CN118812528A

CN118812528A - Heterocyclic SUMO1 small molecule degraders and uses thereof

Info

Publication number: CN118812528A
Application number: CN202410475171.3A
Authority: CN
Inventors: 刘斌; 安妮塔·贝莱尔
Original assignee: Xuanzhu Biopharmaceutical Co Ltd
Current assignee: Xuanzhu Biopharmaceutical Co Ltd
Priority date: 2023-04-20
Filing date: 2024-04-19
Publication date: 2024-10-22
Also published as: WO2024220556A2; WO2024220556A3

Abstract

The invention belongs to the technical field of medicines, and in particular relates to a heterocyclic SUMO1 small molecule degradation agent compound shown in a general formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a deuterated compound thereof, a pharmaceutical composition containing the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof or the deuterated compound thereof, a method for preparing the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof or the deuterated compound thereof, and application of the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof or the deuterated compound thereof.

Description

Heterocyclic SUMO1 small molecule degradation agent and application thereof

Cross Reference to Related Applications

The present application claims priority from U.S. provisional application No. 63/497,393 filed on 4/20 of 2023, the entire contents of which are incorporated herein by reference.

Technical Field

The invention belongs to the technical field of medicines, and in particular relates to a heterocyclic SUMO1 small molecule degradation agent shown in a formula (I), pharmaceutically acceptable salt thereof, stereoisomer thereof or deuterated compound thereof, a pharmaceutical composition containing the compound, a method for preparing the compound and application of the compound.

Background

The discovery of small molecule drugs has focused mainly on binding site occupancy and function inhibitors of the targeted proteins. More recently, a strategy to target protein degradation has been to discover proteolytic degradation agents that transfer drugs from functional inhibitors to target proteins by activating the ubiquitin-proteinase system (UPS). Ubiquitin (UB) is a small regulatory protein covalently linked to a substrate protein by catalytic reactions of ubiquitin activating enzyme (E1), binding enzyme (E2) and ligase (E3). The conjugated UB is removed from the substrate by the deubiquitinase. Through post-translational modification, this ubiquitination process regulates the cellular functions of the substrate protein, including protein degradation. In ubiquitination, the E3 ligase transfers UB directly to the underlying protein and selectively targets the protein to the 26S proteasome for degradation. Mammalian cells express about 660E 3 ligases, regulating 80% of human proteins. The target protein degradation strategy is to identify compounds that bind the E3 ligase and the substrate together, thereby inducing ubiquitination and degradation of the substrate protein, thereby eliminating the function of the target protein.

SUMO (small ubquitin-related modifier) itself is a UB-related modification, and is coupled to a substrate protein by E1 SUMO activating enzyme 1/2 (SAE 1/2), E2 UB coupling enzyme-9 (UBC 9) and E3 SUMO ligase, a process known as SUMO (sumoyization). SUMO has three forms: SUMO1-3; however, SUMO2 and SUMO3 are commonly referred to as SUMO2/3 because they share 96% amino acid sequences. SUMO1-3 has been reported to modify thousands of substrate proteins, thereby modulating cellular functions of these proteins under a variety of physiological and pathological conditions. The normal development and cellular function of many types of normal cells requires the common SUMO enzymes SAE1/2 and UBC9 and homotypic SUMO2/3, which raise safety issues as therapeutic targets. In contrast, SUMO1 is highly expressed in human cancers and drives cancer stem cell renewal, tumorigenesis and cancer progression (Nature Communications, month 6, 23 of 2014; 5:4234). Although SUMO1 may be a target for anticancer drugs, no SUMO1 inhibitor has been found in biochemical SUMO screening. Thus, SUMO1 is considered an intolerable protein.

80% Of human proteins are intolerable, mainly because they lack binding pockets, and thus compounds have difficulty turning on or off the function of the protein. Targeted protein degradation methods utilize natural cellular processes of protein ubiquitination and degradation. Using this advantage, researchers have identified compounds that induce ubiquitination and degradation of the SUMO1 protein (science of transformation, 2021, 10, 13; 13 (615): eabh, 1486). These compounds induce recruitment of SUMO1 to the cullin 1 (CUL 1) E3 ligase, leading to ubiquitination of the protein and subsequent degradation in human cancer cells by the 26S proteasome, but not including normal cells. These compounds inhibit the growth of a number of human cancer cell lines. Targeted participation has shown that compounds selectively reduce SUMO1, but not SUMO2/3 protein in patient-derived xenograft (PDX) cancer models. Treatment with the compounds inhibited the progression of PDX in breast, colon and lung cancers. The present invention relates to compounds collectively referred to as SUMO1 small molecule degradants.

Disclosure of Invention

The present disclosure provides a novel heterocyclic compound having a good selective degradation effect on SUMO proteins. In addition, these compounds are useful in the prevention and/or treatment of cancer and other related diseases.

In one aspect, the present invention provides a compound of the following formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterated compound thereof,

Wherein X is selected from N (R ₃), O or S;

Ring a, ring B are each independently selected from 5-8 membered cycloalkyl, 5-8 membered heterocyclyl, phenyl or 5-8 membered heteroaryl, and ring a and ring B share two adjacent ring atoms;

ring C, ring D are each independently selected from 5-8 membered cycloalkyl, 5-8 membered heterocyclyl, phenyl or 5-8 membered heteroaryl, and ring C and ring D share two adjacent ring atoms;

Cy is selected from hydrogen, R ₂ or 3-11 membered cycloalkyl optionally substituted with 1-3 substituents Q, 3-11 membered heterocyclyl; each Q is independently selected from H, halogen, hydroxy, amino, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy C _1-6 alkoxy, amino C _1-6 alkoxy 、-(CH₂)_p-N(R^a)(R^b)、-(CH₂)_p-O-R^a、-(CH₂)_p-P(O)(R^a)(R^b)、-(CH₂)_p-S(O)(R^a)、-(CH₂)_p-S(O)₂(R^a)、-(CH₂)_p-C(O)(R^a)、-(CH₂)_p-C(O)O(R^a)、-(CH₂)_p-O-C(O)(R^a)、-(CH₂)_p-C(O)N(R^a)(R^b)、-(CH₂)_p-N(R^b)-C(O)(R^a), optionally, 1 or more hydrogens of the C _1-6 alkyl being deuterated;

each R ₁, each R ₂ is independently selected from hydrogen, halogen, hydroxy, amino, cyano, carboxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, halo C _1-6 alkoxy, halo C _1-6 alkylthio, hydroxy C _1-6 alkoxy, amino C _1-6 alkoxy, hydroxy C _1-6 alkylthio, amino C _1-6 alkylthio, C _1-6 alkoxy-C _1-6 alkyl, or a 5 membered heteroaryl;

R ₃ is selected from hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, cyanoC _1-6 alkyl or C _1-6 alkoxy-C _1-6 alkyl;

R ^a、R^b is independently selected from hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, cyanoC _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl;

m is selected from 0,1, 2 or 3;

n is selected from 0,1, 2 or 3;

p is selected from 0,1, 2 or 3;

-represents a single or double bond bridging ring a and ring B, or bridging ring C and ring D.

In certain embodiments, ring a is selected from 5-7 membered cycloalkyl, 5-7 membered heterocyclyl, phenyl, or 5-7 membered heteroaryl, and ring a and ring B share two adjacent ring atoms.

In certain embodiments, ring a is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and ring a and ring B share two adjacent ring atoms.

In certain embodiments, ring a is selected from 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl, phenyl, or 5-6 membered heteroaryl, and ring a and ring B share two adjacent ring atoms.

In certain embodiments, ring A is selected from a 5-6 membered monocyclic cycloalkyl, a 5-6 membered monocyclic heterocyclyl containing 1-3 heteroatoms, phenyl, or a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur atoms.

In certain embodiments, ring B is selected from 5-7 membered cycloalkyl, 5-7 membered heterocyclyl, phenyl, or 5-7 membered heteroaryl, and ring a and ring B share two adjacent ring atoms.

In certain embodiments, ring B is selected from 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and ring a and ring B share two adjacent ring atoms.

In certain embodiments, ring B is selected from 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl, phenyl, or 5-6 membered heteroaryl, and ring a and ring B share two adjacent ring atoms.

In certain embodiments, ring B is from a 5-6 membered monocyclic cycloalkyl, a 5-6 membered monocyclic heterocyclyl containing 1-3 heteroatoms, phenyl, or a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur atoms.

In certain embodiments, ring a, ring B are each independently selected from cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, dihydropyrrolyl, pyrrolidinyl, dihydropyrazolyl, pyrazolidinyl, dihydropyrazolyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, hexahydropyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, dihydropyridazinyl, tetrahydropyrazinyl, hexahydropyridazinyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyranyl, dihydropyranyl, tetrahydropyranyl, thienyl, thiopyranyl, thiazolyl, oxazolyl, triazolyl, thiazolyl, tetrahydrothiazolyl, dihydro oxazolyl, or tetrahydrooxazolyl.

In certain embodiments, ring a is selected from cyclopentenyl, cyclohexenyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, or triazoles.

In certain embodiments, ring a is selected from cyclopentenyl, cyclohexenyl, phenyl, pyrazolyl, or imidazolyl.

In certain embodiments, ring B is selected from pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2, 4-triazinyl, furanyl, pyranyl, thienyl, thiopyranyl, thiazolyl, oxazolyl, or triazolyl.

In certain embodiments, ring B is selected from imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, or 1,2, 4-triazinyl.

In certain embodiments, ring a, ring B together form the following group:

And is also provided with The position is where ring B is attached to group X.

In certain embodiments, ring a, ring B together form the following group:

And is also provided with The position is where ring B is attached to group X.

In certain embodiments, ring C is selected from 5-7 membered cycloalkyl, 5-7 membered heterocyclyl, phenyl, or 5-7 membered heteroaryl, and ring C and ring D share two adjacent ring atoms.

In certain embodiments, ring C is selected from 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl, phenyl, or 5-6 membered heteroaryl, and ring C and ring D share two adjacent ring atoms.

In certain embodiments, ring C is selected from a 5-6 membered monocyclic cycloalkyl, a 5-6 membered monocyclic heterocyclyl containing 1-3 heteroatoms, phenyl, or a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur atoms.

In certain embodiments, ring C is selected from 5-6 membered heteroaryl groups containing 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur atoms.

In certain embodiments, ring C is selected from a 5-membered heteroaryl group containing 1-3 heteroatoms selected from nitrogen atoms, oxygen atoms, or sulfur atoms.

In certain embodiments, ring C is selected from a 5-membered heteroaryl group containing 1 nitrogen atom and 0-2 heteroatoms selected from nitrogen atoms, oxygen atoms, or sulfur atoms.

In certain embodiments, ring C is selected from imidazolyl, 1,2, 4-triazolyl, or oxazolyl.

In certain embodiments, ring D is selected from 5-7 membered cycloalkyl, 5-7 membered heterocyclyl, phenyl, or 5-7 membered heteroaryl, and ring C and ring D share two adjacent ring atoms.

In certain embodiments, ring D is selected from 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl, phenyl, or 5-6 membered heteroaryl, and ring C and ring D share two adjacent ring atoms.

In certain embodiments, ring D is selected from 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl containing 1-3 heteroatoms, phenyl, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur atoms.

In certain embodiments, ring D is selected from phenyl or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur atoms.

In certain embodiments, ring D is selected from phenyl or 6 membered heteroaryl groups containing 1-2 nitrogen atoms. In certain embodiments, ring D is selected from phenyl or pyridinyl.

In certain embodiments, ring C, ring D are each independently selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, pyranyl, thienyl, thiopyranyl, thiazolyl, oxazolyl, triazolyl, or triazinyl.

In certain embodiments, ring C, ring D together form the following group:

And is also provided with The position is where ring C is attached to group X.

In certain embodiments, cy is selected from hydrogen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, halo C _1-6 alkoxy, halo C _1-6 alkylthio, or C _1-6 alkoxy-C _1-6 alkyl.

In certain embodiments, cy is selected from 3-6 membered monocyclic cycloalkyl optionally substituted with 1-2 substituents Q, 3-6 membered monocyclic heterocyclyl, 6-11 membered fused ring groups, 7-11 membered spiro ring groups, 7-9 membered bridged ring groups, 6-11 membered fused heterocyclic groups, 7-11 membered spiro heterocyclic groups, or 7-9 membered bridged heterocyclic groups.

In certain embodiments, cy is selected from 3-6 membered saturated monocyclic cycloalkyl optionally substituted with 1-2 substituents Q, 3-6 membered saturated monocyclic heterocyclyl, 6-11 membered saturated fused ring groups, 7-11 membered saturated spiro ring groups, 7-9 membered saturated bridged ring groups, 6-11 membered saturated fused ring groups, 7-11 membered saturated spiro ring groups, or 7-9 membered saturated bridged heterocyclic groups.

In certain embodiments, cy is selected from 3-6 membered monocyclic cycloalkyl, 3-6 membered monocyclic heterocyclyl optionally substituted with 1-2 substituents Q. In certain embodiments, cy is selected from 3-6 membered monocyclic cycloalkyl optionally substituted with 1-2 substituents Q, 3-6 membered monocyclic heterocyclyl containing 1-2 heteroatoms selected from nitrogen, oxygen or sulfur atoms. In certain embodiments, cy is selected from 3-6 membered monocyclic heterocyclic groups containing 1-2 heteroatoms selected from nitrogen, oxygen or sulfur atoms, optionally substituted with 1-2 substituents Q.

In certain embodiments, cy is selected from a 3-6 membered saturated monocyclic heterocyclic group containing 1-2 heteroatoms selected from nitrogen, oxygen, or sulfur atoms, optionally substituted with 1-2 substituents Q.

In certain embodiments, cy is a radical derived from a compound (e.g., by losing one electron, thereby forming a radical that can readily form a covalent bond with another radical) selected from the following groups optionally substituted with 1-2 substituents Q:

In certain embodiments, cy is selected from the following groups optionally substituted with 1-2 substituents Q:

And is also provided with The position Cy is the position where it is attached to ring D.

In certain embodiments, R ^a is selected from hydrogen, C _1-4 alkyl, halo C _1-4 alkyl, hydroxy C _1-4 alkyl, amino C _1-4 alkyl, or C _1-4 alkoxy-C _1-4 alkyl.

In certain embodiments, R ^a is selected from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, 1-hydroxyisopropyl, aminomethyl, 1-aminoethyl, 1-aminopropyl, 1-aminoisopropyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, or ethoxyethyl.

