CN116589454A

CN116589454A - Aromatic heterocyclic compound, preparation method and medical application thereof

Info

Publication number: CN116589454A
Application number: CN202211696686.3A
Authority: CN
Inventors: 史记周; 刘国标; 闫旭; 费腾; 尚飞
Original assignee: National Institutes of Pharmaceutical R&D Co Ltd
Current assignee: National Institutes of Pharmaceutical R&D Co Ltd
Priority date: 2021-12-29
Filing date: 2022-12-28
Publication date: 2023-08-15

Abstract

The invention relates to an aromatic heterocyclic compound, a preparation method and medical application thereof. In particular, the invention relates to a compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, application of the compound as a P300/CBP inhibitor and application of the compound in treating diseases related to P300/CBP activity. Wherein each group in the general formula (I) is defined as the specification.

Description

Aromatic heterocyclic compound, preparation method and medical application thereof

Technical Field

The invention belongs to the technical field of medicines, and relates to a novel aromatic heterocyclic compound, a preparation method thereof, a pharmaceutical composition containing the novel aromatic heterocyclic compound and application of the novel aromatic heterocyclic compound in inhibiting the activity of p300/CBP protein. The compounds of the invention are useful in the treatment of a variety of tumors such as metastatic prostate cancer, breast cancer, hematological tumors, and other diseases associated with p300/CBP activity.

Background

CREB Binding Proteins (CBP) and p300 (also known as EP 300) are two highly homologous acetyltransferases found in higher eukaryotes. Structurally, both CBP and p300 contain an acetyltransferase domain (HAT/KAT), a Bromodomain (BRD), and several other identical domain modules, KIX, TAZ1, TAZ2, and iBID (Yang et al, mol Cell,2008:31 (4), 449-461). Because of the high similarity of domain sequences, they are commonly referred to as p300/CBP. P300/CBP catalyzes acetyl transfer of acetyl CoA to lysine residues of substrates to regulate protein activity, involving more than 200 of the substrate proteins including P53, a variety of nuclear receptors (retinoic acid X receptor RXR, estrogen receptor ER and androgen receptor AR) and other transcription factors, which are involved in the development of cancer, inflammation and other diseases (Chakravarti et al, nature,1996:383 (6595), 99-103; ghosh et al, J Biol Chem,2016:291 (25), 13014-13027).

Prostate Cancer (PCa) is the disease with the highest number of new Cancer cases and the second highest Cancer mortality rate in American men, and in recent years, the incidence rate in China has also shown a rapid increase (Qia et al, cancer Commun (Lond), 2021:41 (10), 1037-1048). Standard treatments for Castration Resistant PCa (CRPC) are Androgen Deprivation Therapy (ADT) and targeted AR signaling therapy (enzalutamide and abiraterone acetate (abiraterone acetate)) (Scher et al, N Engl J Med,2012:367 (13), 1187-1197; atard et al, J Clin Oncol,2009:27 (23), 3742-3748). However, the inherent and acquired resistance of patients to these drugs is a serious challenge to clinical treatment. There are a number of mechanisms for CRPC involving AR signal amplification, AR Ligand Binding Domain (LBD) point mutation and expression of various AR splice variants (AR-V7 being the most studied) (Karantanos et al, eur Urol,2015:67 (3), 470-479; watson et al, nat Rev Cancer,2015:15 (12), 701-711). p300 is highly overexpressed as an AR transcriptional coactivator in prostate Cancer and induces transcription of the AR response gene and upregulation of AR signaling (Zhong et al, cancer Res,2014:74 (6), 1870-1880). Preclinical studies have shown that targeted inhibition of p300/CBP function reduces AR signal levels in both in vivo and in vitro models, inhibiting tumor growth in animal models of prostate Cancer (Jin et al, cancer Res,2017:77 (20), 5564-5575). Thus, inhibition of AR signaling by blocking p300/CBP may be an effective PCa treatment strategy.

The development of small molecule inhibitors against the bromodomains and HAT domains of CBP/p300 has been ongoing for many years, and eventually several affinity levels up to nanomolar have been found, as well as highly selective small molecule inhibitors. For example FT-7051, GNE-781 (CBP IC ₅₀ ＝0.94nM,BRD4 IC ₅₀ =5100 n μm) (Romero et al, J Med Chem,2017:60 (22), 9162-9183), UMB298 (CBP IC50 72nM,BRD4 IC50 5193nM) (Muthengi et al, J Med Chem,2021:64 (9), 5787-5801). In particular, the inhibitor CCS1477 developed by CellCentric acting on the P300/CBP BRD domain (CBP: kd=1.7 nmolL.L) ^-1 ，p300：Kd＝1.3nmol·L ^-1 ) (Welti et al, cancer discover, 2021:11 (5), 1118-1137) showed better activity and selectivity, and clinical trials are currently underway to try to treat hematological and prostate cancers.

In addition, p300/CBP can be recruited to the CD274 (encoding PD-L1) promoter position by transcription factor IRF-1, inducing acetylation of CD274 promoter histone H3, involved in CD274 transcriptional regulation; while the p300/CBP inhibitor can block the endogenous and IFN-gamma induced PD-L1 expression, obviously enhance the effect of the PD-L1 inhibitor in a PCa model (Liu et al, oncogene,2020:39 (19), 3939-3951), and suggest that targeting the combination of p300/CBP and an immune checkpoint inhibitor is a potential effective way to overcome tumor resistance.

In the future, more novel compound molecules with high selectivity and better activity and safety are still needed to be explored and used for treating advanced tumors.

Disclosure of Invention

Through intensive researches, the inventor designs and synthesizes a series of aryl or heteroaryl imidazole compounds, and screens p300/CBP activity, and research results show that the compounds have outstanding p300/CBP inhibition activity and can be developed into medicaments for treating diseases related to the p300/CBP activity.

In one aspect, the invention provides a compound of formula (I) or a meso, racemic, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x, Y and Z are each independently selected from CR ⁶ And N;

a is CR ⁷ Or N;

R ¹ selected from cycloalkyl, heterocyclylAryl and heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more G ¹ Substitution;

R ² selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, wherein each of said alkyl, cycloalkyl, heterocyclyl is independently optionally substituted with one or more G ² Substitution;

R ³ 、R ⁴ 、R ⁵ each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R ^b 、-O(O)CR ^b 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a R ^b 、-NHC(O)R ^b 、-S(O) _n R ^b 、-S(O) _n NR ^a R ^b and-NHS (O) _n R ^b Wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with one or more G ³ Substitution;

or R is ³ And R is ⁴ Together with the atoms to which they are attached, form a cycloalkyl or heterocyclyl group, wherein the cycloalkyl or heterocyclyl group is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and R is ⁵ Selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more G ³ Substitution;

each R ⁶ Each independently selected from the group consisting of hydrogen, halogen, amino, cyano, oxo, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with a member selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, mercapto Substitution of one or more groups of groups, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ⁷ selected from the group consisting of hydrogen, halogen, amino, cyano, oxo, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

each G ¹ 、G ² 、G ³ Each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR ^a 、-C(O)R ^b 、-O(O)CR ^b 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a R ^b 、-NHC(O)R ^b 、-S(O) _n R ^b 、-S(O) _n NR ^a R ^b and-NHS (O) _n R ^b Wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ^a And R is ^b Each independently selected from hydrogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl groups are each independently optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl groups；

Or R is ^a And R is ^b Together with the nitrogen atom to which they are attached, form a nitrogen-containing heterocyclic group optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

n is 0, 1 or 2.

In a specific embodiment, the compounds of formula (I) according to the invention or the meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein A is CR ⁷ ；R ⁷ Selected from the group consisting of hydrogen, halogen, amino, cyano, oxo, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

In another specific embodiment, the compound of formula (I) according to the invention, or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein a is N.

In a preferred embodiment, the compounds of the general formula (I) according to the invention or the meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, are in the form of a compound of the general formula (II) or the meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

therein, X, Y, Z, R ¹ ～R ⁵ As defined by formula (I).

In a particular embodiment, the compounds of formula (I) or formula (II) according to the invention or the meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein one of X, Y and Z is N and the remainder are CR ⁶ The method comprises the steps of carrying out a first treatment on the surface of the Or one of X, Y and Z is CR ⁶ The rest is N; or X, Y and Z are both N; or X, Y and Z are CR ⁶ ；

R ⁶ Selected from the group consisting of hydrogen, halogen, amino, cyano, oxo, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

In another preferred embodiment, the compound of formula (I) according to the invention or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (III) or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein,,

m is 0, 1, 2 or 3; preferably 0 or 1;

R ¹ ～R ⁶ as defined by formula (I).

In another preferred embodiment, the compounds of the formula (I), the formula (II) or the formula (III) according to the invention or their internalizationA racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ Selected from C ₃ -C ₆ Cycloalkyl, 3-to 6-membered heterocyclyl, C ₆ -C ₁₀ Aryl and 5 to 10 membered heteroaryl, preferably C ₆ -C ₁₀ Aryl and 5 to 10 membered heteroaryl, more preferably 5 to 10 membered heteroaryl, even more preferably 5 to 6 membered heteroaryl, most preferably 5 membered heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally further substituted with one or more G ¹ Substitution; g ¹ As defined by formula (I).

In another preferred embodiment, the compounds of formula (I), formula (II) or formula (III) according to the invention or the meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ Selected from:

preferably

Wherein p is 0, 1 or 2; preferably 1 or 2; more preferably 2;

G ¹ as defined by formula (I).

In another preferred embodiment, the compound of formula (I) according to the invention or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (IVA) or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein,,

p is 0, 1 or 2, preferably 1 or 2, more preferably 2;

X、Y、Z、G ¹ 、R ² ～R ⁵ as defined by formula (I).

In another preferred embodiment, the compound of formula (I) according to the invention or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (IV) or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

Wherein,,

p is 0, 1 or 2, preferably 1 or 2, more preferably 2;

m is 0, 1, 2 or 3; preferably 0 or 1;

G ¹ 、R ² ～R ⁶ as defined by formula (I).

In another preferred embodiment, the compounds of formula (I), formula (II), formula (III), formula (IVA) or formula (IV) according to the invention or their meso, racemate, enantiomer, diastereomer or mixture thereof, or their pharmaceutically acceptable salts, wherein,

R ³ is hydrogen;

R ⁴ is hydrogen or hydroxy;

R ⁵ is C ₆ -C ₁₀ Aryl or 5 to 10 membered heteroaryl, preferably phenyl or 5 to 6 membered heteroaryl, more preferably phenyl, which is further substituted with one or more G ³ Substitution;

G ³ selected from halogen, amino, cyano, hydroxy, mercapto, -C (O) R ^b 、-O(O)CR ^b 、-C(O)OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkoxy, C ₃ -C ₆ Cycloalkyl, 3-to 6-membered heterocyclyl, C ₆ -C ₁₀ Aryl and 5 to 10 membered heteroaryl;

R ^a and R is ^b As defined by formula (I).

In a specific embodiment, the compound of formula (I), formula (II), formula (III), formula (IVA), or formula (IV) according to the present invention, or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: r is R ³ Is hydrogen; r is R ⁴ Is hydrogen or hydroxy; r is R ⁵ Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, preferably phenyl, R ⁵ Further by one or more G ³ Substitution, G ³ Selected from halogen, amino, cyano, hydroxy, mercapto, -C (O) R ^b 、-O(O)CR ^b 、-C(O)OR ^a 、C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkoxy, C ₃ -C ₆ Cycloalkyl, 3-to 6-membered heterocyclyl, C ₆ -C ₁₀ Aryl and 5 to 10 membered heteroaryl; r is R ^a Is hydrogen or C ₁ -C ₆ An alkyl group; r is R ^b Is C ₁ -C ₆ An alkyl group.

In another preferred embodiment, the compounds of formula (I), formula (II), formula (III), formula (IVA) or formula (IV) according to the invention or the meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ And R is ⁴ Together with the atoms to which they are attached form C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocyclyl, wherein the C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocyclyl is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and R is ⁵ Selected from hydrogenHalogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more G ³ Substitution;

G ³ selected from halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR ^a 、-C(O)R ^b 、-O(O)CR ^b 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a R ^b 、-NHC(O)R ^b 、-S(O) _n R ^b 、-S(O) _n NR ^a R ^b and-NHS (O) _n R ^b Wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ^a 、R ^b and n is as defined in formula (I).

In another preferred embodiment, the compound of formula (I) according to the invention or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (VA) or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

Wherein,,

R ³ is hydrogen;

R ⁴ is hydrogen or hydroxy;

each R ⁸ Each independently selected from hydrogen, halogen, amino, cyano, hydroxy, mercapto, carboxyl, ester, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkoxy, C ₃ -C ₆ Cycloalkyl, 3-to 6-membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5 to 10 membered heteroaryl;

q is 0, 1, 2 or 3; preferably 0, 1 or 2;

p is 0, 1 or 2, preferably 1 or 2, more preferably 2;

X、Y、Z、G ¹ 、R ² as defined by formula (I).

In another preferred embodiment, the compound of formula (I) according to the invention or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (V) or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein,,

R ³ is hydrogen;

R ⁴ is hydrogen or hydroxy;

q is 0, 1, 2 or 3; preferably 0, 1 or 2;

p is 0, 1 or 2, preferably 1 or 2, more preferably 2;

m is 0, 1, 2 or 3; preferably 0 or 1;

G ¹ 、R ² 、R ⁶ as defined by formula (I).

In another preferred embodiment, the compounds of formula (I), formula (II), formula (III), formula (IVA), formula (IV), formula (VA) and formula (V) according to the invention or the meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each G ¹ Each independently selected from hydrogen, halogen, cyano, hydroxy, mercapto, and C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, OR ^a Wherein said C ₁ -C ₆ Alkyl is optionally substituted with halogen; r is R ^a Selected from C ₁ -C ₆ An alkyl group; the C is ₁ -C ₆ Alkyl is optionally substituted with halogen;

preferably G ¹ Is C ₁ -C ₆ An alkyl group.

In another preferred embodiment, the compounds of formula (I), formula (II), formula (III), formula (IVA), formula (IV), formula (VA) and formula (V) according to the invention are in the form of their meso, racemate, enantiomer, diastereomer or mixtures thereof, or their pharmaceutically acceptable salts, wherein G ¹ Is C ₁ -C ₆ Alkyl, p is 2.

In another preferred embodiment, the compounds of formula (I), formula (II), formula (III), formula (IVA), formula (IV), formula (VA) and formula (V) according to the invention are in the form of their meso, racemate, enantiomer, diastereomer or mixtures thereof, or their pharmaceutically acceptable salts, wherein R ² Selected from C ₃ -C ₈ Cycloalkyl and 3 to 8 membered heterocyclyl, preferably C ₃ -C ₆ Cycloalkyl and 3 to 6 membered heterocyclyl; the cycloalkyl or heterocyclyl group being optionally substituted with one or more G ² Substitution; g ² As defined by formula (I).

In another preferred embodiment, the compounds of the general formula (I), the general formula (II), the general formula (III), the general formula (IVA), the general formula (IV), the general formula (VA) and the general formula (V) according to the invention or the meso, racemate, enantiomer, diastereomer or mixtures thereof,Or a pharmaceutically acceptable salt thereof, wherein R ² Selected from C ₅ -C ₆ Cycloalkyl and 5 to 6 membered heterocyclyl; the C is ₅ -C ₆ Cycloalkyl and 5-to 6-membered heterocyclyl are optionally substituted with one or more G ² Substitution; g ² As defined by formula (I).

In another preferred embodiment, the compounds of formula (I), formula (II), formula (III), formula (IVA), formula (IV), formula (VA) and formula (V) according to the invention are in the form of their meso, racemate, enantiomer, diastereomer or mixtures thereof, or their pharmaceutically acceptable salts, wherein R ² Selected from cyclohexyl, tetrahydropyranyl, thiacyclohexyl, piperidinyl, piperazinyl, morpholinyl, R ² Optionally by one or more G ² Substitution; g ² As defined by formula (I).

In another preferred embodiment, the compounds of formula (I), formula (II), formula (III), formula (IVA), formula (IV), formula (VA) and formula (V) according to the invention are in the form of their meso, racemate, enantiomer, diastereomer or mixtures thereof, or their pharmaceutically acceptable salts,

each G ² Each independently selected from hydrogen, halogen, amino, cyano, mercapto, oxo, C ₁ -C ₆ Alkyl, OR ^a 、-C(O)R ^b 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、NR ^a R ^b 、NHC(O)R ^b 、-S(O) _n R ^b 、-S(O) _n NR ^a R ^b and-NHS (O) _n R ^b Wherein said C ₁ -C ₆ Alkyl is optionally substituted with one or more groups selected from halogen and cyano;

R ^a selected from hydrogen, C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl; the C is ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl is optionally substituted with halogen;

R ^b selected from C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl; the C is ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl is optionally substituted with halogen;

or R is ^a And R is ^b Together with the nitrogen atom to which they are attached, form a 4-6 membered nitrogen containing heterocyclic group, said 4-6 membered nitrogen containing heterocyclic group optionally being selected from halogen, oxo, hydroxy, mercapto, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, one or more groups substituted.

Each G ² Each independently selected from hydrogen, halogen, cyano, oxo, C ₁ -C ₆ Alkyl, OR ^a 、-C(O)R ^b 、-C(O)OR ^a 、-S(O) _n R ^b Wherein said C ₁ -C ₆ Alkyl is optionally substituted with one or more groups selected from halogen and cyano; r is R ^a Selected from hydrogen and C ₁ -C ₆ An alkyl group; r is R ^b Selected from C ₁ -C ₆ An alkyl group;

n is 1 or 2.

In another preferred embodiment, the compounds of formula (I), formula (II), formula (III), formula (IVA), formula (IV), formula (VA) and formula (V) according to the invention are in the form of their meso, racemate, enantiomer, diastereomer or mixtures thereof, or their pharmaceutically acceptable salts, wherein R ² Selected from the group consisting of

R ⁹ Selected from hydrogen, oxo, C ₁ -C ₆ Alkyl, -C (O) R ^b 、-C(O)OR ^a 、-S(O) _n R ^b Wherein said C ₁ -C ₆ Alkyl is optionally substituted with one or more groups selected from halogen and cyano;

R ^9a and R is ^9b Each independently selected from hydrogen, halogen, cyano, oxo, C ₁ -C ₆ Alkyl, OR ^a 、-C(O)R ^b 、-C(O)OR ^a 、-S(O) _n R ^b Wherein said C ₁ -C ₆ Alkyl is optionally substituted with one or more groups selected from halogen and cyano;

R ^a selected from hydrogen and C ₁ -C ₆ An alkyl group;

R ^b selected from C ₁ -C ₆ An alkyl group.

