, cl, br or I.

In one embodiment, when R ^1a 、R ^1b 、R ^1c 、R ^1d 、R ^1e 、R ^1f 、R ^1g 、R ^1h Or R is ¹ⁱ Is C ₁ -C ₆ Alkyl or C ₁ -C ₆ alkyl-O-, wherein C ₁ -C ₆ Alkyl is independently C _1-4 Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also, for example, methyl.

In one embodiment, when R ² Is C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-or-C (=o) O-C ₁ -C ₆ In the case of alkyl radicals, C therein ₁ -C ₆ Alkyl is independently C _1-4 Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In one embodiment, when R ² Is 3-7 membered cycloalkyl or is substituted by one or more R ^2a When substituted, 3-7 membered cycloalkyl, wherein 3-7 membered cycloalkyl is independently 3-6 membered cycloalkyl, is for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and is also for example cyclopropyl.

In one embodiment, when R ² Is 3-7 membered cycloalkenyl or is substituted by one or more R ^2b In the case of a substituted 3-7 membered cycloalkenyl group, the 3-7 membered cycloalkenyl group is independently a 3-6 membered cycloalkenyl group, such as cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl.

In one embodiment, when R ² Is 4-10 membered heterocyclyl or substituted with one or more R ^2c When the 4-10 membered heterocyclic group is substituted, the hetero atom in the 4-10 membered heterocyclic group is independently selected from one or two of N and O.

In one embodiment, when R ² Is 4-10 membered heterocyclyl or substituted with one or more R ^2c When the heterocyclic group is substituted, the number of hetero atoms in the 4-10 membered heterocyclic group is independently 1 or 2.

In one embodiment, when R ² Is 4-10 membered heterocyclyl or substituted with one or more R ^2c When a 4-10 membered heterocyclic group is substituted, the 4-10 membered heterocyclic group may independently be bicyclic.

In one embodiment, when R ² Is 4-10 membered heterocyclyl or substituted with one or more R ^2c When substituted, the 4-10 membered heterocyclic group may be independently a spiro ring, a fused ring or a bridged ring, for example, a fused ring.

In one embodiment, when R ² Is 4-10 membered heterocyclyl or substituted with one or more R ^2c In the case of substituted 4-10 membered heterocyclic groups, the 4-10 membered heterocyclic groups may independently be 6-10 membered heterocyclic groups, e.g., five membered and five membered rings, further e.g.

In one embodiment, when R ² To be covered by one or more R ^2c Substituted 4-10 membered heterocyclyl, said substituted with one or more R ^2c The substituted 4-10 membered heterocyclic groups may independently be 6-10 membered heterocyclic groups substituted with halogen, such as fluoro five-membered and five-membered rings, also such as

In one embodiment, when R ² Is C ₆ -C ₁₀ Aryl, substituted by one or more R ^2d Substituted C ₆ -C ₁₀ Aryl or-NR ⁶ C(＝O)-C ₆ -C ₁₀ Aryl group, wherein C ₆ -C ₁₀ Aryl is independently phenyl or naphthyl.

In one embodiment, when R ² Is a 5-10 membered heteroaryl or is substituted with one or more R ^2e When the 5-10 membered heteroaryl is substituted, the hetero atom in the 5-10 membered heteroaryl is independently selected from one or two of N and O, and the number of the hetero atom is independently 1 or 2.

In one embodiment, when R ^2a 、R ^2b 、R ^2c 、R ^2d Or R is ^2e When halogen, the halogen is independently F, cl, br or I, such as fluorine.

In one embodiment, when R ^2a 、R ^2b 、R ^2c 、R ^2d And R is ^2e Is C ₁ -C ₄ Alkyl, substituted by one or more R ^2-a Substituted C ₁ -C ₄ Alkyl, C ₁ -C ₄ alkyl-O-or by one or more R ^2-b Substituted C ₁ -C ₄ alkyl-O-, wherein C ₁ -C ₄ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

In one embodiment, when R ^2a 、R ^2b 、R ^2c 、R ^2d Or R is ^2e Is C ₂ -C ₄ Alkenyl, the C ₂ -C ₄ Alkenyl is independently ethenyl, propenyl, or butenyl.

In one embodiment, when R ^2a 、R ^2b 、R ^2c 、R ^2d Or R is ^2e Is C ₂ -C ₄ In the case of alkynyl, the said C ₂ -C ₄ Alkynyl is independently ethynyl, propynyl or butynyl.

In one embodiment, when R ^2a 、R ^2b 、R ^2c 、R ^2d Or R is ^2e Is (C) _l -C ₄ Alkyl) -C (=o) - (C) _l -C ₄ Alkyl) -SO ₂ -、(C _l -C ₄ Alkyl) -O- (C _l -C ₄ Alkyl) -O-, (C _l -C ₄ Alkyl) -O-C (=o) -NHCH ₂ -、(C _l -C ₄ Alkyl) -C (=o) NHCH ₂ -、(C _l -C ₄ Alkyl) -SO ₂ -NHCH ₂ -、(C _l -C ₄ Alkyl) -O- (C _l -C ₄ Alkyl) -NH-C (=o) -O-or phenyl- (C _l -C ₄ Alkyl) -NH-C (=o) -O-, wherein C ₁ -C ₄ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In one embodiment, when R ^2a 、R ^2b 、R ^2c 、R ^2d Or R is ^2e Is (4-10 membered heterocyclic) -C (=O) -OCH ₂ -, (4-10 membered heterocyclyl) -C (=o) -O-, or (4-10 membered heterocyclyl) -CH ₂ -wherein the heteroatoms in the 4-10 membered heterocyclyl are independently selected from one or both of N and O.

In one embodiment, when R ^2a 、R ^2b 、R ^2c 、R ^2d Or R is ^2e Is (4-10 membered heterocyclic) -C (=O) -OCH ₂ -, (4-10 membered heterocyclyl) -C (=o) -O-, or (4-10 membered heterocyclyl) -CH ₂ When the number of heteroatoms in the 4-10 membered heterocyclic group is 1 or 2, the number of heteroatoms in the heterocyclic group is 1 or 2.

In one embodiment, when R ^2a 、R ^2b 、R ^2c 、R ^2d Or R is ^2e Is (4-10 membered heterocyclic group))-C(＝O)-OCH ₂ -, (4-10 membered heterocyclyl) -C (=o) -O-, or (4-10 membered heterocyclyl) -CH ₂ When present, the 4-10 membered heterocyclic group may be a 4-7 membered heterocyclic group, such as a 6 membered heterocyclic group, for example

In one embodiment, when R ^2-a Or R is ^2-b When halogen, the halogen is independently F, cl, br or I, such as fluorine.

In one embodiment, when R ³ Is C ₆ -C ₁₀ Aryl or by one or more R ^3a Substituted C ₆ -C ₁₀ Aryl group, wherein C ₆ -C ₁₀ Aryl is independently phenyl or naphthyl, for example naphthyl.

In one embodiment, when R ³ Is a 5-10 membered heteroaryl or is substituted with one or more R ^3b And when the 5-10 membered heteroaryl is substituted, the heteroatom in the 5-10 membered heteroaryl is independently selected from one or two of N and O.

In one embodiment, when R ³ Is a 5-10 membered heteroaryl or is substituted with one or more R ^3b In the case of substituted 5-10 membered heteroaryl, the number of heteroatoms in the 5-10 membered heteroaryl is independently 1 or 2.

In one embodiment, when R ³ Is a 5-10 membered heteroaryl or is substituted with one or more R ^3b When substituted, a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is independently a 5-6 membered heteroaryl, such as pyridinyl.

In one embodiment, when R ^3a Or R is ^3b When halogen, the halogen is independently F, cl, br or I, such as fluorine.

In one embodiment, when R ^3a Or R is ^3b Is C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ alkyl-S-, substituted by one or more R ^3-a Substituted C ₁ -C ₆ Alkyl, substituted by one or more R ^3-b Substituted C ₁ -C ₆ alkyl-O-or by one or more R ^3-c Substituted C ₁ -C ₆ alkyl-S-, wherein C ₁ -C ₆ Alkyl is independently C _1-4 Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also, for example, methyl.

In one embodiment, when R ^3a Or R is ^3b Is C ₂ -C ₆ Alkenyl or by one or more R ^3-d Substituted C ₂ -C ₆ Alkenyl group, C therein ₂ -C ₆ Alkenyl groups are independently C ₂ -C ₄ Alkenyl is, for example, ethenyl, propenyl or butenyl.

In one embodiment, when R ^3a Or R is ^3b Is C ₂ -C ₆ Alkynyl or by one or more R ^3-e Substituted C ₂ -C ₆ Alkynyl group, C therein ₂ -C ₆ Alkynyl groups are independently C ₂ -C ₄ Alkynyl is, for example, ethynyl, propynyl or butynyl, and also, for example, ethynyl.

In one embodiment, when R ^3a Or R is ^3b Is 3-7 membered cycloalkyl or is substituted by one or more R ^3-f In the case of a substituted 3-7 membered cycloalkyl group, the 3-7 membered cycloalkyl group is independently a 3-6 membered cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In one embodiment, when R ^3-a 、R ^3-b 、R ^3-c 、R ^3-d 、R ^3-e Or R is ^3-f When halogen, the halogen is independently F, cl, br or I, such as fluorine.

In one embodiment, when R ^3-a 、R ^3-b 、R ^3-c 、R ^3-d 、R ^3-e Or R is ^3-f Is C ₁ -C ₄ Alkyl or C ₁ -C ₄ alkyl-O-, wherein C ₁ -C ₄ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In one embodiment, when R ^3-a 、R ^3-b 、R ^3-c 、R ^3-d 、R ^3-e Or R is ^3-f In the case of 3-7 membered cycloalkyl, the 3-7 membered cycloalkyl is independentlyAn in-situ 3-6 membered cycloalkyl group is, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In one embodiment, when R ^4b In the case of halogen, the halogen is F, cl, br or I, for example fluorine.

In one embodiment, when R ^4b Is C ₁ -C ₆ Alkyl, halogenated C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, deuterated C ₁ -C ₆ In the case of alkyl radicals, C therein ₁ -C ₆ Alkyl is C _1-4 Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In one embodiment, when R ^4b Is C ₂ -C ₆ Alkenyl, the C ₂ -C ₆ Alkenyl group is C ₂ -C ₄ Alkenyl is, for example, ethenyl, propenyl or butenyl.

In one embodiment, when R ^4b Is C ₂ -C ₆ In the case of alkynyl radicals, C ₂ -C ₆ Alkynyl is C ₂ -C ₄ Alkynyl is, for example, ethynyl, propynyl or butynyl.

In one embodiment, when R ⁵ When halogen, the halogen is independently F, cl, br or I, such as fluorine or chlorine.

In one embodiment, when R ⁵ Is C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ alkyl-S-, substituted by one or more R ^5a Substituted C ₁ -C ₆ Alkyl, substituted by one or more R ^5b Substituted C ₁ -C ₆ alkyl-O-or by one or more R ^5c Substituted C ₁ -C ₆ alkyl-S-, wherein C ₁ -C ₆ Alkyl is independently C _1-4 Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also, for example, methyl.

In one embodiment, when R ⁵ Is a 5-10 membered heteroaryl or is substituted with one or more R ^5d Substituted 5-10 membered heteroaryl, wherein 5-10 membered heteroaryl is substitutedThe hetero atoms in (a) are independently selected from one or two of N and O, and the number of the hetero atoms is independently 1 or 2.

In one embodiment, when R ^5a 、R ^5b 、R ^5c Or R is ^5d When halogen, the halogen is independently F, cl, br or I, such as fluorine.

In one embodiment, when R ^5a 、R ^5b 、R ^5c Or R is ^5d Is C ₁ -C ₄ Alkyl or C ₁ -C ₄ alkyl-O-, wherein C ₁ -C ₄ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In one embodiment, when R ^5a 、R ^5b 、R ^5c Or R is ^5d In the case of a 3-7 membered cycloalkyl group, the 3-7 membered cycloalkyl group is independently a 3-6 membered cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In one embodiment, when R ⁶ Is C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-or deuterated C ₁ -C ₆ In the case of alkyl radicals, C therein ₁ -C ₆ Alkyl is independently C _1-4 Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also, for example, methyl.

In one embodiment, when R ⁶ In the case of a 5-10 membered heteroaryl group, the heteroatoms in the 5-10 membered heteroaryl group are independently selected from one or two of N and O, and the number of the heteroatoms is independently 1 or 2.

In one embodiment, when R ⁷ Is C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-or deuterated C ₁ -C ₆ In the case of alkyl radicals, C therein ₁ -C ₆ Alkyl is independently C _1-4 Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In one embodiment, when R ⁷ In the case of a 5-10 membered heteroaryl, the heteroatom in the 5-10 membered heteroaryl is independently selected from one or both of N and OThe number of heteroatoms is independently 1 or 2.

In one embodiment, when two R's on a ring atom ⁷ When forming a 3-7 membered cycloalkyl group together with the ring atom to which it is attached, the 3-7 membered cycloalkyl group is independently a 3-6 membered cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In one embodiment, when two R's on a ring atom ⁷ When forming a 3-7 membered heterocyclic group together with the ring atom to which it is attached, the hetero atom in the 3-7 membered heterocyclic group is independently selected from one or both of N and O, and the number of hetero atoms is independently 1 or 2.

In one embodiment, the pharmaceutically acceptable salt may be trifluoroacetate, hydrochloride or formate.

In one embodiment, X ₁ is-CR ⁵ -or-N-;

Y ¹ is-O-, -S-, -NR ⁶ -、-S(O) ₂ -、-SO-、-NR ⁶ C (=o) -, -C (=o) O-, or- (CR) ⁷ R ⁷ ) _p1 ；

p1, p2, p3, p4 and p5 are each independently 0, 1, 2 or 3;

each R ¹ Each independently is deuterium, halogen, -OH, -CN, -N (R) ⁶ ) ₂ 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, substituted by one or more R ^1a Substituted C ₁ -C ₆ Alkyl or by one or more R ^1b Substituted C ₁ -C ₆ alkyl-O-;

alternatively, two R's on the same ring carbon atom ¹ Forming a 4-10 membered heterocyclic group or by one or more R ^1d Substituted 4-10 memberedA heterocyclic group; said 4-10 membered heterocyclyl and is substituted with one or more R ^1d The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or more of N, O and S, and the number of the hetero atom is independently 1, 2 or 3;

n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;

each R ^1a 、R ^1b And R is ^1d Each independently is-CN, halogen, oxo (= O), C ₁ -C ₆ Alkyl or-N (R) ⁶ ) ₂ ；

L is-O- (CR) ⁷ R ⁷ ) _n1 -；

n1 is 0, 1, 2 or 3; (when 0, represents a bond);

R ² is 4-10 membered heterocyclyl, 3-7 membered cycloalkyl, substituted with one or more R ^2a Substituted 3-7 membered cycloalkyl or by one or more R ^2c Substituted 4-10 membered heterocyclyl; said 4-10 membered heterocyclyl and is substituted with one or more R ^2c The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or more of N, O and S, and the number of the hetero atom is independently 1, 2 or 3;

each R ^2a And R is ^2c Each independently is halogen, -OH, deuterium, -CN, -N (R) ⁶ ) ₂ Or (4-10 membered heterocyclyl) -CH ₂ -; the (4-10 membered heterocyclic) -CH ₂ The heteroatoms in the 4-10 membered heterocyclic groups are independently selected from one or more of N, O and S, and the number of the heteroatoms is independently 1, 2 or 3;

R ³ is C ₆ -C ₁₀ Aryl, substituted by one or more R ^3a Substituted C ₆ -C ₁₀ Aryl, 5-to 10-membered heteroaryl, or substituted with one or more R ^3b Substituted 5-10 membered heteroaryl; the 5-10 membered heteroaryl and is substituted with one or more R ^3b The hetero atom in the 5-10 membered heteroaryl group in the substituted 5-10 membered heteroaryl group is independently selected from one or more of N, O and S, and the number of the hetero atom is independently 1, 2 or 3;

Each R ^3a And R is ^3b Each independently is halogen, -OH,-CN、C ₁ -C ₆ Alkyl, substituted by one or more R ^3-a Substituted C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, substituted by one or more R ^3-e Substituted C ₂ -C ₆ Alkynyl or-N (R) ⁶ ) ₂ ；

Each R ^3-a And R is ^3-e Each independently deuterium, halogen or-CN;

R ^4b is independently H, deuterium, -N (R) ⁶ ) ₂ Or halogen;

R ⁵ is hydrogen, halogen or C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ alkyl-S-, substituted by one or more R ^5a Substituted C ₁ -C ₆ Alkyl, substituted by one or more R ^5b Substituted C ₁ -C ₆ alkyl-O-or by one or more R ^5c Substituted C ₁ -C ₆ alkyl-S-;

each R ^5a 、R ^5b And R is ^5c Each independently deuterium, halogen, -CN, or-OH;

each R ⁶ Each independently is hydrogen, C ₁ -C ₆ Alkyl or deuterated C ₁ -C ₆ An alkyl group;

each R ⁷ Each independently is hydrogen or C ₁ -C ₆ An alkyl group.

