Substituted oxazolo six-membered ring compound and application thereof

Abstract

The invention discloses a substituted oxazolo six-membered ring compound and application thereof.The structure of the substituted oxazolo six-membered ring compound is shown in the formula I. The substituted oxazolo six-membered ring compound can be combined with UKL1 protein, so that autophagy is potentially inhibited, the anti-tumor activity is achieved, the substituted oxazolo six-membered ring compound has the anti-tumor effect, and the substituted oxazolo six-membered ring compound can be used for preparing anti-tumor drugs. The medicine is a good candidate medicine for future research. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology. Specifically, the present invention relates to a substituted oxazolo six-membered ring compound and its application. Background Art

[0002] Autophagy is a defense and stress regulation mechanism. Through autophagy and lysosomes, cells eliminate, degrade, and digest damaged, denatured, senescent, and dysfunctional cells, cell organelles, denatured proteins, nucleic acids and other biological macromolecules, providing essential raw materials for cell reconstruction, regeneration, and repair, and realizing cell recycling and reuse. Currently, many important studies have found that autophagy plays a crucial role in tissue homeostasis and human diseases, such as cancer, neurodegenerative diseases, infections, immunity, and aging.

[0003] ULK1 is a serine / threonine protein kinase and one of the important autophagy-related genes in human cells, located at 12q24.3 of human chromosome 12. Current studies have shown that tumors are closely related to autophagy, and small molecule inhibitors of ULK1 have potential uses in tumor treatment. Related reports are as follows: SBI-0206965 can inhibit the phosphorylation of ULK1 at the sites of VPS34 and BECN1, and can selectively inhibit the endogenous ULK1 kinase activity in vivo. This inhibitor has significant efficacy against lung cancer. CN108066336A discloses a drug preparation using meliacamide as an active ingredient or the only active ingredient for preparing a ULK1 inhibitor, an autophagy inhibitor, and blocking tumor immune escape and / or enhancing cellular immunity.

[0004] In view of the connection between ULK1 inhibitors and anti-tumor activity, the applicant initiated a study on the compound structure for inhibiting ULK1 protein activity. During the extensive screening process of binding to ULK1 protein, certain results have been obtained. For example, CN118955391A discloses a substituted N-(2-oxoethyl)benzamide derivative that can bind to the UKL1 protein, thereby potentially inhibiting autophagy and exerting anti-tumor activity. CN 112358435B discloses a substituted aryl heterocyclic compound, its preparation method, and its uses for inhibiting ULK1 and anti-tumor. This application is also generated under the same research background. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a substituted oxazolo six-membered ring compound and its application.

[0006] Term Definition

[0007] The terms used in this description of the present invention are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and biology described herein are well-known and commonly used in the art. Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0008] As used herein, the term "tumor" refers to a local mass formed by abnormal proliferation of cells under the action of various pathogenic factors in the body, including benign tumors, malignant tumors, and borderline tumors.

[0009] As used herein, the purpose of "treatment" is to alleviate or eliminate the targeted disease state or disorder. If a subject has received a therapeutically effective amount of a compound or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof, according to the methods described herein, and one or more indications and symptoms of the subject show an observable and / or detectable reduction or improvement, then the subject has been successfully "treated". It should also be understood that the treatment of the disease state or disorder described herein includes not only complete treatment, but also incomplete treatment that achieves some biologically or medically relevant results.

[0010] In this document, the minimum and maximum number of carbon atoms in a hydrocarbon group are indicated by a prefix. For example, the prefix Ca-Cb refers to a hydrocarbon group containing "a" to "b" carbon atoms. Exemplarily, "C1-Cn" refers to a straight-chain or branched-chain saturated / unsaturated carbon chain containing 1, 2, 3, 4, 5, …… or n carbon atoms; it is further understood that "C1-Cn" should be interpreted to include any sub-range therein, such as C1-C8, C1-C6, C1-C5, C1-C3, etc.

[0011] As used herein, "alkyl" refers to a straight-chain or branched-chain hydrocarbon chain group that is fully saturated (having no double or triple bonds). An alkyl group can have 1 to 8 carbon atoms (whenever a numerical range such as "1 to 8" appears herein, the numerical range refers to each integer within the given range; for example, "1 to 8 carbon atoms" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 8 carbon atoms, although this definition also covers occurrences of the term "alkyl" without specifying a numerical range). The alkyl group can also be a medium-sized alkyl having 1 to 8 carbon atoms, such as "C1-6". The alkyl group can also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group of a compound can be designated as "C1-C4 alkyl", "C1-4 alkyl", or a similar name. By way of example only, "C1-C4 alkyl" or "C1-4 alkyl" means that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.

[0012] C1-C5 straight-chain or branched-chain alkylene refers to a divalent straight-chain or branched-chain saturated hydrocarbon group having 1 to 5 carbon atoms.