In another preferred embodiment, the compounds of formula (I), formula (II), formula (III), formula (IV), formula (VA) and formula (V) according to the invention are in the form of their meso, racemate, enantiomer, diastereomer or mixtures thereof, or their pharmaceutically acceptable salts, wherein R ⁶ Selected from hydrogen, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, m is 0 or 1, preferably 0.

In another preferred embodiment, the compounds of formula (I), formula (II), formula (III), formula (IVA), formula (IV), formula (VA) and formula (V) according to the invention are in the form of their meso, racemate, enantiomer, diastereomer or mixtures thereof, or their pharmaceutically acceptable salts, wherein R ⁶ Is hydrogen.

In another preferred embodiment, the compounds of formula (I), formula (II), formula (III), formula (IV), formula (VA) and formula (V) according to the invention, or the meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R ⁸ Each independently selected from hydrogen, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkoxy groups; preferably hydrogen, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ An alkoxy group; q is 0, 1 or 2.

In another preferred embodiment, the compound of formula (I) according to the invention or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (VIA) or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

Wherein ring E is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably cycloalkyl or heterocyclyl; optionally with one or more G ⁴ Substituted;

G ⁴ selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR ^a 、-C(O)R ^b 、-O(O)CR ^b 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、-NR ^a R ^b 、-NHC(O)R ^b 、-S(O) _n R ^b 、-S(O) _n NR ^a R ^b and-NHS (O) _n R ^b Wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R ^a and R is ^b Each independently selected from hydrogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl; the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are each independently optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

X、Z、Y、G ¹ 、R ³ 、R ⁴ 、R ⁸ p, q are as defined above.

In another preferred embodiment, the compound of formula (I) according to the invention or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (VI) or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

G ¹ 、R ³ 、R ⁴ 、R ⁶ 、R ⁸ m, p, q are as defined above.

In another preferred embodiment, the compounds of the general formula (VIA) and the general formula (VI) according to the invention or the meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring E is selected from

R ^a selected from hydrogen and C ₁ -C ₆ An alkyl group;

R ^b selected from C ₁ -C ₆ An alkyl group.

In another preferred embodiment, the compound of formula (I) according to the invention or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (VIIA) or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein,,

e is selected from-O-, -S (O) ₂ -、-NR ⁹ -、-CR ^9a R ^9b -；

R ^a selected from hydrogen and C ₁ -C ₆ An alkyl group;

R ^b selected from C ₁ -C ₆ An alkyl group;

n is 1 or 2;

G ¹ is C ₁ -C ₆ Alkyl, p is 2;

R ³ is hydrogen;

R ⁴ is hydrogen or hydroxy;

R ⁸ selected from hydrogen, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkoxy groups; preferably hydrogen, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ An alkoxy group; q is 0, 1 or 2.

In another preferred embodiment, the compound of formula (I) according to the invention or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (VII) or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein,,

e is selected from-O-, -S (O) ₂ -、-NR ⁹ -、-CR ^9a R ^9b -；

R ^a selected from hydrogen and C ₁ -C ₆ An alkyl group;

R ^b selected from C ₁ -C ₆ An alkyl group;

n is 1 or 2;

G ¹ is C ₁ -C ₆ Alkyl, p is 2;

R ³ is hydrogen;

R ⁴ is hydrogen or hydroxy;

R ⁶ Is hydrogen; m is 1;

Typical compounds of the invention include, but are not limited to:

/>

or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a prodrug or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a process for preparing a compound of formula (II) according to the present invention or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a prodrug or pharmaceutically acceptable salt thereof, comprising the steps of:

subjecting compound IIh to dehydration under acidic conditions to obtain a compound of formula (II) or a meso, racemic, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof; wherein the reagent providing acidic conditions is preferably acetic acid;

therein, X, Y, Z, R ¹ ～R ⁵ As defined by formula (II).

In another aspect, the present invention provides a process for preparing a compound of formula (III) according to the present invention or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a prodrug or pharmaceutically acceptable salt thereof, comprising the steps of:

Subjecting compound IIIh to dehydration under acidic conditions to give a compound of formula (III) or a meso, racemic, enantiomeric, diastereoisomer or mixture thereof or a pharmaceutically acceptable salt thereof; wherein the reagent providing acidic conditions is preferably acetic acid;

wherein R is ¹ ～R ⁶ M is defined as formula (III).

In another aspect, the present invention provides a process for preparing a compound of formula (IVA) according to the present invention, or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a prodrug or pharmaceutically acceptable salt thereof, comprising the steps of:

subjecting compound IVAh to dehydration reaction under acidic condition to obtain compound shown in general formula (IVA) or its meso, racemic, enantiomer, diastereomer or their mixture or pharmaceutically acceptable salt; wherein the reagent providing acidic conditions is preferably acetic acid;

therein, X, Y, Z, G ¹ 、R ² ～R ⁵ P is defined as formula (IVA).

In another aspect, the present invention provides a process for preparing a compound of formula (IV) according to the present invention or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a prodrug or pharmaceutically acceptable salt thereof, comprising the steps of:

Subjecting compound IVh to dehydration under acidic conditions to provide a compound of formula (IV) or a meso, racemic, enantiomeric, diastereomeric or mixture thereof, or a pharmaceutically acceptable salt thereof; wherein the reagent providing acidic conditions is preferably acetic acid;

wherein G is ¹ 、R ² ～R ⁶ And m and p are defined as a general formula (IV).

In another aspect, the present invention provides a process for preparing a compound of formula (VA) according to the present invention or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a prodrug or pharmaceutically acceptable salt thereof, comprising the steps of:

subjecting compound VAh to dehydration under acidic conditions to give a compound of general formula (VA) or a meso, racemic, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof; wherein the reagent providing acidic conditions is preferably acetic acid;

therein, X, Y, Z, G ¹ 、R ² 、R ³ 、R ⁴ 、R ⁸ And p and q are defined as a general formula (VA).

In another aspect, the present invention provides a process for preparing a compound of formula (V) according to the present invention or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a prodrug or pharmaceutically acceptable salt thereof, comprising the steps of:

Subjecting compound Vh to dehydration under acidic conditions to obtain a compound represented by general formula (V) or a meso, racemic, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof; wherein the reagent providing acidic conditions is preferably acetic acid;

wherein G is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁶ 、R ⁸ M, p and q are defined as in formula (V).

In another aspect, the present invention provides a process for preparing a compound of formula (VIA) according to the present invention or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a prodrug or pharmaceutically acceptable salt thereof, comprising the steps of:

subjecting compound VIA to dehydration under acidic conditions to give a compound of formula (VIA) or a meso, racemic, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof; wherein the reagent providing acidic conditions is preferably acetic acid;

wherein the ring E, X, Y, Z, G ¹ 、R ³ 、R ⁴ 、R ⁸ And p and q are defined as general formula (VIA).

In another aspect, the present invention provides a process for preparing a compound of formula (VI) according to the present invention or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a prodrug or pharmaceutically acceptable salt thereof, comprising the steps of:

Subjecting compound VIh to dehydration under acidic conditions to provide a compound of formula (VI) or a meso, racemic, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof; wherein the reagent providing acidic conditions is preferably acetic acid;

wherein the ring E, G ¹ 、R ³ 、R ⁴ 、R ⁶ 、R ⁸ M, p and q are defined as in formula (VI).

In another aspect, the present invention provides a process for preparing a compound of formula (VIIA) according to the present invention or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a prodrug or pharmaceutically acceptable salt thereof, comprising the steps of:

subjecting compound VIIAD to dehydration under acidic conditions to obtain a compound of formula (VIIA) or a meso, racemic, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof; wherein the reagent providing acidic conditions is preferably acetic acid;

therein, E, X, Y, Z, G ¹ 、R ³ 、R ⁴ 、R ⁸ P, q are as defined for formula (VIIA).

In another aspect, the present invention provides a process for preparing a compound of formula (VII) according to the present invention or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a prodrug or pharmaceutically acceptable salt thereof, comprising the steps of:

Subjecting compound VIId to dehydration under acidic conditions to obtain a compound of formula (VII) or a meso, racemic, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof; wherein the reagent providing acidic conditions is preferably acetic acid;

therein, E, G ¹ 、R ³ 、R ⁴ 、R ⁶ 、R ⁸ M, p and q are defined as in formula (VII).

The present invention further provides a pharmaceutical composition comprising a compound according to the present invention or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

The invention further relates to the use of a compound according to the invention or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the preparation of a p300/CBP inhibitor.

The invention further relates to the use of a compound according to the invention or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a prodrug thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the manufacture of a medicament for the prevention and/or treatment of a disease associated with p300/CBP activity, such as metastatic prostate cancer, breast cancer, hematological tumors, cell proliferative disorders, inflammation, autoimmune diseases, sepsis, viral infections, or neurodegenerative diseases.

The invention further relates to a compound according to the invention or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use in inhibiting p300/CBP.

The invention further relates to a compound according to the invention or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, for use in the prevention and/or treatment of a disease associated with p300/CBP activity, such as metastatic prostate cancer, breast cancer, hematological neoplasm, cell proliferative disorder, inflammation, autoimmune disease, sepsis, viral infection, or neurodegenerative disease.

The invention further relates to a method of inhibiting p300/CBP comprising administering to a subject in need thereof an effective amount of a compound according to the invention or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

The invention further relates to a method for preventing and/or treating a disease associated with p300/CBP activity, comprising administering to a subject in need thereof an effective amount of a compound according to the invention or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, e.g. metastatic prostate cancer, breast cancer, hematological tumors, cell proliferative disorders, inflammation, autoimmune diseases, sepsis, viral infection, or neurodegenerative diseases.

The compounds of the present invention may be combined with a base to form pharmaceutically acceptable base addition salts according to methods conventional in the art to which the present invention pertains. The base includes inorganic bases and organic bases, acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like, and acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders, such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, water-soluble taste masking substances such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, or extended time substances such as ethylcellulose, cellulose acetate butyrate may be used.

Oral formulations may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier, for example polyethylene glycol or an oil vehicle, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone and acacia; the dispersing or wetting agent may be a naturally occurring phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid, such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecaethyleneoxycetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitol monooleate, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, such as polyethylene oxide sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl or Jin Zhengbing esters of nipagin, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

Dispersible powders and granules suitable for use in the preparation of an aqueous suspension by the addition of water provide the active ingredient in combination with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are as described above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.

The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. The emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Acceptable vehicles and solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated to form a microemulsion by adding it to a mixture of water and glycerol. The injection or microemulsion may be injected into the patient's blood stream by local bolus injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain this constant concentration, a continuous intravenous delivery device may be used.

The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend stock oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.

The compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.

It is well known to those skilled in the art that the amount of drug administered depends on a variety of factors, including but not limited to the following: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the patient's integument, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of the drugs, etc. In addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound of formula (I) or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

The invention can contain the compound shown in the general formula and pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, and is mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition and a clinically acceptable dosage form. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not exert other adverse effects such as allergic reactions and the like. The compounds of the present invention may be used as the sole active ingredient, or in combination with other drugs. Combination therapy is achieved by simultaneous, separate or sequential administration of the individual components.

Detailed description of the invention

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

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, oxo, carboxyl or carboxylate.

The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Alkenyl groups generally contain 2 to 20 carbon atoms (C ₂ -C ₂₀ Alkenyl), preferably 2 to 12 carbon atoms (C ₂ -C ₁₂ Alkenyl), more preferably 2 to 8 carbon atoms (C ₂ -C ₈ Alkenyl) or 2 to 6 carbon atoms (C ₂ -C ₆ Alkenyl) or 2 to 4 carbon atoms (C ₂ -C ₄ Alkenyl). Non-limiting examples of alkenyl groups include vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio.

The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups typically contain 2 to 20 carbon atoms (C ₂ -C ₂₀ Alkynyl), preferably 2 to 12 carbon atoms (C ₂ -C ₁₂ Alkynyl), more preferably 2 to 8 carbon atoms (C ₂ -C ₈ Alkynyl) or 2 to 6 carbon atoms (C ₂ -C ₆ Alkynyl) or 2 to 4 carbon atoms (C ₂ -C ₄ Alkynyl). Non-limiting examples of alkynyl groups include ethynyl, propynyl, butynyl, and the like. Alkynyl groups may be substitutedWhen substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio.

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

The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom (referred to as a spiro atom) between 5-to 20-membered monocyclic rings, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monocyclocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "fused ring alkyl" refers to a 5 to 20 membered, all carbon polycyclic group wherein each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, oxo, carboxyl or carboxylate groups.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms in which one or more ring atoms are selected from nitrogen, oxygen or S (O) _m (wherein m is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; may also contain 3 to 8 ring atoms, 1 to 3 of which are heteroatoms; or from 5 to 8 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms; or from 3 to6 ring atoms, 1 to 2 of which are heteroatoms; or contain 5 to 6 ring atoms, 1 to 2 of which are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having a single ring of 5 to 20 members sharing one atom (referred to as the spiro atom) between them, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) _m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spiroheterocyclyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclic group. Non-limiting examples of spiroheterocyclyl groups include:

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

The term "bridged heterocyclyl" refers to a 5 to 14 membered, polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O) _m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:

the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, oxo, carboxyl or carboxylate.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, carboxyl or carboxylate groups.

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl groups are preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms. Non-limiting examples of heteroaryl groups include imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, carboxyl or carboxylate groups.

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

The term "alkylthio" refers to-S- (alkyl), wherein alkyl is as defined above.

The term "alkylamino" refers to-NH- (alkyl), -N (alkyl) ₂ -, -NH- (cycloalkyl) or-N- (cycloalkyl) ₂ Wherein alkyl and cycloalkyl are as defined above.

The term "cycloalkyloxy" refers to-O- (cycloalkyl), wherein cycloalkyl is as defined above.

The term "cycloalkylthio" refers to-S- (cycloalkyl), wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to-O- (heterocyclyl) wherein heterocyclyl is as defined above.

The term "heterocyclylthio" refers to-S- (heterocyclyl) wherein heterocyclyl is as defined above.

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

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

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

The term "hydroxy" refers to an-OH group.

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

The term "amino" refers to-NH ₂ 。

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂ 。

The term "oxo" refers to = O.

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

The term "mercapto" refers to-SH.

The term "ester group" refers to a-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

The term "acyl" refers to compounds containing a-C (O) R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "optionally alkyl-substituted heterocyclyl" means that alkyl groups may be, but need not be, present, and the description includes both cases where heterocyclyl is substituted with alkyl groups and cases where heterocyclyl is not substituted with alkyl groups.

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

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

"pharmaceutically acceptable salts" are used interchangeably with "pharmaceutically acceptable salts" and refer to salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.

Synthesis method of compound of the invention

In order to achieve the purpose of the invention, the invention adopts the following technical scheme.

The compounds of the general formula (II) of the present invention or the meso, racemic, enantiomeric, diastereomeric, or mixture thereof, or pharmaceutically acceptable salts thereof, can be prepared by the following scheme:

step 1: reacting compound IIa with boron compound IIb under alkaline conditions in the presence of a catalyst, preferably Pd (dppf) Cl, to give compound IIc ₂ ；

Step 2: reacting compound IIc with amine compound IId under alkaline conditions to obtain compound IIe, wherein the reagent providing alkaline conditions is preferably potassium carbonate;

step 3: carrying out reduction reaction on the compound IIe in the presence of a catalyst to obtain a compound IIf, wherein the catalyst is preferably sodium dithionite and ammonia water;

step 4: reacting compound IIf with acid compound IIg in the presence of a condensing agent under basic conditions to obtain compound IIh, wherein the reagent providing basic conditions is preferably DIPEA, and the catalyst is preferably HATU;

Step 5: subjecting the compound IIh to dehydration under acidic conditions to obtain a compound of formula (II) or a meso, racemic, enantiomeric, diastereomeric, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the agent providing acidic conditions is preferably acetic acid;

therein, X, Y, Z, R ¹ ～R ⁵ As defined by formula (II).

The compounds of the general formula (IVA) of the present invention or their meso, racemic, enantiomeric, diastereoisomers or mixtures thereof or pharmaceutically acceptable salts thereof may be prepared by the following schemes:

step 1: reacting compound IVaa with a boron compound IIIb under alkaline conditions in the presence of a catalyst, preferably Pd (dppf) Cl, to give compound IVAc, wherein the reagent providing alkaline conditions is preferably potassium carbonate ₂ ；

Step 2: reacting compound IVAc with amine compound IId under alkaline condition to obtain compound IVAd, wherein the reagent providing alkaline condition is preferably potassium carbonate;

step 3: carrying out reduction reaction on a compound IVAd in the presence of a catalyst to obtain a compound IVAe, wherein the catalyst is preferably sodium dithionite and ammonia water;

step 4: reacting compound IVAe with acid compound IIg under alkaline condition and in the presence of condensing agent to obtain compound IVAf, wherein the reagent for providing alkaline condition is preferably DIPEA, and the catalyst is preferably HATU;

Step 5: subjecting compound IVAf to dehydration reaction under acidic conditions to obtain a compound of formula (IVA) or a meso, racemic, enantiomeric, diastereomeric or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the reagent providing acidic conditions is preferably acetic acid;

therein, X, Y, Z, G ¹ 、R ² ～R ⁵ P is defined as formula (IVA).

