Quinoxaline compound and application thereof

Abstract

The invention relates to a quinoxaline compound and application thereof. The quinoxaline compound has the structural characteristics as shown in the following formula (1). The quinoxaline compound provided by the invention has good DDR1 and / or DDR2 receptor inhibition activity. # imgabs0 #

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical chemistry, and in particular to a quinoxaline compound and application thereof. Background Art

[0002] The relationship between receptor tyrosine kinases (RTKs) and cancer progression has long been of interest to researchers. Studies have shown that dysregulation, overexpression, or mutation of one or more RTKs is associated with most cancers. Researchers have conducted a decade-long study of RTKs, RTK-related pathways, and their relevance to cancer development, making them one of the important therapeutic targets for cancer treatment. DDR1 and DDR2 are a unique class of RTKs that belong to transmembrane (TM) receptors that share structural similarities with nearly all RTKs, but are unique in that they are activated upon binding to collagen in the extracellular portion of the receptor.

[0003] DDRs were considered as an orphan receptor class in the early 20th century. In 1997, Shrivastava et al. described DDR as a non-integrin collagen binding receptor that requires collagen binding to initiate cellular responses in the human body. In the same year, Vogel et al. demonstrated that these receptors are a subfamily of RTKs with a catalytic kinase domain (KD) that requires different types of collagen for activation. DDR1 was originally discovered from the slime mold Dictyostelium discoideum. The N-terminal discoidin (DS) domain of DDR has similar homology to the DS-I protein obtained from molds and can mediate cell aggregation. In addition to the extracellular DS homology domain that binds collagen, DDR has a KD in the intracellular part. When collagen binds to the DS domain, both receptors DDR1 and DDR2 are activated and then initiate downstream signaling pathways. Unlike other RTKs, when the ligand (collagen) binds to the DDR, the DDR exhibits abnormal, very slow and delayed autophosphorylation, and the phosphorylation level may last up to 18 hours. Various important functions of DDRs include regulation of cell proliferation, survival, cell differentiation, ECM homeostasis, cytokine secretion, cell aggregation, adhesion, migration and invasion, etc. To date, dysregulation, mutation or differential expression of DDR1, DDR2 or both have been reported in various cancers, especially non-small cell lung cancer (NSCLC) and breast cancer have been extensively studied. Therefore, DDRs can become one of the novel therapeutic targets to combat various cancers and tumor progression.

[0004] Currently, a variety of small molecule kinase inhibitors have been identified or developed to inhibit DDRs. Some multi-target kinase inhibitors, such as dasatinib, nilotinib, imatinib and ponatinib, have shown high inhibitory efficacy against both DDR1 and DDR2. Although progress has been made in the study of DDRs inhibition, it is still of great significance to further develop DDRs inhibitors and improve their selectivity, thereby providing more options for cancer treatment and reducing drug resistance and side effects. Summary of the invention

[0005] Based on this, the present application provides a quinoxaline compound and a preparation method and application thereof. The quinoxaline compound has good DDR1 and / or DDR2 receptor inhibitory activity.

[0006] In a first aspect of the present application, a quinoxaline compound and a pharmaceutically acceptable salt thereof are provided, wherein the quinoxaline compound has a structural feature as shown in the following formula (1):

[0007]

[0008] Among them, R 1 is H, C1-C5 alkyl, C1-C5 alkoxy or C3-C10 cycloalkyl;

[0009] Ring A is a 5- to 10-membered heteroaryl or a 6- to 20-membered spiroheterocycle;

[0010] L 1 is -NH- or -O-;

[0011] L 2 for

[0012] R 2 For-NR 21 R 22 , at least 1 R 23 a substituted or unsubstituted 5- to 10-membered heteroaryl group or at least one R 23 Substituted or unsubstituted 6- to 10-membered aryl group;

[0013] R 21 , R 22 Each independently represents H, C3-C5 cycloalkyl or at least one S 0 a substituted or unsubstituted 5- to 10-membered heteroaryl group, and R 21 , R 22 Not at the same time H;

[0014] S 0 Each is independently C1-C8 alkyl, C1-C5 alkyl-substituted phenyl or halogenated C1-C5 alkyl;

[0015] R23 Each is independently H, =O, C1-C5 alkyl, halogenated C1-C5 alkyl, halogenated 6-10 membered aryl, C1-C5 alkoxy, halogenated C1-C5 alkoxy or 6-10 membered aryl.

[0016] In one embodiment, the quinoxaline compound has the structural features shown in the following formula (I-1):

[0017]

[0018] In one embodiment, Ring A is a 5-10 membered heteroaryl group.

[0019] In one embodiment, for

[0020] In one embodiment, L 1 It is -O-.

[0021] In one embodiment, R 21 For H, R 22 At least 1 S 0 A substituted or unsubstituted 5- to 10-membered heteroaryl group.

[0022] In one embodiment, R 2 is one of the following groups:

[0023]

[0024] In one embodiment, the quinoxaline compound is one of the following compounds:

[0025]

[0026] The second aspect of the present application provides use of the quinoxaline compounds and pharmaceutically acceptable salts thereof described in the first aspect in the preparation of DDR1 and / or DDR2 receptor inhibitors.

[0027] The third aspect of the present application provides the use of the quinoxaline compounds and pharmaceutically acceptable salts thereof described in the first aspect in the preparation of drugs for preventing and treating cancer; optionally, the cancer is a cancer caused by DDR1 and / or DDR2 disorder, mutation or overexpression; further optionally, the cancer is non-small cell lung cancer, gastric cancer, breast cancer or colon cancer.