In one embodiment, X ₁ is-CR ⁵ -or-N-;

Y ¹ is-O-, -S-, -NR ⁶ -、-S(O) ₂ -、-SO-、-NR ⁶ C (=o) - (carbonyl and Y ² Linked), -C (=o) -, -C (=o) O- (oxygen and Y) ² Linked) or- (CR) ⁷ R ⁷ ) _p1 ；

Y ² Is- (CR) ⁷ R ⁷ ) _p2 -、-NR ⁶ -、-C(＝O)(CR ⁷ R ⁷ ) _p3 - (carbonyl and Y) ¹ To be connected), O (CR) ⁷ R ⁷ ) _p4 (carbonyl and Y) ¹ Linked) -or-NR ⁶ (CR ⁷ R ⁷ ) _p5 - (N and Y) ¹ Connected with each other);

p1 is 0 or 1; p2 is 1 or 2; p3 is 0, 1 or 2; p4 is 1 or 2; p5 is 1 or 2;

each R ¹ Each independently is halogen, -OH, -N (R) ⁶ ) ₂ Or C ₁ -C ₆ An alkyl group;

Alternatively, two R's on the same ring carbon atom ¹ Forming a 4-10 membered heterocyclic group or by one or more R ^1d Substituted 4-10 membered heterocyclyl; said 4-10 membered heterocyclyl and is substituted with one or more R ^1d The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or more of N, O and S, and the number of the hetero atom is independently 1, 2 or 3;

n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;

each R ^1d Each independently is oxo (=o), C ₁ -C ₆ Alkyl or-N (R) ⁶ ) ₂ ；

L is-O- (CR) ⁷ R ⁷ ) _n1 -；

n1 is 0, 1, 2 or 3; (when 0, represents a bond);

each R ^2a And R is ^2c Each independently is halogen, -OH, -N (R) ⁶ ) ₂ Or (4-10 membered heterocyclyl) -CH ₂ -; the (4-10 membered heterocyclic) -CH ₂ The hetero atom in the "4-10 membered heterocyclic group" in the formula is independently selected from one or two of N and O, and the number of the hetero atom is independently 1 or 2;

R ³ Is C ₆ -C ₁₀ Aryl, substituted by one or more R ^3a Substituted C ₆ -C ₁₀ Aryl, 5-to 10-membered heteroaryl, or substituted with one or more R ^3b Substituted 5-10 membered heteroaryl; the 5-10 membered heteroaryl and is substituted with one or more R ^3b The heteroatoms in the "5-10 membered heteroaryl" in the substituted 5-10 membered heteroaryl are independently N, O or S, the number of heteroatoms being independently 1, 2 or 3;

each R ^3a And R is ^3b Each independently is halogen, -OH, C ₁ -C ₆ Alkyl, substituted by one or more R ^3-a Substituted C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, substituted by one or more R ^3-e Substituted C ₂ -C ₆ Alkynyl or-N (R) ⁶ ) ₂ ；

Each R ^3-a And R is ^3-e Each independently is halogen;

R ^4b is H, deuterium, -N (R) ⁶ ) ₂ Or halogen;

R ⁵ is hydrogen, halogen or C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-S-, substituted by one or more R ^5a Substituted C ₁ -C ₆ Alkyl or by one or more R ^5c Substituted C ₁ -C ₆ alkyl-S-;

each R ^5a And R is ^5c Each independently is halogen;

each R ⁶ Each independently is hydrogen or C ₁ -C ₆ An alkyl group;

each R ⁷ Independently hydrogen or C ₁ -C ₆ An alkyl group.

In one embodiment, X ₁ is-CR ⁵ -or-N-;

Y ₁ is-O-;

Y ₂ is- (CR) ⁷ R ⁷ ) _p2 -；

p2 is 1 or 2;

each R ¹ Each independently deuterium, halogen, -OH, oxo (= O), -N (R) ⁶ ) ₂ 、C ₁ -C ₆ Alkyl or is oneOr a plurality of R ^1a Substituted C ₁ -C ₆ An alkyl group;

alternatively, two R's on the same ring carbon atom ¹ Forming a 4-10 membered heterocyclic group or by one or more R ^1d Substituted 4-10 membered heterocyclyl; said 4-10 membered heterocyclyl and is substituted with one or more R ^1d The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or two of N and O, and the number of the hetero atom is independently 1, 2 or 3;

n is 0, 1, 2, 3, 4, 5 or 6;

each R ^1d Each independently is oxo (=o) or C ₁ -C ₆ An alkyl group;

l is-O- (CR) ⁷ R ⁷ ) _n1 -；

n1 is 1 or 2;

R ² is 4-10 membered heterocyclyl, substituted with one or more R ^2a Substituted 3-7 membered cycloalkyl or by one or more R ^2c Substituted 4-10 membered heterocyclyl; said 4-10 membered heterocyclyl and is substituted with one or more R ^2c The hetero atoms in the "4-10 membered heterocyclic group" in the substituted 4-10 membered heterocyclic group are independently N, and the number of the hetero atoms is independently 1;

each R ^2a And R is ^2c Independently halogen, -N (R) ⁶ ) ₂ Or (4-10 membered heterocyclyl) -CH ₂ -; the (4-10 membered heterocyclic) -CH ₂ The hetero atom in the "4-10 membered heterocyclic group" in the formula is independently selected from one or two of N and O, and the number of the hetero atom is independently 1 or 2;

Each R ^3a And R is ^3b Independently halogen, -OH, -CN, C ₁ -C ₆ Alkyl groupIs/are R ^3-a Substituted C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, substituted by one or more R ^3-e Substituted C ₂ -C ₆ Alkynyl or-N (R) ⁶ ) ₂ ；

R ^4b Is H or halogen;

each R ^5a And R is ^5c Each independently deuterium or halogen;

each R ⁶ Each independently is hydrogen or C ₁ -C ₆ An alkyl group;

each R ⁷ Independently hydrogen or C ₁ -C ₆ An alkyl group.

In one embodiment, R ⁵ Is hydrogen, halogen or C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ alkyl-S-, substituted by one or more R ^5a Substituted C ₁ -C ₆ Alkyl, substituted by one or more R ^5b Substituted C ₁ -C ₆ alkyl-O-or by one or more R ^5c Substituted C ₁ -C ₆ alkyl-S-.

In one embodiment, each R ^5a 、R ^5b And R is ^5c Each independently is deuterium, halogen, -CN or-OH.

In one embodiment, R ⁵ Is hydrogen, halogen or C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-S-, substituted by one or more R ^5a Substituted C ₁ -C ₆ Alkyl or by one or more R ^5c Substituted C ₁ -C ₆ alkyl-S-.

In one embodiment, each R ^5a And R is ^5c Each independently deuterium or halogen.

In one embodiment, each R ^5a And R is ^5c Each independently is halogen.

In one embodiment, X ¹ is-N-.

In one embodiment, Y ¹ is-O-, -S-, -NR ⁶ -、-S(O) ₂ -、-SO-、-NR ⁶ C (=o) -, -C (=o) O-, or- (CR) ⁷ R ⁷ ) _p1 。

In one embodiment, each R ⁶ Each independently is hydrogen, C ₁ -C ₆ Alkyl or deuterated C ₁ -C ₆ An alkyl group.

In one embodiment, each R ⁶ Each independently is hydrogen or C ₁ -C ₆ An alkyl group.

In one embodiment, each R ⁷ Independently hydrogen or C ₁ -C ₆ An alkyl group.

In one embodiment, each R ⁷ Is hydrogen.

In one embodiment, Y ¹ is-O-, -S-, -NR ⁶ -、-S(O) ₂ -、-SO-、-NR ⁶ C (=o) - (carbonyl and Y ² Linked), -C (=o) -, -C (=o) O- (oxygen and Y) ² Linked) or- (CR) ⁷ R ⁷ ) _p1 。

In one embodiment, Y ₁ is-O-.

In one embodiment, Y ² Is- (CR) ⁷ R ⁷ ) _p2 -、-NR ⁶ -、-C(＝O)(CR ⁷ R ⁷ ) _p3 - (carbonyl and Y) ¹ To be connected), O (CR) ⁷ R ⁷ ) _p4 (carbonyl and Y) ¹ Linked) -or-NR ⁶ (CR ⁷ R ⁷ ) _p5 - (N and Y) ¹ Connected).

In one embodiment, Y ₂ Is- (CR) ⁷ R ⁷ ) _p2 -。

In one embodiment, p1 is 0 or 1.

In one embodiment, p2 is 1 or 2.

In one embodiment, p2 is 1.

In one embodiment, p3 is 0, 1 or 2.

In one embodiment, p4 is 1 or 2.

In one embodiment, p5 is 1 or 2.

In one embodiment, each R ¹ Each independently is deuterium, halogen, -OH, -CN, -N (R) ⁶ ) ₂ 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, substituted by one or more R ^1a Substituted C ₁ -C ₆ Alkyl or by one or more R ^1b Substituted C ₁ -C ₆ alkyl-O-;

alternatively, two R's on the same ring carbon atom ¹ Forming a 4-10 membered heterocyclic group or by one or more R ^1d Substituted 4-10 membered heterocyclyl; said 4-10 membered heterocyclyl and is substituted with one or more R ^1d The hetero atom in the "4-10 membered heterocyclic group" in the substituted 4-10 membered heterocyclic group is independently selected from one or more of N, O and S, and the number of the hetero atom is independently 1, 2 or 3.

In one embodiment, each R ^1a 、R ^1b And R is ^1d Each independently is-CN, halogen, oxo (= O), C ₁ -C ₆ Alkyl or-N (R) ⁶ ) ₂ 。

In one embodiment, each R ¹ Each independently is halogen, -OH, -N (R) ⁶ ) ₂ Or C ₁ -C ₆ An alkyl group;

alternatively, two R's on the same ring carbon atom ¹ Forming a 4-10 membered heterocyclic group or by one or more R ^1d Substituted 4-10 membered heterocyclyl; said 4-10 membered heterocyclyl and is substituted with one or more R ^1d The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or two of N and O, and the number of the hetero atom is independently 1, 2 or 3.

In one embodiment, each R ^1d Each independently is oxo (=o), C ₁ -C ₆ Alkyl or-N (R) ⁶ ) ₂ 。

In one embodiment, each R ¹ Each independently deuterium, halogen, -OH, oxo (= O), -N (R) ⁶ ) ₂ 、C ₁ -C ₆ Alkyl or by one or more R ^1a Substituted C ₁ -C ₆ An alkyl group;

In one embodiment, each R ¹ independently-OH, C ₁ -C ₆ Alkyl or by one or more R ^1a Substituted C ₁ -C ₆ An alkyl group;

In one embodiment, each R ¹ independently-OH, C ₁ -C ₆ Alkyl or by one or more R ^1a Substituted C ₁ -C ₆ An alkyl group.

In one embodiment, each R ¹ independently-OH or C ₁ -C ₆ An alkyl group.

In one embodiment, two R's on the same ring carbon atom ¹ Forming a 4-10 membered heterocyclic group or by one or more R ^1d Substituted 4-10 membered heterocyclyl; said 4-10 membered heterocyclyl and is substituted with one or more R ^1d The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or two of N and O, and the number of the hetero atom is independently 1, 2 or 3.

In one embodiment, two R's on the same ring carbon atom ¹ Formed by one or more R ^1d Substituted 4-10 membered heterocyclyl; said quilt being one or more R' s ^1d "4-10 membered in substituted 4-10 membered heterocyclylThe hetero atom in the heterocyclic group is independently selected from one or two of N and O, and the number of the hetero atom is independently 1, 2 or 3.

In one embodiment, each R ^1d Each independently is oxo (=o) or C ₁ -C ₆ An alkyl group.

In one embodiment, each R ^1d Is oxo (=o).

In one embodiment, each R ^1a Deuterium, -CN, or halogen independently.

In one embodiment, n is 0, 1, 2, 3, 4, 5, or 6.

In one embodiment, n is 1 or 2.

In one embodiment, n is 2.

In one embodiment, L is-O- (CR) ⁷ R ⁷ ) _n1 -。

In one embodiment, n1 is 1 or 2.

In one embodiment, n1 is 1.

In one embodiment, R ² Is 4-10 membered heterocyclyl, 3-7 membered cycloalkyl, substituted with one or more R ^2a Substituted 3-7 membered cycloalkyl or by one or more R ^2c Substituted 4-10 membered heterocyclyl; said 4-10 membered heterocyclyl and is substituted with one or more R ^2c The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is one or more selected from N, O and S, and the number of the hetero atom is 1, 2 or 3.

In one embodiment, each R ^2a And R is ^2c Each independently is halogen, -OH, deuterium, -CN, -N (R) ⁶ ) ₂ Or (4-10 membered heterocyclyl) -CH ₂ -, the (4-10 membered heterocyclic) -CH ₂ The hetero atom in the "4-10 membered heterocyclic group" in the above is independently selected from one or more of N, O and S, and the number of the hetero atom is independently 1, 2 or 3.

In one embodiment, R ² Is 4-10 membered heterocyclyl, 3-7 membered cycloalkyl, substituted with one or more R ^2a Substituted 3-7 membered cycloalkyl or by one or more R ^2c Substituted 4-10 membered heterocyclyl; said 4-10 membered heterocyclyl and is substituted with one or more R ^2c Substituted 4-10 membered heterogeniesThe hetero atom in the "4-10 membered heterocyclic group" in the ring group is independently selected from one or two of N and O, and the number of the hetero atom is independently 1, 2 or 3.

In one embodiment, each R ^2a And R is ^2c Each independently is halogen, -OH, -N (R) ⁶ ) ₂ Or (4-10 membered heterocyclyl) -CH ₂ -; the (4-10 membered heterocyclic) -CH ₂ The hetero atom in the "4-10 membered heterocyclic group" in the above is independently selected from one or both of N and O, and the number of the hetero atom is independently 1 or 2.

In one embodiment, R ² Is 4-10 membered heterocyclyl, substituted with one or more R ^2a Substituted 3-7 membered cycloalkyl or by one or more R ^2c Substituted 4-10 membered heterocyclyl; said 4-10 membered heterocyclyl and is substituted with one or more R ^2c The hetero atoms in the "4-10 membered heterocyclic group" in the substituted 4-10 membered heterocyclic group are independently N, and the number of the hetero atoms is independently 1.