[0013] "Halogenated" and "halogen" refer to atoms selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0014] To solve the above problems, the technical solution adopted by the present invention is:

[0015] A substituted oxazolo six-membered ring compound, the structure of which is shown in Formula I:

[0016]

[0017] Wherein, A is selected from N or C;

[0018] X is selected from -C(O)NH-, -Z 1 -O-Z 2 -O-;

[0019] Z 1 、Z 2 are independently selected from C1-C5 straight-chain or branched-chain alkylene;

[0020] R 1 is selected from hydrogen, C1-C5 straight-chain or branched-chain alkyl, halogen, nitro;

[0021] R 2 、R 3Independently selected from hydrogen, halogen, C1-C5 straight-chain or branched alkyl, C1-C5 straight-chain or branched alkoxy, 1-3 halogenated C1-C5 straight-chain or branched alkyl;

[0022] Said R 4 Selected from hydrogen, C1-C8 straight-chain or branched alkyl,

[0023] Said Y is C1-C5 straight-chain or branched alkylene, and said R 5 Selected from hydrogen, halogen, C1-C5 straight-chain or branched alkyl, 1-3 halogenated C1-C5 straight-chain or branched alkyl.

[0024] As a further improvement of the present invention, said X is selected from —C(O)NH—, —(CH 2 ) n1 —O—(CH 2 ) n2 —O—;

[0025] Said n 1 n 2 Independently selected from 1, 2, 3, 4, 5;

[0026] Said R 4 Selected from hydrogen, C1-C6 straight-chain or branched alkyl,

[0027] Said Y is selected from C1-C5 straight-chain or branched alkylene, and said R 5 Selected from hydrogen, halogen, C1-C5 straight-chain or branched alkyl, 1-3 halogenated C1-C5 straight-chain or branched alkyl.

[0028] As a further improvement of the present invention, said C1-C5 straight-chain or branched alkyl is selected from —CH 3 —CH 2 CH 3 —CH(CH 3 ) 2 —(CH 2 ) 2 CH 3 —(CH 2 ) 3 CH 3 —CH 2 CH(CH 3 ) 2 —C(CH 3 ) 3 —CH(CH 3 )CH 2 CH 3 —(CH 2 ) 4 CH3 , —CH(CH 3 )(CH 2 ) 2 CH 3 , —CH(CH 2 CH 3 ) 2 , —CH 2 C(CH 3 ) 3 , —CH 2 CH(CH 3 )CH 2 CH 3 , —C(CH 3 ) 2 CH 2 CH 3 , —CH(CH 3 )CH(CH 3 ) 2 , —(CH 2 ) 2 CH(CH 3 ) 2 ;

[0029] The halogen is selected from F, Cl, Br, I;

[0030] The 1-3 halo-substituted C1-C5 straight-chain or branched-chain alkyl is selected from —CF 3 , —CH 2 CF 3 , —(CH 2 ) 2 CF 3 , —(CH 2 ) 3 CF 3 , —(CH 2 ) 4 CF 3 ;

[0031] The C1-C5 straight-chain or branched-chain alkoxy is selected from —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —O(CH 2 ) 2 CH 3 , —O(CH 2 ) 3 CH 3 , —OCH 2 CH(CH 3 ) 2 , —OC(CH 3 )3 , —OCH(CH 3 )CH 2 CH 3 , —O(CH 2 ) 4 CH 3 , —OCH(CH 3 )(CH 2 ) 2 CH 3 , —OCH(CH 2 CH 3 ) 2 , —OCH 2 C(CH 3 ) 3 , —OCH 2 CH(CH 3 )CH 2 CH 3 , —OC(CH 3 ) 2 CH 2 CH 3 , —OCH(CH 3 )CH(CH 3 ) 2 , —O(CH 2 ) 2 CH(CH 3 ) 2 .

[0032] As a further improvement of the present invention, A is selected from N or C;

[0033] X is selected from —C(O)NH—, —CH 2 OCH 2 CH 2 O—;

[0034] R 1 is selected from hydrogen, chlorine, methyl, nitro;

[0035] R 2 , R 3 are independently selected from hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl;

[0036] R 4 is selected from hydrogen, methyl, n-propyl, tert-butyl,

[0037] As a further improvement of the present invention, the structure of the compound is as follows:

[0038]

[0039]

[0040] Technical Subject Two

[0041] A pharmaceutical composition comprising the substituted oxazolo-hexacyclic compounds described in Technical Subject One, and optionally, one or more pharmaceutically acceptable carriers or excipients.

[0042] As used herein, the "pharmaceutical composition" contains a therapeutically effective amount of the substituted oxazolo-hexacyclic compounds of Formula I, and one or more pharmaceutically acceptable carriers, and is prepared in the form of tablets, capsules, granules, powders, suspensions, emulsions, powders, solutions, gels, syrups, pills, tinctures, medicated wines, decoction extracts, lozenges, mixtures, suppositories, injections, inhalants or sprays, etc. The pharmaceutical composition preferably contains 0.1%-99.5% by weight of the oxazolo-hexacyclic compounds of the present invention as the active ingredient, and more preferably contains 0.5%-99.5% by weight of the active ingredient.