[0028] The above-mentioned quinoxaline compounds have a dual inhibitory effect on DDR1 and DDR2, and therefore have potential efficacy in preventing and treating cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1This is a graph showing the growth changes of tumor volumes in mice in the compound group of Example 7, the negative solvent control group and the comparative example 1 group;

[0030] Figure 2 This is a graph showing changes in body weight of mice in the Example 7 compound group, negative solvent control group and comparative example 1 group over treatment time. DETAILED DESCRIPTION

[0031] The following is a further detailed description of quinoxaline compounds of the present invention and their application in conjunction with specific examples. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present invention more thoroughly understood.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0033] In the present invention, "the first aspect", "the second aspect", "the third aspect", etc. are only used for descriptive purposes and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "the first", "the second", "the third", etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on quantity.

[0034] In the present invention, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0035] In the present invention, when it comes to numerical ranges, unless otherwise specified, the above numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0036] The percentage content involved in the present invention, unless otherwise specified, refers to mass percentage for solid-liquid mixing and solid-solid mixing, and refers to volume percentage for liquid-liquid mixing.

[0037] The percentage concentrations involved in the present invention, unless otherwise specified, refer to the final concentration. The final concentration refers to the proportion of the added component in the system after the addition of the component.

[0038] The temperature parameters in the present invention, if not specifically limited, allow for both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the precision range controlled by the instrument.

[0039] The room temperature in the present invention generally refers to 4°C to 30°C, preferably 20±5°C.

[0040] As used herein, the term "alkyl" refers to a monovalent residue formed by the loss of a hydrogen atom from a saturated hydrocarbon containing a primary (normal) carbon atom, a secondary carbon atom, a tertiary carbon atom, a quaternary carbon atom, or a combination thereof. Phrases containing this term, for example, "C1-C5 alkyl" refers to an alkyl containing 1 to 5 carbon atoms, and each occurrence may be independently C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, or C5 alkyl. Suitable examples include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH (CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH (CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ).

[0041] The term "alkoxy" refers to a group of the structure -O-alkyl, i.e., an alkyl group as defined above is connected to the adjacent group via an oxygen atom. Phrases containing this term, for example, "C1-C5 alkoxy" means that the alkyl portion contains 1 to 5 carbon atoms, and each occurrence can be independently C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy or C5 alkoxy. Suitable examples include, but are not limited to, methoxy (-O-CH 3 or -OMe), ethoxy (-O-CH 2 CH 3 or -OEt) and tert-butyloxy (-OC(CH 3 ) 3 or -OtBu).

[0042] The term "cycloalkyl" refers to a non-aromatic hydrocarbon containing ring carbon atoms, which may be a monocyclic alkyl, a spirocyclic alkyl, or a bridged cycloalkyl. Phrases containing this term, for example, "C3-C10 cycloalkyl" refers to a cycloalkyl containing 3 to 10 carbon atoms, each occurrence of which may be independently C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl, C8 cycloalkyl, C9 cycloalkyl, or C10 cycloalkyl. Suitable examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0043] As used herein, the term "aryl" refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing a hydrogen atom, which may be a monocyclic aromatic group, a condensed aromatic group, or a polycyclic aromatic group. For polycyclic rings, at least one is an aromatic ring system. For example, "C6-C10 aryl" refers to an aromatic group containing 6 to 10 carbon atoms, and each occurrence may be independently C6 aryl, C7 aryl, C8 aryl, C9 aryl or C10 aryl. Suitable examples include, but are not limited to, benzene, biphenyl, naphthalene, anthracene, phenanthrene, perylene, triphenylene and their derivatives.

[0044] As used herein, the term "heteroaryl" refers to an aryl group in which at least one carbon atom is replaced by a non-carbon atom, which may be an N atom, an O atom, an S atom, etc. For example, a "5-10 membered heteroaryl" refers to a heteroaryl group containing 5 to 10 ring atoms. Suitable examples include, but are not limited to, furan, benzofuran, thiophene, benzothiophene, pyrrole, pyrazole, triazole, imidazole, isoxazole, oxazole, oxadiazole, thiazole, tetrazole, indole, carbazole, pyrroloimidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furopyrrole, furanofuran, thienofuran, benzisoxazole, benzisothiazole, benzimidazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, quinoline, isoquinoline, o-naphthyridine, quinoxaline, phenanthridine, primary dridine, quinazoline, and quinazolinone.

[0045] In a first aspect of the present application, a quinoxaline compound and a pharmaceutically acceptable salt thereof are provided, wherein the quinoxaline compound has a structural feature as shown in the following formula (1):

[0046]

[0047] Among them, R 1 is H, C1-C5 alkyl, C1-C5 alkoxy or C3-C10 cycloalkyl;

[0048] Ring A is a 5- to 10-membered heteroaryl or a 6- to 20-membered spiroheterocycle;

[0049] L 1 is -NH- or -O-;

[0050] L 2 for It can be understood that one end of the amide bond is connected to the benzene ring in the general formula (1), and the other end is connected to R 2 ;

[0051] R 2 For-NR 21 R 22 Or at least 1 R 23 Substituted or unsubstituted 5-10 membered heteroaryl or at least one R 23 Substituted or unsubstituted 6- to 10-membered aryl group;

[0052] R 21 , R 22 Each independently represents H, C3-C5 cycloalkyl or at least one S 0 a substituted or unsubstituted 5- to 10-membered heteroaryl group, and R 21 , R 22 Not at the same time H;

[0053] S 0Each is independently C1-C8 alkyl, C1-C5 alkyl-substituted phenyl or halogenated C1-C5 alkyl;

[0054] R 23 Each is independently H, =O, C1-C5 alkyl, halogenated C1-C5 alkyl, halogenated 6-10 membered aryl, C1-C5 alkoxy, halogenated C1-C5 alkoxy or 6-10 membered aryl.

[0055] In one example, the quinoxaline compound has a structural feature shown in the following formula (I-1):

[0056]

[0057] In one example, ring A is a 5- to 10-membered heteroaryl group. Further, ring A is a pyrazolyl group.

