CN108017643A - A kind of efficient IDO/TDO double inhibitors containing azacyclo- helical structure - Google Patents

Abstract

The invention discloses a high-efficiency IDO/TDO dual inhibitor containing a nitrogen heterocyclic helical structure, in particular, it relates to a compound of formula (I) or its pharmaceutically acceptable salt, its stereoisomer, or its mutual variants, or prodrugs thereof. The compound of formula (I) of the present invention can be used as indoleamine-2,3-dioxygenase inhibitor and tryptophan-2,3-dioxygenase for the preparation of prevention and/or treatment of indoleamine Drugs for ‑2,3‑dioxygenase and tryptophan ‑2,3‑dioxygenase mediated diseases.

Description

A highly efficient IDO/TDO dual inhibitor containing nitrogen heterocyclic helical structure

technical field

The invention belongs to the technical field of medicinal chemistry, and in particular relates to a high-efficiency IDO/TDO inhibitor containing nitrogen heterocyclic helical structure and a preparation method thereof.

Background technique

Indoleamine-2,3-dioxygenase (Indoleamine-2,3-dioxygenase, IDO) is a monomeric enzyme containing heme first discovered in cells by the Hayaishi group in 1967. The cDNA-encoded protein is composed of Composed of 403 amino acids, with a molecular weight of 45kDa, it is the rate-limiting enzyme for the catabolism of the tryptophan-kynurenine pathway, and is widely expressed in various mammalian tissues (Hayaishi O. et al Science, 1969, 164, 389-396). In the cells of tumor patients, IDO often plays an important physiological role in inducing immune tolerance in the tumor microenvironment, and its mediated tryptophan (Trp)-kynurenine (Kynurenine, Kyn) metabolic pathway participates in tumor Immune escape, and IDO also plays an important role in inducing immune tolerance in the tumor microenvironment.

Tryptophan is one of the important essential amino acids in mammals. It needs to be taken in large quantities from food to maintain cell activation and proliferation, as well as the synthesis of proteins and some neurotransmitters. Therefore, its deficiency can lead to malfunction of some important cells. IDO can catalyze the conversion of tryptophan into N-formylkynurenine in the body, reduce the content of tryptophan and cause the deficiency of tryptophan in the body, leading to the occurrence of tumors. Immunohistological studies have shown that the kynurenine pathway can lead to an increase in the excitotoxin quinolinic acid, and can also lead to Alzheimer's and other neurological diseases and other serious human diseases (Guillemin G.J.et al Neuropathol.and Appl. Neurobiol. 2005, 31, 395–404).

Studies have shown that IDO can suppress local T cell immune responses in several ways in the tumor microenvironment: tryptophan depletion, toxic metabolism, and induction of regulatory T cell proliferation. In many cases, it is overexpressed in tumors, thereby consuming local tryptophan and producing a large amount of metabolites such as kynurenine. In fact, under culture conditions without tryptophan or kynurenine, T cells will undergo proliferation inhibition, decreased activity and even apoptosis. In T cells, there is a regulatory point that is very sensitive to the level of tryptophan. IDO can consume tryptophan, which will cause T cells to stagnate in the middle of G1 phase, thereby inhibiting the proliferation of T cells and inhibiting the immunity of T cells. answer. Once T cells stop proliferating, they may not be stimulated again. This is the mechanism of IDO's immune function in vivo (Mellor A.et al Biochem.Biophys.Res.Commun.2005,338(1):20-24)( LeRond S. et al J. Exp. Med. 2002, 196(4):447-457).

TDO is another tryptophan metabolizing enzyme. Its mechanism of action is the same as IDO, but it was originally considered to be endogenous, especially expressed in normal liver and brain cells, especially in the liver. TDO has been verified to be overexpressed in various cancer patient tissues, and the efficacy of TDO inhibitors in mouse tumor models by immune rejection of tumor cell growth was verified (Pilotte, l. et al. Proc. Natl. Acad. Sci. USA; published online, Jan. 30, 2012).

Therefore, IDO, TDO inhibitors or IDO/TDO dual inhibitors are important targets for tumor immunotherapy, and new highly active IDO, TDO or IDO/TDO inhibitors still need to be developed in this field.

Contents of the invention

The object of the present invention is to provide a novel compound containing a nitrogen heterocyclic helical structure that can be used as a highly efficient IDO/TDO dual inhibitor, and a preparation method thereof. The compound of formula (I) of the present invention has anti-tumor and neurological properties. Degenerative disease (Alzheimer's disease), anti-inflammatory and other pharmacological activities.

In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a tautomer thereof, or a prodrug thereof:

In the formula,

A is selected from the group consisting of S, O, -C(R ¹ ) ₂ - or none;

B is selected from the group consisting of: -C(R ^1a ) ₂ - or none;

E and M are independently selected from: N or CR ¹ ;

Each R ¹ is independently selected from the group consisting of H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, OH, substituted or unsubstituted O-C ₁ -C ₆ alkyl, substituted or unsubstituted OC ₃ -C ₈ cycloalkyl;

Each R ^1a is independently selected from the group consisting of H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl;

In the R ¹ and R ^1a , the substitution refers to having one or more (such as 1, 2, 3, 4) substituents selected from group A: halogen, hydroxyl, -NH ₂ , nitro, - CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, OC ₁ -C ₄ alkyl, C ₃ -C ₈ cycloalkyl, OC ₃ -C ₈ cycloalkyl, C ₂ -C ₄ chain Alkenyl, C ₂ -C ₄ alkynyl, phenyl, benzyl;

selected from the group consisting of substituted or unsubstituted C ₆ -C ₁₀ aryl, substituted or unsubstituted C ₃ -C ₁₀ heteroaryl and the heteroaryl has 1-3 selected from S, O or N Heteroatom; wherein, the substitution refers to having one or more (such as 1, 2, 3, 4) substituents selected from group B: halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, hydroxyl, amino, nitro, substituted or unsubstituted C ₁ -C ₆ aldehyde, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl , -COR ^a , -CO ₂ C ₁ -C ₆ alkyl, -CONR ^a R ^b , -SO ₂ R ^b , -SO ₂ NR ^a R ^b ;

X is selected from the group consisting of H, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl, OH, substituted or unsubstituted OC ₁ -C ₆ alkyl, substituted or unsubstituted OC ₃ -C ₈ cycloalkyl, NR ^a R ^b or NR ^a C (O)R ³ ;

And, when X is selected from: H, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, or When substituted or unsubstituted C ₃ -C ₁₄ heteroaryl, Y is selected from the group consisting of substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or Unsubstituted C ₁ -C ₆ alkylthio, substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl, -(CR ¹ ₂ ) _n C(O )NR ² R ³ , -C(CR ¹ ₂ ) _n C(S)NR ² R ³ , -O(CR ¹ ₂ ) _n C(O)NR ² R ³ , -S(CR ¹ ₂ ) _n C( O)NR ² R ³ , -NR ² (CR ¹ ₂ ) _n C(O)NR ² R ³ , -NR ² (CR ¹ ₂ ) _n C(O)R ³ , -NR ² C(O)(CR ¹ ₂ ) _n C(O)R ³ , -NR ² (CR ¹ ₂ ) _n C(O)O(CR ¹ ₂ ) _n R ³ , -NR ² (CR ¹ ₂ ) _n C(S)NR ² R ³ , -NR ² (CR ¹ ₂ ) _n C(O)NR ² R ³ , -NR ² (CR ¹ ₂ ) _n C(S)NR ² R ³ , -(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ R ³ , -(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ NR ² R ³ , -O(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ R ³ , -S(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ R ³ , -NR ² (CR ¹ ₂ ) _n S(O) ₂ NR ² R ³ , -NR ² S( O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n S(O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n NR ² S(O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n NR ² C(O)NR ¹ S(O) ₂ R ³ , -(CR ¹ ₂ ) _n S(O)(=NR ² )R ³ , -(CR ¹ ₂ ) _n S(O)(=NCN )R ³ , -(CR ¹ ₂ ) _n S(O)R ³ , -NR ² S(O) ₂ R ³ , -(CR ¹ ₂ ) _n S(O) ₂ R ³ , NR ² C(=N -CN) NR ² R ³ ; the substitution refers to having one or more ( Such as 1, 2, 3, 4) substituents: halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₃ -C ₁₀ heterocycloalkyl, C ₆ -C ₂₀ aryl, C ₃ -C ₁₄ heteroaryl hydroxyl, OC ₆ -C ₂₀ aryl, OC ₃ -C ₁₄ heteroaryl, hydroxyl, OSO ₂ NH ₂ , NHSO ₂ NH ₂ , amino, nitro, aldehyde, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl, -COR ^a , -CO ₂ C ₁ -C ₆ alkyl, -CONR ^a R ^b , -SO ₂ R ³ , -SO ₂ NR ^a R ^b , -P(O)Me ₂ , -P(O)(OMe) ₂ ;

When X is selected from: OH, OC ₁ -C ₆ alkyl, OC ₃ -C ₈ cycloalkyl, NR ^a R ^b or NR ^a C (O) R ³ , Y is selected from the following group: substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, Substituted or unsubstituted C ₃ -C ₁₀ heterocycloalkyl, -(CR ¹ ₂ ) _n C(O)NR ² R ³ , -(CR ¹ ₂ ) _n C(S)NR ² R ³ , -(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ R ³ , -(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n S( O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n NR ² S(O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n NR ² C(O)NR ¹ S(O) ₂ R ³ , -(CR ¹ ₂ ) _n S(O)(=NR ² )R ³ , -(CR ¹ ₂ ) _n S(O)(=NCN)R ³ , -(CR ¹ ₂ ) _n S(O)R ³ , -(CR ¹ ₂ ) _n S(O) ₂ R ³ ; the substitution refers to having one or more (such as 1, 2, 3, 4) substituents selected from Group D: halogen, C ₁ - C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₃ -C ₁₀ heterocycloalkyl, substituted or unsubstituted C ₆ -C ₂₀ aryl , C ₃ -C ₁₄ heteroaryl hydroxyl, OC ₆ -C ₂₀ aryl, OC ₃ -C ₁₄ heteroaryl, hydroxyl amino, nitro, aldehyde, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl, -COR ^a , -CH ₂ -C ₆ -C ₁₀ aryl, -CH ₂ -C ₆ -C ₁₀ aryl, -CO ₂ C ₁ -C ₆ alkyl, -CONR ^a R ^b , -SO ₂ R ³ , -SO ₂ NR ^a R ^b , -P(O)Me ₂ , -P(O)(OMe) ₂ , hydroxyl, OSO ₂ NH ₂ , NHSO ₂ NH ₂ , C ₃ -C ₆ hetero ring group;

Wherein, each R ^a and each R ^b are independently selected from the following group: hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkenyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl, or R ^a and R ^b and the N atom connected to it Together form a substituted or unsubstituted 4-8 membered heterocyclic ring, and the heterocyclic ring has at least one N and 0-2 heteroatoms selected from S and O, wherein N in the nitrogen-containing heterocyclic ring is NH or NR ^g form, wherein R ^g is independently C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₂₀ aryl, or C ₃ -C ₁₄ heteroaryl; wherein, the Substitution refers to having one or more (such as 1, 2, 3, 4) substituents selected from group E: halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, hydroxyl, OSO ₂ NH ₂ , NHSO ₂ NH ₂ , amino, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl, -COR ^a , -CO ₂ C ₁ -C ₆ alkane group, -CONR ^a R ^b , -SO ₂ R ^b , -SO ₂ NR ^a R ^b ;

Each R ² and each R ³ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkenyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl, substituted or unsubstituted C ₃ -C ₁₀ heterocyclyl, substituted or unsubstituted amino;

is a substituted or unsubstituted 3-10 membered carbocyclic or heterocyclic ring having at least one carbon atom substituted by a heteroatom selected from the group consisting of O, S, S(O), S(O) ₂ , C(O), C(S) and NR ^g ; wherein, the substitution refers to having one or more (such as 1, 2, 3, 4) substituents selected from Group F: OH, halogen, C _{1- 6} alkyl;

Among the substituents in Group A, Group B, Group C, Group D, Group E, Group F, R ² , R ³ , the substitution refers to having one or more (such as 1, 2, 3) selected from Group G , 4) substituents: halogen, C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -CN, -CF ₃ , -O-CF ₃ , C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₈ ester group, C ₆ -C ₁₀ aryl group;

Z is a carbon atom or N; when Z is N, X is absent;

n is an integer of 0 to 8.

In another preferred example, the compound of formula (I) is shown in formula (II):

In the formula,

Select from the group:

Wherein, R ^c is one or more groups selected from the group consisting of halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₁₀ cycloalkoxy, hydroxyl, amino, nitro, substituted or unsubstituted C ₁ -C ₆ aldehyde, -CF ₃ , - CN, -SF ₅ , NR ^a R ^b , carboxyl, -COR ^a , -CO ₂ C ₁ -C ₆ alkyl, -CONR ^a R ^b , -SO ₂ R ³ , -SO ₂ NR ^a R ^b ; where each R ^a and each R ^b are as defined above;

m is an integer from 1 to 4;

q is 1, 2 or 3;

r is 1 or 2;

Z, X, Y are as defined above.

In another preferred example, the is a substituted or unsubstituted C ₆ -C ₁₀ aryl group, preferably a substituted or unsubstituted benzene ring.

In another preferred example, is substituted or unsubstituted thienyl or furyl, preferably, selected from

Next group:

In another preferred example, Is a substituted or unsubstituted pyridyl group, preferably, the Select from the group:

In another preferred example, Select from the group:

In another preferred example, when X is selected from: H, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₆ -C When ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl, Y is selected from the group consisting of substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₆ -C ₂₀ aryl group, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl, -(CR ¹ ₂ ) _n C(O)NR ² R ³ , -C(CR ¹ ₂ ) _n C(S)NR ² R ³ , -O(CR ¹ ₂ ) _n C(O)NR ² R ³ , -S(CR ¹ ₂ ) _n C(O)NR ² R ³ , -NR ² (CR ¹ ₂ ) _n C(O)NR ² R ³ , -NR ² (CR ¹ ₂ ) _n C(O)R ³ , -NR ² C(O)(CR ¹ ₂ ) _n C(O)R ³ , -NR ² (CR ¹ ₂ ) _n C(O )OR ³ , -NR ² (CR ¹ ₂ ) _n C(S)NR ² R ³ , -NR ² (CR ¹ ₂ ) _n C(O)NR ² R ³ , -NR ² (CR ¹ ₂ ) _n C (S)NR ² R ³ , -(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ R ³ , -(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ NR ² R ³ , -NR ² (CR ¹ ₂ ) _n C(S)NR ² R ³ , -NR ₂ C(O)NR ² R ³ , -NR ₂ C(S)NR ² R ³ , -(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ R ³ , -O(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ R ³ , -S(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ R ³ , -NR ² (CR ¹ ₂ ) _n S(O) ₂ NR ₂ R ₃ , -NR ² S(O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n S( O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n NR ² S(O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n NR ² C(O)NR ¹ S(O) ₂ R ³ , -(CR ¹ ₂ ) _n S(O)(=NR ² )R ³ , -(CR ¹ ₂ ) _n S(O)(=NCN)R ³ , -(CR ¹ ₂ ) _n S(O)R ³ 、-(CR ¹ ₂ ) _n S(O) ₂ R ³ , NR ² C(=N-CN)NR ² R ³ ; the substitution refers to having one or more (such as 1, 2, 3, 4) substituents selected from Group C.

In another preferred example, when X is selected from the following group: OH, OC ₁ -C ₆ alkyl, OC ₃ -C ₈ cycloalkyl, NR ^a R ^b or NR ^a C(O)R ³ , Y is selected from From the group below: substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl, -(CR ¹ ₂ ) _n C(O)NR ² R ³ , -(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ R ³ , -(CR ¹ ₂ ) _n S(O) ₂ NR ² R ³ , - (CR ¹ ₂ ) _n NR ² S(O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n NR ² C(O)NR ¹ S(O) ₂ R ³ , -(CR ¹ ₂ ) _n C( O)NR ² S(O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n S(O)(=NR ² )R ³ , -(CR ¹ ₂ ) _n S(O)(=NCN)R ³ , -(CR ¹ ₂ ) _n S(O)R ³ , -(CR ¹ ₂ ) _n S(O) ₂ R ³ ; the substitution refers to having one or more selected from Group D (such as 1, 2 , 3, 4) substituents.

In another preferred example, each R ² and each R ³ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ ring Alkyl, substituted or unsubstituted C ₂ -C ₁₀ alkenyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl.

In another preferred example, each R ^a and each R ^b and the N atom connected to it together form a substituted or unsubstituted 4-8 membered heterocyclic ring, and the heterocyclic ring has at least one N and 0-2 Heteroatoms selected from S and O, wherein N in the nitrogen-containing heterocycle is in the form of NH or NR ^g , wherein R ^g is independently C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₂₀ aryl, or C ₃ -C ₁₄ heteroaryl.

In another preferred example, the compound of formula (I) is represented by formula (III),

In the formula, X, Y, Z, and R ^c are as defined above, and m is an integer of 1 to 4.

In another preferred example, said A is none.

In another preferred example, said B is none.

In another preferred example, the R ¹ is H.

In another preferred example, said E and M are independently CR ¹ .

In another preferred example, the R ¹ is independently selected from the following group: H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, preferably for H.

In another preferred example, the X is selected from the group consisting of H, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, preferably, X is H.

In another preferred example, when X is H, Y is selected from the group consisting of substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ alkylthio, substituted or unsubstituted Substituted C ₃ -C ₁₄ heteroaryl, -NR ² (CR ¹ ₂ ) _n C(O)NR ² R ³ , -NR ² (CR ¹ ₂ ) _n C(O)R ³ , -NR ² C( O)(CR ¹ ₂ ) _n C(O)R ³ , -NR ² (CR ¹ ₂ ) _n C(O)O(CR ¹ ₂ ) _n R ³ , -NR ² (CR ¹ ₂ ) _n C(S )NR ² R ³ , -(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ R ³ , -NR ² (CR ¹ ₂ ) _n S(O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n S(O)R ³ , -(CR ¹ ₂ ) _n S(O) ₂ R ³ or NR ² C(=N-CN)NR ² R ³ .

In another preferred example, X is OH.

In another preferred example, when X is OH, the Y is selected from the group consisting of substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or Unsubstituted C ₃ -C ₁₄ heteroaryl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₃ -C ₁₀ heterocycloalkyl.

In another preferred example, the group D substituent is selected from the following group: substituted or unsubstituted C ₆ -C ₂₀ aryl, hydroxyl, C ₃ -C ₆ heterocyclic group, -CH ₂ -C ₆ -C ₁₀ aryl.

In another preferred example, the compound of formula (I) is shown as formula (IV):

In the formula,

In the formula, R ^c is one or more groups selected from the group consisting of halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted Substituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkoxy, hydroxyl, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl, -COR ^a , -CONR ^a R ^b , -SO ₂ R ³ , -SO ₂ NR ^a R ^b ;

wherein each R ^a and each R ^b are as defined above;

m is an integer from 1 to 4;

is a substituted or unsubstituted 3-7 membered heterocycle selected from the group consisting of:

X is selected from the group consisting of OH, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, alkylOC ₁ -C ₆ alkyl, OC ₃ -C ₈ Cycloalkyl, NR ^a R ^b or NR ^a C (O) R ³ ;

Selected from the following group: substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl, wherein the aromatic ring and the heteroaryl ring can be selected from the following group by one or more The group E is substituted by: halogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₃ -C ₁₀ heterocycloalkyl, C ₆ -C ₂₀ aryl, C ₃ -C ₁₄ heteroaryl hydroxyl, OC ₆ -C ₂₀ aryl, OC ₃ -C ₁₄ Heteroaryl, hydroxyamino, nitro, aldehyde, OH, OSO ₂ NH ₂ , NHSO ₂ NH ₂ , -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl, -COR ^a , -CO ₂ C ₁ -C ₆ alkyl, -CONR ^a R ^b , -SO ₂ R ³ , -SO ₂ NR ^a R ^b , -P(O)Me ₂ , -P(O)(OMe) ₂ ; where each R ^a and each R ^b are independently hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkenyl, Substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl; R ^a and R ^b can together form a four to eight-membered heterocyclic ring, wherein the heteroatom can be sulfur, Oxygen, NH or NR ^g ;

In another preferred example, the compound is shown in formula (V):

In the formula,

R ^c is one or more groups selected from the group consisting of halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, hydroxyl, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl, -COR ^a , -CONR ^a R ^b , -SO ₂ R ³ , -SO ₂ NR ^a R ^b ; wherein each R ^a and each R ^b is as defined above;

m is an integer from 1 to 4;

Select from the group:

R ^d is selected from the group consisting of H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, Substituted or unsubstituted C ₃ -C ₈ cycloalkoxy, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, substituted or unsubstituted C ₃ -C ₁₄ Heteroaryl; said substitution refers to having one or more (such as 1, 2, 3, 4) substituents selected from H group: halogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkane C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₃ -C ₁₀ heterocycloalkyl, C ₆ -C ₂₀ aryl , C ₃ -C ₁₄ heteroaryl hydroxyl, OC ₆ -C ₂₀ aryl, OC ₃ -C ₁₄ heteroaryl, hydroxyl amino, nitro, aldehyde, OH, OSO ₂ NH ₂ , NHSO ₂ NH ₂ , - CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl, -COR ^a , -CO ₂ C ₁ -C ₆ alkyl, -CONR ^a R ^b , -SO ₂ R ³ , -SO ₂ NR ^a R ^b , -P(O)Me ₂ , -P(O)(OMe) ₂ ;

In another preferred example, the compound is shown in formula (VI),

In the formula,

R ^c is one or more groups selected from the group consisting of halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkoxy, hydroxyl, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl, -COR ^a , -CONR ^a R ^b , -SO ₂ R ³ , -SO ₂ NR ^a R ^b ; wherein each R ^a and each R ^b is as defined above;

m is an integer from 1 to 4;

Select from the group:

R ^f is selected from the group consisting of H, SO ₂ NH ₂ , C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkenyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroarylamino; One or more (such as 1, 2, 3, 4) substituents: C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ cycloalkyl, C ₁ -C ₆ Haloalkyl, alkoxy, heterocyclyl, aryl, heteroaryl, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl, hydroxyl, OSO ₂ NH ₂ , NHSO ₂ NH ₂ , amino, -COR ^a , -CONR ^a R ^b , -SO ₂ R ³ , -SO ₂ NR ^a R ^b ; wherein, the R ^a and R ^b and the N atoms connected to them together form a substituted or unsubstituted 4-8 A membered heterocycle, and the heterocycle has at least one N and 0-2 heteroatoms selected from S and O, wherein N in the nitrogen-containing heterocycle is in the form of NH or ^NRg , wherein ^Rg is independently is C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₂₀ aryl, or C ₃ -C ₁₄ heteroaryl.