[0043] As used herein, "pharmaceutically acceptable carriers or excipients" include: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, thickening agents, antioxidants, preservatives, stabilizers, surfactants and buffering agents. Those skilled in the art will understand that certain pharmaceutically acceptable excipients can be used with more than one function and with alternative functions, depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation. For example: When used orally, oral formulations can be prepared, such as tablets, capsules, granules, pills, etc., containing fillers (such as sugar derivatives like lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives like corn starch, potato starch, dextrin and carboxymethyl starch; cellulose derivatives like crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose; gum arabic; dextran; silicate derivatives like magnesium aluminum metasilicate; phosphate derivatives like calcium phosphate; carbonate derivatives like calcium carbonate; sulfate derivatives like calcium sulfate, etc.), binders (such as gelatin, polyvinylpyrrolidone and polyethylene glycol), disintegrants (such as cellulose derivatives like sodium carboxymethyl cellulose, polyvinylpyrrolidone), lubricants (such as talc, calcium stearate, magnesium stearate, cetyl wax, boric acid, sodium benzoate, leucine), stabilizers (methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, etc.), flavoring agents (such as common sweeteners, sour agents and fragrances, etc.). When used parenterally, injectables can be prepared, including sterile powders for injection and solvents for injection. The carriers or excipients used include sterile water, Ringer's solution and isotonic sodium chloride solution. Appropriate additives such as antioxidants, buffering agents and bacteriostatic agents can also be added according to the nature of the drug. When used for rectal administration, the drug can be made into suppositories, etc. When used for pulmonary administration, the drug can be made into inhalants or sprays, etc. There are many resources available to those skilled in the art that describe pharmaceutically acceptable excipients and can be used to select suitable pharmaceutically acceptable excipients, such as books like "Remington: The Science and Practice of Pharmacy", "Chinese Pharmaceutical Yearbook", "Pharmaceutics", etc.

[0044] Technical Subject Three

[0045] Use of the substituted oxazolo-hexacyclic compounds according to Technical Subject One in the preparation of drugs for inhibiting ULK1.

[0046] Technical Subject Four

[0047] Use of the substituted oxazolo-hexacyclic compounds according to Technical Subject One in the preparation of anti-tumor drugs.

[0048] As a further improvement of the present invention, the tumor is liver cancer.

[0049] The beneficial effects of adopting the above technical solutions are as follows:

[0050] The present invention discloses a substituted oxazolo-hexacyclic compound that can bind to the UKL1 protein, thereby potentially inhibiting autophagy and exerting anti-tumor activity. It has anti-tumor effects and is a good candidate for future research. Brief Description of the Drawings

[0051] Figure 1 It is a graph showing the inhibition of tumor cells of the compounds in Examples 1-22 of the present invention on HepG2 cells. Detailed Embodiments

[0052] To make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be clearly and completely described below in conjunction with specific embodiments.

[0053] The compounds in this embodiment are prepared through the following route:

[0054] In the route, R 2 , R 3 , R 5 are defined in the same manner as those in the foregoing general formulas;

[0055] Route 1:

[0056]

[0057] Reaction conditions: (a) polyphosphoric acid, 200 °C, reflux, 6 h; (b) (CH 3 COO) 3 BHNa, DCE, rt, 18 h; (c) dry DMF, K 2 CO 3 , KI, 60 °C, 6 h.

[0058] Route 2:

[0059]

[0060] Reaction conditions: (a) polyphosphoric acid, 200 °C, reflux, 6 h; (b) (CH3COO) 3 BHNa, DCE, rt, 18 h; (c) dry DMF, K 2 CO 3 , KI, 60 °C, 6 h.

[0061] Route 3:

[0062]

[0063] The reaction conditions are as follows: (a) polyphosphoric acid, 200 °C, reflux, 6 h; (b) (CH3COO) 3 BHNa, DCE, rt, 18 h; (c) dry DMF, K 2 CO 3 , KI, 60 °C, 6 h;

[0064] R 6 is a C1-C8 straight-chain or branched-chain alkyl group.

[0065] Route 4:

[0066]

[0067] The reaction conditions are as follows: a) polyphosphoric acid, 200 °C, reflux, 6 h; (b) (CH3COO) 3 BHNa, DCE, rt, 18 h; (c) dry DMF, K 2 CO 3 , KI, 60 °C, 6 h.

[0068] Route 5:

[0069]

[0070] The reaction conditions are as follows: (a) polyphosphoric acid, 200 °C, reflux, 6 h; (b) (CH3COO) 3 BHNa, DCE, rt, 18 h.

[0071] Example 1 Compound Ul-1

[0072]

[0073] Prepared by the method described in Route 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.52 (dd, J = 4.9, 1.4 Hz, 1H), 8.21 (dd, J = 8.2, 1.4 Hz, 1H), 7.47 (td, J = 7.4, 6.5, 3.6 Hz, 2H), 7.45–7.39 (m, 2H), 7.35 (d, J = 10.8 Hz, 2H), 7.33–7.27 (m, 2H), 6.96–6.91 (m, 2H), 6.87 (ddd, J = 8.2, 2.5, 1.0 Hz, 1H), 6.68 (s, 1H), 4.39 (s, 2H), 4.30 (s, 2H). 13 C NMR (101 MHz, DMSO-d 6) δ 169.97, 156.71, 155.59, 149.23, 146.40, 132.07, 129.86, 128.37, 126.35, 120.56, 118.91, 116.48, 115.02, 114.62, 110.75, 66.78, 45.69.

[0074] Example 2 Compound Ul-2

[0075]

[0076] Prepared by the method described in Route 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.77 (td, J = 6.8, 3.4 Hz, 2H), 7.52–7.22 (m, 9H), 6.93 (d, J = 8.5 Hz, 2H), 6.82 (dd, J = 8.1, 2.0 Hz, 1H), 6.61 (t, J = 5.9 Hz, 1H), 4.39 (s, 2H), 4.29 (d, J = 5.8 Hz, 2H).