[0058] In one example, the quinoxaline compound has a structural feature shown in the following formula (I-2):

[0059]

[0060] In another example, for

[0061] In one example, R 1 is H, methyl, ethyl or isopropyl. Further, R 1 It is H or methyl.

[0062] In one example, L 1 For -O-.

[0063] In one example, R 2 For-NR 21 R 22 .

[0064] Furthermore, R 21 , R 22 There is only one H in it.

[0065] Furthermore, R 21 For H, R 22 At least 1 S 0 Substituted or unsubstituted 5- to 10-membered heteroaryl. Further, the 5- to 10-membered heteroaryl is pyrazolyl, oxazolyl or isoxazolyl.

[0066] Furthermore, S 0 It is methyl, ethyl, isopropyl, tert-butyl, methyl-substituted phenyl, monofluoromethyl, difluoromethyl or trifluoromethyl.

[0067] In one example, R 2 At least 1 R 23 Substituted or unsubstituted 5- to 10-membered heteroaryl. Further, the 5- to 10-membered heteroaryl is pyridyl, pyrazolyl or oxopyridyl.

[0068] In one example, R 23 It is H, methyl, ethyl, =O, fluorophenyl, methoxy, ethoxy or phenyl.

[0069] In one example, R 2 At least 1 R 23 A substituted or unsubstituted 6- to 10-membered aryl group. Further, the 6- to 10-membered aryl group is a phenyl group.

[0070] In one example, R 23 It is a halogenated C1~C5 alkoxy group.

[0071] In one example, R 23 It is a halomethyl group or a halomethoxy group.

[0072] In one example, R 2 is one of the following groups:

[0073]

[0074] In one example, the quinoxaline compound is one of the following compounds:

[0075]

[0076] Another example of the present application provides the use of the quinoxaline compounds and pharmaceutically acceptable salts thereof as described above in the preparation of DDR1 and / or DDR2 receptor inhibitors.

[0077] Another example of the present application provides the use of the quinoxaline compounds and pharmaceutically acceptable salts thereof as described above in the preparation of a drug for preventing and treating cancer. Further, the cancer is a cancer caused by DDR1 and / or DDR2 disorder, mutation or overexpression; further optionally, the cancer is non-small cell lung cancer, gastric cancer, breast cancer or colon cancer.

[0078] The following are specific examples.

[0079] Preparation Example

[0080] The compounds of Examples 1 and 5 were synthesized according to the following route:

[0081]

[0082] Wherein, R represents the corresponding group in the compounds of Examples 1 and 5

[0083] Synthesis of Example 1 Compound:

[0084]

[0085] 7-Bromo-2-(1-methyl-1H-pyrazol-4-yl)quinoxaline (1.00 g, 1.00 eq), 1-cyclopropyl-3-(4-hydroxyphenyl)urea (0.73 g, 1.10 eq), cuprous iodide (0.52 g, 0.80 eq), L-Proline (0.32 g, 0.80 eq.), cesium carbonate (2.25 g, 2.00 eq.) were added to a reaction bottle at room temperature, anhydrous DMSO (15 mL) was added, nitrogen was replaced, and the mixture was placed in a 120°C oil bath and stirred for 2 hours. The reaction solution was cooled to room temperature and slowly poured into water (200 mL), solids were precipitated, and the crude product was obtained by suction filtration. 200-300 mesh silica gel was added to mix the sample, and 103 mg of white solid was obtained by column chromatography, which was the compound of Example 1.

[0086] LCMS(ESI):m / z 401[M+H] + .

[0087] 1 H NMR (500MHz, DMSO) δ9.15(s,1H),8.59(s,1H),8.39(s,1H),8.23(s,1H),8.02(d,J=9.1Hz,1H),7.51(t,J=9.7Hz,3 H), 7.12 (d, J = 8.4Hz, 2H), 7.06 (s, 1H), 6.40 (s, 1H), 3.91 (s, 3H), 2.55 (s, 1H), 0.65 (d, J = 6.6Hz, 2H), 0.42 (s, 2H).

[0088] Synthesis of Example 5 Compounds:

[0089]

[0090] Add phenyl (3-hydroxyphenyl) carbamate (520mg, 2.30mmol, 1.00eq) and triethylamine (157mg, 2.80mmol, 1.20eq) to the reaction bottle, add 5mL acetonitrile and stir, control the temperature at about 20℃, add cyclopropylamine (260mg, 0.82mmol, 1.00eq) dropwise to react, the reaction temperature should be raised to 50℃, and the reaction should continue for about 1h. Stand and separate to obtain the upper organic layer and the lower aqueous layer, extract the lower aqueous layer three times with 100ml ethyl acetate, combine all organic layers and wash three times with 10mL saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure at 45℃. Add 200-300 mesh silica gel to mix the sample, and perform column chromatography to obtain 330mg of off-white solid.

[0091] LCMS(ESI):m / z 193[M+H] + .

[0092]

[0093] 7-Bromo-2-(1-methyl-1H-pyrazol-4-yl)quinoxaline (300 mg, 1.04 mmol, 1.0 eq), 1-cyclopropyl-3-(3-hydroxyphenyl)urea (222 mg, 1.15 mmol, 1.10 eq), cesium carbonate (1.01 g, 3.12 mmol, 3.0 eq), cuprous iodide (20 mg, 0.11 mmol, 0.1 eq) were added to the reaction bottle at room temperature, dissolved into a suspension with DMF (3 mL), replaced with nitrogen 3 times, and moved into a 120°C oil bath pot and stirred for 8 h. The reaction solution was cooled to 20°C, slowly poured into a saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (15 mL*7), and the organic phase was washed with saturated brine (40 mL), and the organic phase was dried over anhydrous sodium sulfate. The residue was concentrated under reduced pressure at 40°C, and 200-300 mesh silica gel was added to mix the sample. Column chromatography was performed to obtain 140 mg of an off-white solid, which was the compound of Example 5.