In one embodiment, each R ^2a And R is ^2c Independently halogen, -N (R) ⁶ ) ₂ Or (4-10 membered heterocyclyl) -CH ₂ -; the (4-10 membered heterocyclic) -CH ₂ The hetero atoms in the 4-10 membered heterocyclic group are independently selected from one or two of N and O, and the number of the hetero atoms is independently 1 or 2.

In one embodiment, R ² Is 4-10 membered heterocyclyl or substituted with one or more R ^2c Substituted 4-10 membered heterocyclyl; said 4-10 membered heterocyclyl and is substituted with one or more R ^2c The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or two of N and O, and the number of the hetero atom is independently 1, 2 or 3.

In one embodiment, R ² Is 4-10 membered heterocyclyl or substituted with one or more R ^2c Substituted 4-10 membered heterocyclyl; said 4-10 membered heterocyclyl and is substituted with one or more R ^2c The hetero atom in the "4-10 membered heterocyclic group" in the substituted 4-10 membered heterocyclic group is independently N, and the number of hetero atoms is 1.

In one embodiment, R ² To be covered by one or more R ^2c Substituted 4-10 membered heterocyclyl; said quilt(s)R is a number of ^2c The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or two of N and O, and the number of the hetero atom is independently 1, 2 or 3.

In one embodiment, R ² To be covered by one or more R ^2c Substituted 4-10 membered heterocyclyl; said quilt being one or more R' s ^2c The hetero atom in the "4-10 membered heterocyclic group" in the substituted 4-10 membered heterocyclic group is independently N, and the number of hetero atoms is 1.

In one embodiment, each R ^2c Independently halogen.

In one embodiment, each R ^3a And R is ^3b Each independently is halogen, -OH, -CN, C ₁ -C ₆ Alkyl, substituted by one or more R ^3-a Substituted C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, substituted by one or more R ^3-e Substituted C ₂ -C ₆ Alkynyl or-N (R) ⁶ ) ₂ 。

In one embodiment, each R ^3-a And R is ^3-e Each independently deuterium, halogen or-CN.

In one embodiment, R ³ Is C ₆ -C ₁₀ Aryl, substituted by one or more R ^3a Substituted C ₆ -C ₁₀ Aryl, 5-to 10-membered heteroaryl, or substituted with one or more R ^3b Substituted 5-10 membered heteroaryl; the 5-10 membered heteroaryl and is substituted with one or more R ^3b The heteroatoms in the "5-10 membered heteroaryl" in the substituted 5-10 membered heteroaryl are independently N, O or S, and the number of heteroatoms is independently 1, 2 or 3.

In one embodiment, each R ^3a And R is ^3b Each independently is halogen, -OH, C ₁ -C ₆ Alkyl, substituted by one or more R ^3-a Substituted C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, substituted by one or more R ^3-e Substituted C ₂ -C ₆ Alkynyl or-N (R) ⁶ ) ₂ 。

In one embodiment, R ³ Is C ₆ -C ₁₀ Aryl or by one or more R ^3a Substituted C ₆ -C ₁₀ Aryl groups.

In one embodiment, R ³ To be covered by one or more R ^3a Substituted C ₆ -C ₁₀ Aryl groups.

In one embodiment, each R ^3a Each independently is halogen, -OH, C ₂ -C ₆ Alkynyl or by one or more R ^3-e Substituted C ₂ -C ₆ Alkynyl groups.

In one embodiment, each R ^3a Each independently is halogen, -OH or C ₂ -C ₆ Alkynyl groups.

In one embodiment, each R ^3-a And R is ^3-e Each independently is halogen.

In one embodiment, R ^4b Is H, deuterium, -N (R) ⁶ ) ₂ Or halogen.

In one embodiment, R ^4b Is H or halogen.

In one embodiment, R ^4b Is halogen.

In one embodiment, X ¹ is-N-, -CF-, -CCl-, -CS (CF) ₃ ) -or-C (CF) ₃ )-。

In one embodiment, Y ¹ is-O-, -NH-, -NCH ₃ -、-S-、-S(O) ₂ -、-CH ₂ -C (=o) O-, -C (=o) NH-, or-C (=o) -.

In one embodiment, Y ² is-CH ₂ -、-C(＝O)-、-OCH ₂ -、-NHCH ₂ -、-N(CH ₃ )CH ₂ -、-C(＝O)-CH ₂ -、-CH ₂ CH ₂ -。

In one embodiment, Y ¹ And Y ² Forming-ch=ch-.

In one embodiment, -Y ¹ -Y ² -is

For example

The end a is connected with the aromatic ring, and the end b is connected with the non-aromatic ring.

In one embodiment, each R ¹ Each independently is fluorine, -OH, methyl, -NH ₂ Or, alternatively, two R's on the same ring carbon atom ¹ Formation of

In one embodiment, L is-OCH ₂ -。

In one embodiment, R ² Is that

In one embodiment, R ³ Is that

In one embodiment, R ^4b Is fluorine.

In one aspect of the present invention,is->

In one embodiment, X ¹ is-N-;

Y ¹ is-O-;

Y ² is- (CR) ⁷ R ⁷ ) _p2 -；

p2 is 1 or 2;

each R ⁷ Independently hydrogen or C ₁ -C ₆ An alkyl group;

each R ¹ independently-OH, C ₁ -C ₆ Alkyl or by one or more R ^1a Substituted C ₁ -C ₆ An alkyl group;

each R ^1a Deuterium, -CN, or halogen independently;

n is 1 or 2;

l is-O- (CR) ⁷ R ⁷ ) _n1 -；

n1 is 1 or 2;

R ² is 4-10 membered heterocyclyl or substituted with one or more R ^2c Substituted 4-10 membered heterocyclyl; said 4-10 membered heterocyclyl and is substituted with one or more R ^2c The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or two of N and O, and the number of the hetero atom is independently 1, 2 or 3;

each R ^2c Independently halogen;

R ³ is C ₆ -C ₁₀ Aryl or by one or more R ^3a Substituted C ₆ -C ₁₀ An aryl group;

each R ^3a Independently halogen, -OH, C ₂ -C ₆ Alkynyl or by one or more R ^3-e Substituted C ₂ -C ₆ Alkynyl;

each R ^3-e Independently halogen;

R ^4b is halogen.

In one embodiment, X ¹ is-N-;

Y ¹ is-O-;

Y ² is- (CR) ⁷ R ⁷ ) _p2 -；

p2 is 1 or 2;

each R ⁷ Independently hydrogen;

each R ¹ independently-OH or C ₁ -C ₆ An alkyl group;

n is 1 or 2;

l is-O- (CR) ⁷ R ⁷ ) _n1 -；

n1 is 1 or 2;

R ² to be covered by one or more R ^2c Substituted 4-10 membered heterocyclyl; said quilt being one or more R' s ^2c The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or two of N and O, and the number of the hetero atom is independently 1, 2 or 3;

each R ^2c Independently halogen;

R ³ to be covered by one or more R ^3a Substituted C ₆ -C ₁₀ An aryl group;

each R ^3a Independently halogen, -OH or C ₂ -C ₆ Alkynyl;

R ^4b is halogen.

In one embodiment, X ¹ is-N-;

Y ¹ is-O-;

Y ² is- (CR) ⁷ R ⁷ ) _p2 -；

p2 is 1 or 2;

each R ⁷ Independently hydrogen or C ₁ -C ₆ An alkyl group;

two R's on the same ring carbon atom ¹ Forming a 4-10 membered heterocyclic group or by one or more R ^1d Substituted 4-10 membered heterocyclyl; said 4-10 membered heterocyclyl and is substituted with one or more R ^1d The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or two of N and O, and the number of the hetero atom is independently 1, 2 or 3;

each R ^1d Independently oxo (= O) or C ₁ -C ₆ An alkyl group;

n is 2;

l is-O- (CR) ⁷ R ⁷ ) _n1 -; n1 is 1 or 2;

Each R ^2c Independently halogen;

each R ^3-e Independently halogen;

R ^4b is halogen.

In one embodiment, X ¹ is-N-;

Y ¹ is-O-;

Y ² is- (CR) ⁷ R ⁷ ) _p2 -；

p2 is 1 or 2;

each R ⁷ Independently hydrogen;

two R's on the same ring carbon atom ¹ Formed by one or more R ^1d Substituted 4-10 membered heterocyclyl; said quilt being one or more R' s ^1d The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or two of N and O, and the number of the hetero atom is independently 1, 2 or 3;

each R ^1d Independently oxo (=o);

n is 2;

l is-O- (CR) ⁷ R ⁷ ) _n1 -; n1 is 1 or 2;

each R ^2c Independently halogen;

each R ^3a Independently halogen, -OH or C ₂ -C ₆ Alkynyl;

R ^4b is halogen.

In a certain scheme, the tetraheterocyclic compound shown in the formula I is any one of the following compounds:

The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of substance a and a pharmaceutical adjuvant; the substance A is the tetraheterocyclic compound shown in the formula I, the stereoisomer or the pharmaceutically acceptable salt thereof.

The invention also provides application of a substance A in preparing an RAS inhibitor, wherein the substance A is the tetraheterocycle compound shown in the formula I, a stereoisomer or a pharmaceutically acceptable salt thereof.

In such applications, the RAS inhibitor may be used in mammalian organisms; it is also useful in vitro, mainly as an experimental use, for example: the kit can be used as a standard sample or a control sample for comparison or prepared according to a conventional method in the field, and can be used for rapidly detecting the RAS inhibition effect.

The invention also provides the use of substance a in the manufacture of a medicament for the treatment and/or prophylaxis of a RAS mediated disease; RAS mediated diseases such as cancer as described above; the substance A is the tetraheterocyclic compound shown in the formula I, a stereoisomer or a pharmaceutically acceptable salt thereof; the substance a may be in a therapeutically effective amount.

The invention also provides an application of the substance A in preparing medicines for treating and/or preventing cancers; the substance A is the tetraheterocyclic compound shown in the formula I, a stereoisomer or a pharmaceutically acceptable salt thereof; the substance a may be in a therapeutically effective amount.

The present invention also provides a method of inhibiting RAS comprising administering a therapeutically effective amount of substance a to a patient; the substance A is the tetraheterocyclic compound shown in the formula I, the stereoisomer or the pharmaceutically acceptable salt thereof.

The present invention also provides a method of treating and/or preventing a RAS-mediated disease comprising administering a therapeutically effective amount of substance a to a patient; the substance A is the tetraheterocyclic compound shown in the formula I, the stereoisomer or the pharmaceutically acceptable salt thereof.

The present invention also provides a method of treating and/or preventing cancer comprising administering to a patient a therapeutically effective amount of substance a; the substance A is the tetraheterocyclic compound shown in the formula I, the stereoisomer or the pharmaceutically acceptable salt thereof.

RAS may be KRAS or KRAS mutations as described above; such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61H, KRAS Q61K or KRAS Q61R.

RAS may be KRAS mutant as described above; such as KRAS G12C or KRAS G12D.

As noted above, the cancer may be associated with at least one of KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12R, KRAS G13C, KRAS G13D, KRAS Q61H, KRAS Q61K, and KRAS Q61R, e.g., KRAS G12C, KRAS G12D, or KRAS G12V.

The cancer may be selected from one or more of breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, kidney cancer, head, neck cancer, bone cancer, skin cancer, liver cancer, colorectal cancer, rectal cancer, colon cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia, melanoma and pancreatic cancer as described above; the lung cancer may be non-small cell lung cancer or small cell lung cancer.

The disease as described above may be selected from one or more of breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, kidney cancer, head, neck cancer, bone cancer, skin cancer, liver cancer, colorectal cancer, rectal cancer, colon cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia, melanoma and pancreatic cancer; the lung cancer may be non-small cell lung cancer or small cell lung cancer.

The amount of substance a used in the applications and methods described above is a therapeutically effective amount.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

The term "-" means that the group is attached to the remainder of the molecule through the site. For example, CH3-C (=o) -refers to acetyl.

TerminologyIt is meant that the structural fragment is attached to the remainder of the molecule through this site.

The term "plurality" refers to 2, 3, 4, or 5.

The term "pharmaceutically acceptable" refers to those compositions which are relatively non-toxic, safe, and suitable for use by a patient.

The term "pharmaceutically acceptable salt" refers to a salt of a compound that is obtained by reaction with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, the base addition salt may be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, diethanolamine salt. When the compound contains a relatively basic functional group, the acid addition salt may be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids, organic acids (e.g., trifluoroacetic acid, hydrochloric acid, formic acid). See for example Handbook of Pharmaceutical Salts Properties, selection, and Use (P.Heinrich Stahl, camille G.Wermuth,2011,2nd Revised Edition), for example formate.

The term "pharmaceutical excipients" refers to all substances contained in a pharmaceutical formulation, except the active pharmaceutical ingredient, generally divided into two major classes, excipients and additives. See for details the pharmacopoeia of the people's republic of China (2020 Edition), handbook of Pharmaceutical Excipients (Paul J Shreskey, bruno C Hancock, gary P Moss, david J Goldfarb,2020,9th Edition).

The term "treatment" refers to the elimination of etiology or alleviation of symptoms.

The term "preventing" refers to reducing the risk of developing a disease.

The term "patient" refers to any animal, typically a mammal, such as a human, in need of treatment or prevention of a disease. Mammals include, but are not limited to: cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

The term "therapeutically effective amount" refers to an amount of a compound administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted as appropriate by one skilled in the art.

The expression "group B substituted with one or more groups a" means that one or more hydrogen atoms in group B are independently replaced by group a. When a plurality of A groups are present at the same time, their definitions are independent of each other and do not affect each other unless specifically stated otherwise.

When a substituent is not directly attached to a ring, it means that the substituent may be attached at any position on the ring, e.gRepresenting each R ¹ Any position on the ring carbon atoms may be independently attached.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "oxo" refers to =o, an oxygen atom replacing two hydrogens on the same atom, e.g., methylene (- (CH) ₂ (-) is carbonyl (-C (=o) -) after oxo.

The term "alkyl" refers to a straight or branched, saturated monovalent hydrocarbon radical having the indicated number of carbon atoms. For example, C ₁ -C ₆ Alkyl (C) _1-6 Alkyl) or C ₄ -C ₂₀ Alkyl (C) _4-20 Alkyl), preferably C ₁ -C ₄ Alkyl (C) _1-4 Alkyl) or C ₉ -C ₁₅ Alkyl (C) _1-6 Alkyl). Alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-nonyl, n-pentadecyl, and the like.

In the term "alkyl-O-", alkyl is defined as above. Examples of alkyl-O-groups are C ₁ -C ₆ alkyl-O-or C ₁ -C ₄ alkyl-O-, more for example: CH (CH) ₃ -O-、CH ₃ CH ₂ -O-、CH ₃ CH ₂ CH ₂ -O-or CH ₃ CH(CH ₃ ) -O-, etc. Likewise, the definition of Rx for the remaining "Rx-O-" forms in this application is stated for each of its corresponding definitions, e.g., the definition of "cycloalkyl-O-" and "cycloalkyl" is stated below.

The term "alkenyl" refers to a straight or branched hydrocarbon chain radical having at least one double bond, consisting of only carbon and hydrogen atoms, having, for example, 2 to 6 (preferably 2 to 4) carbon atoms, and linked to the remainder of the molecule by a single bond, examples of alkenyl include, but are not limited to, ethenyl, propenyl, or allyl.

The term "alkynyl" refers to a straight or branched hydrocarbon chain radical having at least one triple bond, consisting of only carbon and hydrogen atoms, having, for example, 2 to 4 carbon atoms, and linked to the remainder of the molecule by a single bond, examples of alkynyl include, but are not limited to

The term "heteroaryl" refers to a cyclic, unsaturated monovalent group of a specified number of ring atoms (e.g., 5-10 or 5-6 members), of a specified number of heteroatoms (e.g., 1, 2, or 3), of a specified heteroatom species (one or more of N, O and S), which has aromaticity.