In certain embodiments, R ^a is selected from hydrogen, methyl, ethyl, propyl, or isopropyl.

In certain embodiments, R ^a is selected from hydrogen or methyl.

In certain embodiments, X is selected from N (R ₃), O, or S; r ₃ is selected from hydrogen or methyl.

In certain embodiments, m is selected from 0 or 1; n is selected from 0 or 1.

In certain embodiments, m is 1; n is selected from 0 or 1.

In certain embodiments, a compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterated compound thereof, wherein,

X is selected from N (R ₃);R₃ is selected from hydrogen or methyl;

ring a, ring B together form the following group:

And is also provided with The position of ring B is the position where ring B is attached to group X;

ring C, ring D together form the following group:

And is also provided with The position is the position where ring C is attached to group X;

Cy is selected from hydrogen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, halo C _1-6 alkoxy, halo C _1-6 alkylthio, C _1-6 alkoxy-C _1-6 alkyl or a group optionally substituted with 1-2 substituents Q:

Each Q is independently selected from H, halogen, hydroxy, amino, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy C _1-6 alkoxy, amino C _1-6 alkoxy, - (CH ₂)_p-S(O)(R^a)、-(CH₂)_p-S(O)₂(R^a) or- (CH ₂)_p-C(O)(R^a), optionally 1 or more hydrogens in the C _1-6 alkyl are deuterated;

R ₁、R₂ is independently selected from hydrogen, halogen, hydroxy, amino, cyano, carboxy, C _1-6 alkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, cyanoC _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, haloC _1-6 alkoxy, haloC _1-6 alkylthio, hydroxyC _1-6 alkoxy, aminoC _1-6 alkoxy, hydroxyC _1-6 alkylthio, aminoC _1-6 alkylthio, C _1-6 alkoxy-C _1-6 alkyl, or a 5 membered nitrogen containing heteroaryl;

R ^a is selected from hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, cyanoC _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl;

m is selected from 0 or 1;

n is selected from 0 or 1;

p is selected from 0,1, 2 or 3.

X is NH;

ring a, ring B together form the following group:

ring C, ring D together form the following group:

Cy is selected from hydrogen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl or the following optionally substituted with 1-2 substituents Q:

Each Q is independently selected from H, halogen, hydroxy, amino, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy C _1-6 alkoxy, amino C _1-6 alkoxy, -S (O) (R ^a)、-S(O)₂(R^a), or-C (O) (R ^a), optionally 1 or more hydrogens in the C _1-6 alkyl are deuterated;

R ^a is selected from hydrogen or C _1-6 alkyl;

m is selected from 0 or 1;

n is selected from 0 or 1.

X is NH;

ring a, ring B together form the following group:

ring C, ring D together form the following group:

cy is selected from the following groups optionally substituted with 1-2 substituents Q:

Each Q is independently selected from H, halogen, hydroxy, amino, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy C _1-6 alkoxy, amino C _1-6 alkoxy, -S (O) ₂(R^a), or-C (O) (R ^a), optionally, 1 or more hydrogens in the C _1-6 alkyl are deuterated;

R ₁、R₂ is independently selected from hydrogen, halogen, cyano, carboxy, C _1-6 alkyl, haloC _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, cyanoC _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, haloC _1-6 alkoxy, haloC _1-6 alkylthio, C _1-6 alkoxy-C _1-6 alkyl, imidazolyl, 1,2, 4-triazolyl or tetrazolyl;

R ^a is selected from hydrogen or methyl;

m is selected from 0 or 1;

n is selected from 0 or 1.

X is NH;

ring a, ring B together form the following group:

ring C, ring D together form the following group:

cy is selected from hydrogen, C _1-6 alkyl or hydroxy C _1-6 alkyl;

R ₁, each R ₂ is independently selected from hydrogen, halogen, hydroxy, amino, cyano, carboxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, halo C _1-6 alkoxy, halo C _1-6 alkylthio, hydroxy C _1-6 alkoxy, amino C _1-6 alkoxy, hydroxy C _1-6 alkylthio, amino C _1-6 alkylthio, C _1-6 alkoxy-C _1-6 alkyl, imidazolyl, 1,2, 4-triazolyl or tetrazolyl;

m is selected from 0 or 1;

n is selected from 1 or 2.

In one aspect, the present invention provides a compound represented by the following general formula (I'), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a deuterated compound thereof,

Wherein,

Y is selected from N, NH, O or S;

y' is selected from N, NH, O or CH;

y' is N or C;

m is N or CH;

M' is N or CH;

(dotted circle within ring) indicates that the ring is aromatic;

-represents a single or double bond bridging ring a and ring B;

ring a, ring B, X, R ₁、R₂、R₃、Cy、Q、R^a、R^b, m, n, p are as defined in any of the previous schemes.

In certain embodiments, a compound represented by the above formula (I'), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterated compound thereof, wherein,

X is selected from N (R ₃), O or S;

Y is selected from NH, O or S;

Y' is selected from N or CH;

y' is N or C;

Cy is selected from hydrogen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl or 3-6 membered monocyclic cycloalkyl optionally substituted with 1-2 substituents Q, 3-6 membered monocyclic heterocyclyl, 6-11 membered fused ring groups, 7-11 membered spirocyclic groups, 7-9 membered bridged ring groups, 6-11 membered fused ring groups, 7-11 membered spiroheterocyclic groups or 7-9 membered bridged ring groups;

R ₃ is selected from hydrogen, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxyC _1-6 alkyl or C _1-6 alkoxy-C _1-6 alkyl;

m is selected from 0, 1 or 2;

n is selected from 0, 1 or 2;

p is selected from 0, 1 or 2;

-represents a single bond or a double bond bridging ring a and ring B.

X is selected from N (R ₃), O or S; r ₃ is selected from hydrogen or C _1-6 alkyl;

ring a, ring B together form the following group:

Y is selected from NH, O or S;

Y' is selected from N or CH;

y' is N or C;

Each Q is independently selected from H, halogen, hydroxy, amino, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy C _1-6 alkoxy, amino C _1-6 alkoxy, -S (O) ₂(R^a), or-C (O) (R ^a), optionally 1 or more hydrogens in the C _1-6 alkyl are deuterated;

Each R ₁, each R ₂ is independently selected from hydrogen, halogen, cyano, carboxy, C _1-6 alkyl, halo C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, halo C _1-6 alkoxy, halo C _1-6 alkylthio, C _1-6 alkoxy-C _1-6 alkyl, imidazolyl, 1,2, 4-triazolyl, or tetrazolyl;

R ^a is selected from hydrogen or C _1-6 alkyl;

m is selected from 0 or 1;

n is selected from 0 or 1.

X is NH;

ring a, ring B together form the following group:

Y is selected from NH, O or S;

Y' is selected from N or CH;

cy is selected from hydrogen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, halo C _1-6 alkyl or hydroxy C _1-6 alkyl;

m is selected from 0 or 1;

n is selected from 1 or 2.

In one aspect, the present invention provides a compound of the following formula (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a deuterated compound thereof,

Wherein each Y is independently selected from NH, O, or S; y ₁ is selected from N or CH; y ₂ is selected from N or CH; x, R ₁、R₂、R₃、Cy、Q、R^a、R^b, m, n, p are as defined in any of the preceding schemes.

In one aspect, the present invention provides a compound of the following formula (IIa), (IIb), (IIc), (IId), (IIe), (IIf) or (IIg), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a deuterated species thereof,

Wherein each Y is independently selected from NH, O, or S;

y ₁ is selected from N or CH; y ₂ is selected from N or CH;

X, R ₁、R₂、R₃、Cy、Q、R^a、R^b, m, n, p are as defined in any of the preceding schemes.

In certain embodiments, a compound represented by formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe), formula (IIf), or formula (IIg), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterated species thereof, wherein,

Each Y is independently selected from NH, O or S;

y ₁ is selected from N or CH; y ₂ is selected from N or CH;

x is NH;

m is selected from 0 or 1;

n is selected from 0 or 1;

p is selected from 0,1, 2 or 3.

R ^a is selected from hydrogen or C _1-6 alkyl;

m is selected from 0 or 1;

n is selected from 0 or 1.

R ^a is selected from hydrogen or methyl;

m is selected from 0 or 1;

n is selected from 0 or 1.

In certain embodiments, a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe) or formula (IIf), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a deuterated species thereof, wherein,

Each Y is independently selected from NH, O or S;

y ₁ is selected from N or CH; y ₂ is selected from N or CH;

x is NH;

Cy is selected from hydrogen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl;

m is selected from 0 or 1;

n is selected from 0, 1 or 2.

In certain embodiments described above, each Q is independently selected from H, halogen, hydroxy, amino, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy C _1-6 alkoxy, amino C _1-6 alkoxy, - (CH ₂)_p-S(O)(R^a)、-(CH₂)_p-S(O)₂(R^a) or- (CH ₂)_p-C(O)(R^a), optionally 1 or more hydrogens in the C _1-6 alkyl are deuterated.

In certain embodiments described above, each Q is independently selected from H, halogen, hydroxy, amino, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy C _1-6 alkoxy, amino C _1-6 alkoxy, -S (O) (R ^a)、-S(O)₂(R^a), or-C (O) (R ^a), optionally, 1 or more hydrogens in the C _1-6 alkyl are deuterated.

In certain embodiments described above, each Q is independently selected from H, halogen, hydroxy, amino, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy C _1-6 alkoxy, amino C _1-6 alkoxy, -S (O) ₂(R^a), or-C (O) (R ^a), optionally, 1 or more hydrogens in the C _1-6 alkyl are deuterated.

In certain embodiments described above, each Q is independently selected from H, hydroxy, amino, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, -S (O) ₂(R^a), or-C (O) (R ^a), optionally, 1 or more hydrogens in the C _1-6 alkyl are deuterated.

In certain embodiments described above, each Q is independently selected from H, hydroxy, amino, C _1-4 alkyl, fluoro C _1-4 alkyl, hydroxy C _1-4 alkyl, amino C _1-4 alkyl, C _1-4 alkoxy-C _1-4 alkyl, -S (O) ₂(R^a), or-C (O) (R ^a), optionally hydrogen in the C _1-4 alkyl is deuterated.

In certain embodiments described above, each Q is independently selected from H, hydroxy, amino, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, 1-hydroxyisopropyl, aminomethyl, 1-aminoethyl, 1-aminopropyl, 1-aminoisopropyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, -S (O) ₂(R^a), or-C (O) (R ^a), optionally hydrogen in the methyl, ethyl, propyl, isopropyl groups is deuterated.

In certain embodiments described above, each R ₁, each R ₂ is independently selected from hydrogen, halogen, cyano, carboxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, halo C _1-6 alkoxy, halo C _1-6 alkylthio, C _1-6 alkoxy-C _1-6 alkyl, imidazolyl, 1,2, 4-triazolyl, or tetrazolyl.

In certain embodiments described above, each R ₁ is independently selected from hydrogen, halogen, hydroxy, amino, cyano, carboxy, C _1-4 alkyl, fluoro C _1-4 alkyl, cyano C _1-4 alkyl, hydroxy C _1-4 alkyl, amino C _1-4 alkyl, C _1-4 alkoxy, fluoro C _1-4 alkoxy, hydroxy C _1-4 alkoxy, amino C _1-4 alkoxy, C _1-4 alkoxy-C _1-4 alkyl, imidazolyl, 1,2, 4-triazolyl, or tetrazolyl.

In certain embodiments described above, each R ₁ is independently selected from the group consisting of hydrogen, halogen, cyano, carboxy, C _1-4 alkyl, fluoro C _1-4 alkyl, cyano C _1-4 alkyl, C _1-4 alkoxy, fluoro C _1-4 alkoxy, C _1-4 alkoxy-C _1-4 alkyl,

In certain embodiments described above, each R ₁ is independently selected from the group consisting of hydrogen, fluoro, chloro, cyano, carboxy, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, cyanomethyl, cyanoethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methoxyethyl, ethoxymethyl, difluoromethoxy, trifluoromethoxy, difluoromethoxy, trifluoromethoxy,

In certain embodiments described above, each R ₂ is independently selected from hydrogen, halogen, hydroxy, amino, cyano, C _1-4 alkyl, fluoro C _1-4 alkyl, cyano C _1-4 alkyl, hydroxy C _1-4 alkyl, amino C _1-4 alkyl, C _1-4 alkoxy, fluoro C _1-4 alkoxy, hydroxy C _1-4 alkoxy, amino C _1-4 alkoxy, or C _1-4 alkoxy-C _1-4 alkyl.

In certain embodiments described above, each R ₂ is independently selected from hydrogen, fluoro, chloro, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, 1-hydroxyisopropyl, aminomethyl, 1-aminoethyl, 1-aminopropyl, 1-aminoisopropyl, cyanomethyl, cyanoethyl, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methoxyethyl, or ethoxymethyl.

In certain embodiments described above, each R ₂ is independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, 1-hydroxyethyl, 1-hydroxypropyl, 1-hydroxyisopropyl, 1-aminoethyl, 1-aminopropyl, 1-aminoisopropyl.

In certain embodiments described above, each R ₂ is independently selected from hydrogen, fluorine, chlorine, propyl, isopropyl, 1-hydroxyethyl, or 1-hydroxypropyl.

In certain embodiments described above, each R ₂ is independently selected from hydrogen, fluorine, or chlorine.

In certain embodiments described above, each R ₂ is independently selected from hydrogen or fluorine.

In one aspect, the invention provides a compound, pharmaceutically acceptable salt thereof, stereoisomer thereof, or deuterate thereof, as shown below:

in another aspect, the invention also provides a pharmaceutical composition comprising a compound as described above, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterated compound thereof, and one or more pharmaceutically acceptable excipients, which pharmaceutical composition may be in any pharmaceutically acceptable dosage form. Pharmaceutically acceptable excipients are non-toxic, compatible with the active ingredient and otherwise biologically compatible substances for use in the organism. The choice of a particular excipient will depend on the mode of administration or type and state of disease used to treat a particular patient.

In certain embodiments, the above pharmaceutical compositions may be administered orally, parenterally, rectally, or pulmonary, etc., to a patient or subject in need of such treatment. For oral administration, the pharmaceutical composition may be formulated into oral preparations, for example, into conventional oral solid preparations such as tablets, capsules, pills, granules, etc.; can also be made into oral liquid preparation such as oral solution, oral suspension, syrup, etc. For parenteral administration, the pharmaceutical compositions described above may also be formulated as injections, including injectable solutions, injectable sterile powders, and injectable concentrated solutions. For rectal administration, the pharmaceutical composition may be formulated as suppositories and the like. For pulmonary administration, the pharmaceutical composition may be formulated as an inhalation, aerosol, powder spray or spray.