[0094] LCMS(ESI):m / z 492[M+H] + .

[0095] 1H NMR (500MHz, DMSO) δ9.18(s,1H),8.60(s,1H),8.50(s,1H),8.24(s,1H),8.04(d,J=9.1Hz,1H),7.51(dd,J=9.0,2.4Hz,1H),7.44(s,1H),7. 33(t,J=8.1Hz,1H),7.19(t,J=6.5Hz,2H),6.75(d,J=7.9Hz,1H),6.41(s,1H),3.92(s,3H),1.23(s,2H),0.60(d,J=5.3Hz,2H),0.38(s,2H).

[0096] The compounds of Examples 2-4 and 6-9 were synthesized according to the following route:

[0097]

[0098] Wherein R represents the corresponding group in the compounds of Examples 2-4 and 6-9

[0099] Synthesis of Example 2 Compounds:

[0100]

[0101] 3-Amino-5-methylisoxazole (1.00 g, 10.20 mmol, 1.00 eq.) and sodium bicarbonate (0.84 g, 6.06 mmol, 1.00 eq.) were added to a 25 mL single-mouth bottle at room temperature, THF (10 mL) was added, stirred under an ice bath, phenyl chloroformate (1.91 g, 12.24 mmol, 1.20 eq.) was slowly added dropwise, and the ice bath reaction was continued for 1 hour, and then transferred to room temperature for 5 hours. The reaction solution was poured into water and stirred, extracted with ethyl acetate, washed with brine, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product. 1.20 g of yellow sticky solid was obtained.

[0102] LCMS(ESI):m / z 219[M+H] + .

[0103]

[0104] 4-((3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)aniline (260 mg, 0.82 mmol, 1.00 eq), phenyl(5-methylisoxazol-3-yl)carbamate (200 mg, 0.92 mmol, 1.10 eq), triethylamine (152 mg, 1.23 mmol, 1.50 eq.) were added to a 10 mL single-mouth bottle at room temperature, anhydrous DMF (3.0 ml) was added, nitrogen was replaced, and the temperature was raised to 80°C for 6 hours. The reaction solution was poured into water and stirred, and a solid was precipitated, and the crude product was obtained by suction filtration. 200-300 mesh silica gel was added to mix the sample, and column chromatography was performed to obtain 208 mg of a white solid, which is the compound of Example 2.

[0105] LCMS(ESI):m / z 442[M+H] + .

[0106] 1 H NMR(500MHz,DMSO)δ9.46(s,1H),9.16(s,1H),8.92(s,1H),8.58(s,1H),8.23(s,1H),8.03(d,J=9.1Hz,1H),7.57( d,J=8.6Hz,2H),7.51(d,J=9.0Hz,1H),7.19(d,J=8.6Hz,2H),7.10(s,1H),6.54(s,1H),3.92(s,3H),2.37(s,3H).

[0107] Synthesis of Example 3 Compounds:

[0108]

[0109] 3-(tert-butyl)-1-(p-tolyl)-1H-pyrazole-5-amine (1.00 g, 4.37 mmol, 1.00 eq.) and sodium bicarbonate (0.37 g, 4.37 mmol, 1.00 eq.) were added to a 25 mL single-mouth bottle at room temperature, THF (10 mL) was added, stirred under ice bath, phenyl chloroformate (0.82 g, 5.24 mmol, 1.20 eq.) was slowly added dropwise, and the reaction was continued in ice bath for 1 hour, and then transferred to room temperature for 5 hours. The reaction solution was poured into water and stirred, extracted with ethyl acetate, washed with brine, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product. 1.40 g of yellow sticky solid was obtained.

[0110] LCMS(ESI):m / z 350[M+H] + .

[0111]

[0112] 4-((3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)aniline (385 mg, 1.21 mmol, 1.00 eq.), phenyl(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate (507 mg, 1.21 mmol, 1.00 eq.), DMAP (74 mg, 0.61 mmol, 0.50 eq.), DIEA (235 mg, 1.82 mmol, 1.50 eq.) were added to a 25 ml single-necked bottle at room temperature, THF (4 ml) was added, nitrogen was replaced, and the reaction was stirred at 60°C for 2 hours. The reaction solution was poured into water and stirred, and a solid was precipitated, which was filtered to obtain a crude product. Silica gel was added to the sample and the sample was purified by column chromatography to obtain 281 mg of a gray solid, which was the compound of Example 3.

[0113] LCMS(ESI):m / z 573[M+H] + .

[0114] 1 H NMR(500MHz,DMSO)δ9.16(s,1H),9.11(s,1H),8.58(s,1H),8.35(s,1H),8.23(s,1H),8.02(d,J=9.1Hz,1H),7.52(dd,J=13.8,8.1Hz,3H), 7.42(d,J=7.9Hz,2H),7.35(d,J=8.1Hz,2H),7.16(d,J=8.4Hz,2H),7.11–7.07(m,1H),6.37(s,1H),3.92(s,3H),2.38(s,3H),1.28(s,9H).

[0115] Synthesis of Example 4 Compounds:

[0116]

[0117] 1-Methyl-5-(trifluoromethyl)-1H-pyrazole-3-amine (1.00 g, 6.06 mmol, 1.00 eq.) and sodium bicarbonate (0.49 g, 6.06 mmol, 1.00 eq.) were added to a 25 mL single-mouth bottle at room temperature, THF (10 mL) was added, stirred under an ice bath, phenyl chloroformate (1.13 g, 7.27 mmol, 1.20 eq.) was slowly added dropwise, and the reaction was continued in an ice bath for 1 hour, and then transferred to room temperature for 5 hours. The reaction solution was poured into water and stirred, extracted with ethyl acetate, washed with brine, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product. 1.20 g of yellow sticky solid was obtained.

[0118] LCMS(ESI):m / z 286[M+H]+ .

