CN112778156B - Bishydrazide structure compound, preparation method and application thereof - Google Patents

Abstract

The invention provides a bishydrazide structural compound, a preparation method and an application thereof. Specifically, the present invention provides compounds of the bishydrazide structure represented by formula I. The compound of the invention can enhance the activity of intestinal stem cells, promote the repair of intestinal epithelium, and reduce the expression of pro-inflammatory cytokines, thereby achieving the treatment of inflammatory intestinal diseases.

Description

Bishydrazide structure compound, its preparation method and application

technical field

The invention belongs to the field of medicinal chemistry, and specifically relates to bishydrazide structural compounds, a preparation method and application thereof.

Background technique

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is characterized by recurrent inflammation of the digestive tract. In recent years, the global incidence rate has increased significantly. The pathogenesis of IBD is not yet clear, and studies have shown that it is related to factors such as heredity, immunity, infection and mental activity. Recurrent disease can cause DNA damage and microsatellite instability in mucosal cells, leading to colon cancer. Studies have confirmed that the risk of colon cancer in IBD patients is significantly higher than that of normal people.

Among the inflammatory cytokines involved in the pathogenesis of IBD, members of the IL-12 family, especially IL-23, have received extensive attention and are considered to be the core factors in experimental enteritis models and the pathogenesis of human IBD. IL-23 can activate CD4+ memory cells, CD8+ cells, NK cells and a few mononuclear macrophages/dendritic cells. By combining with IL-23 receptor (IL-23R), it induces the secretion of IL-10, IL-17 and INF-γ, thereby promoting the development of inflammation. Recent human genetic studies have identified IL-23R variants associated with inflammatory responses in the small intestine (ileal CD) and large intestine (UC). Studies have found that IL-23 can maintain and expand the function of Th17 cells and aggravate the intestinal inflammatory response.

In recent years, the advent of biological therapies such as anti-TNF therapy has greatly improved the treatment of IBD. However, there are still a large number of patients with refractory ulcers or refractory epithelial heterogeneity, making it difficult to achieve "mucosal healing" in these patients. Mucosal healing indicates restoration of intestinal epithelial structure and function in patients with IBD, while also revealing long-term remission or low-risk prognosis for surgery. Currently, the importance of restoring the structure and function of the intestinal epithelium is well established in the treatment of IBD; there is also consensus among clinicians and researchers that mucosal healing is a standard goal of treatment. However, there is currently no suitable treatment. The application of immunosuppressants and anticytokine has improved the relapse rate of IBD patients, but there is still a lack of drugs that can cure IBD.

Therefore, there is an urgent need in this field to find key molecules in the pathogenesis and/or progression of IBD, and to develop new compounds that can be used to treat IBD.

Contents of the invention

The object of the present invention is to provide a class of bishydrazide structural compounds that can be used for treating IBD.

The first aspect of the present invention provides a compound represented by formula I, its optical isomers or cis-trans isomers, pharmaceutically acceptable salts, hydrates, solvates, prodrugs or active metabolites thereof,

in,

表示单键或双键；

Indicates a single or double bond;

X ₁ , X ₂ , and X ₃ are each independently selected from the following group: C(R ₁ ) ₂ , NR ₁ , CR ₁ or N;

为芳香环或非芳香环；and

is an aromatic ring or a non-aromatic ring;

G is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylamino , hydroxymethyl, C ₁ -C ₆ haloalkyl, or -L ₁ -M;

Q is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylamino , hydroxymethyl, C ₁ -C ₆ haloalkyl, or -L ₁ -M;

When G is on _X3 , Q can be on _X1 or _X2 ;

When Q is on _X3 , G can be on _X1 or _X2 ;

R ₁ is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylamino, hydroxymethyl, or C ₁ -C ₆ haloalkyl;

L ₁ is independently selected from the group consisting of -NHC(=O)-, -OC(=O)-, -NHS(=O)-, -OS(=O)-, -NHSO ₂ -, -C(= O)NH-, -C(=O)O-, -S(=O)NH-, -OS(=O)O-, or _-SO2NH- ;

M is independently selected from the following group: C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted 3-20 heterocyclyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, substituted or unsubstituted 6-14 membered heteroaryl; and -L ₁ -M can optionally be further replaced by one or more halogens, 3-12 membered heterocyclic groups or C _3-12 cycloalkyl substituted;

The substitution is one or more selected from the group consisting of halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, C ₃ -C ₆ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ haloalkynyl, C ₃ -C ₆ cycloalkylalkynyl, C ₆ -C ₁₄ aryl, 5-14 membered heterocyclic group, and the aryl, heteroaryl can optionally be further Substituted by one or more substituents selected from the following group: halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino;

A is independently selected from the following group: substituted or unsubstituted C _3-12 cycloalkyl, substituted or unsubstituted 3-20 membered heterocyclic group, substituted or unsubstituted C ₆ -C ₁₄ aryl, substituted or unsubstituted 6- 14-membered heteroaryl; wherein, the substitution is one or more selected from the group consisting of halogen, hydroxyl, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkane Amino, hydroxymethyl or C ₁ -C ₆ haloalkyl;

K is independently selected from the group consisting of R ₂ -C(=O)NH-, R ₂ -C(=O)O-, -C(=O)NH-R ₂ , -C(=O)OR ₂ , R ₂ is independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₆ -C ₁₄ aryl, 6-14 membered heteroaryl.

In another preferred embodiment, the compound, its optical isomer or cis-trans isomer, pharmaceutically acceptable salt, hydrate, solvate, prodrug or active metabolite thereof has the following formula II structure shown

in,

X ₁ , X ₂ , and X ₃ are each independently selected from: CR ₁ or N;

R ₁ is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylamino, hydroxymethyl, halomethyl or -L ₁ -M;

L ₁ is independently selected from the group consisting of -NHC(=O)-, -OC(=O)-, -NHS(=O)-, -OS(=O)-, -NHSO ₂ -, -C(= O)NH-, -C(=O)O-, -S(=O)NH-, -OS(=O)O- or -SO ₂ NH-;

M is independently selected from the group consisting of C ₂ -C ₄ alkyl, C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene Base, substituted or unsubstituted tetrahydronaphthyl, substituted or unsubstituted 6-20 membered fused heterocycle, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted 5-6 membered heteroaryl; said M can be further Substituted by one or more halogens, 3-12 membered heterocyclic groups or C _3-12 membered cycloalkyl groups; and the substitution is selected from one or more of the following groups: halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, C ₃ -C ₆ cycloalkenyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ haloalkynyl, C3-C6 cycloalkyl-C3-C6 alkynyl, phenyl , or a 5-14 membered heterocyclic group, and the phenyl, 5-14 membered heterocyclic group can optionally be further substituted by one or more substituents selected from the group: halogen, nitro, cyano , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ alkylamino;

A is independently selected from the group consisting of substituted or unsubstituted C _3-12 cycloalkyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, or substituted or unsubstituted 6-14 membered heteroaryl; wherein the substituted One or more selected from the following group: halogen, hydroxyl, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, hydroxymethyl or halomethyl;

K is independently selected from the group consisting of -C(=O)NH-R ₂ , -C(=O)OR ₂ , R ₂ is independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₆ - C ₁₄ aryl or 6-14 membered heteroaryl.