In another aspect, the pharmaceutical compositions of the present invention comprise a compound as described above, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterated thereof, and may further comprise one or more second therapeutically active agents.

In a further aspect, the invention also relates to the use of a compound as described hereinbefore, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a deuterated thereof for the manufacture of a medicament for the prophylaxis and/or treatment of cancer or an autoimmune disease.

Further, the present invention also relates to the use of a compound as described above, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a deuterated product thereof for the preparation of a medicament for preventing and/or treating a cancer or an autoimmune disease associated with SUMO.

In a further aspect, the present invention also relates to the use of a pharmaceutical composition comprising a compound as described hereinbefore, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a deuterated form thereof, for the manufacture of a medicament for the prevention and/or treatment of cancer or an autoimmune disease.

Further, the present invention also relates to the use of a pharmaceutical composition comprising the compound as described above, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a deuterated product thereof for the preparation of a medicament for preventing and/or treating a cancer or an autoimmune disease associated with SUMO.

In certain embodiments, the cancer is selected from melanoma, lung cancer, kidney cancer, lymphoma, head and neck cancer, urothelial cancer, prostate cancer, bladder cancer, breast cancer, gastric cancer, colorectal cancer, leukemia, cervical cancer, liver cancer, ovarian cancer, pancreatic cancer, endometrial cancer, myeloma, cholangiocarcinoma, brain cancer, sarcoma, vascular endothelial cell tumor, epithelial cancer, esophageal cancer, testicular cancer, glioma, bone cancer, nasopharyngeal cancer, skin cancer, squamous cell cancer, oral cancer, or thyroid cancer.

In certain embodiments, the autoimmune disease is selected from Rheumatoid Arthritis (RA), granulomatous Polyangiitis (GPA), microscopic Polyangiitis (MPA), pemphigus Vulgaris (PV), thrombotic Thrombocytopenic Purpura (TTP), or placian Mu Sen encephalitis (RE).

In another aspect, the present invention also provides a method for preventing and/or treating cancer or autoimmune disease, comprising administering to a patient in need thereof a prophylactically and/or therapeutically effective amount of a compound as described above, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutical composition comprising the same.

In another aspect, the invention also provides a kit comprising an effective amount of one or more of the compounds described above, pharmaceutically acceptable salts thereof, stereoisomers thereof, or deuterates thereof.

In another aspect, the invention also provides a kit comprising:

(a) An effective amount of one or more of the compounds described hereinbefore, pharmaceutically acceptable salts thereof, stereoisomers thereof, or deuterated forms thereof,

And (b) an effective amount of one or more anticancer agents.

An "effective amount" as used herein refers to a dosage of a drug that is capable of preventing, alleviating, delaying, inhibiting or curing a condition in a subject. The size of the dose administered is related to the mode of administration of the drug, the pharmacokinetics of the agent, the severity of the disease, the individual sign (sex, weight, height, age) of the subject, etc.

Interpretation of the terms

In the present invention, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art, however, for a better understanding of the present invention, the following definitions of some terms are provided. When the definition and interpretation of terms provided by the present invention are not identical to the meanings commonly understood by those skilled in the art, the definition and interpretation of terms provided by the present invention is in control.

"Halogen" as used herein refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

"C _1-6 alkyl" as used herein means a straight or branched chain alkyl group containing 1 to 6 carbon atoms, optionally, the hydrogen in the C _1-6 alkyl group may be deuterated, for example, 1,2,3, 4, 5 or 6 hydrogens may be deuterated. C _1-6 alkyl includes, for example, "C _1-4 alkyl", "C _1-3 alkyl", "C _1-2 alkyl", "C _2-6 alkyl", "C _2-5 alkyl", "C _2-4 alkyl", "C _2-3 alkyl", and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. As used herein, "C _1-4 alkyl" refers to a specific example of C _1-6 alkyl containing 1 to 4 carbon atoms.

As used herein, "C _1-6 alkoxy" refers to "C _1-6 alkyl-O-", and "C _1-6 alkyl" is as defined above. As used herein, "C _1-4 alkoxy" refers to "C _1-4 alkyl-O-", and "C _1-4 alkyl" is as defined above.

The term "C _1-6 alkylthio" as used herein refers to "C _1-6 alkyl-S-", and "C _1-6 alkyl" is as defined above. The term "C _1-4 alkylthio" as used herein refers to "C _1-4 alkyl-S-", and "C _1-4 alkyl" is as defined above.

"HydroxyC _1-6 alkyl, aminoC _1-6 alkyl, haloC _1-6 alkyl, cyanoC _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl" as used herein means that one or more hydrogens of the C _1-6 alkyl group are replaced with one or more (e.g., 1,2,3,4, 5 or 6) hydroxyl, amino, halogen (preferably fluorine), cyano or C _1-6 alkoxy groups, respectively. C _1-6 alkyl, C _1-6 alkoxy are as defined above.

The term "hydroxy C _1-6 alkoxy, amino C _1-6 alkoxy, halo C _1-6 alkoxy, cyano C _1-6 alkoxy" as used herein means that one or more hydrogens of the "C _1-6 alkoxy" are replaced with one or more hydroxy, amino, halogen or cyano groups.

The term "hydroxy C _1-6 alkylthio, amino C _1-6 alkylthio, halogenated C _1-6 alkylthio" as used herein means that one or more hydrogens in the "C _1-6 alkylthio" are replaced with one or more hydroxy, amino or halogen groups.

As used herein, "fluoro C _1-6 alkyl", "fluoro C _1-6 alkoxy" refer to "C _1-6 alkyl" and "C _1-6 alkoxy", respectively, wherein one or more hydrogens are replaced with one or more fluorine atoms.

"3-11 Membered heterocyclic group" as used herein refers to a saturated or partially saturated and non-aromatic, monocyclic or polycyclic cyclic group containing at least one heteroatom or group (e.g., containing 1,2, 3, 4 or 5) and having 3 to 11 ring atoms, said heteroatom or group being selected from nitrogen, oxygen, sulfur, optionally, a ring atom (e.g., carbon, nitrogen or sulfur) in the cyclic structure may be oxo. "3-11 membered heterocyclyl" includes, but is not limited to, "3-10 membered heterocyclyl", "3-8 membered mono-heterocyclyl", "6-11 membered fused heterocyclyl", "7-11 membered spiro heterocyclyl", "7-9 membered bridged heterocyclyl".

"3-8 Membered mono-heterocyclic group" as used herein means a saturated or partially saturated and non-aromatic monocyclic ring group containing at least one heteroatom (e.g., containing 1,2, 3, 4 or 5) and having 3 to 8 ring atoms, the heteroatom being a nitrogen atom, an oxygen atom and/or a sulfur atom, optionally, a ring atom in the ring structure (e.g., carbon atom, nitrogen atom or sulfur atom) may be oxo. The "3-8 membered monocyclic group" described in the present invention includes "3-8 membered saturated monocyclic group" and "3-8 membered partially saturated monocyclic group". Preferably, the "3-8 membered mono-heterocyclic group" according to the present invention contains 1-3 heteroatoms; preferably, the "3-8 membered mono-heterocyclic group" according to the present invention contains 1-2 hetero atoms, and the hetero atoms are selected from nitrogen atoms and/or oxygen atoms; preferably, the "3-8 membered mono-heterocyclic group" according to the present invention contains 1 hetero atom, which is a nitrogen atom, an oxygen atom or a sulfur atom. The "3-8 membered mono-heterocyclic group" is preferably "3-7 membered mono-heterocyclic group", "3-6 membered mono-heterocyclic group", "4-7 membered mono-heterocyclic group", "4-6 membered mono-heterocyclic group", "6-8 membered mono-heterocyclic group", "5-8 membered saturated mono-heterocyclic group", "5-8 membered partially saturated mono-heterocyclic group", "5-7 membered saturated mono-heterocyclic group", "5-7 membered partially saturated mono-heterocyclic group", "5-6 membered saturated mono-heterocyclic group", "5-6 membered partially saturated mono-heterocyclic group", "3-6 membered nitrogen mono-heterocyclic group", "3-6 membered saturated nitrogen mono-heterocyclic group", "5-6 membered saturated nitrogen mono-heterocyclic group", "6 membered saturated nitrogen mono-heterocyclic group" or the like. Specific examples of "3-8 membered mono-heterocyclyl" include, but are not limited to: aziridinyl, 2H-aziridinyl, diazinoalkyl, 3H-diazinopropenyl, azetidinyl, oxetanyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, 1, 4-dioxadienyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridinyl, piperidonyl, tetrahydropyridinonyl, piperazinyl, morpholinyl, 4, 5-dihydro-oxazolyl, 4, 5-dihydro-isoxazolyl, 2, 3-dihydro-isoxazolyl, oxazolidinyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, and the like.

The term "6-11 membered condensed ring heterocyclic group" as used herein refers to a saturated or partially saturated, non-aromatic cyclic group containing 6 to 11 ring atoms and having at least one ring atom as a heteroatom, wherein one of the condensed rings may be an aromatic ring, but the whole condensed ring does not have aromaticity, and the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom, which is formed by sharing two or more adjacent atoms with each other. Wherein the ring atoms (e.g., carbon, nitrogen, or sulfur atoms) in the cyclic structure may optionally be oxo. Specific examples thereof include, but are not limited to: dihydrofuropyridines, 3, 4-dihydro-2H-pyranopyridines, 3, 4-dihydro-2H-oxazinopyridines, dihydrooxazinopyrimidines, benzodihydrofuranyl groups,Etc.

The "7-11 membered spiroheterocyclic group" in the present invention means a saturated or partially saturated cyclic structure containing 7 to 11 ring atoms formed by sharing 1 ring atom with each other by two or more cyclic structures, wherein at least one ring atom is a heteroatom or a group, for example N, NH, O, S, CO, SO, SO ₂ or the like, preferably the number of heteroatoms or groups is 1,2, 3, 4 or 5, more preferably 1 or 2. Examples include "9-11 membered spiroheterocyclyl", "9-11 membered saturated spiroheterocyclyl", "9-11 membered partially saturated spiroheterocyclyl", and the like. Specific examples include, but are not limited to:

The "7-to 9-membered bridged heterocyclic group" as used herein refers to a saturated or partially saturated cyclic structure containing 7 to 9 ring atoms formed by sharing two or more cyclic structures with each other, not adjacent ring atoms, wherein at least one ring atom is a heteroatom or a group, for example N, NH, O, S, CO, SO, SO ₂ or the like, preferably the number of heteroatoms or groups is 1,2,3, 4 or 5, more preferably 1 or 2. Examples include "7-8 membered bridged heterocyclic group", "7-8 membered saturated bridged heterocyclic group", "8 membered saturated bridged heterocyclic group", and the like. Specific examples include, but are not limited to:

"3-11 membered cycloalkyl" as used herein refers to a saturated or partially saturated and non-aromatic monocyclic or polycyclic cyclic group containing 3-11 ring atoms, and "3-11 membered cycloalkyl" as used herein includes, but is not limited to, "3-10 membered cycloalkyl", "3-8 membered monocyclic cycloalkyl", "3-6 membered monocyclic cycloalkyl", "5-8 membered monocyclic cycloalkyl", "5-7 membered monocyclic cycloalkyl", "5-6 membered monocyclic cycloalkyl", "6-11 membered fused ring alkyl", "7-11 membered spirocyclic group", "7-9 membered bridged cyclic group". Wherein "3-8 membered monocyclic cycloalkyl" includes, but is not limited to, cyclopentyl, cyclohexyl,

The "7-11 membered spirocyclic group" as used herein refers to a saturated or partially saturated cyclic structure containing 7-11 ring carbon atoms, which is formed by sharing 1 ring atom with two or more cyclic structures, for example, "8-11 membered spirocyclic group", "8-11 membered saturated spiroheterocyclic group", "8-11 membered partially saturated spiroheterocyclic group", "9-11 membered spirocyclic group", "9-11 membered saturated spiroheterocyclic group", "9-11 membered partially saturated spiroheterocyclic group" and the like. Specific examples include, but are not limited to:

the term "7-9 membered bridged ring group" as used herein refers to a saturated or partially saturated cyclic structure containing 7 to 9 ring carbon atoms, which is formed by two or more cyclic structures sharing two non-adjacent ring atoms with each other, and includes, for example, "7-8 membered bridged ring group", "7-8 membered saturated bridged ring group", "8 membered bridged heterocyclic group", "8 membered saturated bridged ring group", "8 membered partially saturated bridged ring group", and the like. Specific examples include, but are not limited to:

The term "6-11 membered condensed ring alkyl" as used herein refers to a saturated or partially saturated, non-aromatic cyclic group containing 6 to 11 ring carbon atoms, which is formed by sharing two or more adjacent atoms with each other by two or more cyclic structures, wherein one ring of the condensed rings may be an aromatic ring, but the whole condensed ring does not have aromaticity, and examples include, but are not limited to: Etc.

"5-8 Membered heteroaryl" as used herein refers to a monocyclic cyclic group having aromaticity which contains 5-8 ring atoms, at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. "5-8 membered heteroaryl" includes, for example, "5-7 membered heteroaryl", "5-6 membered nitrogen containing heteroaryl", "6 membered nitrogen containing heteroaryl", etc., wherein the heteroatom in the "nitrogen containing heteroaryl" contains at least one nitrogen atom, for example, contains only 1 or 2 nitrogen atoms, or contains one nitrogen atom and 1 or 2 other heteroatoms (e.g., oxygen and/or sulfur atoms), or contains 2 nitrogen atoms and 1 or 2 other heteroatoms (e.g., oxygen and/or sulfur atoms). Specific examples of "5-7 membered heteroaryl" include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, azepanyl, 1, 3-diazinohepttrienyl, azocyclotetraenyl and the like. The "5-6 membered heteroaryl" refers to a specific example in which 5-8 membered heteroaryl contains 5-6 ring atoms.

"Oxo" as used herein refers to a structure in which a carbon, nitrogen or sulfur atom is substituted and the carbon, nitrogen or sulfur atom is oxo to form c= O, N = O, S =o or SO ₂.

"Optionally substituted" as used herein refers to both cases where one or more hydrogen atoms on the substituted group may be "substituted" or "unsubstituted" with one or more substituents.

