Application of amide derivative in preparation of medicine for treating or preventing skin radiation injury

Abstract

The invention provides application of a compound shown in a formula (I) in preparation of a medicine for treating or preventing skin radiation injury. # imgabs0 #

Description

Technical Field

[0001] The invention relates to application of an amide derivative in preparing a medicine for treating or preventing skin radiation damage. Background Art

[0002] Radiation therapy is used to treat localized or regional advanced cancers. Radiation exposure during this treatment can cause severe burns to the skin and surrounding tissues as well as permanent changes in pigmentation. Up to 95% of people who receive radiation therapy for cancer will experience a skin reaction. For example, some skin reactions caused by radiation therapy given to people with breast cancer are called "radiation dermatitis."

[0003] Since the incidence of skin radiation damage is high in cancer patients receiving radiotherapy, and the frequency of radiotherapy in cancer treatment continues to increase, there is a lack of effective drugs to prevent or treat skin radiation damage, which cannot meet the needs of cancer patients. Therefore, a radioprotectant is urgently needed to solve the above problem. Summary of the invention

[0004] The purpose of the present invention is to provide an application of an amide derivative in the preparation of a drug for treating or preventing skin radiation damage, so as to overcome the shortcomings of the prior art.

[0005] One or more embodiments of the present application provide a compound represented by formula (I), or use of a stereoisomer, tautomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof in the preparation of a drug for treating or preventing skin radiation damage:

[0006]

[0007] in:

[0008] Q is selected from 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein the heteroaryl contains 1 to 3 heteroatoms selected from N, O or S, and the aryl or heteroaryl is optionally substituted by 0 to 4 R q0 replace;

[0009] R q0 The same or different, each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, OH, cyano, nitro, -NH2, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6Alkyl, -OC(=O)C 1-6 Alkyl, -C(=O)OC 3-8 Cycloalkyl, -OC(=O)C 3-8 Cycloalkyl, -OC(=O)C 3-8 Heterocycloalkyl, -C(=O)OC 3-8 Heterocycloalkyl, -C(=O)C 6-10 Aryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -C(=O)C 5-10 Heteroaryl, -C(=O)OC 5-10 Heteroaryl, -OC(=O)C 5-10 Heteroaryl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NHC(=O)C 1-6 Alkyl, -NHC(=O)(C 1-6 Alkyl)2, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 3-8 Cycloalkyl, -NHC(=O)C 2-6 Alkynyl, -NHC(=O)C 2-6 Alkenyl, -NH(C=NR q1 )NR q2 R q3 、-C(=O)NR q4 R q5 、-SH、-SC 1-6 Alkyl, -S(=O)C 1-6 Alkyl, -S(=O)2C 1-6 Alkyl or -S(=O)2NR q2 R q3 , the heterocycloalkyl or heteroaryl each contains 1 to 3 heteroatoms selected from N, O or S, and the alkyl, alkoxy, -NH2, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, aryl, heteroaryl are optionally further substituted by one or more deuterium, OH, halogen, cyano, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR q4 R q5 , =NR q6 、-C(=O)OC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl, -C(=O)NR q4R q5 , C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -OC(=O)C 5-10 Heteroaryl, -C(=O)OC 5-10 Heteroaryl, -OC(=O)C 3-8 Heterocycloalkyl, -C(=O)OC 3-8 Heterocycloalkyl, -OC(=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 1-6 Alkyl, -NHC(=O)C 2-6 Alkenyl or -NHC(=O)C 2-6 substituted by a substituent of an alkynyl group, and wherein the substituent C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3-8 Heterocycloalkyl or -NHC(=O)C 3-8 The cycloalkyl group is optionally further substituted by 1 to 3 groups selected from OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 or substituted by a substituent of =O;

[0010] Or at least a pair of R q0 and the atoms connected thereto form a 4- to 10-membered carbocyclic ring or a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring contains 1 to 2 heteroatoms selected from N, O or S, and the carbocyclic ring or heterocyclic ring is optionally further substituted by one or more atoms selected from OH, halogen, C 1-6 Alkyl, C1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR q4 R q5 , =NR q6 、-C(=O)OC 1-6 Alkyl or -C(=O)NR q4 R q5 Substituents, and the substituents C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further selected from OH, halogen, =O, -NR q4 R q5 , =NR q6 、-C(=O)OC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl or -C(=O)NR q4 R q5 substituted by a substituent;

[0011] R q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl;

[0012] R q2 , R q3 Select from H or C 1-6 alkyl;