[0077] 13 C NMR (101 MHz, DMSO-d 6 ) δ 169.97, 162.96, 156.70, 150.10, 149.19, 141.52, 132.14, 129.75, 128.35, 126.88, 125.27, 124.74, 119.67, 115.72, 114.70, 114.61, 110.81, 110.45, 66.78, 45.70.

[0078] Example 3 Compound Ul-3

[0079]

[0080] Prepared by the method described in Route 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.37 (s, 1H), 8.04 (s, 1H), 7.46 (d, J = 18.2 Hz, 2H), 7.37 (d, J = 7.3 Hz, 2H), 7.31 (dd, J = 12.5, 8.3 Hz, 3H), 6.93 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 7.8 Hz, 1H), 6.66 (t, J = 5.9 Hz, 1H), 4.39 (s, 2H), 4.29 (d, J = 5.8 Hz, 2H), 2.46 (s, 3H).

[0081] 13 C NMR (101 MHz, DMSO) δ 169.97, 164.91, 156.70, 153.62, 149.21, 146.90, 142.64, 132.09, 130.57, 129.82, 128.36, 126.50, 118.88, 116.24, 114.86, 114.61, 110.64, 66.78, 45.69, 18.16.

[0082] Example 4 Compound Ul-4

[0083]

[0084] Prepared by the method described in Route 1. 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.57 (d, J = 2.1 Hz, 1H), 8.51 (d, J = 2.1 Hz, 1H), 7.49–7.27 (m, 8H), 6.92 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.2 Hz, 1H), 4.38 (s, 2H), 4.30 (s, 2H).

[0085] 13 C NMR (151 MHz, DMSO) δ 169.92, 166.53, 156.70, 154.43, 149.23, 144.98, 142.72, 131.99, 129.90, 128.33, 127.00, 125.97, 119.31, 116.74, 115.11, 114.61, 110.79, 66.77, 45.66.

[0086] Example 5 Compound Ul-6

[0087]

[0088] Prepared by the method described in Route 2. 1 H NMR (400 MHz, DMSO-d 6)δ8.52(dd, J = 4.9, 1.3Hz, 1H), 8.20(dd, J = 8.1, 1.3Hz, 1H), 7.47(s, 1H), 7.46–7.42(m, 1H), 7.42–7.38(m, 2H), 7.35–7.27(m, 2H), 7.22–7.13(m, 2H), 6.90–6.84(m, 1H), 6.79(d, J = 8.3Hz, 1H), 6.65(t, J = 5.7Hz, 1H), 4.41(s, 2H), 4.26(d, J = 5.5Hz, 2H), 2.22(s, 3H).

[0089] 13 C NMR(101MHz, DMSO)δ170.55, 166.02, 156.07, 155.29, 149.75, 146.87, 143.11, 132.13, 130.32, 130.11, 126.80, 126.52, 126.09, 121.02, 119.36, 116.92, 115.44, 111.72, 111.22, 67.48, 46.25, 16.77.

[0090] Example 6 Compound Ul-7

[0091]

[0092] Prepared by the method described in Route 2. 1 H NMR(400MHz, DMSO-d 6 )δ8.53(d, J = 4.3Hz, 1H), 8.21(d, J = 8.0Hz, 1H), 7.49(s, 1H), 7.48–7.38(m, 4H), 7.34(t, J = 7.9Hz, 1H), 7.27(dd, J = 11.5, 7.0Hz, 1H), 7.03(dd, J = 11.0, 7.2Hz, 1H), 6.89(d, J = 7.6Hz, 1H), 6.66(s, 1H), 4.56(s, 2H), 4.38–4.29(m, 2H).

[0093] 1313C NMR (101 MHz, DMSO) δ 169.49, 165.89, 157.52, 156.05, 155.13, 149.55, 149.53, 149.23, 147.17, 147.14, 146.90, 145.98, 145.87, 145.75, 143.14, 130.51, 126.96, 121.08, 119.40, 119.16, 119.11, 118.99, 118.93, 116.80, 116.49, 116.43, 116.29, 116.22, 115.98, 111.26, 103.89, 103.61, 68.06, 68.05.

[0094] Example 7 Compound Ul-8

[0095]

[0096] Prepared by the method described in Route 2. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.53 (dd, J = 4.9, 1.4 Hz, 1H), 8.21 (dd, J = 8.1, 1.4 Hz, 1H), 7.50–7.48 (m, 1H), 7.46–7.36 (m, 3H), 7.34–7.27 (m, 2H), 7.08 (s, 1H), 6.91–6.86 (m, 3H), 6.67 (t, J = 5.9 Hz, 1H), 4.38 (s, 2H), 4.30 (d, J = 5.9 Hz, 2H), 3.80 (s, 3H).

[0097] 13 13C NMR (101 MHz, DMSO) δ 170.60, 165.99, 156.05, 149.73, 149.66, 146.87, 146.70, 143.10, 133.82, 130.33, 126.80, 121.03, 119.66, 119.36, 117.00, 115.53, 114.97, 112.14, 111.26, 68.71, 56.06, 46.59.