The compounds of the general formula (VA) of the present invention or a meso, racemic, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof, can be prepared by the following scheme:

step 1: reacting compound IVAe with acid compound VAa under alkaline condition and condensing agent to obtain compound VAb, wherein the reagent for providing alkaline condition is preferably DIPEA, and the catalyst is preferably HATU;

step 2: subjecting a compound VAb to dehydration under acidic conditions to obtain a compound of formula (VA) or a meso, racemic, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the agent providing acidic conditions is preferably acetic acid;

The compounds of the general formula (V) of the present invention or a meso, racemic, enantiomeric, diastereomeric, or mixture thereof, or pharmaceutically acceptable salt thereof, can be prepared by the following scheme:

step 1: reacting compound IVAc with amine compound VIAa under alkaline condition to obtain compound VIAb, wherein the reagent providing alkaline condition is preferably potassium carbonate;

step 2: carrying out reduction reaction on the compound VIAb in the presence of a catalyst to obtain a compound VIAc, wherein the catalyst is preferably sodium dithionite and ammonia water;

step 3: reacting compound VIAc with acid compound VIAd under alkaline condition and condensing agent to obtain compound VIAd, wherein the reagent for providing alkaline condition is preferably DIPEA, and the catalyst is preferably HATU;

step 4: subjecting compound VIA to dehydration under acidic conditions to obtain a compound of formula (VIA) or a meso, racemic, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the agent providing acidic conditions is preferably acetic acid;

therein, X, Y, Z, G ¹ 、R ³ 、R ⁴ 、R ⁸ And p and q are defined as general formula (VIA).

Detailed Description

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

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift at 10 ^-6 Units of (ppm) are given. NMR was performed using Bruker dps300 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard is Tetramethylsilane (TMS).

Determination of Mass Spectra (MS) A1100 Series LC/MSD Trap (ESI) mass spectrometer (manufacturer: agilent) was used.

The examples are not specifically described, and lc3000 high performance liquid chromatography and lc6000 high performance liquid chromatography (manufacturer: innovation) were used for the preparation of the liquid chromatography.

As a High Performance Liquid Chromatography (HPLC), shimadzu LC-20AD high pressure liquid chromatography (Agilent TC-C18X 250.4.6 mm5 μm column) and Shimadzu LC-2010AHT high pressure liquid chromatography (Phenominex C18X 250X 4.6mm5 μm column) were used.

The thin layer chromatography silica gel plate uses Qingdao ocean chemical GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Column chromatography generally uses Qingdao ocean silica gel of 100-200 meshes and 200-300 meshes as a carrier.

The known starting materials of the present invention may be synthesized using or according to methods known in the art or may be purchased from commercial establishments, beijing couplings, sigma, carbofuran, yi Shiming, shanghai book, inoki, nanjing, an Naiji chemistry, and the like.

The examples are not particularly described, and the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.

An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.

The microwave reaction used was a CEM Discover SP type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using the following system of developing agents: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: the volume ratio of acetone and solvent is adjusted according to the polarity of the compound.

The eluent system for column chromatography and the developing agent system for thin layer chromatography used for purifying the compound include: a: dichloromethane and methanol system, B: petroleum ether, ethyl acetate and dichloromethane system, C: petroleum ether and ethyl acetate system, the volume ratio of the solvent is regulated according to the polarity of the compound, and small amount of alkaline or acidic reagent such as triethylamine and acetic acid can be added for regulation.

Examples

Example 1: preparation of 4- (2- (3, 4-difluorobenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (1)

Step 1: preparation of 4- (4-fluoro-3-nitrophenyl) -3, 5-dimethylisoxazole (1 c)

At room temperature, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf) Cl) ₂ ) (3.33 g,4.54 mmol) and potassium carbonate (18.8 g,136.3 mmol) were added 4-bromo-1-fluoro-2-nitrobenzene (1 a) (10.0 g,45.45 mmol) and (3, 5-dimethylisoxazol-4-yl) boronic acid (1 b) (7.69 g,54.54 mmol) in a dioxane and water mixture (60 ml, v/v=5:1) and stirred overnight at 90℃under nitrogen. The reaction solution was concentrated under reduced pressure, water (100 mL) was added, extracted with EA (100 ml×3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/ea=100:1-4:1) to give the title compound 9.44g as a yellow solid, yield: 87.9%.

LC-MS：m/z 237[M+H] ⁺ 。

Step 2: preparation of 4- (3, 5-dimethylisoxazol-4-yl) -N- (((1 r,4 r) -4-methoxycyclohexyl) -2-nitroaniline (1 e)

At room temperature, the (1 r,4 r) -4-methoxy ringHexadec-1-amine (1 d) (5.14 g,39.80 mmol) was added to a solution of 4- (4-fluoro-3-nitrophenyl) -3, 5-dimethylisoxazole (1 c) (9.40 g,39.80 mmol) and potassium carbonate (13.7 g,99.50 mmol) in acetonitrile (190 mL) and stirred overnight at 80℃under nitrogen. The reaction was concentrated under reduced pressure, water (150 mL) was added, extracted with DCM (150 mL. Times.3), the organic phase was washed with brine, and anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE/ea=50:1-10:1) gave the title compound as a red solid 11.95g, yield: 86.9%.

LC-MS：m/z 346[M+H] ⁺ 。

Step 3:4- (3, 5-dimethylisoxazol-4-yl) -N ¹ Preparation of- ((1 r,4 r) -4-methoxycyclohexyl) benzene-1, 2-diamine (1 f)

Dissolving 4- (3, 5-dimethylisoxazol-4-yl) -N- (((1 r,4 r) -4-methoxycyclohexyl) -2-nitroaniline (1 e) (11.95 g,34.6 mmol) in tetrahydrofuran (120 mL) and water (120 mL) at room temperature, adding sodium dithionite (66.30 g,380.6 mmol) followed by aqueous ammonia (102.0 g,726.6 mmol) and stirring overnight at room temperature under nitrogen, adding the reaction solution to ice water, stirring for 5 min, extracting with EA (150 mL. Times.3), washing the organic phase with brine, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating and purifying the residue by silica gel column chromatography (mobile phase: PE/EA=50:1-1:1) to give 8.37g of the title compound as a red solid in 76.7% yield.

LC-MS：m/z 316[M+H] ⁺ 。

Step 4: preparation of 2- (3, 4-difluorophenyl) -N- (5- (3, 5-dimethylisoxazol-4-yl) -2- ((((1 r,4 r) -4-methoxycyclohexyl) amino) phenyl) acetamide (1 h)

2- (7-Benzotriazolyl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (361 mg,0.951 mmol) was added to a solution of 2- (3, 4-difluorophenyl) acetic acid (1 g) (164 mg,0.951 mmol) in N, N-dimethylformamide (10 mL) at room temperature and stirred at room temperature for 30 minutes. Adding 4- (3, 5-dimethyl isoxazol-4-yl) -N ¹ - ((1 r,4 r) -4-methoxycyclohexyl) benzene-1, 2-diamine (1 f) (300 mg,0.951 mmol) and Triethylamine (TEA) (115 mg,1.14 mmol) were stirred at room temperature overnight. The reaction mixture was diluted with EA (40 mL),washing with water (50 mL. Times.2), extraction of the aqueous phase with EA (40 mL. Times.3), washing of the organic phase with brine, anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE/ea=20:1-1:1) gave 415mg of the title compound as a pale pink solid, yield: 92.9%.

LC-MS：m/z 470[M+H] ⁺ 。

Step 5: preparation of 4- (2- (3, 4-difluorobenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (1)

Dissolving 2- (3, 4-Difluorophenyl) -N- (5- (3, 5-dimethylisoxazol-4-yl) -2- ((((1 r,4 r) -4-methoxycyclohexyl) amino) phenyl) acetamide (1 h) (150 mg,0.319 mmol) in acetic acid (AcOH) (3 mL) at room temperature, stirring overnight at 60 ℃, cooling the reaction solution, concentrating under reduced pressure, adjusting pH to about 8 with saturated aqueous sodium bicarbonate solution, extracting with EA (40 mL. Times.3), washing the organic phase with brine, anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation of the residue by preparative liquid chromatography (column type: daisosei 30mm x 250mm, c18, 10um,100a; mobile phase: acetonitrile/water solution, gradient: 30% -80%) gave 93mg of the title compound as a white solid, yield: 64.5%.

LC-MS：m/z 452[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.78(d,J＝8.0Hz,1H),7.58(s,1H),7.45-7.36(m,2H),7.17-7.12(m,2H),4.38(s,3H),3.41-3.35(m,2H),3.27(s,2H),2.40(s,3H),2.27-2.17(m,5H),2.10-2.06(m,2H),1.57-1.54(m,2H),1.34-1.25(m,2H)。

Example 2: preparation of 4- (1-cyclohexyl-2- (3, 4-difluorobenzyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (2)

The procedure of example 1 was followed, except that cyclohexylamine was used instead of (1 r,4 r) -4-methoxycyclohex-1-amine (1 d), to obtain the title compound 2.

LC-MS：m/z 422[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.78(d,J＝8.0Hz,1H),7.58(s,1H),7.44-7.36(m,2H),7.16-7.12(m,2H),4.38(s,2H),4.36-4.28(m,1H),2.40(s,3H),2.23(s,3H),2.16-2.06(m,2H),1.84-1.79(m,2H),1.67-1.62(m,1H),1.57-1.54(m,2H),1.39-1.34(m,3H)。

Example 3: preparation of 4- (2- (3, 4-difluorobenzyl) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (3)

The title compound 3 was obtained in the same manner as the preparation method of example 1 except that tetrahydro-2H-pyran-4-amine was used instead of (1 r,4 r) -4-methoxycyclohex-1-amine (1 d).

LC-MS：m/z 424[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.71(d,J＝8.0Hz,1H),7.60(s,1H),7.45-7.36(m,2H),7.18-7.14(m,2H),4.70-4.62(m,1H),4.42(s,2H),4.01-3.97(m,2H),3.49-3.46(m,2H),2.42-2.31(m,5H),2.22(s,3H),1.56-1.52(m,2H)。

Example 4: preparation of 4- (2- (3, 4-difluorobenzyl) -1- (tetrahydro-2H-pyran-3-yl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (4)

The title compound 4 was obtained in the same manner as in the preparation method of example 1 except that tetrahydro-2H-pyran-3-amine hydrochloride was used instead of (1 r,4 r) -4-methoxycyclohex-1-amine (1 d).

LC-MS：m/z 424[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.89(d,J＝8.0Hz,1H),7.60(s,1H),7.43-7.36(m,2H),7.17-7.11(m,2H),4.53-4.45(m,1H),4.41(s,2H),4.01-3.96(m,1H),3.87-3.84(m,1H),3.66-3.63(m,1H),3.58-3.52(m,1H),2.43-2.35(m,4H),2.23(s,3H),1.76-1.68(m,3H)。

Example 5: preparation of 4- (2- (4-fluorobenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (5)

The procedure was followed in the same manner as in example 1 except that 2- (4-fluorophenyl) acetic acid was used in place of 2- (3, 4-difluorophenyl) acetic acid (1 g), to obtain the title compound 5.

LC-MS：m/z 434[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.76(d,J＝8.0Hz,1H),7.58(s,1H),7.37-7.33(m,2H),7.18-7.11(m,3H),4.39-4.32(m,3H),3.43-3.38(m,1H),3.26(s,3H),2.40(s,3H),3.23(s,3H),2.18-2.14(m,2H),2.07-2.00(m,2H),1.54-1.48(m,2H),1.29-1.20(m,2H)。

Example 6: preparation of 4- (1- ((1 r,4 r) -4-methoxycyclohexyl) -2- (4-methylbenzyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (6)

The procedure was followed in the same manner as in example 1 except that 2- (p-tolyl) acetic acid was used instead of 2- (3, 4-difluorophenyl) acetic acid (1 g), to obtain the title compound 6.

LC-MS：m/z 430[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.74(d,J＝8.0Hz,1H),7.57(s,1H),7.19-7.17(m,2H),7.14-7.10(m,3H),4.42-4.35(m,1H),4.31(s,2H),3.41-3.36(m,1H),3.25(s,3H),2.40(s,3H),2.26(s,3H),2.23(s,3H),2.19-2.13(m,2H),2.07-2.03(m,2H),1.50-1.47(m,2H),1.26-1.16(m,2H)。

Example 7: preparation of 4- (2- (4-methoxybenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (7)

The procedure was followed in the same manner as in example 1 except that 2- (4-methoxyphenyl) acetic acid was used instead of 2- (3, 4-difluorophenyl) acetic acid (1 g), to obtain the title compound 7.

LC-MS：m/z 446[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.74(d,J＝8.0Hz,1H),7.57(s,1H),7.23-7.21(m,2H),7.11(d,J＝8.0Hz,1H),6.90-6.87(m,2H),4.40-4.35(m,1H),4.29(s,2H),3.71(s,3H),3.38-3.34(m,1H),3.26(s,3H),2.40(s,3H),2.23(s,3H),2.19-2.11(m,2H),2.06-2.03(m,2H),1.48-1.46(m,2H),1.26-1.19(m,2H)。

Example 8: preparation of 4- (2- (3-fluorobenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (8)

The procedure was followed in the same manner as in example 1 except that 2- (3-fluorophenyl) acetic acid was used in place of 2- (3, 4-difluorophenyl) acetic acid (1 g), to obtain the title compound 8.

LC-MS：m/z 434[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.77(d,J＝8.0Hz,1H),7.59(s,1H),7.40-7.35(m,1H),7.19-7.06(m,4H),4.41(s,2H),4.38-4.34(m,1H),3.38-3.36(m,1H),3.26(s,3H),2.40(s,3H),2.25-2.15(m,5H),2.08-2.05(m,2H),1.52-1.50(m,2H),1.30-1.21(m,2H)。

Example 9: preparation of 4- (1- ((1 r,4 r) -4-methoxycyclohexyl) -2- (3-methylbenzyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (9)

The procedure was followed in the same manner as in example 1 except that 2- (m-tolyl) acetic acid was used instead of 2- (3, 4-difluorophenyl) acetic acid (1 g), to obtain the title compound 9.

LC-MS：m/z 430[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.74(d,J＝8.0Hz,1H),7.58(s,1H),7.22-7.19(m,1H),7.13-7.04(m,4H),4.40-4.35(m,1H),4.32(s,2H),3.39-3.35(m,1H),3.25(s,3H),2.40(s,3H),2.26(s,3H),2.23(s,3H),2.19-2.13(m,2H),2.07-2.02(m,2H),1.47-1.44(m,2H),1.25-1.16(m,2H)。

Example 10: preparation of 4- (2- (3-methoxybenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (10)

The procedure was followed in the same manner as in example 1 except that 2- (3-methoxyphenyl) acetic acid was used instead of 2- (3, 4-difluorophenyl) acetic acid (1 g), to obtain the title compound 10.

LC-MS：m/z 446[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.75(d,J＝8.0Hz,1H),7.59(s,1H),7.23(t,J＝8.0Hz,1H),7.11(d,J＝8.0Hz,1H),6.93-6.92(m,1H),6.85-6.80(m,2H),4.43-4.34(m,3H),3.72(s,3H),3.43-3.37(m,1H),3.26(s,3H),2.40(s,3H),2.23-2.13(m,5H),2.07-2.03(m,2H),1.49-1.46(m,2H),1.27-1.21(m,2H)。

Example 11: preparation of 4- (2- (2-fluorobenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (11)

The procedure was followed in the same manner as in example 1 except that 2- (2-fluorophenyl) acetic acid was used in place of 2- (3, 4-difluorophenyl) acetic acid (1 g), to obtain the title compound 11.

LC-MS：m/z 434[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.81(d,J＝8.0Hz,1H),7.56(s,1H),7.36-7.11(m,5H),4.44-4.40(m,1H),4.39(s,2H),3.45-3.40(m,1H),3.28(s,3H),2.39(s,3H),2.33-2.23(m,2H),2.22(s,3H),2.12-2.11(m,2H),1.69-1.66(m,2H),1.32-1.23(m,2H)。

Example 12: preparation of 4- (1- ((1 r,4 r) -4-methoxycyclohexyl) -2- (2-methylbenzyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (12)

The procedure was followed in the same manner as in example 1 except that 2- (2-tolyl) acetic acid was used instead of 2- (3, 4-difluorophenyl) acetic acid (1 g), to obtain the title compound 12.

LC-MS：m/z 430[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δppm 7.84(d,J＝8.4Hz,1H),7.58(s,1H),7.24-7.11(m,4H),7.05-7.02(m,1H),4.37(s,2H),4.34-4.30(m,1H),3.40-3.35(m,1H),3.26(s,3H),2.40(s,3H),2.32(s,3H),2.30-2.20(m,5H),2.09-2.07(m,2H),1.69-1.66(m,2H),1.27-1.17(m,2H)。

Example 13: preparation of 4- (2- (2-methoxybenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (13)

The procedure was followed in the same manner as in example 1 except that 2- (2-methoxyphenyl) acetic acid was used instead of 2- (3, 4-difluorophenyl) acetic acid (1 g), to obtain the title compound 13.

LC-MS：m/z 446[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δppm 7.75(d,J＝8.4Hz,1H),7.55(s,1H),7.28-7.23(m,1H),7.13-7.00(m,3H),6.89-6.85(m,1H),4.34-4.27(m,1H),4.25(s,2H),3.86(s,3H),3.38 -3.36(m,1H),3.26(s,3H),2.39(s,3H),2.29-2.15(m,5H),2.11-2.06(m,2H),1.58-1.55(m,2H),1.23-1.11(m,2H)。

Example 14: preparation of 4- (2- (4-chlorobenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (14)

The procedure was followed in the same manner as in example 1 except that 2- (4-chlorophenyl) acetic acid was used instead of 2- (3, 4-difluorophenyl) acetic acid (1 g), to obtain the title compound 14.