The term "heterocyclyl" refers to a specified heteroatom species or heteroatom group (N, O, S, S (=o) and S (=o) having a specified number of ring atoms (e.g., 4-12, 4-10, 3-7, 6-10, 4-7, 5-6) ₂ One or more of them) or a partially unsaturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more bridged, fused or spiro ring system) heterocyclic group, e.g., is

The term "cycloalkyl" means a saturated carbocyclic substituent, and which may be attached to the remainder of the molecule by a single bond via any suitable carbon atom; c having 3 to 7 carbon atoms ₃ -C ₇ Cycloalkyl, preferably C having 3 to 6 carbon atoms ₃ -C ₆ Cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "aryl" refers to a compound having a specified number of carbon atoms (e.g., C ₆ -C ₁₀ ) A cyclic, unsaturated monovalent hydrocarbon group. Examples of aryl groups include, but are not limited to: phenyl or naphthyl.

The term "cycloalkenyl" refers to a carbocyclic ring having at least one double bond, and which may be attached to the remainder of the molecule (e.g., a 3-7 membered cycloalkenyl) by a single bond via any suitable carbon atom, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.

In the term "alkyl-S-", alkyl is defined as above. Examples of alkyl-S-groups are C ₁ -C ₆ alkyl-S-, C _1-6 alkyl-S-, C _1-4 alkyl-S-or C ₁ -C ₄ alkyl-S-, more for example: CH (CH) ₃ -S-、CH ₃ CH ₂ -S-、CH ₃ CH ₂ CH ₂ -S-or CH ₃ CH(CH ₃ ) -S-, etc. Likewise, the remaining "Rx-S-" forms are herein defined as Rx, respectivelyThe definition of cycloalkyl is described, for example, "cycloalkyl-S-" and the definition of cycloalkyl is described below as "cycloalkyl".

The term "heteroaryl" refers to a cyclic, unsaturated monovalent group of a specified number of ring atoms (e.g., 5-10 membered, 5-6 membered), of a specified number of heteroatoms (e.g., 1, 2, or 3), of a specified heteroatom species (one or more of N, O and S), which is monocyclic or polycyclic, (at least one ring per ring) having aromaticity. Heteroaryl groups are attached to the remainder of the molecule through a carbon atom or heteroatom; heteroaryl groups are attached to the remainder of the molecule through a ring with a heteroatom or a ring without a heteroatom; heteroaryl groups are attached to the remainder of the molecule through rings that are aromatic or rings that are not aromatic. Heteroaryl groups include, but are not limited to: pyridyl, pyrazolyl, and the like.

The reagents and materials used in the present invention are commercially available.

The invention has the positive progress effects that: the compounds of the invention have inhibitory activity against proliferation of one or more of cells Ba/F3 KRAS G12C, ba/F3 KRAS G12D, ba/F3 KRAS G12V, ba/F3 KRAS G12A, ba/F3 KRAS G12R, ba/F3 KRAS G12S, ba/F3 KRAS G13C, ba/F3 KRAS G13D, ba/F3 KRAS Q61H, ba/F3 KRAS Q61K, ba/F3 KRAS Q61R, H358, asPC-1, capan-1, H727, A549, HCT116, H460, MKN-1 and PSN-1, and are expected to treat and/or prevent a variety of diseases mediated by KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, KRAS G13C, KRAS G13D, KRAS 61H, KRAS Q61K and KRAS 61R.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

Synthetic route

The compounds of formula (I) of the present invention may be prepared by various synthetic methods well known to those skilled in the art, and are not particularly limited, and may be prepared, for example, by the following scheme one or scheme two provided in the present invention, it being understood that the synthetic method of the compounds of formula (I) of the present invention is not limited to this scheme, and those skilled in the art may make routine substitutions and modifications.

Scheme one:

wherein X is ¹ 、Y ¹ 、Y ² 、L、R ¹ 、R ² 、R ³ 、R ^4b As defined above; hal is halogen, P ¹ And P ² Each independently is an amino, hydroxy or alkynyl protecting group, P ¹ And Y is equal to ¹ Amino, hydroxy or alkynyl groups in (a); p (P) ² And R is R ³ Amino, hydroxy or alkynyl groups in (B) are attached, when Y ¹ And R is ³ P when not containing amino, hydroxy or alkynyl ¹ And P ² Absence of P ¹ And P ² May be the same or different.Is an organometallic group, including but not limited to +.>Etc.

Nucleophilic substitution on the aromatic ring is carried out by the compound a-1 and the compound a-2 to obtain a compound a-3; nucleophilic substitution on aromatic ring is carried out on the compound a-3 and the compound a-4 to obtain a compound a-5; removal of Y from Compound a-5 ¹ The protecting group on the compound is obtained to be a-6, and the compound a-7 is further obtained by nucleophilic substitution reaction or metal catalyzed coupling reaction for ring closure; compounds a-5 may also be used in the removal of Y ¹ Directly closing a ring under the condition of upper protecting groups to obtain a compound a-7; carrying out metal-catalyzed carbon-carbon bond coupling reaction on the compound a-7 and the compound a-8 to obtain a compound a-9; or converting the compound a-7 into a compound a-7-1, and carrying out metal-catalyzed carbon-carbon bond coupling reaction with the compound a-8-1 to obtain a compound a-9; finally removing the protecting group to obtain the tetrafused heterocyclic compound shown in the formula I.

Scheme II:

wherein X is ¹ 、Y ¹ 、Y ² 、L、R ¹ 、R ² 、R ³ 、R ^4b 、Hal、P ¹ 、P ² 、As defined above.

Carrying out nucleophilic substitution reaction on aromatic rings by using the compound b-1 and the compound b-2 to obtain a compound b-3; removing the protecting group on N from the compound b-3 to obtain a compound b-4, and further closing the ring in the presence of condensing agents (including but not limited to bis (2-oxo-3-oxazolidinyl) hypophosphorous acid chloride, tripyrrolidinyl phosphonium bromide hexafluorophosphate and the like) to obtain a compound b-5; carrying out nucleophilic substitution reaction on the compound b-5 and the compound a-4 to obtain a compound a-7; carrying out metal-catalyzed carbon-carbon bond coupling reaction on the compound a-7 and the compound a-8 to obtain a compound a-9; or converting the compound a-7 into a compound a-7-1, and carrying out metal-catalyzed carbon-carbon bond coupling reaction with the compound a-8-1 to obtain a compound a-9; finally removing the protecting group to obtain the tetrafused heterocyclic compound shown in the formula I.

The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) And deuterated chloroform (CDCl) ₃ ) The internal standard is Tetramethylsilane (TMS).

Agilent 6410 Triple Quad LC/MS was used for LC-MS measurement.

The thin layer chromatography silica gel plate is prepared from yellow sea HSGF254 or Qingdao GF254 silica gel plate, and TLC has a specification of 0.15-0.20 mm, and the thin layer chromatography separation and purification product has a specification of 0.4-0.5 mm. Column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.

The abbreviations of the Chinese and English words in the invention are as follows:

bn: a benzyl group; me: a methyl group; boc: t-butoxycarbonyl; TBDPS: tert-butyldiphenyl silyl; TIPS: triisopropyl silicon group; MOM: methoxymethyl (CH) ₃ OCH ₂ -)；CDCl ₃ : deuterated chloroform.

Example 1: (5 aR) -2- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-11- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -6-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxo-3, 9a,10, 12-tetraazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-6-ol formate

Step 1: (R) - (3- (benzyloxy) -1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamic acid tert-butyl ester

O-benzyl-N- (tert-butoxycarbonyl) -D-serine (5.0 g,16.9 mmol) was dissolved in dichloromethane (100 mL) and dimethylamine hydrochloride (2.15 g,22.0 mmol) and N-methylmorpholine (2.4 g,23.7 mmol) were added under nitrogen at-10 ℃. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.5 g,22.0 mmol) was added in portions at-10℃over 20 minutes, followed by stirring at room temperature for 2 hours. Aqueous hydrochloric acid (50 mL,3M in H) was added at 0deg.C ₂ O) diluting and stirring for 5 min. Dichloromethane (150 ml x 2) was added for extraction. The organic phase was washed with saturated aqueous sodium bicarbonate (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=3:1, volume ratio) to give the product as a colorless liquid (5.6 g, yield 98%). ESI-MS m/z 361.1[ M+23 ]] ⁺ . ¹ H NMR(400MHz,CDCl ₃ )δ7.36-7.27(m,5H),5.43(d,J＝8.8Hz,1H),4.88(d,J＝8.0Hz,1H),4.57(d,J＝12.0Hz,1H),4.50(d,J＝12.0Hz,1H),3.71(s,3H),3.68(m,2H),3.21(s,3H),1.44(s,9H).

Step 2: (R) -2-amino-3- (benzyloxy) -N-methoxy-N-methylpropanamide

Dioxahexacyclic hydrochloride solution (55mL,220mmol,4.0M 1,4-dioxane) was added dropwise to tert-butyl (R) - (3- (benzyloxy) -1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamate (6.2 g,18.3 mmol) at 0℃and the reaction was allowed to warm to room temperature and stirred for 0.5 h. The organic phase was concentrated under reduced pressure to give the product as a colourless liquid (7.0 g, crude). ESI-MS m/z 239.1[ M+1 ] ] ⁺ .

Step 3: (R) -allyl (3- (benzyloxy) -1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamic acid tert-butyl ester

(R) -2-amino-3- (benzyloxy) -N-methoxy-N-methylpropanamide (7.0 g,18.3mmol, crude) was dissolved in methanol (80 mL) and N, N-diisopropylethylamine (7.1 g,55.0 mmol) and allyl bromide (4.0 g,33.0 mmol) were added at 0deg.C. The reaction was stirred at 50℃for 6 hours, cooled to room temperature, and di-tert-butyl carbonate (6.0 g,27.5 mmol) was added thereto, followed by stirring for 16 hours. The organic phase was concentrated under reduced pressure, diluted with ethyl acetate (400 mL), washed with aqueous hydrochloric acid (400 mL,1m aqueous solution) and saturated aqueous sodium bicarbonate (400 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=9:2, volume ratio) to give the product as a colorless liquid (3.2 g, yield 46%). ESI-MS m/z 401.1[ M+23 ]] ⁺ . ¹ H NMR(400MHz,CDCl ₃ )δ7.36-7.25(m,5H),5.80(s,1H),5.48(s,1H),5.19-4.97(m,2H),4.59(d,J＝12.0Hz,1H),4.48(d,J＝12.0Hz,1H),3.91(d,J＝15.3Hz,1H),3.85(d,J＝5.9Hz,1H),3.83-3.76(m,1H),3.75-3.63(m,4H),3.17(s,3H),1.45(s,9H).

Step 4: (R) -allyl (1- (benzyloxy) -3-oxobutan-2-yl) carbamic acid tert-butyl ester

(R) -allyl (3- (benzyloxy) -1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamic acid tert-butyl ester (1.0 g,2.65 mmol) was dissolved in tetrahydrofuran (30 mL), methyl magnesium bromide (4.4 mL,13.2mmol,3.0M in tetrahydrofuran) was added under nitrogen protection at 0deg.C, and the reaction was warmed to room temperature and stirred for 1 hour. Aqueous hydrochloric acid (20 mL,3M in H) was added at 0deg.C ₂ O), ethyl acetate (100 ml x 2) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=9:1, volume ratio) to give the product as a colorless liquid (840 mg, yield 95%). ESI-MS m/z 356.1[ M+23 ]] ⁺ . ¹ H NMR(400MHz,CDCl ₃ )δ7.39-7.25(m,5H),6.00-5.77(m,1H),5.29-5.06(m,2H),4.56(dd,J＝12.0,6.0Hz,1H),4.47(d,J＝12.0Hz,1H),4.43-4.27(m,1H),4.17-3.63(m,4H),2.14(d,J＝2.8Hz,3H),1.50-1.35(m,9H).

Step 5: allyl ((2R) -1- (benzyloxy) -3-hydroxy-3-methylpent-4-en-2-yl) carbamic acid tert-butyl ester

Tert-butyl (R) -allyl (1- (benzyloxy) -3-oxobutan-2-yl) carbamate (840 mg,2.52 mmol) was dissolved in tetrahydrofuran (20 mL), vinylmagnesium bromide (3.8 mL,3.78mmol,1.0M in tetrahydrofuran) was added under nitrogen at 0deg.C, and the reaction was warmed to room temperature and stirred for 1 hour. Saturated aqueous ammonium chloride (40 mL) was added at 0deg.C for dilution, and ethyl acetate (60 mL. Times.2) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=20:1, volume ratio) to give the product as a yellow liquid (550 mg, yield 60%). ESI-MS m/z 384.2[ M+23 ]] ⁺ . ¹ H NMR(400MHz,CDCl ₃ )δ7.36-7.26(m,5H),6.00-5.66(m,2H),5.34(dd,J＝17.1,1.5Hz,1H),5.27-5.00(m,4H),4.49(d,J＝12.0Hz,1H),4.41(d,J＝12.0Hz,1H),4.11-3.96(m,2H),3.94-3.50(m,3H),1.46(s,9H),1.44(d,J＝6.5Hz,3H).

Step 6: (2R) -2- (benzyloxy) methyl) -3-hydroxy-3-methyl-3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

Allyl ((2R) -1- (benzyloxy) -3-hydroxy-3-methylpent-4-en-2-yl) carbamic acid tert-butyl ester (550 mg,1.52 mmol) was dissolved in dichloromethane (20 mL), 1, 3-bis (2, 4, 6-trimethylphenyl) -2- (imidazolidinylidene) (dichlorobenzylidene) (tricyclohexylphosphine) ruthenium benzylidene-1, 3-bis (2, 4, 6-trimethylphenyl) -2- (imidazoline carbene) (tricyclohexylphosphine) ruthenium dichloride (129 mg,0.152 mmol) was added under nitrogen protection and the reaction was stirred at 40℃for 2 hours. The organic phase was concentrated under reduced pressure and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=3:1, vol) to give the product as a brown liquid (550 mg, 79% yield). ESI-MS m/z 356.1[ M+23 ] ] ⁺ . ¹ H NMR(400MHz,CDCl3)δ7.37-7.25(m,5H),5.83-5.65(m,2H),4.70-4.35(m,3H),4.25(d,J＝19.2Hz,1H),3.56-3.27(m,3H),1.46(s,9H),1.23(s,3H).

Step 7: (2R) -3-hydroxy-2- (hydroxymethyl) -3-methylpiperidine-1-carboxylic acid tert-butyl ester

(2R) -2- (benzyloxy) methyl) -3-hydroxy-3-methyl-3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (240 mg,0.721 mmol) was dissolved in methanol (20 mL), palladium on carbon (50 mg,10% wet) was added and the reaction stirred under hydrogen atmosphere for 16 hours. The organic phase was filtered and concentrated under reduced pressure to give the product as a colorless oil (220 mg, crude). ESI-MS m/z:268.1[ M+23 ]] ⁺ .

Step 8: (2R) -2- ((tert-Butyldiphenylsilyl) oxy) methyl) -3-hydroxy-3-methylpiperidine-1-carboxylic acid tert-butyl ester

(2R) -3-hydroxy-2- (hydroxymethyl) -3-methylpiperidine-1-carboxylic acid tert-butyl ester (220 mg,0.721mmol, crude) was dissolved in N, N-dimethylformamide (4 mL), imidazole (147 mg,2.16 mmol) and tert-butyldiphenylchlorosilane (292 mg,1.08 mmol) were added and the reaction stirred at room temperature for 2 hours. Water (100 mL) was added for dilution, and ethyl acetate (60 mL. Times.2) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=10:1, volume ratio) to give the product as a colorless oil (320 mg, yield 92%). ESI-MS m/z 506.2[ M+23 ]] ⁺ .