[0098] Example 8 Compound Ul-9

[0099]

[0100] Prepared by the method described in Route 2. 11H NMR (400 MHz, Chloroform-d) δ 8.67 (d, J = 5.1 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.62 (s, 1H), 7.50–7.45 (m, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.17 (dd, J = 17.1, 10.0 Hz, 2H), 6.98 (d, J = 8.3 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 4.57 (s, 2H), 4.41 (s, 2H).

[0101] 13 13C NMR (101 MHz, CDCl 3 ) δ 172.72, 167.93, 160.36, 159.95, 159.55, 159.14, 154.41, 154.08, 151.62, 147.88, 143.62, 134.19, 134.13, 130.28, 126.43, 123.62, 121.11, 120.64, 118.52, 118.44, 116.50, 116.24, 115.99, 115.80, 113.67, 112.73, 68.30, 47.50.

[0102] Example 9 Compound Ul-10

[0103]

[0104] Prepared by the method described in Route 2. 1 1H NMR (500 MHz, Chloroform-d) δ 7.95 (dd, J = 4.9, 2.1 Hz, 1H), 7.48–7.41 (m, 2H), 7.35 (dd, J = 9.9, 7.8 Hz, 1H), 7.27–7.17 (m, 2H), 7.11 (dd, J = 7.7, 4.8 Hz, 1H), 6.71 (d, J = 8.5 Hz, 1H), 6.64 (ddd, J = 7.9, 2.1, 1.2 Hz, 1H), 6.57 (t, J = 2.1 Hz, 1H), 5.87 (d, J = 7.7 Hz, 1H), 5.47 (d, J = 7.7 Hz, 1H), 4.47 (s, 2H), 4.27 (dt, J = 5.3, 0.8 Hz, 2H), 4.06 (t, J = 5.3 Hz, 1H).

[0105] 1313C NMR (125 MHz, Chloroform-d) δ 169.02, 166.46, 156.10, 152.99, 152.97, 148.65, 146.77, 143.72, 135.49, 135.46, 132.43, 129.10, 128.40, 128.37, 125.98, 123.72, 123.51, 120.16, 119.36, 118.31, 117.23, 117.19, 117.16, 115.56, 67.58, 46.80.

[0106] Example 10 Compound Ul-11

[0107]

[0108] Prepared by the method described in Route 2. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.52 (dd, J = 4.9, 1.4 Hz, 1H), 8.21 (dd, J = 8.1, 1.4 Hz, 1H), 7.47 (d, J = 2.0 Hz, 2H), 7.46–7.42 (m, 2H), 7.41 (s, 1H), 7.34–7.28 (m, 3H), 7.01 (d, J = 8.5 Hz, 1H), 6.89–6.84 (m, 1H), 6.74 (s, 1H), 4.52 (s, 2H), 4.32 (s, 2H).

[0109] 13 13C NMR (101 MHz, DMSO) δ 169.79, 165.94, 156.05, 152.57, 149.46, 146.88, 143.12, 134.16, 130.42, 129.09, 127.38, 126.88, 121.80, 121.05, 119.38, 116.93, 115.71, 114.48, 111.37, 67.89, 45.55.

[0110] Example 11 Compound Ul-13

[0111]

[0112] Prepared by the method described in Route 1. 11H NMR (500 MHz, Chloroform-d) δ 9.17 (d, J = 1.6 Hz, 1H), 8.59 (d, J = 1.6 Hz, 1H), 7.48–7.41 (m, 3H), 7.38–7.31 (m, 1H), 6.90–6.84 (m, 2H), 6.64 (ddd, J = 7.9, 2.1, 1.2 Hz, 1H), 6.57 (t, J = 2.2 Hz, 1H), 5.87 (d, J = 7.7 Hz, 1H), 5.47 (d, J = 7.7 Hz, 1H), 4.47 (s, 2H), 4.34 (dt, J = 5.3, 0.9 Hz, 2H), 4.06 (t, J = 5.3 Hz, 1H).

[0113] 13 13C NMR (125 MHz, Chloroform-d) δ 169.92, 166.46, 158.35, 158.19, 148.65, 144.72, 144.51, 141.23, 134.01, 132.43, 129.10, 127.93, 123.51, 117.23, 115.56, 115.29, 112.48, 67.01, 53.57.

[0114] Example 12 Compound Ul-14

[0115]

[0116] Prepared by the method described in Route 3. 1 1H NMR (600 MHz, Chloroform-d) δ 8.58 (d, J = 4.7 Hz, 1H), 7.88 (dd, J = 8.1, 1.4 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.63–7.61 (m, 1H), 7.37–7.30 (m, 4H), 6.93–6.89 (m, 2H), 6.84 (dd, J = 7.8, 2.1 Hz, 1H), 4.49 (s, 2H), 4.38 (s, 2H), 3.35–3.27 (m, 2H), 1.56 (dt, J = 14.6, 7.3 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H).

[0117] 13 13C NMR (151 MHz, CDCl 3)δ168.39, 166.65, 156.76, 156.11, 148.35, 146.03, 143.49, 132.43, 130.04, 129.25, 127.20, 120.19, 118.81, 117.69, 117.62, 115.11, 112.16, 67.60, 47.76, 40.92, 22.92, 11.41.