[0013] R q4 , R q5 Selected from H, C 1-6 Alkyl, -NH(C=NR q1 )NR q2 R q3 、-S(=O)2NR q2 R q3 、-C(=O)R q1 or -C(=O)NR q2 R q3 , where the C 1-6 The alkyl group is optionally further substituted with one or more groups selected from OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 Heteroaryl, C 3-8 Cycloalkyl or C 3-8 is substituted by a substituent of a heterocycloalkyl group; or R q4 With R q5and N atom to form a 3- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O or S;

[0014] R q6 C 1-6 alkyl;

[0015] W is selected from O or NH;

[0016] W1 is O;

[0017] X is NH;

[0018] Y is CR b R c ;

[0019] R b , R c Each independently selected from H, C 1-6 alkyl or 3 to 10 membered carbocyclic group, the C 1-6 The alkyl group is optionally further substituted with 1 to 4 groups selected from F, Cl, Br, I, C 1-6 Alkyl, C 1-6 substituted by an alkoxy group, a 3- to 10-membered carbocyclic group, or a 3- to 10-membered heterocyclic group, wherein the heterocyclic group optionally contains 1 to 3 heteroatoms selected from N, O or S;

[0020] or R b With R c Formation of double bonds;

[0021] R and R1 are each independently selected from deuterium, H, F, Cl, Br, I, CN, NH2, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -(C=O)-C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -O(C=O)-C 1-6 alkyl, -O(C=O)-3 to 10-membered carbocyclyl, -O(C=O)-3 to 10-membered heterocyclyl, -(C=O)O-3 to 10-membered carbocyclyl, -O(C=O)OC 1-6 Alkyl, 3- to 10-membered carbocyclic group, 4- to 10-membered heterocyclic group, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2 or (C=O)NR a1 R a2 , wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S, wherein the alkyl, alkenyl, alkoxy, carbocyclic or heterocyclic ring is optionally further substituted by 1 to 4 heteroatoms selected from OH, F, Cl, Br, I, CN, NR a1 Ra2 , =O, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -(C=O)-C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -O(C=O)-C 1-6 alkyl, -(C=O)O-3 to 10-membered carbocyclic group, -O(C=O)-3 to 10-membered carbocyclic group, -O(C=O)-3 to 10-membered heterocyclic group, -O(C=O)- 1-6 alkyl, 3- to 10-membered carbocyclic group, 5- to 10-membered heterocyclic group, -NHCOC 1-6 alkyl, -NH(C=O)-3 to 10-membered carbocyclic group, -NH(C=O)-3 to 10-membered heterocyclic group, or -(C=O)NR a1 R a2 substituted by a substituent;

[0022] Alternatively, R and R1 together with the atom to which they are attached form a 4- to 8-membered ring containing 0 to 4 heteroatoms selected from N, O or S, and the 4- to 8-membered ring is optionally further substituted by 0 to 4 heteroatoms selected from H, F, Cl, Br, I, OH, -NR a1 R a2 , =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -(C=O)OC 1-6 substituted by a substituent of an alkyl group, a 3- to 10-membered carbocyclic group, or a 5- to 10-membered heterocyclic group;

[0023] C is a 3- to 10-membered cycloalkyl group;

[0024] R2 is selected from H, F, Cl, Br, I, OH, -NR a1 R a2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 Alkoxy;

[0025] G1, G2, and G3 are each independently selected from N or CH;

[0026] q, r are selected from 0, 1 or 2;

[0027] n is selected from 0, 1, 2 or 3.

[0028] In one or more embodiments of the present application, the above compound is selected from the compounds represented by general formula (II), (II-1), (III) or (III-1):

[0029]

[0030] Q, R, R1, G1, G2, G3, C, R2, n, r, and q are defined the same as those in the general formula (I).

[0031] In one or more embodiments of the present application, Q is selected from a 5-membered heteroaryl group, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S, and the aryl or heteroaryl group is optionally substituted by 0 to 4 R q0 replace;

[0032] R q0 The same or different, each independently selected from C 1-4 Alkyl, halogen, OH, cyano, -NH2, C 2-4 Alkenyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, -NHC 1-4 Alkyl or -N(C 1-4 alkyl) 2, each of the heterocycloalkyl groups contains 1 to 3 heteroatoms selected from N or O, and the alkyl, heterocycloalkyl, and cycloalkyl groups are optionally further substituted by one or more groups selected from deuterium, OH, halogen, cyano, C 1-4 Alkyl or -NR q4 R q5 substituted by a substituent;