Step 9: (2R) -2- ((tert-Butyldiphenylsilyl) oxy) methyl) -3-methylpiperidin-3-ol trifluoroacetate

(2R) -2- ((tert-Butyldiphenylsilyl) oxy) methyl) -3-hydroxy-3-methylpiperidine-1-carboxylic acid tert-butyl ester was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the reaction was stirred at room temperature for 1 hour. The organic phase was concentrated under reduced pressure to give the product as a yellow oil (320 mg, crude). ESI-MS m/z 383.3[ M+1 ]] ⁺ .

Step 10: (2R) -2- (tert-Butyldiphenylsilyl) oxy) methyl) -3-methyl-1- (2, 5, 7-trichloro-8-fluoropyridin [4,3-d ] pyrimidin-4-yl) piperidin-3-ol

2,4,5, 7-tetrachloro-8-fluoropyrido [4,3-d ]]Pyrimidine (570 mg,1.99 mmol) was dissolved in dichloromethane (20 mL) and N, N-diisopropylethylamine (427 mg,3.32 mmol) and (2R) -2- ((tert-butyldiphenylsilyl) oxy) methyl) -3-methylpiperidin-3-ol trifluoroacetate (320 mg,0.66 mmol) was added at-40℃under nitrogen. The reaction was stirred at-40℃for 1 hour. Water (100 mL) was added for dilution, and ethyl acetate (100 mL. Times.2) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=)6:1, volume ratio) to give the product as a yellow oil (350 mg, 84% yield). ESI-MS m/z 633.1[ M+1 ]] ⁺ .

Step 11: (2R) -2- ((tert-Butyldiphenylsilyl) oxy) methyl) -1- (5, 7-dichloro-8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) -3-methylpiperidin-3-ol

(2R) -2- (tert-Butyldiphenylsilyl) oxy) methyl) -3-methyl-1- (2, 5, 7-trichloro-8-fluoropyridine [4,3-d]Pyrimidin-4-yl) piperidin-3-ol (350 mg,0.553 mmol) was dissolved in dichloromethane (5 mL) and (2R, 8S) -2-fluoro-1, 2,3,5,6, 7-hexahydropyrrolizin-7-yl was added at 0deg.C]Methanol (88 mg,0.553 mmol) and sodium t-butoxide (106 mg,1.11 mmol). The reaction was warmed to room temperature and stirred for 1 hour. Water (100 mL) was added for dilution, and ethyl acetate (100 mL. Times.2) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=1:2, volume ratio) to give the product as a yellow oil (200 mg, yield 48%). ESI-MS m/z 756.3[ M+1 ]] ⁺ .

Step 12: (5 aR) -2-chloro-1-fluoro-11- ((2R, 7 aS) -2-fluorotetrahydrofuran-1H-pyrrolin-7 a (5H) -yl) methoxy) -6-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-6-ol

(2R) -2- ((tert-Butyldiphenylsilyl) oxy) methyl) -1- (5, 7-dichloro-8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolidin-7 a (5H) -yl) methoxy) pyridine [4,3-d]Pyrimidin-4-yl) -3-methylpiperidin-3-ol (200 mg,12.4 mmol) was dissolved in tetrahydrofuran (3 mL), tetrabutylammonium fluoride (0.397 mL,0.397mmol,1.0M in tetrahydrofuran) was added, and the reaction was stirred for 8 hours at 50 ℃. The organic phase was concentrated under reduced pressure and the residue was chromatographed on silica gel (dichloromethane/methanol=13:1, vol) to give the product as a colourless liquid (75 mg, 59% yield) 。ESI-MS m/z:482.1[M+1] ⁺ .

Step 13: (5 aR) -1-fluoro-2- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -11- (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -6-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxo-3, 9a,10, 12-tetraazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-6-ol

(5 aR) -2-chloro-1-fluoro-11- ((2R, 7 aS) -2-fluorotetrahydrofuran-1H-pyrrolin-7 a (5H) -yl) methoxy) -6-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5]Cyclohepta [1,2,3-de ]]Naphthalene-6-ol (75 mg,0.156 mmol) methanesulfonic acid [ n-butyldi (1-adamantyl) phosphine](2-amino-1, 1' -biphenyl-2-yl) palladium [ cataCXium A Pd G3](23 mg,0.031 mmol), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (96 mg,0.187 mmol) and cesium carbonate (152 mg,0.467 mmol) were dissolved in a mixed solution of 1, 4-dioxane/water (1.5 mL/0.15 mL). The reaction was stirred at 80℃for 4 hours under nitrogen protection. After cooling to room temperature, concentration under reduced pressure, silica gel column chromatography of the residue (dichloromethane/methanol=16:1, volume ratio) gave the product as a yellow solid (23 mg, yield 18%). ESI-MS m/z:832.4[ M+1 ]] ⁺ .

Step 14: (5 aR) -2- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-11- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -6-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxo-3, 9a,10, 12-tetraazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-6-ol formate

(5 aR) -1-fluoro-2- (7-fluoro-3- (methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -11- (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -6-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxo-3, 9a,10, 12-tetraazabenzo [4,5]The positions of the cyclohepta [1,2,3-de]naphthalene-6-ol (23 mg,0.028 mmol) was dissolved in acetonitrile (1 mL), and dioxane hydrochloride solution (0.5 mL,4M dioxane solution) was added and stirred at room temperature for 1 hour. The solvent was dried, dissolved in N, N-dimethylformamide (1 mL), cesium fluoride (252 mg,1.66 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and purified by preparative high performance liquid chromatography (0.1% formic acid as additive) to give the product as a white solid (6 mg, yield 34%) after lyophilization. ESI-MS m/z:632.3[ M+1 ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ10.15(brs,1H),8.17(s,1H),8.04-7.90(m,1H),7.50-7.40(m,1H),7.36(d,J＝2.4Hz,1H),7.16(dd,J＝23.6,2.8Hz,1H),5.40-5.10(m,3H),4.88(dt,J＝15.4,3.2Hz,1H),4.49-4.30(m,1H),4.19-3.90(m,3H),3.56(d,J＝14.2Hz,1H),3.15-2.60(m,5H),2.16-2.06(m,2H),2.05-1.96(m,1H),1.86-1.69(m,6H),1.30-1.14(m,3H).

Example 2: (5 aS) -2- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-11- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5,5a,8, 9-tetrahydro-7H-4-oxo-3, 9a,10, 12-tetraazaspiro [ benzo [4,5] cyclohepta [1,2,3-de ] naphthalene-6, 4' -imidazolidine ] -1 (12 a), 2,3a,9b, 11-pentene-2 ',5' -dione formate (isomer 1)

Step 1: (R) -allyl (1- (benzyloxy) -3-oxopent-4-en-2-yl) carbamic acid tert-butyl ester

(R) -allyl (3- (benzyloxy) -1- (methoxy (methyl) amino) -1-oxopropan-2-yl) carbamic acid tert-butyl ester (5 g,13.2 mmol) was dissolved in tetrahydrofuran (150 mL), vinylmagnesium bromide (66 mL,66mmol,1.0M in tetrahydrofuran) was added under nitrogen protection at 0deg.C, and the reaction was warmed to room temperature and stirred for 1 hour. Dilute hydrochloric acid solution (100 ml,3 m) was added dropwise at 0 ℃ and extracted with ethyl acetate (100 ml x 2). The organic phase was washed with saturated sodium bicarbonate solution (100 mL), saturated sodium chloride solution (100 m) L) dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=10:1, volume ratio) to give the product as a yellow liquid (1.74 g, yield 38%). ESI-MS m/z 368.1[ M+23 ]] ⁺ .

Step 2: (R) -2- ((benzyloxy) methyl) -3-oxo-3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

(R) -allyl (1- (benzyloxy) -3-oxopent-4-en-2-yl) carbamic acid tert-butyl ester (1.74 g,5.04 mmol) was dissolved in methylene chloride (50 mL), and 1, 3-bis (2, 4, 6-trimethylphenyl) -2- (imidazolidinylidene) (dichlorobenzylidene) (tricyclohexylphosphine) ruthenium was added to react under nitrogen atmosphere at an external temperature of 40℃for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=4:1, volume ratio) to give the product as a pale yellow solid (1.6 g, yield 84%). ESI-MS m/z 340.1[ M+23 ]] ⁺ .

Step 3: (R) -2- ((benzyloxy) methyl) -3-oxopiperidine-1-carboxylic acid tert-butyl ester

(R) -2- ((benzyloxy) methyl) -3-oxo-3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (1.35 g,4.25 mmol) was dissolved in ethyl acetate (30 mL), and wet palladium on carbon (300 mg, palladium content 10%) was added to react under hydrogen atmosphere (15 Psi) for 1 hour. The reaction solution was filtered and concentrated under reduced pressure to give a pale yellow liquid (1.35 g, crude product). ESI-MS m/z 342.1[ M+23 ] ] ⁺ .

Step 4: (6S) -6- ((benzyloxy) methyl) -2, 4-dioxo-1, 3, 7-triazaspiro [4.5] decane-7-carboxylic acid tert-butyl ester

(R) -2- ((benzyloxy) methyl) -3-oxopiperidine-1-carboxylic acid tert-butyl esterThe ester (1.0 g,3.13 mmol) was dissolved in ethanol (25 mL), ammonium carbonate (1.5 g,15.7 mmol), potassium carbonate (2.16 g,15.7 mmol), trimethylcyanosilane (1.55 g,15.7 mmol) and concentrated ammonia (25 mL,28% in water) were added and the reaction was stirred at 80℃for 16 h. Concentrated under reduced pressure, diluted with water (50 mL), and extracted with ethyl acetate (150 mL. Times.2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate=3:2, volume ratio) to give the product as a white solid (1.0 g, yield 82%). ESI-MS m/z 412.1[ M+23 ]] ⁺ . ¹ H NMR(400MHz,CDCl ₃ )δ9.73-8.28(m,1H),7.43-7.24(m,5H),7.18-6.26(m,1H),4.70-4.56(m,1H),4.49-4.37(m,1H),4.09(dd,J＝14.0,4.1Hz,1H),4.01-3.86(m,1H),3.86-3.73(m,1H),3.06-2.73(m,1H),2.32-1.99(m,2H),1.97-1.79(m,1H),1.79-1.55(m,2H),1.48(d,J＝17.2Hz,9H).

Step 5: (6S) -6- (hydroxymethyl) -2, 4-dioxo-1, 3, 7-triazaspiro [4.5] decane-7-carboxylic acid tert-butyl ester

(6S) -6- ((benzyloxy) methyl) -2, 4-dioxo-1, 3, 7-triazaspiro [4.5]Tert-butyl decane-7-carboxylate (1.1 g,2.82 mmol) was dissolved in methanol (20 mL), palladium on carbon hydroxide (200 mg, palladium content 20%) and hydrochloric acid methanol solution (0.05 mL,1.0M methanol solution) were added, and the reaction was stirred under a hydrogen atmosphere for 2 hours. The organic phase was filtered through celite and concentrated under reduced pressure to give the product as a colorless oil (1.2 g, crude). ESI-MS m/z:321.9[ M+23 ] ] ⁺ .

Step 6: (6S) -6- (((tert-Butyldiphenylsilyl) oxy) methyl) -2, 4-dioxo-1, 3, 7-triazaspiro [4.5] decane-7-carboxylic acid tert-butyl ester

The synthesis procedure of this compound was the same as in example 1 and step 8. In (6S) -6- (hydroxymethyl) -2, 4-dioxo-1, 3, 7-triazaspiro [4.5]]And (3) the decane-7-carboxylic acid tert-butyl ester is used as a raw material to react. ESI-MSm/z:559.9[M+23] ⁺ . ¹ H NMR(400MHz,CDCl ₃ )δ8.46-7.92(m,1H),7.73-7.58(m,4H),7.51-7.31(m,6H),6.67 -5.97(m,1H),4.65-4.32(m,1H),4.10-3.76(m,3H),2.77(td,J＝13.2,4.0Hz,1H),2.30-2.03(m,1H),1.97-1.85(m,1H),1.69-1.51(m,2H),1.48-1.36(m,9H),1.05(d,J＝9.3Hz,9H).

Step 7: (6S) -6- ((tert-Butyldiphenylsilyl) oxy) methyl) -1,3, 7-triazaspiro [4.5] decane-2, 4-dione trifluoroacetate salt

The synthetic procedure for this compound was the same as step 9 in example 1. With tert-butyl (6S) -6- (((tert-butyldiphenylsilyl) oxy) methyl) -2, 4-dioxo-1, 3, 7-triazaspiro [4.5]]Decane-7-carboxylic acid ester is used as raw material for reaction. ESI-MS m/z 438.3[ M+1 ]] ⁺ .

Step 8: (6S) -6- ((tert-Butyldiphenylsilyl) oxy) methyl) -7- (2, 5, 7-trichloro-8-fluoropyridin [4,3-d ] pyrimidin-4-yl) -1,3, 7-triazaspiro [4.5] decane-2, 4-dione

The synthesis procedure of this compound was the same as in example 1 and step 10. The preparation method takes 2,4,5, 7-tetrachloro-8-fluoropyrido [4,3-d ] pyrimidine and (6S) -6- ((tert-butyldiphenylsilyl) oxy) methyl) -1,3, 7-triazaspiro [4.5] decane-2, 4-dione trifluoroacetate as raw materials to react. Purifying by silica gel column chromatography, and separating two diastereomers.

Isomer 1 (more polar sheet chromatography): ESI-MS m/z 687.1[ M+1 ]] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ10.80(s,1H),8.24(s,1H),7.64(t,J＝6.3Hz,4H),7.50-7.33(m,6H),5.58(s,1H),4.23(t,J＝9.6Hz,1H),4.12-4.02(m,1H),3.94(dd,J＝11.0,5.1Hz,1H),3.70(s,1H),1.98-1.77(m,2H),1.70(s,1H),1.59(s,1H),0.86(s,9H).

Isomer 2 (less polar sheet chromatography): ESI-MS m/z 687.1[M+1] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ10.77(s,1H),8.38(s,1H),7.67-7.59(m,4H),7.50-7.36(m,6H),5.48(d,J＝9.5Hz,1H),4.44(t,J＝11.0Hz,1H),4.20(dd,J＝11.8,3.5Hz,2H),3.55(d,J＝13.2Hz,1H),2.12-1.99(m,1H),1.62(s,2H),1.49(d,J＝13.2Hz,1H),0.85(s,9H).

Step 9: (6S) -6- (((tert-Butyldiphenylsilyl) oxy) methyl) -7- (5, 7-dichloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -1,3, 7-triazaspiro [4.5] decane-2, 4-dione (isomer 1)

The procedure for the synthesis of this compound was the same as in example 1, step 11. With (6S) -6- ((tert-butyldiphenylsilyl) oxy) methyl) -7- (2, 5, 7-trichloro-8-fluoropyridine [4,3-d ]]Pyrimidin-4-yl) -1,3, 7-triazaspiro [4.5]Decane-2, 4-dione (isomer 1) and (2R, 8S) -2-fluoro-1, 2,3,5,6, 7-hexahydropyrrolizin-7-yl]Methanol is used as raw material for reaction. ESI-MS m/z 812.5[ M+1 ]] ⁺ .

Step 10: (5 aS) -2-chloro-1-fluoro-11- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5,5a,8, 9-tetrahydro-7H-4-oxa-3, 9a,10, 12-tetraazaspiro [ benzo [4,5] cyclohepta [1,2,3-de ] naphthalene-6, 4' -imidazolidine ] -1 (12 a), 2,3a,9b, 11-pentadiene-2 ',5' -dione (isomer 1)

(6S) -6- (((tert-Butyldiphenylsilyl) oxy) methyl) -7- (5, 7-dichloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ]Pyrimidin-4-yl) -1,3, 7-triazaspiro [4.5]Decane-2, 4-dione (isomer 1) (70 mg,0.0863 mmol) and tetrabutylammonium fluoride (0.129 mL,0.129mmol,1M tetrahydrofuran solution) were added to tetrahydrofuran (5 mL), stirred at room temperature for 16 hours, and then heated to 50℃and stirred for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane/methyl acetate)Alcohol=10:1, volume ratio) to give the product as an off-white solid (28 mg, 60.5% yield). ESI-MS m/z 535.9[ M+1 ]] ⁺ .