In another preferred embodiment, the compound of formula (I) is selected from the following group:

(cis/trans) 3-phenylspiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-ol;

(cis) 4-methyl-N-((1S,3S)-spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzenesulfonamide;

(Trans) 4-methyl-N-((1S,3S)-spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzenesulfonamide amides;

(trans) 4-methyl-N-((1S,3S)-spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide;

(cis/trans) 3-fluoro-N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide;

(cis) 4-fluoro-N-spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzenesulfonamide;

(cis) N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)cyclohexylsulfonamide;

(cis) 3-chloro-4-fluoro-N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)benzamide;

(trans) 3-bromo-4-fluoro-N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)benzamide;

(trans) N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)propane-2-sulfonamide;

(trans) N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)naphthalene-2-sulfonamide;

(trans) N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)naphthalene-1-sulfonamide;

(trans) 2-fluoro-N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide;

(trans) 2,4-dichloro-N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)benzamide;

(trans) 4-methoxy-N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide;

(trans) N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)-2-naphthylcarboxamide;

(trans) 3-chloro-N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide;

(trans) 3-bromo-N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide;

(trans) N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)-3-(trifluoromethyl)benzamide;

(trans)phenyl spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-ylcarbamate;

(trans)nitro-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindol]-3-yl)methylsulfonamide;

(trans) 3,4-dichloro-nitrogen-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindole]-3-yl)benzamide;

(trans) 4-bromo-nitrogen-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindol]-3-yl)benzamide;

(trans) N-(3-bromo-4-fluorophenyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide;

(trans) N-(3-chlorophenyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide;

(trans)-N-(3-bromophenyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide;

(cis)-N-(3-bromophenyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide;

(trans)N-(4-fluorophenyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide;

(cis/trans) 3-(1-Benzyl-1H-1,2,3-triazol-4-yl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole ]-3-ol;

(trans) 3-(-spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindole]-3-yl)sulfonylurea;

(trans)1-phenyl-3-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindol]-3-yl)thiourea;

(cis) 1-(3-fluorophenyl)-3-(spiro[cyclobutane-1,5'-imidazole 5,1-a]isoindoll]-3-yl)thiourea;

(cis) 1-(4-chlorophenyl)-3-(spiro[cyclobutane-1,5'-imidazole 5,1-a]isoindol 1]-3-yl)thiourea;

(cis)1-(4-trifluoromethylphenyl)-3-(spiro[cyclobutane-1,5'-imidazole 5,1-a]isoindoll]-3-yl)thiourea ;

(cis)1-(3-trifluoromethylphenyl)-3-(spiro[cyclobutane-1,5'-imidazole 5,1-a]isoindoll]-3-yl)thiourea ;

(cis)1-(3-Chloro-4-(trifluoromethyl)phenyl)-3-(spiro[cyclobutane 1,5'-imidazol[5,1-a]isoindole]-3 - base) urea;

(cis)1-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindol]-3-yl)-3-(3-(trifluoromethyl)phenyl) urea;

(cis)1-(3,5-bis(trifluoromethyl)phenyl)-3-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindole]-3 - base) thiourea;

(cis)1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindole]- 3-yl) thiourea;

(cis)1-(3,5-bis(trifluoromethyl)phenyl)-3-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindole]-3 - base) urea;

(cis) 1-(3,4-dichlorophenyl)-3-(spiro[cyclobutyl-1,5’-imidazol[5,1-a]isoindol]-3-yl)urea;

(trans)1-(3-trifluoromethylphenyl)-3-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)thiourea ;

(trans)1-(3-fluorophenyl)-3-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)thiourea;

(trans)1-(4-chlorophenyl)-3-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)thiourea;

(trans) 1-(3-fluorophenyl)-3-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)sulfonylurea;

(cis) 1-methyl-3-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)sulfonylurea;

(cis/trans)1-(spiro[cyclohexyl-1,5'-imidazo[5,1-α]isoindol]-4-yl)-3-(3-(trifluoromethyl)phenyl ) thiourea;

(cis/trans) 1-(4-chlorophenyl)-3-(spiro[cyclohexyl-1,5'-imidazo[5,1-α]isoindol]-4-yl)thiourea;

(cis/trans)1-(spiro[cyclohexyl-1,5'-imidazo[5,1-α]isoindol]-4-yl)-3-(4-(trifluoromethyl)phenyl ) thiourea;

(cis/trans)1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(spiro[cyclohexyl-1,5'-imidazo[5,1-α]isoindole] -4-yl)urea;

(cis/trans)6'-fluoro-1-(3-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)spiro[azetidine-3,5'-imidazo [5,1-a]isoindole]; or

(cis/trans)6-fluoro-1'-(3-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)spiro[imidazo[5,1-a]isoindole -5,4'-piperidine].

In another preferred embodiment, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, trifluoromethanesulfonate, benzenesulfonic acid Salt, p-toluenesulfonate (toluenesulfonate), 1-naphthalenesulfonate, 2-naphthalenesulfonate, acetate, trifluoroacetate, malate, tartrate, citrate, milk Salicylate, Oxalate, Succinate, Fumarate, Maleate, Benzoate, Salicylate, Phenylacetate, Mandelate.

In another preferred embodiment, the compound is compound 1-117 prepared in the examples.

In another preferred example, the compound is cis-trans isomers.

In another preferred example, the compound is a cis isomer.

In another preferred example, the compound is a trans isomer.

In another preferred example, the compound is a racemate.

In another preferred embodiment, the compounds are enantiomers.

In a second aspect, the present invention provides a pharmaceutical composition comprising:

(1) The compound of formula (I) according to the first aspect of the present invention, or its pharmaceutically acceptable salt, its stereoisomer or its tautomer, or its prodrug;

(2) Pharmaceutically acceptable carrier and/or antitumor drug.

In another preferred embodiment, the anti-tumor drug is selected from the group consisting of checkpoint protein antibodies, such as PD-1 antibody, PD-L1 antibody or CTLA4 antibody.

In another preferred example, the anti-tumor drug is an immunotherapy drug for cancer.

In another preferred example, the cancer immunotherapy drug is selected from the group consisting of PD-1 antibody, CTLA-4 antibody, PD-L1 antibody, PD-L2 antibody, chemotherapy drug or targeted therapy drug.

In another preferred example, the targeted therapy drug is selected from the group consisting of HDAC inhibitors, kinase inhibitors, EP4 antagonists, or combinations thereof.

The third aspect of the present invention provides a compound of formula (I) as described in the first aspect of the present invention or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a tautomer thereof, or a prodrug thereof for use in:

(i) preparing IDO/TDO inhibitors;

(ii) Preparation of medicaments for preventing and/or treating diseases mediated by IDO and TDO.

In another preferred example, the IDO/TDO-mediated disease is a disease characterized by the pathology of the IDO/TDO-mediated tryptophan metabolic pathway.

In another preferred example, the IDO/TDO-mediated disease is selected from the group consisting of cancer, neurodegenerative disease, eye disease, heart disorder, depression, anxiety, Alzheimer's disease, or autoimmune disease.

In another preferred example, the cancers include, but are not limited to: colon cancer, breast cancer, gastric cancer, lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer, liver cancer, brain cancer, melanoma, multiple Myeloma, chronic myelogenous leukemia, hematological neoplasms, lymphoid neoplasms, including metastatic lesions in other tissues or organs distant from the primary site of the tumor.

The fourth aspect of the present invention provides a method for preventing and/or treating IDO/TDO-mediated diseases, comprising administering the compound of formula (I) described in the first aspect or the pharmaceutical composition described in the second aspect to the patient step.

In another preferred example, the IDO/TDO-mediated disease is cancer, and the method further comprises administering an additional anti-cancer agent (also called an anti-tumor drug, the anti-tumor drug is as described above) to the patient step.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to the limited space, I won't go into details here.

specific implementation plan

After extensive and in-depth research, the present inventors have first developed a novel compound containing a nitrogen-heterocyclic helical structure, which can be used as an efficient inhibitor of a nitrogen-heterocyclic helical structure for the prevention and/or treatment of IDO/ TDO-mediated diseases can also be used as an anti-inflammatory drug. On this basis, the present invention has been accomplished.

definition

The term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, including straight and branched chain hydrocarbon groups, such as methyl (ie CH ₃ -), ethyl (ie CH ₃ CH ₂ -) , n-propyl (ie CH ₃ CH ₂ CH ₂ -), isopropyl (ie (CH ₃ ) ₂ CH-), n-butyl (ie CH ₃ CH ₂ CH ₂ CH ₂ -), isobutyl (ie (CH ₃ ) ₂ CHCH ₂ -), sec-butyl (ie (CH ₃ )(CH ₃ CH ₂ )CH-), tert-butyl (ie (CH ₃ ) ₃ C-), n-pentyl (ie CH _{3 CH2CH2CH2CH2-} ), _{neopentyl ( ie} ( _CH3 ) _{3CCH2- )} . In the present invention, the term includes substituted or unsubstituted alkyl groups.

As used herein, the term "substituted or unsubstituted" means that the group can be unsubstituted, or that H in the group is replaced by one or more (preferably 1-6, more preferably 1- 3) Substituents are substituted.

As used herein, the "substituted" or "substituted" means that the group has one or more (preferably 1-6, more preferably 1-3) substituents selected from the following group: Halogen, hydroxyl, -NH ₂ , nitro, -CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, phenyl, benzyl.

As used herein, the term "cycloalkyl" refers to substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl.

As used herein, the term "alkoxy" refers to an -O-alkyl group, wherein the alkyl group may be saturated or unsaturated, branched, straight chained, or cyclic. Preferably, the alkoxy group has 1-10 carbon atoms, preferably 1-6 carbon atoms. Representative examples include, but are not limited to: methoxy, ethoxy, propoxy.

As used herein, the term "aryl" refers to a monovalent aromatic carbocyclic group of 6 to 20 (preferably 6-14) carbon atoms, which has a single ring (such as phenyl) or condensed rings (such as naphthyl or anthracenyl), if the point of attachment is on an aromatic carbon, the fused ring may be non-aromatic (such as 2-benzoxazolone, 2H-1,4-benzoxazin-3(4H)-one-7 -base, etc.). Preferred aryl groups include phenyl and naphthyl. The term includes substituted or unsubstituted forms wherein the substituents are as defined above.

As used herein, the term "alkenyl" refers to an alkenyl group having 2 to 10 (such as 2 to 6 or 2 to 4) carbon atoms and having at least 1 (such as 1 to 2) ethylenically unsaturated bonds (>C =C<). Examples of such groups are vinyl, allyl, but-3-enyl. As used herein, the term "cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms, having a single ring or multiple rings (including fused systems, bridged ring systems and spiro ring systems). In fused ring systems, one or more rings can be cycloalkyl, heterocyclic, aryl, or heteroaryl as long as the point of attachment is through the cycloalkyl ring. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclooctyl.

As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

As used herein, the term "heteroaryl" refers to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring, such heteroaryl groups may be monocyclic (such as pyridyl or furyl) or fused ring (such as indolizinyl (indolizinyl) or benzothienyl), wherein the fused ring can be non-aromatic and/or contain a heteroatom as long as the point of attachment is through An atom of an aromatic heteroaryl group. In one embodiment, the ring atom nitrogen and/or sulfur of the heteroaryl is optionally oxidized to N-oxide (N-O), sulfinyl or sulfonyl. Preferred heteroaryl groups include pyridyl, pyrrolyl, indolyl, benzoxadiazole, imidazolyl, quinolinyl, oxazolyl, isoxazolyl, thiazolyl, tetrazolyl, 1,2 ,3-triazolyl, 1,2,4-triazolyl, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, thiophene base and furyl. The term includes substituted or unsubstituted heteroaryl groups.

As used herein, the term "substituted heteroaryl" refers to a heteroaryl group substituted by 1 to 5, preferably 1 to 3, more preferably 1 to 2, substituents selected from and substituted The same substituents defined for the aryl group.

As used herein, the term "heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated, partially saturated or unsaturated group (but not aromatic), Has a single ring or condensed ring (including bridged ring system and spiro ring system, with 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen in the ring, in the condensed ring system, one or more Each ring can be a cycloalkyl, aryl or heteroaryl as long as the point of attachment is through a non-aromatic ring. In one embodiment, the nitrogen and/or sulfur atoms of the heterocyclic group are optionally oxidized to provide N-oxide, sulfinyl and sulfonyl moieties.

As used herein, the term "substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to a heterocyclyl group substituted with 1 to 5 (eg 1 to 3) substituents group, the substituents are the same as defined for substituted cycloalkyl groups.

As used herein, the term "stereoisomer" refers to compounds that differ in chirality at one or more stereocenters. Stereoisomers include enantiomers and diastereomers.

As used herein, the term "tautomer" refers to alternative forms of compounds that differ in the position of the proton, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups , the heteroaryl group contains ring atoms attached to the -NH- portion of the ring and the =N- portion of the ring, such as pyrazole, imidazole, benzimidazole, triazole and tetrazole.

"Prodrug" refers to any derivative of a compound of the Examples that, when administered to a subject, is capable of providing, directly or indirectly, a compound of the Examples or an active metabolite or residue thereof. Particularly preferred derivatives and prodrugs are those which, when administered to a subject, increase the bioavailability of the compounds of the Examples (e.g., an orally administered compound is more readily absorbed into the bloodstream) or increase the parent compound relative to the parent species. Delivery of derivatives and prodrugs to biological compartments such as the brain or lymphatic system. Prodrugs include ester forms of the compounds of the invention.

Compounds of the invention

As used herein, the term "compound of the present invention" refers to the compound of general formula (I), its racemate, its stereoisomer or its tautomer, or its pharmaceutically acceptable salt.

The present invention relates to: racemic mixtures of these compounds, mixtures enriched in either enantiomer, and either isolated enantiomer. For the scope of the present invention, it is understood that said racemic mixture refers to a 50%:50% mixture of the two R and S enantiomers. The separated enantiomers should be understood as pure enantiomers (i.e. 100%) or highly enriched enantiomers (purity ≥ 98%, ≥ 95%, ≥ 93%, ≥ 90%, ≥ 88% , ≥85%, ≥80%) mixture.

Where a compound described herein exists as a stereoisomer, the present invention includes all stereoisomers of the compound.

Where compounds described herein exist as tautomers, the present invention includes all tautomers of the compounds.

The present invention also includes deuterated compounds in which any one or more hydrogen atoms in the compounds are replaced by its stable isotope deuterium.

Preparation

The preparation methods provided below are for illustrative purposes only, and are not intended to be a further generalization of the preparation methods for the compounds of the present invention. Also, each novel intermediate and its use in the preparation of the compounds of the present invention are provided in the following preparation methods.

The compound of formula (I) of the present invention can be obtained by following preparation method:

(a) Compound A reacts with epichlorohydrin under the above conditions to obtain Compound B; (b) Compound B is hydrolyzed with excess alkali to obtain Compound C; (c) Compound C reacts with (PhO)2P(O)Cl to obtain rearrangement Product compound D; (d) compound D is hydrolyzed with alkali to obtain compound E; (e) compound E obtains imidazole compound F under the above-mentioned reaction conditions; (f) compound F is ring-closed to generate compound G under the action of a palladium catalyst; (g) Compound G was reacted with MsCl to generate Compound H; (h) Compound H was substituted with NaN ₃ to obtain Compound I; (i) Compound I was hydrogenated under the catalysis of Pd/C to obtain intermediate Compound J.

The cis isomer N can be synthesized by following steps:

(a) partial hydrolysis of compound B to obtain amide compound K; (b) oxidative rearrangement of compound K to generate compound L; (c) compound L to obtain intermediate compound M and compound N through the same reaction steps as described above to generate compound J.

The compound of formula (I) of the present invention can be obtained by following preparation method:

The present invention also provides another preparation method of compound Q of formula (I), comprising the following steps:

(a) compound H reacts with NaCN to obtain compound O; (b) compound O is hydrolyzed with alkali to obtain compound carboxylic acid P; (c) compound P reacts with a suitable amine under the synthesis conditions of amides to produce formula (I) compound Q .

The cis isomer T can be synthesized by following steps:

Compound M can be synthesized by the same reaction steps as compound Q to obtain compound T of formula (I).

The present invention also provides another preparation method of formula (I) compound X, comprising the following steps:

(a) carboxylic acid compound S is converted into methyl ester; (b) methyl ester compound U is oxidized to obtain compound V; (c) compound V is hydrolyzed under alkaline conditions to obtain compound W; (d) compound W is reacted with a suitable amine in the amide Reaction under synthetic conditions yields compound X.

The present invention also provides another preparation method of formula (I) compound Z, comprising the following steps:

(a) compound G is oxidized to obtain compound Y; (b) compound Y is subjected to a metal reagent nucleophilic addition reaction to obtain compound Z of formula (I).

The present invention also provides another preparation method of formula (I) compound Z, comprising the following steps:

(a) compound Y is obtained by addition reaction of acetylene Grignard reagent to obtain compound AA; (b) compound AA is obtained by click reaction with an azide compound to obtain compound BB of formula (I).

The present invention also provides a preparation method of another formula (I) compound FF, comprising the following steps:

(a) compound H was reacted with NaO ₂ SCH ₂ CH ₂ O ₂ Me to obtain compound CC; (b) compound CC was eliminated under alkaline conditions to obtain compound DD; (c) compound DD was reacted with H ₂ NOSO ₃ H to obtain Compound EE; (d) Compound EE is condensed with carboxylic acid to obtain formula (I) compound FF.

The present invention also provides a preparation method of another formula (I) compound HH, comprising the following steps:

(a) compound EE reacts with ClC(O)OEt to obtain compound GG; (b) compound GG reacts with corresponding amine to obtain formula (I) compound HH.

The present invention also provides a preparation method for another formula (I) compound, comprising the following steps:

(a) compound O reacts with Ti(Oi-Pr) ₄ and EtMgBr to obtain compound II; (b) reacts compound II with corresponding reagents to obtain the above compound of formula (I).

The present invention also provides a preparation method for another formula (I) compound, comprising the following steps:

(a) Compound JJ is obtained by reacting 2-bromocyanobenzyl and 3-chloropropionate methyl ester under alkaline conditions to obtain compound JJ; (b) compound JJ is decarboxylated to obtain compound KK; (c) compound KK is reacted with Ethylene glycol is reacted to obtain compound LL; (d) compound LL is partially hydrolyzed with alkali to obtain compound MM; (e) compound MM is rearranged under oxidation reaction conditions to obtain compound NN; (f) compound NN obtains imidazole compound under the above reaction conditions OO; (g) ring closure of compound OO under the action of a palladium catalyst to generate compound PP; (h) acid hydrolysis of compound PP to generate compound QQ; (i) reductive amination of compound QQ to obtain compound RR;

Similar to compound J and compound N, compound RR is reacted with the corresponding reagent to give the compound of formula (I) above.

The present invention also provides a preparation method for another formula (I) compound, comprising the following steps:

(a) compound JJ is obtained by reacting 2-bromocyanobenzyl and bis(2-chloroethyl) tert-butyl carbamate under basic phase catalytic conditions to obtain compound SS; (b) compound SS is partially hydrolyzed with alkali to obtain compound TT; (c) compound TT is rearranged under oxidation reaction conditions to obtain compound UU; (d) compound UU is obtained under the above reaction conditions to obtain imidazole compound VV; (e) compound VV is ring-closed under the action of a palladium catalyst to generate compound WW (i) compound Deprotection under acidic conditions affords compound XX.

Similar to compound RR, compound XX is reacted with a corresponding reagent to give the compound of formula (I) above.

The present invention also provides a preparation method for another formula (I) compound, comprising the following steps:

(a) compound YY reacts with formaldehyde aqueous solution under alkaline conditions to obtain compound ZZ; (b) compound ZZ obtains compound AAA through trifluoromethanesulfonation and substitution ring closure of benzylamine; (c) compound AAA is reassembled after hydrolysis (d) compound BBB obtains imidazole compound CCC under the above-mentioned reaction conditions; (e) compound CCC ring-closes and generates compound DDD under the action of palladium catalyst; (f) compound DDD is debenzylated under palladium catalytic hydrogenation conditions The base generates compound EEE.

Similar to compound XX, compound EEE is reacted with a corresponding reagent to give the compound of formula (I) above.

pharmaceutical composition

The present invention also provides a pharmaceutical composition, which contains active ingredients in a safe and effective dose range, and a pharmaceutically acceptable carrier.

The "active ingredient" in the present invention refers to the compound of formula (I) or its pharmaceutically acceptable salt, its stereoisomer or its tautomer, or its prodrug in this invention.

The "active ingredients" and pharmaceutical compositions described in the present invention can be used as IDO or TDO inhibitors. In another preferred embodiment, it is used for preparing drugs for preventing and/or treating tumors. In another preferred embodiment, it is used for preparing medicines for preventing and/or treating diseases mediated by IDO or TDO.