[0033] R q4 , R q5 Select from H or C 1-4 alkyl;

[0034] R and R1 are each independently selected from deuterium, H, F, CN, OH, C 1-6 An alkyl group or a 4- to 6-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N or O, wherein the alkyl group or heterocyclic ring is optionally further substituted by 1 to 4 heteroatoms selected from OH, F, CN or C 1-6 substituted by an alkoxy substituent;

[0035] Alternatively, R and the atom to which R1 is attached together form a 4-membered ring or a 5-membered ring;

[0036] G1, G2, G3 are each independently selected from CH;

[0037] q, r are selected from 0, 1 or 2.

[0038] In one or more embodiments of the present application, the compound is selected from the compounds represented by general formula (IV):

[0039]

[0040] Q, W, R, R1, r, q are defined as in the general formula (I);

[0041] m is selected from 1, 2 or 3.

[0042] In one or more embodiments of the present application, Q is selected from a 5-membered heteroaryl group, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S, and the aryl or heteroaryl group is optionally substituted by 0 to 4 R q0 replace;

[0043] R q0 The same or different, each independently selected from C 1-4 Alkyl, halogen, OH, cyano, -NH2, C 2-4 Alkenyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, -NHC 1-4 Alkyl or -N(C 1-4 alkyl) 2, each of the heterocycloalkyl groups contains 1 to 3 heteroatoms selected from N or O, and the alkyl, heterocycloalkyl, and cycloalkyl groups are optionally further substituted by one or more groups selected from deuterium, OH, halogen, cyano, C 1-4 Alkyl, -NR q4 R q5 , C 3-6 Cycloalkyl or C 3-6 substituted by a substituent of a heterocycloalkyl group;

[0044] R q4 , R q5 Select from H or C 1-4 alkyl;

[0045] W is selected from O or NH;

[0046] R and R1 are each independently selected from deuterium, H, F, CN, OH, C 1-6 An alkyl group or a 4- to 6-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N or O, wherein the alkyl group or heterocyclic ring is optionally further substituted by 1 to 4 heteroatoms selected from OH, F, CN or C 1-6 substituted by an alkoxy substituent;

[0047] Alternatively, R and the atom to which R1 is attached together form a 4-membered ring or a 5-membered ring;

[0048] q, r are selected from 0, 1 or 2;

[0049] m is selected from 1, 2 or 3.

[0050] In one or more embodiments of the present application, the compound is selected from the compound represented by the general formula (V) or the compound represented by the general formula (VI):

[0051]

[0052] Q, W, R b , R c The definitions are the same as those in general formula (I);

[0053] m is selected from 1, 2 or 3.

[0054] In one or more embodiments of the present application, Q is selected from a 5-membered heteroaryl group, wherein the heteroaryl group contains 1 to 3 heteroatoms selected from N, O or S, and the aryl or heteroaryl group is optionally substituted by 0 to 4 R q0 replace;

[0055] R q0 The same or different, each independently selected from C 1-4 Alkyl, halogen, OH, cyano, -NH2, C 2-4 Alkenyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, -NHC 1-4 Alkyl or -N(C 1-4 alkyl) 2, each of the heterocycloalkyl groups contains 1 to 3 heteroatoms selected from N or O, and the alkyl, heterocycloalkyl, and cycloalkyl groups are optionally further substituted by one or more groups selected from deuterium, OH, halogen, cyano, C 1-4 Alkyl or -NR q4 R q5 substituted by a substituent;

[0056] R q4 , R q5 Select from H or C 1-4 alkyl;

[0057] W is selected from O or NH;

[0058] R b , R c Each independently selected from H, C 1-4 alkyl or a 3- to 5-membered carbocyclic group, or R b With R c Formation of double bonds;

[0059] q, r are selected from 0, 1 or 2;

[0060] m is selected from 1, 2 or 3.

[0061] In one or more embodiments of the present application:

[0062] Q is selected from

[0063] Selected from

[0064] or In one or more embodiments of the present application, the compound is selected from one of the following structures:

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071] In one or more embodiments of the present application, the compound is selected from the following structures: These two structures are tautomers and are essentially the same substance.

[0072] In one or more embodiments of the present application, the compound is selected from one of the following structures:

[0073]

[0074] In one or more embodiments of the present application, treating skin radiation damage includes reducing the incidence or recurrence of skin radiation damage, inhibiting, improving or reducing the severity of skin radiation damage, or reversing skin radiation damage.

