Application of dibenzo nitrogen heterocyclic compound in preparation of medicine for treating gastrointestinal diseases

Abstract

The invention discloses application of a dibenzo nitrogen heterocyclic compound in preparation of a medicine for treating gastrointestinal diseases, and relates to the technical field of medicinal chemistry. A large amount of screening and verification show that the dibenzo nitrogen heterocyclic compound with the structural general formula can significantly reduce core pathological characteristics of gastric ulcer, such as significant reduction of ulcer lesion, significant reduction of bleeding degree and specific reduction of mucosal edema, and has an ulcer inhibition rate of 36.51%-47.22% for a gastric ulcer animal model. A new thought and a new choice are provided for the development of medicines for treating gastrointestinal diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry, and particularly relates to application of a dibenzazepine compound in preparation of a drug for treating gastrointestinal diseases. BACKGROUND

[0002] Gastrointestinal diseases are a kind of diseases occurring in esophagus, stomach, small intestine, large intestine and other parts, and are common and frequently-occurring diseases. The incidence rate of gastrointestinal diseases is high in the world. For example, about 10% of people in the world will suffer from peptic ulcer in their life. In recent years, gastrointestinal diseases show a trend of youth. Unhealthy lifestyles, such as long-term overtime, high mental stress, smoking, alcohol abuse, irregular diet and the like, make more and more young people suffer from gastrointestinal diseases. The etiology and pathogenesis of gastrointestinal diseases are complex, mainly involving biological factors, physical and chemical factors, genetic factors, immune factors, mental and psychological factors and the like. The physical and chemical factors involve drug stimulation, such as non-steroidal anti-inflammatory drugs (NSAIDS), glucocorticoids and the like, which can inhibit the activity of cyclooxygenase (COX), reduce the synthesis of prostaglandin, weaken the protective effect of gastrointestinal mucosa, and cause mucosal damage and ulcer formation. Excessive secretion of gastric acid and enhanced digestion of pepsin can directly damage the gastrointestinal mucosa, which is an important factor for the occurrence of peptic ulcer.

[0003] At present, different drug treatment schemes exist for gastric ulcer. The key to the treatment of gastrointestinal diseases caused by non-steroidal anti-inflammatory drugs (NSAIDs) stimulation lies in relieving symptoms, promoting mucosal repair and preventing complications. The main treatment drugs include proton pump inhibitors (PPI), H2 receptor antagonists, bismuth agents, aluminum magnesium carbonate and the like.

[0004] Although there are various drugs for treating gastrointestinal diseases at present, there are still many adverse reactions, such as increasing the risk of intestinal infection, affecting the absorption of minerals such as calcium and magnesium, causing osteoporosis and hypomagnesemia and the like; and limited efficacy, such as for some chronic gastrointestinal diseases, such as inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, the existing drug treatment is often difficult to achieve complete cure. In view of the many deficiencies of existing drugs in efficacy and safety, it is still necessary to further develop new drugs for preventing and / or treating gastrointestinal diseases to fill the gap in existing treatment and improve the treatment effect and life quality of patients. SUMMARY

[0005] The purpose of the present application is to overcome the deficiencies of the prior art and provide application of a dibenzazepine compound in preparation of a drug for treating gastrointestinal diseases.

[0006] To achieve the above object, the technical scheme adopted by the present application is: application of a dibenzazepine compound in the preparation of a drug for treating gastrointestinal diseases, wherein the dibenzazepine compound has the following general structure or a pharmaceutically acceptable salt or an analogue thereof: Among them, X is NH, O, S, SO, SO2 or CO; R1 is H, halogen, C1-C6 alkyl or C1-C6 alkoxy; R2 is H, halogen, C1-C6 alkyl, C3-C8 cycloalkyl or C1-C6 alkoxy; wherein the C1-C6 alkyl, C3-C8 cycloalkyl and C1-C6 alkoxy can be substituted by one or more substituents selected from halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy and C3-C8 cycloalkyl; R3 is H, halogen, C1-C6 alkyl, C3-C8 cycloalkyl or C1-C6 alkoxy; wherein the C1-C6 alkyl, C3-C8 cycloalkyl and C1-C6 alkoxy can be substituted by one or more substituents selected from halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy and C3-C8 cycloalkyl; or R2 and R3, together with the N atom to which they are attached, form a saturated heterocyclic ring containing a nitrogen atom, and the heterocyclic ring is selected from a 5-8 membered monocyclic nitrogen-containing heterocyclic ring or an 8-11 membered nitrogen-containing spiro ring; the spiro ring is composed of a 4-6 membered first heterocyclic ring and a 5-7 membered second heterocyclic ring sharing a spiro atom.