"Safe and effective amount" means: the amount of the active ingredient is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg active ingredient/dose, more preferably 10-200 mg active ingredient/dose. Preferably, the "one dose" is a tablet.

"Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low toxicity. "Compatibility" here means that each component in the composition can be blended with the active ingredient of the present invention and with each other without significantly reducing the efficacy of the active ingredient.

The compounds of the preferred embodiments of the present invention may be administered as the sole active agent or in combination with one or more other agents useful in the treatment of cancer. Compounds of the preferred embodiments of this invention are also effective in combination with known therapeutic and anticancer agents, and combinations of currently known compounds with other anticancer or chemotherapeutic agents are within the scope of the preferred embodiments. Examples of such agents can be found in Cancer Principles and Practice of Oncology, V.T. Devita and S. Hellman (Eds.), 6th Edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. One of ordinary skill in the art will be able to discern effective combinations of agents based on the particular properties of the drugs and the cancer involved. Such anticancer agents include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, amyloid Alkenyl protein transferase inhibitors, deacetylase (HDAC) inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, cell proliferation and survival signaling inhibitors, apoptosis inducers and interference with cell cycle checkpoints ( cell cycle checkpoint), CTLA4 antibody, PD-1 antibody, PD-L1 antibody, etc. The compounds of the preferred embodiments are also effective when administered concurrently with radiation therapy.

For the purposes of preferred embodiments, the therapeutically effective dose can generally be a total daily dose administered to the patient once or in divided doses, for example, about 0.001 to about 1000 mg/kg body weight per day, preferably about 1.0 to about 30 mg/kg body weight. Dosage unit compositions may contain dosage factors thereof to yield a daily dose. The choice of dosage form depends on various factors, such as the mode of administration and the bioavailability of the drug substance. In general, the compounds of the preferred embodiments can be administered as pharmaceutical compositions by any of the following routes: oral, systemic (such as transdermal, intranasal, or via suppository), or parenteral (such as intramuscular, intravenous or subcutaneous). The preferred mode of administration is oral administration, and the convenient daily dose can be adjusted according to the degree of bitterness. The compositions may take the form of tablets, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition. Another preferred mode of administering the compounds of the preferred embodiments is by inhalation. This is an effective method of delivering therapeutic agents directly to the respiratory tract (see, eg, US Patent No. 5,607,915).

Suitable pharmaceutically acceptable carriers or excipients include, for example, treating agents and drug delivery modifiers and enhancers such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose , sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting point wax, ion exchange resin, etc., and any combination of two or more thereof. Liquid and semisolid excipients can be selected from glycerol, propylene glycol, water, ethanol and various oils, including petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Preferred liquid carriers, especially for injectable solutions, include water, saline, aqueous dextrose and glycol. Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991 ), incorporated herein by reference.

As used herein, the term "pharmaceutically acceptable salt" refers to non-toxic acid or alkaline earth metal salts of compounds of general formula I. These salts can be prepared in situ during the final isolation and purification of the compounds of general formula I, or by reacting suitable organic or inorganic acids or bases with basic or acidic functional groups, respectively. Representative salts include, but are not limited to: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate , camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, lauryl sulfate, ethanesulfonate, glucose heptanoate, glycerophosphate, hemisulfate, heptanoic acid Salt, Caproate, Fumarate, Hydrochloride, Hydrobromide, Hydroiodide, 2-Hydroxyethanesulfonate, Lactate, Maleate, Methanesulfonate, Nicotinate , 2-naphthylsulfonate, oxalate, pamoate, pectate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, Succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. In addition, nitrogen-containing basic groups can be quaternized with the following reagents: alkyl halides, such as chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl groups; dialkyl sulfates , such as dimethyl, diethyl, dibutyl, and dipentyl sulfate; long-chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; arane Halides such as benzyl and phenethyl bromide, etc. Water-soluble or oil-soluble or dispersible products are thus obtained. Examples of acids which can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, citric acid. Base addition salts can be prepared in situ during the final isolation and purification of the compounds of general formula I, or by separately reacting the carboxylic acid moiety with a suitable base such as a pharmaceutically acceptable metal cation hydroxide, carbonate or carbonic acid Hydrogen salt) or ammonia, or organic primary, secondary or tertiary amine reaction. Pharmaceutically acceptable salts include, but are not limited to, alkali metal and alkaline earth metal based cations, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations, including , but not limited to: ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Other representative organic amines for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

As used herein, the term "pharmaceutically acceptable prodrug" refers to those prodrugs of the compounds of the preferred embodiments, which are rapidly converted into the parent compound of the above general formula in vivo, eg, by hydrolysis in blood. In "T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (Pro-drugs as Novel Delivery Systems), Volume 14 of A.C.S. 15 Symposium Series" and "Edward B. Roche, eds., Bioreversible carriers in drug design (Bioreversible Carriers in Drug Design), American Pharmaceutical Association and Pergamon Press, 1987", both of which are incorporated herein by reference.

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods not indicating specific conditions in the following examples are usually according to conventional conditions such as Sambrook et al., molecular cloning: the conditions described in the laboratory manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer's instructions suggested conditions. Percentages and parts are by weight unless otherwise indicated.

The benefits of the present invention are:

(1) provide a compound of formula (I) with novel structure;

(2) The compounds of the present invention can be used as efficient IDO/TDO enzyme inhibitors;

(3) The synthesis method is mild, the operation is simple and easy, the yield is high, and it is easy to derivatize, and is suitable for large-scale industrial production;

(4) It has various pharmacological activities such as anti-tumor, neurodegenerative diseases (Alzheimer's disease), and anti-inflammation.

Unless otherwise defined, all professional and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

Example 1

Preparation of (cis/trans) 3-phenylspiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-ol

The first step: (cis/trans) 1-(2-bromophenyl)-3-hydroxycyclobutanenitrile

Add the compound 2-bromobenzylcyanide (10.2g, 52.0mmol) into the reaction flask, cool to minus 78 degrees, add methyllithium (44mL, 52.0mmol) dropwise, after the dropwise addition, stir at this temperature for 1 hour, add Epichlorohydrin (5.3g, 57.2mmol), stirred at this temperature for 3 hours, TLC detected that the raw material disappeared, then added dropwise methylmagnesium bromide Grignard reagent (19ml, 57.2mmol), after the dropwise addition, naturally returned to room temperature , and then slowly warming up to 60 degrees, stirring overnight. TLC monitors that the reaction is complete. Under cooling in an ice bath, 2N hydrochloric acid solution was added dropwise, and the pH of the reaction system was adjusted to about 7. Ethyl acetate (150 mL) and water (150 mL) were added for extraction, the aqueous phase was extracted again with ethyl acetate (100 mL x 2), and the organic phases were combined and dried over solid sodium sulfate. Concentrated by filtration, purified and separated by column chromatography to obtain 11.5 g of the target compound as a yellow liquid (cis/trans = 2:1.4), with a yield of 88%.

MS ESI: m/z=253.1, [M+H] ⁺ .

The second step: (cis/trans) 1-(2-bromophenyl)-3-hydroxycyclobutanecarboxylic acid

Dissolve the product of the first step (24.0g, 197.0mmol) in 230mL of ethanol, add 230mL of water and potassium hydroxide (53.3g, 952.0mmol) respectively, heat to 105°C, react for 24 hours, and the raw materials completely disappear. Cool to an ice bath, adjust the pH to 4-5 with 6N hydrochloric acid, add 200 mL of ethyl acetate, extract, and then extract twice with 100 mL of ethyl acetate, combine the organic phases, dry, filter, and concentrate to obtain 20.8 g of the target compound as a white solid (cis/trans=2:1.4), the yield was 81%.

MS ESI: m/z=272.1, [M+H] ⁺ .

The third step: (cis) 5-(2-bromophenyl)-2-oxo-4-azabicyclo[3.1.1]heptan-3-one

The product of the second step (10.6g, 39.1mmol) was dissolved in 100mL of dioxane, diphenylphosphoryl azide (13.0g, 46.9mmol) was added to the reaction solution, and diisopropylethylamine (10.1g , 78.2mmol), and tert-butanol (50mL), argon was replaced several times, stirred for ten minutes, heated to 80 degrees, and reacted for 4 hours. After cooling to room temperature, a white solid was precipitated in the reaction system, and 7.7 g of the target compound was obtained by filtration, with a yield of 73%.

¹ H NMR (500MHz,DMSO-d ₆ ):δ8.22(s,1H),7.60(d,1H),7.40(t 1H),7.26-7.32(m,2H),4.88(s,1H), 2.51(d,2H),2.28(d,2H).

MS ESI: m/z=267.1, [M+H] ⁺ .

The fourth step: (cis) 3-amino-3-(2-bromophenyl) cyclobutanol

Add the product of the third step (7.7g, 28.7mol) into 100mL of water and 100mL of isopropanol, add potassium hydroxide (80.0g, 1.4mol), and reflux for 24 hours. Cool to room temperature, extract 3 times with 150 mL of dichloromethane, combine the organic layers, dry, spin to dry the solvent, and dry to obtain the target compound (7.5 g, yield 100%) as a yellow oil.

¹ H NMR (500MHz,DMSO-d ₆ ):δ8.22(s,1H),7.60(d,1H),7.40(t 1H),7.26-7.32(m,2H),4.88(s,1H), 2.51(d,2H),2.28(d,2H).

MS ESI: m/z=243.1, [M+H] ⁺ .

The fifth step: (cis) 3-(2-bromophenyl)-3-(1H-imidazol-1-yl)cyclobutanol

The product of the fourth step (5.0g, 20.7mmol) was dissolved in 50mL of methanol, and glyoxal (6.0g, 41.3mmol), formaldehyde (3.4g, 41.3mmol) and ammonium acetate (3.2g, 41.3mmol) were added respectively. After the addition, the reaction temperature was slowly raised to 70° C., and the reaction was carried out for 4 hours. After the reaction, it was directly concentrated, the sample was mixed, and separated by column chromatography to obtain the target compound as a yellow solid (5.5 g, yield 91%).

¹ H NMR (500MHz, methanol-d ₄ ): δ7.88-7.86(m,1H),7.68-7.67(m,1H),7.59(s,1H),7.59-7.53(m,1H),7.34- 7.30(m,1H),7.04(s,1H),6.94(s,1H),4.05-4.03(m,2H),3.50-3.46(m,2H),2.84-2.80(m,2H).

MS ESI: m/z=294.1, [M+H] ⁺ .

Step 6: (cis) spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-ol

The product of the fifth step (2.5g, 8.5mmol) was put into the reaction flask, dimethyl sulfoxide (50mL) was added, the argon was replaced several times, and ferrocene palladium chloride (624mg, 0.853mmol) was added, Cesium carbonate (5.6g, 17.1mmol) was added, and the argon gas was replaced several times, then heated to 120°C and reacted for 5 hours. The reaction was monitored by LCMS. After the raw materials disappeared, cool to room temperature, distill off dimethyl sulfoxide under reduced pressure, then add ethyl acetate (100mL) and water (50mL) for extraction, and then extract the aqueous phase with ethyl acetate (50mL). Combine the organic phases. Purified and separated by column chromatography to obtain the target compound (1.3 g, yield 70%).

¹ H NMR (500MHz, methanol-d ₄ ): δ8.11(s, 1H), 7.56-7.52(m, 2H), 7.35-7.33(m, 2H), 7.08(s, 1H), 4.80-4.77( m,1H),3.08-3.03(m,2H),2.4-2.69(m,2H),

MS ESI: m/z=213.1, [M+H] ⁺ .

Step 7: Spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-one

Put the product of the sixth step (0.5g, 2.4mmol) into a bottle, add 5mL of dichloromethane, stir under ice bath, add sodium bicarbonate (1.9g, 23.4mmol), add Dess-Martin oxidant (1.5g ,3.5mmol), stirred at room temperature until the raw material disappeared. Add 20 mL of dichloromethane and 10 mL of water for extraction to obtain an organic phase, which is dried, filtered, concentrated, and purified by column chromatography. The target compound (400 mg, yield 80%) was obtained.

¹ H NMR (500MHz, methanol-d ₄ ): δ7.86(s,1H),7.59(d,1H),7.47-7.42(m,2H),7.37-7.35(m,1H),7.25(s, 1H),3.872.82(m,4H),

MS ESI: m/z=211.1, [M+H] ⁺ .

Step 8: (cis/trans) 3-phenylspiro[cyclobutane 1,5’-imidazo[5,1-α]isoindole]-3-ol

Add 1 mL of anhydrous tetrahydrofuran to the reaction flask, add anhydrous cerium chloride (450 mg, 1.5 mmol), add phenylmagnesium bromide (1.5 mL 1.5 mmol), stir at room temperature for 1 hour, under ice-cooling, the seventh step The tetrahydrofuran solution of the product (100 mg, 0.5 mmol) was added dropwise to the above reaction solution. After the drop was completed, the reaction was carried out at room temperature for 2 hours. TLC showed that the starting material disappeared. The reaction was quenched by dropwise addition of saturated ammonium chloride. Add 20 mL of ethyl acetate and 10 mL of water, extract, dry the organic phase, filter, and concentrate to obtain a crude product, which is purified and separated by column chromatography to obtain the target compound (100 mg, yield 70%).

¹ H NMR (500MHz, methanol-d ₄ ): δ8.43(s,1H),7.62(d,2H),7.48-7.44(m,2H),7.37-7.33(m,2H),7.27(d, 1H), 7.14(s,1H), 3.49(d,2H), 2.92(d,2H).

MS ESI: m/z=289.3, [M+H] ⁺ .

Example 2

(cis/trans)(3-fluorophenyl)(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)methanol

Step 1: (cis)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl methanesulfonate

(cis)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-ol (212mg, 1.0mmol) was dissolved in 5mL of dichloromethane, triethylamine ( 202mg, 2.0mmol), methanesulfonyl chloride (216mg, 1.5mmol) was added dropwise, after the dropwise completion, it was naturally returned to room temperature, and reacted for 1 hour in total. Add saturated brine 10mL, respectively add dichloromethane 2x 20mL for extraction, combine the organic phases to obtain the target compound (300mg, yield 100%).

MS ESI: m/z=291.0, [M+H] ⁺ .

The second step: spiro[cyclobutane 1,5'-imidazo[5,1-α]is indole]-3-carbonitrile

The product of the first step (300mg, 1.0mmol) was dissolved in 10mL of DMF, sodium cyanide (150mg, 3.0mmol) was added, heated to 100°C, and reacted for 10 hours. Raw material disappears. After cooling to room temperature, 30 mL of ethyl acetate was added, washed 5 times with 10 mL of water, the organic phase was dried over magnesium sulfate, filtered, concentrated, and subjected to column chromatography to obtain the crude product of the target compound (220 mg, yield 100%).

MS ESI: m/z=222.1, [M+H] ⁺ .

Step 3: Spiro[cyclobutane 1,5'-imidazo[5,1-α]is indole]-3-carboxylic acid

The second step product (220mg, 1.0mmol) was added to ethanol (10mL), then water (10mL), potassium hydroxide (1.1g, 20.0mmol) was added, heated to 100°C, and reacted for 10 hours. TLC showed the starting material had disappeared. Cool to room temperature, add 2N hydrochloric acid to adjust the pH to 6-7, spin the solution, dissolve the product with 10% dichloromethane methanol solution, filter out the solid inside, and collect the filtrate. Combined, dried, filtered and concentrated. The crude product of the target compound (200 mg, yield 83%) was obtained.

MS ESI: m/z=241.1, [M+H] ⁺ .

The fourth step: N-methoxy-nitrogen-methyl-spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide

The third step product (48mg, 0.2mmol) was added in dichloromethane, triethylamine (44mg, 0.4mmol) was added, N, O-dimethyl hydrochloride (20mg, 0.2mmol) was added, EDCI (76mg , 0.4mmol), HOBT (27mg, 0.2mmol) were reacted overnight at room temperature, and the raw materials disappeared. The reaction solution was spin-dried, and directly purified by column chromatography to obtain the target compound (56 mg, yield 100%).

MS ESI: m/z=284.2, [M+H] ⁺ .

The fifth step: (trans)3-fluorophenyl)(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)methanone

Put the product of the fourth step (60mg, 0.2mmol) into a reaction flask, add tetrahydrofuran (2mL), cool in an ice bath, add 3-fluorophenylmagnesium bromide (0.9mL, 0.90mmol) dropwise, dropwise, Until the starting material disappeared, the reaction was quenched by adding saturated ammonium chloride (2 mL), extracted by adding ethyl acetate (2 x 10 mL), and the organic phase was combined, dried over sodium sulfate, filtered, and concentrated to give the crude product. Purified by column chromatography to obtain 50 mg of the trans product, which (50 mg, 0.16 mmol) was dissolved in tetrahydrofuran (2 mL), and DBU (62 mg, 0.3 mmol) was added under ice cooling, and stirred for 1 hour. TLC showed 2 very close spots, LCMS showed the same molecular weight, the reaction was quenched with saturated ammonium chloride (1 mL), extracted with ethyl acetate (2 x 5 mL), and the organic phase was dried over sodium sulfate and filtered to obtain, 50 mg of the cis-trans target compound was obtained with a yield of 100%.

Step 6: (cis/trans)(3-fluorophenyl)(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)methanone

The product of the fifth step (50 mg, 0.2 mmol) was dissolved in tetrahydrofuran (2 mL), and DBU (62 mg, 0.3 mmol) was added under ice-cooling, and stirred for 1 hour. TLC showed 2 very close spots, LCMS showed the same molecular weight, the reaction was quenched with saturated ammonium chloride (1 mL), extracted with ethyl acetate (2 x 5 mL), and the organic phase was dried over sodium sulfate and filtered to obtain, 50 mg of crude product was obtained with a yield of 100%.

The seventh step: (cis/trans)-(3-fluorophenyl)(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)methanol

The product of the sixth step (50 mg, 0.2 mmol) was added to the reaction flask, tetrahydrofuran (2 mL) was added, and sodium borohydride (12 mg, 0.3 mmol) was added under ice cooling until the reaction was complete. The sample was directly mixed, spin-dried, and subjected to column chromatography to obtain compound 2, 21 mg of white solid, with a yield of 63%.

1H NMR (400MHz, CDCl ₃ ): δ7.89(s, 1H), 7.58-7.48(m, 2H), 7.35-7.31(m, 3H), 7.24-7.14(m, 3H), 7.03-6.96(m ,1H),5.30(s,1H),4.95-4.90(m,1H),3.29-2.12(m,2H),2.99-2.95(m,2H).

MS ESI: m/z = 321.1, [M+H] ⁺ .

Example 3

(cis/trans) 3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoind Indole]-3-ol

According to the conditions in the eighth step of Example 1, the target compound was obtained as a white solid (10 mg, Yield 29%).

¹ H NMR (400MHz, CDCl ₃ ): δ8.35(s, 1H), 7.42-7.41(m, 1H), 7.37-7.35(m, 1H), 7.34-7.31(m, 1H), 7.27-7.25( m,1H),7.18(s,1H),5.75(s,1H),3.86(s,4H),3.15(d,2H),2.64(d,2H),2.40-2.36(m,4H),1.83 -1.80(m,2H).

MS ESI: m/z=351.2, [M+H] ⁺ .

Example 4

(cis)4-Methyl-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzenesulfonamide

The first step: (trans)-spiro[cyclobutanyl-1,5'-imidazo[5,1-α]isoindole]-3-ylbenzoate

Triphenylphosphine (393mg, 1.5mmol), benzoic acid (92mg, 0.8mmol) and (cis)spiro[cyclobutanyl-1,5'-imidazo[5,1-α]isoind Indole]-3-ol (159mg, 0.8mmol) was added into a 50mL two-necked flask, Ar ₂ was replaced three times, and 4mL of tetrahydrofuran was injected. Then a solution of DIAD (273 mg, 1.4 mmol) in THF (2 mL) was added dropwise to the above system under ice-cooling, raised to room temperature for 4 h, and then stopped the reaction. The reaction solution was concentrated and purified by column (mobile phase DCM:MeOH=20:1) to obtain 187 mg of the target compound as a light red solid with a yield of 79%.

¹ H NMR (400MHz, CDCl ₃ ): δ8.01(s,1H),7.70-7.65(m,4H),7.57-7.53(m,3H),7.39(t,1H),7.34(t,1H) ,7.27(s,1H),5.79(quint,1H),3.16(m,4H).

MS ESI: m/z=317.1, [M+H] ⁺ .

The second step: trans-spiro[cyclobutanyl-1,5'-imidazo[5,1-α]isoindole]-3-ol

LiOH-H ₂ O (243 mg, 5.8 mmol)/H ₂ O (2 mL) aqueous solution was added dropwise to the first step product (610 mg, 1.9 mmol)/MeOH (15.0 mL) solution at room temperature. After reacting at room temperature for 10 minutes, the reaction solution was concentrated and the above solution was extracted with 3 x 5 mL EA, and the organic phases were combined and dried over anhydrous Na ₂ SO ₄ . The reaction solution was concentrated and purified by column (mobile phase DCM:MeOH=20:1) to obtain 316 mg of the target compound as a light brown solid, with a yield of 77%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.76(s,1H),7.66(dd,1H),7.49(dd,1H),7.37-7.31(m,2H),7.16(s,1H),4.99 (q,1H),2.90(m,4H).

MS ESI: m/z=213.1, [M+H] ⁺ .

The third step: (trans)-spiro[cyclobutanyl-1,5'-imidazo[5,1-α]isoindole]-3-yl methanesulfonate

MsCl (339mg, 3.0mmol) and Et ₃ N (599mg, 5.9mmol) were successively added dropwise to the second step product (315mg, 1.5mmol)/DCM (10mL) solution under ice-cooling. After reacting at 0°C for 10 minutes, 2 mL of saturated saline was added to the reaction solution and the above solution was extracted with 3x 5 mL of DCM. The organic phases were combined and dried with anhydrous Na ₂ SO ₄ to obtain 412 mg of the target compound as a light brown solid with a yield of 96%. .