[0075] In one or more embodiments of the present application, skin radiation damage comes from environmental radiation.

[0076] In one or more embodiments of the present application, the skin radiation damage is from radiation from military weapons.

[0077] In one or more embodiments of the present application, the skin radiation damage comes from medical radiation treatment for cancer.

[0078] In one or more embodiments of the present application, the treatment of skin radiation damage is radiation inflammation.

[0079] In one or more embodiments of the present application, the skin radiation damage is radiation dermatitis and / or oral mucositis.

[0080] In one or more embodiments of the present application, the skin radiation damage is radiation dermatitis.

[0081] One or more embodiments of the present application also provide a method for treating skin radiation damage, wherein the skin radiation damage drug is applied to a target skin area of ​​a patient and / or the patient orally takes the skin radiation damage drug before, during or after radiotherapy.

[0082] One or more embodiments of the present application provide a method for treating skin radiation damage, wherein the skin radiation damage drug is applied to a target skin area of ​​a patient before, during or after radiotherapy and the patient orally takes the skin radiation damage drug.

[0083] One or more embodiments of the present application provide a method for treating skin radiation damage, wherein the patient orally takes the above-mentioned skin radiation damage drug before, during or after radiotherapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0084] Figure 1 This is a trend chart of dermatitis scores in each group after irradiation in the efficacy test of the mouse radiation dermatitis model.

[0085] Figure 2 This is a trend chart of the body weight change rate of each group after irradiation in the efficacy test of the mouse radiation dermatitis model.

[0086] Figure 3 This is a bar graph of epithelial thickness in each group of mice after irradiation in the drug efficacy test of the mouse radiation dermatitis model.

[0087] Figure 4 This is a bar graph showing the inflammatory cell infiltration scores of mice in each group after irradiation in the drug efficacy test of the mouse radiation dermatitis model.

[0088] Figure 5 This is a bar graph showing the skin fibrosis scores of mice in each group after irradiation in the drug efficacy test of the mouse radiation dermatitis model. DETAILED DESCRIPTION

[0089] The implementation process of the present invention and the beneficial effects produced are described in detail below through specific embodiments, which is intended to help readers better understand the essence and characteristics of the present invention, and is not intended to limit the scope of implementation of the present invention.

[0090] The present invention is further described in detail below in conjunction with the accompanying drawings:

[0091] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example,

[0092] Compound 1, compound 1-1, compound 1-2, compound 1-3, and compound 1-4 were prepared according to the preparation method of WO2021093820.

[0093] Drug efficacy test on mouse radiation dermatitis model

[0094] 1. Experimental steps

[0095] 1.1 Animal adaptation

[0096] Before the experiment, a total of 30 female C57BL / 6J mice were purchased. After acclimating to the environment for 5 days, healthy mice were selected as test animals, and 30 qualified animals were used in this experiment.

[0097] 1.2 Animal grouping

[0098] The mice were randomly divided into three groups according to their body weight using the S-shaped grouping method, namely the control group (normal mice), the model group -20 Gy, and the compound 1-1 (100 mg / kg) experimental group, with 10 mice in each group.

[0099] 1.3 Irradiation model

[0100] The hair on the front of the chest (2 cm×2 cm) of the animals in the model group (-20 Gy) and the compound 1-1 (100 mg / kg) experimental group was shaved with a razor before irradiation.

[0101] The irradiation site was the Institute of Blood Transfusion, Chinese Academy of Medical Sciences. The irradiation instrument was RAD SOURCE RS2000 X-ray biological irradiator. The irradiation conditions were 160KV, 25mA, 0.3mm copper alloy filter, plus reflector, Level 1, and the irradiation time was 910 seconds.

[0102] 1.4 Animal Dosing

[0103] The day of irradiation was set as day 0 (D0) of the experiment, and administration of compound 1-1 began on day 1 (D1). The test article was administered by gavage once a day (QD), and the dosage of compound 1-1 was 100 mg / kg, and the administration was continued for 35 days.

[0104] 1.5 Animal sampling

[0105] After administration on the 35th day, the mice were euthanized, and skin tissues were collected, fixed with paraformaldehyde, embedded in paraffin, and sectioned. Skin thickness and inflammatory infiltration were evaluated by hematoxylin-eosin staining, and skin fibrosis was evaluated by Masson staining.

[0106] 2. Determination method

[0107] 2.1 Dermatitis (skin lesion) score

[0108] The mice were scored twice a week according to the dermatitis scoring criteria, and all animals were scored until day 33. The scoring criteria are detailed in Table 1.