In another preferred example, the compound, its optical isomer or cis-trans isomer, pharmaceutically acceptable salt, hydrate, solvate, prodrug or active metabolite thereof has the following formula III structure shown,

Wherein, the definitions of G, Q, A, and K are as above.

In another preferred example, the compound, its optical isomer or cis-trans isomer, pharmaceutically acceptable salt, hydrate, solvate, prodrug or active metabolite thereof has the following formula IV structure shown,

Wherein, the definitions of G, Q, A, and K are as above.

In another preferred embodiment, the compound, its optical isomer or cis-trans isomer, pharmaceutically acceptable salt, hydrate, solvate, prodrug or active metabolite thereof has the following formula V structure shown,

Wherein, the definitions of G, Q, A, and K are as above.

In another preferred embodiment, the compound is selected from the following compounds:

2-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

Methyl 2-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylate;

2-(2-(4-(3-methylbutanylamino)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(4-Acetamidobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(4-Benzamidobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(4-(cyclohexanecarboxamido)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(4-(cyclopropylcarbamoyl)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(4-chlorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(4-fluorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(4-(trifluoromethoxy)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(4-(tert-butyl)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(4-(trifluoromethyl)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(4-(oxazol-5-yl)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(3-chlorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(2-chlorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(2,4-Dichlorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(6-chloronicotinoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(6-bromonicotinoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(4-(cyclopropanecarboxamido)-3-fluorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(4-(cyclopropanecarboxamido)-2-fluorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(2-chloro-4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(3-chloro-4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(3-(cyclopropanecarboxamido)-4-fluorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

3-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid;

2-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)benzoic acid;

3-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid;

2-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)cyclopropane-1-carboxylic acid;

4,5-Dibromo-2-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid;

2-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)-3,6-difluorobenzoic acid;

2-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)-3,6-difluorobenzoic acid;

2-(2-(4-fluorobenzoyl)hydrazine-1-carbonyl)benzoic acid;

3-(2-(4-fluorobenzoyl)hydrazine-1-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid;

3-(2-(4-chlorobenzoyl)hydrazine-1-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid;

3-(2-(3-Chlorobenzoyl)hydrazine-1-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid;

3-(2-(2-Chlorobenzoyl)hydrazine-1-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid;

3-(2-(2,4-dichlorobenzoyl)hydrazine-1-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid;

3-(2-(4-(Cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)-2-naphthoic acid.

The second aspect of the present invention provides the preparation of the compound of formula I described in the first aspect, its optical isomers or cis-trans isomers, pharmaceutically acceptable salts, hydrates, solvates, prodrugs or active metabolites thereof method, including the following steps:

In the first inert solvent, compound _a2 reacts with compound b, and optionally further reacts to obtain compound I;

Wherein, X ₁ , X ₂ , X ₃ , G, Q, A, and K are as defined above.

In another preferred example, the further reaction refers to substitution with halogenated alkanes, or condensation reaction with alcohol or amine to obtain compound I; the alcohol is C ₁ -C ₆ alkyl-OH, and the The above-mentioned amine is C ₁ -C ₆ alkyl-NH ₂ or C ₁ -C ₆ alkyl-NC ₁ -C ₆ alkyl.

In another preferred example, the first inert solvent is selected from: CH ₃ CN, toluene, xylene, methylene chloride, DMF, or a combination thereof.

In another preferred embodiment, the preparation method of the salt comprises making the compound of formula I and free base or acid and chemical equivalent or excess acid (inorganic acid or organic acid) or base (inorganic base or organic base), in Prepared by reaction in a suitable solvent or solvent composition.

In another preferred embodiment, the preparation method of the compound of formula I, its optical isomers or cis-trans isomers, pharmaceutically acceptable salts, hydrates, solvates, prodrugs or active metabolites thereof, further includes the following steps :

In a second inert solvent, compound a ₁ is reacted with hydrazine hydrate to form compound a ₂ ;

Wherein, X ₁ , X ₂ , X ₃ , G, and Q are as defined above.

In another preferred example, the second inert solvent is alcohol, preferably C ₁ -C ₆ alkyl alcohol, more preferably methanol or ethanol.

The third aspect of the present invention provides a pharmaceutical composition, which comprises the compound described in the first aspect, its optical isomers or cis-trans isomers, pharmaceutically acceptable salts, hydrates, solvates, prodrugs or an active metabolite; and a pharmaceutically acceptable carrier.

The fourth aspect of the present invention provides the compound described in the first aspect, its optical isomers or cis-trans isomers, pharmaceutically acceptable salts, hydrates, solvates, prodrugs or active metabolites, or the third aspect Use of the pharmaceutical composition in the preparation of medicines and pharmaceutical compositions for treating or preventing inflammatory bowel disease.

In another preferred example, the inflammatory bowel disease includes Crohn's disease or intestinal lesions associated with Behcet's disease, ulcerative colitis, bleeding rectal ulcer and ileal bursitis.

In another preferred example, the treatment includes: promoting mucosal healing, restoring intestinal epithelial structure, or a combination thereof.

In another preferred example, the treatment includes: promoting the activity of intestinal stem cells, reducing the expression of pro-inflammatory cytokines, or a combination thereof.

The fifth aspect of the present invention provides a method for inhibiting IL-23 and upregulating cyclinD1 in vitro, comprising the steps of: taking the compound described in the first aspect of the present invention, its optical isomers or cis-trans isomers, pharmaceutically acceptable Salts, hydrates, solvates, prodrugs or active metabolites of β-β, contact with somatic cells (or tissues), thereby inhibiting IL-23 and upregulating cyclinD1.

In another preferred example, said inhibiting IL-23 includes inhibiting the formation of IL-23 miRNA and inhibiting the expression of IL-23 protein.

In another preferred example, the up-regulation of cyclinD1 includes promoting the formation of cyclinD1 miRNA and the expression of cyclinD1 protein.

In another preferred embodiment, the somatic cells are selected from the group consisting of macrophages, intestinal cells (including intestinal stem cells, intestinal epithelial cells), or combinations thereof.

In another preferred example, the somatic cells are from rodents (such as mice, rats), or primates (such as humans).

The fifth aspect of the present invention provides a method for treating inflammatory bowel disease, comprising the step of: administering the compound described in the first aspect of the present invention, its optical isomers or cis-trans isomers to a subject in need of treatment , a pharmaceutically acceptable salt, hydrate, solvate, prodrug or active metabolite, or the pharmaceutical composition described in the third aspect.

In another preferred example, the inflammatory bowel disease includes Crohn's disease or intestinal lesions associated with Behcet's disease, ulcerative colitis, bleeding rectal ulcer and ileal bursitis.

In another preferred example, the subject is a mammal, preferably a human.

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 space limitations, we will not repeat them here.

Description of drawings

Figure 1 shows the therapeutic effect of Compound A ₁ on a mouse colitis model.

Figure 2 shows the blood concentration changes of Compound A ₁ administered orally to mice at two concentrations.

Figure 3 shows the growth-promoting effect of Compound A ₁ on mouse-derived intestinal organoids.