¹ H NMR (400MHz, CDCl ₃ ): δ7.79(s,1H),7.62(dd,1H),7.50(dd,1H),7.40-7.35(m,2H),7.18(s,1H),5.57 (quint,1H),3.25-3.20(m,2H),3.14(s,3H),3.13-3.09(m,2H).

MS ESI: m/z=291.0, [M+H] ⁺ .

The fourth step: (cis) 3-azido-spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]

The product of the third step (300 mg, 1.0 mmol) was dissolved in 10 mL of DMF, sodium azide (200 mg, 3.0 mmol) was added, heated to 100 degrees, and reacted for 3 hours. After cooling to room temperature, 30 mL of ethyl acetate was added, washed 5 times with 10 mL of water, the organic phase was dried over magnesium sulfate, filtered, concentrated, and subjected to column chromatography to obtain the target compound (220 mg, yield 92%).

MS ESI: m/z=238.1, [M+H] ⁺ .

Step 5: (cis)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-amine

The product of the fourth step (220 mg, 0.9 mmol) was dissolved in ethanol, Pd/C (20 mg, 10%) was added, and hydrogen gas was introduced to react overnight. Pd/C was filtered off, and the filtrate was concentrated to obtain the crude product of the target compound (190 mg, yield 96%).

The target compound can also be obtained through the following conditions: in an argon atmosphere, 5% Pd/C (20 mg) is added to the fourth step product cis-3-azidospiro[cyclobutanyl-1,5'- Imidazo[5,1-α]isoindole] (209 mg, 0.9 mmol) in EtOH (4 mL). After reacting at room temperature in ₁ atm H for 24 h, diatomaceous earth was added to filter, the filter cake was washed with 5 mL of EtOH, the organic phases were combined, and spin-dried to obtain 170 mg of the target compound as a pale yellow solid, with a yield of 87%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.92(s,1H),7.49(t,2H),7.35(t,1H),7.28(t,1H),7.15(s,1H),3.95(q ,1H),3.12-3.04(m,2H),2.52-2.47(m,2H).

MS ESI: m/z=212.1, [M+H] ⁺ .

Step 6: (cis) 4-methyl-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)benzenesulfonamide

The product of the fifth step (21 mg, 0.1 mmol) was placed in a flask, and dichloromethane (5 mL), triethylamine (22 mg, 0.2 mmol), and p-toluenesulfonyl chloride (19 mg, 0.1 mmol) were sequentially added. After reacting for 2 hours, the reaction solution was spin-dried, and directly purified by column chromatography to obtain the target compound (20 mg, yield 54%).

¹ H NMR (500MHz, CDCl ₃ ): δ7.85(d,3H),7.55(d,1H),7.45(d,1H),7.35-7.32(m,3H),7.27-7.24(m,1H) 7.16(s,1H),6.52(s,1H),4.35(s,1H),2.89-2.83(m,2H),2.76-2.73(m,2H),2.47(s,3H).

MS ESI: m/z=366.1, [M+H] ⁺ .

Example 5

(Trans) 4-Methyl-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzenesulfonamide

Step 1: (trans)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-amine

Using the (cis)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl methanesulfonate, the second step product of Example 2, as a raw material, according to Example 4 The reaction conditions described in the fourth and fifth steps yielded the target compound.

¹ H NMR (500MHz, CDCl ₃ ): δ7.81(s,1H),7.59(d,1H),7.48(d,1H),7.31-7.36(dd,2H),7.16(s,1H),4.14 -4.18(m,1H),2.84-2.89(m,2H),2.59-2.65(m,2H).

MS ESI: m/z=212.0, [M+H] ⁺ .

The second step (trans) 4-methyl-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)benzenesulfonamide

Using the product of the first step as a raw material, the target compound was obtained according to the reaction conditions described in the sixth step of Example 4.

¹ H NMR (500MHz, CDCl ₃ ): δ7.90(s,1H),7.83(d,2H),7.48(d,1H),7.44(d,1H),7.38-7.30(m,4H),7.14 (s,1H),5.61(s,1H),4.24-4.23(m,1H),2.98-2.94(m,2H),2.67-2.70(m,2H),2.42(s,3H).

MS ESI: m/z=366.1, [M+H] ⁺ .

Example 6

(cis)4-Methyl-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide

¹ H NMR (500MHz, CDCl ₃ ): δ8.00(s,1H),7.76(d,2H),7.71(d,1H),7.63(d,1H),7.53-7.51(m,2H),7.39 -7.35(m,3H),7.16(s,1H),7.09(d,1H),4.99-4.93(m,1H),3.23-3.18(m,2H),3.04-2.99(m,2H).

MS ESI: m/z=330.2, [M+H] ⁺ .

Example 7

(Trans) 4-Methyl-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide

¹ H NMR (500MHz, CDCl ₃ ): δ7.98(s,1H),7.76(d,2H),7.65(d,1H),7.51(d,1H),7.39-7.36(m,1H),7.33 -7.28(m,2H),6.75(s,1H),5.09-5.07(m,1H),3.20-3.14(m,2H),3.03-2.98(m,2H).

MS ESI: m/z=330.2, [M+H] ⁺ .

Example 8

(cis/trans) 3-fluoro-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)benzamide

MS ESI: m/z=334.1, [M+H] ⁺ .

Example 9

(cis)4-fluoro-nitrogen-spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)benzenesulfonamide

MS ESI: m/z=370.1, [M+H] ⁺ .

Example 10

(Trans) 4-fluoro-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzenesulfonamide

MS ESI: m/z=370.1, [M+H] ⁺ .

Example 11

(trans)nitro-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)cyclohexanecarboxamide

¹ H NMR (500MHz, CDCl ₃ ): δ7.94(s,1H),7.60(d,1H),7.49(d,1H),7.36-7.28(m,2H),7.18(s,1H),4.91 -4.85(m,1H),3.05-3.00(m,2H),2.93-2.88(m,2H),2.18-1.13(m,1H),1.93-1.90(m,2H),1.84-1.81(m, 2H),1.51-1.48(m,2H),1.48-1.43(m,2H),1.31-1.28(m,2H).

MS ESI: m/z=322.2, [M+H] ⁺ .

Example 12

(cis)N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)cyclohexylsulfonamide

¹ H NMR (500MHz, CDCl ₃ ): δ8.03(s,1H),7.67(d,1H),7.50(d,1H),7.44-7.37(m,3H),7.13(s,1H),5.05 -5.01(m,1H),3.67-6.61(m,1H),3.53-3.47(m,2H),3.20-3.17(m,2H),2.24-2.27(m,2H),1.75-1.78(m, 2H),1.58-1.55(m,2H),1.52-1.49(m,2H),1.25-1.30(m,2H).

MS ESI: m/z=358.2, [M+H] ⁺ .

Example 13

(cis)3-Chloro-4-fluoro-N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)benzamide

¹ H NMR (500MHz, CDCl ₃ ): δ8.18(s,1H),8.16(d,1H),7.84(d,2H),7.64(d,1H),7.49(d,1H),7.38-7.35 (m,1H),7.30-7.27(m,1H),7.22-7.15(m,2H),5.29(s,1H),3.29-3.23(m,2h),2.98-2.95(m,2H).

MS ESI: m/z=368.8, [M+H] ⁺ .

Example 14

(Trans) 3-Bromo-4-fluoro-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)benzamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.36(d,1H),8.15-8.12(m,2H),7.86-7.83(m,1H),7.67(d,1H),7.52(d,1H) ,7.41-7.31(m,3H),7.23-7.14(m,2H),5.08-5.02(m,1H),3.28-3.23(m,2H),2.99-2.96(m,2H).

MS ESI: m/z=413.7, [M+H] ⁺ .

Example 15

(Trans)N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)cyclopropanesulfonamide

¹ H NMR (500MHz, CDCl ₃ ): δ7.75(s,1H),7.48(d,1H),7.37-7.34(m,1H),7.32-7.28(m,2H),7.10-7.07(m, 1H),5.10-5.07(m,1H),3.77(s,1H),3.30-3.26(m,2H),2.88-2.85(m,2H),1.38-1.39(m,2H),1.02-1.00( m,2H).

MS ESI: m/z=316.2, [M+H] ⁺ .

Example 16

(trans)nitro-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)cyclopropanecarboxamide

¹ H NMR (500MHz, CDCl ₃ ): δ7.93(s,1H),7.61(d,1H),7.49(d,1H),7.38-7.35(m,2H),7.19(s,1H),6.52 (s,1H),4.95-4.89(m,1H),3.14-3.09(m,2H),2.94-2.89(m,2H),1.04-1.02(m,2H),0.83-0.78(m,2H) .

MS ESI: m/z=280.1, [M+H] ⁺ .

Example 17

(Trans)N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)propane-2-sulfonamide

¹ H NMR (500MHz, CDCl ₃ ): δ8.03(s, 1H), 7.64-7.62(m, 1H), 7.51-7.49(m, 1H)), 7.39-7.34(m, 3H), 7.11(s ,1H),5.87(s,1H),4.59-4.54(m,1H),3.27-3.22(m,1H),3.09-2.98(m,4H),1.45-1.43(d,6H).

MS ESI: m/z=318.2, [M+H] ⁺ .

Example 18

(Trans)N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)naphthalene-2-sulfonamide

¹ H NMR (500MHz, CDCl ₃ ): δ8.52(s, 1H), 7.94-7.92(m, 3H), 7.86-7.84(m, 2H), 7.62-7.52(m, 3H), 7.41-7.39( m,1H),7.29-7.26(m,1H),7.23-7.20(m,1H),7.16(s,1H),4.46-4.42(m,1H),2.91-2.86(m,2H),2.74- 2.69(m,2H).

MS ESI: m/z=402.2, [M+H] ⁺ .

Example 19

(trans)N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)naphthalene-1-sulfonamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.80(d,1H),8.36(d,1H),8.07(d,1H),7.95(d,1H),7.72-7.68(m,2H),7.61 -7.55(m,2h),7.40(d,1H),7.35(d,1H),7.27(d,1H),7.16-7.12(m,1H),7.10(s,1H),6.74(s,1H ), 4.33 (d, 1H), 2.77-2.72 (m, 2H), 2.65-2.59 (m, 2H). MS ESI: m/z=480.1, [M+H] ⁺ .

Example 20

(trans)4-fluoro-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide

¹ H NMR (500MHz, CDCl ₃ ): δ8.32(s, 1H), 8.12-8.09(m, 2H), 7.92-7.90(m, 1H), 7.91-7.89(m, 1H), 7.69-7.67( m,1H),4.48(d,1H),7.38-7.34(m,1H),7.36-7.32(m,1H),7.27-7.22(m,1H),7.10(s,1H),5.10-5.03( m,1H),3.34-3.24(m,2H),2.95-2.87(m,2H).

MS ESI: m/z=334.1, [M+H] ⁺ .

Example 21

(trans)2-fluoro-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide

¹ H NMR (500MHz, CDCl ₃ ): δ8.22(s, 1H), 8.14-8.10(m, 1H), 7.73-7.71(m, 1H), 7.55-7.45(m, 2H), 7.39-7.28( m,4H),7.20-7.14(m,2H),5.10-5.04(m,1H),3.24-3.19(m,2H),3.07-3.01(m,2H).

MS ESI: m/z=334.1, [M+H] ⁺ .

Example 22

(trans)2,4-dichloro-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)benzamide

¹ H NMR (500MHz, CDCl ₃ ): δ8.16(s, 1H), 7.70-7.64(m, 2H), 7.55-7.51(m, 1H), 7.44-7.36(m, 3H), 7.34-7.26( m,2H),7.20(s,1H),5.08-5.02(m,1H),3.27-3.21(m,2H),3.05-2.98(m,2H).

MS ESI: m/z=385.1, [M+H] ⁺ .

Example 23

(trans) 4-Methoxy-nitro-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide

¹ H NMR (500MHz, CDCl ₃ ): δ8.13(s,1H),8.08(d,1H),7.88(d,2H),7.72(d,1H),7.48(d,1H),7.37-7.33 (m,2H),7.30-7.27(m,1H),6.92(d,2H),5.10-5.04(m,1H),3.83(s,3H),3.26-3.22(m,2H),2.96-2.90 (m,2H).

MS ESI: m/z 346.1, [M+H] ⁺ .

Example 24

(trans)nitro(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)-2-naphthylcarboxamide

¹ H NMR (500MHz, CDCl ₃ ): δ8.41(s,1H),8.03(s,1H),7.95-7.91(m,1H),7.87-7.77(m,4H),7.67(d,1H) ,7.55-7.45(m,3H),7.35-7.31(m,1H),7.26-7.22(m,1H),7.19(s,1H),5.15-5.06(m,1H),3.34-3.23(m, 2H),2.95-2.90(m,2H).

MS ESI: m/z=366.1, [M+H] ⁺ .

Example 25

(trans) 3-Chloro-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide

¹ H NMR (500MHz, CDCl ₃ ): δ8.29(s, 1H), 8.09(s, 1H), 8.00(d, 1H), 7.88(s, 1H), 7.78-7.76(m, 1H), 7.72 -7.66(m,2H),7.50-7.45(m,2H),7.37-7.31(m,3H),7.24-7.22(m,1H),5.03-4.98(m,1H),3.33-3.27(m, 2H),2.97-2.91(m,2H)

MS ESI: m/z = 350.1, [M+H] ⁺ .

Example 26

(trans)4-cyano-nitro-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide

¹ H NMR (500MHz, CDCl ₃ ): δ9.21(s,1H),8.30(s,1H),8.10-8.03(m,4H),8.87(d,1H),7.57(d,1H),7.41 -7.40(m,2H),7.15(s,1H),5.19-5.14(m,1H),3.11-3.08(m,2H),2.90-2.85(m,2H).

MS ESI: m/z=341.1, [M+H] ⁺ .

Example 27

(Trans) 3-Bromo-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide

¹ H NMR (500MHz, CDCl ₃ ): δ8.26(s,1H),8.21(s,1H),8.04(d,1H),7.84-7.70(m,1H),7.67(d,1H),7.62 -7.60(m,1H),7.49(d,1H),7.38-7.35(m,1H),7.32-7.27(m,2H),7.21(s,1H),5.09-5.03(m,1H),3.32 -3.26(m,2H),2.97-2.91(m,2H).

MS ESI: m/z = 395.1 [M+H] ⁺ .

Example 28

(trans) 2-methoxy-nitro-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide

¹ H NMR (500MHz, CDCl ₃ ): δ8.35(s,1H),8.24(d,1H),8.03(s,1H),7.70(d,1H),7.52-7.48(m,2H),7.40 -7.32(m,2H),7.21(s,1H),7.15-7.13(m,1H),7.11-7.05(m,1H),5.04-4.99(m,1H),3.17-3.11(m,2H) ,3.07-3.01(m,2H).

MS ESI: m/z=346.1, [M+H] ⁺ .

Example 29

(trans)N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)-3-(trifluoromethyl)benzamide

¹ H NMR (500MHz, CDCl ₃ ): δ8.38(s,1H),8.29(d,1H),8.18(s,1H),8.11(d,1H),1.96(d,1H),7.77-7.73 (m,2H),7.57-7.49(m,2H),7.39-7.29(m,2H),5.14-5.08(m,1H),3.39-3.33(m,2H),2.99-2.93(m,2H) .

MS ESI: m/z = 384.1, [M+H] ^+. .

Example 30

(trans)tert-butyl benzylspiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-ylcarbamate

¹ H NMR (500MHz, CDCl ₃ ): δ7.90(s,1H),7.58(s,1H),7.49(d,1H),7.39-7.31(m,7H),7.17(s,1H),5.51 (s,1H),5.17-5.10(m,2H),4.69-4.67(m,1H),3.06-3.02(m,2H),2.93-2.88(m,2H).

MS ESI: m/z=346.1, [M+H] ⁺ .

Example 31

(trans)nitro-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)propionamide

¹ H NMR (500MHz, CDCl ₃ ): δ7.96(s,1H),7.60(d,1H),7.49(d,1H),7.36-7.29(m,2H),7.18(s,1H),6.77 (s,1H),4.95-4.89(m,1H),3.10-3.05(m,2H),2.93-2.89(m,2H),2.32-2.28(m,2H),1.26-1.20(m,3H) .

MS ESI: m/z = 268.1, [M+H] ⁺ .

Example 32

(Trans)N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)isobutyramide

¹ H NMR (400MHz, CDCl ₃ ): δ7.97(s,1H),7.61(d,1H),7.49(d,1H),7.38-7.29(m,2H),7.19(s,1H),6.51 (d,1H),4.93-4.88(m,1H),3.10-3.04(m,2H),2.93-2.88(m,2H),2.47-2.43(m,1H),1.23-1.21(m,6H) .

MS ESI: m/z=282.1, [M+H] ⁺ .

Example 33

(trans)(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-ylphenylcarbamate

¹ H NMR (400MHz, CDCl ₃ ): δ8.50(d,1H),8.28(s,1H),7.87(d,1H),7.56(s,1H),7.55-7.43(m,3H),7.38 -8.13(m,5H),4.82-4.78(m,1H),3.07-3.01(m,2H),2.86-2.81(m,2H);

MS ESI: m/z=332.1, [M+H] ⁺ .

Example 34

(trans)nitro(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindole]-3-yl)acrylamide

¹ H NMR (500MHz, CDCl ₃ ): δ8.05(s,1H),7.65(d,1H),7.49(d,1H),7.32-7.36(m,2H),6.34-6.39(d,1H) ,6.12-6.19(m,2H),5.71(d,1H),4.92(s,2H);

MS ESI: m/z = 266.1, [M+H] ⁺ .

Example 35

(trans)nitro-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindole]-3-yl)benzamide

¹ H NMR (500MHz, CDCl ₃ ): δ7.85(d,2H),7.66(d,1H),7.44-7.55(m,5H),7.30-7.40(m,3H),6.85(s,1H) ,5.00-5.85(m,1H),3.15-3.23(m,2H),2.93-3.02(m,2H);

MS ESI: m/z=316.0, [M+H] ⁺ .

Example 36

(trans)nitro-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindol]-3-yl)methylsulfonamide

¹ H NMR (500MHz, CDCl ₃ ): δ7.91(s,1H),7.53(d,1H),7.46(d,1H),7.35(t,1H),7.30(t,1H),7.18(s ,1H),6.21(s,1H),4.55(s,1H),3.06(s,3H),2.97-3.01(m,4H).

MS ESI: m/z = 290.1, [M+H] ⁺ .

Example 37

(cis/trans) 3-methoxy-nitro-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindole]-3-yl)benzamide

(cis:anti=2:1)

MS ESI: m/z=347.1, [M+H] ⁺ .

Example 38

(trans)3,4-dichloro-nitro-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindole]-3-yl)benzamide

¹ H NMR (500MHz, acetone-d ₆ ): δ8.39(s,1H), 8.09(s,1H), 7.81-7.91(m,2H), 7.59-7.70(m,2H), 7.36-7.40( m,2H),7,21(s,1H),5.17-5.21(m,1H),3.19-3.25(m,2H),2.95-3.01(m,2H);

MS ESI: m/z=386.1, [M+H] ⁺ .

Example 39

Preparation of (cis/trans) 2-methyl-nitrogen-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindol]-3-yl)benzamide

(cis:anti=2:1)

MS ESI: m/z=330.1, [M+H] ⁺ .

Example 40

Preparation of (trans) 3-methyl-nitrogen-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindol]-3-yl)benzamide

¹ H NMR (500MHz, acetone-d ₆ ): δ8.23(s,1H),7.85(d,1H),7.76-7.77(m,2H),7.57-7.59(d,1H),7.32-7.39( m,4H),7.15(s,1H),5.18-5.24(m,1H),3.24-3.29(t,2H),2.92-2.98(t,3H),2.38(s,3H).

MS ESI: m/z=330.1, [M+H] ⁺ .

Example 41

(trans)2,4,6-Trimethyl-nitro-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindole]-3-yl)benzamide

¹ H NMR (500MHz, acetone-d ₆ ): δ8.49(s,1H),7.89-7.90(d,1H),7.70-7.72(d,1H),7.30-7.58(m,6H),4.98- 5.00(m,1H),3.39-3.44(m,2H)3.08-3.12(m,2H);2.60-2.70(m,9H).

MS ESI: m/z = 358.2, [M+H] ⁺ .

Example 42

(trans)2-chloro-nitrogen-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindol]-3-yl)benzamide

¹ H NMR (500MHz, acetone-d ₆ ): δ8.34(s, 1H), 7.79-7.81(m, 1H), 7.53-7.57(m, 2H), 7.32-7.48(m, 5H), 7.16( s,1H),5.17-5.21(m,1H),3.16-3.22(m,2H)2.98-3.04(m,2H);

MS ESI: m/z = 351.1, [M+H] ⁺ .

Example 43

(trans)3-fluoro-nitrogen-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindol]-3-yl)benzamide

¹ H NMR (500MHz, acetone-d ₆ ): δ8.42(s,1H), 8.40(s,1H), 7.79-7.88(m,2H), 7.68-7.71(d,1H), 7.51-7.58( m,2H),7.25-7.40(m,2H),7.14(s,1H),5.18-5.24(m,1H),3.23-3.29(t,2H); 2.86-2.91(m,2H);

MS ESI: m/z=334.1, [M+H] ⁺ .

Example 44

(trans)3-Trifluoromethoxy-nitrogen-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindole]-3-yl)benzamide

¹ H NMR (500MHz, acetone-d ₆ ): δ8.52(s,1H),8.24(s,1H),8.09(d,2H),7.86(d,1H),7.57(d,1H),7.25 -7.45(m,3H),7.15(s,1H),5.20-5.26(m,1H),3.25-3.30(m,2H); 2.86-2.91(m,2H);

MS ESI: m/z = 400.1, [M+H] ⁺ .