[0007] As a preferred embodiment of the application, X is S or SO.

[0008] As a preferred embodiment of the application, R1 is H, fluorine, chlorine, bromine, methyl or methoxy.

[0009] As a preferred embodiment of the application, R1 is fluorine, chlorine or bromine.

[0010] More preferably, R1 is fluorine or chlorine.

[0011] As a preferred embodiment of the application, R2 is H, cyclopentyl, cyclohexyl or cycloheptyl; wherein the cyclopentyl, cyclohexyl and cycloheptyl can be substituted by one or more substituents selected from methyl, ethyl and propyl; and R3 is H, cyclopentyl, cyclohexyl or cycloheptyl; wherein the cyclopentyl, cyclohexyl and cycloheptyl can be substituted by one or more substituents selected from methyl, ethyl and propyl.

[0012] More preferably, R2 is H, cyclohexyl; wherein the cyclohexyl can be substituted with 2 methyl groups; R3 is H, cyclohexyl; wherein the cyclohexyl can be substituted with 2 methyl groups.

[0013] As a preferred embodiment of the application, when the heterocycle is a 5-8 membered monocyclic nitrogen heterocycle, the monocyclic nitrogen heterocycle is azepane.

[0014] As a preferred embodiment of the application, when the heterocycle is an 8-11 membered nitrogen-containing spirocycle, the 4-6 membered first heterocycle comprises at least one oxygen atom; the 5-7 membered second heterocycle comprises a nitrogen atom.

[0015] More preferably, when the heterocycle is an 8-11 membered nitrogen-containing spirocycle, the 8-11 membered nitrogen-containing spirocycle is 1,4-dioxa-8-azaspiro[4.5]decanyl.

[0016] Preferably, the dibenzazepine compound comprises a compound having the following structure: , , .

[0017] As a preferred embodiment of the application, the gastrointestinal disease comprises gastritis, gastric ulcer, stress-induced gastric mucosal injury, stress ulcer, erosive gastritis, or gastric ulcer.

[0018] More preferably, the gastrointestinal disease is associated with mucosal barrier dysfunction or mucosal injury.

[0019] More preferably, the gastrointestinal disease is caused by one of the following factors: use of non-steroidal anti-inflammatory drugs (NSAIDs); or stress factors; or mucosal erosion caused by abnormal secretion of gastric acid.

[0020] As a preferred embodiment of the application, the gastric ulcer is NSAID-induced gastric ulcer; the gastritis is NSAID-associated gastritis.

[0021] The application also provides a pharmaceutical composition for treating gastrointestinal diseases, the pharmaceutical composition comprising a dibenzazepine compound having the following general structure: wherein, X is NH, O, S, SO, SO2, or CO; R1 is H, halogen, C1-C6 alkyl, or C1-C6 alkoxy; R2is H, halogen, C1-C6alkyl, C3-C8cycloalkyl or C1-C6alkoxy; wherein said C1-C6alkyl, C3-C8cycloalkyl and C1-C6alkoxy can be substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, halogen-substituted C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkoxy and C3-C8cycloalkyl; R3is H, halogen, C1-C6alkyl, C3-C8cycloalkyl or C1-C6alkoxy; wherein said C1-C6alkyl, C3-C8cycloalkyl and C1-C6alkoxy can be substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, halogen-substituted C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkoxy and C3-C8cycloalkyl; or R2, R3and the N atom to which they are attached form a saturated heterocyclic ring containing a nitrogen atom, said heterocyclic ring being selected from the group consisting of: 5-8 membered monocyclic nitrogen heterocyclic ring or 8-11 membered nitrogen-containing spiro ring; said spiro ring consists of a 4-6 membered first heterocyclic ring and a 5-7 membered second heterocyclic ring sharing a spiro atom.