Detailed ways

After extensive and in-depth research, the inventors unexpectedly developed a class of bishydrazide structural compounds that can both inhibit IL-23 and up-regulate cyclinD1. The compound of the present invention can not only inhibit the excessively activated intestinal inflammatory response and immune response, thereby significantly reducing colonic inflammation in IBD mice, but also can effectively promote the healing of intestinal mucosa and maintain homeostasis, so it can be effectively and synergistically used for the treatment of inflammatory Intestinal disease. The present invention has been accomplished on this basis.

the term

The term "alkyl" means a straight or branched chain alkane group comprising 1-18 carbon atoms, especially 1-6 carbon atoms. Typical "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, isopentyl, heptyl, 4,4-dimethylpentyl Base, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc. The term "(C ₁ -C ₆ )alkyl" refers to straight or branched chain alkyl, including from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, Tert-butyl, isobutyl. "Substituted alkyl" means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or _Cl3 containing alkyl), Nitrile, nitro, oxygen (eg =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR _a , SR _a , S(=O)R _e , S(=O) ₂ R _e , P(=O) ₂ R _e , S(=O) ₂ OR _e , P(=O) ₂ OR _e , NR _b R _c , NR _b S(=O) ₂ R _e , NR _b P(=O) ₂ R _e , S(=O) ₂ NR _b R _c , P(=O) ₂ NR _b R _c , C(=O)OR _d , C(=O)R _a , C(=O)NR _b R _c , OC(=O)R _a , OC(=O)NR _b R _c , NR _b C(=O)OR _e ,NR _d C (=O)NR _b R _c , NR _d S(=O) ₂ NR _b R _c , NR _d P(=O) ₂ NR _b R _c , NR _b C(=O)R _a , or NR _b P( =O) ₂ R _e , wherein R _a appearing here can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R _b , R _c and R _d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R _b and R _c can form a heterocyclic ring together with N atoms; _Re can independently represent hydrogen, alkyl, cycloalkane group, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The typical substituents mentioned above, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic rings may be optionally substituted.

The term "alkenyl" refers to a substituent of a linear or branched chain hydrocarbon group containing 2-18 carbon atoms and at least one carbon-carbon double bond. The term "(C ₂ -C ₆ )alkenyl" refers to a linear or branched group containing 2-6 carbon atoms and at least one carbon-carbon double bond, such as vinyl, propenyl, 2-propenyl , (E)-2-butenyl, (Z)-2-butenyl, (E)-2-methyl-2-butenyl, (Z)-2-methyl-2-butenyl , 2,3-Dimethyl-2-butenyl, (Z)-2-pentenyl, (E)-1-pentenyl, (E)-2-pentenyl, (Z)-2 -Hexenyl, (E)-1-hexenyl, (Z)-1-hexenyl, (E)-2-hexenyl, (Z)-3-hexenyl, (E)-3 -hexenyl, (E)-1,3-hexadienyl, 4-methyl-3-pentenyl or norbornene. "Substituted alkenyl" means that one or more positions in the alkenyl group are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or _Cl3 containing alkyl), Nitrile, nitro, oxygen (eg =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR _a , SR _a , S(=O)R _e , S(=O) ₂ R _e , P(=O) ₂ R _e , S(=O) ₂ OR _e , P(=O) ₂ OR _e , NR _b R _c , NR _b S(=O) ₂ R _e , NR _b P(=O) ₂ R _e , S(=O) ₂ NR _b R _c , P(=O) ₂ NR _b R _c , C(=O)OR _d , C(=O)R _a , C(=O)NR _b R _c , OC(=O)R _a , OC(=O)NR _b R _c , NR _b C(=O)OR _e ,NR _d C (=O)NR _b R _c , NR _d S(=O) ₂ NR _b R _c , NR _d P(=O) ₂ NR _b R _c , NR _b C(=O)R _a , or NR _b P( =O) ₂ R _e , wherein R _a appearing here can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R _b , R _c and R _d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic ring or aromatic ring, or R _b and R _c can form a heterocyclic ring together with N atoms; R _e can independently represent hydrogen, deuterium, alkyl, ring Alkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The typical substituents mentioned above, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic rings may be optionally substituted.

The term "alkynyl" refers to a substituent of a straight or branched chain hydrocarbon group containing 2 to 18 carbon atoms and at least one carbon-carbon triple bond. Typical groups include ethynyl. The term "(C ₂ -C ₆ )alkynyl" refers to a straight-chain or branched group containing 2-6 carbon atoms and at least one carbon-carbon double bond, such as ethynyl, 1-propynyl, 2 -propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl. "Substituted alkynyl" means that one or more positions in the alkynyl group are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (eg, monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl ₃ ), Nitrile, nitro, oxygen (eg =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR _a , SR _a , S(=O)R _e , S(=O) ₂ R _e , P(=O) ₂ R _e , S(=O) ₂ OR _e , P(=O) ₂ OR _e , NR _b R _c , NR _b S(=O) ₂ R _e , NR _b P(=O) ₂ R _e , S(=O) ₂ NR _b R _c , P(=O) ₂ NR _b R _c , C(=O)OR _d , C(=O)R _a , C(=O)NR _b R _c , OC(=O)R _a , OC(=O)NR _b R _c , NR _b C(=O)OR _e ,NR _d C (=O)NR _b R _c , NR _d S(=O) ₂ NR _b R _c , NR _d P(=O) ₂ NR _b R _c , NR _b C(=O)R _a , or NR _b P( =O) ₂ R _e , wherein R _a appearing here can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R _b , R _c and R _d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic ring or aromatic ring, or R _b and R _c can form a heterocyclic ring together with N atoms; R _e can independently represent hydrogen, deuterium, alkyl, ring Alkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. Typical substituents can be optionally substituted.

The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group, including 1-4 rings, each containing 3-8 carbon atoms, such as 3-18 carbon atoms, especially 3 - 14 carbon atoms, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbornane. "Substituted cycloalkyl" means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or _Cl3 containing alkyl), Nitrile, nitro, oxygen (eg =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR _a , SR _a , S(=O)R _e , S(=O) ₂ R _e , P(=O) ₂ R _e , S(=O) ₂ OR _e , P(=O) ₂ OR _e , NR _b R _c , NR _b S(=O) ₂ R _e , NR _b P(=O) ₂ R _e , S(=O) ₂ NR _b R _c , P(=O) ₂ NR _b R _c , C(=O)OR _d , C(=O)R _a , C(=O)NR _b R _c , OC(=O)R _a , OC(=O)NR _b R _c , NR _b C(=O)OR _e ,NR _d C (=O)NR _b R _c , NR _d S(=O) ₂ NR _b R _c , NR _d P(=O) ₂ NR _b R _c , NR _b C(=O)R _a , or NR _b P( =O) ₂ R _e , wherein R _a appearing here can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R _b , R _c and R _d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic ring or aromatic ring, or R _b and R _c can form a heterocyclic ring together with N atoms; R _e can independently represent hydrogen, deuterium, alkyl, ring Alkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents may be optionally substituted. Typical substitutions also include spiro, bridged or fused ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spiroheterocycle (excluding heteroaryl rings), bridged cycloalkyl, bridged cycloalkenyl, Bridged ring heterocycle (excluding heteroaryl ring), fused ring alkyl group, fused ring alkenyl group, condensed ring heterocyclic group or condensed ring aromatic ring group, the above-mentioned cycloalkyl group, cycloalkenyl group, heterocyclic group and heterocyclic aromatic ring group The groups can be optionally substituted.