LC-MS：m/z 450[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.76(d,J＝8.0Hz,1H),7.57(s,1H),7.41-7.39(m,2H),7.35-7.32(m,2H),7.12(d,J＝8.0Hz,1H),4.38(s,2H),4.36-4.30(m,1H),3.40-3.36(m,1H),3.26(s,3H),2.40(s,3H),2.29-2.15(m,5H),2.11-2.01(m,2H),1.54-1.51(m,2H),1.28-1.22(m,2H)。

Example 15: preparation of 4- (2-benzyl-1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (15)

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Step 1: preparation of 4- (2-benzyl-1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (15)

Sodium dithionite (138 mg,0.792 mmol) was added to 4- (3, 5-dimethylisoxazol-4-yl) -N at room temperature ¹ - ((1 r,4 r) -4-methoxycyclohexyl) benzene-1, 2-diamine (1 f) (100 mg,0.317 mmol) and 2-phenylacetaldehyde (15 b) (57 mg,0.475 mmol) in N-methylpyrrolidone (3 mL) were added and stirred overnight at 60 ℃. The reaction mixture was cooled, aqueous sodium bicarbonate (30 mL) was added, extracted with EA (20 mL. Times.3), the organic phase was washed with brine, and the aqueous phase was dried over anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation of the residue by preparative liquid chromatography (column type: daisosei 30 mm. Times.250 mm, C18, 10um,100A; mobile phase: acetonitrile/0.1% aqueous formic acid; gradient: 10% -60%) gave 66mg of the title compound as a white solid, yield: 50.1%.

LC-MS：m/z 416[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.74(d,J＝8.0Hz,1H),7.58(s,1H),7.35-7.29(m,4H),7.26-7.22(m,1H),7.13-7.10(m,1H),4.38(s,2H),4.36-4.27(m,1H),3.43-3.36(m,1H),3.25(s,3H),2.40(s,3H),2.23-2.13(m,5H),2.04-2.01(m,2H),1.47-1.44(m,2H),1.25-1.15(m,2H)。

Example 16: preparation of (5- (3, 5-dimethylisoxazol-4-yl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-2-yl) (phenyl) methanol (16)

The procedure used for the preparation of example 1 was identical except that 2-hydroxy-2-phenylacetic acid was used in place of 2- (3, 4-difluorophenyl) acetic acid (1 g) to give the title compound 16.

LC-MS：m/z 432[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.74(d,J＝8.0Hz,1H),7.66-7.61(m,1H),7.42-7.35(m,4H),7.30-7.26(m,1H),7.14(d,J＝8.0Hz,1H),6.67-6.66(m,1H),6.17-6.16(m,1H),4.59-4.53(m,1H),3.28-3.26(m,1H),3.23(s,3H),2.40(s,3H),2.23(s,3H),2.13-2.00(m,2H),1.93-1.76(m,2H),1.24-1.14(m,2H),1.01-0.84(m,2H)。

Example 17: preparation of (5- (3, 5-dimethylisoxazol-4-yl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-2-yl) (5-fluoro-2-methoxyphenyl) methanol (17)

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Step 1: preparation of 2- (5-fluoro-2-methoxyphenyl) -2- ((trimethylsilyl) oxy) acetonitrile (17 b)

5-fluoro-2-methoxybenzaldehyde (17 a) (1.00 g,6.49 mmol), zinc iodide (2 mg, 0.006mmol) and trimethylcyanosilane (706 mg,7.14 mmol) were mixed at room temperature and stirred at room temperature for 1 hour. The reaction mixture was taken up in water (15 mL), extracted with EA (20 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Dried, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: PE/ea=50:1-4:1) to give the title compound as a colourless oil, 520mg, yield: 31.6%.

Step 2: preparation of 2- (5-fluoro-2-methoxyphenyl) -2-hydroxyacetic acid (17 c)

2- (5-fluoro-2-methoxyphenyl) -2- ((trimethylsilyl) oxy) acetonitrile (17 b) (520 mg,2.05 mmol) was dissolved in concentrated hydrochloric acid (8 mL, 12M) at room temperature, stirred at room temperature for 1 hour, and stirred at 70℃for 2 hours. The reaction mixture was cooled, water (15 mL) was added, extracted with EA (20 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Dried, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: PE/ea=10:1-2:1) to give 155mg of the title compound as a colorless oily liquid, yield: 37.7%.

LC-MS：m/z 201[M+H] ⁺ 。

Step 3: preparation of N- (5- (3, 5-dimethylisoxazol-4-yl) -2- (((1 r,4 r) -4-methoxycyclohexyl) amino) phenyl) -2- (5-fluoro-2-methoxyphenyl) -2-hydroxyacetamide (17 d)

1-Propylphosphoric anhydride (672 mg,1.06 mmol) and N, N-diisopropylethylamine (2793 mg,2.11 mmol) were added to 4- (3, 5-dimethylisoxazol-4-yl) -N at room temperature ¹ - ((1 r,4 r) -4-methoxycyclohexyl) benzene-1, 2-diamine (1 f) (222 mg,0.704 mmol) and 2- (5-fluoro-2-methoxyphenyl) -2-hydroxyacetic acid (17 c) (155 mg,0.774 mmol) in N, N-dimethylformamide (5 mL) were stirred at room temperature overnight. The reaction was diluted with EA (20 mL), washed with aqueous sodium bicarbonate (30 mL. Times.2), the aqueous phase was extracted with EA (25 mL. Times.2), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Dried, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: DCM/meoh=100:1-20:1) to give the title compound as a brown oil, 50mg, yield: 14.3%.

LC-MS：m/z 515[M+H ₂ O] ⁺ 。

Step 4: preparation of methyl (5- (3, 5-dimethylisoxazol-4-yl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-2-yl) (5-fluoro-2-methoxyphenyl) acetate (17 e)

N- (5- (3, 5-dimethylisoxazol-4-yl) -2- (((1 r,4 r) -4-methoxycyclohexyl) amino) phenyl) -2- (5-fluoro-2-methoxyphenyl) -2-hydroxyacetamide (17 d) (50 mg,0.100 mmol) was dissolved with acetic acid (5 mL) at room temperature and stirred overnight at 60 ℃. The reaction solution was concentrated under reduced pressure to remove the solvent, and was used directly in the next step.

LC-MS：m/z 522[M+H] ⁺ 。

Step 5: preparation of (5- (3, 5-dimethylisoxazol-4-yl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-2-yl) (5-fluoro-2-methoxyphenyl) methanol (17).

NaOH (12 mg,0.300 mmol) was added to (5- (3, 5-dimethylisoxazol-4-yl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d) at room temperature]Imidazol-2-yl) (5-fluoro-2-methoxyphenyl) methyl acetate (17 e) (crude, 0.100 mmol) in THF (1 mL), meOH (1 mL) and water (0.25 mL) was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, water (10 mL) was added, extracted with EA (15 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation of the residue by preparative liquid chromatography (column type: daisosei 30 mm. Times.250 mm, C18,10um,100A, mobile phase: acetonitrile/0.1% aqueous formic acid, gradient: 10% -50%) gave 17mg of the title compound as a white solid, two-step yield: 35.4%.

LC-MS：m/z 480[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.81(d,J＝8.0Hz,1H),7.55(s,1H),7.41-7.38(m,1H),7.16-7.09(m,2H),6.99-6.96(m,1H),6.34(s,1H),6.25(s,1H),4.70-4.61(m,1H),3.64(s,3H),3.33-3.28(m,4H),2.38-2.30(m,5H),2.20-2.16(m,5H),1.85-1.77(m,2H),1.38-1.28(m,2H)。

Example 18: preparation of (5- (3, 5-dimethylisoxazol-4-yl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-2-yl) (4-methoxy-3-methylphenyl) methanol (18)

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Step 1: preparation of 2- (4-methoxy-3-methylphenyl) -2- ((trimethylsilyl) oxy) acetonitrile (18 b)

4-methoxy-3-methylbenzaldehyde (18 a) (500 mg,3.33 mmol), zinc iodide (1 mg, 0.003mmol) and trimethylcyano silane (803 mg,3.66 mmol) were mixed at room temperature, and stirred at room temperature for 1 hour. The reaction mixture was taken up in water (10 mL), extracted with EA (15 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Dried, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: PE/ea=50:1-2:1) to give 435mg of the title compound as a colorless oil, yield: 52.4%.

Step 2: preparation of 2-hydroxy-2- (4-methoxy-3-methylphenyl) acetic acid (18 c)

2- (4-methoxy-3-methylphenyl) -2- ((trimethylsilyl) oxy) acetonitrile (18 b) (435 mg,1.74 mmol) was dissolved in concentrated hydrochloric acid (5 mL, 12M) at room temperature, stirred at room temperature for 1 hour, and stirred at 70℃for 2 hours. The reaction mixture was cooled, water (10 mL) was added, extracted with EA (15 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE/ea=10:1-2:1) gave 380mg of crude title compound as a pale yellow oily liquid.

LC-MS：m/z 197[M+H] ⁺ 。

Step 3: preparation of N- (5- (3, 5-dimethylisoxazol-4-yl) -2- ((((1 r,4 r) -4-methoxycyclohexyl) amino) phenyl) -2-hydroxy-2- (4-methoxy-3-methylphenyl)) acetamide (18 d)

1-Propylphosphoric anhydride (1.38 g,2.17 mmol) and N, N-diisopropylethylamine (560 mg,4.35 mmol) were added to 4- (3, 5-dimethylisoxazol-4-yl) -N at room temperature ¹ - ((1 r,4 r) -4-methoxycyclohexyl) benzene-1, 2-diamine (1 f) (457 mg,1.45 mmol) and 2-hydroxy-2- (4-methoxy-3-methylphenyl) acetic acid (18 c) (380 mg crude, 1.74 mmol) in N, N-dimethylformamide (10 mL) were stirred overnight at room temperature. The reaction was diluted with EA (20 mL), washed with aqueous sodium bicarbonate (50 mL. Times.2), the aqueous phase was extracted with EA (30 mL. Times.2), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtering, concentrating the filtrate under reduced pressure to give 680mg of crude title compound as a brown oily liquid

LC-MS：m/z 494[M+H] ⁺ 。

Step 4: preparation of (5- (3, 5-dimethylisoxazol-4-yl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-2-yl) (4-methoxy-3-methylphenyl) methanol (18)

N- (5- (3, 5-dimethylisoxazol-4-yl) -2- (((((1 r,4 r) -4-methoxycyclohexyl) amino) phenyl) -2-hydroxy-2- (4-methoxy-3-methylphenyl)) acetamide (18 d) (680 mg, crude) was dissolved with acetic acid (10 mL) at room temperature and stirred overnight at 60 ℃. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate was added to adjust the pH to about 8, extracted with EA (10 mL. Times.3), and the organic phase was washed with brine, anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation of the residue by preparative liquid chromatography (column type: daisosei 30 mm. Times.250 mm, C18,10um,100A, mobile phase: acetonitrile/0.1% aqueous formic acid, gradient: 20% -60%) gave 10mg of the title compound as a reddish brown solid, three-step yield: 1.2%.

LC-MS：m/z 476[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.74(d,J＝8.0Hz,1H),7.62(s,1H),7.22-7.20(m,1H),7.15-7.12(m,2H),6.92(d,J＝8.0Hz,1H),6.49(s,1H),6.07(s,1H),4.66-4.58(m,1H),3.76(s,3H),3.27-3.22(m,4H),2.40(s,3H),2.23(s,3H),2.12-2.02(m,5H),1.99-1.95(m,1H),1.75-1.72(m,1H),1.26-1.14(m,2H),1.10-0.94(m,2H)。

Example 19: preparation of (5- (3, 5-dimethylisoxazol-4-yl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-2-yl) (3-fluoro-4-methoxyphenyl) methanol (19)

The title compound 19 was obtained in the same manner as in the preparation method of example 17 except that 3-fluoro-4-methoxybenzaldehyde was used instead of 5-fluoro-2-methoxybenzaldehyde (17 a).

LC-MS：m/z 480[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.77(d,J＝8.0Hz,1H),7.62(s,1H),7.24-7.13(m,4H),6.66-6.65(m,1H),6.11-6.10(m,1H),4.62-4.56(m,1H),3.82(s,3H),3.40-3.25(m,1H),3.26(s,3H),2.40(s,3H),2.23(s,3H),2.15-2.09(m,2H),2.03-1.99(m,1H),1.80-1.77(m,1H),1.28-1.19(m,3H),1.06-0.99(m,1H)。

Example 20: preparation of 4- (2- (4-methoxy-3-methylbenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (20)

Step 1: preparation of 1-methoxy-4- (2-methoxyvinyl) -2-methylbenzene (20 b)

Potassium tert-butoxide (17.3 mL,1mol/L in THF) was added to a mixture of (methoxymethyl) triphenylphosphine chloride (5.48 g,15.98 mmol) in THF (50 mL) under nitrogen at 0deg.C. A solution of 4-methoxy-3-methylbenzaldehyde (20 a) (2.00 g,13.31 mmol) in THF (15 mL) was added with stirring at 0deg.C for 20 min, and the mixture was stirred overnight at room temperature. The reaction mixture was taken up in water (80 mL), extracted with EA (50 mL. Times.3), the organic phase washed with brine, and dried over Na ₂ SO ₄ Drying, filtration and concentration of the filtrate under reduced pressure gave 6.97g of crude title compound as a brown solid.

Step 2: preparation of 2- (4-methoxy-3-methylphenyl) acetaldehyde (20 c)

Hydrogen chloride-dioxane (30 mL, 4M) was added to a solution of 1-methoxy-4- (2-methoxyvinyl) -2-methylbenzene (20 b) (6.97 g, crude) in DCM (35 mL) at room temperature and stirred at room temperature for 1 hour. The reaction solution was concentrated, water (50 mL) was added, extracted with EA (40 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE/ea=50:1-10:1) gave the title compound as a colorless oil, 1.41g, two-step yield: 64.5%.

Step 3: preparation of 4- (2- (4-methoxy-3-methylbenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (20)

Sodium dithionite (207 mg,1.187 mmol) was added at room temperatureAdding 4- (3, 5-dimethyl isoxazol-4-yl) -N ¹ - ((1 r,4 r) -4-methoxycyclohexyl) benzene-1, 2-diamine (1 f) (150 mg,0.475 mmol) and 2- (4-methoxy-3-methylphenyl) acetaldehyde (20 c) (117 mg,0.713 mmol) in N-methylpyrrolidone (5 mL) were stirred overnight at 100 ℃. The reaction solution was cooled, diluted with EA (10 mL), washed with water (30 mL. Times.2), the aqueous phase extracted with EA (20 mL. Times.2), the organic phase washed with brine, and dried over Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation of the residue by preparative liquid chromatography (column type: daisosei 30 mm. Times.250 mm, C18,10um,100A, mobile phase: acetonitrile/0.1% aqueous formic acid, gradient: 15-60%) gave 82mg of the title compound as a white solid, yield: 37.6%.

LC-MS：m/z 460[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.74(d,J＝8.0Hz,1H),7.57(s,1H),7.12-7.07(m,3H),6.88-6.86(m,1H),4.43-4.37(m,1H),4.25(s,2H),3.74(s,3H),3.38-3.35(m,1H),3.26(s,3H),2.40(s,3H),2.23-2.16(m,5H),2.10(s,3H),2.07-2.04(m,2H),1.48-1.45(m,2H),1.25-1.21(m,2H)。

Example 21: preparation of 4- (2- (3-fluoro-4-methoxybenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (21)

The title compound 21 was obtained in the same manner as in the preparation method of example 20 except that 3-fluoro-4-methoxybenzaldehyde was used instead of 4-methoxy-3-methylbenzaldehyde (20 a).

LC-MS：m/z 464[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.76(d,J＝8.0Hz,1H),7.58(s,1H),7.19-7.16(m,1H),7.14-7.06(m,3H),4.42-4.35(m,1H),4.31(s,2H),3.80(s,3H),3.39-3.34(m,1H),3.27(s,3H),2.40(s,3H),2.24-2.16(m,5H),2.08-2.05(m,2H),1.53-1.50(m,2H),1.32-1.23(m,2H)。

Example 22: preparation of 4- (2- (5-fluoro-2-methoxybenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (22)

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Step 1: preparation of 4-fluoro-1-methoxy-2- (2-methoxyvinyl) benzene (22 b)

Potassium tert-butoxide (16.9 mL,1mol/L in THF) was added to a mixture of (methoxymethyl) triphenylphosphine chloride (5.34 g,15.57 mmol) in THF (50 mL) at 0deg.C under nitrogen, stirred at 0deg.C for 20 min, a solution of 5-fluoro-2-methoxybenzaldehyde (22 a) (2.00 g,12.98 mmol) in THF (15 mL) was added and the mixture was naturally warmed to room temperature and stirred overnight. The reaction mixture was taken up in water (80 mL), extracted with EA (50 mL. Times.3), the organic phase washed with brine, and dried over Na ₂ SO ₄ Drying and concentrating under reduced pressure to obtain 7.27g of crude brown solid title compound.

Step 2: preparation of 2- (5-fluoro-2-methoxyphenyl) acetaldehyde (22 c)

Hydrogen chloride-dioxane (30 mL, 4M) was added to a solution of 4-fluoro-1-methoxy-2- (2-methoxyvinyl) benzene (22 b) (7.27 g, crude) in DCM (35 mL) at room temperature and stirred at room temperature for 1 h. The reaction solution was concentrated, water (50 mL) was added, extracted with EA (40 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE/ea=50:1-10:1) gave the title compound as a colorless oil, 1.34g, two-step yield: 61.4%.

Step 3: preparation of 4- (2- (5-fluoro-2-methoxybenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (22)

Anhydrous copper sulfate (25 mg,0.158 mmol) was added to 4- (3, 5-dimethylisoxazol-4-yl) -N at room temperature ¹ - ((1 r,4 r) -4-methoxycyclohexyl) benzene-1, 2-diamine (1 f) (100 mg,0.317 mmol) and 2- (5-fluoro-2-methoxyphenyl) acetaldehyde (22 c) (69 mg,0.412 mmol) in acetic acid (3 mL),stir at room temperature overnight. The reaction solution was concentrated under reduced pressure to remove the solvent, saturated aqueous sodium bicarbonate and sodium carbonate were added to adjust the pH to about 8, extracted with EA (10 mL. Times.3), the organic phase was washed with brine, and anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation of the residue by preparative liquid chromatography (column type: daisosei 30 mm. Times.250 mm, C18,10um,100A, mobile phase: acetonitrile/0.05% aqueous ammonia, gradient: 47% isocratic) gave 30mg of the title compound as a white solid, yield: 20.5%.