[0022] The application provides application of a dibenzazepine compound in preparation of a drug for treating gastrointestinal diseases. The dibenzazepine compound with the structural general formula can significantly reduce the core pathological features of gastric ulcer, such as significantly reducing ulcer foci, significantly reducing the degree of hemorrhage, and specifically reducing mucosal edema, and the ulcer inhibition rate of a gastric ulcer animal model reaches 36.51%-47.22%, which provides a new idea and a new choice for development of the drug for treating gastrointestinal diseases. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 Gastric mucosa section of a mouse after administration of compound C529-0714.

[0024] Figure 2 Gastric mucosa section of a mouse after administration of compound K788-8384 and K788-1614.

[0025] Figure 3 Gastric ulcer score statistics of a mouse after administration of compound C529-0714.

[0026] Figure 4 Gastric ulcer score statistics of a mouse after administration of compound K788-8384 and K788-1614. DETAILED DESCRIPTION

[0027] The foregoing will be further appreciated based on the following detailed description of the application, when taken in conjunction with the following examples. However, it should be understood that the following examples are intended to be illustrative only and are not intended to limit the scope of the application as set forth in the appended claims.

[0028] Unless otherwise indicated, the terms used in the specification and claims are intended to have the meanings as set forth below.

[0029] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described herein include their isotopic cases, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described herein are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12C, 13C and 14C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super-heavy hydrogen), the isotopes of oxygen include 160, 170 and 180, the isotopes of sulfur include 32S, 33S, 34S and 36S, the isotopes of nitrogen include 14N and 15N, the isotopes of fluorine include 17F and 19F, the isotopes of chlorine include 35Cl and 37Cl, the isotopes of bromine include 79Br and 81Br.

[0030] "Alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group of 1 to 30 carbon atoms, preferably 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, neo-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl, and the like. The alkyl group can be optionally further substituted with one or more substituents.

[0031] "Alkoxy" refers to a group formed by the attachment of an alkyl group to an oxygen atom. The definition of the alkyl group is the same as that described above for "alkyl". Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, s-butyloxy, t-butyloxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy, cyclobutyloxy, and the like. The alkoxy group can be optionally further substituted with one or more substituents.

[0032] "Cycloalkyl" means a saturated cyclic hydrocarbon group, which can be a monocyclic 3- to 10-membered (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-membered), bicyclic 4- to 12-membered (e.g., 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-membered), or polycyclic 10- to 20-membered (e.g., 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, 20-membered) ring system, with the ring carbon atoms preferably being 3- to 10-carbon atoms, and further preferably 3- to 8-carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The cycloalkyl group can be optionally further substituted with one or more substituents.

[0033] Halogen includes F, Cl, Br, and I.

[0034] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group can or can not be present, and that the description includes instances where the heterocyclyl group is substituted with alkyl, and instances where the heterocyclyl group is not substituted with alkyl.

[0035] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present application which retains the biological effectiveness and properties of the free acid or the free base, and which is obtained by reaction of the free acid with a non-toxic inorganic or organic base, or the free base with a non-toxic inorganic or organic acid. Non-limiting examples of the inorganic bases include nitrate, chloride, carbonate, bicarbonate, sulfate, bisulfate or hydroxide of Al, Ca, Li, Mg, K, Na, ammonium and Zn; non-limiting examples of the organic bases include ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tetramethylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, phenylamine penicillin, ethylenediamine, glucosamine, N-methylglucosamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine and polyamine resin; non-limiting examples of the inorganic and organic acids include sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropanoic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, lysine, arginine, aspartic acid, cinnamic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid and trifluoromethanesulfonic acid.

[0036] Unless otherwise specified, the various starting materials, reaction equipment, testing equipment and testing methods employed in the following examples are those conventionally known in the art.

[0037] Example 1: Establishment of Gastric Ulcer Animal Model and Evaluation of Therapeutic Effect In this example, a gastric ulcer animal model was constructed, and the therapeutic effect of the dibenzazepine compound on gastric ulcer was evaluated. The specific experimental methods are as follows: 1. Experimental materials: 33 C57 BL / 6J mice, 8 weeks old, weighing 23-25 g (purchased from Beijing Huafukang); the compounds to be evaluated C529-0741, K788-8384, K788-1614, indomethacin, and carboxymethylcellulose sodium (CMC-Na) were commercially available; the CAS numbers and structures of the compounds to be evaluated are shown in Table 1.