The invention relates to an N (R ₃) which is the following structure:

The "N" of the invention refers to the following structure:

the term "CH" as used herein refers to the following structure:

As used herein, "- (CH ₂)_p-P(O)(R^a)(R^b)" means Other similar groups are defined as "- (CH ₂)_p-P(O)(R^a)(R^b)".

The term "each R ₁" as used herein means that each R ₁ in the plurality of R ₁ is independently selected from the group described in the above technical scheme when m is 2 or 3.

The term "each R ₂" as used herein means that each R ₂ in the plurality of R ₂ is independently selected from the group described in the above technical scheme when n is 2 or 3.

When ring A contains NH, H in the NH on the ring may be substituted with R ₁.

When ring D contains NH, H in the NH on its ring may be substituted with R ₂.

When NH is contained in Cy, H in NH on its ring may be substituted with Q.

When Cy is selected from hydrogen, the hydrogen may be substituted with R ₂.

The term "pharmaceutically acceptable salt" as used herein refers to salts of acidic functional groups (e.g., -COOH, -OH, -SO ₃ H, etc.) present in the compound with suitable inorganic or organic cations (bases), including salts with alkali metals or alkaline earth metals, ammonium salts, salts with nitrogen-containing organic bases; and salts of basic functional groups (e.g., -NH ₂, etc.) present in the compounds with suitable inorganic or organic anions (acids), including salts with inorganic or organic acids (e.g., carboxylic acids, etc.).

"Stereoisomers" as used herein means that the compounds of the present invention contain one or more asymmetric centers and are thus useful as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention may have asymmetric centers that each independently produce two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof.

"Deuterated" as used herein means that 1 or more hydrogens in the structure of the compounds of the invention are replaced with 1 or a corresponding plurality of deuterium.

The compounds of the present invention, if they contain olefinic double bonds, include cis-isomers and trans-isomers unless specified otherwise. The compounds of the invention may exist in tautomeric (one of the functional group isomers) forms having different points of attachment of hydrogen through displacement of one or more double bonds, for example, the keto and enol forms thereof are keto-enol tautomers, for example,Are tautomers. Each tautomer and mixtures thereof are included within the scope of the present invention.

Stereoisomers, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof and the like of all compounds are included within the scope of the present invention.

The compounds of the invention may be prepared by enantiospecific synthesis or resolution from mixtures of enantiomers to give the individual enantiomers. Conventional resolution techniques include resolution of mixtures of enantiomers of the starting material or final product using various well-known chromatographic methods.

When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60 wt%, 70 wt%, 80 wt%, 90 wt%, 99 wt%, or 99.9 wt% pure relative to the other stereoisomers. When a single isomer is named or depicted by structure, the depicted or named enantiomer is at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight, or 99.9% by weight pure. Optical purity wt% is the ratio of the weight of an enantiomer to the weight of the enantiomer plus the weight of its optical isomer.

Advantageous effects of the invention

1. The compound, the pharmaceutically acceptable salt, the stereoisomer or the deuterated substance thereof have excellent SUMO1 degradation effect, can effectively inhibit the growth of tumor cells, has good pharmacokinetic properties in organisms (such as mice, rats, dogs and the like), and has durable effect and high bioavailability.

2. The compound, the pharmaceutically acceptable salt, the stereoisomer or the deuterated compound thereof have better treatment effect on cancers, and the stability of liver microsomes is high.

3. The compound of the invention has simple preparation process, high purity of the medicine and stable quality, and is suitable for large-scale industrial production.

Detailed description of the preferred embodiments

The technical scheme of the present invention will be described in detail below with reference to specific embodiments, but the scope of the subject matter of the present invention should not be construed as being limited to the following examples. All techniques implemented based on the above description of the invention are within the scope of the invention.

Abbreviations:

Pd ₂(dba)₃: tris (dibenzylideneacetone) dipalladium; xantphos:4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene; EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide; DAST: diethylaminosulfur trifluoride; DMB-NH ₂:2, 4-dimethoxy benzylamine; DMF: n, N-dimethylformamide; NBS: n-bromosuccinimide; TBSCl, tert-butyl dimethyl silicon chloride; prep-TLC: preparing thin layer chromatography; XPhos Pd G2 chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II); DIPEA: n, N-diisopropylethylamine; DIEA: N, N-diisopropylethylamine; pdppfCl ₂: 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride; PE is petroleum ether; EA: ethyl acetate.

Embodiment one: preparation of N- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -6- (trifluoromethyl) benzo [ d ] thiazol-2-amine (Compound 1)

1. Preparation of 5- (4-methylpiperazin-1-yl) -2-nitroaniline

5-Fluoro-2-nitroaniline (20 g,128.1 mmol) was dissolved in DMSO (200 mL), N-methylpiperazine (17 g,169.7 mmol) and potassium carbonate (35 g,253.3 mmol) were added and the reaction was completed at 70℃for 3 hours. Slowly poured into ice water (800 mL), filtered, the filter cake washed with water (500 mL) and dried to give the product (29 g) which is used directly in the next step.

2. Preparation of 4- (4-methylpiperazin-1-yl) -1, 2-phenylenediamine

5- (4-Methylpiperazin-1-yl) -2-nitroaniline (26 g,110.0 mmol) was dissolved in methanol (600 mL), palladium on carbon (8 g) was added, the mixture was purged 3 times with hydrogen, and the reaction was performed under hydrogen for 48 hours. The solids were removed by filtration and concentrated to give crude (25 g). The crude product was used directly in the next step.

3. Preparation of dimethyl (6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) carbodiimide disulfate

6- (Trifluoromethyl) benzo [ d ] thiazol-2-amine (10 g,45.8 mmol) was dissolved in DMF (46 mL), sodium hydroxide (20M) (4.6 mL,92.0 mmol) was added, stirred at 15℃for 10min, carbon disulphide (7.0 mL,116.5 mmol) was added, reacted at 15℃for 10min, sodium hydroxide (20M) (4.6 mL,92.0 mmol) was added, stirred at 15℃for 10min, methyl iodide (7.0 mL,112.5 mmol) was added, and reacted at 15℃for 1 h. After the completion of the reaction, water (300 mL) and ethyl acetate (300 mL) were added and extracted, and the organic phase was washed with water (3X 200 mL) and concentrated to give a crude product (15 g).

4. Preparation of N- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -6- (trifluoromethyl) benzo [ d ] thiazol-2-amine

4- (4-Methylpiperazino) -1, 2-phenylenediamine (9.6 g,46.5 mmol) and dimethyl (6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) carbodiimide disulfate (15.0 g,46.5 mmol) were dissolved in DMF (100 mL), stirred at 10℃for 10 minutes, and heated to 110℃for reaction for 5 hours. After completion of the reaction, ethyl acetate (200 mL) was added, poured into ice water (300 mL), filtered, washed with ethyl acetate (100 mL), dried, and washed with methanol (100 mL) and methylene chloride (20 mL) to give the objective compound (12.5 g, two-step yield: 63.1%).

Molecular formula C ₂₀H₁₉F₃N₆ S molecular weight 432.5LC-MS (M/e): 433.2 (M+H ⁺)

¹H-NMR(400MHz,DMSO)δ:12.03(s,2H),8.18(s,1H),7.71(d,J＝8.4Hz,1H),7.69(d,J＝6.8Hz,1H),7.29(d,J＝8.8Hz,1H),6.95(s,1H),6.88(dd,J＝2.4,8.8Hz,1H),3.13-3.10(m,4H),2.54-2.50(m,4H),2.25(s,3H).

Embodiment two: preparation of 7-fluoro-5- (4-methylpiperazin-1-yl) -N- (6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) benzo [ d ] oxazol-2-amine (Compound 5)

1. Preparation of 2- (benzyloxy) -5-bromo-1-fluoro-3-nitrobenzene

4-Bromo-2-fluoro-6-nitrophenol (10 g,43 mmol), potassium carbonate (17.8 g,129 mmol) and benzyl bromide (9.5 g,56 mmol) were dissolved in DMF (100 mL) and reacted at 20℃for 16h. After the reaction, the reaction mixture was poured into water, suction filtration was performed, and the cake was dried to obtain a crude product (12.2 g).

2. Preparation of 1- (4- (benzyloxy) -3-fluoro-5-nitrophenyl) -4-methylpiperazine

2- (Benzyloxy) -5-bromo-1-fluoro-3-nitrobenzene (7 g crude), N-methylpiperazine (6 g,59.6 mmol), pd ₂(dba)₃ (5.5 g,6.0 mmol), xantphos (5.2 g,8.9 mmol), cesium carbonate (29 g,89.4 mmol) were dissolved in toluene (150 mL) and reacted at 100deg.C under nitrogen for 2h. After the reaction was completed, the filtrate was suction-filtered, extracted three times with EA and water, the organic phase was spin-dried and separated by normal phase preparation (DCM: meoh=50:1) to give the target compound (1 g, yield 13.5%).

3. Preparation of 2-amino-6-fluoro-4- (4-methylpiperazin-1-yl) phenylphenol hydrochloride

1- (4- (Benzyloxy) -3-fluoro-5-nitrophenyl) -4-methylpiperazine (500 mg,1.4 mmol) was dissolved in methanol (6 mL), concentrated hydrochloric acid (0.5 mL) was added dropwise, pd/C (100 mg) was added, and the mixture was reacted at 20℃for 8h. After the reaction, suction filtration was carried out, and the filtrate was dried by spin to obtain a crude product (350 mg).

4. Preparation of 7-fluoro-5- (4-methylpiperazin-1-yl) -N- (6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) benzo [ d ] oxazol-2-amine

2-Amino-6-fluoro-4- (4-methylpiperazin-1-yl) phenol hydrochloride (300 mg crude) was dissolved in DMF (10 mL), the system was replaced three times under nitrogen, naH (180 mg,4.4 mmol) was added at 0deg.C under nitrogen protection, the reaction was carried out at 0deg.C for 1h, dimethyl (6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) carbodiimide disulfate (370 mg,1.1 mmol) was added, and then the system was warmed to 80deg.C for 2h. After the reaction was completed, water was slowly added to quench, EA was added and water was extracted three times, the organic phase was dried by spinning, and the crude product was obtained by normal phase preparation and separation (DCM: meoh=10:1), the crude product was added with DCM and stirred for 10min, suction filtration, and the filter cake was dried to obtain the objective compound (80 mg, yield 16.1%).

Molecular formula C ₂₀H₁₇F₄N₅ OS molecular weight 451.4LC-MS (M/e): 452.1 (M+H2 ⁺)

¹H-NMR(400MHz,DMSO)δ:12.03(s,1H),8.35(s,1H),7.74(d,J＝8Hz,1H),7.55(d,J＝8Hz,1H),7.00(s,1H),6.85(d,J＝12Hz,1H),3.61-3.54(m,4H),3.34-3.21(m,4H),2.75(s,3H).

Embodiment III: preparation of N- (5- (1-methylpiperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) -6- (trifluoromethyl) benzo [ d ] thiazol-2-amine (Compound 8)

1. Preparation of 4- (3-amino-4-nitrophenyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

5-Bromo-2-nitroaniline (3.0 g,13.8 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (5.5 g,17.8 mmol), pdppfCl ₂ (1.2 g,1.6 mmol) and sodium carbonate (3.7 g,34.9 mmol) were dissolved in 1, 4-dioxane (100 mL) and water (20 mL) and reacted at 90℃for 5H. After the completion of the reaction, the concentrated residue was purified by column chromatography (EA: pe=40%) to give the objective product (3.0 g, yield 67.9%).

2. Preparation of 2-nitro-5- (1, 2,3, 6-tetrahydropyridin-4-yl) aniline hydrochloride

4- (3-Amino-4-nitrophenyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (3.0 g) was dissolved in HCl/EA and reacted at 30℃for 2H. After the reaction is finished, the filtrate is dried by spin to obtain a crude product which is directly used for the next step.

3. Preparation of 5- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -2-nitroaniline

2-Nitro-5- (1, 2,3, 6-tetrahydropyridin-4-yl) aniline hydrochloride (crude from the previous step) was dissolved in methanol (50 mL), and a system of 37% aqueous formaldehyde (1.4 g,17.3 mmol), naBH ₃ CN (1.3 g,20.7 mmol) and acetic acid (1 mL) was added and reacted at 30℃for 2h. After the reaction was completed, a sodium bicarbonate solution was slowly added to adjust the pH to 7, EA and water were added to extract three times, and the organic phase spin-dried residue was subjected to column chromatography (MeOH: DCM=10%) to obtain the objective compound (1.2 g, yield 54.8%)

4. Preparation of 4- (1-methylpiperidin-4-yl) benzene-1, 2-diamine

5- (1-Methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -2-nitroaniline (600 mg,2.57 mmol) was dissolved in methanol (20 mL) and the Pd/C (600 mg) system was added to react for 10H at 30℃H ₂. After the completion of the reaction, the reaction mixture was filtered, and the organic phase was dried by spinning to give the objective compound (400 mg, yield: 75.8%).

5. Preparation of N- (5- (1-methylpiperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) -6- (trifluoromethyl) benzo [ d ] thiazol-2-amine

4- (1-Methyl-piperidin-4-yl) phenyl-1, 2-diamine (300 mg,1.5 mmol) was dissolved in DMF (10 mL) and the system of dimethyl (6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) carbodiimide disulfate (520 mg,1.6 mmpl) was added and reacted at 110℃for 5h. After the reaction is finished, EA and water are added for extraction for three times, and the organic phase spin-dry residue is subjected to column chromatography

(MeOH: dcm=15%), the title compound (140 mg, yield 22.2%)

Molecular formula C ₂₁H₂₀F₃N₅ S molecular weight 431.5LC-MS (M/e): 432.1 (M+H ⁺)

¹H-NMR(400MHz,DMSO)δ:8.00(s,1H),7.81-7.79(d,J＝8Hz,1H),7.65(s,1H),7.45(m,1H),7.28(s,1H),7.18(m,1H),3.19-3.09(m,2H),2.7-2.6(m,1H),2.45(s,3H),2.29-2.18(m,2H),2.08-1.9(m,4H)

Embodiment four: preparation of 7-fluoro-5- (1-methylpiperidin-4-yl) -N- (6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) benzo [ d ] oxazol-2-amine (Compound 10)

1. Preparation of 4- (3-amino-5-fluoro-4-hydroxyphenyl) piperidine-1-carboxylic acid tert-butyl ester

4- (3-Amino-5-fluoro-4-hydroxyphenyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (400 mg,1.2 mmol) was dissolved in methanol (10 mL), palladium on carbon (100 mg, 10%) was added, after hydrogen substitution, the reaction was carried out at 25℃under a hydrogen atmosphere for 3 hours, and then filtration was carried out, and the filtrate was concentrated and directly fed into the next reaction.