LC-MS：m/z 464[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.78(d,J＝8.0Hz,1H),7.55(s,1H),7.13-7.07(m,3H),6.92-6.89(m,1H),4.39-4.32(m,1H),4.26(s,2H),3.82(s,3H),3.42-3.37(m,1H),3.28(s,3H),2.39(s,3H),2.27-2.21(m,5H),2.13-2.10(m,2H),1.65-1.62(m,2H),1.25-1.22(m,2H)。

Example 23: preparation of 4- (2- (3-fluoro-2-methoxybenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (23)

The title compound 23 was obtained in the same manner as the preparation method of example 22 by substituting 3-fluoro-2-methoxybenzaldehyde for 5-fluoro-2-methoxybenzaldehyde (22 a).

LC-MS：m/z 464[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.78(d,J＝8.0Hz,1H),7.55(s,1H),7.21-7.16(m,1H),7.13-7.11(m,1H),7.08-7.02(m,1H),6.97-6.95(m,1H),4.40-4.34(m,3H),3.83(s,3H),3.42-3.35(m,1H),3.27(s,3H),2.39(s,3H),2.27-2.22(m,5H),2.14-2.08(m,2H),1.70-1.63(m,2H),1.28-1.21(m,2H)。

Example 24: preparation of 4- (2- (4-chloro-2-methoxybenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (24)

The title compound 24 was obtained in the same manner as the preparation method of example 20 by substituting 4-chloro-2-methoxybenzaldehyde for 4-methoxy-3-methylbenzaldehyde (20 a).

LC-MS：m/z 480[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.77(d,J＝8.0Hz,1H),7.55(s,1H),7.14-7.06(m,3H),6.97-6.95(m,1H),4.36-4.29(m,1H),4.22(s,2H),3.86(s,3H),3.42-3.37(m,1H),3.28(s,3H),2.39(s,3H),2.30-2.22(m,5H),2.13-2.09(m,2H),1.67-1.64(m,2H),1.28-1.19(m,2H)。

Example 25: preparation of 4- (2- (4-fluoro-2-methoxybenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (25)

The title compound 25 was obtained in the same manner as the preparation method of example 22 by substituting 4-fluoro-2-methoxybenzaldehyde for 5-fluoro-2-methoxybenzaldehyde (22 a).

LC-MS：m/z 464[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.77(d,J＝8.0Hz,1H),7.54(s,1H),7.12-7.05(m,2H),6.99-6.96(m,1H),6.74-6.69(m,1H),4.35-4.27(m,1H),4.21(s,2H),3.86(s,3H),3.40-3.35(m,1H),3.27(s,3H),2.39(s,3H),2.29-2.19(m,5H),2.14-2.08(m,2H),1.66-1.59(m,2H),1.25-1.19(m,2H)。

Example 26: preparation of 4- (2- (3-fluoro-5-methylbenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (26)

The title compound 26 was obtained in the same manner as the preparation method of example 22 by substituting 3-fluoro-5-methylbenzaldehyde for 5-fluoro-2-methoxybenzaldehyde (22 a).

LC-MS：m/z 448[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.76(d,J＝8.0Hz,1H),7.59(s,1H),7.14-7.11(m,1H),6.98-6.90(m,3H),4.44-4.35(m,3H),3.30-3.23(m,4H),2.40(s,3H),2.27(s,3H),2.23-2.16(m,5H),2.09-2.03(m,2H),1.54-1.48(m,2H),1.28-1.23(m,2H)。

Example 27: preparation of 4- (2- (3, 5-difluorobenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (27)

The title compound 27 was obtained in the same manner as the preparation method of example 20 by substituting 3, 5-difluorobenzaldehyde for 4-methoxy-3-methylbenzaldehyde (20 a).

LC-MS：m/z 452[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.77(d,J＝8.0Hz,1H),7.59(s,1H),7.16-7.11(m,2H),7.09-7.06(m,2H),4.42-4.37(m,3H),3.43-3.36(m,1H),3.27(s,3H),2.40(s,3H),2.29-2.19(m,5H),2.12-2.05(m,2H),1.61-1.53(m,2H),1.35-1.25(m,2H)。

Example 28: preparation of 4- (2- (4, 5-difluoro-2-methoxybenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (28)

Step 1: preparation of 4, 5-difluoro-2-methoxybenzaldehyde (28 b)

1-bromo-4, 5-difluoro-2-methoxybenzene (28 a) (5.00 g,22.42 mmol) was dissolved in THF (200 mL) at room temperature under nitrogen, cooled to-78℃and N-butyllithium (10.8 mL,26.90mmol, 2.5M) was slowly added, stirred at-78℃for 30 min, N-dimethylformamide (3.28 g,44.84 mmol) was added, and stirring was continued at-78℃for 30 min. . The reaction solution was poured into an aqueous ammonium chloride solution (150 mL), stirred for 5 minutes, extracted with EA (150 mL. Times.3), and the organic phase was washed with brine Anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE/ea=50:1-4:1) gave the title compound as an orange oily liquid, 3.10g, yield: 80.3%.

Step 2: preparation of 1, 2-difluoro-4-methoxy-5- (2-methoxyvinyl) benzene (28 c)

Potassium tert-butoxide (11.3 mL,1mol/L in THF) was added to a mixture of (methoxymethyl) triphenylphosphine chloride (3.59 g,10.46 mmol) in THF (30 mL) under nitrogen at 0deg.C, stirred for 20 min at 0deg.C, a solution of 4, 5-difluoro-2-methoxybenzaldehyde (28 b) (1.50 g,8.72 mmol) in THF (10 mL) was added and the mixture was naturally warmed to room temperature and stirred overnight. The reaction mixture was taken up in water (50 mL), extracted with EA (50 mL. Times.3), the organic phase washed with brine, and dried over Na ₂ SO ₄ Drying, filtration and concentration of the filtrate under reduced pressure gave 4.51g of crude title compound as a brown solid.

Step 3: preparation of 2- (4, 5-difluoro-2-methoxyphenyl) acetaldehyde (28 d)

Hydrogen chloride-dioxane (20 mL, 4M) was added to a solution of 1, 2-difluoro-4-methoxy-5- (2-methoxyvinyl) benzene (28 c) (4.51 g, crude) in DCM (25 mL) at room temperature and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water (30 mL) was added, extracted with EA (40 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE/ea=50:1-10:1) gave the title compound as a pale yellow oil 685mg, two-step yield: 42.2%.

Step 4: preparation of 4- (2- (4, 5-difluoro-2-methoxybenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (28)

Sodium dithionite (207 mg,1.19 mmol) was added to 4- (3, 5-dimethylisoxazol-4-yl) -N at room temperature ¹ - ((1 r,4 r) -4-methoxycyclohexyl) benzene-1, 2-diamine (1 f) (150 mg,0.47 mmol) and 2- (4, 5-difluoro-2-methoxyphenyl) acetaldehyde (28 d) (133 mg,0.71 mmol) in N-methylpyrrolidone (5 mL) were added and stirred overnight at 100 ℃. The reaction mixture was cooled, diluted with EA (10 mL), washed with water (30 mL. Times.2), the aqueous phase extracted with EA (20 mL. Times.2), and the saltsWashing the organic phase with water, anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation of the residue by preparative liquid chromatography (column type: daisosei 30 mm. Times.250 mm, C18,10um,100A, mobile phase: acetonitrile/0.1% aqueous formic acid, gradient: 10-60%) gave 80mg of the title compound as an off-white solid, yield: 34.9%.

LC-MS：m/z 482[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.80(d,J＝8.0Hz,1H),7.50(s,1H),7.39-7.32(m,1H),7.13-7.10(m,1H),6.90-6.86(m,1H),4.60-4.54(m,1H),4.30(s,2H),3.02(s,3H),3.46-3.41(m,1H),3.30(s,3H),2.37-2.39(m,5H),2.20-2.16(m,5H),1.86-1.83(m,2H),1.44-1.35(m,2H)。

Example 29: preparation of 4- (2- (3, 4-difluorobenzyl) -1- (1-methylpiperidin-4-yl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (29)

The title compound 29 was obtained in the same manner as in example 1 except that 1-methylpiperidin-4-amine hydrochloride was used instead of (1 r,4 r) -4-methoxycyclohex-1-amine (1 d).

LC-MS：m/z 437[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.68(d,J＝8.0Hz,1H),7.60(s,1H),7.43-7.36(m,2H),7.17-7.12(m,2H),4.40-4.32(m,3H),2.93-2.90(m,2H),2.40-2.32(m,5H),2.26(s,3H),2.22(s,3H),2.11-2.05(m,2H),1.54-1.51(m,2H)。

Example 30: preparation of 4- (2- (3, 4-difluorobenzyl) -1- (1-isopropylpiperidin-4-yl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (30)

The title compound 30 was obtained in the same manner as the preparation method of example 1 by substituting 1-isopropylpiperidin-4-amine for (1 r,4 r) -4-methoxycyclohex-1-amine (1 d).

LC-MS：m/z 465[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.68(d,J＝8.0Hz,1H),7.60(s,1H),7.43-7.36(m,2H),7.18-7.12(m,2H),4.42-4.32(m,3H),2.95-2.93(m,2H),2.87-2.80(m,1H),2.40(s,3H),2.36-2.27(m,4H),2.22(s,3H),1.62-1.54(m,2H),1.03(d,J＝8.0Hz,6H)。

Example 31: preparation of 4- (2- (3, 4-difluorobenzyl) -1- (tetrahydrofuran-3-yl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (31)

The procedure used for the preparation of example 1 was repeated except for using tetrahydrofuran-3-amine hydrochloride instead of (1 r,4 r) -4-methoxycyclohex-1-amine (1 d) to give the title compound 31.

LC-MS：m/z 410[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.71(d,J＝8.0Hz,1H),7.60(s,1H),7.42-7.35(m,2H),7.22-7.19(m,1H),7.13-7.09(m,1H),5.39-5.33(m,1H),4.41(s,2H),4.28-4.23(m,1H),4.07-4.04(m,1H),3.84-3.80(m,1H),3.70-3.63(m,1H),2.40(s,3H),2.28-2.23(m,4H),2.06-1.98(m,1H)。

Example 32: preparation of 4- (2- (3, 4-difluorobenzyl) -1- (3-methoxycyclobutyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (32)

The title compound 32 was obtained in the same manner as the preparation method of example 1 except that 3-methoxycyclobutane-1-amine hydrochloride was used instead of (1 r,4 r) -4-methoxycyclohex-1-amine (1 d).

LC-MS：m/z 424[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.83(d,J＝8.0Hz,1H),7.61(s,1H),7.39-7.33(m,2H),7.25-7.18(m,1H),7.09-7.05(m,1H),4.83-4.74(m,1H),4.34(s,2H),3.84-3.77(m,1H),3.25(s,3H),2.98-2.67(m,4H),2.40(s,3H),2.23(s,3H)。

Example 33: preparation of 4- (2- (3, 4-difluorobenzyl) -1- (2-oxaspiro [3.3] heptane-6-yl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (33)

The procedure used for the preparation of example 1 was repeated except for using 2-oxaspiro [3.3] heptane-6-amine hydrochloride instead of (1 r,4 r) -4-methoxycyclohex-1-amine (1 d) to obtain the title compound 33.

LC-MS：m/z 436[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.67(d,J＝8.0Hz,1H),7.58(s,1H),7.42-7.33(m,2H),7.19-7.17(m,1H),7.11-7.07(m,1H),5.02-4.93(m,1H),4.71(s,2H),4.66(s,2H),4.31(s,2H),3.02-2.96(m,2H),2.73-2.68(m,2H),2.39(s,3H),2.22(s,3H)。

Example 34: preparation of 4- (2- (3, 4-difluorobenzyl) -5- (3, 5-dimethylisoxazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) -N, N-dimethylcyclohexane-1-amine (34)

The same preparation as in example 1 is carried out, except that N ¹ ,N ¹ The title compound 34 was prepared from-dimethylcyclohexane-1, 4-diamine hydrochloride instead of (1 r,4 r) -4-methoxycyclohex-1-amine (1 d).

LC-MS：m/z 465[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.64(d,J＝8.0Hz,1H),7.59(s,1H),7.45-7.36(m,2H),7.22-7.20(m,1H),7.17-7.13(m,1H),4.51-4.45(m,1H),4.38(s,2H),3.33-3.30(m,1H),2.44-2.40(m,5H),2.27-2.23(m,9H),2.06-2.00(m,2H),1.51-1.44(m,2H),1.32-1.29(m,2H)。

Example 35: preparation of 4- (2- (3, 4-difluorobenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-imidazo [4,5-b ] pyridin-5-yl) -3, 5-dimethylisoxazole (35)

Step 1: preparation of N- ((1 r,4 r) -4-methoxycyclohexyl) -2-nitropyridin-3-amine (35 b)

Triethylamine (5.33 g,52.8 mmol) was added to a solution of 3-fluoro-2-nitropyridine (5.00 g,35.2 mmol) and (1 r,4 r) -4-methoxycyclohex-1-amine (1 d) (1.75 g,12.7 mmol) in tetrahydrofuran (300 mL) at room temperature and stirred overnight at room temperature. The reaction mixture was taken up in water (200 mL), extracted with EA (250 mL. Times.3), the organic phase washed with brine, and dried over Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE/ea=50:1-1:1) gave the title compound as an orange solid 4.93g, yield: 55.7%

LC-MS：m/z 252[M+H] ⁺ 。

Step 2: preparation of 6-bromo-N- ((1 r,4 r) -4-methoxycyclohexyl) -2-nitropyridin-3-amine (35 c)

Bromine (4.68 g,29.3 mmol) was added to a mixture of N- ((1 r,4 r) -4-methoxycyclohexyl) -2-nitropyridin-3-amine (35 b) (4.90 g,19.52 mmol) and sodium acetate (1.60 g,19.52 mmol) in acetic acid (70 mL) at room temperature and stirred overnight at room temperature. The reaction solution was added with water (500 mL), the pH was adjusted to about 8 with sodium carbonate, extracted with EA (150 ml×3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/ea=50:1-1:1) to give 6.10g of the title compound as an orange solid. Yield: 94.6%.

LC-MS：m/z 330[M+H] ⁺ 。

Step 3: 6-bromo-N ³ - ((1 r,4 r) -4-methoxycyclohexyl) pyridine-2, 3-diamine(35d) Is prepared from

Iron powder (10.34 g,184.7 mmol) and ammonium chloride (9.88 g,184.7 mmol) were added to a solution of 6-bromo-N- ((1 r,4 r) -4-methoxycyclohexyl) -2-nitropyridin-3-amine (35 c) (6.10 g,18.47 mmol) in ethanol (20 mL) and water (20 mL) at room temperature and stirred at 75℃for 2 hours. The reaction solution was cooled, filtered, the filtrate was added with water (100 mL), extracted with EA (150 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE/ea=50:1-1:1) gave the title compound as a brown solid 4.69g. Yield: 84.6%.

LC-MS：m/z 300[M+H] ⁺ 。

Step 4: preparation of N- (6-bromo-3- (((1 r,4 r) -4-methoxycyclohexyl) amino) pyridin-2-yl) -2- (3, 4-difluorophenyl) acetamide (35 e)

1-Propylphosphoric anhydride (2.86 g,4.50mmol,50% in DMF) and N, N-diisopropylethylamine (774 mg,6.00 mmol) were added to 6-bromo-N at room temperature ³ - ((1 r,4 r) -4-methoxycyclohexyl) pyridine-2, 3-diamine (35 d) (900 mg,3.00 mmol) and 2- (3, 4-difluorophenyl) acetic acid (1 g) (775 mg,4.50 mmol) in N, N-dimethylformamide (35 mL) were stirred overnight at room temperature. The reaction was diluted with EA (30 mL), washed with water (200 mL. Times.2), the aqueous phase was extracted with EA (150 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE/ea=50:1-2:1) gave 700mg of the title compound as a brown solid, yield: 51.4%

LC-MS：m/z 454[M+H] ⁺ 。

Step 5: preparation of 5-bromo-2- (3, 4-difluorobenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-imidazo [4,5-b ] pyridine (35 f)

Compound 35e (700 mg,1.54 mmol) was dissolved with acetic acid (15 mL) at room temperature and stirred overnight at 60 ℃. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate and sodium carbonate were added, the pH was adjusted to about 8, extracted with EA (20 mL. Times.3), the organic phase was washed with brine, and anhydrous Na ₂ SO ₄ Drying, filtering, concentrating the filtrate under reduced pressure, and separating the residue by silica gel column chromatographyThe reaction mixture was quenched (mobile phase: PE/ea=50:1-1:1) to give 460mg of the title compound as a pale violet solid, yield: 68.4%.

LC-MS：m/z 436[M+H] ⁺ 。

Step 6: preparation of 4- (2- (3, 4-difluorobenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-imidazo [4,5-b ] pyridin-5-yl) -3, 5-dimethylisoxazole (35)

At room temperature, 1' -bis (diphenylphosphine) ferrocene]Palladium dichloride (Pd (dppf) Cl) ₂ ) (16.8 mg,0.023 mmol) 5-bromo-2- (3, 4-difluorobenzyl) -1- ((1 r,4 r) -4-methoxycyclohexyl) -1H-imidazo [4,5-b]Pyridine (35 f) (100 mg,0.229 mmol), (3, 5-dimethylisoxazol-4-yl) boronic acid (1 b) (38.7 mg,0.275 mmol) and potassium carbonate (95 mg,0.687 mmol) in dioxane (2 mL) and water (0.4 mL) under nitrogen atmosphere were stirred overnight at 90 ℃. The reaction mixture was taken up in water (10 mL), extracted with EA (20 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation of the residue by preparative liquid chromatography (column type: daisosei 30 mm. Times.250 mm, C18,10um,100A, mobile phase: acetonitrile/0.1% aqueous formic acid, gradient: 30% -70%) afforded 66mg of the title compound as a white solid, yield: 63.7%.