[0109] Table 1 Skin damage degree scores

[0110]

[0111] 2.2 Mouse weight

[0112] During the drug treatment period, the mice were weighed at least twice a week.

[0113] 2.3 Pathological histochemical scoring

[0114] Hematoxylin-eosin staining and Masson's staining were graded and scored as follows: 0 (no change), 1 (slight), 2 (mild), 3 (moderate), 4 (obvious), and 5 (severe).

[0115] 2.4 Statistical analysis

[0116] The data were statistically analyzed using GraphPad Prism 8. The dermatitis score and weight change rate were analyzed using two-way ANOVA, and the pathological tissue score results were analyzed using t-test. The evaluation criteria for inflammatory cell infiltration and fibrosis were based on the common pathological evaluation criteria, as shown in Table 2.

[0117] Table 2 Pathological evaluation 5 grades

[0118]

[0119] 3. Experimental results

[0120] 3.1 Dermatitis scores in each group after irradiation

[0121] During the entire experiment from D0 to D33, mice were scored twice a week according to the dermatitis scoring criteria, and all animals were scored until day 33. After irradiation, the dermatitis of each group was scored, and the scoring results are shown in Figure 1 Results are expressed as mean ± SEM as shown.

[0122] from Figure 1It can be seen that the dermatitis scores began to increase significantly at the end of the second week after irradiation (D15), and the scores of each group reached the highest value at the end of the third week (D22). The dermatitis scores of the control group, model group -20Gy, and compound 1-1 (100 mg / kg) experimental group were 0.0±0.0, 3.1±0.2, and 2.0±0.4, respectively. The score of the model group -20Gy was significantly higher than that of the control group, which was statistically significant (P<0.01 on the 15th day, P<0.001 on the 19-33rd day), indicating that the dermatitis model was successfully constructed.

[0123] The score of the compound 1-1 (100 mg / kg) experimental group was significantly lower than that of the model group -20 Gy group, with statistical significance (P<0.01 on days 19, 26, 29, and 33, and P<0.001 on day 22); and the compound 1-1 (100 mg / kg) experimental group showed a downward trend on D29, while the model group PG-D29 had no downward trend. This shows that compound 1-1 can reduce dermatitis scores, relieve dermatitis symptoms, and reduce the severity of dermatitis.

[0124] 3.2. Statistics of dermatitis in each group after irradiation

[0125] During the entire experiment from D0 to D33, the most severe grade of dermatitis in each mouse was counted, and the number of dermatitis of different grades was counted. The statistical results are shown in Table 2.

[0126] Table 3 Number of animals at each level of dermatitis

[0127]

[0128] From the data in Table 2, it can be seen that the total incidence of dermatitis in the model group -20Gy was 100% (10 / 10), and that in the compound 1-1 (100 mg / kg) experimental group was 80% (8 / 10); according to the incidence of dermatitis of each grade, the incidence of severe dermatitis (3.5 points-4 points) was 60% in the model group -20Gy, and 20% in the compound 1-1 (100 mg / kg) experimental group, which was statistically significant (P < 0.05), indicating that the compound 1-1 (100 mg / kg) experimental group could not only reduce the total incidence of dermatitis, but also significantly reduce the incidence of severe dermatitis.

[0129] 3.3 Body weight change rate of each group after irradiation

[0130] During the drug treatment period, the mice were weighed at least twice a week. Figure 2 Figure 2 is a trend chart of the body weight change rate of each group after irradiation. The results are expressed as mean ± SEM.

[0131] from Figure 2It can be seen that the weight of mice in the model group -20Gy and the compound 1-1 (100mg / kg) experimental group decreased after irradiation, and the decrease was most serious on the 8th day. The weight change rates of the model group -20Gy and the compound 1-1 (100mg / kg) experimental group on the 8th day were -8.3% and -4.4%, respectively. The weight loss of mice in the compound 1-1 (100mg / kg) experimental group was weaker than that in the model group -20Gy, indicating that the compound 1-1 (100mg / kg) experimental group had an improvement effect on the weight loss of mice. Subsequently, the weight of animals in each group showed an upward trend, indicating that the compound 1-1 (100mg / kg) experimental group had no toxic effect on the weight of mice.