2. Preparation of tert-butyl 4- (7-fluoro-2- ((6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) amino) benzo [ d ] oxazol-5-yl) piperidine-1-carboxylate

Tert-butyl 4- (3-amino-5-fluoro-4-hydroxyphenyl) piperidine-1-carboxylate (product concentrated above, 1.2 mmol) and (6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) carboaminothio-dimethyl ester (387 mg,1.2 mmol) were dissolved in DMF (10 mL), stirred at 110 ℃ for 16 hours, and after washing the separated liquid with water and ethyl acetate to give ethyl acetate phase, which was purified by silica gel column chromatography (dichloromethane: methanol=20:1) to give the product (340 mg, yield 52.9%).

3. Preparation of 7-fluoro-5- (piperidin-4-yl) -N- (6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) benzo [ d ] oxazol-2-amine hydrochloride

Tert-butyl 4- (7-fluoro-2- ((6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) amino) benzo [ d ] oxazol-5-yl) piperidine-1-carboxylate (340 mg,0.63 mmol) was dissolved in dichloromethane (10 mL), ethyl hydrogen chloride solution (4M, 5.0 mL) was added and reacted at 15℃for 2h. Concentrating to obtain 270mg of crude product. The crude product was used directly in the next step.

4. Preparation of 7-fluoro-5- (1-methylpiperidin-4-yl) -N- (6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) benzo [ d ] oxazol-2-amine

7-Fluoro-5- (piperidin-4-yl) -N- (6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) benzo [ d ] oxazol-2-amine hydrochloride (50 mg,0.11 mmol) was dissolved in methanol (5 mL) and aqueous formaldehyde (45 mg,37%,0.55 mmol) and sodium cyanoborohydride (34 mg,0.55 mmol) were added sequentially. The reaction was carried out at 15℃for 1h. Concentrated, and the separated liquid was washed with water and ethyl acetate to obtain an ethyl acetate phase, which was purified by silica gel column chromatography (dichloromethane: methanol=10:1) to obtain a product (30 mg, yield 63.0%).

Molecular formula C ₂₁H₁₈F₄N₄ OS molecular weight 450.5LC-MS (M/e): 451.1 (M+H ⁺)

¹H-NMR(400MHz,CDCl₃)δ:7.82(d,J＝8.2Hz,1H),7.72(s,1H),7.52(d,J＝8.2Hz,1H),7.15(s,1H),6.76(d,J＝11.1Hz,1H),3.30-3.15(m,2H),2.65-2.46(m,1H),2.46(s,3H),2.30-2.15(m,2H),2.00-1.80(m,4H).

Fifth embodiment: preparation of 2- (4- (7-fluoro-2- ((6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) amino) benzo [ d ] oxazol-5-yl) piperidin-1-yl) ethan-1-ol (Compound 11)

1. Preparation of 5- (1- (2- ((tert-butyldimethylsilyloxy) ethyl) piperidin-4-yl) -7-fluoro-N- (6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) benzo [ d ] oxazol-2-amine

7-Fluoro-5- (piperidin-4-yl) -N- (6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) benzo [ d ] oxazol-2-amine hydrochloride (50 mg,0.11 mmol) was dissolved in methanol (5 mL) and 2- ((tert-butyldimethylsilyl) oxy) acetaldehyde (96 mg,0.55 mmol) and sodium cyanoborohydride (34 mg,0.55 mmol) were added sequentially. The reaction was carried out at 15℃for 1h. The reaction solution is directly put into the next reaction.

2. Preparation of 2- (4- (7-fluoro-2- ((6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) amino) benzo [ d ] oxazol-5-yl) piperidin-1-yl) ethan-1-ol

To 5- (1- (2- ((tert-butyldimethylsilyloxy) ethyl) piperidin-4-yl) -7-fluoro-N- (6- (trifluoromethyl) benzo [ d ] thiazol-2-yl) benzo [ d ] oxazol-2-amine (reaction solution above) was added dilute hydrochloric acid (1M, 1 mL). The reaction was carried out at 15℃for 1h. After methanol was removed by concentration and the pH of the system was adjusted to 7-8 with saturated aqueous sodium bicarbonate, the organic phase was obtained by extraction with a mixed solution of dichloromethane and methanol (dichloromethane: methanol=10:1) and purification by silica gel column chromatography (dichloromethane: methanol=10:1) to give the product (20 mg, two-step yield: 37.8%).

Molecular formula C ₂₂H₂₀F₄N₄O₂ S molecular weight 480.5LC-MS (M/e): 481.1 (M+H ⁺)

¹H-NMR(400MHz,CDCl₃)δ:7.84(d,J＝8.5Hz,1H),7.73(s,1H),7.53(d,J＝8.5Hz,1H),7.15(s,1H),6.79(d,J＝11.1Hz,1H),3.72(t,J＝5.3Hz,2H),3.20-3.10(m,2H),2.67(t,J＝5.3Hz,2H),2.60-2.50(m,1H),2.35-2.20(m,2H),2.00-1.70(m,4H).

Example six: preparation of N- (6- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -5,6,7, 8-tetrahydroquinolin-2-amine (Compound 16)

1. Preparation of 1, 1-diphenyl-N- (5, 6,7, 8-tetrahydroquinolin-2-yl) toluidine

To a solution of 2-chloro-5, 6,7, 8-tetrahydroquinoline (1.0 g,6.0 mmol) in 1, 4-dioxane (50 mL) was added benzophenone imine (1.2 g,6.6 mmol), dibenzylideneacetone dipalladium (275 mg,0.30 mmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (417 mg,0.72 mmol) and cesium carbonate (3.9 g,12.0 mmol), and the mixture was reacted at 100℃under nitrogen for 8 hours. Water and ethyl acetate were added for extraction, and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=6:1) to give the product (1.0 g, yield 51.1%).

2. Preparation of 5,6,7, 8-tetrahydroquinolin-2-amine

To 1, 1-diphenyl-N- (5, 6,7, 8-tetrahydroquinolin-2-yl) toluidine (1.0 g,3.2 mmol) in tetrahydrofuran (10 mL) was added (2M) hydrochloric acid (6.4 mL,12.8 mmol), and the mixture was reacted at 25℃for 1 hour. A small amount of saturated sodium bicarbonate solution was added to adjust pH to basicity, the organic phase was extracted with ethyl acetate, the aqueous phase was concentrated, dichloromethane was added to filter, and the filtrate was concentrated to give crude product (395 mg).

3. Preparation of 2-isothiocyanato-5, 6,7, 8-tetrahydroquinoline

5,6,7, 8-Tetrahydroquinolin-2-amine (399mg, 2.7 mmol) was dissolved in tetrahydrofuran (10 mL), triethylamine (820 mg,8.1 mmol) was added, cooled to 0℃and thiophosgene (460 mg,4.0 mmol) was added to react at 0℃for 2 hours, water quenching was added, extraction with ethyl acetate was performed, and the crude product was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=10:1) to give the product (300 mg, yield (two steps) 49.3%).

4. Preparation of N- (6- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -5,6,7, 8-tetrahydroquinolin-2-amine

To tetrahydrofuran (20 mL) of 2-isothiocyanato-5, 6,7, 8-tetrahydroquinoline (270 mg,1.4 mmol) were added 4- (4-methylpiperazin-1-yl) -1, 2-phenylenediamine (318 mg,1.5 mmol) and EDCI (537 mg,2.8 mmol), and the reaction was carried out at 80℃for 4 hours, and the system was extracted with saturated sodium hydrogencarbonate solution and ethyl acetate, and the crude product was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=7:1) to give the product (131 mg, yield 25.5%).

Molecular formula C21H26N6 molecular weight 362.5LC-MS (M/e): 363.2 (M+H+)

¹H-NMR(400MHz,DMSO-d6)δ:11.60-11.45(m,1H),10.35-10.15(m,1H),7.35(d,J＝8.0Hz,1H),7.20(s,1H),7.02-6.97(m,2H),6.70(d,J＝8.4Hz,1H),3.15-2.98(m,4H),2.95-2.85(m,2H),2.70-2.60(m,2H),2.56-2.45(m,4H),2.23(s,3H),1.80-1.65(m,4H).

Embodiment seven: preparation of N- (6- (1-methylpiperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) -6- (trifluoromethyl) quinolin-2-amine (Compound 17)

4- (1-Methylpiperidin-4-yl) benzene-1, 2-diamine (290 mg,1.4 mmol) and 2-isothiocyanato-6- (trifluoromethyl) quinoline (300 mg,1.2 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (370 mg,1.9 mmol) were dissolved in DMF (15 mL), reacted at 100℃for 1 hour, concentrated, and subjected to reverse phase column chromatography (MeOH: H ₂ O=50%) to give the crude product, which was purified by normal phase column chromatography (MeOH: DCM=20%) to give the product (195 mg, yield 38.8%).

Molecular formula C ₂₃H₂₂N₅F₃ molecular weight 425.5LC-MS (M/e): 426.1 (M+H ⁺)

¹H-NMR(400MHz,DMSO-d₆)δ:13.60-11.45(m,1H),8.36-8.34(m,2H),8.27(s,1H),7.95-7.93(m,1H),7.38-7.36(m,3H),6.98-6.96(m,1H),3.15-2.98(m,2H),2.56-2.53(m,1H),2.30-2.30(m,3H),2.28-2.15(m,2H),1.8-1.65(m,4H).

Example eight: preparation of N- (6- (difluoromethyl) quinolin-2-yl) -7-fluoro-5- (4-methylpiperazin-1-yl) benzo [ d ] oxazol-2-amine (Compound 19)

1. Preparation of 2-chloroquinoline-6-carbaldehyde

6-Bromo-2-chloroquinoline (6.0 g,24.7 mmol) was dissolved in tetrahydrofuran (100 mL), -n-butyllithium (14.8 mL,37.0 mmol) was added dropwise at 70℃and stirring was continued for 1 hour. N, N-dimethylformamide (4.5 g,61.6 mmol) was added, gradually warmed to 0 ℃, quenched with water, the organic phase extracted with ethyl acetate, dried, concentrated, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate=9:1) to give the product (2.8 g, 59.1% yield).

2. Preparation of 2-chloro-6- (difluoromethyl) quinoline

To 2-chloroquinoline-6-carbaldehyde (2.8 g,14.6 mmol) in methylene chloride (100 mL) was added diethylaminosulfur trifluoride (9.4 g,58.3 mmol), and the mixture was reacted at 25℃for 16 hours. The reaction was quenched by addition of saturated aqueous sodium bicarbonate at 25 ℃, the organic phase extracted with dichloromethane and the concentrated crude was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=13:1) to give the product (2.6 g, 83.3% yield).

3. Preparation of 6- (difluoromethyl) -N- (2, 4-dimethoxybenzyl) quinolin-2-amine

To 2-chloro-6- (difluoromethyl) quinoline (2.7 g,12.6 mmol) was added 2, 4-dimethoxybenzylamine (5 mL), and the mixture was reacted at 130℃for 1.5 hours. Ethyl acetate was added for dilution, filtration, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=7:3) to give the product (4.3 g, yield 98.8%).

4. Preparation of 6- (difluoromethyl) quinolin-2-amines

6- (Difluoromethyl) -N- (2, 4-dimethoxybenzyl) quinolin-2-amine (4.3 g,12.5 mmol) was dissolved in trifluoroacetic acid (55 mL), reacted at 25℃for 2 hours, concentrated, added with saturated sodium hydrogen carbonate solution, extracted with dichloromethane, concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=3:7) to give the product (2.1 g, yield 86.6%).

5. Preparation of 6- (difluoromethyl) -2-isothiocyanato quinoline

6- (Difluoromethyl) quinolin-2-amine (1.1 g,5.7 mmol) was dissolved in tetrahydrofuran (50 mL), triethylamine (1.7 mg,16.8 mmol) was added, cooled to 0℃and thiophosgene (983 mg,8.5 mmol) was added to react for 2 hours at 0℃and quenched with water, extracted with ethyl acetate, and the crude concentrate was purified by column chromatography over silica gel (petroleum ether: ethyl acetate=5:1) to give the product (800 mg, 59.5% yield).

6. Preparation of N- (6- (difluoromethyl) quinolin-2-yl) -7-fluoro-5- (4-methylpiperazin-1-yl) benzo [ d ] oxazol-2-amine

2-Amino-6-fluoro-4- (4-methylpiperazin-1-yl) phenol hydrochloride (211 mg crude) was dissolved in DMF (5 mL), the system was replaced three times under nitrogen, and 6- (difluoromethyl) -2-isothiocyanaoquinoline (190 mg,0.81 mmol) was added under nitrogen protection and reacted at 10℃for 1h. EDCI (311 mg,1.6 mmol) was added and reacted at 25℃for 16h. After the completion of the reaction, a saturated sodium hydrogencarbonate solution and ethyl acetate were added (extraction, washing of the organic phase with saturated brine, concentration of the organic phase, purification by silica gel column chromatography (dichloromethane: methanol=10:1) to give a product (120 mg, yield 34.9%).

Molecular formula C ₂₂H₂₀F₃N₅ O molecular weight 427.4LC-MS (M/e): 428.2 (M+H ⁺)

¹H-NMR(400MHz,DMSO-d₆)δ:12.65-12.15(m,1H),8.45(d,J＝8.8Hz,1H),8.42-8.12(m,2H),8.01-7.82(m,2H),7.18-7.04(m,1H),6.92(s,1H),6.76(d,J＝13.2Hz,1H),3.25-3.09(m,4H),2.48-2.45(m,4H),2.21(s,3H).

Example nine: preparation of 2- ((7-fluoro-5- (4-methylpiperazin-1-yl) benzo [ d ] oxazol-2-yl) amino) quinoline-6-carbonitrile (Compound 20)

2-Amino-6-fluoro-4- (4-methylpiperazin-1-yl) phenol hydrochloride (100 mg crude) was dissolved in DMF (5 mL), the system was replaced three times under nitrogen, and 2-isothiocyanazine-6-carbonitrile (80 mg,0.38 mmol) was added under nitrogen protection, and reacted at 10℃for 1h. EDCI (147 mg,0.77 mmol) was added and reacted at 10℃for 16h. After the completion of the reaction, saturated sodium bicarbonate solution (10 mL) was added, and extracted with ethyl acetate (20 mL x 2), and the organic phase was washed with water (30 mL x 2), concentrated, and purified by silica gel column chromatography (dichloromethane: methanol=10:1) to give the product (70 mg, yield 45.9%).