[0118] Example 13 Compound Ul-15

[0119]

[0120] Prepared by the method described in Route 3. 1 H NMR(400MHz, DMSO-d 6 )δ8.52(dd, J = 4.9, 1.4Hz, 1H), 8.21(dd, J = 8.1, 1.4Hz, 1H), 7.48–7.38(m, 3H), 7.36–7.27(m, 3H), 6.96–6.91(m, 2H), 6.87(dd, J = 8.1, 1.6Hz, 1H), 4.42(s, 2H), 4.30(s, 2H), 2.64(d, J = 4.7Hz, 3H).

[0121] 13 C NMR(101MHz, DMSO)δ168.51, 166.00, 157.13, 156.06, 149.70, 146.88, 143.11, 132.68, 130.34, 128.87, 126.83, 121.04, 119.38, 116.96, 115.49, 115.13, 111.21, 67.58, 46.14, 25.80.

[0122] Example 14 Compound Ul-16

[0123]

[0124] Prepared by the method described in Route 3. 1 H NMR(600MHz, Chloroform-d)δ8.67–8.60(m, 1H), 8.00(dd, J = 8.1, 1.2Hz, 1H), 7.75–7.71(m, 2H), 7.42(dd, J = 8.0, 5.2Hz, 1H), 7.35(dd, J = 15.7, 8.2Hz, 3H), 6.99–6.95(m, 1H), 6.90(d, J = 8.7Hz, 2H), 4.40(d, J = 6.0Hz, 3H), 1.40(s, 9H).

[0125] 13 C NMR(151MHz,CDCl 3 )δ168.18,167.07,156.69,154.82,146.61,144.40,143.97,132.18,130.99,130.14,129.58,126.65,120.47,120.23,119.34,115.10,113.77,67.45,51.79,48.80,28.65.

[0126] Example 15 Compound Ul-17

[0127]

[0128] Prepared by the method described in Route 4. 1 H NMR(500MHz,Chloroform-d)δ7.95(dd,J=4.9,2.1Hz,1H),7.48–7.41(m,3H),7.38–7.22(m,5H),7.19(ddt,J=7.5,1.5,0.9Hz,2H),7.16–7.08(m,2H),6.90–6.84(m,2H),6.64(ddd,J=7.9,2.1,1.2Hz,1H),6.57(t,J=2.2Hz,1H),4.56(s,2H),4.35(ddt,J=9.9,5.3,0.9Hz,4H),4.06(t,J=5.3Hz,1H).

[0129] 13 C NMR(125MHz,Chloroform-d)δ169.36,166.46,158.35,156.10,148.65,146.77,143.72,139.61,134.01,132.43,129.10,128.45,128.16,127.93,127.66,123.51,120.16,118.31,117.23,115.56,115.29,68.08,53.57,43.86.

[0130] Example 16 Compound Ul-18

[0131]

[0132] Prepared by the method described in Route 4. 1 H NMR(400MHz,DMSO-d 6)δ8.63(t, J = 6.1 Hz, 1H), 8.52(dd, J = 4.9, 1.4 Hz, 1H), 8.20(dd, J = 8.1, 1.4 Hz, 1H), 7.50–7.46(m, 1H), 7.46–7.38(m, 2H), 7.35–7.31(m, 2H), 7.30–7.27(m, 2H), 7.27–7.23(m, 2H), 7.12–7.05(m, 2H), 6.94(d, J = 8.7 Hz, 2H), 6.87(dd, J = 8.1, 1.7 Hz, 1H), 4.51(s, 2H), 4.30(d, J = 6.2 Hz, 4H).

[0133] 13 C NMR(101 MHz, DMSO)δ167.83, 165.53, 162.33, 159.92, 156.62, 155.59, 149.22, 146.39, 142.64, 135.53, 135.50, 132.25, 129.85, 129.23, 129.14, 128.35, 126.36, 120.55, 118.89, 116.47, 114.99, 114.78, 114.69, 110.77, 67.04, 45.64, 41.07.

[0134] Example 17 Compound Ul-19

[0135]

[0136] Prepared by the method described in Route 4. 1 H NMR(400 MHz, DMSO-d 6 )δ8.58–8.49(m, 2H), 8.18(dd, J = 8.1, 1.4 Hz, 1H), 7.51–7.46(m, 1H), 7.42(dd, J = 8.1, 4.9 Hz, 2H), 7.36–7.26(m, 3H), 7.14–7.03(m, 4H), 6.95(d, J = 8.7 Hz, 2H), 6.87(dd, J = 8.2, 1.7 Hz, 1H), 6.68(t, J = 5.9 Hz, 1H), 4.50(s, 2H), 4.30(dd, J = 12.0, 6.0 Hz, 4H), 2.24(s, 3H).

[0137] 1313C NMR (101 MHz, DMSO) δ 167.68, 165.54, 156.65, 155.61, 149.21, 146.34, 142.62, 136.22, 135.75, 132.20, 129.78, 128.69, 128.31, 127.17, 126.36, 120.47, 118.79, 116.44, 115.01, 114.65, 110.76, 67.05, 45.69, 41.5 20.60.

[0138] Example 18 Compound Ul-20

[0139]

[0140] Prepared by the method described in Route 4. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.65 (t, J = 6.1 Hz, 1H), 8.52 (dd, J = 4.9, 1.4 Hz, 1H), 8.21 (dd, J = 8.1, 1.4 Hz, 1H), 7.49–7.47 (m, 1H), 7.46–7.39 (m, 2H), 7.35 (s, 1H), 7.33 (d, J = 3.2 Hz, 2H), 7.32–7.27 (m, 2H), 7.24 (d, J = 8.5 Hz, 2H), 6.95 (dd, J = 9.1, 2.2 Hz, 2H), 6.87 (dd, J = 7.8, 1.9 Hz, 1H), 6.70 (s, 1H), 4.52 (s, 2H), 4.31 (d, J = 6.1 Hz, 4H).