Step 11: (5 aS) -1-fluoro-2- (7-fluoro-3-methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -11- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5,5a,8, 9-tetrahydro-7H-4-oxa-3, 9a,10, 12-tetrazaspiro [ benzo [4,5] cyclohepta [1,2,3-de ] naphthalene-6, 4' -imidazoline ] -1 (12 a), 2,3a,9b, 11-pentene-2 ',5' -dione (isomer 1)

(5 aS) -2-chloro-1-fluoro-11- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5,5a,8, 9-tetrahydro-7H-4-oxa-3, 9a,10, 12-tetraazaspiro [ benzo [4,5]]Cyclohepta [1,2,3-de ]]Naphthalene-6, 4' -imidazolidine]-1 (12 a), 2,3a,9b, 11-pentadiene-2 ',5' -dione (isomer 1) (28 mg,0.052 mmol), (2-fluoro-6-methoxymethoxy) -8- (4, 5-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (32 mg,0.0624 mmol), methanesulfonyloxy (di-adamantyl-n-butylphosphino) -2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (7.57 mg,0.0104 mmol), cesium carbonate (50.8 mg,0.156 mmol) dissolved in 1, 4-dioxa-cyclic (6 mL) and water (0.6 mL) were reacted under nitrogen atmosphere at microwave 130 ℃ for 15 minutes. The reaction solution was concentrated under reduced pressure after filtration, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol=10:1, volume ratio) to give the product as a pale yellow solid (18 mg, yield 38.9%). ESI-MS m/z 886.9[ M+1 ] ] ⁺ .

Step 12: (5 aS) -2- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-11- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5,5a,8, 9-tetrahydro-7H-4-oxo-3, 9a,10, 12-tetraazaspiro [ benzo [4,5] cyclohepta [1,2,3-de ] naphthalene-6, 4' -imidazolidine ] -1 (12 a), 2,3a,9b, 11-pentene-2 ',5' -dione formate (isomer 1)

(5 aS) -1-fluoro-2- (7)-fluoro-3-methoxymethoxy) -8- (triisopropylsilyl) ethynyl) naphthalen-1-yl) -11- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5,5a,8, 9-tetrahydro-7H-4-oxa-3, 9a,10, 12-tetraazaspiro [ benzo [4,5]]Cyclohepta [1,2,3-de ]]Naphthalene-6, 4' -imidazolines]-1 (12 a), 2,3a,9b, 11-pentene-2 ',5' -dione (isomer 1) (18 mg,0.0203 mmol) was dissolved in acetonitrile (2 mL), cooled to 0 ℃ under nitrogen atmosphere, and then 1, 4-dioxane solution (1 mL,4m dioxane solution) of hydrogen chloride was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and N, N-dimethylformamide (1.5 mL) and cesium fluoride (185.3 mg,1.22 mmol) were added thereto to react at room temperature for 2 hours. The reaction solution was purified by preparative high performance liquid chromatography (0.1% formic acid aS additive), and lyophilized to give the product aS a white solid (1.04 mg, yield 7.5%) of (5 aS) -2- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-11- (((2 r,7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -5,5a,8, 9-tetrahydro-7H-4-oxo-3, 9a,10, 12-tetraazaspiro [ benzo [4,5] ]Cyclohepta [1,2,3-de ]]Naphthalene-6, 4' -imidazolidine]-1 (12 a), 2,3a,9b, 11-pentene-2 ',5' -dione formate. ESI-MS m/z:685.8[ M+1 ]] ⁺ .

Biological test examples

Test example 1: proliferation inhibitory Activity of example Compounds against cells Ba/F3KRAS G12C, ba/F3KRAS G12D, ba/F3KRAS G12V, ba/F3KRAS G12A, ba/F3KRAS G12R, ba/F3KRAS G12S, ba/F3KRAS G13C, ba/F3KRAS G13D, ba/F3KRAS Q61H, ba/F3KRAS Q61K, ba/F3KRAS Q61R, H358, asPC-1, capan-1, H727, A549, HCT116, H460, MKN-1 and PSN-1.

Inoculating the above cells in logarithmic growth phase into 96-well plate at 37deg.C with 5% CO ₂ After 1 day of incubation, a gradient of diluted test compound was added. The method comprises the following steps: stock solutions of the compounds (10 mM) dissolved in DMSO beforehand were diluted to 10 gradient concentrations at a ratio of 4 times and diluted to 10 times the target concentration with medium in another 96-well plate, and then 10. Mu.l/well of the compound solution was added to the 96-well plate inoculated with cells, i.e., the target concentrations (10000, 2500,625,156,39,10,2.5,0.6,0.15,0.04 nM) were reached. 3 duplicate wells were set for each concentration, and a blank was set. Placing in 37 ℃ and 5 percent CO ₂ Continuous culture in the middleAfter 72h incubation, 50. Mu.l of each well was added 2.0 reagent (luciferase ATP bioluminescence detection reagent, available from Promega, cat No. G9243), shaking for 2min, incubating at room temperature for 8min, and detecting fluorescence intensity (light receiving time 100 ms). The inhibition ratio of each concentration of the compound to cell proliferation was calculated, and the inhibition ratio of cell proliferation (%) = [ (luminous intensity) _{72 hour cell-containing Medium control group} Luminous intensity _{72 hour group of compounds} ) (luminous intensity) _{72 hour cell-containing Medium control group} Luminous intensity _{72 hour cell-free Medium control group} )]X 100%. Analysis of data using GraphPad Prism 8.3 software, fitting data to derive dose-response curves using nonlinear S-curve regression, and calculating IC therefrom ₅₀ Values, results are shown in Table 1.

TABLE 1

The compounds of the invention inhibit the proliferation of cells Ba/F3 KRAS G12C and Ba/F3 KRAS G12D.

Claims

1. A tetraheterocyclic compound shown in a formula I, a stereoisomer or a pharmaceutically acceptable salt thereof,

wherein,

X ¹ is-CR ⁵ -or-N-;

C(＝O)NR ⁶ -；

p1, p2, p3, p4 and p5 are each independently 0, 1, 2 or 3;

each R ¹ Each independently is deuterium, halogen, -CN, -OH, oxo (= O), -N (R) ⁶ ) ₂ 、-C(＝O)N(R ⁶ ) ₂ 、C ₁ -C ₆ Alkyl, substituted by one or more R ^1a Substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, substituted by one or more R ^1b Substituted C ₁ -C ₆ alkyl-O-, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, substituted by one or more R ^1c Substituted C ₂ -C ₆ Alkenyl, substituted by one or more R ^1d Substituted C ₂ -C ₆ Alkynyl, -C (=o) H, -CO ₂ R ⁵ Or a 5-to 10-membered heteroaryl; when the substituents are plural, the same or different;

n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;

n3 is 1,2 or 3;

each R ^2a 、R ^2b 、R ^2c 、R ^2d And R is ^2e Each independently is halogen, -OH, deuterium, -CN, -C (=O) H, C ₁ -C ₄ Alkyl, C ₂ -C ₄ Alkenyl, C ₂ -C ₄ Alkynyl, substituted by one or more R ^2-a Substituted C ₁ -C ₄ Alkyl, C ₁ -C ₄ alkyl-O-, is monoOne or more R ^2-b Substituted C ₁ -C ₄ alkyl-O-, -N (R) ⁶ ) ₂ 、(C _l -C ₄ Alkyl) -C (=o) -, oxo (=o), -SO ₂ F、(C _l -C ₄ Alkyl) -SO ₂ -、(C _l -C ₄ Alkyl) -O- (C _l -C ₄ Alkyl) -O-, -CH ₂ OC(＝O)N(R ⁶ ) ₂ 、(C _l -C ₄ Alkyl) -O-C (=o) -NHCH ₂ -、-CH ₂ NHC(＝O)N(R ⁶ ) ₂ 、(C _l -C ₄ Alkyl) -C (=o) NHCH ₂ -, (pyrazolyl) -CH ₂ -、(C _l -C ₄ Alkyl) -SO ₂ -NHCH ₂ -, (4-10 membered heterocyclyl) -C (=o) -OCH ₂ -、(R ⁶ ) ₂ N-C(＝O)-O-、(C _l -C ₄ Alkyl) -O- (C _l -C ₄ Alkyl) -NH-C (=o) -O-, phenyl-C (=o) NH-, phenyl- (C) _l -C ₄ Alkyl) -NH-C (=o) -O-, (4-10 membered heterocyclyl) -C (=o) -O-, or (4-10 membered heterocyclyl) -CH ₂ -; the phenyl-C (=O) NH-and phenyl- (C) _l -C ₄ Alkyl) -NH-C (=o) -O-phenyl optionally substituted with-C (=o) H, halogen, -CN or-OH; the (4-10 membered heterocyclic) -C (=O) -OCH ₂ -, (4-10 membered heterocyclyl) -C (=o) -O-, and (4-10 membered heteroalkyl) -CH ₂ -the 4-10 membered heterocyclyl in is optionally substituted with =o; when the substituents are plural, the same or different;

each R ^2-a And R is ^2-b Each independently deuterium, -CN, halogen or-OH;

each R ^3a And R is ^3b Each independently is deuterium, halogen, -OH, -CN, C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ alkyl-S-, substituted by one or more R ^3-a Substituted C ₁ -C ₆ Alkyl groupIs/are R ^3-b Substituted C ₁ -C ₆ alkyl-O-, substituted by one or more R ^3-c Substituted C ₁ -C ₆ alkyl-S-, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, substituted by one or more R ^3-d Substituted C ₂ -C ₆ Alkenyl, substituted by one or more R ^3-e Substituted C ₂ -C ₆ Alkynyl, -N (R) ⁶ ) ₂ 、-(CH ₂ )-C(＝O)N(R ⁶ ) ₂ 3-7 membered cycloalkyl, substituted with one or more R ³ ^-f Substituted 3-7 membered cycloalkyl or triazolyl; when the substituents are plural, the same or different;

the 5-10 membered heteroaryl, 4-10 membered heterocyclyl, 3-7 membered heterocyclyl, substituted with one or more R ^1d "4-10 membered heterocyclyl", in substituted 4-10 membered heterocyclyl, is substituted with one or more R ^1e "5-10 membered heteroaryl" in substituted 5-10 membered heteroaryl, substituted with one or more R ^1g "4-10 membered heterocyclyl", in substituted 4-10 membered heterocyclyl, is substituted with one or more R ^1h "5-10 membered heteroaryl" in substituted 5-10 membered heteroaryl, substituted with one or more R ^2c "4-10 membered heterocyclyl", in substituted 4-10 membered heterocyclyl, is substituted with one or more R ^2e "5-10 membered heteroaryl", (4-10 membered heterocyclyl) -C (=o) -OCH in substituted 5-10 membered heteroaryl ₂ "4-10 membered heterocyclyl" in (4-10 membered heterocyclyl) -C (=o) -O-in "4-10 membered heterocyclyl", (4-10 membered heterocyclyl) -CH ₂ "4-10 membered heterocyclyl", in "one or more R ^3b "5-10 membered heteroaryl" in a substituted 5-10 membered heteroaryl and substituted with one or more R ^5d The hetero atom in the '5-10 membered heteroaryl' in the substituted 5-10 membered heteroaryl is independently selected from one or more of N, O and S, and the number of the hetero atom is independently 1, 2 or 3.

2. The tetraheterocyclic compound shown in formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein the tetraheterocyclic compound shown in formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions:

(1)Y ¹ In said formula (I), said-NR ⁶ In C (=O) -, carbonyl and Y ² Are connected;

(2)Y ¹ in the-C (=O) O-, oxygen and Y ² Are connected;

(2)Y ¹ in the formula, the-C (=O) NR ⁶ In-nitrogen and Y ² Are connected;

(3)Y ² in the formula (I), the formula (I) is that the formula (I) ⁷ R ⁷ ) _p3 in-C, carbonyl and Y ¹ Are connected;

(4)Y ² in said formula (I), said-NR ⁶ (CR ⁷ R ⁷ ) _p5 In-nitrogen and Y ¹ Are connected;

(5)Y ² in the above, the above-mentioned-O (CR ⁷ R ⁷ ) _p4 In-oxygen and Y ¹ Are connected;

(6) When R is ¹ When halogen, the halogen is independently F, cl, br or I, such as fluorine;

(7) When R is ¹ Is C ₁ -C ₆ Alkyl, substituted by one or more R ^1a Substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, substituted by one or more R ^1b Substituted C ₁ -C ₆ alkyl-O-, wherein C ₁ -C ₆ Alkyl is independently C _1-4 Alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also such as methyl;

(8) When R is ¹ Is C ₂ -C ₆ Alkenyl or by one or more R ^1c Substituted C ₂ -C ₆ Alkenyl group, C therein ₂ -C ₆ Alkenyl groups are independently C ₂ -C ₄ Alkenyl groups such as ethenyl, propenyl, or butenyl;

(9) When R is ¹ Is C ₂ -C ₆ Alkynyl or by one or more R ^1d Substituted C ₂ -C ₆ Alkynyl group, C therein ₂ -C ₆ Alkynyl groups are independently C ₂ -C ₄ Alkynyl, for example, ethynyl, propynyl or butynyl;

(10) When R is ¹ In the case of a 5-10 membered heteroaryl, the heteroatom in the 5-10 membered heteroaryl is independently selected from one or both of N and O;

(11) When R is ¹ In the case of a 5-10 membered heteroaryl, the number of heteroatoms in the 5-10 membered heteroaryl is independently 1 or 2;

(12) When R is ¹ In the case of a 5-10 membered heteroaryl, the 5-10 membered heteroaryl is independently a 5-6 membered heteroaryl;

(13) When two R's on the same ring carbon atom ¹ Forming a 4-10 membered heterocyclic group or by one or more R ^1d When the 4-10 membered heterocyclic group is substituted, the hetero atom in the 4-10 membered heterocyclic group is independently selected from one or two of N and O;

(14) When two R's on the same ring carbon atom ¹ Forming a 4-10 membered heterocyclic group or by one or more R ^1d When the 4-10 membered heterocyclic group is substituted, the number of heteroatoms in the 4-10 membered heterocyclic group is independently 1 or 2;

(15) When two R's on the same ring carbon atom ¹ Forming a 4-10 membered heterocyclic group or by one or more R ^1d When substituted, 4-10 membered heterocyclyl, wherein 4-10 membered heterocyclyl is independently 5-6 membered heterocyclyl; preferably a 5-6 membered heterocyclic group substituted by oxo and/or methyl, for example

(16) When two R's on the same ring carbon atom ¹ Forming a 5-to 10-membered heteroaryl or by one or more R ^1e When the 5-10 membered heteroaryl is substituted, the hetero atom in the 5-10 membered heteroaryl is independently selected from one or two of N and O, and the number of the hetero atom is independently 1 or 2;

(17) When two R's on the same ring carbon atom ¹ Forming 3-7 membered cycloalkyl or by one or more R ^1f When substituted 3-7 membered cycloalkyl, wherein 3-7 membered cycloalkyl is independently 3-6 membered cycloalkyl, e.g., cyclopropyl, cyclobutyl,Cyclopentyl or cyclohexyl;

(18) When two R's on adjacent ring carbon atoms ¹ Condensed into 4-10 membered heterocyclic groups or by one or more R ^1g When the 4-10 membered heterocyclic group is substituted, the hetero atom in the 4-10 membered heterocyclic group is independently selected from one or two of N and O;