Molecular formula C ₂₂H₁₉FN₆ O molecular weight 402.4LC-MS (M/e): 403.2 (M+H2 ⁺)

¹H-NMR(400MHz,CDCl₃)δ:14.35(brs,1H),8.70(s,1H),7.83-7.80(m,2H),7.61(d,J＝8.8Hz,1H),7.13(d,J＝9.6Hz,1H),6.92(s,1H),7.13(d,J＝12.8Hz,1H),3.49(s,4H),2.63(s,4H),2.38(s,3H).

Example ten: preparation of 2- ((6- (1- (2-hydroxyethyl) piperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) amino) quinoline-6-carbonitrile (Compound 21)

1. Preparation of 5- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1,2,3, 6-tetrahydropyridin-4-yl) -2-nitroaniline

2-Nitro-5- (1, 2,3, 6-tetrahydropyridin-4-yl) aniline hydrochloride (3.0 g of crude product) was dissolved in methanol (50 mL), to which acetic acid (0.82 g,13.7 mmol) and 2- ((tert-butyldimethylsilyl) oxy) acetaldehyde (3.6 g,20.5 mmol) were added in this order, and after stirring at 15℃for 15 minutes, sodium cyanoborohydride (1.3 g,20.5 mmol) was added. After completion of LCMS detection, the solvent was removed under reduced pressure, dichloromethane was added, the organic phase was washed with saturated sodium bicarbonate solution, and the separated organic phase was purified by silica gel column chromatography (mobile phase was ethyl acetate and n-heptane, ratio of ethyl acetate was 0% to 80%) to obtain the product (2.8 g, two-step yield 65.8%).

2. Preparation of 4- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) piperidin-4-yl) benzene-1, 2-diamine

5- (1- (2- ((Tert-Butyldimethylsilyl) oxy) ethyl) -1,2,3, 6-tetrahydropyridin-4-yl) -2-nitroaniline (2.8 g,7.4 mmol) was dissolved in methanol (30 mL), palladium on carbon (2.0 g, 10%) was added, after displacement of the gas by a hydrogen balloon, the reaction was carried out at 45℃under a hydrogen atmosphere for 6 hours, and after filtration, the filtrate was concentrated to give crude product (2.5 g).

3. Preparation of 2- ((6- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) piperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) amino) quinoline-6-carbonitrile

4- (1- (2- ((Tert-Butyldimethylsilyl) oxy) ethyl) piperidin-4-yl) benzene-1, 2-diamine (200 mg,0.57 mmol) was dissolved in DMF (5 mL) and 2-isothiocyanazine-6-carbonitrile (120 mg,0.57 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (211 mg,1.1 mmol) were added sequentially. The reaction was carried out at 100℃for 2 hours. After the solvent was removed under reduced pressure, the separated liquid was washed with water and ethyl acetate to obtain an ethyl acetate phase, and after the ethyl acetate phase was further washed with a saturated sodium hydrogencarbonate solution, the separated liquid was separated, and the organic phase was purified by silica gel column chromatography (mobile phase: methylene chloride and methanol, ratio of methanol was 0% to 15%), to obtain (product 200mg, yield 66.7%).

4. Preparation of 2- ((6- (1- (2-hydroxyethyl) piperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) amino) quinoline-6-carbonitrile

2- ((6- (1- (2- ((Tert-butyldimethylsilyl) oxy) ethyl) piperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) amino) quinoline-6-carbonitrile (100 mg,0.19 mmol) was dissolved in tetrahydrofuran (2 mL), and diluted hydrochloric acid (1M, 1 mL) was added thereto for reaction at 15℃for 1H. The reaction solution was purified by silica gel column chromatography (mobile phase is water and methanol, methanol ratio is 0% -30%) to obtain the product (13 mg, yield 16.6%).

Molecular formula C ₂₄H₂₄N₆ O molecular weight 412.2LC-MS (M/e): 413.2 (M+H ⁺)

¹H-NMR(400MHz,DMSO-d₆)δ:13.34(br,1H),8.70-8.40(m,3H),8.20-8.10(m,1H),7.83-7.55(m,3H),7.33-7.25(m,1H),3.92-3.80(m,2H),3.75-3.60(m,2H),3.30-2.95(m,5H),2.28-1.90(m,4H).

Example eleven: preparation of 2- (4- (2- ((6- (trifluoromethyl) quinolin-2-yl) amino) -1H-benzo [ d ] imidazol-6-yl) piperidin-1-yl) ethan-1-ol (Compound 22)

1. Preparation of 4- (3, 4-diaminophenyl) piperidine-1-carboxylic acid tert-butyl ester

Tert-butyl 4- (3-amino-4-nitrophenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate (2.0 g,6.3 mmol) was dissolved in methanol (30 mL), palladium on carbon (2.0 g, 10%) was added, the gases were replaced by a hydrogen balloon, reacted under a hydrogen atmosphere at 40℃for 6 hours, filtered, and the filtrate was concentrated to give the product (1.3 g, yield 71.2%).

2. Preparation of tert-butyl 4- (2- ((6- (trifluoromethyl) quinolin-2-yl) amino) -1H-benzo [ d ] imidazol-6-yl) piperidine-1-carboxylate

Tert-butyl 4- (3, 4-diaminophenyl) piperidine-1-carboxylate (1.1 g,3.8 mmol) was dissolved in DMF (20 mL), to which 2-isothiocyanato-6- (trifluoromethyl) quinoline (1.1 g,4.3 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.8 g,4.2 mmol) were added in this order, and after stirring at 100℃for 2 hours, the solvent was removed under reduced pressure, and purified by silica gel column chromatography (dichloromethane: methanol=20:1) to give the product (1.7 g, yield 88.0%).

3. Preparation of N- (6- (piperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) -6- (trifluoromethyl) quinolin-2-amine hydrochloride

Tert-butyl 4- (2- ((6- (trifluoromethyl) quinolin-2-yl) amino) -1H-benzo [ d ] imidazol-6-yl) piperidine-1-carboxylate (1.5 g,2.9 mmol) was dissolved in a solution of hydrogen chloride in ethyl acetate (4M, 50 mL), the reaction was stirred at 30℃for 1 hour and the solvent was removed under reduced pressure to give the crude product which was used directly in the subsequent reaction.

4. Preparation of N- (6- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) piperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) -6- (trifluoromethyl) quinolin-2-amine

N- (6- (piperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) -6- (trifluoromethyl) quinolin-2-amine hydrochloride (crude above) was dissolved in methanol (50 mL) and formic acid (1 mL), and 2- ((tert-butyldimethylsilyl) oxy) acetaldehyde (800 mg,4.6 mmol) and sodium cyanoborohydride (400 mg,6.4 mmol) were added sequentially. After 2h reaction at 30 ℃, the reaction solution was concentrated, ph=7 was adjusted with saturated sodium bicarbonate solution, the ethyl acetate was extracted and separated to give ethyl acetate phase, and the organic phase was purified by silica gel column chromatography (mobile phase: dichloromethane: methanol=15:1) to give the product (500 mg, two step yield 29.9%).

5. Preparation of 2- (4- (2- ((6- (trifluoromethyl) quinolin-2-yl) amino) -1H-benzo [ d ] imidazol-6-yl) piperidin-1-yl) ethan-1-ol

N- (6- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) piperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) -6- (trifluoromethyl) quinolin-2-amine (400 mg,0.70 mmol) was dissolved in dilute hydrochloric acid (1M, 10 mL) and reacted at 25℃for 1H. The reaction solution was saturated with sodium bicarbonate to adjust ph=8, a solid was precipitated, and filtered to give the product (180 mg, yield 56.3%).

Molecular formula C ₂₄H₂₄F₃N₅ O molecular weight 455.2LC-MS (M/e): 456.2 (M+H ⁺)

¹H-NMR(400MHz,DMSO-d₆)δ:12.2(br,1H),8.45-8.35(m,2H),8.29(s,1H),8.00-7.92(m,1H),7.60-7.25(m,3H),7.99(d,J＝8.4Hz,1H),4.43-4.30(m,1H),3.60-3.20(m,2H),3.10-2.95(m,2H),2.62-2.40(m,3H),2.15-2.00(m,2H),1.85-1.60(m,4H).

Embodiment twelve: preparation of 2- (4- (4-fluoro-2- ((6- (trifluoromethyl) quinolin-2-yl) amino) -1H-benzo [ d ] imidazol-6-yl) piperidin-1-yl) ethan-1-ol (Compound 23)

1. Preparation of N- (6- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) piperidin-4-yl) -4-fluoro-1H-benzo [ d ] imidazol-2-yl) -6- (trifluoromethyl) quinolin-2-amine

5- (1- (2- ((Tert-Butyldimethylsilyl) oxy) ethyl) piperidin-4-yl) -3-fluorobenzene-1, 2-diamine (2.2 g,6.0 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.3 g,12.0 mmol) and 2-isothiocyanato-6- (trifluoromethyl) quinoline (1.5 g,5.9 mmol) were dissolved in THF (100 mL) and reacted at 50℃for 4h. Extraction with water and ethyl acetate, concentration and purification by silica gel column chromatography (dichloromethane and methanol as mobile phase, methanol ratio from 0% to 5%) gave the product (2.2 g, yield 63.4%).

2. Preparation of 2- (4- (4-fluoro-2- ((6- (trifluoromethyl) quinolin-2-yl) amino) -1H-benzo [ d ] imidazol-6-yl) piperidin-1-yl) ethan-1-ol

N- (6- (1- (2- ((tert-butyldimethylsilyloxy) ethyl) piperidin-4-yl) -4-fluoro-1H-benzo [ d ] imidazol-2-yl) -6- (trifluoromethyl) quinolin-2-amine (2.2 g,3.7 mmol) was dissolved in methanol (150 mL), and a solution of hydrogen chloride in ethyl acetate (4M, 30 mL) was added and reacted at 15℃for 2H. Concentrating, adding a mixed solvent of ethyl acetate (100 mL) and methanol (10 mL), pulping, washing, filtering to obtain a filter cake, adding the filter cake into water (100 mL), regulating pH to 8 with saturated sodium bicarbonate solution, extracting the water phase with a mixed solvent of dichloromethane and methanol (dichloromethane: methanol=10:1), separating to obtain an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate to obtain a product (1.55 g, yield 87.4%)

Molecular formula C ₂₄H₂₃F₄N₅ O molecular weight 473.5LC-MS (M/e): 474.2 (M+H2 ⁺)

¹H NMR(400MHz,DMSO-d₆)δ:12.00(br,1H),8.45-8.33(m,2H),8.29(s,1H),7.97(d,J＝8.2Hz,1H),7.58-7.40(m,1H),7.32(s,1H),6.82(d,J＝12.2Hz,1H),4.38(br,1H),3.53(t,J＝6.2Hz,2H),3.10-2.97(m,2H),2.65-2.45(m,1H),2.43(t,J＝6.2Hz,2H),2.15-2.05(m,2H),1.87-1.78(m,2H),1.75-1.60(m,2H).

Embodiment thirteen: preparation of 2- ((7-fluoro-5- (1-methylpiperidin-4-yl) benzo [ d ] oxazol-2-yl) amino) quinoline-6-carbonitrile (Compound 24)

1. Preparation of 6-bromo-N- (2, 4-dimethoxybenzyl) quinolin-2-amine

6-Bromo-2-chloroquinoline (10.0 g,41.2 mmol), DIEA (11.0 g,85.1 mmol) and 2, 4-dimethoxybenzylamine (20 mL) were added and reacted at 130℃for 3h. Extraction with water (300 mL) and ethyl acetate (300 mL) and concentration was purified by column chromatography on silica gel (n-heptane: ethyl acetate=2:1) to give the product (13.5 g, yield 95.9%).

2. Preparation of 2- ((2, 4-dimethoxybenzyl) amino) quinoline-6-carbonitrile

6-Bromo-N- (2, 4-dimethoxybenzyl) quinolin-2-amine (13.5 g,39.6 mmol) was dissolved in DMF (200 mL), zinc cyanide (6.9 g,58.8 mmol) and palladium tetraphenylphosphine (4.6 g,4.0 mmol) were added, the system was replaced three times under nitrogen and reacted at 120℃for 5h under nitrogen. Concentrate, extract with water (200 mL) and ethyl acetate (400 mL), purify by silica gel column chromatography (n-heptane: ethyl acetate=2:1) to give the product (8.0 g, yield 70.4%).

3. Preparation of 2-aminoquinoline-6-carbonitrile

2- ((2, 4-Dimethoxybenzyl) amino) quinoline-6-carbonitrile (8.0 g,27.8 mmol) was dissolved in trifluoroacetic acid (100 mL) and reacted at 20℃for 16h. Concentrate, extract with water (100 mL) and ethyl acetate (100 mL), filter to remove solids, purify by column chromatography on silica gel (dichloromethane: methanol=15:1) to give the product (3.4 g, yield 72.2%).

4. Preparation of 2-isothiocyanaoquinoline-6-carbonitrile

2-Aminoquinoline-6-carbonitrile (1.0 g,5.9 mmol) and triethylamine (1.8 g,17.8 mmol) were dissolved in tetrahydrofuran (30 mL), cooled to 0℃and thiophosgene (1.0 g,8.7 mmol) was added dropwise thereto for reaction at 0℃for 1 hour. Concentrate and purify by silica gel column chromatography (n-heptane: ethyl acetate=6:1) to give the product (300 mg, yield 24.0%).

5. Preparation of tert-butyl 4- (2- ((6-cyanoquinolin-2-yl) amino) -7-fluorobenzo [ d ] oxazol-5-yl) piperidine-1-carboxylate

2-Isothiocyano quinoline-6-carbonitrile (231 mg,1.1 mmol) and tert-butyl 4- (3-amino-5-fluoro-4-hydroxyphenyl) piperidine-1-carboxylate (3411 mg,1.1 mmol) were dissolved in DMF (6 mL) and stirred at 20℃for 0.5 h. EDCI (418 mg,2.2 mmol) was added and reacted at 40℃for 5h. After the completion of the reaction, the mixture was extracted with water (20 mL) and ethyl acetate (30 mL), and purified by silica gel column chromatography (dichloromethane: ethyl acetate=5:2) to give a product (250 mg, yield 46.9%).