The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group, including 1-4 rings, and each ring contains 3-8 carbon atoms, such as 3-18 carbon atoms, especially 3-14 carbon atoms. Typical cycloalkenyl groups are cyclobutenyl, cyclopentenyl, cyclohexenyl and the like. "Substituted cycloalkenyl" means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or _Cl3 containing alkyl), Nitrile, nitro, oxygen (eg =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR _a , SR _a , S(=O)R _e , S(=O) ₂ R _e , P(=O) ₂ R _e , S(=O) ₂ OR _e , P(=O) ₂ OR _e , NR _b R _c , NR _b S(=O) ₂ R _e , NR _b P(=O) ₂ R _e , S(=O) ₂ NR _b R _c , P(=O) ₂ NR _b R _c , C(=O)OR _d , C(=O)R _a , C(=O)NR _b R _c , OC(=O)R _a , OC(=O)NR _b R _c , NR _b C(=O)OR _e ,NR _d C (=O)NR _b R _c , NR _d S(=O) ₂ NR _b R _c , NR _d P(=O) ₂ NR _b R _c , NR _b C(=O)R _a , or NR _b P( =O) ₂ R _e , wherein R _a appearing here can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R _b , R _c and R _d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic ring or aromatic ring, or R _b and R _c can form a heterocyclic ring together with N atoms; R _e can independently represent hydrogen, deuterium, alkyl, ring Alkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents may be optionally substituted. Typical substitutions also include bridged, spiro, or fused ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spiroheterocycle (excluding heteroaryl rings), fused cycloalkyl, fused cycloalkenyl, The fused-ring heterocyclic group or the condensed-ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic group and heterocyclic aryl group may be optionally substituted.

The term "cycloalkylalkynyl" refers to alkynyl substituted by cycloalkyl, including C3-C8 cycloalkyl-C≡CR _a , R _a can independently represent none, hydrogen, deuterium, alkyl, cycloalkyl, alkenyl , cycloalkenyl, alkynyl, heterocyclic or aromatic ring, for example: cyclopropylacetylene, cyclobutylacetylene, cyclopentylacetylene, cyclohexylacetylene. Wherein, the cycloalkyl group can be substituted, and the substituents can be the substituents in the term "cycloalkyl group".

The term "aryl" refers to an aromatic cyclic hydrocarbon group, having 1-5 rings, for example containing 6-18 carbon atoms, especially 6-14 carbon atoms. Especially monocyclic and bicyclic radicals such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be connected by a single bond (such as biphenyl), or fused (such as naphthalene, anthracene, etc.). "Substituted aryl" means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or _Cl3 containing alkyl), Nitrile, nitro, oxygen (eg =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR _a , SR _a , S(=O)R _e , S(=O) ₂ R _e , P(=O) ₂ R _e , S(=O) ₂ OR _e , P(=O) ₂ OR _e , NR _b R _c , NR _b S(=O) ₂ R _e , NR _b P(=O) ₂ R _e , S(=O) ₂ NR _b R _c , P(=O) ₂ NR _b R _c , C(=O)OR _d , C(=O)R _a , C(=O)NR _b R _c , OC(=O)R _a , OC(=O)NR _b R _c , NR _b C(=O)OR _e ,NR _d C (=O)NR _b R _c , NR _d S(=O) ₂ NR _b R _c , NR _d P(=O) ₂ NR _b R _c , NR _b C(=O)R _a , or NR _b P( =O) ₂ R _e , wherein R _a appearing here can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R _b , R _c and R _d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic ring or aromatic ring, or R _b and R _c can form a heterocyclic ring together with N atoms; R _e can independently represent hydrogen, deuterium, alkyl, ring Alkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents may be optionally substituted. Typical substitutions also include fused ring substituents, especially fused cycloalkyl, fused cycloalkenyl, fused heterocyclic or fused aromatic ring, the above cycloalkyl, cycloalkenyl, heterocyclic and heteroaryl The groups can be optionally substituted.

The term "heteroaryl" refers to a heteroaromatic system comprising 1-4 heteroatoms (preferably 1 or 2), 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. Heteroaryl is preferably a 5- to 10-membered ring, more preferably 5- or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazole Base, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazazinyl, triazolyl, purine, carbazole, indolyl, indazolyl, benzothienyl , benzofuryl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, isomerized quinolinyl, phthalazinyl, quinoxaline base, quinazolinyl, cinnolinyl or naphthyridinyl and tetrazolyl, etc. "Heteroaryl" may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkane Thio, oxo, carboxyl and carboxylate groups.

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

"Haloalkyl" refers to straight chain or branched haloalkyl, such as "C ₁ -C ₆ haloalkyl", which refers to a straight chain having 1 to 6 carbon atoms containing one or more same or different halogen atoms or branched chain haloalkyl, including without limitation -CH ₂ Cl, -CHCl ₂ , -CCl ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ Br, -CHBr ₂ , -CBr ₃ , _{CF3CH2 , CCl3CH2 , CBr3CH2 .}

The term "alkoxy" refers to a straight chain or branched chain alkoxy group, such as "C1-C6 alkoxy group", which refers to a straight chain or branched chain alkoxy group with 1 to 6 carbon atoms, without limitation Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. Preference is given to C1-C4 alkoxy.

The term "haloalkoxy" refers to a straight chain or branched chain alkoxy group substituted by halogen, such as "C1-C6 haloalkoxy group", which refers to a straight chain or branched chain haloalkoxy group having 1 to 6 carbon atoms, Including, but not limited to, chloromethoxy, chloroethoxy, chloropropoxy, chloroisopropoxy, chlorobutoxy, bromomethoxy, bromoethoxy, bromo Propoxy, bromoisopropoxy and bromobutoxy, etc.

The term "alkylamino" refers to a straight chain or branched chain alkyl substituted with an amino group, such as "C1-C6 alkylamino", which refers to a straight chain or branched chain alkyl group substituted with an amino group having 1 to 6 carbon atoms. groups, including without limitation H ₂ N-CH ₂ -, H ₂ N-CH ₂ CH ₂ -, H ₂ N-CH ₂ CH ₂ CH ₂ -, H ₂ N-CH(CH ₃ )CH ₂ -, etc. .

The term "haloalkenyl" refers to substituents containing 2 to 18 carbon atoms and at least one carbon-carbon double bond. The term "(C ₂ -C ₆ )halogenated alkenyl" refers to a linear or branched group containing 2-6 carbon atoms, at least one carbon-carbon double bond, and one or more same or different halogen atom groups , including -CH=CHCl, -CH=CCl ₂ , -CH=CHF, -CH=CF ₂ , -CH=CHBr, -CH=CBr ₂ , -CH=CH-CH ₂ F, -CH=CHCHF ₂ , -CH=CH-CF ₃ , -CH=CHCH ₂ Br , -CH=CHCHBr ₂ , -CH=CHCBr ₃ and the like.

The term "haloalkynyl" refers to substituents containing 2 to 18 carbon atoms and at least one carbon-carbon triple bond. The term "(C ₂ -C ₆ )haloalkynyl" refers to a linear or branched group containing 2-6 carbon atoms, at least one carbon-carbon triple bond, and one or more identical or different halogen atom groups , including -C≡CCl, -C≡CF, -C≡CBr, -C≡C-CH ₂ F, -C≡CCHF ₂ , -C≡C-CF ₃ , -C≡CCH ₂ Br, -C≡ CCHBr ₂ , -C≡CCBr ₃ , etc.