(19) When two R's on adjacent ring carbon atoms ¹ Condensed into 4-10 membered heterocyclic groups or by one or more R ^1g When the 4-10 membered heterocyclic group is substituted, the number of heteroatoms in the 4-10 membered heterocyclic group is independently 1 or 2;

(20) When two R's on adjacent ring carbon atoms ¹ Condensed into 4-10 membered heterocyclic groups or by one or more R ^1g When substituted, 4-10 membered heterocyclyl, wherein 4-10 membered heterocyclyl is independently 5-6 membered heterocyclyl;

(21) When two R's on adjacent ring carbon atoms ¹ Condensed into 5-to 10-membered heteroaryl groups or into one or more R groups ^1h When the 5-10 membered heteroaryl is substituted, the hetero atom in the 5-10 membered heteroaryl is independently selected from one or two of N and O, and the number of the hetero atom is independently 1 or 2;

(22) When two R's on adjacent ring carbon atoms ¹ Condensed into 3-7 membered cycloalkyl groups or by one or more R ¹ⁱ When substituted, 3-7 membered cycloalkyl, wherein 3-7 membered cycloalkyl is independently 3-6 membered cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(23) When R is ^1a 、R ^1b 、R ^1c 、R ^1d 、R ^1e 、R ^1f 、R ^1g 、R ^1h Or R is ¹ⁱ When halogen, the halogen is independently F, cl, br or I;

(24) When R is ^1a 、R ^1b 、R ^1c 、R ^1d 、R ^1e 、R ^1f 、R ^1g 、R ^1h Or R is ¹ⁱ Is C ₁ -C ₆ Alkyl or C ₁ -C ₆ alkyl-O-, wherein C ₁ -C ₆ Alkyl is independently C _1-4 Alkyl radicals, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl radical, and also, for example, methyl radical；

(25) When R is ² Is C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-or-C (=o) O-C ₁ -C ₆ In the case of alkyl radicals, C therein ₁ -C ₆ Alkyl is independently C _1-4 Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

(26) When R is ² Is 3-7 membered cycloalkyl or is substituted by one or more R ^2a When substituted 3-7 membered cycloalkyl, wherein 3-7 membered cycloalkyl is independently 3-6 membered cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, also such as cyclopropyl;

(27) When R is ² Is 3-7 membered cycloalkenyl or is substituted by one or more R ^2b When substituted 3-7 membered cycloalkenyl, wherein 3-7 membered cycloalkenyl is independently 3-6 membered cycloalkenyl, e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl;

(28) When R is ² Is 4-10 membered heterocyclyl or substituted with one or more R ^2c When the 4-10 membered heterocyclic group is substituted, the hetero atom in the 4-10 membered heterocyclic group is independently selected from one or two of N and O;

(29) When R is ² Is 4-10 membered heterocyclyl or substituted with one or more R ^2c When the 4-10 membered heterocyclic group is substituted, the number of heteroatoms in the 4-10 membered heterocyclic group is independently 1 or 2;

(30) When R is ² Is 4-10 membered heterocyclyl or substituted with one or more R ^2c When substituted, the 4-10 membered heterocyclic group may be bicyclic;

(31) When R is ² Is 4-10 membered heterocyclyl or substituted with one or more R ^2c When substituted, 4-10 membered heterocyclyl, wherein 4-10 membered heterocyclyl may independently be spiro, fused or bridged, e.g., fused;

(32) When R is ² Is 4-10 membered heterocyclyl or substituted with one or more R ^2c In the case of substituted 4-10 membered heterocyclic groups, the 4-10 membered heterocyclic groups may independently be 6-10 membered heterocyclic groups, e.g., five membered and five membered rings, further e.g.

(33) When R is ² To be covered by one or more R ^2c Substituted 4-10 membered heterocyclyl, said substituted with one or more R ^2c Substituted 4-10 membered heterocyclyl groups are independently 6-10 membered heterocyclyl groups substituted with halogen, e.g., fluoro five membered and five membered rings, also e.g.

(34) When R is ² Is C ₆ -C ₁₀ Aryl, substituted by one or more R ^2d Substituted C ₆ -C ₁₀ Aryl or-NR ⁶ C(＝O)-C ₆ -C ₁₀ Aryl group, wherein C ₆ -C ₁₀ Aryl is independently phenyl or naphthyl;

(35) When R is ² Is a 5-10 membered heteroaryl or is substituted with one or more R ^2e When the 5-10 membered heteroaryl is substituted, the hetero atom in the 5-10 membered heteroaryl is independently selected from one or two of N and O, and the number of the hetero atom is independently 1 or 2;

(36) When R is ^2a 、R ^2b 、R ^2c 、R ^2d Or R is ^2e When halogen, the halogen is independently F, cl, br or I, such as fluorine;

(37) When R is ^2a 、R ^2b 、R ^2c 、R ^2d And R is ^2e Is C ₁ -C ₄ Alkyl, substituted by one or more R ^2-a Substituted C ₁ -C ₄ Alkyl, C ₁ -C ₄ alkyl-O-or by one or more R ^2-b Substituted C ₁ -C ₄ alkyl-O-, wherein C ₁ -C ₄ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl;

(38) When R is ^2a 、R ^2b 、R ^2c 、R ^2d Or R is ^2e Is C ₂ -C ₄ Alkenyl, the C ₂ -C ₄ Alkenyl is independently ethenyl, propenyl, or butenyl;

(39) When R is ^2a 、R ^2b 、R ^2c 、R ^2d Or R is ^2e Is C ₂ -C ₄ In the case of alkynyl, the said C ₂ -C ₄ Alkynyl is independently ethynyl, propynyl or butynyl;

(40) When R is ^2a 、R ^2b 、R ^2c 、R ^2d Or R is ^2e Is (C) _l -C ₄ Alkyl) -C (=o) - (C) _l -C ₄ Alkyl) -SO ₂ -、(C _l -C ₄ Alkyl) -O- (C _l -C ₄ Alkyl) -O-, (C _l -C ₄ Alkyl) -O-C (=o) -NHCH ₂ -、(C _l -C ₄ Alkyl) -C (=o) NHCH ₂ -、(C _l -C ₄ Alkyl) -SO ₂ -NHCH ₂ -、(C _l -C ₄ Alkyl) -O- (C _l -C ₄ Alkyl) -NH-C (=o) -O-or phenyl- (C _l -C ₄ Alkyl) -NH-C (=o) -O-, wherein C ₁ -C ₄ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

(41) When R is ^2a 、R ^2b 、R ^2c 、R ^2d Or R is ^2e Is (4-10 membered heterocyclic) -C (=O) -OCH ₂ -, (4-10 membered heterocyclyl) -C (=o) -O-, or (4-10 membered heterocyclyl) -CH ₂ -wherein the heteroatoms in the 4-10 membered heterocyclyl are independently selected from one or both of N and O;

(42) When R is ^2a 、R ^2b 、R ^2c 、R ^2d Or R is ^2e Is (4-10 membered heterocyclic) -C (=O) -OCH ₂ -, (4-10 membered heterocyclyl) -C (=o) -O-, or (4-10 membered heterocyclyl) -CH ₂ -wherein the number of heteroatoms in the 4-10 membered heterocyclyl is independently 1 or 2;

(43) When R is ^2a 、R ^2b 、R ^2c 、R ^2d Or R is ^2e Is (4-10 membered heterocyclic) -C (=O) -OCH ₂ -, (4-10 membered heterocyclyl) -C (=o) -O-, or (4-10 membered heterocyclyl) -CH ₂ -when, whereinIs a 4-to 7-membered heterocyclic group, for example a 6-membered heterocyclic group, and also for example

(44) When R is ^2-a Or R is ^2-b When halogen, the halogen is independently F, cl, br or I, such as fluorine;

(45) When R is ³ Is C ₆ -C ₁₀ Aryl or by one or more R ^3a Substituted C ₆ -C ₁₀ Aryl group, wherein C ₆ -C ₁₀ Aryl is independently phenyl or naphthyl, such as naphthyl;

(46) When R is ³ Is a 5-10 membered heteroaryl or is substituted with one or more R ^3b When the 5-10 membered heteroaryl is substituted, the heteroatom in the 5-10 membered heteroaryl is independently selected from one or two of N and O;

(47) When R is ³ Is a 5-10 membered heteroaryl or is substituted with one or more R ^3b When substituted, the number of heteroatoms in the 5-10 membered heteroaryl is independently 1 or 2;

(48) When R is ³ Is a 5-10 membered heteroaryl or is substituted with one or more R ^3b When substituted, a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is independently a 5-6 membered heteroaryl, such as pyridinyl;

(49) When R is ^3a Or R is ^3b When halogen, the halogen is independently F, cl, br or I, such as fluorine;

(50) When R is ^3a Or R is ^3b Is C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ alkyl-S-, substituted by one or more R ^3-a Substituted C ₁ -C ₆ Alkyl, substituted by one or more R ^3-b Substituted C ₁ -C ₆ alkyl-O-or by one or more R ^3-c Substituted C ₁ -C ₆ alkyl-S-, wherein C ₁ -C ₆ Alkyl is independently C _1-4 Alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also such as methyl;

(51) When R is ^3a Or R is ^3b Is C ₂ -C ₆ Alkenyl or by one or more R ^3-d Substituted C ₂ -C ₆ Alkenyl group, C therein ₂ -C ₆ Alkenyl groups are independently C ₂ -C ₄ Alkenyl groups such as ethenyl, propenyl, or butenyl;

(52) When R is ^3a Or R is ^3b Is C ₂ -C ₆ Alkynyl or by one or more R ^3-e Substituted C ₂ -C ₆ Alkynyl group, C therein ₂ -C ₆ Alkynyl groups are independently C ₂ -C ₄ Alkynyl, for example, ethynyl, propynyl or butynyl, for example also ethynyl;

(53) When R is ^3a Or R is ^3b Is 3-7 membered cycloalkyl or is substituted by one or more R ^3-f When substituted, 3-7 membered cycloalkyl, wherein 3-7 membered cycloalkyl is independently 3-6 membered cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(54) When R is ^3-a 、R ^3-b 、R ^3-c 、R ^3-d 、R ^3-e Or R is ^3-f When halogen, the halogen is independently F, cl, br or I, such as fluorine;

(55) When R is ^3-a 、R ^3-b 、R ^3-c 、R ^3-d 、R ^3-e Or R is ^3-f Is C ₁ -C ₄ Alkyl or C ₁ -C ₄ alkyl-O-, wherein C ₁ -C ₄ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

(56) When R is ^3-a 、R ^3-b 、R ^3-c 、R ^3-d 、R ^3-e Or R is ^3-f In the case of a 3-7 membered cycloalkyl group, the 3-7 membered cycloalkyl group is independently a 3-6 membered cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(57) When R is ^4b When halogen, the halogen is F, cl, br or I, such as fluorine;

(58) When R is ^4b Is C ₁ -C ₆ Alkyl, halogenated C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, deuterated C ₁ -C ₆ In the case of alkyl radicals, C therein ₁ -C ₆ Alkyl is C _1-4 Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

(59) When R is ^4b Is C ₂ -C ₆ Alkenyl, the C ₂ -C ₆ Alkenyl group is C ₂ -C ₄ Alkenyl groups such as ethenyl, propenyl, or butenyl;

(60) When R is ^4b Is C ₂ -C ₆ In the case of alkynyl radicals, C ₂ -C ₆ Alkynyl is C ₂ -C ₄ Alkynyl, for example, ethynyl, propynyl or butynyl;

(61) When R is ⁵ When halogen, the halogen is independently F, cl, br or I, such as fluorine or chlorine;

(62) When R is ⁵ Is C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ alkyl-S-, substituted by one or more R ^5a Substituted C ₁ -C ₆ Alkyl, substituted by one or more R ^5b Substituted C ₁ -C ₆ alkyl-O-or by one or more R ^5c Substituted C ₁ -C ₆ alkyl-S-, wherein C ₁ -C ₆ Alkyl is independently C _1-4 Alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also such as methyl;

(63) When R is ⁵ Is a 5-10 membered heteroaryl or is substituted with one or more R ^5d When the 5-10 membered heteroaryl is substituted, the hetero atom in the 5-10 membered heteroaryl is independently selected from one or two of N and O, and the number of the hetero atom is independently 1 or 2;

(64) When R is ^5a 、R ^5b 、R ^5c Or R is ^5d When halogen, the halogen is independently F, cl, br or I, such as fluorine;

(65) When R is ^5a 、R ^5b 、R ^5c Or R is ^5d Is C ₁ -C ₄ Alkyl or C ₁ -C ₄ alkyl-O-, wherein C ₁ -C ₄ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

(66) When R is ^5a 、R ^5b 、R ^5c Or R is ^5d In the case of a 3-7 membered cycloalkyl group, the 3-7 membered cycloalkyl group is independently a 3-6 membered cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(67) When R is ⁶ Is C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-or deuterated C ₁ -C ₆ In the case of alkyl radicals, C therein ₁ -C ₆ Alkyl is independently C _1-4 Alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also such as methyl;

(68) When R is ⁶ In the case of a 5-10 membered heteroaryl, the heteroatoms in the 5-10 membered heteroaryl are independently selected from one or two of N and O, and the number of the heteroatoms is independently 1 or 2;

(69) When R is ⁷ Is C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-or deuterated C ₁ -C ₆ In the case of alkyl radicals, C therein ₁ -C ₆ Alkyl is independently C _1-4 Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

(70) When R is ⁷ In the case of a 5-10 membered heteroaryl, the heteroatoms in the 5-10 membered heteroaryl are independently selected from one or two of N and O, and the number of the heteroatoms is independently 1 or 2;

(71) When two R's on a ring atom ⁷ When taken together with the ring atom to which it is attached, form a 3-7 membered cycloalkyl, the 3-7 membered cycloalkyl is independently 3-6 membered cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(72) When two R's on a ring atom ⁷ When the 3-7 membered heterocyclic group is formed together with the ring atom to which the heterocyclic group is connected, the hetero atom in the 3-7 membered heterocyclic group is independently selected from one or two of N and O, and the number of the hetero atom is independently 1 or 2;

And (73) the pharmaceutically acceptable salt is trifluoroacetate, hydrochloride or formate.