6. Preparation of 2- ((7-fluoro-5- (piperidin-4-yl) benzo [ d ] oxazol-2-yl) amino) quinoline-6-carbonitrile hydrochloride

Tert-butyl 4- (2- ((6-cyanoquinolin-2-yl) amino) -7-fluorobenzo [ d ] oxazol-5-yl) piperidine-1-carboxylate (250 mg,0.51 mmol) was dissolved in dichloromethane (10 mL), and ethyl hydrogen chloride solution (4M, 2.5 mL) was added to react at 20℃for 2h. Concentrating, and directly using the crude product in the next step.

7. Preparation of 2- ((7-fluoro-5- (1-methylpiperidin-4-yl) benzo [ d ] oxazol-2-yl) amino) quinoline-6-carbonitrile

2- ((7-Fluoro-5- (piperidin-4-yl) benzo [ d ] oxazol-2-yl) amino) quinoline-6-carbonitrile hydrochloride (crude above) was dissolved in methanol (15 mL) followed by formaldehyde (35%) (90 mg,1.1 mmol) and sodium cyanoborohydride (40 mg,0.64 mmol). The reaction was carried out at 25℃for 3 hours. Concentrated, purified by C18 column (methanol: water (0.05% hcl) =3:2), added saturated sodium bicarbonate solution (10 mL) and ethyl acetate (10 mL) and extracted to give 60mg of crude product. Ethyl acetate (5 mL) was added and filtered, and the mixture was washed with methyl tert-butyl ether (5 mL) and methanol (5 mL) to give the product (20 mg, 9.8% yield in two steps).

Molecular formula C ₂₃H₂₀FN₅ O molecular weight 401.4LC-MS (M/e): 402.2 (M+H ⁺)

¹H-NMR(400MHz,DMSO-d₆)δ:8.50(s,1H),8.45-8.30(m,2H),8.00(dd,J＝8.6,2.0Hz,1H),7.87(d,J＝8.8Hz,1H),7.27(s,1H),7.03(d,J＝11.8Hz,1H),3.05-3.02(m,2H),2.75-2.57(m,1H),2.41-2.20(m,5H),1.90-1.72(m,4H).

Fourteen examples: preparation of 2- ((7-fluoro-5- (1- (2-hydroxyethyl) piperidin-4-yl) benzo [ d ] oxazol-2-yl) amino) quinoline-6-carbonitrile (Compound 25)

1. Preparation of 2-isothiocyanaoquinoline-6-carbonitrile

2-Aminoquinoline-6-carbonitrile (400 mg,2.4 mmol) was dissolved in dichloromethane (20 mL), and 1,1' -thiocarbonylbis (pyridin-2 (1H) -one) (660 mg,2.8 mmol) was added and reacted at 20℃for 16 hours. Concentrate and purify by silica gel column chromatography (n-heptane: ethyl acetate=3:1) to give the product (300 mg, yield 60.1%).

2. Preparation of tert-butyl 4- (2- ((6-cyanoquinolin-2-yl) amino) -7-fluorobenzo [ d ] oxazol-5-yl) piperidine-1-carboxylate

2-Isothiocyano-quinoline-6-carbonitrile (157 mg,0.74 mmol) and 4- (3-amino-5-fluoro-4-hydroxyphenyl) piperidine-1-carboxylic acid tert-butyl ester (231 mg,0.74 mmol) were dissolved in DMF (6 mL) and stirred at 20℃for 0.5 h. EDCI (298 mg,1.6 mmol) was added and reacted at 40℃for 5h. After the completion of the reaction, the mixture was extracted with water (30 mL) and ethyl acetate (50 mL), and purified by silica gel column chromatography (dichloromethane: ethyl acetate=3:1) to give a product (200 mg, yield 55.3%).

3. Preparation of 2- ((7-fluoro-5- (piperidin-4-yl) benzo [ d ] oxazol-2-yl) amino) quinoline-6-carbonitrile hydrochloride

Tert-butyl 4- (2- ((6-cyanoquinolin-2-yl) amino) -7-fluorobenzo [ d ] oxazol-5-yl) piperidine-1-carboxylate (200 mg,0.41 mmol) was dissolved in dichloromethane (8 mL), and ethyl hydrogen chloride solution (4M, 2.0 mL) was added and reacted at 25℃for 2h. Concentrating to obtain crude product 180mg. The crude product was used directly in the next step.

4. Preparation of 2- ((5- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) piperidin-4-yl) -7-fluorobenzo [ d ] oxazol-2-yl) amino) quinoline-6-carbonitrile

2- ((7-Fluoro-5- (piperidin-4-yl) benzo [ d ] oxazol-2-yl) amino) quinoline-6-carbonitrile hydrochloride (crude above) was dissolved in dichloromethane (35 mL) and 2- ((tert-butyldimethylsilyl) oxy) acetaldehyde (360 mg,2.1 mmol) followed by sodium triacetoxyborohydride (270 mg,1.3 mmol). The reaction was carried out at 25℃for 2h. Concentrate, extract with water (20 mL) and ethyl acetate (30 mL), purify by silica gel column chromatography (dichloromethane: methanol=15:1) to give the product (160 mg, two-step yield 71.5%).

5. Preparation of 2- ((7-fluoro-5- (1- (2-hydroxyethyl) piperidin-4-yl) benzo [ d ] oxazol-2-yl) amino) quinoline-6-carbonitrile

2- ((5- (1- (2- ((Tert-butyldimethylsilyloxy) ethyl) piperidin-4-yl) -7-fluorobenzo [ d ] oxazol-2-yl) amino) quinoline-6-carbonitrile (160 mg,0.29 mmol) was dissolved in tetrahydrofuran (30 mL) and hydrochloric acid (3M, 1.6 mL) was added. The reaction was carried out at 25℃for 1h. The pH was adjusted to 8-9 with saturated sodium bicarbonate solution, tetrahydrofuran was removed by concentration, extraction with methylene chloride/methanol mixed solvent (methylene chloride: methanol=10:1) (30 mL), purification by silica gel column chromatography (methylene chloride: methanol=8:1) gave 40mg of the product. Purification by Prep-HPLC (methanol: water (0.01% h ₃PO₄) =1:2), concentration, adjustment of ph=8-9 by addition of saturated sodium bicarbonate solution, extraction with dichloromethane/methanol mixed solvent (dichloromethane: methanol=9:1) (20 mL), concentration gave the product (6 mg, yield 4.7%).

Molecular formula C ₂₄H₂₂FN₅O₂ molecular weight 431.5LC-MS (M/e): 432.2 (M+H ⁺)

¹H-NMR(400MHz,CDCl₃)δ:7.99(s,1H),7.88-7.81(m,2H),7.64(d,J＝8.4Hz,1H),7.28-7.25(m,1H),7.16(d,J＝9.2Hz,1H),6.91(d,J＝11.0Hz,1H),3.68(t,J＝5.4Hz,2H),3.12-3.05(m,2H),2.64-2.60(m,2H),2.28-2.22(m,2H),1.95-1.72(m,4H),0.90-0.85(m,1H).

Example fifteen: preparation of 2- (4- (2- ((6- (trifluoromethyl) quinoxalin-2-yl) amino) -1H-benzo [ d ] imidazol-6-yl) piperidin-1-yl) ethan-1-ol (Compound 30)

1. Preparation of 6- (trifluoromethyl) quinoxalin-2-ol

4- (Trifluoromethyl) benzene-1, 2-diamine (5.0 g,28.4 mmol) was dissolved in ethanol (100 mL), ethyl 2-oxoacetate (3.5 g,34.1 mmol) was added thereto, and after reacting at 80℃for 4 hours, the solvent was removed under reduced pressure, and the product (4.0 g, yield 65.8%) was obtained by beating with ethyl acetate.

2. Preparation of 2-chloro-6- (trifluoromethyl) quinoxaline

6- (Trifluoromethyl) quinoxalin-2-ol (3.5 g,16.3 mmol) was dissolved in phosphorus oxychloride (100 mL), after stirring and reacting at 80℃for 1 hour, the solvent was removed under reduced pressure, and the reaction mixture was slurried with a mixed solvent of ethyl acetate and n-heptane (ethyl acetate: n-heptane=1:10) to give a product (2.0 g, yield 52.7%).

3. Preparation of 6- (trifluoromethyl) quinoxalin-2-amine

2-Chloro-6- (trifluoromethyl) quinoxaline (1.0 g,4.3 mmol) was dissolved in isopropyl alcohol (5 mL), aqueous ammonia (3 mL) was added thereto, and after microwave reaction at 110℃for 1 hour, the solvent was removed under reduced pressure to obtain a crude product (1.0 g).

4. Preparation of 2-isothiocyanato-6- (trifluoromethyl) quinoxaline

6- (Trifluoromethyl) quinoxalin-2-amine (0.9 g,4.2 mmol) was dissolved in methylene chloride (20 mL), 1' -thiocarbonylbis (pyridin-2 (1H) -one) (1.2 g,5.0 mmol) was added thereto, and after reacting at 25℃for 4 hours, the reaction mixture was stirred with silica gel and purified by silica gel column chromatography (n-heptane and ethyl acetate as mobile phase, ethyl acetate ratio of 0% to 10%) to give the product (800 mg, yield 74.7%).

5. Preparation of N- (6- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) piperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) -6- (trifluoromethyl) quinoxalin-2-amine

4- (1- (2- ((Tert-Butyldimethylsilyl) oxy) ethyl) piperidin-4-yl) benzene-1, 2-diamine (309 mg,0.78 mmol) was dissolved in N, N-dimethylformamide (10 mL), 2-isothiocyanato-6- (trifluoromethyl) quinoxaline (200 mg,0.78 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (298 mg,1.6 mmol) were added thereto, and after stirring at 100℃for 30 minutes, the reaction mixture was dried by spin-drying, stirred with silica gel, and purified by column chromatography on silica gel (N-heptane and ethyl acetate as mobile phase, ethyl acetate ratio was 0% to 100%) to give the product (130 mg, yield 29.3%).

6. Preparation of 2- (4- (2- ((6- (trifluoromethyl) quinoxalin-2-yl) amino) -1H-benzo [ d ] imidazol-6-yl) piperidin-1-yl) ethan-1-ol

N- (6- (1- (2- ((tert-Butyldimethylsilyl) oxy) ethyl) piperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) -6- (trifluoromethyl) quinoxalin-2-amine (100 mg,0.17 mmol) was dissolved in methanol (2 mL), a1, 4-dioxane solution (4M, 2 mL) of hydrogen chloride was added thereto, after reaction at 15℃for 30 minutes, the reaction solution was adjusted to pH=8 with saturated sodium hydrogencarbonate solution, the crude product was extracted with ethyl acetate, and then the organic phase was separated, the solvent was removed under reduced pressure, and slurried with a mixed solution of dichloromethane and N-heptane (dichloromethane: N-heptane=1:5) to give the product (37 mg, yield 47.6%).

Molecular formula C ₂₃H₂₃F₃N₆ O molecular weight 456.5LC-MS (M/e): 457.2 (M+H2 ⁺)

¹H-NMR(400MHz,DMSO-d₆)δ:12.2(br,2H),8.67(s,1H),8.55(s,1H),8.05(d,J＝8.8Hz,1H),7.72(d,J＝8.8Hz,1H),7.37(d,J＝8.4Hz,2H),7.04(d,J＝8.4Hz,1H),4.35(br,1H),3.60-3.45(m,2H),3.08-2.95(m,2H),2.60-2.35(m,3H),2.15-2.05(m,2H),1.80-1.55(m,4H).

Example sixteen: preparation of 2- ((6- (1- (2-hydroxyethyl) piperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) amino) quinoxaline-6-carbonitrile (Compound 33)

1. Preparation of 2-aminoquinoxaline-6-carbonitrile

2-Chloroquinoxaline-6-carbonitrile (890 mg) was dissolved in isopropyl alcohol (19.0 mL), aqueous ammonia (4.2 mL) was added thereto, and after microwave reaction at 110℃for 0.5 hours, the solvent was removed under reduced pressure to give a crude product (680 mg).

2. Preparation of 2-isothiocyanaquinoxaline-6-carbonitrile

2-Aminoquinoxaline-6-carbonitrile (670 mg,3.9 mmol) was dissolved in methylene chloride (20 mL), thiophosgene (679 mg,5.9 mmol) and pyridine (1.2 g,15.6 mmol) were added thereto, and after reacting at 25℃for 4 hours, the reaction mixture was stirred with silica gel and purified by silica gel column chromatography (n-heptane and ethyl acetate as mobile phases, ethyl acetate ratio was 0% to 20%) to obtain a product (200 mg, yield 23.9%).

3. Preparation of 2- ((6- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) piperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) amino) quinoxaline-6-carbonitrile

4- (1- (2- ((Tert-Butyldimethylsilyl) oxy) ethyl) piperidin-4-yl) benzene-1, 2-diamine 315mg,0.9 mmol) was dissolved in N, N-dimethylformamide (10 mL), 2-isothiocyanato quinoxaline-6-carbonitrile (190 mg,0.9 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (345 mg,1.8 mmol) were added thereto, and after stirring at 40℃for 60 minutes, the reaction mixture was dried by spin-drying, stirred with silica gel, and purified by silica gel column chromatography (N-heptane and ethyl acetate as mobile phase, ethyl acetate ratio was 0% to 100%) to give the product (50 mg, yield 10.6%).

4. Preparation of 2- ((6- (1- (2-hydroxyethyl) piperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) amino) quinoxaline-6-carbonitrile

2- ((6- (1- (2- ((Tert-Butyldimethylsilanyloxy) ethyl) piperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) amino) quinoxaline-6-carbonitrile (45 mg) was dissolved in methanol (5 mL), and a1, 4-dioxane solution (4M, 1 mL) of hydrogen chloride was added thereto, and after reacting at 15℃for 30 minutes, it was dried by spin, and washed with methanol to give a product (20 mg, yield 56.7%).

Molecular formula C ₂₃H₂₃N₇ O molecular weight 413.5LC-MS (M/e): 414.2 (M+H ⁺)

¹H-NMR(400MHz,DMSO-d₆)δ:10.35(br,1H),9.08(s,1H),8.91(s,1H),8.18(d,J＝8.4Hz,1H),8.05(d,J＝8.4Hz,1H),7.70(d,J＝8.2Hz,1H),7.62(s,1H),7.30(d,J＝8.2Hz,1H),4.89-4.81(m,2H),4.69-4.61(m,2H),3.22-3.16(m,2H),3.12-3.09(m,2H),3.02-2.92(m,1H),2.20-2.10(m,2H),2.05-1.95(m,2H).