The term "carboxy" refers to -COOH.

The term "hydroxymethyl" refers to _-CH2OH .

The term "condensation reaction" means that the carboxylic acid compound obtained in the present invention reacts with alcohol or amine in the presence of a condensing agent; the condensing agent can use a commonly used condensing agent well known in the art, such as: DMAP, EDCI, HOBT, HOAT, HATU, HBTU, etc.

Unless otherwise stated, it is assumed that any heteroatom with a dissatisfied valence has sufficient hydrogen atoms to fill its valence.

The salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise stated, the compounds of the present invention are understood to include their salts. The term "salt" as used herein refers to an acidic or basic salt formed with an inorganic or organic acid and a base. Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in isolation or purification steps during preparation. The compound of the present invention may form a salt, for example, compound I reacts with a certain amount, such as an equivalent amount of acid or base, and salts it out in a medium, or freeze-dries it in an aqueous solution.

As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to broaden their scope. Generally, whether the term "substitution" appears before or after the term "optional", the general formula including the substituent in the formula of the present invention means that the hydrogen radical is replaced by the specified structural substituent. When multiple positions in a specific structure are substituted with multiple specific substituents, the substituents may be the same or different for each position. The term "substitution" as used herein includes all permissible organic compound substitutions. Broadly speaking, the permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds.

In the present invention eg heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to complement its valence.

In this specification, inflammatory bowel disease not only refers to inflammatory bowel disease in the strict sense such as Crohn's disease and ulcerative colitis, but also refers to inflammatory bowel disease in a broad sense, including those associated with Behcet's disease Intestinal lesions, bleeding rectal ulcer, ileal bursitis, intestinal tuberculosis, ischemic enteritis, drug-induced colitis, radiation enteritis, infectious enteritis, etc.

Furthermore, this invention is not intended to be limiting in any way to the organic compounds permissible to be substituted. Combinations of substituents and variables are contemplated by the present invention to be beneficial in the treatment of diseases, such as infectious or proliferative diseases, in the form of stable compounds. The term "stable" herein means having a compound that is stable, detectable for a sufficient period of time to maintain the structural integrity of the compound, preferably active for a sufficient period of time, and is used herein for the above purposes.

Metabolites of the compounds involved in the application and their pharmaceutically acceptable salts, as well as prodrugs that can be transformed into the structures of the compounds involved in the application and their pharmaceutically acceptable salts in vivo are also included in the scope of the present invention.

active ingredient

As used herein, the term "compound of the present invention" or "bishydrazide compound of the present invention" can be used interchangeably and refers to the compound represented by formula I. The term also includes compounds of formula I, optical isomers or cis-trans isomers thereof, pharmaceutically acceptable salts, hydrates, solvates, prodrugs or active metabolites thereof.

Wherein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compound of the present invention with an acid or a base which is suitable for use as a medicine. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are the salts of the compounds of the invention with acids. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and other organic acids; Amino acids such as amino acid, phenylalanine, aspartic acid, and glutamic acid. Another preferred class of salts are the salts of the compounds of the present invention with bases, such as alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. magnesium or calcium salts), ammonium salts (e.g. lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butyl amine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

The term "solvate" refers to a complex in which a compound of the present invention coordinates with solvent molecules to form a specific ratio. "Hydrate" refers to a complex formed by coordination between the compound of the present invention and water.

In addition, the compound of the present invention also includes the prodrug of the bishydrazide structure shown in formula I. The term "prodrug" includes itself may be biologically active or inactive, when administered in an appropriate manner, it undergoes metabolism or chemical reactions in the human body to convert into a class of compounds of formula I, or formula I A salt or solution of a compound. The prodrugs include (but are not limited to) carboxylates, carbonates, phosphates, nitrates, sulfates, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds of the compounds , phosphoramide, glucoside, ether, acetal and other forms.

Preparation

The preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.

Usually, in the preparation process, each reaction is usually carried out in an inert solvent at 0°C or room temperature to reflux temperature (such as 0°C-160°C, preferably 0°C-120°C). The reaction time is usually 0.1-60 hours, preferably 0.5-48 hours.

The following general preparation route can be used for the compound of synthetic formula I structure of the present invention:

In the first inert solvent, compound a ₂ is reacted with compound b to prepare compound I.

In the present invention, the compound a2 can be prepared by the following steps:

In the above reaction formula, the definition of each group is as above.

Pharmaceutical compositions and methods of administration

Since the compound of the present invention has the effect of inhibiting IL-23 (such as inhibiting IL-23mRNA) and upregulating cyclinD1 (such as increasing cyclinD1 mRNA), the compound of the present invention, its optical isomers or cis-trans isomers, pharmaceutically acceptable Salts, hydrates, solvates, prodrugs or active metabolites thereof, and pharmaceutical compositions containing the compound of the present invention as the main active ingredient can be used to treat, prevent and relieve IBD.

The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier. Wherein, "safe and effective dose" refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。"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 enough toxicity. "Compatibility" herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween

), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.

The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner. Examples of usable embedding components are polymeric substances and waxy substances. The active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.

Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.

The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily The dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.

The main advantages of the present invention include:

1. The bishydrazide structural compound of the present invention can enhance the activity of intestinal stem cells, promote the repair of intestinal epithelium, and reduce the expression of pro-inflammatory cytokines, thereby achieving the treatment of inflammatory bowel disease (IBD).

2. The bishydrazide structural compound of the present invention can not only inhibit IL-23mRNA but also upregulate cyclinD1mRNA, so it can treat IBD synergistically and more efficiently.

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 method that does not indicate specific condition in the following examples, 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 suggested conditions. Percentages and parts are by weight unless otherwise indicated.

The synthesis of embodiment 1 compound A ₁ :

Step 1: Dissolve compound 1 (500 mg) in DCM (10 mL), cool down to 0°C, add compound 3 (348 mg), slowly warm up to room temperature, and keep at room temperature for 30 minutes. The reaction was quenched by adding water, extracted with ethyl acetate, concentrated under reduced pressure, and the residue was purified by column chromatography using petroleum ether: ethyl acetate = 5:1 as eluent to obtain compound 2 (610 mg, yield 84%). ¹ HNMR (400MHz, CDCl3): δ8.00 (d, J = 8.8Hz, 2H), 7.60 (d, J = 8.8Hz, 2H), 3.90 (s, 3H), 1.53 (m, 1H), 1.12 ( m,2H), 0.88(m,2H).

Step 2: Dissolve compound 2 (400 mg) in CH3CH2OH (25 mL), add hydrazine hydrate (5 mL), and reflux for 4 h. After the reaction was completed, it was concentrated under reduced pressure, and the solid was washed with ice water, and then recrystallized from ethanol to obtain compound 4 (120 mg, yield 40%). ¹ HNMR (400MHz, CD3OD): δ7.74(d, J=9.2Hz, 2H), 7.65(d, J=9.2Hz, 2H), 1.89(s, 3H), 1.77(m, 1H), 1.28( s,2H), 0.95(m,2H), 0.87(m,2H).