[0141] 13 13C NMR (101 MHz, DMSO) δ 168.40, 166.00, 157.08, 156.07, 149.69, 146.88, 143.11, 138.88, 132.75, 131.75, 130.34, 129.54, 128.83, 128.60, 126.83, 121.04, 119.37, 116.93, 115.50, 115.17, 111.26, 67.51, 46.11, 41.61.

[0142] Example 19 Compound Ul-21

[0143]

[0144] Prepared by the method described in Route 4. 11H NMR (600 MHz, Chloroform-d) δ 8.57 (dd, J = 4.9, 1.2 Hz, 1H), 7.84 (dd, J = 8.1, 1.4 Hz, 1H), 7.69–7.61 (m, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.37–7.27 (m, 4H), 7.02–6.97 (m, 1H), 6.92–6.82 (m, 3H), 4.60 (d, J = 6.2 Hz, 2H), 4.56 (s, 2H), 4.39 (s, 2H).

[0145] 13 13C NMR (151 MHz, CDCl 3 ) δ 168.44, 166.21, 156.65, 156.52, 146.72, 143.25, 142.00, 130.04, 129.36, 128.04, 127.49, 125.87, 125.85, 125.82, 125.80, 123.28, 120.11, 118.25, 117.97, 117.75, 115.10, 67.59, 42.62, 0.14.

[0146] Example 20 Compound Ul-22

[0147]

[0148] Prepared by the method described in Route 5. 1 1H NMR (400 MHz, Chloroform-d) δ 8.62 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 7.7 Hz, 2H), 7.38 (dt, J = 15.3, 7.6 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 6.98 (d, J = 7.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 2H), 4.37 (s, 2H), 4.11 (s, 2H), 3.85 (s, 2H), 3.77 (d, J = 3.8 Hz, 2H), 3.67 (d, J = 4.2 Hz, 2H). 13 13C NMR (101 MHz, CDCl 3 ) δ 167.02, 158.47, 155.18, 146.64, 144.85, 143.96, 130.25, 129.56, 129.41, 126.86, 120.53, 120.08, 119.54, 115.02, 114.24, 113.92, 72.61, 69.78, 67.58, 61.87, 49.17.

[0149] Example 21 Compound Ul-23

[0150]

[0151] Prepared by the method described in Route 5. 1 H NMR(400MHz,Chloroform-d)δ8.62(d,J=4.9Hz,1H),7.96(d,J=8.2Hz,1H),7.81(s,1H),7.70(d,J=7.4Hz,1H),7.34(ddd,J=26.9,12.4,7.1Hz,7H),7.22(d,J=7.9Hz,2H),7.04(d,J=7.0Hz,1H),6.88(d,J=7.6Hz,2H),4.71(d,J=14.5Hz,4H),4.15–4.08(m,2H),3.88–3.83(m,2H),3.80–3.73(m,2H),3.70–3.64(m,2H).

[0152] 13 C NMR(101MHz,CDCl 3 )δ163.80,158.23,155.27,148.52,144.82,143.95,139.91,133.27,130.24,128.95,128.75,127.63,126.84,123.42,120.35,119.98,118.41,115.07,113.32,72.61,69.82,69.77,67.58,61.92,54.69.

[0153] Example 22 Compound Ul-24

[0154]

[0155] Prepared by the method described in Route 5. 11H NMR (400 MHz, Chloroform-d) δ 8.66 (d, J = 5.1 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.77 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.49–7.41 (m, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.25–7.15 (m, 4H), 7.01 (t, J = 8.2 Hz, 3H), 6.89 (d, J = 7.7 Hz, 2H), 4.68 (d, J = 6.6 Hz, 4H), 4.15–4.08 (m, 2H), 3.86 (s, 2H), 3.80–3.75 (m, 2H), 3.70–3.65 (m, 2H).

[0156] 13 13C NMR (101 MHz, CDCl 3 ) δ 167.87, 163.50, 161.06, 160.30, 159.90, 158.17, 154.61, 148.76, 144.30, 143.87, 132.85, 130.33, 129.32, 128.85, 128.77, 128.55, 126.54, 120.88, 120.54, 118.62, 118.13, 116.86, 115.95, 115.74, 115.09, 114.01, 112.93, 72.50, 69.83, 67.58, 61.90, 54.45, 54.18.

[0157] Effect Example 1 Surface plasmon resonance analysis (SPR).

[0158] To detect the binding effect of the target compound and ULK1 protein (OriGene Technologies), this application uses surface plasmon resonance analysis on the second channel of a CM5 sensor chip (GE Healthcare) through the protein coupling program on a BIAcore S200 system (GE Healthcare). To measure the binding kinetics, the compounds in the examples or XST-14 (100 nM) and a buffer blank for baseline subtraction were injected sequentially, and a regeneration step was performed with a glycine solution at pH = 2.5 between each cycle. The results are shown in Table 1 below.