Example seventeenth: preparation of 2- (4- (4-fluoro-2- ((7- (trifluoromethyl) benzo [ e ] [1,2,4] triazin-3-yl) amino) -1H-benzo [ d ] imidazol-6-yl) piperidin-1-yl) ethan-1-ol (Compound 35)

1. Preparation of 4- (2-benzamide-7-fluoro-1H-benzo [ d ] imidazol-5-yl) piperidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4- (3, 4-diamino-5-fluorophenyl) piperidine-1-carboxylate (28.0 g,96.1 mmol) in DMF (400 mL) was added benzoyl isothiocyanate (23.5 g,144.2 mmol) and EDCI (36.8 g,192.2 mmol) and reacted at 100℃for 16 hours. Concentrate and purify by column chromatography on silica gel (n-heptane: ethyl acetate=5:1) to give the product (21 g, yield 52.0%).

2. Preparation of 4- (2-amino-7-fluoro-1H-benzo [ d ] imidazol-5-yl) piperidine-1-carboxylic acid tert-butyl ester

Tert-butyl 4- (2-benzamide-7-fluoro-1H-benzo [ d ] imidazol-5-yl) piperidine-1-carboxylate (21.0 g,49.9 mmol) and sodium hydroxide (12.0 g,29.4 mmol) were dissolved in methanol (500.0 mL) and stirred at 72℃for 12 hours. Spin-drying and washing with water gave the product (8.0 g, yield 50.6%).

3. Preparation of tert-butyl 4- (4-fluoro-2- ((7- (trifluoromethyl) benzo [ e ] [1,2,4] triazin-3-yl) amino) -1H-benzo [ d ] imidazol-6-yl) piperidine-1-carboxylate

Tert-butyl 4- (2-amino-7-fluoro-1H-benzo [ d ] imidazol-5-yl) piperidine-1-carboxylate (234 mg,1.0 mmol), 3-chloro-7- (trifluoromethyl) benzo [ e ] [1,2,4] triazine (334 mg,1.0 mmol), pd ₂(dba)₃ (92 mg,0.1 mmol), xanthos (116 mg,0.2 mmol) and Cs ₂(CO)₃ (652 mg,2.0 mmol) were dissolved in1, 4-dioxane (16 mL) and reacted at 100℃for 2H. Concentrate and purify by silica gel column chromatography (dichloromethane: methanol=20:1) to give the product (120 mg, yield 32.3%).

4. Preparation of N- (4-fluoro-6- (piperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) -7- (trifluoromethyl) benzo [ e ] [1,2,4] triazin-3-amine hydrochloride

4- (4-Fluoro-2- ((7- (trifluoromethyl) benzo [ e ] [1,2,4] triazin-3-yl) amino) -1H-benzo [ d ] imidazol-6-yl) piperidine-1-carboxylic acid tert-butyl ester (120 mg,0.22 mmol) was dissolved in dichloromethane (8 mL), and ethyl hydrogen chloride acetate solution (4M, 20.0 mL) was added and reacted at 25℃for 0.5H. Concentration gave the product (90 mg, 85.2% yield).

5. Preparation of N- (6- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) piperidin-4-yl) -4-fluoro-1H-benzo [ d ] imidazol-2-yl) -7- (trifluoromethyl) benzo [ e ] [1,2,4] triazin-3-amine

N- (4-fluoro-6- (piperidin-4-yl) -1H-benzo [ d ] imidazol-2-yl) -7- (trifluoromethyl) benzo [ e ] [1,2,4] triazin-3-amine hydrochloride (90 mg,0.19 mmol) was dissolved in methanol (10.0 mL) and 2- ((tert-butyldimethylsilyl) oxy) acetaldehyde (66 mg,0.38 mmol) and sodium cyanoborohydride (60 mg,0.95 mmol) were added sequentially. The reaction was carried out at 40℃for 6 hours. Concentrate, extract with water (20 mL) and ethyl acetate (30 mL), purify by silica gel column chromatography (dichloromethane: methanol=15:1) to give the product (40 mg, yield 35.3%).

6. Preparation of 2- (4- (4-fluoro-2- ((7- (trifluoromethyl) benzo [ e ] [1,2,4] triazin-3-yl) amino) -1H-benzo [ d ] imidazol-6-yl) piperidin-1-yl) ethan-1-ol

N- (6- (1- (2- ((tert-butyldimethylsilyloxy) ethyl) piperidin-4-yl) -4-fluoro-1H-benzo [ d ] imidazol-2-yl) -7- (trifluoromethyl) benzo [ e ] [1,2,4] triazin-3-amine (40 mg,0.68 mmol) was dissolved in methanol (2.0 mL) and hydrochloric acid (3M, 1.0 mL) was added. The reaction was carried out at 40℃for 0.5h. Purification by Prep-HPLC (methanol: water=10% -70%) afforded the product (7 mg, yield 21.7%).

Molecular formula C ₂₂H₂₁F₄N₇ O molecular weight 475.5LC-MS (M/e): 476.2 (M+H ⁺)

¹H-NMR(400MHz,CDCl₃)δ:8.67(s,1H),8.20-8.05(m,2H),7.22(s,1H),6.89-6.79(m,1H),4.33(s,1H),3.50-3.45(m,2H),2.99-2.92(m,2H),2.15-2.05(m,2H),1.99-1.92(m,2H),1.81-1.76(m,2H),1.70-1.61(m,2H).

Other example compounds of the application were prepared according to the same or similar methods as the examples above, with the following specific characterization data:

Experimental protocol

Exemplary protocols for some of the compounds of the present invention are provided below to demonstrate the advantageous activity and beneficial technical effects of the compounds of the present invention. It should be understood that the following experimental schemes are merely illustrative of the present disclosure and are not intended to limit the scope of the present disclosure.

Experimental example A SUMO1 protein degradation test

The test method comprises the following steps:

Degradation of SUMO1 by compounds was screened in a dose-dependent manner using an HCT116 cell line genetically modified to express the HiBit tag in the N-terminal domain of SUMO1 protein.

Degradation was tested under two media conditions: contains 2% and 10% FBS (fetal bovine serum).

24 Hours prior to testing, cells were plated with 10% fbs medium at a density of 1000/well or with 2% fbs medium at a density of 2000/well in white 96-well plates, respectively. Compounds were first dissolved in DMSO as a 50mM stock solution, further diluted to 10mM in DMSO, then diluted in DMEM medium to 10 test concentrations in a gradient, and added to 96-well plates where cells had been plated for 24 h. The final concentrations of the test drugs were respectively 20uM,10uM,5uM,2.5uM,1.25uM,0.625uM,0.312uM,0.156uM,0.078uM,0.039uM. Cells were exposed to the drug for 5 days. On day 5, SUMO1HiBit levels were detected using the Nano-Glo HiBit Lytic detection system (Promega). That is, 100. Mu. L Nano Glo HiBiT Lytic detection reagent was added to each well and incubated with shaking (450 rpm) for 10 minutes, and then luminescence values were recorded on a multi-well plate detector (Synergy H1 microplate detector). And further calculate IC ₅₀ values.

Test results:

The compounds of the application have good SUMO1 degradation and the test results are shown in Table 1, wherein the IC ₅₀ value range: a is less than or equal to 0.5uM;0.5uM < B.ltoreq.1.0 uM; c is less than or equal to 3.0uM and less than or equal to 1.0uM; d is less than or equal to 5.0uM and is less than or equal to 3.0uM; 5.0 mu M < E.ltoreq.15.0 mu M.

TABLE 1 degradation Activity of the inventive Compound SUMO1

N/T: not tested.

Claims

1. A compound represented by general formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a deuterated product thereof,

in,

X is selected from N(R ₃ ), O or S;

Ring A and Ring B are independently selected from 5-8 membered cycloalkyl, 5-8 membered heterocyclyl, phenyl or 5-8 membered heteroaryl, and Ring A and Ring B share two adjacent ring atoms;

Ring C and ring D are independently selected from 5-8 membered cycloalkyl, 5-8 membered heterocyclyl, phenyl or 5-8 membered heteroaryl, and ring C and ring D share two adjacent ring atoms;

Cy is selected from hydrogen, _R2 or 3-11 membered cycloalkyl or 3-11 membered heterocyclyl optionally substituted by 1-3 substituents Q; each Q is independently selected from H, halogen, hydroxy, amino, _C1-6 alkyl, haloC1-6 alkyl, _hydroxyC1-6 alkyl, _aminoC1-6 alkyl, _C1-6 alkoxy- _C1-6 alkyl _, _C1-6 alkoxy, _haloC1-6 alkoxy, hydroxyC1-6 alkoxy, _aminoC1-6 alkoxy, -( _CH2 ) _p -N(R ^a )(R ^b ), -( _CH2 ) _p _- OR ^a , -( _CH2 ) _p -P(O)(R ^a )(R ^b ), -( _CH2 ) _p -S(O)(R ^a ), -( _CH2 ) _p -S(O) ₂ (R ^a ), -( _CH2 ) _p -C(O)(R ^a ), -(CH2 _)p- ) _p -C(O)O(R ^a ), -(CH ₂ ) _p -OC(O)(R ^a ), -(CH ₂ ) _p -C(O)N(R ^a )(R ^b ), -(CH ₂ ) _p -N(R ^b )-C(O)(R ^a ), optionally, one or more hydrogen atoms in the C _1-6 alkyl group are deuterated;

each R ₁ and each R ₂ are independently selected from hydrogen, halogen, hydroxy, amino, cyano, carboxyl, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, halo C _1-6 alkoxy, halo C _1-6 alkylthio, hydroxy C _1-6 alkoxy, amino C _1-6 alkyloxy, hydroxy C _1-6 alkylthio, amino C _1-6 alkylthio, C _1-6 alkoxy-C _1-6 alkyl or 5-membered heteroaryl;

_R3 is selected from hydrogen, _C1-6 alkyl, halogenated _C1-6 alkyl, hydroxy _C1-6 alkyl, amino _C1-6 alkyl, cyano _C1-6 alkyl or _C1-6 alkoxy- _C1-6 alkyl;

^Ra and ^Rb are independently selected from hydrogen, _C1-6 alkyl, halogenated _C1-6 alkyl, hydroxyl _C1-6 alkyl, amino _C1-6 alkyl, cyano _C1-6 alkyl, _C1-6 alkoxy- _C1-6 alkyl;

m is selected from 0, 1, 2 or 3;

n is selected from 0, 1, 2 or 3;

p is selected from 0, 1, 2 or 3;

--- represents a single bond or a double bond bridging ring A and ring B or bridging ring C and ring D.

2. The compound according to claim 1, its pharmaceutically acceptable salt, its stereoisomer or its deuterated product,

Among them, ring A and ring B together form the following group:

and Position is the position where ring B is attached to group X;

Ring C and ring D together form the following group:

and The position is the position at which ring C is attached to group X.

3. The compound according to any one of claims 1 to 2, its pharmaceutically acceptable salt, its stereoisomer or its deuterated product, wherein:

Cy is selected from hydrogen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, halo C _1-6 alkoxy, halo C _1-6 alkylthio or C _1-6 alkoxy-C _1-6 alkyl.

4. The compound according to any one of claims 1 to 2, its pharmaceutically acceptable salt, its stereoisomer or its deuterated product, wherein:

Cy is selected from the following groups optionally substituted by 1-2 substituents Q:

and The position is where Cy is attached to ring D.

5. The compound according to claim 1, its pharmaceutically acceptable salt, its stereoisomer or its deuterated product, wherein the compound of general formula (I) further has a structure represented by the following general formula (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig),

wherein each Y is independently selected from NH, O or S;

_Y1 is selected from N or CH; _Y2 is selected from N or CH.

6. The compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, its stereoisomer or its deuterated product, wherein:

X is NH;

Cy is selected from hydrogen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl or the following groups optionally substituted by 1-2 substituents Q:

each Q is independently selected from H, halogen, hydroxy, amino, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkoxy, amino C _1-6 alkoxy, -(CH ₂ ) _p -S(O)(R ^a ), -(CH ₂ ) _p -S(O) ₂ (R ^a ) or -(CH ₂ ) _p -C(O)(R ^a ), optionally, one or more hydrogen atoms in the C _1-6 alkyl are deuterated;

R ₁ and R ₂ are each independently selected from hydrogen, halogen, hydroxy, amino, cyano, carboxyl, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, cyano C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, halo C _1-6 alkoxy, halo C _1-6 alkylthio, hydroxy C _{1-6 alkoxy, amino C 1-6 alkoxy, hydroxy C 1-6} _alkylthio _, amino C _1-6 alkylthio, C _1-6 alkoxy-C _1-6 alkyl or a 5-membered nitrogen-containing heteroaryl group;

^Ra is selected from hydrogen, _C1-6 alkyl, halogenated _C1-6 alkyl, hydroxy _C1-6 alkyl, amino _C1-6 alkyl, cyano _C1-6 alkyl, _C1-6 alkoxy- _C1-6 alkyl;

m is selected from 0 or 1;

n is selected from 0 or 1;

p is selected from 0, 1, 2 or 3.

7. The compound according to claim 1, its pharmaceutically acceptable salt, its stereoisomer or its deuterated product, selected from the following compounds:

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, its stereoisomer or its deuterated product, and one or more pharmaceutically acceptable carriers and/or excipients.

9. Use of the compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt, its stereoisomer or its deuterated product, and the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and/or treating cancer or autoimmune diseases.

10. The method of claim 9, wherein the cancer is selected from melanoma, lung cancer, kidney cancer, lymphoma, head and neck cancer, urothelial carcinoma, prostate cancer, bladder cancer, breast cancer, gastric cancer, colorectal cancer, leukemia, cervical cancer, liver cancer, ovarian cancer, pancreatic cancer, endometrial cancer, myeloma, bile duct cancer, brain cancer, sarcoma, hemangioendothelioma, epithelial cancer, esophageal cancer, testicular cancer, glioma, bone cancer, nasopharyngeal cancer, skin cancer, squamous cell carcinoma, oral cancer or thyroid cancer; and the autoimmune disease is selected from rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, pemphigus vulgaris, thrombotic thrombocytopenic purpura or Rasmussen's encephalitis.