[0038] Table 1 2. Experimental steps: 1) Solution preparation: 1% CMC-Na solution preparation: 20 g CMC-Na was dissolved in 2000 ml pure water solution, mixed uniformly.

[0039] 2) Dose 1: 18 C57 BL / 6J mice were randomly selected and divided into 3 groups, namely control group (n=6), model group (n=6), and C529-0741 group (n=6, 20 mg / kg). Before the experiment, the mice were fasted for 48 h and only allowed to drink water. The control group was orally administered with 1% CMC-Na solution, the model group was orally administered with indomethacin 40 mg / Kg, and the C529-0741 group was orally administered with C529-0741 drug 20 mg / kg first, and then indomethacin 40 mg / Kg after 30 min. The samples were taken after 12 h. 3) Dose 2: 15 C57 BL / 6J mice were randomly selected and divided into 3 groups, namely model group (n=5), K788-8384 group (n=5, 20 mg / kg), and K788-1614 group (n=5, 20 mg / kg). Before the experiment, the mice were fasted for 48 h and only allowed to drink water. The model group was orally administered with indomethacin 40 mg / Kg, the K788-8384 group was orally administered with K788-8384 compound (20 mg / kg) first, and then indomethacin 40 mg / Kg after 30 min, and the K788-1614 group was orally administered with K788-1614 compound (20 mg / kg) first, and then indomethacin 40 mg / Kg after 30 min. The samples were taken after 12 h.

[0040] 4) Sample collection: After the mice were anesthetized, 0.5 ml of blood was taken from the orbital vein, and after standing at room temperature for 10-20 min, it was centrifuged at 4000 rpm for 10 min. The supernatant was taken and stored at -80℃. The abdominal cavity was exposed and the field of view was exposed. The stomach was cut short at the junction of the cardia and the lower esophagus, the pylorus and the upper duodenum, and then freed in pre-cooled physiological saline. From the beginning of the cardia, the stomach wall was carefully cut with tissue scissors along the greater curvature until the pylorus was cut through, making the stomach into a single layer. The edge of the cardia was gently clamped with tissue forceps and washed repeatedly in clean pre-cooled physiological saline, 3-5 times, to wash away the gastric contents attached to the stomach wall. The washed stomach was placed on a sterile drape with the inner wall facing up, and the animal number was marked. A high-definition camera was used to take pictures. Then the gastric mucosa was observed for congestion, edema, erosion, bleeding, etc. and scored.

[0041] 5) Inspection: The gastric mucosa was observed for congestion, edema, erosion, bleeding, etc. and scored: 1 point for a shallow yellow spot, 2 points for a black spot, 1 mm for a yellow strip, 2 points for a black strip, 1 mm for a yellow block, and 2 points for a black block. 2 2 ​2 points (block area calculation method S = long diameter / 2 x short diameter / 2 x π); ulcer perforation: 3 points for one hole; each animal is scored according to the above method, and then the total ulcer score is calculated, and the ulcer inhibition rate of the administration group can be further calculated according to the ulcer score. Ulcer inhibition rate = (model group ulcer score - administration group ulcer score) / model group ulcer score.

[0042] 3、The experimental results are shown in Tables 1-2. Figures 1-4 、As shown in Tables 1-2, Figure 1 、 Figure 2 It can be seen that compared with the model group, the yellow spots, block ulcer degree and edema degree of the C529-0741 group were reduced; the black spots, block ulcer and bleeding degree of the K788-8384 group and the K788-1614 group were significantly reduced. Figure 3 、 4 As shown in Tables 1, 2, the ulcer inhibition rate of the C529-0741 group reached 47.22%, the ulcer inhibition rate of the K788-8384 group reached 44.44%, and the ulcer inhibition rate of the K788-1614 group reached 36.51%, indicating that the compounds C529-0741, K788-8384 and K788-1614 have the effects of reducing the symptoms of gastric ulcer and treating gastric ulcer.