Step 3: Dissolve compound 5 (352 mg) in CH ₃ CN (15 mL), heat to reflux, then add compound 4 (500 mg), and keep reflux for 30 min. After the reaction was completed, the solid was obtained by suction filtration, washed with CH3CN, and dried under vacuum at 70° C. for 2 h to obtain compound A ₁ (605 mg, yield 71%). ¹ H NMR (400MHz, DMSO-d6): δ10.45(s, 1H), 10.11(s, 1H), 9.64(s, 1H), 7.82(d, J=6.0Hz, 2H), 7.66(d, J＝5.6Hz, 2H), 2.87(m, 1H), 2.12(m, 1H), 2.06(m, 1H), 1.97(m, 1H), 1.80(m, 1H), 1.72(m, 1H), 1.65(m,1H),1.57(m,1H),1.41(m,2H),1.29(m,1H),0.82(m,5H); ¹³ CNMR(125MHz,DMSO-d ₆ ):δ175.37,173.35, ^{LRMS (} ):calcd for C ₁₉ H ₂₂ N ₃ O ₅ (MH) ^- :372.1565,found:372.1561.

The synthesis of embodiment 2 compound A ₂

Compound A ₁ (100 mg) and K ₂ CO ₃ (74 mg) were dissolved in DMF (2 mL), CH ₃ I was added dropwise with stirring, and stirring was continued overnight. After the reaction was completed, the reaction was quenched with water, extracted with EA, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography with petroleum ether: ethyl acetate = 5: 1 eluent to obtain compound A ₂ (90 mg, 85% yield). ¹ H NMR (400MHz, DMSO-d ₆ ): δ10.37(s, 1H), 7.57(d, J=8.8Hz, 1H), 7.20(d, J=8.8Hz, 1H), 3.12(s, 3H ),2.94(s,1H),1.75(m,1H),1.45(m,3H),1.19(m,2H),0.88(m,4H),0.79(d,J=5.6Hz,4H).LRMS (ESI):387.0(M) ⁺ .

Synthesis of Embodiment 3-37 Compound A ₃ -A ₃₇

Referring to the methods of Examples 1-2, the corresponding substrates were used to replace the substrates in Example 1, thereby synthesizing compounds A ₃ -A ₃₇ .

The structures and characterization results of compounds A3-A37 are as follows:

Table A

Example 38 Animal and Cell Experiments

1. Experimental materials

cells and animals

HCT116 cells and Raw264.7 cells were provided by the Cell Bank of the Chinese Academy of Sciences; intestinal organoids were derived from the intestinal crypt culture isolated from Lgr5-EGFP mice; Lgr5-EGFP mice were donated by the Hua Guoqiang Research Group of Fudan Institute of Radiological Medicine Yu, the genetic background is C57/BL6, and the mice were bred in the SPF animal room on the second floor of the Experimental Animal Center, School of Pharmacy, Fudan University.

main reagent

2. Experimental method

A. Cell experiments

Compound Activity Screening:

1. Detection of IL-23mRNA:

DMSO was used to prepare all the test compounds into a stock solution with a concentration of 50 mM, and stored in a -20°C refrigerator. Raw264.7 cells were inoculated on a 12-well plate, and the cell density was about 70-80% after 24 hours. Compounds with different dilution ratios were added, and 20 μl (ie, 0.5 μg/ml) of LPS was added to each well 1 hour after adding the drug. Shake the plate to mix. The blank group was not added. Discard the medium after 6 hours, wash with ice-cold PBS buffer three times, add 1ml Trizol, let stand for 10min, collect the lysate, centrifuge to obtain the supernatant, add 1/5 volume of chloroform to shake for 1min, let stand for 3min, 4 Centrifuge at 12000g. Take the supernatant, add an equal volume of isopropanol to mix, let stand for 10min, and centrifuge at 12000xg for 10min. Remove the supernatant, wash the precipitate with 70% ethanol, centrifuge at 7500 g for 5 min, dry the precipitate, and add 20 μL of DEPC water. The RNA concentration of the sample was detected and adjusted to 100-1000 ng/μL, and the change of IL-23 mRNA level was detected using a commercially available reverse transcription kit and SYBR-qPCR kit.

(1) cDNA synthesis by reverse transcription

According to the operating instructions of the reverse transcription kit, prepare the following mixture in an RNase free centrifuge tube, and gently blow and mix with a pipette. Incubate at 42°C for 2 minutes. The reverse transcription reaction program is as follows: Stage 1: 25°C, 5min; Stage 2: 42°C, 30min; Stage 3: 85°C, 5min; Stage 4: 4°C, keep, and store the product at -20°C, or directly use it in RT- qPCR.

(2) RT-PCR amplification

The primer sequences involved in Real-Time PCR are as follows:

方法来分析数据，计算

的数值即为实验组的目的基因表达相对于对照组的倍数。use

methods to analyze data, calculate

The value of is the multiple of the target gene expression in the experimental group relative to the control group.

2. Detection of CyclinD1 mRNA:

Colorectal cancer HCT 116 cell line was used for compound screening, and the medium used was McCOY's 5A medium containing 10% FBS. Cells were seeded in 12-well plates so that the density of adherent cells was 70%-80% the next day. Take 1 μL of stock solution (50 mM) in 1 ml of medium to prepare 50 μM drug-containing medium (0.1% DMSO medium for the control group). The original medium was discarded, and the drug-containing medium was added, and cultured at 37°C for 6h. Discard the medium, wash 3 times with ice-cold PBS buffer, add 1ml Trizol, let stand for 10min, collect the lysate, centrifuge to obtain the supernatant, add 1/5 volume of chloroform, shake for 1min, let stand for 3min, centrifuge at 12000xg at 4°C . Take the supernatant, add an equal volume of isopropanol to mix, let stand for 10min, and centrifuge at 12000xg for 10min. Remove the supernatant, wash the precipitate with 70% ethanol, centrifuge at 7500×g for 5 min, dry the precipitate, and add 20 μL of DEPC water. The RNA concentration of the sample was detected and adjusted to 100-1000 ng/μL, and changes in the mRNA level of cyclinD1 were detected using a commercially available reverse transcription kit and a SYBR-qPCR kit.

(1) cDNA synthesis by reverse transcription

According to the operating instructions of the reverse transcription kit, prepare the following mixture in an RNase free centrifuge tube, and gently blow and mix with a pipette. Incubate at 42°C for 2 minutes. The reverse transcription reaction program is as follows: Stage 1: 25°C, 5min; Stage 2: 42°C, 30min; Stage 3: 85°C, 5min; Stage 4: 4°C, keep, and store the product at -20°C, or directly use it in RT- qPCR.

(2) RT-PCR amplification

The primer sequences involved in Real-Time PCR are as follows:

The target cDNA fragment was amplified with Bio-Rad's CFX100 fluorescent quantitative PCR instrument.

Collect instrument data, use 2- ^△△Ct method to analyze the data, and calculate the value of 2- ^△△Ct, which is the multiple of the target gene expression in the experimental group relative to the control group.

B. Animal experiments

Animal Breeding and Gene Identification

Breeding of Lgr5-EGFP mice

Mouse genotyping

Genotyping of Lgr5-EGFP mice

gene identification sequence

Carry out PCR according to the following reaction system:

The reaction program was set up as described.