[0132] 3.4 Skin tissue pathological staining results

[0133] At the end of the experiment, the mouse skin tissue was stained and scored for pathological tissue. Figure 3-Figure 5 The results are shown as mean ± SEM. At the end of the experiment, the skin thickness of the model group mice increased (compared with the control group, P < 0.01), inflammatory cell infiltration was upregulated (compared with the control group, P < 0.01), and fibrosis occurred (compared with the control group, P < 0.001). Continuous administration of compound 1-1 (100 mg / kg) for 35 days significantly reduced the epithelial thickness of mice ( Figure 3 , compared with the model group, P<0.05), reduced inflammatory cell infiltration ( Figure 4 , compared with the model group, P<0.05), improved skin fibrosis ( Figure 5 , compared with the model group, P<0.05).

[0134] 4. Conclusion

[0135] In summary, compound 1 can reduce the overall incidence of dermatitis in mice after irradiation, and can significantly reduce the incidence of severe dermatitis, reduce the severity of dermatitis, have no effect on reducing the weight of mice, and can even improve the weight loss of mice after irradiation; and reduce the thickness of mouse epithelium, reduce inflammatory cell infiltration, and improve skin fibrosis. Therefore, compound 1 can be used to treat radiation inflammation, such as dermatitis, oral mucositis, etc.