[0119]

[0120] 4-((3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)aniline (260 mg, 0.82 mmol, 1.00 eq), phenyl(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)carbamate (262 mg, 0.92 mmol, 1.10 eq), triethylamine (152 mg, 1.23 mmol, 1.50 eq.) were added to a 10 mL single-mouth bottle at room temperature, anhydrous DMF (3.0 mL) was added, nitrogen was replaced, and the temperature was raised to 80°C for 6 hours. The reaction solution was poured into water and stirred, and a solid was precipitated, which was filtered to obtain a crude product. 200-300 mesh silica gel was added to mix the sample, and column chromatography was performed to obtain 120 mg of a light yellow solid, which is the compound of Example 4.

[0121] LCMS(ESI):m / z 509[M+H] + .

[0122] 1 H NMR(500MHz,DMSO)δ9.22(s,1H),9.16(s,1H),8.90(s,1H),8.59(s,1H),8.23(s,1H),8.03(d,J=9.1Hz,1H ),7.64–7.46(m,3H),7.18(d,J=8.8Hz,2H),7.10(d,J=2.4Hz,1H),6.86(s,1H),3.92(s,3H),3.86(s,3H).

[0123] Synthesis of Example 6 Compounds:

[0124]

[0125] 4-((3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)aniline (260 mg, 0.82 mmol, 1.00 eq.), 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (227 mg, 0.92 mmol, 1.10 eq.), HATU (467 mg, 1.23 mmol, 1.50 eq.), DIEA (317 mg, 2.46 mmol, 3.00 eq.) were added to a 10 ml single-mouth bottle at room temperature, anhydrous DMF (3.0 ml) was added, nitrogen was replaced, and the reaction was carried out at room temperature for 6 hours. The reaction solution was poured into water and stirred, and a solid was precipitated. The crude product was obtained by suction filtration, and 200-300 mesh silica gel was added to stir the sample. Column chromatography was performed to obtain 330 mg of a white solid, which was the compound of Example 6.

[0126] LCMS(ESI):m / z 547[M+H] + .

[0127] 1 H NMR (500MHz, DMSO) δ11.92(s,1H),9.17(s,1H),8.58(s,1H),8.49(d,J=7.5Hz,1H),8.22(s,1H),8.03(d,J=9.1Hz,1H),7.80(d,J=8.7Hz,2H) ,7.50(t,J=8.0Hz,3H),7.43(t,J=8.6Hz,2H),7.20(d,J=8.7Hz,2H),7.14(d,J=2.3Hz,1H),6.69(d,J=7.6Hz,1H),3.91(s,3H),2.07(s,3H).

[0128] Synthesis of Example 7 Compounds:

[0129]

[0130] 4-((3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)aniline (260 mg, 0.82 mmol, 1.00 eq.), 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (210 mg, 0.92 mmol, 1.10 eq.), HATU (467 mg, 1.23 mmol, 1.50 eq.), DIEA (317 mg, 2.46 mmol, 3.00 eq.) were added to a 10 ml single-mouth bottle at room temperature, anhydrous DMF (3.0 ml) was added, nitrogen was replaced, and the reaction was carried out at room temperature for 6 hours. The reaction solution was poured into water and stirred, and a solid was precipitated, and the crude product was obtained by suction filtration. 200-300 mesh silica gel was added to stir the sample. Column chromatography was performed to obtain 320 mg of a white solid, which was the compound of Example 7.

[0131] LCMS(ESI):m / z 533[M+H] + .

[0132] 1 H NMR (500MHz, DMSO) δ13.02(s,1H),9.17(s,1H),8.61(d,J=17.2Hz,2H),8.23(s,1H),8.14–8.00(m,2H),7.83(d,J= 8.7Hz,2H),7.81–7.65(m,2H),7.53(dd,J=9.1,2.4Hz,1H),7.25(dd,J=21.8,8.8Hz,4H),7.16(s,1H),3.92(s,3H).

[0133] Synthesis of Example 8 Compounds:

[0134]

[0135] 4-((3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)aniline (50 mg, 0.16 mmol, 1.00 eq.), 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (45 mg, 0.17 mmol, 1.00 eq.), HATU (90 mg, 0.23 mmol, 1.50 eq.), DIEA (61 mg, 0.47 mmol, 3.00 eq.) were added to a 10 mL single-mouth bottle at room temperature, anhydrous DMF (1.0 mL) was added, nitrogen was replaced, and the reaction was stirred at room temperature for 8 hours. The reaction solution was poured into water and stirred, and a solid was precipitated, which was filtered to obtain a crude product. The crude product was mixed with silica gel and separated by column chromatography to obtain 15 mg of a white solid, which was the compound of Example 8.

[0136] LCMS(ESI):m / z 577[M+H] + .

[0137] 1 H NMR(500MHz,DMSO)δ10.35(s,1H),9.17(s,1H),8.60(s,1H),8.24(s,1H),8.03(d,J =9.1Hz,1H),7.83(d,J=7.8Hz,1H),7.79(d,J=8.4Hz,2H),7.55–7.50(m,1H),7.47( dd,J=8.8,4.9Hz,2H),7.37(t,J=8.6Hz,2H),7.20(d,J=8.4Hz,2H),7.10(d,J=2.8H z, 1H), 6.50 (d, J = 7.8Hz, 1H), 4.26 (q, J = 7.0Hz, 2H), 3.91 (s, 3H), 1.33–1.29 (m, 3H).