3. The tetraheterocyclic compound shown in formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein the tetraheterocyclic compound shown in formula I satisfies one or more of the following conditions:

(1)R ⁵ is hydrogen, halogen or C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ alkyl-S-, substituted by one or more R ^5a Substituted C ₁ -C ₆ Alkyl, substituted by one or more R ^5b Substituted C ₁ -C ₆ alkyl-O-or by one or more R ^5c Substituted C ₁ -C ₆ alkyl-S-; preferably, R ⁵ Is hydrogen, halogen or C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-S-, substituted by one or more R ^5a Substituted C ₁ -C ₆ Alkyl or by one or more R ^5c Substituted C ₁ -C ₆ alkyl-S-;

(2) Each R ^5a 、R ^5b And R is ^5c Each independently deuterium, halogen, -CN, or-OH; preferably, each R ^5a And R is ^5c Each independently deuterium or halogen; more preferably, each R ^5a And R is ^5c Each independently is halogen;

(3)Y ¹ is-O-, -S-, -NR ⁶ -、-S(O) ₂ -、-SO-、-NR ⁶ C (=o) -, -C (=o) O-, or- (CR) ⁷ R ⁷ ) _p1 The method comprises the steps of carrying out a first treatment on the surface of the Preferably Y ¹ is-O-, -S-, -NR ⁶ -、-S(O) ₂ -、-SO-、-NR ⁶ C (=o) - (carbonyl and Y ² Linked), -C (=o) -, -C (=o) O- (oxygen and Y) ² Linked) or- (CR) ⁷ R ⁷ ) _p1 The method comprises the steps of carrying out a first treatment on the surface of the More preferably, Y ₁ is-O-;

(4) Each R ⁶ Each independently is hydrogen, C ₁ -C ₆ Alkyl or deuterated C ₁ -C ₆ An alkyl group; preferably, each R ⁶ Each independently is hydrogen or C ₁ -C ₆ An alkyl group;

(5) Each R ⁷ Independently hydrogen or C ₁ -C ₆ An alkyl group; preferably, each R ⁷ Is hydrogen;

(6)Y ² is- (CR) ⁷ R ⁷ ) _p2 -、-NR ⁶ -、-C(＝O)(CR ⁷ R ⁷ ) _p3 - (carbonyl and Y) ¹ To be connected), O (CR) ⁷ R ⁷ ) _p4 (carbonyl and Y) ¹ Linked) -or-NR ⁶ (CR ⁷ R ⁷ ) _p5 - (N and Y) ¹ Connected with each other); preferably Y ₂ Is- (CR) ⁷ R ⁷ ) _p2 -；

(7) p1 is 0 or 1;

(8) p2 is 1 or 2; preferably, p2 is 1;

(9) p3 is 0, 1 or 2;

(10) p4 is 1 or 2;

(11) p5 is 1 or 2;

(12) Each R ¹ Each independently is deuterium, halogen, -OH, -CN, -N (R) ⁶ ) ₂ 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl-O-, substituted by one or more R ^1a Substituted C ₁ -C ₆ Alkyl or by one or more R ^1b Substituted C ₁ -C ₆ alkyl-O-;

alternatively, two R's on the same ring carbon atom ¹ Forming a 4-10 membered heterocyclic group or by one or more R ^1d Substituted 4-10 membered heterocyclyl; said 4-10 membered heterocyclyl and is substituted with one or more R ^1d The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or more of N, O and S, and the number of the hetero atom is independently 1, 2 or 3; preferably, each R ¹ Each independently deuterium, halogen, -OH, oxo (= O), -N (R) ⁶ ) ₂ 、C ₁ -C ₆ Alkyl or by one or more R ^1a Substituted C ₁ -C ₆ An alkyl group;

alternatively, two R's on the same ring carbon atom ¹ Forming a 4-10 membered heterocyclic group or by one or more R ^1d Substituted 4-10 membered heterogeniesA cyclic group; said 4-10 membered heterocyclyl and is substituted with one or more R ^1d The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or two of N and O, and the number of the hetero atom is independently 1, 2 or 3;

more preferably, each R ¹ independently-OH, C ₁ -C ₆ Alkyl or by one or more R ^1a Substituted C ₁ -C ₆ An alkyl group;

optimally, each R ¹ independently-OH or C ₁ -C ₆ An alkyl group;

alternatively, two R's on the same ring carbon atom ¹ Formed by one or more R ^1d Substituted 4-10 membered heterocyclyl; said quilt being one or more R' s ^1d The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or two of N and O, and the number of the hetero atom is independently 1, 2 or 3;

further preferably, two R's on the same ring carbon atom ¹ Formed by one or more R ^1d Substituted 4-10 membered heterocyclyl; said quilt being one or more R' s ^1d The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or two of N and O, and the number of the hetero atom is independently 1, 2 or 3;

(13) Each R ^1a 、R ^1b And R is ^1d Each independently is-CN, halogen, oxo (= O), C ₁ -C ₆ Alkyl or-N (R) ⁶ ) ₂ The method comprises the steps of carrying out a first treatment on the surface of the Preferably, each R ^1d Each independently is oxo (=o), C ₁ -C ₆ Alkyl or-N (R) ⁶ ) ₂ The method comprises the steps of carrying out a first treatment on the surface of the More preferably, each R ^1d Each independently is oxo (=o) or C ₁ -C ₆ An alkyl group; optimally, each R ^1d Is oxo (=o);

alternatively, each R ^1a Deuterium, -CN or halogen;

(14) n is 0, 1, 2, 3, 4, 5 or 6; preferably, n is 1 or 2; more preferably, n is 2;

(15) L is-O- (CR) ⁷ R ⁷ ) _n1 -; preferably, n1 is 1;

(16) n1 is 1 or 2;

(17)R ² is 4-10 membered heterocyclyl, 3-7 membered cycloalkyl, substituted with one or more R ^2a Substituted 3-7 membered cycloalkyl or by one or more R ^2c Substituted 4-10 membered heterocyclyl; said 4-10 membered heterocyclyl and is substituted with one or more R ^2c The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or more of N, O and S, and the number of the hetero atom is independently 1, 2 or 3; preferably, R ² Is 4-10 membered heterocyclyl, 3-7 membered cycloalkyl, substituted with one or more R ^2a Substituted 3-7 membered cycloalkyl or by one or more R ^2c Substituted 4-10 membered heterocyclyl; said 4-10 membered heterocyclyl and is substituted with one or more R ^2c The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or two of N and O, and the number of the hetero atom is independently 1, 2 or 3; more preferably, R ² Is 4-10 membered heterocyclyl, substituted with one or more R ^2a Substituted 3-7 membered cycloalkyl or by one or more R ^2c Substituted 4-10 membered heterocyclyl; said 4-10 membered heterocyclyl and is substituted with one or more R ^2c The hetero atoms in the "4-10 membered heterocyclic group" in the substituted 4-10 membered heterocyclic group are independently N, and the number of the hetero atoms is independently 1;

alternatively, R ² Is 4-10 membered heterocyclyl or substituted with one or more R ^2c Substituted 4-10 membered heterocyclyl; said 4-10 membered heterocyclyl and is substituted with one or more R ^2c The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or two of N and O, and the number of the hetero atom is independently 1, 2 or 3; preferably, the 4-10 membered heterocyclyl and is substituted with one or more R ^2c "4" in a substituted 4-10 membered heterocyclic groupThe heteroatoms in the-10 membered heterocyclyl "are independently N, the number of heteroatoms being 1;

Alternatively, R ² To be covered by one or more R ^2c Substituted 4-10 membered heterocyclyl; said quilt being one or more R' s ^2c The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or two of N and O, and the number of the hetero atom is independently 1, 2 or 3; preferably, said quilt is one or more R ^2c The hetero atoms in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group are independently N, and the number of the hetero atoms is 1;

(18) Each R ^2a And R is ^2c Each independently is halogen, -OH, deuterium, -CN, -N (R) ⁶ ) ₂ Or (4-10 membered heterocyclyl) -CH ₂ -, the (4-10 membered heterocyclic) -CH ₂ The heteroatoms in the "4-10 membered heterocyclic group" in the group are independently selected from one or more of N, O and S, and the number of the heteroatoms is independently 1, 2 or 3; preferably, each R ^2a And R is ^2c Each independently is halogen, -OH, -N (R) ⁶ ) ₂ Or (4-10 membered heterocyclyl) -CH ₂ -; the (4-10 membered heterocyclic) -CH ₂ The hetero atom in the "4-10 membered heterocyclic group" in the formula is independently selected from one or two of N and O, and the number of the hetero atom is independently 1 or 2; more preferably, each R ^2a And R is ^2c Independently halogen, -N (R) ⁶ ) ₂ Or (4-10 membered heterocyclyl) -CH ₂ -; the (4-10 membered heterocyclic) -CH ₂ The hetero atom in the "4-10 membered heterocyclic group" in the formula is independently selected from one or two of N and O, and the number of the hetero atom is independently 1 or 2; optimally, each R ^2c Independently halogen;

(19)R ³ is C ₆ -C ₁₀ Aryl, substituted by one or more R ^3a Substituted C ₆ -C ₁₀ Aryl, 5-to 10-membered heteroaryl, or substituted with one or more R ^3b Substituted 5-10 membered heteroaryl; the 5-10 membered heteroaryl and is substituted with one or more R ^3b The heteroatoms in the "5-10 membered heteroaryl" in the substituted 5-10 membered heteroaryl are independently N, O or S, the number of heteroatoms being independently 1, 2 or 3; preferably, R ³ Is C ₆ -C ₁₀ Aryl or by one or more R ^3a Substituted C ₆ -C ₁₀ An aryl group; optimally, R ³ To be covered by one or more R ^3a Substituted C ₆ -C ₁₀ An aryl group;

(20) Each R ^3a And R is ^3b Each independently is halogen, -OH, -CN, C ₁ -C ₆ Alkyl, substituted by one or more R ^3-a Substituted C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, substituted by one or more R ^3-e Substituted C ₂ -C ₆ Alkynyl or-N (R) ⁶ ) ₂ The method comprises the steps of carrying out a first treatment on the surface of the Preferably, each R ^3a And R is ^3b Each independently is halogen, -OH, C ₁ -C ₆ Alkyl, substituted by one or more R ^3-a Substituted C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkynyl, substituted by one or more R ^3-e Substituted C ₂ -C ₆ Alkynyl or-N (R) ⁶ ) ₂ The method comprises the steps of carrying out a first treatment on the surface of the More preferably, each R ^3a Each independently is halogen, -OH, C ₂ -C ₆ Alkynyl or by one or more R ^3-e Substituted C ₂ -C ₆ Alkynyl; optimally, each R ^3a Each independently is halogen, -OH or C ₂ -C ₆ Alkynyl;

(21) Each R ^3-a And R is ^3-e Each independently deuterium, halogen or-CN; preferably, each R ^3-a And R is ^3-e Each independently is halogen;

and (22) R ^4b Is H, deuterium, -N (R) ⁶ ) ₂ Or halogen; preferably, R ^4b Is H or halogen; optimally, R ^4b Is halogen.

4. A tetraheterocycle compound as set forth in any one of claims 1-3, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as set forth in formula I wherein the tetraheterocycle compound as set forth in formula I satisfies one or more of the following conditions:

(1)X ¹ is-N-, -CF-, -CCl-, -CS (CF) ₃ ) -or-C (CF) ₃ ) -; preferably X ¹ is-N-;

(2)Y ¹ is-O-, -NH-, -NCH ₃ -、-S-、-S(O) ₂ -、-CH ₂ -C (=o) O-, -C (=o) NH-, or-C (=o) -;

(3)Y ² is-CH ₂ -、-C(＝O)-、-OCH ₂ -、-NHCH ₂ -、-N(CH ₃ )CH ₂ -、-C(＝O)-CH ₂ -、-CH ₂ CH ₂ -；

(4)Y ¹ And Y ² Form-ch=ch-;

(5) Each R ¹ Each independently is fluorine, -OH, methyl, -NH ₂ Or, alternatively, two R's on the same ring carbon atom ¹ Formation of

(6)R ² Is that

(7)R ³ Is that

And (8) R ^4b Is fluorine.

5. A tetraheterocycle compound as set forth in any one of claims 1-3, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as set forth in formula I wherein the tetraheterocycle compound as set forth in formula I satisfies one or more of the following conditions:

the tetraheterocyclic compound shown in the formula I meets one or more of the following conditions:

(1)-Y ¹ -Y ² -is For example-> The end a is connected with an aromatic ring, and the end b is connected with a non-aromatic ring;

(2)Is->

6. The tetraheterocyclic compound shown in formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein the tetraheterocyclic compound shown in formula I is scheme 1, scheme 2, scheme 3 or scheme 4 as follows:

scheme 1: x is X ¹ is-N-;

Y ¹ is-O-;

Y ² is- (CR) ⁷ R ⁷ ) _p2 -；

p2 is 1 or 2;

each R ⁷ Independently hydrogen or C ₁ -C ₆ An alkyl group;

each R ^1a Deuterium, -CN, or halogen independently;

n is 1 or 2;

l is-O- (CR) ⁷ R ⁷ ) _n1 -; n1 is 1 or 2;

each R ^2c Independently halogen;

each R ^3-e Independently halogen;

R ^4b is halogen;

scheme 2: x is X ¹ is-N-;

Y ¹ is-O-;

Y ² is- (CR) ⁷ R ⁷ ) _p2 -；

p2 is 1 or 2;

each R ⁷ Independently hydrogen;

each R ¹ independently-OH or C ₁ -C ₆ An alkyl group;

n is 1 or 2;

l is-O- (CR) ⁷ R ⁷ ) _n1 -；

n1 is 1 or 2;

R ² to be covered by one or more R ^2c Substituted 4-a 10 membered heterocyclyl; said quilt being one or more R' s ^2c The hetero atom in the 4-10 membered heterocyclic group in the substituted 4-10 membered heterocyclic group is independently selected from one or two of N and O, and the number of the hetero atom is independently 1, 2 or 3;

each R ^2c Independently halogen;

each R ^3a Independently halogen, -OH or C ₂ -C ₆ Alkynyl;

R ^4b is halogen;

scheme 3: x is X ¹ is-N-;

Y ¹ is-O-;

Y ² is- (CR) ⁷ R ⁷ ) _p2 -；

p2 is 1 or 2;

each R ⁷ Independently hydrogen or C ₁ -C ₆ An alkyl group;

each R ^1d Independently oxo (= O) or C ₁ -C ₆ An alkyl group;

n is 2;

l is-O- (CR) ⁷ R ⁷ ) _n1 -; n1 is 1 or 2;

each R ^2c Independently halogen;

each R ^3-e Independently halogen;

R ^4b is halogen;

scheme 4: x is X ¹ is-N-;

Y ¹ is-O-;

Y ² is- (CR) ⁷ R ⁷ ) _p2 -；

p2 is 1 or 2;

each R ⁷ Independently hydrogen;

each R ^1d Independently oxo (=o);

n is 2;

l is-O- (CR) ⁷ R ⁷ ) _n1 -; n1 is 1 or 2;

Each R ^2c Independently halogen;

each R ^3a Independently halogen, -OH or C ₂ -C ₆ Alkynyl;

R ^4b is halogen.

7. The tetraheterocyclic compound shown in formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein the tetraheterocyclic compound shown in formula I is any one of the following compounds:

8. a pharmaceutical composition comprising a therapeutically effective amount of substance a and a pharmaceutically acceptable adjuvant; substance a is a tetraheterocyclic compound as described in any one of claims 1-7, as described in formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

9. Use of a substance a, which is a tetrahydric compound according to any one of claims 1 to 7, as shown in formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for the preparation of a RAS inhibitor;

the RAS inhibitors are useful in mammalian organisms; the method can also be used in vitro, and is mainly used for experiments;

and/or, the RAS may be KRAS or a KRAS mutation; such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61H, KRAS Q61K or KRAS Q61R; preferably, the RAS is a KRAS mutation; such as KRAS G12C or KRAS G12D.

10. Use of substance a for the preparation of a medicament for the treatment and/or prophylaxis of a RAS-mediated disease; substance a is a tetraheterocyclic compound as described in any one of claims 1-7, as shown in formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof; the substance a may be in a therapeutically effective amount;

and/or, the RAS may be KRAS or a KRAS mutation; such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61H, KRAS Q61K or KRAS Q61R; preferably, the RAS is a KRAS mutation; such as KRAS G12C or KRAS G12D;

and/or the disease may be selected from one or more of breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, kidney cancer, head, neck cancer, bone cancer, skin cancer, liver cancer, colorectal cancer, rectal cancer, colon cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia, melanoma, and pancreatic cancer; the lung cancer may be non-small cell lung cancer or small cell lung cancer.

11. Use of substance a in the manufacture of a medicament for the treatment and/or prevention of cancer; substance a is a tetraheterocyclic compound as described in any one of claims 1-7, as shown in formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof; the substance a may be in a therapeutically effective amount;

And/or the cancer may be associated with at least one of KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS Q61H, KRAS Q61K, and KRAS Q61R, e.g., KRAS G12C, KRAS G12D, or KRAS G12V;

and/or the cancer may be selected from one or more of breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, kidney cancer, head, neck cancer, bone cancer, skin cancer, liver cancer, colorectal cancer, rectal cancer, colon cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia, melanoma, and pancreatic cancer; the lung cancer may be non-small cell lung cancer or small cell lung cancer.