Example 45

(Trans) 4-bromo-nitrogen-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindol]-3-yl)benzamide

¹ H NMR (500MHz, acetone-d ₆ ): δ8.32(s,1H),7.81-7.87(m,3H),7.66(d,2H),7.58(d,1H),7.34-7.41(m, 2H),7.17(s,1H),5.17-5.22(m,1H),3.19-3.24(m,2H),2.94-3.00(m,2H);

MS ESI: m/z=396.0, [M+H] ⁺ .

Example 46

(trans)4-fluoro-nitrogen-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindol]-3-yl)benzamide

¹ H NMR (500MHz, acetone-d ₆ ): δ8.12(s,1H),8.00-8.04(m,2H),7.72(d,1H),7.51(d,2H),7.28-7.37(m, 4H),7.08(s,1H),4.57-4.64(m,1H),2.90-2.91(m,2H),2.74-2.79(m,2H);

MS ESI: m/z = 370.1, [M+H] ⁺ .

Example 47

(trans)4-Oxo-4-phenyl-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)butanamide

(trans)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-amine (21 mg, 0.1 mmol) and 4-oxo-4-phenylbutanoic acid ( 18mg, 0.1mmol) into the reaction flask, add dichloromethane (2mL) and stir in a water bath. Add triethylamine (51 mg, 0.5 mmol), HOBT (14 mg, 0.1 mmol), and EDCI (38 mg, 0.2 mmol), and return to room temperature naturally while stirring. The reaction was monitored by TLC. After completion, saturated aqueous sodium bicarbonate solution (5 mL) was added to extract with 10 mL of dichloromethane, which was repeated twice. The organic phases were combined and dried over anhydrous sodium sulfate solids. Filtration and concentration gave crude product. Separation and purification by column chromatography (petroleum ether/ethyl acetate) gave the target compound (20 mg, 54% yield) as a solid.

¹ H NMR (500MHz, CDCl ₃ ): δ8.01(d,2H),7.93(s,1H),7.61-7.57(m,2H),7.49-7.46(m,2H),7.37-7.27(m, 3H).7.17(s,1H),6.93(d,1H),4.92-4.86(m,1H),3.45-3.42(m,2H),3.04-2.98(m,2H),2.94-2.88(m, 2H),2.73-2.70(m,2H).

MS ESI: m/z = 372.2, [M+H] ⁺ .

Example 48

(trans)2-([1,1'-biphenyl]-4-yl)-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3 -yl)acetamide

¹ H NMR (500MHz, CDCl ₃ ): δ7.86(s, 1H), 7.66-7.61(m, 4H), 7.52-7.45(m, 3H), 7.41-7.38(m, 2H), 7.36-7.32( m,1H),7.28-7.24(m,3H),7.16(s,1H),4.83-4.77(m,1H),3.70(s,2H),3.00-2.98(m,2H),2.91-2.89( m,2H).

MS ESI: m/z=406.2, [M+H] ⁺ .

Example 49

(Trans)N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)cyclopentanecarboxamide

¹ H NMR (500MHz, CDCl ₃ ): δ7.98(s,1H),7.61(d,1H),7.49(d,1H),7.38-7.34(m,2H),7.19(s,1H),4.93 -4.86(m,1H),3.09-3.03(m,2H),2.93-2.88(m,2H),2.61-2.58(m,1H),1.92-1.76(m,6H),1.62-1.59(m, 2H).

MS ESI: m/z=308.1, [M+H] ⁺ .

Example 50

(trans) 3-cyclopentyl-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)propionamide

¹ H NMR (500MHz, CDCl ₃ ): δ7.96(s,1H),7.62(d,1H),7.50(d,1H),7.37-7.34(m,2H),7.18(s,1H),6.02 (d,1H),4.89-4.83(m,1H),3.08-3.03(m,2H),2.95-2.89(m,2H),2.29-2.25(m,2H),1.80-1.53(m,9H) ,1.15-1.13(m,3H).

MS ESI: m/z=336.2, [M+H] ⁺ .

Example 51

(trans) 2-Cyclopropyl-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)acetamide

¹ H NMR (500MHz, CDCl ₃ ): δ8.03(s,1H),7.65(d,1H),7.50(d,1H),7.37-7.32(m,2H),7.19(s,1H),6.64 (d,1H),4.93-4.87(m,1H),3.14-3.08(m,2H),2.94-2.90(m,2H),2.24-2.23(m,2H),1.07-1.03(m,1H) ,0.68-0.66(m,2H),0.27-0.26(m,2H).

MS ESI: m/z=294.1, [M+H] ⁺ .

Example 52

(Trans) tert-butyl-2-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-ylcarbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester

¹ H NMR (500MHz, CDCl ₃ ): δ7.96(s,1H),7.94(s,1H),7.62(d,1H),7.49(d,1H),7.39-7.34(m,2H),7.18 (s,1H),4.90-4.87(m,1H),4.35-4.34(m,1H),3.65-3.28(m,2H),3.05-2.93(m,2H),2.21(s,4H), 1.93(s,2H),1.51(s,9H).

MS ESI: m/z=409.2, [M+H] ⁺ .

Example 53

(Trans) 4-Hydroxy-nitrogen-(spiro[cyclobutane-1,5’-imidazol[5,1-a]isoindol]-3-yl)benzamide

¹ H NMR (500MHz, acetone-d ₆ ): δ8.49(s,1H),7.86-7.92(m,3H),7.72(d,1H),7.50(d,1H),7.42(d,1H) ,7.25-7.26(m,2H),6.92-6.93(m,1H),5.63(s,1H),5.20-5.25(m,1H),3.26-3.31(m,2H),2.98-3.03(m, 2H);

MS ESI: m/z=332.1, [M+H] ⁺ .

Example 54

(cis/trans)nitro-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindol]-3-yl)-[1,1'-diphenyl]-4- Formamide

(cis/trans=9:1)

MS ESI: m/z=392.2, [M+H] ⁺ .

Example 55

(cis)2-Methyl-2-phenyl-nitrogen-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindole]-3-yl)propionamide

¹ H NMR (400MHz, CDCl ₃ ): δ7.73(s,1H),7.48(d,1H),7.39-7.42(m,2H),7.34-7.36(m,3H),7.20-7.31(m, 3H), 7.01(s,1H), 5.80(d,1H), 4.53-4.59(m,1H), 2.93-2.99(m,2H), 2.61-2.66(m,2H); 1.55(s,6H) ;

MS ESI: m/z = 358.1 [M+H] ⁺ .

Example 56

(cis)2-Phenyl-nitrogen-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindol]-3-yl)propionamide

¹ H NMR (400MHz, CDCL3-d ₆ ): δ7.96(s,1H),7.46-7.52(m,2H),7.36-7.40(m,3H),7.23-7.36(m,4H),7.01( s,1H),6.67(d,1H),4.64-6.70(m,1H),3.61(q,1H),2.93-3.06(m,2H),2.67-2.80(m,2H);1.54-1.57( m,3H);

MS ESI: m/z=344.1, [M+H] ⁺ .

Example 57

(trans)2-Bromo-5-methoxy-nitro-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindole]-3-yl)benzamide

¹ H NMR (500MHz, acetone-d ₆ ): δ8.22(s,1H),8.13(s,1H),7.83(d,1H),7.51-7,57(m,2H),7.30-7.39( m,2H),7.13(s,1H),7.07(d,2H),6.94-6.98(dd,1H),5.14-5.20(m,1H),3.83(s,3H),3.21-3.27(m, 2H),2.96-3.01(m,2H);

MS ESI: m/z=424.1, [M+H] ⁺ .

Example 58

(Trans) 2-Bromo-nitrogen-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindol]-3-yl)nicotinamide

¹ H NMR (500MHz, acetone-d ₆ ): δ8.40-8.41(m,1H),7.88(d,1H),7.74(d,1H),7.56(d,1H),7.48-7.51(m, 2H),7.33-7.39(m,2H),7.18(s,1H),5.10-5.1(m,1H),3.12-3,17(m,2H),2.98-3.03(m,2H);

MS ESI: m/z=397.0, [M+H] ⁺ .

Example 59

(cis/trans)3-fluoro-nitrogen-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindol]-3-yl)benzamide

(cis:anti=4:1)

MS ESI: m/z=335.0, [M+H] ⁺ .

Example 60

(trans)nitro-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindol]-3-yl)tetrahydrofuran-3-carboxamide

¹ H NMR (500MHz, acetone-d ₆ ): δ8.28(s,1H),7.88(t,1H),7.57(d,1H),7.33-7.40(d,2H),7.16(s,1H) ,5.01-5.04(m,1H),4.28(t,1H),3.91-3.96(m,1H),3.79-3.85(m,1H),3.10-3.15(m,2H),2.82-2.87(m, 2H),2.18-2.23(m,1H),1.97-2.00(m,1H),1.85-1.90(m,2H);

MS ESI: m/z=310.1, [M+H] ⁺ .

Example 61

(trans)nitro-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindole]-3-yl)furan-3-carboxamide

¹ H NMR (500MHz, acetone-d ₆ ): δ8.29(s,1H),8.14(s,1H),7.77(d,1H),7.56-7.62(m,2H),7.35-7.38(m, 2H),7.16(s,1H),6.86(s,1H),5.11-5.15(m,1H),3.14-3,20(m,2H),2.90-2.95(m,2H);

MS ESI: m/z = 307.1 [M+H] ⁺ .

Example 62

(trans)nitro-(naphthaleneacetamido-2-yl)spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindole]-3-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.23(s,1H),8.20(s,1H),7.79-7.89(m,4H),7.36-7.54(m,6H),9.31-7.33(m, 2H),7.17(s,1H),3.46-3.50(m,1H),3.25-3.31(m,2H),3.01-3.06(m,2H).

MS ESI: m/z=366.1, [M+H] ⁺ .

Example 63

3-(Benzyloxy)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]

(cis/trans)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-ol (22mg, 0.1mmol) was dissolved in THF, and sodium hydride was added under ice cooling (4mg, 60%, 0.1mmol), stirred for 15 minutes, added benzyl bromide (20mg, 1.2mmol), stirred until the raw material disappeared. Add 5 mL of water to the reaction solution, extract with 10 mL of ethyl acetate, dry the organic phase with sodium sulfate, filter, concentrate, and column chromatography to obtain the target compound (25 mg, yield 80%, cis/trans = 2:1)

MS ESI: m/z=303.1, [M+H] ⁺ .

Example 64

(cis/trans) 3-Methylspiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]

(cis/trans=2:1)

MS ESI: m/z=269.1, [M+H] ⁺ .

Example 65

(cis/trans) 3-ethylspiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]

MS ESI: m/z = 240.1, [M+H] ⁺ .

Example 66

(cis/trans) 3-Methylspiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]

(cis/trans=2:1)

MS ESI: m/z=227.1, [M+H] ⁺ .

Example 67

(trans)1-phenyl-2-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-ylamino)ethanol

The intermediate (21mg, 0.1mmol) prepared in the first step in Example 5 and 2-bromo-1-phenylethanone (30mg, 0.2mmol), triethylamine (20mg, 0.2mmol) were added to the reaction flask In, dichloromethane (3 mL) was added, and the reaction was heated to 40°C for 2 hours. TLC showed the reaction was complete. Dichloromethane (10 mL) and water (10 mL) were added to the reaction solution for extraction, and the organic phase was collected and dried over sodium sulfate. Filtration, concentration, separation and purification by column chromatography gave 20 mg, yield 60.0%.

¹ H NMR (500MHz, CDCl ₃ ): δ7.94(s, 1H), 7.51-7.46(m, 2H), 7.41-7.38(m, 2H), 7.35-7.32(m, 4H), 7.27-7.25( m,2H),4.81-4.76(m,1H),3.65(s,2H),3.03-3.00(m,2H),2.87-2.83(m,2H).

MS ESI: m/z=330.2, [M+H] ⁺ .

Example 68

(trans)nitro-(3-bromo-4-fluorophenyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide

(trans)spiro[cyclobutane 1,5'-imidazo[5,1-α]is indole]-3-carboxylic acid (24mg, 0.1mmol), 4-fluoro-3 bromo-aniline (19mg, 0.1mmol) into the reaction flask, add 3ml of dichloromethane, add HOBT (14mg, 0.1mmol) and triethylamine (50mg, 0.5mmol), cool to ice bath, add EDCI (39mg, 2mmol), return to room temperature naturally , reacted overnight. After the reaction solution was concentrated, it was separated and purified by direct column chromatography to obtain the target compound (5 mg, yield 15%) as a light yellow solid.

H NMR (500MHz, CDCl ₃ ): δ8.15(s,1H),7.94-7.93(m,1H),7.56-7.52(m,2H),7.50-7.46(m,1H),7.40-7.37(m ,1H),7.33-7.29(m,1H),7.13-7.07(m,1h),3.40-3.37(m,1H),3.25-3.20(m,2H),3.04-2.99(m,2H).

MS ESI: m/z=413.1, [M+H] ⁺ .

Example 69

(trans)nitro-(p-tolyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide

¹ H NMR (500MHz, CDCl ₃ ): δ8.13(s, 1H), 7.92-7.90(m, 1H), 7.54-7.50(m, 2H), 7.48-7.46(m, 1H), 7.40-7.37( m,1H),7.33-7.29(m,2H),7.13-7.07(m,1H),3.40-3.37(m,1H),3.25-3.20(m,2H),3.04-2.99(m,2H), 2.48(s,3H).

MS ESI: m/z=330.2, [M+H] ⁺ .

Example 70

(trans)nitro-(3-chloro-4-fluorophenyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-formyl

¹ H NMR (400MHz, CDCl ₃ ): δ8.25(s,1H),7.88(s,1H),7.70-7.68(m,1H),7.62-7.51(m,2H),7.48-7.45(m, 1H),7.43-7.38(m,1H),7.31-7.29(m,1H),7.20(s,1H),7.15-7.12(m,1H),5.4-5.35(m,1H),3.50-3.45( m,1H),3.28-3.23(m,2H),3.10-3.02(m,2H).

MS ESI: m/z=368.1, [M+H] ⁺ .

Example 71

(trans)nitro-(3-fluorophenyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ9.12(s,1H),8.63(s,1H),7.80-7.78(m,1H),7.73-7.68(m,1H),7.62-7.49(m, 2H),7.45-7.30(m,6H),6.79-7.78(m,1H),4.18-4.15(m,1H),3.5-3.40(m,2H),2.80-7.70(m,2H).

MS ESI: m/z=334.1, [M+H] ⁺ .

Example 72

(trans)nitro-(3-chlorophenyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.48(s,1H),8.20(s,1H),7.79(s,1H),7.54-7.49(m,3H),7.46-7.38(m,2H) ,7.27-7.24(m,1H),7.18-7.18(s,1H),7.16(d,1H),3.51-3.46(m,1H),3.26-2.21(m,2H),3.05-2.99(m, 2H).

MS ESI: m/z=350.1[M+H] ⁺ .

Example 73

(trans)-nitrogen-(3-bromophenyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.23(s,2H),7.91(s,1H),7.55-7.51(m,3H),7.40-7.36(m,1H),7.31-7.26(m, 1H),7.22-7.18(m,1H),3.49-3.45(m,1H),3.24-3.18(m,2H),3.03-2.97(m,2H).

MS ESI: m/z = 395.1 [M+H] ⁺ .

Example 74

(cis)-nitrogen-(3-bromophenyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.80(s,1H),8.27(s,1H),8.03(s,1H),7.80-7.78(m,1H),7.65-7.51(m,2H) ,7.43-7.41(m,2H),7.25-7.20(m,2H),3.88-3.86(m,1H),3.46-3.38(m,2H),2.33-2.25(m,2H).

MS ESI: m/z = 395.1 [M+H] ⁺ .

Example 75

(trans)nitro-(4-fluorophenyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide

(cis/trans 2:1.7).

MS ESI: m/z=334.1, [M+H] ⁺ .

Example 76

(trans)nitro-(naphthalene-2-ylsulfonyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide

(Trans)spiro[cyclobutane 1,5'-imidazo[5,1-α]is indole]-3-carboxylic acid (24mg, 0.1mmol), added to the reaction flask, added HATU (76mg, 0.20 mmol), add dichloromethane (3mL), stir for 5 minutes, add DIPEA (64mg, 0.5mmol, stir for one hour, add 2-naphthalenesulfonamide (47mg, 0.3mmol), and DMAP (48mg, 0.40mmol), react Overnight, the raw material disappeared, and dichloromethane (10mL) was added to the reaction solution, water (10mL) was added, extracted, the aqueous phase was extracted with dichloromethane (10mL), the organic phases were combined, and dried over sodium sulfate. Filtered, concentrated, mixed sample , column chromatography afforded the title compound (10 mg,) as a pale yellow solid.

¹ H NMR (400MHz, MeOH-d ₄ ): δ8.53(s,1H),8.46(s,1H),8.00-7.94(m,2H),7.92-7.91(m,2H),7.87(d, 1H),7.67-7.65(m,1H),7.58-7.1(m,3H),7.35-7.33(m,2H),7.18(s,1H),3.37-3.33(m,1H),2.91-2.78( m,4H).

MS ESI: m/z = 430.1, [M+H] ⁺ .

Example 77

(trans)nitro-((4-fluorophenyl)sulfonyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide

1H NMR (400MHz, CDCl ₃ ): δ8.21-8.20(m,2H),8.19-8.17(m,1H),7.74-7.73(m,1H),7.58-7.56(m,1H),7.49-7.30 (m,4H),7.12(s,1H),3.68-3.67(m,1H),3.00-2.93(m,2H),2.90-2.83(m,2H).

MS ESI: m/z=398.1, [M+H] ⁺ .

Example 78

(trans)nitro-((3-fluorophenyl)sulfonyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ7.85-7.83(d, 1H), 7.75-7.73(d, 1H), 7.63-7.57(m, 3H), 7.48-7.39(m, 4H), 7.18- 7.13(m,1H),3.66-3.64(m,1H),3.50-3.48(m,1H),3.21-3.18(m,3H).

MS ESI: m/z=398.1, [M+H] ⁺ .

Example 79

(trans)nitro-((3-chlorophenyl)sulfonyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.02(s, 1H), 7.88-7.85(d, 1H), 7.69-7.64(m, 3H), 7.60-7.48(m, 5H), 3.51-3.48( m,1H),3.45-3.40(m,4H).

MS ESI: m/z=414.5, [M+H] ⁺ .

Example 80

(trans)3-(methylthio)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]

(cis)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl methanesulfonate (290mg, 1.0mmol) was dissolved in 5mL DMF, and methylthio Sodium alkoxide (105mg, 1.5mmol), stirred overnight at room temperature. After the reaction is complete. Add 20 mL of ethyl acetate, add 10 mL of water, extract, then wash with 10 mL of water, dry the organic phase, filter, and concentrate. Column chromatography gave the target compound (240 mg, yield 99%).

¹ H NMR (500MHz, CDCl ₃ ): δ7.88(s,1H),7.74(d,1H),7.48(d,1H),7.41-7.30(m,2H),7.16(s,1H),3.93 -3.84(m,1H),3.09-2.97(m,2H),2.89-2.84(m,2H),2.20(s,3H).

MS ESI: m/z=243.1, [M+H] ⁺ .

Example 81

(trans) 3-(methylsulfonyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]

Example 80 (48mg, 0.2mmol) was added to 5mL of dichloromethane, MMPP (98mg, 0.2mmol) was added under an ice bath, and reacted at this temperature until the raw materials disappeared, adding sodium thiosulfate solution to quench the reaction, dichloromethane Extraction (3x10 mL), combined organic phases, drying, filtration, concentration, column chromatography. The target compound (20 mg, yield 37%) was obtained.

¹ H NMR (500MHz, CDCl ₃ ): δ7.91(s,1H),7.84(d,1H),7.49(d,1H),7.41-38(m,2H),7.18(s,1H),4.33 -4.29(m,1H),3.55-3.49(m,2H),2.97-2.95(m,2H).

MS ESI: m/z=275.1, [M+H] ⁺ .

Example 82

(trans)(methylsulfinyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]

Example 80 (48mg, 0.2mmol) was added to 5mL of dichloromethane, MMPP (74mg, 0.2mmol) was added under ice-cooling, and reacted at this temperature until the raw materials disappeared, adding sodium thiosulfate solution to quench the reaction, dichloromethane Extract (3x10mL), combine the organic phases, dry, filter, concentrate, and column chromatography to obtain the target compound (20mg, yield 39%).

¹ H NMR (500MHz, CDCl ₃ ): δ7.94(s,1H),7.81(d,1H),7.48(d,1H),7.38-7.32(m,2H),7.17(s,1H),3.85 -3.80(m,1H),3.78-3.70(m,1H),3.39-3.34(m,1H),2.52(s,3H).

MS ESI: m/z=259.1, [M+H] ⁺ .

Example 83

(cis/trans) 3-(1-Benzyl-1H-1,2,3-triazol-4-yl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole ]-3-ol

Step 1: (cis/trans) 4-ethynyl-spiro[cyclohexane 1,5’-imidazo[5,1-α]isoindole]-4-ol

Add 5 mL of anhydrous tetrahydrofuran to the reaction flask, add ethynylmagnesium bromide (1.7 mL, 0.8 mmol), stir in an ice bath, and spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindo Indol]-3-one (20mg, 0.08mmol) was dissolved in tetrahydrofuran (1mL) and dropped into ethynylmagnesium bromide. After the drop was completed, it was allowed to return to room temperature and react for 1 hour. TLC showed that the raw material disappeared. The reaction was quenched by dropwise addition of saturated ammonium chloride. Add 20 mL of ethyl acetate and 10 mL of water, extract, dry the organic phase, filter, and concentrate to obtain a crude product, which is purified and separated by column chromatography to obtain the target compound (20 mg, yield 100%).