[0138] Synthesis of Example 9 Compounds:

[0139]

[0140] 4-((3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)aniline (50 mg, 0.16 mmol, 1.00 eq.), 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (40 mg, 0.17 mmol, 1.10 eq.), HATU (90 mg, 0.23 mmol, 1.50 eq.), DIEA (61 mg, 0.47 mmol, 3.00 eq.) were added to a 10 ml single-mouth bottle at room temperature, anhydrous DMF (1.0 ml) was added, nitrogen was replaced, and the reaction was carried out at room temperature for 6 hours. The reaction solution was poured into water and stirred, and a solid was precipitated. The crude product was obtained by suction filtration, and 200-300 mesh silica gel was added to stir the sample. Column chromatography was performed to obtain 30 mg of a white solid, which was the compound of Example 9.

[0141] LCMS(ESI):m / z 532[M+H] + .

[0142] 1H NMR (500MHz, DMSO) δ10.81(s,1H),9.17(s,1H),8.59(s,1H),8.23(s,1H),8.03(d,J=9.1Hz,1H),7.71(d,J=8.4Hz,2H),7.59(t,J=7 .7Hz,2H),7.52(d,J=7.6Hz,2H),7.44(d,J=7.7Hz,2H),7.20(d,J=8.4Hz,2H),7.11(s,1H),3.91(s,3H),3.35(s,3H),2.71(s,3H).

[0143] The compounds of Examples 10 and 11 were synthesized by the following route:

[0144]

[0145] Wherein, R represents the corresponding group in the compounds of Examples 10 and 11

[0146] Synthesis of Example 10 Compounds:

[0147]

[0148] 7-Bromo-2-(1-methyl-1H-pyrazol-4-yl)quinoxaline (2.66 g, 9.20 mmol, 1.0 eq.), methyl p-hydroxybenzoate (1.4 g, 9.20 mmol, 1 eq.), DMSO (20 mL), Cs 2 CO 3 (11.99 g, 36.81 mmol, 4 eq.), (Bu 4 N + ) 2 (Cu 2 I 4 )(2.06g, 1.84mmol, 0.2eq.), 2,2,6,6-tetramethyl-3,5-heptanedione (1.36g, 7.36mmol, 0.8eq.) were added to the reaction bottle at room temperature, the nitrogen was replaced, and the reaction was stirred in a 100℃ oil bath for 3 hours. The reaction solution was poured into 50mL of water, 50mL of EA was added, and the filter residue was washed with EA. The filtrate was separated, the aqueous phase was extracted with EA 30mL*3, the organic phase was washed with saturated brine, and anhydrous Na 2 SO 4 Dry, filter, spin dry, add 200-300 mesh silica gel to mix the sample, and separate by column chromatography to obtain 700 mg of yellow solid.

[0149] LCMS(ESI):m / z 361[M+H] + .

[0150]

[0151] Methyl 4-((3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)benzoate (150 mg, 0.416 mmol, 1 eq.), MeOH (3 mL), H 2 O (3mL), THF (3mL) were added to a single-mouth bottle, NaOH (33.3mg, 0.832mmol, 2eq.) was added, and stirred at room temperature overnight. The reaction solution was concentrated, 10mL of water was added, and hydrochloric acid was added to adjust the pH to about 5, and 30mL*3 of EA was extracted. The organic phase was collected and the organic phase was washed with anhydrous Na 2 SO 4 Dry, filter and spin dry to obtain 100 mg of light yellow solid.

[0152] LCMS(ESI):m / z 347[M+H] + .

[0153]

[0154] 4-((3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)benzoic acid (200 mg, 0.577 mmol, 1.0 eq.), pyridine (5 mL), EDCI (132.8 mg, 0.692 mmol, 1.2 eq.), HOBT (93.6 mg, 0.692 mmol, 1.2 eq.) were added to a single-mouth bottle and stirred for 0.5 h. m-trifluoromethylaniline (93.04 mg, 0.577 mmol, 1.00 eq.) was added and stirred at room temperature overnight. The reaction solution was poured into 30 mL of water, extracted with EA, and separated. The aqueous phase was extracted with EA 30 mL*3, and the organic phase was washed 3 times with dilute hydrochloric acid. The organic phase was washed with anhydrous Na 2 SO 4 Dry, filter, and spin dry. Add 200-300 mesh silica gel to mix the sample, and perform column chromatography to separate 15 mg of white solid, which is the compound of Example 10.

[0155] LCMS(ESI):m / z 490[M+H] +

[0156] 1 H NMR(500MHz,DMSO-d6)δ10.56(s,1H),9.22(s,1H),8.58(s,1H),8.24(s,2H),8.13–8.07(m,3H), 8.04(d,J=8.3Hz,1H),7.64–7.54(m,2H),7.46(d,J=7.8Hz,1H),7.42–7.31(m,3H),3.93(s,3H).

[0157] Synthesis of Example 11 Compound:

[0158]

[0159] 4-((3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-yl)oxy)benzoic acid (200 mg, 0.577 mmol, 1 eq), pyridine (5 mL), EDCI (132.8 mg, 0.692 mmol, 1.2 eq), HOBT (93.6 mg, 0.692 mmol, 1.2 eq.) were added to a single-mouth bottle and stirred for 0.5 h. 3-difluoromethoxyaniline (91.9 mg, 0.577 mmol, 1 eq) was added and stirred at room temperature overnight. The reaction solution was poured into 30 mL of water, extracted with EA, and separated. The aqueous phase was extracted with EA 30 mL*3, and the organic phase was washed 3 times with dilute hydrochloric acid. The organic phase was washed with anhydrous Na 2 SO 4 Dry, filter and spin dry to obtain 64 mg of white solid, which is the compound of Example 11.

[0160] LCMS(ESI):m / z 486[MH] - .

[0161] 1 H NMR (500MHz, DMSO-d6) δ10.41(s,1H),9.23(s,1H),8.59(s,1H),8.25(s,1H),8.09(t,J=7.8Hz,3H),7.75(s,1H),7. 64(d,J=8.0Hz,1H),7.59–7.54(m,1H),7.41(t,J=8.2Hz,1H),7.37–7.19(m,4H),6.92(d,J=7.9Hz,1H),3.93(s,3H).