LC-MS：m/z 453[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 8.25(d,J＝8.0Hz,1H),7.49-7.38(m,2H),7.30(d,J＝8.0Hz,1H),7.21-7.17(m,1H),4.47-4.41(m,3H),3.41-3.36(m,1H),3.27(s,3H),2.55(s,3H),2.38(s,3H),2.21-2.15(m,2H),2.10-2.06(m,2H),1.64-1.56(m,2H),1.34-1.25(m,2H)。

Example 36: preparation of 4- (2- (3, 4-difluorobenzyl) -3- ((1 r,4 r) -4-methoxycyclohexyl) -3H-imidazo [4,5-c ] pyridin-6-yl) -3, 5-dimethylisoxazole (36)

Step 1: preparation of N- ((1 r,4 r) -4-methoxycyclohexyl) -4-nitropyridin-3-amine (36 b)

Triethylamine (9.56 g,94.62 mmol) was added at room temperatureInto a solution of 3-chloro-4-nitropyridine (36 a) (5.00 g,31.54 mmol) and (1 r,4 r) -4-methoxycyclohex-1-amine (1 d) hydrochloride (5.75 g,34.7 mmol) in acetonitrile (250 mL) was added and stirred overnight at 80 ℃. The reaction mixture was concentrated under reduced pressure, water (70 mL) was added, extracted with EA (100 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE/ea=50:1-1:10) gave 514mg of the title compound as an orange solid, yield: 6.5%.

LC-MS：m/z 252[M+H] ⁺ 。

Step 2: preparation of 6-bromo-N- ((1 r,4 r) -4-methoxycyclohexyl) -4-nitropyridin-3-amine (36 c)

Bromine (487 mg,3.04 mmol) was added to a mixture of N- ((1 r,4 r) -4-methoxycyclohexyl) -4-nitropyridin-3-amine (36 b) (510 mg,2.03 mmol) and sodium acetate (166 mg,2.03 mmol) in acetic acid (10 mL) at room temperature and stirred overnight at room temperature. The reaction solution was added with water (15 mL), the pH was adjusted to about 8 with sodium carbonate, extracted with EA (30 ml×3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/ea=50:1-4:1) to give 230mg of the title compound as an orange-red solid. Yield: 34.3%.

LC-MS：m/z 330[M+H] ⁺ 。

Step 3: preparation of 6- (3, 5-dimethylisoxazol-4-yl) -N- ((1 r,4 r) -4-methoxycyclohexyl) -4-nitropyridin-3-amine (36 d)

At room temperature, 1' -bis (diphenylphosphine) ferrocene]Palladium dichloride (Pd (dppf) Cl) ₂ ) (45 mg,0.061 mmol) was added to a solution of 6-bromo-N- ((1 r,4 r) -4-methoxycyclohexyl) -4-nitropyridin-3-amine (36 c) (200 mg,0.61 mmol), (3, 5-dimethylisoxazol-4-yl) boronic acid (1 b) (102 mg,0.73 mmol) and potassium carbonate (251 mg,1.82 mmol) in dioxane (5 mL) and water (1 mL) under a nitrogen atmosphere and stirred overnight at 90 ℃. The reaction solution was concentrated under reduced pressure, water (15 mL) was added, extracted with EA (25 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtering, concentrating the filtrate under reduced pressure, and separating and purifying the residue by silica gel column chromatography (mobile phase: PE/ea=50:1-1:1) to obtain orange-red solid standard180mg of the title compound, yield: 85.7%

LC-MS：m/z 347[M+H] ⁺ 。

Step 4:6- (3, 5-dimethylisoxazol-4-yl) -N ³ Preparation of- ((1 r,4 r) -4-methoxycyclohexyl) pyridine-3, 4-diamine (36 e)

Palladium on carbon (20 mg) was added to a mixture of 6- (3, 5-dimethylisoxazol-4-yl) -N- ((1 r,4 r) -4-methoxycyclohexyl) -4-nitropyridin-3-amine (36 d) (180 mg,0.52 mmol) in methanol (7 mL) under nitrogen atmosphere at room temperature, replaced with hydrogen three times, and stirred overnight at 35 ℃. The reaction was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to give 150mg of the title compound as a pale purple solid, yield: 91.1%.

LC-MS：m/z 317[M+H] ⁺ 。

Step 5: preparation of 2- (3, 4-difluorophenyl) -N- (2- (3, 5-dimethylisoxazol-4-yl) -5- ((((1 r,4 r) -4-methoxycyclohexyl) amino) pyridin-4-yl) acetamide (36 f)

1-Propylphosphoric anhydride (452mg,0.71mmol,50%in EA) and N, N-diisopropylethylamine (153 mg,1.18 mmol) were added to 6- (3, 5-dimethylisoxazol-4-yl) -N at room temperature ³ - ((1 r,4 r) -4-methoxycyclohexyl) pyridine-3, 4-diamine (36 e) (150 mg,0.47 mmol) and 2- (3, 4-difluorophenyl) acetic acid (1 g) (90 mg,0.52 mmol) in N, N-dimethylformamide (5 mL) were stirred overnight at room temperature. The reaction was diluted with EA (15 mL), washed with water (30 mL. Times.2), the aqueous phase was extracted with EA (15 mL. Times.2), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtration and concentration of the filtrate under reduced pressure gave 250mg of crude title compound as a brown oily liquid.

LC-MS：m/z 471[M+H] ⁺ 。

Step 6: preparation of 4- (2- (3, 4-difluorobenzyl) -3- ((1 r,4 r) -4-methoxycyclohexyl) -3H-imidazo [4,5-c ] pyridin-6-yl) -3, 5-dimethylisoxazole (36)

2- (3, 4-Difluorophenyl) -N- (2- (3, 5-dimethylisoxazol-4-yl) -5- ((((1 r,4 r) -4-methoxycyclohexyl) amino) pyridin-4-yl) acetamide (36 f) (250 mg crude product) was dissolved with acetic acid (5 mL) at room temperature, stirred overnight at 60 ℃ C.,. The reaction solution was concentrated under reduced pressure, saturated carbon was added Sodium bicarbonate aqueous solution and sodium carbonate, adjusting pH to about 8, extracting with EA (20 mL. Times.3), washing the organic phase with brine, anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation of the residue by preparative liquid chromatography (column type: daisosei 30 mm. Times.250 mm, C18,10um,100A, mobile phase: acetonitrile/0.1% aqueous formic acid, 20-60%) gave 33mg of the title compound as a white solid, two-step yield: 15.5%.

LC-MS：m/z 453[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 9.29(s,1H),7.85(s,1H),7.49-7.39(m,2H),7.21-7.17(m,1H),4.54-4.49(m,3H),3.49-3.43(m,1H),3.28(s,3H),2.53(s,3H),2.35(s,3H),2.29-2.20(m,2H),2.12-2.09(m,2H),1.71-1.64(m,2H),1.38-1.28(m,2H)。

Example 37: preparation of 4- (2- (3, 4-difluorobenzyl) -3- ((1 r,4 r) -4-methoxycyclohexyl) -3H-imidazo [4,5-b ] pyridin-6-yl) -3, 5-dimethylisoxazole (37)

Step 1: preparation of 5-bromo-N- ((1 r,4 r) -4-methoxycyclohexyl) -3-nitropyridin-2-amine (37 b)

Triethylamine (6.38 g,63.2 mmol) was added to a solution of 5-bromo-2-chloro-3-nitropyridine (37 a) (5.00 g,21.1 mmol) and (1 r,4 r) -4-methoxycyclohex-1-amine (1 d) hydrochloride (3.84 g,23.2 mmol) in acetonitrile (200 mL) at room temperature and stirred overnight at 80 ℃. The reaction mixture was concentrated under reduced pressure, water (100 mL) was added, extracted with EA (150 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE/ea=50:1-4:1) gave the title compound as an orange solid 6.81g, yield: 97.9%.

LC-MS：m/z 330[M+H] ⁺ 。

Step 2: preparation of 5- (3, 5-dimethylisoxazol-4-yl) -N- ((1 r,4 r) -4-methoxycyclohexyl) -3-nitropyridin-2-amine (37 c)

At room temperature, 1' -bis (diphenylphosphine) ferrocene]Palladium dichloride (Pd (dppf) Cl) ₂ ) (1.48 g,2.03 mmol) to a solution of 5-bromo-N- ((1 r,4 r) -4-methoxycyclohexyl) -3-nitropyridin-2-amine (37 b) (6.70 g,20.3 mmol), (3, 5-dimethylisoxazol-4-yl) boronic acid (1 b) (3.43 mg,24.3 mmol) and potassium carbonate (8.40 g,60.9 mmol) in dioxane (150 mL) and water (40 mL) was added and stirred overnight at 90℃under nitrogen. The reaction solution was concentrated under reduced pressure, water (150 mL) was added, extracted with EA (100 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE/ea=50:1-4:1) gave the title compound as an orange solid 6.10g, yield: 86.8%.

LC-MS：m/z 347[M+H] ⁺ 。

Step 3:5- (3, 5-dimethylisoxazol-4-yl) -N ² Preparation of- ((1 r,4 r) -4-methoxycyclohexyl) pyridine-2, 3-diamine (37 d)

Palladium on carbon (1.00 g) was added to a mixture of 5- (3, 5-dimethylisoxazol-4-yl) -N- ((1 r,4 r) -4-methoxycyclohexyl) -3-nitropyridin-2-amine (37 c) (6.00 g,17.3 mmol) in methanol (250 mL) under nitrogen atmosphere at room temperature, replaced with hydrogen three times, and stirred overnight at 35 ℃. The reaction was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound as a pale purple solid 5.21g. Yield: 95.1%.

LC-MS：m/z 317[M+H] ⁺ 。

Step 4: preparation of 2- (3, 4-difluorophenyl) -N- (5- (3, 5-dimethylisoxazol-4-yl) -2- ((((1 r,4 r) -4-methoxycyclohexyl) amino) pyridin-3-yl) acetamide (37 e)

1-Propylphosphoric anhydride (603mg,0.95mmol,50%in EA) and N, N-diisopropylethylamine (163 mg,1.26 mmol) were added to 5- (3, 5-dimethylisoxazol-4-yl) -N at RT ² - ((1 r,4 r) -4-methoxycyclohexyl) pyridine-2, 3-diamine (37 d) (200 mg,0.63 mmol) and 2- (3, 4-difluorophenyl) acetic acid (1 g) (120 mg,0.69 mmol) in N, N-dimethylformamide (5 mL) were stirred overnight at room temperature. The reaction was diluted with EA (15 mL), washed with water (30 mL. Times.2), the aqueous phase was extracted with EA (15 mL. Times.2), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtering, and filteringThe solution was concentrated under reduced pressure to give 360mg of the crude title compound as a brown oily liquid.

LC-MS：m/z 471[M+H] ⁺ 。

Step 5: preparation of 4- (2- (3, 4-difluorobenzyl) -3- ((1 r,4 r) -4-methoxycyclohexyl) -3H-imidazo [4,5-b ] pyridin-6-yl) -3, 5-dimethylisoxazole (37)

Dissolving 2- (3, 4-difluorophenyl) -N- (5- (3, 5-dimethylisoxazol-4-yl) -2- ((((1 r,4 r) -4-methoxycyclohexyl) amino) pyridin-3-yl) acetamide (37 e) (360 mg crude) in acetic acid (5 mL) at room temperature, heating to 60 ℃ overnight stirring the reaction mixture under reduced pressure, concentrating the reaction mixture under reduced pressure, adding saturated aqueous sodium bicarbonate and sodium carbonate, adjusting pH to about 8, extracting with EA (20 mL. Times.3), washing the organic phase with brine, anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation of the residue by preparative liquid chromatography (column type: daisosei 30 mm. Times.250 mm, C18,10um,100A, mobile phase: acetonitrile/0.1% aqueous formic acid, 50% isocratic) gave 130mg of the title compound as an off-white solid in two-step yield: 45.6%.

LC-MS：m/z 453[M+H] ⁺ 。

¹ H NMR(400MHz,Methanol-d ₄ ):δppm 8.29(s,1H),7.95(s,1H),7.31-7.24(m,2H),7.16-7.12(m,1H),4.46(s,2H),4.43-4.35(m,1H),3.41-3.36(m,4H),2.82-2.72(m,2H),2.45(s,3H),2.28(s,3H),2.22-2.17(m,2H),1.65-1.61(m,2H),1.35-1.26(m,2H)。

Example 38: preparation of (1 r,4 r) -4- (5- (3, 5-dimethylisoxazol-4-yl) -2- (3-fluoro-4-methoxybenzyl) -1H-benzo [ d ] imidazol-1-yl) cyclohexane-1-carboxylic acid (38)

Step 1: preparation of methyl (1 r,4 r) -4- ((4- (3, 5-dimethylisoxazol-4-yl) -2-nitrophenyl) amino) cyclohexane-1-carboxylate (38 b)

Methyl (1 r,4 r) -4-aminocyclohexane-1-carboxylate hydrochloride (38 a) (2.95 g,15.24 mmol) was added to 4- (4-fluoro-3-nitrophenyl) -3, 5-dimethylisoxazole (1 c) (3.00 g,12.70 mmol) and potassium carbonate (4.38 g,31.75 mmol) in acetonitrile (100 mL), raised to 80℃and stirred overnight. The reaction solution was concentrated under reduced pressure, aqueous sodium bicarbonate (80 mL) was added, extracted with EA (70 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE/ea=50:1-2:1) gave 4.70g of the title compound as an orange solid, yield: 99.1%.

LC-MS：m/z 374[M+H] ⁺ 。

Step 2: preparation of methyl (1 r,4 r) -4- ((2-amino-4- (3, 5-dimethylisoxazol-4-yl) phenyl) amino) cyclohexane-1-carboxylate (38 c)

Pd/C (500 mg) was added to a mixture of methyl (1 r,4 r) -4- ((4- (3, 5-dimethylisoxazol-4-yl) -2-nitrophenyl) amino) cyclohexane-1-carboxylate (38 a) (4.70 g,12.59 mmol) in methanol (120 mL) under nitrogen atmosphere at room temperature, hydrogen was replaced three times, and the mixture was stirred overnight at 30 ℃. The reaction was filtered through celite, the filter cake was rinsed with DCM and MeOH, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (mobile phase: DCM/meoh=50:1-20:1) to give the title compound as a brown oil 1.47g, yield: 34.0%.

LC-MS：m/z 344[M+H] ⁺ 。

Step 3: preparation of methyl (1 r,4 r) -4- (5- (3, 5-dimethylisoxazol-4-yl) -2- (3-fluoro-4-methoxybenzyl) -1H-benzo [ d ] imidazol-1-yl) cyclohexane-1-carboxylate (38 e)

Sodium dithionite (317 mg,1.82 mmol) was added to a solution of methyl (1 r,4 r) -4- ((2-amino-4- (3, 5-dimethylisoxazol-4-yl) phenyl) amino) cyclohexane-1-carboxylate (38 c) (250 mg,0.73 mmol) and 2- (3-fluoro-4-methoxyphenyl) acetaldehyde (38 d) (135 mg,0.80 mmol) in N-methylpyrrolidone (8 mL) at room temperature and stirred overnight at 100 ℃. The reaction mixture was diluted with EA (20 mL), washed with aqueous sodium bicarbonate (30 mL. Times.2), the aqueous phase was extracted with EA (30 mL. Times.2), the organic phase was washed with brine, and the aqueous phase was dried over anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE to EA) gave 155mg of the title compound as a brown oily liquid, yield: 43.3%.

LC-MS：m/z 492[M+H] ⁺ 。

Step 4: preparation of (1 r,4 r) -4- (5- (3, 5-dimethylisoxazol-4-yl) -2- (3-fluoro-4-methoxybenzyl) -1H-benzo [ d ] imidazol-1-yl) cyclohexane-1-carboxylic acid (38)

Sodium hydroxide (38 mg,0.95 mmol) was added to (1 r,4 r) -4- (5- (3, 5-dimethylisoxazol-4-yl) -2- (3-fluoro-4-methoxybenzyl) -1H-benzo [ d) at room temperature]Imidazole-1-yl) cyclohexane-1-carboxylic acid methyl ester (38 e) (155 mg,0.32 mmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (0.25 mL) was stirred overnight at room temperature. The reaction mixture was taken up in water (10 mL), adjusted to pH 5 with HCl/dioxane, extracted with EA (15 mL. Times.3), the organic phase washed with brine, and dried over Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation of the residue by preparative liquid chromatography (column type: daisosei 30 mm. Times.250 mm, C18,10um,100A, mobile phase: acetonitrile/0.1% aqueous trifluoroacetic acid, gradient: 10-50%) gave 44mg of the title compound as a white solid, yield: 29.2%.

LC-MS：m/z 478[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 12.22(s,1H),8.13(d,J＝8.0Hz,1H),7.71(s,1H),7.37(d,J＝8.0Hz,1H),7.32-7.29(m,1H),7.21-7.16(m,2H),4.65-4.56(m,1H),4.52(s,2H),3.82(s,3H),2.60-2.54(m,1H),2.42(s,3H),2.33-2.21(m,5H),2.07-1.98(m,2H),1.72-1.63(m,2H),1.60-1.49(m,2H)。

Example 39: preparation of (1 r,4 r) -4- (5- (3, 5-dimethylisoxazol-4-yl) -2- (3-fluoro-5-methylbenzyl) -1H-benzo [ d ] imidazol-1-yl) cyclohexane-1-carboxylic acid (39)

The title compound 39 was obtained in the same manner as in example 38 except that 2- (3-fluoro-5-methylphenyl) acetaldehyde was used instead of 2- (3-fluoro-4-methoxyphenyl) acetaldehyde (38 d).

LC-MS：m/z 462[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 12.15(s,1H),7.83(d,J＝8.0Hz,1H),7.59(s,1H),7.15-7.10(m,1H),7.00-6.95(m,2H),6.94-6.89(m,1H),4.42-4.33(m,3H),2.57-2.52(m,1H),2.40(s,3H),2.27(s,3H),2.23-2.17(m,5H),2.02-1.95(m,2H),1.56-1.43(m,4H)。

Example 40: preparation of (1 r,4 r) -4- (2- (3, 5-difluorobenzyl) -5- (3, 5-methylisoxazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) cyclohexane-1-carboxylic acid (40)

The title compound 39 was obtained in the same manner as in example 38 except that 2- (3, 5-difluorophenyl) acetaldehyde was used instead of 2- (3-fluoro-4-methoxyphenyl) acetaldehyde (38 d).