[0136] The specification of the present invention describes the specific implementation scheme in detail. Those skilled in the art should recognize that the above implementation scheme is exemplary and cannot be understood as limiting the present invention. For those skilled in the art, without departing from the principle of the present invention, by making several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. Use of a compound represented by formula (I), or a stereoisomer, tautomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof in the preparation of a drug for treating or preventing skin radiation damage: in: Q is selected from 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein the heteroaryl contains 1 to 3 heteroatoms selected from N, O or S, and the aryl or heteroaryl is optionally substituted by 0 to 4 R q0 replace; R q0 The same or different, each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, OH, cyano, nitro, -NH2, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl, -C(=O)OC 3-8 Cycloalkyl, -OC(=O)C 3-8 Cycloalkyl, -OC(=O)C 3-8 Heterocycloalkyl, -C(=O)OC 3-8 Heterocycloalkyl, -C(=O)C 6-10 Aryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -C(=O)C 5-10 Heteroaryl, -C(=O)OC 5-10 Heteroaryl, -OC(=O)C 5-10 Heteroaryl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NHC(=O)C 1-6 Alkyl, -NHC(=O)(C 1-6 Alkyl)2, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 3-8 Cycloalkyl, -NHC(=O)C 2-6 Alkynyl, -NHC(=O)C 2-6 Alkenyl, -NH(C=NR q1 )NR q2 R q3 、-C(=O)NR q4 R q5 、-SH、-SC 1-6 Alkyl, -S(=O)C 1-6 Alkyl, -S(=O)2C 1-6 Alkyl or -S(=O)2NR q2 R q3 , the heterocycloalkyl or heteroaryl each contains 1 to 3 heteroatoms selected from N, O or S, and the alkyl, alkoxy, -NH2, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, aryl, heteroaryl are optionally further substituted by one or more deuterium, OH, halogen, cyano, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR q4 R q5 , =NR q6 、-C(=O)OC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl, -C(=O)NR q4 R q5 , C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -OC(=O)C 5-10 Heteroaryl, -C(=O)OC 5-10 Heteroaryl, -OC(=O)C 3-8 Heterocycloalkyl, -C(=O)OC 3-8 Heterocycloalkyl, -OC(=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3-8 Cycloalkyl, -NHC(=O)C 3-8 Heterocycloalkyl, -NHC(=O)C 1-6 Alkyl, -NHC(=O)C 2-6 Alkenyl or -NHC(=O)C 2-6 substituted by a substituent of an alkynyl group, and wherein the substituent C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 Heteroaryl, -NHC(=O)C 3-8 Heterocycloalkyl or -NHC(=O)C 3-8 The cycloalkyl group is optionally further substituted by 1 to 3 groups selected from OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 or substituted by a substituent of =O; Or at least a pair of R q0 and the atoms connected thereto form a 4- to 10-membered carbocyclic ring or a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring contains 1 to 2 heteroatoms selected from N, O or S, and the carbocyclic ring or heterocyclic ring is optionally further substituted by one or more atoms selected from OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR q4 R q5 , =NR q6 、-C(=O)OC 1-6 Alkyl or -C(=O)NR q4 R q5 Substituents, and the substituents C 1-6 Alkyl or C 1-6 The alkoxy group is optionally further selected from OH, halogen, =O, -NR q4 R q5 , =NR q6 、-C(=O)OC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, C 6-10 Aryl, C 5-10 Heteroaryl or -C(=O)NR q4 R q5 substituted by a substituent; R q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl; R q2 , R q3 Select from H or C 1-6 alkyl; R q4 , R q5 Selected from H, C 1-6 Alkyl, -NH(C=NR q1 )NR q2 R q3 、-S(=O)2NR q2 R q3 、-C(=O)R q1 or -C(=O)NR q2 R q3 , where the C 1-6 The alkyl group is optionally further substituted with one or more groups selected from OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 Heteroaryl, C 3-8 Cycloalkyl or C 3-8 is substituted by a substituent of a heterocycloalkyl group; or R q4 With R q5 and N atom to form a 3- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O or S; R q6 C 1-6 alkyl; W is selected from O or NH; W1 is O; X is NH; Y is CR b R c ; R b , R c Each independently selected from H, C 1-6 alkyl or 3 to 10 membered carbocyclic group, the C 1-6 The alkyl group is optionally further substituted with 1 to 4 groups selected from F, Cl, Br, I, C 1-6 Alkyl, C 1-6 substituted by an alkoxy group, a 3- to 10-membered carbocyclic group, or a 3- to 10-membered heterocyclic group, wherein the heterocyclic group optionally contains 1 to 3 heteroatoms selected from N, O or S; or R b With R c Formation of double bonds; R and R1 are each independently selected from deuterium, H, F, Cl, Br, I, CN, NH2, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -(C=O)-C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -O(C=O)-C 1-6 alkyl, -O(C=O)-3 to 10-membered carbocyclyl, -O(C=O)-3 to 10-membered heterocyclyl, -(C=O)O-3 to 10-membered carbocyclyl, -O(C=O)OC 1-6 Alkyl, 3- to 10-membered carbocyclic group, 4- to 10-membered heterocyclic group, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2 or (C=O)NR a1 R a2 , wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S, wherein the alkyl, alkenyl, alkoxy, carbocyclic or heterocyclic ring is optionally further substituted by 1 to 4 heteroatoms selected from OH, F, Cl, Br, I, CN, NR a1 R a2 , =O, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -(C=O)-C 1-6 Alkyl, -(C=O)OC 1-6 Alkyl, -O(C=O)-C 1-6 alkyl, -(C=O)O-3 to 10-membered carbocyclic group, -O(C=O)-3 to 10-membered carbocyclic group, -O(C=O)-3 to 10-membered heterocyclic group, -O(C=O)- 1-6 alkyl, 3- to 10-membered carbocyclic group, 5- to 10-membered heterocyclic group, -NHCOC 1-6 alkyl, -NH(C=O)-3 to 10-membered carbocyclic group, -NH(C=O)-3 to 10-membered heterocyclic group, or -(C=O)NR a1 R a2 substituted by a substituent; Alternatively, R and R1 together with the atom to which they are attached form a 4- to 8-membered ring containing 0 to 4 heteroatoms selected from N, O or S, and the 4- to 8-membered ring is optionally further substituted by 0 to 4 heteroatoms selected from H, F, Cl, Br, I, OH, -NR a1 R a2 , =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -(C=O)OC 1-6 substituted by a substituent of an alkyl group, a 3- to 10-membered carbocyclic group, or a 5- to 10-membered heterocyclic group; C is a 3- to 10-membered cycloalkyl group; R2 is selected from H, F, Cl, Br, I, OH, -NR a1 R a2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 Alkoxy; G1, G2, G3 are each independently selected from N or CH; q, r are selected from 0, 1 or 2; n is selected from 0, 1, 2 or 3.

2. The use according to claim 1, characterized in that The compound is selected from the compounds represented by general formula (II), (II-1), (III) or (III-1): or Q, R, R1, G1, G2, G3, C, R2, n, r, and q are defined the same as those in the general formula (I).