1. Establishment of acute IBD model in mice and in vivo efficacy experiment of compound A ₁

The experimental groups were set as control group, model group, mesalazine administration group, A ₁ -10mg/kg administration group and compound A ₁ -20mg/kg administration group, a total of five groups, each group 8 8-week-old male C57/BL6 mice, except the control group, were given 3% dextran sulfate sodium salt (DSS) water to drink freely, reconstituted and replaced every other day, and continued for 7 days.

Compound A ₁ was dissolved in DMSO to make mother liquor, and then dissolved in ultrapure water respectively to prepare 4% DMSO aqueous solutions with final concentrations of 1mg/ml and 2mg/ml respectively, and mesalazine was prepared into 50mg/ml with 0.5% CMC-Na Oral gavage was started at the same time as the modeling, and the gavage dose was 10 μL/g (corresponding to the administration doses of 10 mg/kg, 20 mg/kg and 50 mg/kg) for 10 days.

The body weight changes of the mice were recorded every day, and the mice were sacrificed for sampling after 10 days.

2. Determination of serum inflammatory factors

After 10 days of the above-mentioned administration, the mice were taken from eyeballs to collect blood, and after the whole blood was collected, the blood was allowed to coagulate undisturbed at room temperature for 15-30 minutes. Serum was obtained by centrifugation at 1,000 xg for 10 min at 4°C in a centrifuge. The serum levels of IL-1β and IL-23 were detected by Daktronics IL-1β and IL-23 ELISA kits.

3. Mouse Colon Length Measurement

After blood was taken from the above eyeballs, the mice were sacrificed, and the entire colon was taken for photographing and length measurement.

4. Detection of inflammatory factor mRNA levels in colon tissue

Use PBS to wash the colon tissue repeatedly, scrape off the mucus, separate the colonic mucosa of the mouse, add Trizol for tissue homogenization, let it stand for 10 minutes and centrifuge to obtain the supernatant, add 1/5 volume of chloroform to shake for 1 minute, and let it stand for 3 minutes. Centrifuge at 12000xg at 4°C. Take the supernatant, add an equal volume of isopropanol to mix, let stand for 10min, and centrifuge at 12000xg for 10min. Remove the supernatant, wash the precipitate with 70% ethanol, centrifuge at 7500×g for 5 min, dry the precipitate, and add appropriate amount of DEPC water. The RNA concentration of the sample was detected and adjusted to 100-1000 ng/μL, and the mRNA levels of corresponding inflammatory factors were detected using a commercially available reverse transcription kit and SYBR-qPCR kit.

5.RT-qPCR

According to the operating instructions of the reverse transcription kit, proceed as follows:

Prepare the following mixture in an RNase free centrifuge tube, and gently blow and mix with a pipette. Incubate at 42°C for 2 minutes.

Reverse transcription reaction system preparation (20μL system)

Obtain the cDNA according to the following table and prepare the working solution system:

The qPCR primers of each inflammatory factor are as follows

Collect instrument data, use 2-△△Ct method to analyze the data, and calculate the value of 2-△△Ct as the multiple of the target gene expression in the experimental group relative to the control group.

6. Observation of inflammatory infiltration and mucosal injury

The colon of about 0.5 cm in the middle section of the mouse was taken, fixed with paraformaldehyde at 4°C for 16 hours, entrusted to Wuhan Sewell Biological Co., Ltd. for paraffin embedding, sectioned, and stained with hematoxylin-eosin (H&E).

7. Pharmacokinetic experiment

Eighteen mice (C57), male, weighing 18-22 g, were randomly divided into 6 groups, 3 in each group, given the test compound by intragastric administration, fasted for 12 hours before the test, drank water freely, and ate uniformly 2 hours after the administration. The experimental plan is as follows:

According to the time points in the table, blood was collected from the retro-orbital venous plexus of the mice, collected in EP tubes treated with sodium heparin, and centrifuged to obtain plasma. Accurately draw 15 μL of plasma into the EP tube corresponding to the sample number, add 300 μL of methanol/acetonitrile equal volume mixed solution containing internal standard 50 ng/mL tolbutamide, the mixture is vortexed for 1 min, and centrifuged at 12000 rpm for 10 min at room temperature. Take 35 μL supernatant and mix with 65 μL acetonitrile/water equal volume mixed solution, transfer to 96-well plate for LC-MS/MS analysis, the injection volume is 2 μL. Ultra-high performance liquid chromatography (Waters Company) was used for gradient separation, triple quadrupole mass spectrometry (API5000, SCIEX Company) used electrospray ionization source, and multiple reaction monitoring mode (MRM, multi reaction monitoring) was used for detection under negative ion conditions. The linear range of compound A ₁ is 1-3000ng/mL.

The chromatographic conditions are as follows

Chromatographic column: Waters Acquity C18 column (2.1*50mm, 1.7μm)

Column temperature: 45°C

Mobile phase: MPA in water with 0.1% formic acid

MPB Acetonitrile/Methanol (9/1, v/v) with 0.1% Formic Acid

Flow rate: 0.5mL/min

Gradient elution program:

The mass spectrometry conditions are as follows

Compound Transition

A1 372.3>218.0

tolbutamide 269.2>169.8

8. Isolation and Culture of Colon Organoids

Take the entire colon of a 6-8 week old mouse, cut it from the middle, wash it with pre-cooled PBS, divide the small intestine into several sections with a length of 5-8 cm, and carefully scrape off the mucus on the surface of the colon with a glass slide , put the scraped colon into a 50 mL centrifuge tube and place on ice. Transfer the centrifuge tube to a safety cabinet, wash with PBS containing double antibody for 3-4 times, and transfer the colon to 25ml of 2mM EDTA solution for digestion at 4°C for 25 minutes. Transfer the digested colon to a 50ml centrifuge tube, add 25ml PBS containing double antibody, shake properly for 50 times, filter the suspension with a 70um cell strainer, transfer the colon to a new centrifuge tube containing 25ml PBS containing double antibody In the tube, continue to shake properly for 50 times, and filter the suspension with a 70um cell strainer, transfer the twice-filtered suspension to the same 50ml centrifuge tube, and centrifuge at 900rpm for 5 minutes at room temperature. Discard the supernatant, resuspend the pellet with 2 mL of Advanced-DMEM/F12, and take an appropriate amount of the suspension for counting. The number of crypts is 5-10/ul is the best. Take an appropriate volume of the suspension and add it to a 1.5ml centrifuge tube, and centrifuge at 900rpm for 5 minutes at room temperature. Resuspend the pellet in Matrigel that has been pre-chilled on ice. Preheat the 96-well plate in the incubator, and then add 5ul of the resuspension to each well. Place the inoculated plate in the incubator for 10-15 minutes. Add 100ul medium to each well, and then change the medium every 2-3 days.

WNER medium consists of:

9. Testing the Effect of Compounds on Organoid Growth

Prepare 50 μM DMSO solution according to the Mw of compound A ₁ , add organoid medium respectively, take pictures to observe the morphology, remove the medium on the 7th day, cool on ice for 10 minutes to melt Matrigel, and collect organoids by centrifugation with PBS. According to the above operation, mRNA was extracted to detect the expression of stem cell-related genes.

10. Data Analysis

SPSS 13.0 was used to analyze the data, the comparison between two groups was performed by paired t-test, and the comparison between multiple groups was performed by one-way analysis of variance, and P<0.05 was considered as a difference in test results. Data are presented as mean ± standard deviation (mean ± SD). GraphPad Prism 7.0 software makes histograms and line graphs.