[0043] Table 2: Gastric ulcer score table of mice after administration of compound C529-0714 Table 2: Gastric ulcer score table of mice after administration of compound C529-0714 Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present application and not to limit the scope of protection of the present application. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or replaced by equivalents without departing from the essence and scope of the technical solutions of the present application.

Claims

1. The application of dibenzo-azo heterocyclic compounds in the preparation of drugs for treating gastrointestinal diseases, characterized in that, The dibenzo-azo heterocyclic compounds have the following general formula or their pharmaceutically acceptable salts or analogs: in, X is NH, O, S, SO, SO2 or CO; R1 is H, halogen, C1-C6 alkyl, or C1-C6 alkoxy; R2 is H, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 alkoxy; wherein the C1-C6 alkyl, C3-C8 cycloalkyl, and C1-C6 alkoxy may be substituted by one or more substituents selected from halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, and C3-C8 cycloalkyl; R3 is H, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 alkoxy; wherein the C1-C6 alkyl, C3-C8 cycloalkyl, and C1-C6 alkoxy may be substituted by one or more substituents selected from halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, and C3-C8 cycloalkyl; Alternatively, R2 and R3 may form a nitrogen-containing saturated heterocycle with the connected N atom, wherein the heterocycle is selected from: 5-8 member monocyclic nitrogen heterocycles or 8-11 member nitrogen-containing spirocycles; the spirocycle is composed of a 4-6 member first heterocycle and a 5-7 member second heterocycle sharing spiro atoms.

2. The application according to claim 1, characterized in that, X is S or SO.

3. The application according to claim 1, characterized in that, R1 is H, fluorine, chlorine, bromine, methyl, or methoxy.

4. The application according to claim 3, characterized in that, R1 is fluorine, chlorine, or bromine.

5. The application according to claim 1, characterized in that, R2 is H, cyclopentyl, cyclohexyl, or cycloheptyl; wherein the cyclopentyl, cyclohexyl, or cycloheptyl may be substituted by one or more substituents selected from methyl, ethyl, or propyl; R3 is H, cyclopentyl, cyclohexyl, or cycloheptyl; wherein the cyclopentyl, cyclohexyl, or cycloheptyl may be substituted by one or more substituents selected from methyl, ethyl, or propyl.

6. The application according to claim 1, characterized in that, When the heterocycle is a 5- to 8-membered monocyclic nitrogen heterocycle, the monocyclic nitrogen heterocycle is a nitrogen-containing heptane.

7. The application according to claim 1, characterized in that, When the heterocycle is an 8- to 11-membered nitrogen-containing spirocycle, the 4- to 6-membered first heterocycle contains at least one oxygen atom; the 5- to 7-membered second heterocycle contains a nitrogen atom.

8. The application according to claim 1, characterized in that, The gastrointestinal diseases include gastritis, gastric ulcer, stress-induced gastric mucosal injury, stress ulcer, erosive gastritis, or gastric ulcer.

9. The application according to claim 8, characterized in that, The gastric ulcer is an NSAID-induced gastric ulcer; the gastritis is an NSAID-associated gastritis.

10. A pharmaceutical composition for treating gastrointestinal diseases, characterized in that, The pharmaceutical composition comprises a dibenzo-azo heterocyclic compound having the following general formula: in, X is NH, O, S, SO, SO2 or CO; R1 is H, halogen, C1-C6 alkyl, or C1-C6 alkoxy; R2 is H, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 alkoxy; wherein the C1-C6 alkyl, C3-C8 cycloalkyl, and C1-C6 alkoxy may be substituted by one or more substituents selected from halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, and C3-C8 cycloalkyl; R3 is H, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 alkoxy; wherein the C1-C6 alkyl, C3-C8 cycloalkyl, and C1-C6 alkoxy may be substituted by one or more substituents selected from halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, and C3-C8 cycloalkyl; Alternatively, R2 and R3 may form a nitrogen-containing saturated heterocycle with the connected N atom, wherein the heterocycle is selected from: 5-8 member monocyclic nitrogen heterocycles or 8-11 member nitrogen-containing spirocycles; the spirocycle is composed of a 4-6 member first heterocycle and a 5-7 member second heterocycle sharing spiro atoms.

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