LC-MS：m/z 466[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 12.24(s,1H),8.09(d,J＝8.0Hz,1H),7.70(s,1H),7.36-7.32(m,1H),7.24-7.15(m,3H),4.59(s,2H),4.55-4.48(m,1H),2.59-2.54(m,1H),2.42(s,3H),2.33-2.24(m,5H),2.06-1.98(m,2H),1.73-1.65(m,2H),1.60-1.50(m,2H)。

Example 41: preparation of (1 r,4 r) -4- (5- (3, 5-dimethylisoxazol-4-yl) -2- ((5-fluoro-2-methoxyphenyl) (hydroxy) methyl) -1H-benzo [ d ] imidazol-1-yl) cyclohexane-1-carboxylic acid (41)

Step 1: preparation of methyl (1 r,4 r) -4- ((4- (3, 5-dimethylisoxazol-4-yl) -2- (2- (5-fluoro-2-methoxyphenyl) -2-hydroxyacetamido) phenyl) amino) cyclohexane-1-carboxylate (41 a)

1-Propylphosphoric anhydride (504 mg,0.792 mmol) and N, N-diisopropylethylamine (225 mg,1.746 mmol) were added to a solution of methyl (1 r,4 r) -4- ((2-amino-4- (3, 5-dimethylisoxazol-4-yl) phenyl) amino) cyclohexane-1-carboxylate (38 c) (200 mg,0.582 mmol) and 2- (5-fluoro-2-methoxyphenyl) -2-hydroxyacetic acid (17 c) (128 mg,0.641 mmol) in N, N-dimethylformamide (6 mL) at room temperature and stirred overnight at room temperature. The reaction mixture was diluted with EA (20 mL), and aqueous sodium bicarbonate (30 mL×) 2) Washing, extraction of aqueous phase with EA (25 mL. Times.2), washing of organic phase with brine, anhydrous Na ₂ SO ₄ Dried, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: DCM/meoh=100:1-20:1) to give the title compound as a brown oil, 210mg, yield: 68.6%.

LC-MS：m/z 544[M+H ₂ O] ⁺ 。

Step 2: preparation of methyl (1 r,4 r) -4- (2- (acetoxy (5-fluoro-2-methoxyphenyl) methyl) -5- (3, 5-dimethylisoxazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) cyclohexane-1-carboxylate (41 b)

(1 r,4 r) -4- ((4- (3, 5-dimethylisoxazol-4-yl) -2- (2- (5-fluoro-2-methoxyphenyl) -2-hydroxyacetamido) phenyl) amino) cyclohexane-1-carboxylic acid methyl ester (41 a) (210 mg,0.399 mmol) was dissolved with acetic acid (5 mL) at room temperature and stirred overnight at 60 ℃. The reaction solution was concentrated under reduced pressure to remove the solvent, saturated aqueous sodium bicarbonate was added to adjust the pH to about 8, extracted with EA (10 mL. Times.3), and the organic phase was washed with brine, anhydrous Na ₂ SO ₄ Drying, filtering, and concentrating the filtrate under reduced pressure to give 197mg of the title compound as a brown solid, yield: 89.8%.

LC-MS：m/z 550[M+H] ⁺ 。

Step 3: preparation of (1 r,4 r) -4- (5- (3, 5-dimethylisoxazol-4-yl) -2- ((5-fluoro-2-methoxyphenyl) (hydroxy) methyl) -1H-benzo [ d ] imidazol-1-yl) cyclohexane-1-carboxylic acid (41)

Sodium hydroxide (43 mg,1.064 mmol) was added to (1 r,4 r) -4- (2- (acetoxy (5-fluoro-2-methoxyphenyl) methyl) -5- (3, 5-dimethylisoxazol-4-yl) -1H-benzo [ d) at room temperature ]Imidazole-1-yl) methyl cyclohexane-1-carboxylate (41 b) (195, 0.355 mmol) in THF (2 mL), meOH (2 mL) and water (0.5 mL) were stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, water (10 mL) was added, extracted with EA (15 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation of the residue by preparative liquid chromatography (column type: daisosei 30 mm. Times.250 mm, C18,10um,100A, mobile phase: acetonitrile/0.1% aqueous formic acid, gradient: 10% -50%) gave 41mg of the title compound as a white solid, yield: 23.4%.

LC-MS：m/z 494[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 12.19(s,1H),7.88(d,J＝8.0Hz,1H),7.55(s,1H),7.41-7.38(m,1H),7.15-7.09(m,2H),6.99-6.96(m,1H),6.33-6.24(m,2H),4.68-4.59(m,1H),3.64(s,3H),2.60-2.54(m,1H),2.38-2.29(m,5H),2.21(s,3H),2.13-2.06(m,2H),1.88-1.77(m,2H),1.61-1.50(m,2H)。

Example 42: preparation of (1 r,4 r) -4- (5- (3, 5-dimethylisoxazol-4-yl) -2- ((3-fluoro-4-methoxyphenyl) (hydroxy) methyl) -1H-benzo [ d ] imidazol-1-yl) cyclohexane-1-carboxylic acid (42)

The title compound 42 was obtained in the same manner as in the preparation method of example 41 except that 2- (3-fluoro-4-methoxyphenyl) -2-glycolic acid was used instead of 2- (5-fluoro-2-methoxyphenyl) -2-glycolic acid (17 c).

LC-MS：m/z 494[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 12.31(s,1H),7.83(d,J＝8.0Hz,1H),7.62(s,1H),7.24-7.12(m,4H),6.65(s,1H),6.11(s,1H),4.60-4.54(m,1H),3.82(s,3H),2.48-2.44(m,1H),2.40(s,3H),2.23(s,3H),2.14-2.03(m,2H),1.94-1.78(m,2H),1.45-1.22(m,4H)。

Example 43: preparation of 4- (2- (3, 4-difluorobenzyl) -1- (1- (ethylsulfonyl) piperidin-4-yl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (43)

The title compound 43 was obtained in the same manner as in the preparation method of example 1 except that 1- (ethylsulfonyl) piperidin-4-amine was used instead of (1 r,4 r) -4-methoxycyclohex-1-amine (1 d).

LC-MS：m/z 515[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.66(d,J＝8.0Hz,1H),7.60(s,1H),7.45-7.36(m,2H),7.19-7.15(m,2H),4.66-4.57(m,1H),4.40(s,2H),3.81-3.75(m,2H),3.17(q,J＝8.0Hz,2H),3.04-2.98(m,2H),2.39-2.30(m,5H),2.22(s,3H),1.75-1.69(m,2H),1.26(d,J＝8.0Hz,3H)。

Example 44: preparation of 4- (2- (3, 4-difluorobenzyl) -1- (4- (trifluoromethyl) cyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (44)

The title compound 44 was obtained in the same manner as the preparation method of example 1 except that 4- (trifluoromethyl) cyclohexane-1-amine was used instead of (1 r,4 r) -4-methoxycyclohex-1-amine (1 d).

LC-MS：m/z 490[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.91-7.81(m,1H),7.61-7.58(m,1H),7.47-7.36(m,2H),7.21-7.12(m,2H),4.54-4.39(m,3H),2.73-2.61(m,1H),2.40(s,3H),2.36-2.23(m,5H),2.08-1.95(m,2H),1.87-1.77(m,1H),1.68-1.61(m,1H),1.57-1.44(m,2H)。

Example 45: preparation of 4- (2- (3, 4-difluorobenzyl) -1- (4, 4-difluorocyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (45)

The title compound 45 was obtained in the same manner as in example 1 except that 4, 4-difluorocyclohexane-1-amine was used instead of (1 r,4 r) -4-methoxycyclohex-1-amine (1 d).

LC-MS：m/z 458[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.61(s,1H),7.54(d,J＝8.0Hz,1H),7.47-7.44(m,1H),7.42-7.37(m,1H),7.21-7.18(m,2H),4.73-4.65(m,1H),4.39(s,2H),2.43-2.38(m,4H),2.37-2.33(m,1H),2.22(s,3H),2.17-2.02(m,4H),1.73-1.70(m,2H)。

Example 46: preparation of 4- (2- (3, 4-difluorobenzyl) -1- (4- (trifluoromethyl) cyclohexyl) -1H-benzo [ d ] imidazol-5-yl) -3, 5-dimethylisoxazole (46)

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The title compound 46 was obtained in the same manner as the preparation method of example 1 except that 4-aminocyclohexane-1-carbonitrile was used instead of (1 r,4 r) -4-methoxycyclohex-1-amine (1 d).

LC-MS：m/z 447[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.83(d,J＝8.0Hz,1H),7.58(s,1H),7.45-7.37(m,2H),7.19-7.13(m,2H),4.49-4.41(m,1H),4.37(s,2H),3.07-2.99(m,1H),2.39(s,3H),2.30-2.20(m,5H),2.15-2.12(m,2H),1.77-1.71(m,2H),1.60-1.54(m,2H)。

Example 47: preparation of 4- (2- (3, 4-difluorobenzyl) -5- (3, 5-dimethylisoxazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) tetrahydro-2H-thiopyran 1, 1-dioxide (47)

The procedure used for the preparation of example 1 was identical except for replacing (1 r,4 r) -4-methoxycyclohex-1-amine (1 d) with 4-aminotetrahydro-2H-thiopyran 1, 1-dioxide to give title compound 47.

LC-MS：m/z 472[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.62(s,1H),7.58(d,J＝8.0Hz,1H),7.49-7.44(m,1H),7.42-7.37(m,1H),7.27-7.24(m,1H),7.23-7.19(m,1H),4.95-4.86(m,1H),4.37(s,2H),3.63-3.46(m,2H),3.23-3.20(m,2H),2.86-2.76(m,2H),2.40(s,3H),2.23(s,3H),2.03-2.00(m,2H)。

Example 48: preparation of (1 r,4 r) -4- (2- (3, 4-difluorobenzyl) -5- (3, 5-dimethylisoxazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) cyclohexan-1-ol (48)

The procedure used for the preparation of example 1 was repeated except for using (1 r,4 r) -4-aminocyclohexane-1-ol instead of (1 r,4 r) -4-methoxycyclohex-1-amine (1 d) to give the title compound 48.

LC-MS：m/z 438[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.76(d,J＝8.0Hz,1H),7.58(s,1H),7.45-7.36(m,2H),7.16-7.11(m,2H),4.70-4.65(m,1H),4.39-4.29(m,3H),3.68-3.59(m,1H),2.40(s,3H),2.26-2.14(m,5H),1.90-1.84(m,2H),1.55-1.46(m,2H),1.38-1.28(m,2H)。

Example 49: preparation of 2- ((1 r,4 r) -4- (2- (3, 4-difluorobenzyl) -5- (3, 5-dimethylisoxazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) cyclohexyl) acetonitrile (49)

The procedure is as for the preparation of example 1, except that (1 r,4 r) -4-methoxycyclohex-1-amine (1 d) is replaced with 2- ((1 r,4 r) -4-aminocyclohexyl) acetonitrile to afford the title compound 49.

LC-MS：m/z 461[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.83(d,J＝8.0Hz,1H),7.58(s,1H),7.43-7.36(m,2H),7.14-7.12(m,2H),4.39-4.32(m,3H),2.54-2.52(m,2H),2.40(s,3H),2.29-2.20(m,5H),1.93-1.85(m,3H),1.61-1.58(m,2H),1.28-1.24(m,2H)。

Example 50: preparation of methyl (1 r,4 r) -4- (2- (3, 4-difluorobenzyl) -5- (3, 5-dimethylisoxazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) cyclohexane-1-carboxylate (50)

The title compound 50 was obtained in the same manner as in example 1 except that (1 r,4 r) -4-aminocyclohexane-1-carboxylic acid methyl ester (38 a) was used instead of (1 r,4 r) -4-methoxycyclohex-1-amine (1 d).

LC-MS：m/z 480[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 7.85(d,J＝8.0Hz,1H),7.58(s,1H),7.45-7.36(m,2H),7.17-7.12(m,2H),4.42-4.34(m,3H),3.63(s,3H),2.68-2.61(m,1H),2.40(s,3H),2.30-2.20(m,5H),2.01-1.98(m,2H),1.61-1.50(m,4H)。

Example 51: preparation of (1 r,4 r) -4- (2- (3, 4-difluorobenzyl) -5- (3, 5-dimethylisoxazol-4-yl) -1H-benzo [ d ] imidazol-1-yl) cyclohexane-1-carboxylic acid (51)

The title compound 51 was obtained in the same manner as in example 38 except that 2- (3, 4-difluorophenyl) acetaldehyde was used instead of 2- (3-fluoro-4-methoxyphenyl) acetaldehyde (38 d).

LC-MS：m/z 466[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 12.23(s,1H),7.84(d,J＝8.0Hz,1H),7.58(s,1H),7.45-7.36(m,2H),7.17-7.11(m,2H),4.38-4.36(m,3H),2.48-2.39(m,4H),2.28-2.19(m,5H),2.01-1.98(m,2H),1.59-1.46(m,4H)。

Example 52: preparation of (1 r,4 r) -4- (5- (3, 5-dimethylisoxazol-4-yl) -2- (5-fluoro-2-methoxybenzyl) -1H-benzo [ d ] imidazol-1-yl) cyclohexane-1-carboxylic acid (52)

The title compound 52 was obtained in the same manner as in example 38 except that 2- (5-fluoro-2-methoxyphenyl) acetaldehyde was used instead of 2- (3-fluoro-4-methoxyphenyl) acetaldehyde (38 d).

LC-MS：m/z 478[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 12.15(s,1H),7.84(d,J＝8.0Hz,1H),7.55(s,1H),7.16-7.06(m,3H),6.92-6.89(m,1H),4.38-4.31(m,1H),4.26(s,2H),3.82(s,3H),2.56-2.54(m,1H),2.39(s,3H),2.28-2.22(m,5H),2.05-2.01(m,2H),1.69-1.62(m,2H),1.50-1.41(m,2H)。

Example 53: preparation of (6- (3, 5-dimethylisoxazol-4-yl) -3- ((S) -tetrahydro-2H-pyran-3-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) (3-fluoro-4-methoxyphenyl) methanol (53)

Step 1: preparation of 2- (3-fluoro-4-methoxyphenyl) -2- ((trimethylsilyl) oxy) acetonitrile (53 b)

3-fluoro-4-methoxybenzaldehyde (53 a) (3.00 g,19.5 mmol), zinc iodide (6 mg,0.02 mmol) and trimethylcyanosilane (2.13 g,21.5 mmol) were mixed at room temperature and stirred at room temperature for 1 hour. The reaction mixture was taken up in water (15 mL), extracted with EA (20 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE/ea=50:1-4:1) gave the title compound as a colorless oil 2.68g, yield: 54.2%.

Step 2: preparation of 2- (3-fluoro-4-methoxyphenyl) -2-hydroxyacetic acid (53 c)

2- (3-fluoro-4-methoxyphenyl) -2- ((trimethylsilyl) oxy) acetonitrile (53 b) (2.65 g,10.46 mmol) was dissolved in concentrated hydrochloric acid (25 mL, 12M) at room temperature, stirred at room temperature for 1 hour, and stirred at 70℃for 2 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, extracted with EA (40 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE/ea=10:1-2:1) gave the title compound as a yellow oil, 1.55g, yield: 74.0%.

LC-MS：m/z 201[M+H] ⁺ 。

Step 3: preparation of (S) -5-bromo-3-nitro-N- (tetrahydro-2H-pyran-3-yl) pyridin-2-amine (53 f)

Triethylamine (6.38 g,63.2 mmol) was added to a solution of 5-bromo-2-chloro-3-nitropyridine (53 d) (5.00 g,21.1 mmol) and (S) -tetrahydro-2H-pyran-3-amine hydrochloride (53 e) (3.19 g,23.2 mmol) in acetonitrile (200 mL) at room temperature, and stirred overnight at 80 ℃. The reaction solution was concentrated under reduced pressure, water (100 mL) was added, extracted with EA (150 mL. Times.3), the organic phase was washed with brine, and anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE/ea=50:1-4:1) gave the title compound as an orange solid 5.91g, yield: 92.9%

LC-MS：m/z 303[M+H] ⁺ 。

Step 4: preparation of (S) -5- (3, 5-dimethylisoxazol-4-yl) -3-nitro-N- (tetrahydro-2H-pyran-3-yl) pyridin-2-amine (53 g)

At room temperature, 1' -bis (diphenylphosphine) ferrocene]Palladium dichloride (Pd (dppf) Cl) ₂ ) (1.43 g,1.95 mmol) was added to a solution of (S) -5-bromo-3-nitro-N- (tetrahydro-2H-pyran-3-yl) pyridin-2-amine (53 f) (5.90 g,19.5 mmol), (3, 5-dimethylisoxazol-4-yl) boronic acid (1 b) (3.30 mg,23.4 mmol) and potassium carbonate (8.07 g,58.5 mmol) in dioxane (150 mL) and water (40 mL) under a nitrogen atmosphere, and stirred overnight at 90 ℃. The reaction solution was concentrated under reduced pressure, water (150 mL) was added, extracted with EA (100 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE/ea=50:1-2:1) gave the title compound as an orange solid 5.38g, yield: 86.7%.

LC-MS：m/z 319[M+H] ⁺ 。

Step 5: (S) -5- (3, 5-dimethylisoxazol-4-yl) -N ² Preparation of- (tetrahydro-2H-pyran-3-yl) pyridine-2, 3-diamine (53H)

Palladium on carbon (600 mg) was added to a mixture of (S) -5- (3, 5-dimethylisoxazol-4-yl) -3-nitro-N- (tetrahydro-2H-pyran-3-yl) pyridin-2-amine (53 g) (5.38 g,16.9 mmol) in methanol (250 mL) at room temperature under nitrogen atmosphere, replaced with hydrogen three times, and stirred overnight at 25 ℃. The reaction was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid, 4.51g, yield: 92.5%.