MS ESI: m/z=237.1, [M+H] ⁺ .

The second step: 4-(1-benzyl-1H-1,2,3-triazol-4-yl)spiro[cyclohexane 1,5'-imidazo[5,1-α]isoindole] -4-ol

Add the first step product (20mg, 0.076mmol), benzyl azide (20mg, 0.2mmol), copper sulfate pentahydrate (14mg, 0.08mmol) and sodium ascorbate (15mg, 0.08mmol) into dichloromethane, water, methanol (2mL, 1mL, 1mL), stirred at room temperature for 24 hours, TLC showed that the raw materials disappeared, dichloromethane (10ml) was added to the reaction solution, filtered with diatomaceous earth, the filtrate was concentrated, sample was mixed, and column chromatography was performed to obtain 10 mg of the target compound. Yield 36%.

MS ESI: m/z = 370.1 [M+H] ⁺ .

Example 84

(trans)3-(4-Cyclohexyl-1-hydrogen-1,2,3-triazol-1-yl)spiro[c-cyclobutane-1,5'-imidazol[5,1-a]isoindole]

¹ H NMR (500MHz, acetone-d ₆ ): δ8.63(s,1H),8.53(s,1H),7.98(d,2H),7.89(d,1H),7.72(s,1H),7.35 -7.49(m,6H),6.20(s,1H),3.76-3.80(m,2H),3.48(s,2H).

MS ESI: m/z=346.1, [M+H] ⁺ .

Example 85

(trans)3-(4-Phenyl-1-hydrogen-1,2,3-triazol-1-yl)spiro[c-cyclobutane-1,5’-imidazol[5,1-a]isoindole]

¹ H NMR (500MHz, CDCl ₃ ): δ8.00(s,1H),7.82(d,1H),7.50(d,1H),7.35-7.39(m,3H),5.46-5.48(m,1H) ,3.71-3.75(m,2H),3.14-3.22(m,2H);2.80-2.81(m,1H),2.08-2.09(m,2H),1.75-1.83(m,2H),1.43-1.44( m,2H),1.22-1.23(m,2H).

MS ESI: m/z=340.0, [M+H] ⁺ .

Example 86

(trans)3-(4-Cyclopropyl 1-hydrogen-1,2,3-triazol-1-yl)spiro[c-cyclobutane-1,5'-imidazol[5,1-a]isoindole]

¹ H NMR (300MHz, CDCl ₃ ): δ7.77(s,1H),7.64(s,1H),7.33-7.41(m,3H),7.0(s,1H),5.54(s,1H),3.89 -3.95(m,2H),3.70(s,1H),3.33-3.42(m,2H),1.96-1.99(m,1H),0.96-1.00(m,2H),0.84-0.90(m,2H) ;

MS ESI: m/z=304.1, [M+H] ⁺ .

Example 87

(trans)1-phenyl-3-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindol]-3-yl)urea

Dissolve (cis) spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-amine (40mg, 0.2mol), triethylamine (27uL, 0.2mmol) in 5mL DMF, add carbonyldiimidazole (31mg, 0.2mmol) and stir at room temperature for 1.5 hours, add aniline (20mg, 0.2mmol) and stir overnight. Add saturated bicarbonate solution 20mL, extract with dichloromethane (10mL*3), and combine the organic layer , washed with brine, dried over anhydrous sodium sulfate, and filtered. Solvent concentration, column chromatography (DCM:MeOH=100:5) gave the target compound as a yellow solid (60mg, 96%).

¹ H NMR (500MHz, acetone-d ₆ ): δ8.11(s,1H),7.80(d,1H),7.63(s,2H),7.33-7.37(m,1H),7.21-7.25(m, 1H),7.11(s,1H),6.93(s,1H),6.50(d,1H),4.87-4.93(m,1H),3.09-3.15(m,2H),2.86-2.91(m,2H) ;

MS ESI: m/z=331.1, [M+H] ⁺ .

Example 88

(trans)3-(-spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindole]-3-yl)sulfonylurea

Dissolve chlorosulfonyl isocyanate (37mg, 0.2mmol) in 1mL of dichloromethane under ice bath, add 25uL tert-butanol, stir at room temperature for ten minutes, add compound (trans) spiro[cyclobutane 1,5'- Imidazo[5,1-α]isoindole]-3-amine (25mg, 0.2mmol) and triethylamine (68uL), the reaction was stirred for ten minutes, then quenched with 20mL of water, extracted with dichloromethane (10mL* 3), the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and column chromatography (dichloromethane:methanol=20:1) to obtain a yellow solid (45mg, 50%). The obtained compound Dissolve in 1 mL of dichloromethane and 1 mL of trifluoroacetic acid, stir at room temperature for 2 hours, spin to dry the solvent, and perform column chromatography (dichloromethane:methanol=20:1), to obtain the target compound as a yellow solid (14 mg, 52%).

¹ H NMR (500MHz, methanol-d ₄ ): δ8.22(s,1H),7.73-7.75(m,1H),7.74-7.56(m,1H),7.38-7,41(m,2H), 7.15(s,1H),4.53-4,58(m,1H),2.88-3.01(m,4H);

MS ESI: m/z = 291.1 [M+H] ⁺ .

Example 89

(trans)1-phenyl-3-(spiro[cyclobutane-1,5’-imidazol[5,1-a]isoindol]-3-yl)thiourea

Under ice bath, (cis) spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-amine (30mg, 0.1mmol) and triethylamine (40uL, 0.3 mmol) was dissolved in 5 mL of dichloromethane, and phenylisothiocyanate (17 uL, 0.1 mmol) was added. Stir at room temperature for ten minutes, then quench the reaction with water (20 mL), extract with dichloromethane (10 mL*3), combine the organic layers, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (2 Chloromethane:methanol=20:1), drying to obtain the target compound as a yellow solid (40mg, 81%).

¹ H NMR (500MHz, CDCl ₃ ): δ8.10(s,1H),7.86(s,1H),7.31-7.40(m,3H),7.14-7.27(m,2H),7.02-7.06(m, 2H),6.96(d,1H),6.82(s,1H),5.30-5.32(m,1H),2.92-2.95(m,2H),2.79-2.81(m,2H);

MS ESI: m/z=347.1, [M+H] ⁺ .

Example 90

(cis)1-(3-fluorophenyl)-3-(spiro[cyclobutane-1,5’-imidazole 5,1-a]isoindol]-3-yl)thiourea

¹ H NMR (400MHz, CDCl ₃ ): δ8.05(s,1H),7.83(s,1H),7.55(d,1H),7.44(d,1H),7.27-7.37(m,3H),7.04 -7.11(m,2H),6.95-6.98(m,1H),5.13-5.15(m,1H),3.07-3.24(m,2H),2.63-2.67(m,2H).

MS ESI: m/z=365.1, [M+H] ⁺ .

Example 91

(cis)1-(4-Chlorophenyl)-3-(spiro[cyclobutane-1,5’-imidazole 5,1-a]isoindol]-3-yl)thiourea

¹ H NMR (400MHz, CDCl ₃ ): δ7.82-7.86(m,2H),7.62(d,1H),7.46-7.52(m,3H),7.35-7.39(m,2H),7.15(s, 1H),6.42(s,1H),5.19-5.21(m,1H),3.24-3.27(m,2H),2.68-2.71(m,2H).

MS ESI: m/z=381.0, [M+H] ⁺ .

Example 92

(cis)1-(4-trifluoromethylphenyl)-3-(spiro[cyclobutane-1,5’-imidazole 5,1-a]isoindol]-3-yl)thiourea

¹ H NMR (400MHz, CDCl ₃ ): δ8.35(s,1H),7.86(s,1H),7.49-7.60(m,6H),7.29-7.33(m,2H),7.09(s,1H) ,6.89(s,1H),5.10(s,1H),3.23-3.25(m,2H),2.64-2.66(m,2H);

MS ESI: m/z = 415.1, [M+H] ⁺ .

Example 93

(cis)1-(3-trifluoromethylphenyl)-3-(spiro[cyclobutane-1,5’-imidazole 5,1-a]isoindol]-3-yl)thiourea

¹ H NMR (400MHz, CDCl ₃ ): δ9.14(s,1H),8.00(s,1H),7.66(s,1H),7.44(s,2H),7.31(s,2H),7.19(s ,2H),7.09(s,1H),5.09(s,1H),3.23-3.25(m,2H),2.64-2.66(m,2H);

MS ESI: m/z = 415.1, [M+H] ⁺ .

Example 94

(cis)1-(3-Chloro-4-(trifluoromethyl)phenyl)-3-(spiro[cyclobutane 1,5'-imidazol[5,1-a]isoindole]-3 -yl)urea

¹ H NMR (400MHz, methanol-d ₄ ): δ8.18(s,1H),7.99(s,1H),7.74-7.76(m,1H),7.58-7.64(m,2H),7.48-7.50( m,1H),7.40-7.42(s,2H),7.13(s,1H),4.66-4.70(m,1H),3.09-3.12(m,2H),2.97-3.02(m,2H);

MS ESI: m/z=432.9, [M+H] ⁺ .

Example 95

(cis)1-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindol]-3-yl)-3-(3-(trifluoromethyl)phenyl) Urea

¹ H NMR (400MHz, methanol-d ₄ ): δ8.18(s,1H),7.89(s,1H),7.75-7.77(m,1H),7.57-7.61(m,2H),7.40-7.48( m,2H),7.27-7.29(m,1H),7.14(s,1H),4.65-4.71(m,1H),3.10-3.13(m,2H),2.97-3.02(m,2H);

MS ESI: m/z=398.9, [M+H] ⁺ .

Example 96

(cis)1-(3,5-bis(trifluoromethyl)phenyl)-3-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindole]-3 -yl)thiourea

¹ H NMR (400MHz, methanol-d ₄ ): δ8.22(s,1H),8.09(s,1H),7.73-7.75(m,1H),7.67(s,1H),7.58-7.60(m, 1H),7.40-7.44(m,2H),7.13(s,1H),5.16-5.20(m,1H),3.17-3.22(m,2H),2.89-2.94(m,2H);

MS ESI: m/z=483.1, [M+H] ⁺ .

Example 97

(cis)1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindole]- 3-yl)thiourea

¹ H NMR (400MHz, methanol-d4): δ8.01(s,1H),7.93(s,1H),7.60-7.65(m,2H),7.46-7.50(m,2H),7.31-7.34(m ,2H),7.03(s,1H),5.12(s,1H),3..04-3.09(m,2H),2.79-2.85(m,2H);

MS ESI: m/z=449.0, [M+H] ⁺ .

Example 98

(cis)1-(3,5-bis(trifluoromethyl)phenyl)-3-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindole]-3 -yl)urea

¹ H NMR (400MHz, methanol-d ₄ ): δ8.08(s,1H),7.98(s,1H),7.64-7.66(m,1H),7.47-7.50(m,1H),7.42(s, 1H),7.30-7.42(m,2H),7.03(s,1H),4.57-4.61(m,1H),2.97-3.03(m,2H),2.88-2.94(m,2H);

MS ESI: m/z = 467.1, [M+H] ⁺ .

Example 99

(cis)1-(3,4-dichlorophenyl)-3-(spiro[cyclobutyl-1,5’-imidazol[5,1-a]isoindol]-3-yl)urea

¹ H NMR (400MHz, methanol-d ₄ ): δ8.06(s,1H),7.62-7.67(m,1H),7.62-7.65(m,1H),7.47-7.49(m,1H),7.27- 7.33(m,3H),7.17-7.20(dd,2H),7.02(s,1H),4.52-4.60(m,1H),2.95-3.00(m,2H),2.85-2.90(m,2H);

MS ESI: m/z = 401.0 [M+H] ⁺ .

Example 100

(cis)1-Benzyl-3-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)urea

¹ H NMR (400MHz, methanol-d ₄ ): δ8.01(s,1H),7.60-7.62(m,1H),7.46-7.48(m,1H),7.27-7.30(m,2H),7.19- 7.22(m,4H),7.01(s,1H),2.92-2.97(m,2H),2.75-2.80(m,2H);

MS ESI: m/z = 345.2 [M+H] ⁺ .

Example 101

(cis)1-Phenylethyl-3-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)urea

¹ H NMR (400MHz, methanol-d ₄ ): δ7.99(s,1H),7.59-7.61(m,1H),7.46-7.48(m,1H),7.25-7.31(m,2H),7.07- 7.20(m,7H),7.01(s,1H),4.43-4.52(m,1H),3.29-3.31(t,2H),2.89-2.94(m,2H),2.69-2.75(m,4H);

MS ESI: m/z = 359.2 [M+H] ⁺ .

Example 102

(trans)1-(3-trifluoromethylphenyl)-3-(spiro[cyclobutane 1,5’-imidazo[5,1-α]isoindol]-3-yl)thiourea

¹ H NMR (400MHz, methanol-d ₄ ): δ8.08(s,1H),7.79(s,1H),7.57-7.62(m,2H),7.41-7.45(m,2H),7.26-7.36( m,3H), 7.03(s,1H), 5.25(s,1H), 2.87-2.89(d,4H);

MS ESI: m/z = 415.0 [M+H] ⁺ .

Example 103

(trans)1-(3-fluorophenyl)-3-(spiro[cyclobutane 1,5’-imidazo[5,1-α]isoindole]-3-yl)thiourea

¹ H NMR (400MHz, methanol-d ₄ ): δ8.09(s,1H),7.58(d,1H),7.45(d,1H),7.26-7.31(m,4H),7.04-7.11(m, 2H), 5.28(m, 1H), 2.87(d, 4H);

MS ESI: m/z = 365.1 [M+H] ⁺ .

Example 104

(trans)1-(4-Chlorophenyl)-3-(spiro[cyclobutane 1,5’-imidazo[5,1-α]isoindole]-3-yl)thiourea

¹ H NMR (400MHz, methanol-d ₄ ): δ8.09(s,1H),7.58(d,1H),7.45(d,1H),7.22-7.34(m,6H),7.04(m,1H) ,5.29(s,1H), 2.87(d,4H);

MS ESI: m/z = 381.0 [M+H] ⁺ .

Example 105

(Trans) 4-Chloro-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-ylcarbamoyl)benzenesulfonamide

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.15(s,1H),7.88(d,2H),7.82(d,1H),7.61(d,2H),7.53(d,1H),7.36 -7.40(m,2H),7.12(s,1H),4.67-4.73(m,1H),3.06-3.12(m,2H),2.86(t,2H),2.66-2.67(m,2H);

MS ESI: m/z = 429.0 [M+H] ⁺ .

Example 106

(Trans) 4-Methyl-nitrogen-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-ylcarbamoyl)benzenesulfonamide

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.11(s,1H),7.79-7.81(m,3H),7.54-7.55(m 1H),7.37-7.39(m,3H),7.20(s ,1H), 7.13(d,1H), 4.70-4.72(m,1H), 2.86-2.91(m,2H), 2.67(s,2H), 2.39(s,3H);

MS ESI: m/z = 409.0 [M+H] ⁺ .

Example 107

(trans)1-(3-fluorophenyl)-3-(spiro[cyclobutane 1,5’-imidazo[5,1-α]isoindole]-3-yl)sulfonylurea

Under a nitrogen-protected ice bath, chlorosulfonyl isocyanate (9uL, 0.1mmol) was dissolved in 2mL of dichloromethane, 2-bromoethanol (7uL, 0.1mmol) was dissolved in 1mL of dichloromethane and added to the reaction solution, and stirred for 10 minutes. Compound (trans)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-amine (20mg, 0.1mmol) and triethylamine (35uL) were dissolved in 1mL of dichloro Methane, react at room temperature, LC-MS detects that the reaction is complete, spin the crude product to dryness, add 3mL of acetonitrile, triethylamine (35uL), 3-fluoroaniline (20uL), reflux for 10h, then quench the reaction with water (20mL), Dichloromethane extraction (10mL*3), combined organic layers, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, column chromatography (dichloromethane:methanol=20:1), dried to obtain The title compound as a yellow solid (10 mg, 28%).

¹ H NMR (400MHz, methanol-d ₄ ): δ8.11(s, 1H), 7.52-7.57(m, 1H), 7.28-7.31(m, 3H), 7.12(s, 1H), 7.03-7.07( m,1H),6.95-6.98(m,1H),6.75-6.79(m,1H),4.58-4.52(m,1H),2.78(d,4H);

MS ESI: m/z = 385.0 [M+H] ⁺ .

Example 108

(cis)1-methyl-3-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)sulfonylurea

¹ H NMR (400MHz, CDCl ₃ ): δ8.02(s,1H),7.58-7.60(m,1H),7.47-7.49(m,1H),7.28-7.33(m,2H),7.03(s, 1H),4.11-4.16(m,1H),2.98-3.06(m,2H),2.77-2.82(m,2H);

MS ESI: m/z = 305.1, [M+H] ⁺ .

Example 109

(cis)2-cyano-1-methyl-3-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindole]-3-yl)guanidine

Dissolve (cis)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-amine (25mg, 0.1mmol) in 2mL tetrahydrofuran, add N-cyanocarbene Amine diphenyl ester (41mg, 0.2mmol), triethylamine (66uL), after stirring at room temperature for 2 hours, add 0.6mL of methylamine solution, continue stirring for two hours, add dropwise 2mL of 1N sodium hydroxide aqueous solution, and stir at room temperature for 1 hour , then quenched the reaction with water (20mL), extracted with dichloromethane (10mL x 3), combined the organic layers, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, column chromatography (dichloromethane:methanol =20:1), dried to give a yellow solid (40mg, 81%).

¹ H NMR (400MHz, CDCl ₃ ): δ8.03(s,1H),7.63(d,1H),7.47(d,1H),7.29-7.32(m,2H),7.02(s,1H),4.57 -4.61(m,1H),2.97-3.02(m,2H),2.80-2.91(m,2H); 2.74(s,3H);

MS ESI: m/z=293.1, [M+H] ⁺ .

Example 110

(cis/trans)1-(spiro[cyclohexyl-1,5'-imidazo[5,1-α]isoindol]-4-yl)-3-(3-(trifluoromethyl)phenyl ) Thiourea

Step 1: Methyl 5-(2-bromophenyl)-5-cyano-2-oxocyclohexane-1-carboxylate

2-Bromophenylacetonitrile (10.0 g, 51 mmol) and methyl 3-chloropropionate (13.4 g, 107 mmol) were added to ^KOtBu (28.6 g, 255 mmol)/THF (100 mL) emulsion at room temperature. After reacting at room temperature for 6 h, the reaction solution was concentrated and acidified with 2M HCl to pH=6-7. The above solution was extracted with 3*50 mL DCM, and the combined organic phases were dried over anhydrous Na ₂ SO ₄ and concentrated. After column purification (mobile phase PE:EA=4:1), 9.8 g of the target compound was obtained as a light yellow solid, with a yield of 57%.

¹ H NMR (400MHz, CDCl ₃ ): δ12.24(s,1H),7.70(dd,1H),7.43(dd,1H),7.36(t,1H),7.23(t,1H),3.81(s ,3H),3.39(d,1H),2.85–2.78(m,2H),2.56–2.49(m,2H),2.44–2.38(m,1H).

MS ESI: m/z = 336.0, 338.0, [M+H] ⁺ .

The second step: the preparation of 1-(2-bromophenyl)-4-oxocyclohexane-1-carbonitrile

Sodium chloride (1.9g, 31.9mmol) and the first step product 5-(2-bromophenyl)-5-cyano-2-oxocyclohexane-1-carboxylic acid methyl ester (9.76g , 29.03mmol) into a 50mL two-necked bottle, pumped argon three times, and injected 12mL of dimethyl sulfoxide. After reacting at 150°C for 6h, it was cooled to room temperature. The reaction solution was diluted with 200 mL of saturated brine and extracted with 3×100 mL of DCM. The combined organic phases were dried over anhydrous Na ₂ SO ₄ and concentrated. After column purification (mobile phase PE:DCM=1:1), 4.6 g of the target compound was obtained as a white solid, with a yield of 57%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.72(dd,1H),7.44(dd,1H),7.39(t,1H),7.25(t,1H),3.01–2.88(m,4H),2.63 –2.58(m,2H),2.34-2.27(t,2H).

MS ESI: m/z = 278.0, 280.0, [M+H] ⁺ .

The third step: 8-(2-bromophenyl)-1,4-dioxaspiro[4,5]decane-8-carbonitrile

Ethylene glycol (1.1g, 18.0mmol) and p-toluenesulfonic acid monohydrate (1.6g, 8.2mmol) were added to the second step product 1-(2-bromophenyl)-4-oxocyclohexane at room temperature -1-carbonitrile (4.6g, 16.4mmol)/Toluene (100mL) solution. After reacting at 120°C for 6h, it was cooled to room temperature. The reaction solution was diluted with 300mL saturated brine and the above solution was extracted with 3*50mL EA. The organic phases were combined, washed successively with saturated NaHCO ₃ and saturated brine, dried with anhydrous Na ₂ SO ₄ , and spin-dried to obtain 5.2 g of the target compound as a light yellow solid, with a yield of 98%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.68(dd,1H),7.45(dd,1H),7.34(t,1H),7.20(t,1H),4.02(t,2H),3.95(t ,2H),2.60–2.58(m,2H),2.24–2.13(m,4H),1.91–1.89(m,2H).

MS ESI: m/z=322.0,324.0,[M+H] ⁺ .