3. The use according to claim 2, characterized in that: in: Q is selected from 5-membered heteroaryl, wherein the heteroaryl contains 1 to 3 heteroatoms selected from N, O or S, and the aryl or heteroaryl is optionally substituted by 0 to 4 R q0 replace; R q0 The same or different, each independently selected from C 1-4 Alkyl, halogen, OH, cyano, -NH2, C 2-4 Alkenyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, -NHC 1-4 Alkyl or -N(C 1-4 alkyl) 2, each of the heterocycloalkyl groups contains 1 to 3 heteroatoms selected from N or O, and the alkyl, heterocycloalkyl, and cycloalkyl groups are optionally further substituted by one or more groups selected from deuterium, OH, halogen, cyano, C 1-4 Alkyl or -NR q4 R q5 substituted by a substituent; R q4 , R q5 Select from H or C 1-4 alkyl; R and R1 are each independently selected from deuterium, H, F, CN, OH, C 1-6 An alkyl group or a 4- to 6-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N or O, wherein the alkyl group or heterocyclic ring is optionally further substituted by 1 to 4 heteroatoms selected from OH, F, CN or C 1-6 substituted by an alkoxy substituent; Alternatively, R and the atom to which R1 is attached together form a 4-membered ring or a 5-membered ring; G1, G2, G3 are each independently selected from CH; q, r are selected from 0, 1 or 2.

4. The use according to claim 1, characterized in that The compound is selected from the compounds represented by general formula (IV): Q, W, R, R1, r, q are defined as in the general formula (I); m is selected from 1, 2 or 3.

5. The use according to claim 4, characterized in that in: Q is selected from 5-membered heteroaryl, wherein the heteroaryl contains 1 to 3 heteroatoms selected from N, O or S, and the aryl or heteroaryl is optionally substituted by 0 to 4 R q0 replace; R q0 The same or different, each independently selected from C 1-4 Alkyl, halogen, OH, cyano, -NH2, C 2-4 Alkenyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, -NHC 1-4 Alkyl or -N(C 1-4 alkyl) 2, each of the heterocycloalkyl groups contains 1 to 3 heteroatoms selected from N or O, and the alkyl, heterocycloalkyl, and cycloalkyl groups are optionally further substituted by one or more groups selected from deuterium, OH, halogen, cyano, C 1-4 Alkyl, -NR q4 R q5 , C 3-6 Cycloalkyl or C 3-6 is substituted by a substituent of a heterocycloalkyl group; R q4 , R q5 Select from H or C 1-4 alkyl; W is selected from O or NH; R and R1 are each independently selected from deuterium, H, F, CN, OH, C 1-6 An alkyl group or a 4- to 6-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N or O, wherein the alkyl group or heterocyclic ring is optionally further substituted by 1 to 4 heteroatoms selected from OH, F, CN or C 1-6 substituted by an alkoxy substituent; Alternatively, R and the atom to which R1 is attached together form a 4-membered ring or a 5-membered ring; q, r are selected from 0, 1 or 2; m is selected from 1, 2 or 3.

6. The use according to claim 1, characterized in that: The compound is selected from the compound represented by the general formula (V) or the compound represented by the general formula (VI): Q, W, R b , R c The definitions are the same as those in general formula (I); m is selected from 1, 2 or 3.

7. The use according to claim 6, characterized in that in: Q is selected from 5-membered heteroaryl, wherein the heteroaryl contains 1 to 3 heteroatoms selected from N, O or S, and the aryl or heteroaryl is optionally substituted by 0 to 4 R q0 replace; R q0 The same or different, each independently selected from C 1-4 Alkyl, halogen, OH, cyano, -NH2, C 2-4 Alkenyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, -NHC 1-4 Alkyl or -N(C 1-4 alkyl) 2, each of the heterocycloalkyl groups contains 1 to 3 heteroatoms selected from N or O, and the alkyl, heterocycloalkyl, and cycloalkyl groups are optionally further substituted by one or more groups selected from deuterium, OH, halogen, cyano, C 1-4 Alkyl or -NR q4 R q5 substituted by a substituent; R q4 , R q5 Select from H or C 1-4 alkyl; W is selected from O or NH; R b , R c Each independently selected from H, C 1-4 alkyl or a 3- to 5-membered carbocyclic group, or R b With R c Formation of double bonds; q, r are selected from 0, 1 or 2; m is selected from 1, 2 or 3.

8. The use according to claim 1, characterized in that in: Q is selected from Selected from or 9. The use according to claim 1, characterized in that The compound is selected from one of the following structures:

10. The use according to any one of claims 1 to 9, characterized in that The skin radiation damage to be treated is radiation inflammation.

11. The use according to claim 10, characterized in that The skin radiation damage is radiation dermatitis and / or oral mucositis.

12. The use according to claim 11, characterized in that The skin radiation damage is radiation dermatitis.

13. A method for treating skin radiation damage, comprising applying the skin radiation damage drug of claims 1 to 12 to a target skin area of ​​a patient before, during or after radiotherapy and / or orally taking the skin radiation damage drug of claims 1 to 12 to the patient.

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