[0162] Synthesis of Example 12 Compounds:

[0163]

[0164] 7-Bromo-2-chloroquinoxaline (2.00 g, 8.30 mmol, 1.00 eq) and 7-oxa-2-azaspiro[3.5]nonane (1.58 g, 12.44 mmol, 1.50 eq) were added to a reaction bottle at room temperature, 1N, N-dimethylformamide (20 ml, 10 V) was added, nitrogen was replaced, and the mixture was moved into a 70°C oil bath pot for reaction for 3 hours. The reaction solution was cooled to room temperature, poured into water (250 mL) and stirred, solids precipitated, and the crude product was obtained by suction filtration, and 200-300 mesh silica gel was added to mix the sample. Column chromatography was performed to obtain 1.37 g of light yellow solid.

[0165] LCMS(ESI):m / z 334[M] + .

[0166]

[0167] 2-(7-Bromoquinoxaline-2-yl)-7-oxa-2-azaspiro[3.5]nonane (0.80 g, 2.40 mmol, 1.00 eq), N-(4-hydroxyphenyl)pivalamide (0.57 g, 2.88 mmol, 1.20 eq), cuprous iodide (0.14 g, 0.72 mmol, 0.3 eq), L-Proline (1.65 g, 1.44 mmol, 0.6 eq), cesium carbonate (1.56 g, 4.80 mmol, 2.00 eq) were added to the reaction bottle at room temperature, anhydrous DMSO (12 ml) was added, nitrogen was replaced, and the mixture was placed in a 120°C oil bath and stirred for 7 hours. The reaction solution was cooled to room temperature and slowly poured into water (200 mL) to precipitate a solid, which was filtered to obtain a crude product, and 200-300 mesh silica gel was added to mix the sample, and column chromatography was performed to obtain 300 mg of a light yellow solid.

[0168] LCMS(ESI):m / z 447[M+H] + .

[0169]

[0170] N-(4-((3-(7-oxa-2-azaspiro[3.5]non-2-yl)quinoxalin-6-yl)oxy)phenyl)pivalamide (0.57 g, 0.63 mmol, 1.00 eq) was added to a 10 ml single-necked bottle at room temperature, acetic acid (3 ml) was added, concentrated hydrochloric acid (1 ml) was added dropwise, and the mixture was stirred and refluxed at 110°C for 6 hours. The reaction solution was cooled to room temperature, poured into a saturated sodium bicarbonate solution and stirred, solids were precipitated, and the crude product was obtained by suction filtration, and 200-300 mesh silica gel was added to mix the sample, and column chromatography was performed to obtain 180 mg of yellow solid.

[0171] LCMS(ESI):m / z 363[M+H] + .

[0172]

[0173] 4-((3-(7-oxa-2-azaspiro[3.5]non-2-yl)quinoxalin-6-yl)oxy)aniline (151 mg, 0.42 mmol, 1.00 eq), 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (105 mg, 0.46 mmol, 1.10 eq), HATU (233 mg, 0.61 mmol, 1.50 eq.), DIEA (159 mg, 1.23 mmol, 3.00 eq.) were added to a 10 ml single-mouth bottle at room temperature, anhydrous DMF (1.5 ml) was added, nitrogen was replaced, and the reaction was carried out at room temperature for 6 hours. The reaction solution was poured into water and stirred, and a solid was precipitated, and the crude product was obtained by suction filtration. The crude product was mixed with silica gel and separated by column chromatography. 180 mg of off-white solid was obtained, which was the compound of Example 12.

[0174] LCMS(ESI):m / z 578[M+H] + .

[0175] 1 H NMR (500MHz, DMSO) δ12.97(s,1H),12.60(s,1H),8.61(s,1H),8.19(s,1H),8.07(s,1H),7.80(dd,J=11.7,9.0Hz,3H),7.71(dd,J=8.5,5 .8Hz,2H),7.26(t,J=8.9Hz,2H),7.12(dd,J=16.3,5.8Hz,3H),6.85(d,J=2.5Hz,1H),3.93(s,4H),3.62–3.47(m,4H),1.82–1.69(m,4H).

[0176] Test Example 1:

[0177] The inhibitory effects of the compounds on the enzymatic activities of kinases DDR1 and DDR2 (IC 50 )

[0178] This experiment uses the mobility shift assay method to screen the test compounds on DDR1 and DDR2 kinases. The starting concentration of the test compound solution is 10000nM, 4-fold dilution, 10 concentrations, and duplicate well detection.

[0179] 1. Experimental steps

[0180] Prepare 2× kinase substrate-ATP solution and 2× kinase-Metal solution using assay buffer. Transfer 25nL of the test compound solution to the 384 assay plate via Echo655. Add 2.5μL of 2× kinase-Metal solution and incubate in a 384-well plate at 25°C for 10 minutes. Add 2.5μL of 2× kinase substrate-ATP solution to the wells and incubate at 25°C for 50 minutes. Prepare 2× XL665-antibody solution with detection buffer. Add 5μL of kinase detection reagent to the wells and incubate at 25°C for 60 minutes. Read the fluorescence signals at 620nm (Cryptate) and 665nm (XL665) with a microtiter plate reader.

[0181] 2. Data Analysis

[0182] 1. Calculate the ratio of each hole (665 / 620nm)

[0183] %inhibition is calculated as follows:

[0184] %Inhibition=100%-(compound-positive control) / (negative control-positive control)*100%

[0185] 2. Calculate IC50 and draw the dose-effect curve of the compound:

[0186] The log value of the concentration of the test substance was used as the X-axis and the %inhibition as the Y-axis. The log(inhibitor) vs.response-Variable slope of the analysis software GraphPad 7.0 was used to fit the dose-effect curve to obtain the IC value of each compound on the enzyme activity. 50 value.