The fourth step: 8-(2-bromophenyl)-1,4-dioxaspiro[4,5]decane-8-carboxamide

KOH (18.0g, 322mmol) was added to the third step product 8-(2-bromophenyl)-1,4-dioxaspiro[4,5]decane-8-carbonitrile (5.2g, 16.1 mmol)/ ^t BuOH (50mL) solution. After reacting at 100°C for 6h, it was cooled to room temperature. 20m water was added to the system and the above solution was extracted with 3*50mL DCM. The organic phases were combined, washed with saturated brine, dried with anhydrous Na ₂ SO ₄ , and spin-dried to obtain 4.5 g of the target compound as a light yellow solid, with a yield of 82%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.63(dd,1H),7.59(dd,1H),7.35(t,1H),7.16(t,1H),5.18-5.04(br,2H),3.97 (t,2H),3.92(t,2H),2.58–2.52(m,2H),2.36–2.29(m,2H),2.10–2.04(m,2H),1.69–1.62(m,2H).

MS ESI: m/z=340.1, 342.1, [M+H] ⁺ .

The fifth step: 8-(2-bromophenyl)-1,4-dioxaspiro[4,5]decane-8-amine

At room temperature, 5.2% NaClO aqueous solution (48.7mL, 33.2mmol) was slowly added dropwise to the fourth step product 8-(2-bromophenyl)-1,4-dioxaspiro[4,5]decane-8- Carboxamide (4.5g, 13.3mmol)/1,4-dioxane (100mL) solution. After overnight reaction at room temperature, 20 mL of water was added to the reaction solution and the above solution was extracted with 3 x 50 mL of DCM. The organic phases were combined, washed with saturated brine, dried with anhydrous Na ₂ SO ₄ , and spin-dried to obtain 3.8 g of the target compound as a light yellow solid, with a yield of 90%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.59(dd,1H),7.52(dd,1H),7.26(t,1H),7.06(td,1H),3.98(t,2H),3.94(t ,2H),2.22–2.12(m,6H),1.67–1.64(m,2H).

MS ESI: m/z=312.0,314.0,[M+H] ⁺ .

The sixth step: 1-(8-(2-bromophenyl)-1,4-dioxaspiro[4,5]decane-8-yl)-1H-imidazole

At room temperature, 40% glyoxal aqueous solution (4.4g, 30.0mmol), 37% formaldehyde aqueous solution (2.4g, 30.0mmol) and ammonium acetate (2.3g, 30.0mmol) were slowly added dropwise to the fifth step product 8-(2 -bromophenyl)-1,4-dioxaspiro[4,5]decane-8-amine (3.75g, 12.01mmol)/MeOH (60mL) solution. After reacting at 70°C for 6h, it was cooled to room temperature. The reaction solution was concentrated and purified by column (mobile phase DCM:MeOH=30:1) to obtain 3.4 g of the target compound as a light yellow solid with a yield of 77%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.83(s,1H),7.51(dd,1H),7.27(t,1H),7.15(dd,1H),7.13(s,1H),6.95(d ,1H),6.89(s,1H),3.98(t,4H),3.22–3.17(m,2H),2.53–2.46(m,2H),1.76(t,4H).

MS ESI: m/z=363.0,365.0,[M+H] ⁺ .

Step 7: Disspiro[imidazo[5,1-α]isoindole-5,1′-cyclohexane-4′,2″-[1,3]dioxolane]

Cs ₂ CO ₃ (2.1g, 6.4mmol), Pd(dppf)Cl ₂ (471mg, 0.6mmol) and the sixth step product 1-(8-(2-bromophenyl)-1,4-di Oxaspiro[4,5]decane-8-yl)-1H-imidazole (1.2g, 3.2mmol) was added into a 50mL two-neck flask, the argon gas was pumped three times, and 10mL of dimethyl sulfoxide was injected. After reacting at 120°C for 4h, it was cooled to room temperature. The reaction solution was diluted with 200 mL saturated brine and the above solution was extracted with 3x 50 mL EA. The combined organic phases were dried over _{anhydrous Na2SO4} and concentrated. After column purification (mobile phase PE:EA=1:2), 476 mg of the target compound was obtained as a light brown solid, with a yield of 52%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.88(s,1H),7.54(d,1H),7.39(d,1H),7.35(dd,1H),7.26(t,1H),7.21(s ,1H),4.07(t,4H),2.36(t,2H),2.11(t,2H),1.99(t,1H),1.96(t,1H),1.87-1.82(m,2H).

MS ESI: m/z=283.1, [M+H] ⁺ .

Step 8: Spiro[cyclohexane-1,5'-imidazo[5,1-α]isoindole]-4-one

At room temperature, 2N HCl aqueous solution (0.5mL) was added dropwise to the seventh step product disspiro[imidazo[5,1-α]isoindole-5,1′-cyclohexane-4′,2″-[1 , 3] in dioxolane] (28mg, 0.1mmol)/THF (1mL) solution. After reacting at 50°C for 1.5h, cool to room temperature. Concentrate the reaction solution and adjust to pH=10 with 5N NaOH. Use The above solution was extracted with 3x 5mL DCM, the combined organic phases were dried with anhydrous Na ₂ SO ₄ , and spin-dried to obtain 23 mg of light brown solid compound, with a yield of 97%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.90(s,1H),7.60(d,1H),7.42(t,1H),7.34(dd,1H),7.32(dd,1H),7.28(s ,1H),2.93-2.86(m,2H),2.73(t,1H),2.69(t,1H),2.53(t,2H),2.22-2.16(m,2H).

MS ESI: m/z=239.1, [M+H] ⁺ .

Step 9: (cis/trans) spiro[cyclohexane-1,5'-imidazo[5,1-α]isoindole]-4-amine

Ammonium formate (127mg, 2.0mmol), water (0.1mL) and 10% Pd/C (20mg) and the eighth step product spiro[cyclohexane-1,5'-imidazo[5,1-α ]isoindole]-4-one (24mg, 0.1mmol) was added to a 50mL two-necked bottle, Ar was replaced three times, and 1mL methanol was injected. After 24h and 48h at room temperature, ammonium formate (39mg, 0.6mmol) was added. After reacting for 60 h, add 5 mL of methanol, and then filter out Pd/C. The filtrate was adjusted to pH=12 with 40% NaOH aqueous solution and the above solution was extracted with 3*5 mL DCM, the combined organic phases were dried over anhydrous Na ₂ SO ₄ and concentrated. After column purification (mobile phase DCM:MeOH=15:1, 0.5% NH ₃ -H ₂ O), 16 mg of the target compound was obtained as a pale yellow solid, with a yield of 67% (cis:trans=1:1).

MS ESI: m/z=240.1, [M+H] ⁺ .

The tenth step 1-(spiro[cyclohexyl-1,5'-imidazo[5,1-α]isoindol]-4-yl)-3-(3-(trifluoromethyl)phenyl)sulfur Urea

(cis:anti=1:1)

3-(trifluoromethyl)phenyl isothiocyanate (20mg, 0.1mmol) was added to the ninth step product (cis/trans)spiro[cyclohexane-1,5'-imidazo[ 5. In a mixed solution of 1-α]isoindole]-4-amine (20mg, 0.1mmol) and Et ₃ N (17mg, 0.2mmol) in 1 mL of dichloromethane. After warming to room temperature and reacting for 10 minutes, the reaction was quenched with 0.5 mL and concentrated. After column purification (mobile phase DCM:MeOH=15:1), 24 mg of light yellow solid compound was obtained, with a yield of 63% (cis:trans=1:1).

MS ESI: m/z=442.8, [M+H] ⁺ .

Example 111

(cis/trans)1-phenyl-3-(spiro[cyclohexyl-1,5'-imidazo[5,1-α]isoindol]-4-yl)thiourea

(cis:anti=1:1)

MS ESI: m/z = 375.0, [M+H] ⁺ .

Example 112

(cis/trans)1-(4-chlorophenyl)-3-(spiro[cyclohexyl-1,5’-imidazo[5,1-α]isoindol]-4-yl)thiourea

(cis:anti=1:1)

MS ESI: m/z=409.0, [M+H] ⁺ .

Example 113

(cis/trans)1-(spiro[cyclohexyl-1,5'-imidazo[5,1-α]isoindol]-4-yl)-3-(4-(trifluoromethyl)phenyl ) Thiourea

(cis:anti=1:1)

MS ESI: m/z=443.0, [M+H] ⁺ .

Example 114

(cis/trans)1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(spiro[cyclohexyl-1,5'-imidazo[5,1-α]isoindole] -4-yl)urea

(cis:anti=1:1)

MS ESI: m/z = 461.0, [M+H] ⁺ .

Example 115

(cis/trans)nitro-(spiro[cyclohexyl-1,5'-imidazo[5,1-α]isoindol]-4-yl)naphthyl-2-sulfonamide

(cis:anti=1:1)

According to the method of Example 2, 2-naphthalenesulfonyl chloride was used instead of 3-(trifluoromethyl)phenyl isothiocyanate as a raw material to obtain 17 mg of white solid compound with a yield of 47%.

MS ESI: m/z=430.0, [M+H] ⁺ .

Example 116

(cis/trans) 3-bromo-nitrogen-(spiro[cyclohexyl-1,5'-imidazo[5,1-α]isoindol]-4-yl)benzamide

(cis:anti=1:1)

MS ESI: m/z = 422.0, 424.0 [M+H] ⁺ .

Example 117

(cis/trans) 4-(1-Benzyl-1H-1,2,3-triazol-4-yl)spiro[cyclohexane 1,5'-imidazo[5,1-α]isoindole ]-4-ol

Step 1: Preparation of (cis/trans) 4-ethynyl-spiro[cyclohexane 1,5'-imidazo[5,1-α]isoindole]-4-ol

Add 5 mL of anhydrous tetrahydrofuran to the reaction flask, add ethynylmagnesium bromide (1.7 mL, 0.8 mmol), stir in an ice bath, and mix the raw material spiro[cyclohexane-1,5'-imidazo[5,1-α] Isoindol]-4-one (20mg, 0.1mmol) was dissolved in tetrahydrofuran (1mL) and dropped into ethynylmagnesium bromide. After the drop was completed, it was allowed to return to room temperature and react for 1 hour. TLC showed that the raw material disappeared. The reaction was quenched by dropwise addition of saturated ammonium chloride. Add 20 mL of ethyl acetate and 10 mL of water, extract, dry the organic phase, filter, and concentrate to obtain a crude product, which is purified and separated by column chromatography to obtain the target compound (20 mg, yield 90%).

MS ESI: m/z=265.1, [M+H] ⁺ .

The second step: 4-(1-benzyl-1H-1,2,3-triazol-4-yl)spiro[cyclohexane 1,5'-imidazo[5,1-α]isoindole] -4-ol

(cis:anti=2:1)

The first step product (20mg, 0.076mmol), and benzyl azide (20mg, 0.2mmol) copper sulfate pentahydrate (14mg, 0.1mmol) and sodium ascorbate (15.00mg, 0.1mmol), add dichloromethane, water , methanol (2mL, 1mL, 1mL), stirred at room temperature for 24 hours, TLC showed that the raw material disappeared, dichloromethane (10mL) was added to the reaction solution, filtered with diatomaceous earth, the filtrate was concentrated, mixed, and column chromatography to obtain the target compound 10mg, yield 33%

MS ESI: m/z = 398.1 [M+H] ⁺ .

Example 118

(cis)spiro[cyclobutanyl-1,5'-imidazo[5,1-α]isoindole]-3-amine

The first step: cis-spiro[cyclobutanyl-1,5'-imidazo[5,1-α]isoindole]-3-ol

Cs ₂ CO ₃ (7.9g, 24.3mmol), Pd(dppf)Cl ₂ (1.8g, 2.4mmol) and cis 3-(2-bromophenyl)-3-(1H-imidazole-1- Base) cyclobutyl-1-ol (3.6g, 12.1mmol) was added into a 50mL two-necked flask, Ar was replaced three times, and 8mL of dimethyl sulfoxide was injected. After reacting at 120°C for 8h, it was cooled to room temperature. The solvent was concentrated, the residue was diluted with 200mL saturated brine and the above solution was extracted with 3x 50mL EA and 3x 50mL DCM, the combined organic phases were dried over anhydrous Na ₂ SO ₄ and concentrated. After column purification (mobile phase DCM:MeOH=25:1), 1.8 g of the target compound was obtained as a reddish-brown solid, with a yield of 70%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.95(s,1H),7.50(d,1H),7.40(d,1H),7.35(t,1H),7.30(t,1H),7.14(s ,1H),4.79(quint,1H),3.17-3.09(m,2H),2.81-2.76(m,2H).

MS ESI: m/z=213.1, [M+H] ⁺ .

Step 2: trans-spiro[cyclobutanyl-1,5'-imidazo[5,1-α]isoindole]-3-ylbenzoate

At room temperature, triphenylphosphine (393mg, 1.5mmol), benzoic acid (92mg, 0.8mmol) and the first step product cis-spiro[cyclobutanyl-1,5'-imidazo[5,1-α] Isoindole]-3-ol (159mg, 0.8mmol) was added into a 50mL two-necked flask, Ar was replaced three times, and 4mL of tetrahydrofuran was injected. Then a THF/2mL solution of DIAD (273mg, 1.4mmol) was added dropwise to the above system under ice-cooling, raised to room temperature for 4h, and the reaction was stopped. The reaction solution was concentrated and purified by column (mobile phase DCM:MeOH=20:1) to obtain 187 mg of the target compound as a light red solid with a yield of 79%.

¹ H NMR (400MHz, CDCl ₃ ): δ8.01(s,1H),7.70-7.65(m,4H),7.57-7.53(m,3H),7.39(t,1H),7.34(t,1H) ,7.27(s,1H),5.79(quint,1H),3.16(m,4H).

MS ESI: m/z=317.1, [M+H] ⁺ .

The third step: trans-spiro[cyclobutanyl-1,5'-imidazo[5,1-α]isoindole]-3-ol

LiOH-H ₂ O (243mg, 5.8mmol)/H ₂ O (2mL) aqueous solution was added dropwise to the second step product trans-spiro[cyclobutanyl-1,5'-imidazo[5,1- α]isoindol]-3-ylbenzoate (610mg, 1.9mmol)/MeOH (15mL) solution. After reacting at room temperature for 10 minutes, the reaction solution was concentrated and the above solution was extracted with 3 x 5 mL EA, and the organic phases were combined and dried over anhydrous Na ₂ SO ₄ . The reaction solution was concentrated and purified by column (mobile phase DCM:MeOH=20:1) to obtain 316 mg of the target compound as a light brown solid, with a yield of 77%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.76(s,1H),7.66(dd,1H),7.49(dd,1H),7.37-7.31(m,2H),7.16(s,1H),4.99 (quint,1H),2.90(m,4H).

MS ESI: m/z=213.1, [M+H] ⁺ .

The fourth step: trans-spiro[cyclobutanyl-1,5'-imidazo[5,1-α]isoindole]-3-yl methanesulfonate

MsCl (339mg, 2.96mmol) and Et ₃ N (599mg, 5.9mmol) were added dropwise to the third step product trans-spiro[cyclobutanyl-1,5'-imidazo[5,1- α]isoindole]-3-ol (315mg, 1.5mmol)/DCM (10mL) solution. After reacting at 0°C for 10 minutes, 2 mL of saturated saline was added to the reaction liquid and the above solution was extracted with 3x 5 mL of DCM. The organic phases were combined and dried with anhydrous Na ₂ SO ₄ to obtain 412 mg of the target compound as a light brown solid with a yield of 96%. .

¹ H NMR (400MHz, CDCl ₃ ): δ7.79(s,1H),7.62(dd,1H),7.50(dd,1H),7.40-7.35(m,2H),7.18(s,1H),5.57 (quint,1H),3.25-3.20(m,2H),3.14(s,3H),3.13-3.09(m,2H).

MS ESI: m/z=291.0, [M+H] ⁺ .

The fifth step: cis-3-azidospiro[cyclobutanyl-1,5'-imidazo[5,1-α]isoindole]

NaN ₃ (277mg, 4.3mmol) was added to the fourth step product trans-spiro[cyclobutanyl-1,5'-imidazo[5,1-α]isoindol]-3-ylmethanol under ice bath Sulfonate (412mg, 1.4mmol)/DMF (6mL) solution. After reacting at 75°C for 5 h, 50 mL of saturated brine was added to the reaction liquid and the above solution was extracted with 3 x 15 mL of EA, and the organic phases were combined and dried over anhydrous Na ₂ SO ₄ . The reaction solution was concentrated and purified by column (mobile phase DCM:MeOH=25:1) to obtain 209 mg of light brown oily compound with a yield of 67%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.90(s,1H),7.51(d,1H),7.44(d,1H),7.38(t,1H),7.31(t,1H),7.17(s ,1H),4.41(quint,1H),3.18-3.12(m,2H),2.88-2.81(m,2H).

MS ESI: m/z=238.1, [M+H] ⁺ .

Step 6: Preparation of cis-spiro[cyclobutanyl-1,5'-imidazo[5,1-α]isoindole]-3-amine

In an argon atmosphere, 5% Pd/C (20 mg) was added to the fifth step product cis-3-azidospiro[cyclobutanyl-1,5'-imidazo[5,1-α]iso Indole] (209mg, 0.9mmol)/EtOH (4mL) solution. After reacting in 1atm _H2 at room temperature for 24h, diatomaceous earth was added to filter, the filter cake was washed with 5mL EtOH, the organic phases were combined and spin-dried to obtain 170mg of light yellow solid compound with a yield of 87%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.92(s,1H),7.49(t,2H),7.35(t,1H),7.28(t,1H),7.15(s,1H),3.95(quint ,1H),3.12-3.04(m,2H),2.52-2.47(m,2H).

MS ESI: m/z=212.1, [M+H] ⁺ .

The compounds prepared in the above examples are shown in Table 1 below.

Table 1. List of compounds of the present invention

Example 119

activity test

(1) Induced expression and purification method of IDO or TDO protein

First, the IDO gene was amplified by PCR, and the amplified PCR product was recovered, and then the pET28a plasmid (purchased from Shanghai Baoman Biotechnology Co., Ltd.) and the product recovered from IDO gel were digested with two restriction enzymes, EcoR I and Xho I. (37°C, enzyme digestion for 2h), gel run, recovery, T4 ligase linked overnight ligation product was added to DH5α competent, placed on ice for 30min, heat shock at 42°C for 90s, shake the plate, pick a single clone, PCR identification , Sequencing identification, all correct, that is, the pET28a-IDO plasmid was successfully constructed.

Shake the constructed BL21 containing the pET28a-IDO plasmid at 37°C until the OD ₆₀₀ is 0.6-0.8, and add hemin and 1 mM IPTG (isopropyl-β-D-thiol) to a final concentration of 7 μM galactoside), induced at 28°C for 4h; after induction, the cells were collected by centrifugation at 4°C at 6000rpm, washed once with 20mM PBS (pH6.5), and collected by centrifugation again.

Resuspend the collected bacteria with lysate (20mM PBS pH6.5), ultrasonically lyse (power 40% for 20min, place on ice), centrifuge the lysed bacteria at 13000rpm for 15min, discard the precipitate, and keep the supernatant ; Equilibrate the nickel column with lysate (20mM PBS pH6.5) for 3 column volumes, then load the lysed supernatant onto the nickel column, after loading, wash with rinse solution (20mM PBS pH6.5, 20mM imidazole) 4 column volumes, and finally elute the protein with eluent (20mM PBS pH6.5, 250mM imidazole); dialyze the eluted protein solution for 4h, and the dialyzed solution is 20mM PBS pH6.5. After dialysis, the protein sample is concentrated and analyzed. Packed, quick-frozen in liquid nitrogen, and stored at -80°C for later use.

TDO was expressed and purified by the same method as above.

(2) Test method for IDO enzyme inhibitory activity

Firstly, the compound was serially diluted 3 times, and 1 μL of each concentration was added to a 96-well plate; 50 μL of prepared IDO enzyme solution (final concentration 600ng/100 μL) was added: 25 μL of substrate 1 mixed solution was added, and 25 μL of substrate 2 was added. The mixed solution initiates the reaction. The final OD ₃₂₁ nm reading was 60 min.

(3) Cell Viability Test Method

Hela cells (100 μL) were inoculated on a 96-well plate at an inoculum size of 5×10 ³ per well, and grown overnight. On the second day, after the compound was diluted, 1 μL was added to a 96-well plate, and then 100 μL of a medium containing human interferon-γ (final concentration 50 ng/mL) was added to the 96-well plate to make the final volume 200 μL. After 48 hours of incubation, transfer 140 μL of supernatant from each well to a new 96-well plate. Add 10 μL of 6.1N trichloroacetic acid to each well to mix and incubate at 50°C for 30 minutes. IDO catalyzes N-formyl kynurene into kynurene. The reaction mixture was centrifuged at 2500 rpm for 10 minutes to remove the precipitate. Transfer 100 μL supernatant from each well to a new 96-well plate and mix with 100 μL 2% dimethylaminobenzaldehyde acetic acid solution. After separation of kynurene, the value was measured at 480nm with SPECTRAmaxi3reader.

The test results of IDO enzyme inhibitory activity and cell inhibitory activity of each compound are shown in Table 2.

Table 2. IDO enzyme, IDO cell and TDO enzyme inhibitory activity test results (IC ₅₀ , uM)

The above results show that the compounds of the present invention (including all isomers) have inhibitory activity against IDO enzyme and TDO enzyme.