3. Experimental results

1. Cell experiment compound activity table

Form B

The formula for calculating the inhibition rate is:

As shown in Table B, experiments show that most of the compounds of the present invention have an inhibitory rate of more than 50% to IL-23mRNA (better than mesalamine or equivalent to mesalamine), and most of the compounds have a certain up-regulation effect on cyclinD1 mRNA , among which, there are 19 compounds whose up-regulation degree exceeds 1.5. In addition, there are 14 compounds with an inhibitory rate of more than 50% (average) on IL-23 mRNA and more than 1.5 (average) on the up-regulation of cyclinD1 mRNA. In contrast, the positive control drug mesalazine could only inhibit the expression of IL-23 mRNA, but had no up-regulation effect on cyclinD1 mRNA, and even showed a slight down-regulation effect (the average value was 0.9).

2. Animal experiment results

Figure 1 shows the therapeutic effect of Compound A ₁ on a mouse colitis model. Wherein A is the body weight change (N=5-7) of C57 mice during DSS modeling and simultaneous oral administration (10 mg/kg and 20 mg/kg of compound A ₁ and 50 mg/kg of mesalamine). B is the photograph of the mouse colon and the statistics of colon length (N=5-7) after 7 days of DSS modeling and 10 days after administration. C is the detection result of mRNA expression of IBD-related proteins in mouse colon tissue. D is the ELISA detection result of serum inflammatory factor levels in mice. E is the result of H&E staining of mouse colon specimens, showing crypt destruction and inflammatory infiltration in the colon. *P<0.05, **P<0.01, ***P<0.001.

The results showed that compound A ₁ could dose-dependently improve the intestinal mucosal destruction and inflammatory infiltration in IBD mice induced by DSS, promote the recovery of body weight and colon length in mice, and reduce peripheral blood and intestinal TNFα, IL-1β and IL- 23 levels and the mRNA expression of these inflammatory cytokines in the intestine, and increased the mRNA expression of cyclin D1. The above data show that Compound A ₁ can significantly improve the condition of acute IBD in mice.

Figure 2 shows the change of blood drug concentration in mice within 24 hours after compound A ₁ was administered orally at two concentrations of 3 mg/kg and 20 mg/kg. The results showed that the peak plasma concentrations of the mice after oral administration of 3 mg/kg and 20 mg/kg of Compound A ₁ were 175 ng/mL and 700 ng/mL, respectively, and the peak time was about 1 hour; the half-life was about 1.72 hours; the drug-time curve The lower areas were 410(h*ng/mL) and 2363(h*ng/mL), suggesting a linear relationship between exposure and dose.

Figure 3 shows the growth-promoting effect of compound _A1 on mouse-derived intestinal organoids. Among them, A is the isolation of mouse colonic crypts and growth in Matrigel matrigel covered with WNER medium, the concentration of compound A ₁ is 50 μM, and the size and sprouting of the organoids were photographed using a Zeiss 710 live cell imager The rate was statistically analyzed using Image J software (N=5). B: After the organoids were collected on the 7th day, RNA was extracted for detection of intestinal stem cell marker genes (N=5). *P<0.05, **P<0.01, ***P<0.001.

The results showed that Compound A ₁ could significantly promote the growth of mouse-derived intestinal organoids.

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.

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Fudan University

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Claims (4)

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds: Methyl 2-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylate, 2-(2-(4-Acetamidobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-Benzamidobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-(cyclopropylcarbamoyl)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-fluorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-(trifluoromethoxy)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-(trifluoromethyl)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-(oxazol-5-yl)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(6-chloronicotinoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(6-bromonicotinoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-(cyclopropanecarboxamido)-3-fluorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-(cyclopropanecarboxamido)-2-fluorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(2-chloro-4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(3-chloro-4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(3-(cyclopropanecarboxamido)-4-fluorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 3-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid, 3-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid, 2-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)cyclopropane-1-carboxylic acid, 4,5-dibromo-2-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)-3,6-difluorobenzoic acid, 2-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)-3,6-difluorobenzoic acid, 2-(2-(4-fluorobenzoyl)hydrazine-1-carbonyl)benzoic acid, 3-(2-(4-fluorobenzoyl)hydrazine-1-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid, 3-(2-(2-chlorobenzoyl)hydrazine-1-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid, 3-(2-(2,4-dichlorobenzoyl)hydrazine-1-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid, 3-(2-(4-(Cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)-2-naphthoic acid. 2. The use of a compound of formula III or a pharmaceutically acceptable salt thereof in the preparation of medicines and pharmaceutical compositions for the treatment or prevention of inflammatory bowel disease; In the formula,

Q is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylamino , hydroxymethyl, C ₁ -C ₆ haloalkyl, or -L ₁ -M; G is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylamino , hydroxymethyl, C ₁ -C ₆ haloalkyl, or -L ₁ -M; A is independently selected from the following group: substituted or unsubstituted C _3-12 cycloalkyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, substituted or unsubstituted 6-14 membered heteroaryl; wherein the substitution is selected from One or more from the following group: halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, hydroxymethyl or C ₁ -C ₆ haloalkane base; _L is -NHC(=O)-; M is independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, Substituted or unsubstituted 6-14 membered heteroaryl; and the substitution is one or more selected from the group consisting of halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylamino; K is independently -C(=O)OR ₂ , wherein R ₂ is independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl. 3. The use of a compound or a pharmaceutically acceptable salt thereof in the preparation of medicines and pharmaceutical compositions for the treatment or prevention of inflammatory bowel disease, characterized in that the compound is selected from: 2-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, Methyl 2-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylate, 2-(2-(4-(3-methylbutyramino)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-Acetamidobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-Benzamidobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-(cyclohexanecarboxamido)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-(cyclopropylcarbamoyl)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-Chlorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-fluorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-(trifluoromethoxy)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-(tert-butyl)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-(trifluoromethyl)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-(oxazol-5-yl)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(3-Chlorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(2-Chlorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(2,4-dichlorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(6-chloronicotinoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(6-bromonicotinoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-(cyclopropanecarboxamido)-3-fluorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-(cyclopropanecarboxamido)-2-fluorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(2-chloro-4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(3-chloro-4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(3-(cyclopropanecarboxamido)-4-fluorobenzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 3-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid, 2-(2-(4-(Cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)benzoic acid, 3-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid, 2-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)cyclopropane-1-carboxylic acid, 4,5-dibromo-2-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid, 2-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)-3,6-difluorobenzoic acid, 2-(2-(4-(cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)-3,6-difluorobenzoic acid, 2-(2-(4-fluorobenzoyl)hydrazine-1-carbonyl)benzoic acid, 3-(2-(4-fluorobenzoyl)hydrazine-1-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid, 3-(2-(4-chlorobenzoyl)hydrazine-1-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid, 3-(2-(3-chlorobenzoyl)hydrazine-1-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid, 3-(2-(2-chlorobenzoyl)hydrazine-1-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid, 3-(2-(2,4-dichlorobenzoyl)hydrazine-1-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid, 3-(2-(4-(Cyclopropanecarboxamido)benzoyl)hydrazine-1-carbonyl)-2-naphthoic acid. 4. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

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