[0187] The formula is as follows:

[0188] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0189] 3. Results

[0190] The inhibitory activities of the compounds in the examples against kinases DDR1 and DDR2 are shown in Table 1 below:

[0191] Table 1 Inhibitory activity of compounds against kinases DDR1 and DDR2

[0192]

[0193]

[0194] The experimental results show that the compounds of the examples can effectively inhibit the activities of DDR1 and DDR2 kinases.

[0195] Test Example 2:

[0196] The compounds of the examples were tested for their in vivo anti-tumor activity in a heterotopic transplantation model of the DDR1-highly expressed human colon cancer cell line HCT116.

[0197] Fifteen female Balb / c nude mice aged 6-8 weeks were selected and inoculated subcutaneously with 5×10 HCT116 tumor cells. 6 After 15 days of inoculation of tumor cells, when the tumor grows to 90 mm 3 ~150mm 3 At 14:00, the mice were gavaged with the test samples.

[0198] The mice were divided into a negative solvent control group, a compound group (compound of Example 7) (30 mg / kg) and a comparative example 1 group (30 mg / kg), with 5 mice in each group. All dose groups were administered with equal volumes and different concentrations by oral gavage once a day, with a dosing volume of 10 mL / kg. The negative solvent control group was given the same volume of blank solvent (DMSO: Solutol: water = 1:2:7), and the dosing frequency was once a day for 18 consecutive days.

[0199] After the start of drug administration, the body weight and tumor size of the mice were measured twice a week. Tumor size calculation formula:

[0200] Tumor volume (mm 3 ) = 0.5 × (long diameter of tumor × short diameter of tumor 2 ).

[0201] The anti-tumor efficacy is evaluated based on the growth curve of the tumor during treatment (i.e., the tumor volume measured each time relative to the number of days of treatment) and the relative tumor volume. The relative tumor inhibition rate (TGI) is calculated according to the following formula:

[0202] Relative tumor inhibition rate TGI (%): TGI% = (1-T / C) × 100%.

[0203] T / C% is the relative tumor growth rate, that is, the percentage of the relative tumor volume or tumor weight of the treatment group and the control group at a certain time point. T and C are the relative tumor volume (RTV) or tumor weight (TW) of the treatment group and the control group at a specific time point, respectively. The calculation formula is as follows: T / C% = T RTV / C RTV ×100%(T RTV : Average RTV of the treatment group; C RTV: Average RTV of vehicle control group; RTV=Vt-V0, V0 is the tumor volume of the animal when grouped, and Vt is the tumor volume of the animal after treatment).

[0204] The test results are as follows Figure 1 and 2 shown. Figure 1 The growth changes of tumor volume of mice in the compound group of Example 7, the negative solvent control group and the comparative example 1 group are shown. As shown in the figure, the compound of Example 7 can effectively inhibit the growth of tumor cells in the model mice, and the relative tumor inhibition rate (TGI) is 79.88% by volume, which is higher than 16.8% of the comparative example 1. Figure 2 The figure shows the changes in the body weight of mice in the Example 7 compound group, the negative solvent control group and the comparative example 1 group over the treatment time. As shown in the figure, the body weight of the tumor-bearing mice did not change significantly during the experiment, and the Example 7 compound has good safety and tolerability.

[0205] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0206] The above-described embodiments only express several implementation methods of the present invention, which are convenient for understanding the technical solutions of the present invention in detail, but they cannot be understood as limiting the scope of protection of the invention patent. It should be pointed out that for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided by the present invention are all within the protection scope of the claims attached to the present invention. Therefore, the protection scope of the patent of the present invention shall be based on the contents of the attached claims, and the description and drawings can be used to interpret the contents of the claims.

Claims

1. A quinoxaline compound and a pharmaceutically acceptable salt thereof, characterized in that: The quinoxaline compound has the structural characteristics shown in the following formula (1): Wherein, R1 is H, C1-C5 alkyl, C1-C5 alkoxy or C3-C10 cycloalkyl; Ring A is a 5- to 10-membered heteroaryl or a 6- to 20-membered spiroheterocycle; L1 is -NH- or -O-; L2 is R2 is -NR 21 R 22 , at least 1 R 23 a substituted or unsubstituted 5- to 10-membered heteroaryl group or at least one R 23 Substituted or unsubstituted 6- to 10-membered aryl group; R 21 , R 22 Each is independently H, C3-C5 cycloalkyl or at least one S0 substituted or unsubstituted 5-10 membered heteroaryl, and R 21 , R 22 are not H at the same time; S0 are each independently C1-C8 alkyl, C1-C5 alkyl substituted phenyl or halogenated C1-C5 alkyl; R 23 Each is independently H, =O, C1-C5 alkyl, halogenated C1-C5 alkyl, halogenated 6-10 membered aryl, C1-C5 alkoxy, halogenated C1-C5 alkoxy or 6-10 membered aryl.

2. The quinoxaline compound and pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The quinoxaline compound has the structural characteristics shown in the following formula (I-1):

3. The quinoxaline compound and pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: Ring A is a 5- to 10-membered heteroaryl group.

4. The quinoxaline compound and pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: for 5. The quinoxaline compound and pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: L1 is -O-.

6. The quinoxaline compound and pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: R 21 For H, R 22 is at least one S0-substituted or unsubstituted 5- to 10-membered heteroaryl group.

7. The quinoxaline compound and pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: R2 is one of the following groups:

8. The quinoxaline compound and pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The quinoxaline compound is one of the following compounds:

9. Use of the quinoxaline compound and a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 in the preparation of a DDR1 and / or DDR2 receptor inhibitor.

10. Use of the quinoxaline compound and a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 in the preparation of a drug for preventing and treating cancer; optionally, the cancer is a cancer caused by DDR1 and / or DDR2 disorder, mutation or overexpression; further optionally, the cancer is non-small cell lung cancer, gastric cancer, breast cancer or colon cancer.

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