LC-MS：m/z 289[M+H] ⁺ 。

Step 6: preparation of N- (5- (3, 5-dimethylisoxazol-4-yl) -2- (((S) -tetrahydro-2H-pyran-3-yl) amino) pyridin-3-yl) -2- (3-fluoro-4-methoxyphenyl) -2-hydroxyacetamide (53 i)

1-Propylphosphoric anhydride (1.32g,2.08mmol,50%in EA) and N, N-diisopropylethylamine (537 mg,4.16 mmol) were added to (S) -5- (3, 5-dimethylisoxazol-4-yl) -N at RT ² In a solution of- (tetrahydro-2H-pyran-3-yl) pyridine-2, 3-diamine (53H) (400 mg,1.39 mmol) and 2- (3-fluoro-4-methoxyphenyl) -2-hydroxyacetic acid (53 c) (305 mg,1.52 mmol) in N, N-dimethylformamide (10 mL) was stirred overnight at room temperature. The reaction was diluted with EA (30 mL), washed with water (50 mL. Times.2), the aqueous phase was extracted with EA (35 mL. Times.2), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: DCM/meoh=50:1-20:1) gave the title compound as a brown oil, 440mg, yield: 67.4%.

LC-MS：m/z 489[M+H ₂ O+H] ⁺ 。

Step 7: preparation of methyl (6- (3, 5-dimethylisoxazol-4-yl) -3- ((S) -tetrahydro-2H-pyran-3-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) (3-fluoro-4-methoxyphenyl) acetate (53 j)

N- (5- (3, 5-dimethylisoxazol-4-yl) -2- (((S) -tetrahydro-2H-pyran-3-yl) amino) pyridin-3-yl) -2- (3-fluoro-4-methoxyphenyl) -2-hydroxyacetamide (53 i) (440 mg,0.93 mmol) was dissolved with acetic acid (10 mL) at room temperature and stirred overnight at 60 ℃. The reaction solution was concentrated under reduced pressure to remove the solvent, saturated aqueous sodium bicarbonate was added to adjust the pH to about 8, extracted with EA (10 mL. Times.3), and the organic phase was washed with brine, anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation and purification of the residue by silica gel column chromatography (mobile phase: PE/ea=50:1-1:1) gave the title compound as a colorless oil, 95mg, yield: 20.5%.

LC-MS：m/z 495[M+H] ⁺ 。

Step 8: preparation of (6- (3, 5-dimethylisoxazol-4-yl) -3- ((S) -tetrahydro-2H-pyran-3-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) (3-fluoro-4-methoxyphenyl) methanol (53)

Sodium hydroxide (23 mg,0.58 mmol) was added to (6- (3, 5-dimethylisoxazol-4-yl) -3- ((S) -tetrahydro-2H-pyran-3-yl) -3H-imidazo [4, 5-b) at room temperature]Pyridin-2-yl) (3-fluoro-4-methoxyphenyl) acetic acid methyl ester (53 j) (95 mg,0.19 mmol) in THF (2 mL), meOH (2 mL) and water (0.5 mL) were stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, water (10 mL) was added, extracted with EA (15 mL. Times.3), the organic phase was washed with brine, and the anhydrous Na ₂ SO ₄ Drying, filtration, concentration of the filtrate under reduced pressure, and separation of the residue by preparative liquid chromatography (column type: daisosei 30 mm. Times.250 mm, C18,10um,100A, mobile phase: acetonitrile/0.1% aqueous formic acid, gradient: 42% isocratic) gave 50mg of the title compound as a white solid, yield: 57.5%.

LC-MS：m/z 453[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 8.35-8.34(m,1H),8.12-8.10(m,1H),7.28-7.24(m,1H),7.20-7.13(m,2H),6.85-6.77(m,1H),6.14(d,J＝4.0Hz,1H),4.79-4.70(m,1H),4.36-4.20(m,1H),3.88-3.83(m,4H),3.42-3.34(m,2H),2.89-2.66(m,1H),3.42(s,3H),2.24(s,3H),2.08-1.95(m,1H),1.81-1.69(m,1H),1.49-1.37(m,1H)。

Example 54: preparation of (3, 5-difluorophenyl) (6- (3, 5-methylisoxazol-4-yl) -3- ((S) -tetrahydro-2H-pyran-3-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) methanol (54)

The title compound 54 was obtained in the same manner as in the preparation method of example 53 except that 3, 5-difluorobenzaldehyde was used instead of 3-fluoro-4-methoxybenzaldehyde (53 a).

LC-MS：m/z 441[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 8.37-8.36(m,1H),8.13-8.12(m,1H),7.23-7.13(m,3H),7.06-6.77(m,1H),6.26-6.23(m,1H),4.79-4.70(m,1H),4.41-4.23(m,1H),3.98-3.54(m,2H),3.43-3.37(m,1H),2.95-2.71(m,1H),2.41(s,3H),2.24(s,3H),2.08-1.81(m,1H),1.75-1.72(m,1H),1.56-1.49(m,1H)。

Example 55: preparation of (6- (3, 5-dimethylisoxazol-4-yl) -3- ((R) -tetrahydro-2H-pyran-3-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) (3-fluoro-4-methoxyphenyl) methanol (55)

The title compound 55 was obtained in the same manner as in example 53 except that (S) -tetrahydro-2H-pyran-3-amine hydrochloride was used instead of (R) -tetrahydro-2H-pyran-3-amine hydrochloride (53 e).

LC-MS：m/z 453[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 8.36-8.35(m,1H),8.12-8.11(m,1H),7.28-7.24(m,1H),7.21-7.13(m,2H),6.86-6.78(m,1H),6.14(d,J＝4.0Hz,1H),4.79-4.72(m,1H),4.37-4.20(m,1H),3.89-3.87(m,1H),3.84(s,3H),3.45-3.36(m,2H),2.89-2.67(m,1H),3.43(s,3H),2.25(s,3H),1.99-1.78(m,1H),1.71-1.66(m,1H),1.50-1.38(m,1H)。

Example 56: preparation of (3, 5-difluorophenyl) (6- (3, 5-methylisoxazol-4-yl) -3- ((R) -tetrahydro-2H-pyran-3-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) methanol (56)

The title compound 56 was obtained in the same manner as in the preparation method of example 53 except that (S) -tetrahydro-2H-pyran-3-amine hydrochloride was used instead of (R) -tetrahydro-2H-pyran-3-amine hydrochloride (53 e) and 3, 5-difluorobenzaldehyde was used instead of 3-fluoro-4-methoxybenzaldehyde (53 a).

LC-MS：m/z 441[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 8.37-8.36(m,1H),8.13-8.12(m,1H),7.23-7.13(m,3H),7.05-6.97(m,1H),6.26-6.23(m,1H),4.77-4.70(m,1H),4.41-4.23(m,1H),3.97-3.54(m,2H),3.43-3.37(m,1H),2.95-2.71(m,1H),2.41(s,3H),2.24(s,3H),2.08-1.81(m,1H),1.76-1.71(m,1H),1.56-1.51(m,1H)。

Example 57: preparation of ((1 r,4 r) -4- (5- (3, 5-dimethylisoxazol-4-yl) -2- (3-fluoro-4-methoxybenzyl) -4-methyl-1H-benzo [ d ] imidazol-1-yl) cyclohexane-1-carboxylic acid (57)

The title compound 57 was obtained in the same manner as in the preparation methods of examples 1 and 38 except that 1-bromo-4-fluoro-2-methyl-3-nitrobenzene was used instead of 4-bromo-1-fluoro-2-nitrobenzene (1 a).

LC-MS：m/z 492[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 12.11(s,1H),7.54(d,J＝8.0Hz,1H),7.13-6.99(m,3H),6.85(d,J＝8.0Hz,1H),4.32-4.22(m,3H),3.72(s,3H),2.40-2.34(m,1H),2.25(s,3H),2.14-2.06(m,5H),1.96(s,3H),1.92-1.85(m,2H),1.45-1.34(m,4H)。

Example 58: preparation of (trans) -4- (5- (3, 5-dimethylisoxazol-4-yl) -2- (3-fluoro-4-methoxybenzyl) -6-methyl-1H-benzo [ d ] imidazol-1-yl) cyclohexane-1-carboxylic acid (58)

The title compound 58 was obtained in the same manner as in the preparation methods of examples 1 and 38 except that 1-bromo-4-fluoro-2-methyl-5-nitrobenzene was used instead of 4-bromo-1-fluoro-2-nitrobenzene (1 a).

LC-MS：m/z 492[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ):δppm 12.22(s,1H),7.72(s,1H),7.34(s,1H),7.18-7.05(m,3H),4.39-4.32(m,1H),4.28(s,2H),3.80(s,3H),2.59-2.53(m,1H),2.28-2.16(m,8H),2.01-1.93(m,5H),1.54-1.44(m,4H)。

Biological evaluation

Test example 1: TR-FRET method for detecting CBP inhibitory Activity of Compounds of the invention

Materials and reagents: recombinant human CREBBP protein (Abcam, ab 198130), H4 substrate peptide (SangonBiotech), streptavidin-d 2 (cisbio, 610 SADLB) and GST-Eu cocktail (cisbio, 61 GSTKLA).

The experimental steps are as follows: 1 Xreaction buffer (150mM NaCl;0.01%Triton X-100;0.1%BSA;20mM HEPES) was prepared. The diluted working solution of the compound was transferred to each well of the reaction plate (784075, greiner) by using Echo 655 (sample preparation: stock solution of the compound in DMSO at 10mM, initial concentration of 10,000nM, 3-fold dilution, 10 gradients, 2 multiplex wells per gradient). The reaction plate was sealed with a seal plate membrane and centrifuged at 1000 f g for 1 min. A2 XCBP protein solution was prepared with 1 Xreaction buffer at a final concentration of 200℃ 200 nM. To each well of the reaction plate was added 5. Mu.L of the protein solution prepared above. The plates were sealed with a sealing plate membrane, centrifuged at 1000g for 1 min and left at room temperature for 30 min. A2 XH 4 substrate peptide solution was prepared with 1 Xreaction buffer at a final concentration of 0.2. Mu.M. To the reaction plate, 5. Mu.L of the above-prepared 2 XH 4 substrate peptide solution was added, and the mixture was centrifuged at 1000g for 30 seconds and reacted at room temperature for 30 minutes. 10. Mu.L of a mixture of streptavidin-d 2 and GST-Eu was added to each well, and the mixture was centrifuged at 1000g for 30 seconds and reacted at room temperature for 90 minutes. Using Envision 2104 to read 615 nm and 665 nm).

Data analysis, percent inhibition was calculated as follows:

inhibition% = 100- (Signal Cmpd-Signal ave_pc)/(Signal ave_vc-Signal ave_pc)

×100

Signal Cmpd: signal value for compound 665/615nm ratio.

Signal Ave_PC: average of 665/615nm ratio for all positive control wells of the whole plate.

Signal Ave_VC: average of 665/615nm ratio for all negative control wells of the whole plate.

Compound dose response curves were generated using GraphPad 8.0 and IC for the compounds were obtained using the following nonlinear fitting equation ₅₀ ：

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*HillSlope))

X: log of compound concentration; y: percentage of inhibition of the compound; top and Bottom are the Y values of the highest and lowest plateau of the curve; hillslope is Hillconstant.

The CBP inhibitory activity of the compounds of the present invention is shown in table 1 below. IC (integrated circuit) ₅₀ Values from 0 to 100 nM labeled A,100 to 300nM labeled B,300 to 1000 nM labeled C,greater than 1000 nM is labeled D and NT represents untested.

TABLE 1 inhibition of CBP by the inventive Compounds IC ₅₀ Value of

/>

From the above table, the compounds of the present invention have a remarkable inhibitory effect on CBP activity.

Claims

1. A compound of formula (I) or a meso, racemic, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

X, Y and Z are each independently selected from CR ⁶ And N;

a is CR ⁷ Or N;

R ¹ selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more G ¹ Substitution;

each R ⁶ Each independently selected from the group consisting of hydrogen, halogen, amino, cyano, oxo, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

n is 0, 1 or 2.

2. The compound of the formula (I) according to claim 1, which is in the form of a compound of the formula (II) or a meso, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

therein, X, Y, Z, R ¹ ～R ⁵ As defined in claim 1.

3. The compound of the formula (I) according to claim 1 or 2, or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (III) or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein,,

m is 0, 1, 2 or 3; preferably 0 or 1;

R ¹ ～R ⁶ as defined in claim 1.

4. A compound of the formula (I) according to claim 1 to 3, or a meso, racemic, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein R is ¹ Selected from C ₃ -C ₆ Cycloalkyl, 3-to 6-membered heterocyclyl, C ₆ -C ₁₀ Aryl and 5 to 10 membered heteroaryl, preferably C ₆ -C ₁₀ Aryl and 5 to 10 membered heteroaryl, more preferably 5 to 10 membered heteroaryl, even more preferably 5 to 6 membered heteroaryl, most preferably 5 membered heteroaryl; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally further substituted with one or more G ¹ Substitution; g ¹ As defined in claim 1。

5. A compound of formula (I) according to any one of claims 1 to 4, or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ Selected from:

preferably

Wherein p is 0, 1 or 2; preferably 1 or 2; more preferably 2;

G ¹ as defined in claim 1.

6. A compound of the formula (I) according to claim 1 to 5, or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (IVA) or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein,,

p is 0, 1 or 2, preferably 1 or 2, more preferably 2;

X、Y、Z、G ¹ 、R ² ～R ⁵ As defined in claim 1.

7. A compound of the formula (I) according to claim 1 to 6, or a meso, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (IV) or a meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein,,

p is 0, 1 or 2, preferably 1 or 2, more preferably 2;

m is 0, 1, 2 or 3; preferably 0 or 1;

G ¹ 、R ² ～R ⁶ as defined in claim 1.

8. A compound of the general formula (I) according to claim 1 to 7, or a meso, racemic, enantiomeric, diastereomeric, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein,,

R ³ is hydrogen;

R ⁴ is hydrogen or hydroxy;

R ^a And R is ^b As defined in claim 1.

9. The compound of the formula (I) or its meso, racemic, enantiomeric, diastereomeric according to any one of claims 1 to 8A form of a body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: r is R ³ And R is ⁴ Together with the atoms to which they are attached form C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocyclyl, wherein the C ₃ -C ₈ Cycloalkyl or 3-to 8-membered heterocyclyl is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and R is ⁵ Selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each of said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more G ³ Substitution;

R ^a 、R ^b And n is as defined in claim 1.

10. A compound of the general formula (I) or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9, which is a compound of the general formula (VA) or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein,,

R ³ is hydrogen;

R ⁴ is hydrogen or hydroxy;

q is 0, 1, 2 or 3; preferably 0, 1 or 2;

p is 0, 1 or 2, preferably 1 or 2, more preferably 2;

X、Y、Z、G ¹ 、R ² as defined in claim 1.

11. A compound of the general formula (I) or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 10, which is a compound of the general formula (V) or a meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

Wherein,,

R ³ is hydrogen;

R ⁴ is hydrogen or hydroxy;

each R ⁸ Each independently selected from hydrogen, halogen, amino, cyano, hydroxy, mercapto, carboxyl, ester, C ₁ -C ₆ Alkyl group、C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkoxy, C ₃ -C ₆ Cycloalkyl, 3-to 6-membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5 to 10 membered heteroaryl;

q is 0, 1, 2 or 3; preferably 0, 1 or 2;

p is 0, 1 or 2, preferably 1 or 2, more preferably 2;

m is 0, 1, 2 or 3; preferably 0 or 1;

G ¹ 、R ² 、R ⁶ as defined in claim 1.

12. A compound of formula (I) according to any one of claims 1 to 11, or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each G ¹ Each independently selected from hydrogen, halogen, cyano, hydroxy, mercapto, and C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, OR ^a Wherein said C ₁ -C ₆ Alkyl is optionally substituted with halogen; r is R ^a Selected from C ₁ -C ₆ An alkyl group; the C is ₁ -C ₆ Alkyl is optionally substituted with halogen;

preferably G ¹ Is C ₁ -C ₆ An alkyl group.

13. A compound of formula (I) according to any one of claims 1 to 12, or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² Selected from C ₃ -C ₁₂ Cycloalkyl and 3 to 12 membered heterocyclyl, said C ₃ -C ₁₂ Cycloalkyl or 3-to 12-membered heterocyclyl optionally substituted with one or more G ² Substitution;

G ² as defined in claim 1.

14. A compound of the general formula (I) or its meso form according to any one of claims 1 to 13A form of a body, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each G ² Each independently selected from hydrogen, halogen, amino, cyano, mercapto, oxo, C ₁ -C ₆ Alkyl, OR ^a 、-C(O)R ^b 、-C(O)OR ^a 、-C(O)NR ^a R ^b 、NR ^a R ^b 、NHC(O)R ^b 、-S(O) _n R ^b 、-S(O) _n NR ^a R ^b and-NHS (O) _n R ^b Wherein said C ₁ -C ₆ Alkyl is optionally substituted with one or more groups selected from halogen and cyano;

or R is ^a And R is ^b Together with the nitrogen atom to which they are attached, form a 4-6 membered nitrogen containing heterocyclic group, said 4-6 membered nitrogen containing heterocyclic group optionally being selected from halogen, oxo, hydroxy, mercapto, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, one or more groups substituted;

preferably, the method comprises the steps of,

n is 1 or 2, preferably 2.

15. A compound of formula (I) according to any one of claims 1 to 14, or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁶ Selected from hydrogen, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, preferably hydrogen.

16. A compound of formula (I) according to any one of claims 10 to 15, or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R ⁸ Each independently selected from hydrogen, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkoxy groups; preferably hydrogen, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ An alkoxy group; q is 0, 1 or 2, preferably 1 or 2.

17. A compound of formula (I) according to any one of claims 1 to 16, or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from:

18. a process for preparing a compound of formula (II) or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

Subjecting compound IIh to dehydration under acidic conditions to obtain a compound of formula (II) or a meso, racemic, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof;

therein, X, Y, Z, R ¹ ～R ⁵ As defined in claim 2.

19. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 17 or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

20. Use of a compound of general formula (I) according to any one of claims 1 to 17 or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, for the preparation of a p300/CBP inhibitor.

21. Use of a compound of general formula (I) according to any one of claims 1 to 17 or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, for the preparation of a medicament for the prevention and/or treatment of a disease associated with p300/CBP activity.

22. The use according to claim 21, wherein the disease associated with p300/CBP activity is selected from the group consisting of metastatic prostate cancer, breast cancer, hematological neoplasm, cell proliferative disorder, inflammation, autoimmune disease, sepsis, viral infection and neurodegenerative disease.