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (10)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a tautomer thereof, or a prodrug thereof: In the formula, A is selected from the group consisting of S, O, -C(R ¹ ) ₂ - or none; B is selected from the group consisting of: -C(R ^1a ) ₂ - or none; E and M are independently selected from: N or CR ¹ ; Each R ¹ is independently selected from the group consisting of H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, OH, substituted or unsubstituted O-C ₁ -C ₆ alkyl, substituted or unsubstituted OC ₃ -C ₈ cycloalkyl; Each R ^1a is independently selected from the group consisting of H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl; In the R ¹ and R ^1a , the substitution refers to having one or more (such as 1, 2, 3, 4) substituents selected from group A: halogen, hydroxyl, -NH ₂ , nitro, - CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, OC ₁ -C ₄ alkyl, C ₃ -C ₈ cycloalkyl, OC ₃ -C ₈ cycloalkyl, C ₂ -C ₄ chain Alkenyl, C ₂ -C ₄ alkynyl, phenyl, benzyl; selected from the group consisting of substituted or unsubstituted C ₆ -C ₁₀ aryl, substituted or unsubstituted C ₃ -C ₁₀ heteroaryl and the heteroaryl has 1-3 selected from S, O or N Heteroatom; wherein, the substitution refers to having one or more (such as 1, 2, 3, 4) substituents selected from group B: halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, hydroxyl, amino, nitro, substituted or unsubstituted C ₁ -C ₆ aldehyde, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl , -COR ^a , -CO ₂ C ₁ -C ₆ alkyl, -CONR ^a R ^b , -SO ₂ R ^b , -SO ₂ NR ^a R ^b ; X is selected from the group consisting of H, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl, OH, substituted or unsubstituted OC ₁ -C ₆ alkyl, substituted or unsubstituted OC ₃ -C ₈ cycloalkyl, NR ^a R ^b or NR ^a C (O)R ³ ; And, when X is selected from: H, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, or When substituted or unsubstituted C ₃ -C ₁₄ heteroaryl, Y is selected from the group consisting of substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or Unsubstituted C ₁ -C ₆ alkylthio, substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl, -(CR ¹ ₂ ) _n C(O )NR ² R ³ , -C(CR ¹ ₂ ) _n C(S)NR ² R ³ , -O(CR ¹ ₂ ) _n C(O)NR ² R ³ , -S(CR ¹ ₂ ) _n C( O)NR ² R ³ , -NR ² (CR ¹ ₂ ) _n C(O)NR ² R ³ , -NR ² (CR ¹ ₂ ) _n C(O)R ³ , -NR ² C(O)(CR ¹ ₂ ) _n C(O)R ³ , -NR ² (CR ¹ ₂ ) _n C(O)O(CR ¹ ₂ ) _n R ³ , -NR ² (CR ¹ ₂ ) _n C(S)NR ² R ³ , -NR ² (CR ¹ ₂ ) _n C(O)NR ² R ³ , -NR ² (CR ¹ ₂ ) _n C(S)NR ² R ³ , -(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ R ³ , -(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ NR ² R ³ , -O(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ R ³ , -S(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ R ³ , -NR ² (CR ¹ ₂ ) _n S(O) ₂ NR ² R ³ , -NR ² S( O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n S(O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n NR ² S(O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n NR ² C(O)NR ¹ S(O) ₂ R ³ , -(CR ¹ ₂ ) _n S(O)(=NR ² )R ³ , -(CR ¹ ₂ ) _n S(O)(=NCN )R ³ , -(CR ¹ ₂ ) _n S(O)R ³ , -NR ² S(O) ₂ R ³ , -(CR ¹ ₂ ) _n S(O) ₂ R ³ , NR ² C(=N -CN) NR ² R ³ ; the substitution refers to having one or more ( Such as 1, 2, 3, 4) substituents: halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₃ -C ₁₀ heterocycloalkyl, C ₆ -C ₂₀ aryl, C ₃ -C ₁₄ heteroaryl hydroxyl, OC ₆ -C ₂₀ aryl, OC ₃ -C ₁₄ heteroaryl, hydroxyl, OSO ₂ NH ₂ , NHSO ₂ NH ₂ , amino, nitro, aldehyde, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl, -COR ^a , -CO ₂ C ₁ -C ₆ alkyl, -CONR ^a R ^b , -SO ₂ R ³ , -SO ₂ NR ^a R ^b , -P(O)Me ₂ , -P(O)(OMe) ₂ ; When X is selected from: OH, OC ₁ -C ₆ alkyl, OC ₃ -C ₈ cycloalkyl, NR ^a R ^b or NR ^a C (O) R ³ , Y is selected from the following group: substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, Substituted or unsubstituted C ₃ -C ₁₀ heterocycloalkyl, -(CR ¹ ₂ ) _n C(O)NR ² R ³ , -(CR ¹ ₂ ) _n C(S)NR ² R ³ , -(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ R ³ , -(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n S( O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n NR ² S(O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n NR ² C(O)NR ¹ S(O) ₂ R ³ , -(CR ¹ ₂ ) _n S(O)(=NR ² )R ³ , -(CR ¹ ₂ ) _n S(O)(=NCN)R ³ , -(CR ¹ ₂ ) _n S(O)R ³ , -(CR ¹ ₂ ) _n S(O) ₂ R ³ ; the substitution refers to having one or more (such as 1, 2, 3, 4) substituents selected from Group D: halogen, C ₁ - C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₃ -C ₁₀ heterocycloalkyl, substituted or unsubstituted C ₆ -C ₂₀ aryl , C ₃ -C ₁₄ heteroaryl hydroxyl, OC ₆ -C ₂₀ aryl, OC ₃ -C ₁₄ heteroaryl, hydroxyl amino, nitro, aldehyde, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl, -COR ^a , -CH ₂ -C ₆ -C ₁₀ aryl, -CH ₂ -C ₆ -C ₁₀ aryl, -CO ₂ C ₁ -C ₆ alkyl, -CONR ^a R ^b , -SO ₂ R ³ , -SO ₂ NR ^a R ^b , -P(O)Me ₂ , -P(O)(OMe) ₂ , hydroxyl, OSO ₂ NH ₂ , NHSO ₂ NH ₂ , C ₃ -C ₆ hetero ring group; Wherein, each R ^a and each R ^b are independently selected from the following group: hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkenyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl, or R ^a and R ^b and the N atom connected to it Together form a substituted or unsubstituted 4-8 membered heterocyclic ring, and the heterocyclic ring has at least one N and 0-2 heteroatoms selected from S and O, wherein N in the nitrogen-containing heterocyclic ring is NH or NR ^g form, wherein R ^g is independently C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₂₀ aryl, or C ₃ -C ₁₄ heteroaryl; wherein, the Substitution refers to having one or more (such as 1, 2, 3, 4) substituents selected from group E: halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, hydroxyl, OSO ₂ NH ₂ , NHSO ₂ NH ₂ , amino, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl, -COR ^a , -CO ₂ C ₁ -C ₆ alkane group, -CONR ^a R ^b , -SO ₂ R ^b , -SO ₂ NR ^a R ^b ; Each R ² and each R ³ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkenyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl, substituted or unsubstituted C ₃ -C ₁₀ heterocyclyl, substituted or unsubstituted amino; is a substituted or unsubstituted 3-10 membered carbocyclic or heterocyclic ring having at least one carbon atom substituted by a heteroatom selected from the group consisting of O, S, S(O), S(O) ₂ , C(O), C(S) and NR ^g ; wherein, the substitution refers to having one or more (such as 1, 2, 3, 4) substituents selected from Group F: OH, halogen, C _{1- 6} alkyl; Among the substituents in Group A, Group B, Group C, Group D, Group E, Group F, R ² , R ³ , the substitution refers to having one or more (such as 1, 2, 3) selected from Group G , 4) substituents: halogen, C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -CN, -CF ₃ , -O-CF ₃ , C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₈ ester group, C ₆ -C ₁₀ aryl group; Z is a carbon atom or N; when Z is N, X is absent; n is an integer of 0 to 8. 2. the compound of formula (I) as claimed in claim 1 or its pharmaceutically acceptable salt, its stereoisomer or its tautomer or its prodrug, it is characterized in that, the formula ( I) compound is selected from the formula (II)-formula (VI) compound shown in following group: Compound of formula (II): In the formula, Select from the group: Wherein, R ^c is one or more groups selected from the group consisting of halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₁₀ cycloalkoxy, hydroxyl, amino, nitro, substituted or unsubstituted C ₁ -C ₆ aldehyde, -CF ₃ , - CN, -SF ₅ , NR ^a R ^b , carboxyl, -COR ^a , -CO ₂ C ₁ -C ₆ alkyl, -CONR ^a R ^b , -SO ₂ R ³ , -SO ₂ NR ^a R ^b ; where each R ^a and each R ^b are as defined above; m is an integer from 1 to 4; q is 1, 2 or 3; r is 1 or 2; Z, X, Y are as defined above; or Compound of formula (III): In the formula, X, Y, Z, R ^c are as defined above, m is an integer from 1 to 4; or Compound of formula (IV): In the formula, In the formula, R ^c is one or more groups selected from the group consisting of halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted Substituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkoxy, hydroxyl, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl, -COR ^a , -CONR ^a R ^b , -SO ₂ R ³ , -SO ₂ NR ^a R ^b ; wherein each R ^a and each R ^b are as defined above; m is an integer from 1 to 4; is a substituted or unsubstituted 3-7 membered heterocycle selected from the group consisting of: X is selected from the group consisting of OH, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, alkylOC ₁ -C ₆ alkyl, OC ₃ -C ₈ Cycloalkyl, NR ^a R ^b or NR ^a C (O) R ³ ; Selected from the following group: substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl, wherein the aromatic ring and heteroaryl ring can be selected from the following group by one or more The group E is substituted by: halogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₃ -C ₁₀ heterocycloalkyl, C ₆ -C ₂₀ aryl, C ₃ -C ₁₄ heteroaryl hydroxyl, OC ₆ -C ₂₀ aryl, OC ₃ -C ₁₄ Heteroaryl, hydroxyamino, nitro, aldehyde, OH, OSO ₂ NH ₂ , NHSO ₂ NH ₂ , -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl, -COR ^a , -CO ₂ C ₁ -C ₆ alkyl, -CONR ^a R ^b , -SO ₂ R ³ , -SO ₂ NR ^a R ^b , -P(O)Me ₂ , -P(O)(OMe) ₂ ; where each R ^a and each R ^b are independently hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkenyl, Substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl; R ^a and R ^b can together form a four to eight-membered heterocyclic ring, wherein the heteroatom can be sulfur, Oxygen, NH or NR ^g ; or Compound of formula (V): In the formula, R ^c is one or more groups selected from the group consisting of halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, hydroxyl, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl, -COR ^a , -CONR ^a R ^b , -SO ₂ R ³ , -SO ₂ NR ^a R ^b ; wherein each R ^a and each R ^b is as defined above; m is an integer from 1 to 4; Select from the group: R ^d is selected from the group consisting of H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, Substituted or unsubstituted C ₃ -C ₈ cycloalkoxy, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, substituted or unsubstituted C ₃ -C ₁₄ Heteroaryl; said substitution refers to having one or more (such as 1, 2, 3, 4) substituents selected from H group: halogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkane C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₃ -C ₁₀ heterocycloalkyl, C ₆ -C ₂₀ aryl , C ₃ -C ₁₄ heteroaryl hydroxyl, OC ₆ -C ₂₀ aryl, OC ₃ -C ₁₄ heteroaryl, hydroxyl amino, nitro, aldehyde, OH, OSO ₂ NH ₂ , NHSO ₂ NH ₂ , - CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl, -COR ^a , -CO ₂ C ₁ -C ₆ alkyl, -CONR ^a R ^b , -SO ₂ R ³ , -SO ₂ NR ^a R ^b , -P(O)Me ₂ , -P(O)(OMe) ₂ ; or Compound of formula (VI): In the formula, R ^c is one or more groups selected from the group consisting of halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkoxy, hydroxyl, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl, -COR ^a , -CONR ^a R ^b , -SO ₂ R ³ , -SO ₂ NR ^a R ^b ; wherein each R ^a and each R ^b is as defined above; m is an integer from 1 to 4; Select from the group: R ^f is selected from the group consisting of H, SO ₂ NH ₂ , C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkenyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroarylamino; One or more (such as 1, 2, 3, 4) substituents: C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ cycloalkyl, C ₁ -C ₆ Haloalkyl, alkoxy, heterocyclyl, aryl, heteroaryl, -CF ₃ , -CN, -SF ₅ , NR ^a R ^b , carboxyl, hydroxyl, OSO ₂ NH ₂ , NHSO ₂ NH ₂ , amino, -COR ^a , -CONR ^a R ^b , -SO ₂ R ³ , -SO ₂ NR ^a R ^b ; wherein, the R ^a and R ^b and the N atoms connected to them together form a substituted or unsubstituted 4-8 A membered heterocycle, and the heterocycle has at least one N and 0-2 heteroatoms selected from S and O, wherein N in the nitrogen-containing heterocycle is in the form of NH or ^NRg , wherein ^Rg is independently is C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₂₀ aryl, or C ₃ -C ₁₄ heteroaryl. 3. the compound of formula (I) as claimed in claim 1 or its pharmaceutically acceptable salt, its stereoisomer or its tautomer or its prodrug, it is characterized in that, the is selected from the group consisting of substituted or unsubstituted thienyl, substituted or unsubstituted furyl, or substituted or unsubstituted pyridyl. 4. the compound of formula (I) as claimed in claim 1 or its pharmaceutically acceptable salt, its stereoisomer or its tautomer or its prodrug, it is characterized in that, the Select from the group: 5. The formula (I) compound or its pharmaceutically acceptable salt, its stereoisomer or its tautomer or its prodrug as claimed in claim 1, it is characterized in that, when X is selected from : H, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C When ₃ -C ₁₄ heteroaryl, Y is selected from the group consisting of substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ - C ₁₄ heteroaryl, -(CR ¹ ₂ ) _n C(O)NR ² R ³ , -C(CR ¹ ₂ ) _n C(S)NR ² R ³ , -O(CR ¹ ₂ ) _n C(O )NR ² R ³ , -S(CR ¹ ₂ ) _n C(O)NR ² R ³ , -NR ² (CR ¹ ₂ ) _n C(O)NR ² R ³ , -NR ² (CR ¹ ₂ ) _n C(O)R ³ , -NR ² C(O)(CR ¹ ₂ ) _n C(O)R ³ , -NR ² (CR ¹ ₂ ) _n C(O)OR ³ , -NR ² (CR ¹ ₂ ) _n C(S)NR ² R ³ , -NR ² (CR ¹ ₂ ) _n C(O)NR ² R ³ , -NR ² (CR ¹ ₂ ) _n C(S)NR ² R ³ , -(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ R ³ , -(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ NR ² R ³ , -NR ² (CR ¹ ₂ ) _n C(S)NR ² R ³ , -NR ₂ C(O)NR ² R ³ , -NR ₂ C(S)NR ² R ³ , -(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ R ³ , -O(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ R ³ , -S(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ R ³ , -NR ² (CR ¹ ₂ ) _n S(O) ₂ NR ₂ R ₃ , -NR ² S(O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n S(O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n NR ² S(O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n NR ² C(O)NR ¹ S(O) ₂ R ³ , -(CR ¹ ₂ ) _n S(O) (=NR ² )R ³ , -(CR ¹ ₂ ) _n S(O)(=NCN)R ³ , -(CR ¹ ₂ ) _n S(O)R ³ , -(CR ¹ ₂ ) _n S(O) ₂ R ³ , NR ² C(=N-CN)NR ² R ³ ; the substitution refers to having One or more (such as 1, 2, 3, 4) substituents selected from Group C. 6. The formula (I) compound or its pharmaceutically acceptable salt, its stereoisomer or its tautomer or its prodrug as claimed in claim 1, it is characterized in that, when X is selected from When the lower group: OH, OC ₁ -C ₆ alkyl, OC ₃ -C ₈ cycloalkyl, NR ^a R ^b or NR ^a C (O) R ³ , Y is selected from the lower group: substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl, -(CR ¹ ₂ ) _n C(O)NR ² R ³ , -(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ R ³ , -(CR ¹ ₂ ) _n S(O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n NR ² S(O ) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n NR ² C(O)NR ¹ S(O) ₂ R ³ , -(CR ¹ ₂ ) _n C(O)NR ² S(O) ₂ NR ² R ³ , -(CR ¹ ₂ ) _n S(O)(=NR ² )R ³ , -(CR ¹ ₂ ) _n S(O)(=NCN)R ³ , -(CR ¹ ₂ ) _n S(O )R ³ , -(CR ¹ ₂ ) _n S(O) ₂ R ³ ; the substitution refers to having one or more (such as 1, 2, 3, 4) substituents selected from Group D. 7. The formula (I) compound or its pharmaceutically acceptable salt, its stereoisomer or its tautomer or its prodrug as claimed in claim 1, it is characterized in that, each R ² and each R ³ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ - C ₁₀ alkenyl, substituted or unsubstituted C ₆ -C ₂₀ aryl, or substituted or unsubstituted C ₃ -C ₁₄ heteroaryl. 8. the compound of formula (I) as claimed in claim 1 or its pharmaceutically acceptable salt, its stereoisomer or its tautomer or its prodrug, it is characterized in that, the formula ( I) The compound is selected from the group consisting of: (cis/trans) 3-phenylspiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-ol; (cis) 4-methyl-N-((1S,3S)-spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzenesulfonamide; (Trans) 4-Methyl-N-((1S,3S)-spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzenesulfonamide Formamide; (trans) 4-methyl-N-((1S,3S)-spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide; (cis/trans) 3-fluoro-N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide; (cis) 4-fluoro-N-spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzenesulfonamide; (cis) N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)cyclohexylsulfonamide; (cis) 3-chloro-4-fluoro-N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)benzamide; (trans) 3-bromo-4-fluoro-N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)benzamide; (trans) N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)propane-2-sulfonamide; (trans) N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)naphthalene-2-sulfonamide; (trans) N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)naphthalene-1-sulfonamide; (trans) 2-fluoro-N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide; (trans) 2,4-dichloro-N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)benzamide; (trans) 4-methoxy-N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide; (trans) N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)-2-naphthylcarboxamide; (trans) 3-chloro-N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide; (trans) 3-bromo-N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)benzamide; (trans) N-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)-3-(trifluoromethyl)benzamide; (trans)phenyl spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-ylcarbamate; (trans)nitro-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindol]-3-yl)methylsulfonamide; (trans) 3,4-dichloro-nitrogen-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindole]-3-yl)benzamide; (trans) 4-bromo-nitrogen-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindol]-3-yl)benzamide; (trans) N-(3-bromo-4-fluorophenyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide; (trans) N-(3-chlorophenyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide; (trans)-N-(3-bromophenyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide; (cis)-N-(3-bromophenyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide; (trans)N-(4-fluorophenyl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-carboxamide; (cis/trans) 3-(1-Benzyl-1H-1,2,3-triazol-4-yl)spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole ]-3-ol; (trans) 3-(-spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindole]-3-yl)sulfonylurea; (trans)1-phenyl-3-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindol]-3-yl)thiourea; (cis) 1-(3-fluorophenyl)-3-(spiro[cyclobutane-1,5'-imidazole 5,1-a]isoindoll]-3-yl)thiourea; (cis) 1-(4-chlorophenyl)-3-(spiro[cyclobutane-1,5'-imidazole 5,1-a]isoindol 1]-3-yl)thiourea; (cis)1-(4-trifluoromethylphenyl)-3-(spiro[cyclobutane-1,5'-imidazole 5,1-a]isoindoll]-3-yl)thiourea ; (cis)1-(3-trifluoromethylphenyl)-3-(spiro[cyclobutane-1,5'-imidazole 5,1-a]isoindoll]-3-yl)thiourea ; (cis)1-(3-Chloro-4-(trifluoromethyl)phenyl)-3-(spiro[cyclobutane 1,5'-imidazol[5,1-a]isoindole]-3 - base) urea; (cis)1-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindol]-3-yl)-3-(3-(trifluoromethyl)phenyl) urea; (cis)1-(3,5-bis(trifluoromethyl)phenyl)-3-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindole]-3 - base) thiourea; (cis)1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(spiro[cyclobutyl-1,5'-imidazol[5,1-a]isoindole]- 3-yl) thiourea; (cis)1-(3,5-bis(trifluoromethyl)phenyl)-3-(spiro[cyclobutane-1,5'-imidazol[5,1-a]isoindole]-3 - base) urea; (cis) 1-(3,4-dichlorophenyl)-3-(spiro[cyclobutyl-1,5’-imidazol[5,1-a]isoindol]-3-yl)urea; (trans)1-(3-trifluoromethylphenyl)-3-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)thiourea ; (trans)1-(3-fluorophenyl)-3-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)thiourea; (trans)1-(4-chlorophenyl)-3-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)thiourea; (trans) 1-(3-fluorophenyl)-3-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindole]-3-yl)sulfonylurea; (cis) 1-methyl-3-(spiro[cyclobutane 1,5'-imidazo[5,1-α]isoindol]-3-yl)sulfonylurea; (cis/trans)1-(spiro[cyclohexyl-1,5'-imidazo[5,1-α]isoindol]-4-yl)-3-(3-(trifluoromethyl)phenyl ) thiourea; (cis/trans) 1-(4-chlorophenyl)-3-(spiro[cyclohexyl-1,5'-imidazo[5,1-α]isoindol]-4-yl)thiourea; (cis/trans)1-(spiro[cyclohexyl-1,5'-imidazo[5,1-α]isoindol]-4-yl)-3-(4-(trifluoromethyl)phenyl ) thiourea; (cis/trans)1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(spiro[cyclohexyl-1,5'-imidazo[5,1-α]isoindole] -4-yl)urea; (cis/trans)6'-fluoro-1-(3-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)spiro[azetidine-3,5'-imidazo [5,1-a]isoindole]; or (cis/trans)6-fluoro-1'-(3-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)spiro[imidazo[5,1-a]isoindole -5,4'-piperidine]. 9. A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises: (1) The compound of formula (I) as claimed in claim 1, or its pharmaceutically acceptable salt, its stereoisomer or its tautomer, or its prodrug; (2) Pharmaceutically acceptable carrier and/or antitumor drug. 10. A compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a tautomer thereof, or a prodrug thereof, for: (i) preparing IDO/TDO inhibitors; (ii) Preparation of medicaments for preventing and/or treating diseases mediated by IDO and TDO.