[0159] Table 1

[0160]

[0161]

[0162] Effect Example 2

[0163] Measuring cell viability with CCK-8: HepG2 cells were seeded in 96-well plates at a density of 2000 cells / well. After culturing the cells at 38 °C for 24 h, the corresponding 50 μM drug was added, and the cells were cultured at 38 °C for 48 h. Subsequently, 100 μL of complete medium containing 10 μL of CCK-8 solution was added to each well, and the mixture was incubated at 38 °C in the dark for 2 h. Finally, the absorbance was measured at 450 nm, with ZZY-19 sorafenib as the positive control group. Each sample was measured in parallel three times, and the cell survival rate was calculated using software. The results are shown in the appendix Figure 1 as follows

[0164] Effect Example 3

[0165] Measuring the IC of HepG2 cells of the compound with CCK-8 50 : HepG2 cells were seeded in 96-well plates at a density of 2000 cells / well, and the cells were cultured at 38 °C for 24 h. The test drugs were respectively prepared into concentrations of 400 μL, 300 μL, 200 μL, 100 μL, 50 μL, 25 μL, 12.5 μL, 6.25 μL, and 3.125 μL by serial dilution method using DMEM medium (Gibco). The original culture medium in the wells was aspirated, and 100 μL of drug-containing medium with the corresponding concentration was added to each well, and the cells were cultured at 38 °C for 24 h. Then, 100 μL of complete medium containing 10 μL of CCK-8 solution was added to each well, and the mixture was incubated at 38 °C in the dark for 2 h. Finally, the absorbance was measured at 450 nm, and the cell IC was calculated using software 50 The results are shown in Table 2

[0166] Table 2

[0167] Name <![CDATA[IC 50 (HepG2)]]> UL-11 19.68±2.56 UL-23 7.33±1.03 UL-24 9.65±0.81 Sorafenib 3.18±0.45

[0168] Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present invention

Claims

1. A substituted oxazolo six-membered ring compound, characterized in that , whose structure is shown in Formula I: Wherein, the A is selected from N or C; The X is selected from —C(O)NH—, —Z1—O—Z2—O—; The Z1 and Z2 are independently selected from C1-C5 straight or branched alkylene groups; The R1 is selected from hydrogen, C1-C5 straight or branched alkyl, halogen, and nitro; Said R2 and R3 are independently selected from hydrogen, halogen, C1-C5 straight chain or branched alkyl, C1-C5 straight chain or branched alkoxy, 1-3 halogenated C1-C5 straight chain or branched alkyl; The R4 is selected from hydrogen, C1-C8 straight or branched alkyl, The Y is a C1-C5 straight or branched alkylene group, and the R5 is selected from hydrogen, halogen, a C1-C5 straight or branched alkyl group, and a 1-3 halogenated C1-C5 straight or branched alkyl group.

2. A substituted oxazolo six-membered ring compound according to claim 1, characterized in that: The X is selected from -C(O)NH-, -(CH2) n1 —O—(CH2) n2 —O—; Said n1 and n2 are independently selected from 1, 2, 3, 4, and 5; The R4 is selected from hydrogen, C1-C6 straight or branched alkyl, The Y is selected from C1-C5 straight or branched alkylene, and the R5 is selected from hydrogen, halogen, C1-C5 straight or branched alkyl, 1-3 halogenated C1-C5 straight or branched alkyl.

3. A substituted oxazolo six-membered ring compound according to claim 1, characterized in that: The C1-C5 straight or branched alkyl group is selected from —CH3, —CH2CH3, —CH(CH3)2, —(CH2)2CH3, —(CH2)3CH3, —CH2CH(CH3)2, —C(CH3)3, —CH(CH3)CH2CH3, —(CH2)4CH3, —CH(CH3)(CH2)2CH3, —CH(CH2CH3)2, —CH2C(CH3)3, —CH2CH(CH3)CH2CH3, —C(CH3)2CH2CH3, —CH(CH3)CH(CH3)2, —(CH2)2CH(CH3)2; The halogen is selected from F, Cl, Br, I; The 1-3 halogenated C1-C5 straight or branched alkyl group is selected from -CF3, -CH2CF3, -(CH2)2CF3, -(CH2)3CF3, -(CH2)4CF3; The C1-C5 straight or branched alkoxy group is selected from -OCH3, -OCH2CH3, -OCH(CH3)2, -O(CH2)2CH3, -O(CH2)3CH3, -OCH2CH(CH3)2, -OC(CH3)3, —OCH(CH3)CH2CH3, —O(CH2)4CH3, —OCH(CH3)(CH2)2CH3, —OCH(CH2CH3)2, —OCH2C(CH3)3, —OCH2CH(CH3)CH2CH3, —OC(CH3)2CH2CH3, —OCH(CH3)CH(CH3)2, —O(CH2)2CH(CH3)2.

4. A substituted oxazolo six-membered ring compound according to claim 1, characterized in that: Said A is selected from N or C; The X is selected from —C(O)NH—, —CH2OCH2CH2O—; The R1 is selected from hydrogen, chlorine, methyl, and nitro; Said R2 and R3 are independently selected from hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl; The R4 is selected from hydrogen, methyl, n-propyl, tert-butyl, 5. A substituted oxazolo six-membered ring compound according to claim 1, characterized in that: Its structure is as follows:

6. A pharmaceutical composition comprising the substituted oxazolo six-membered ring compound according to any one of claims 1 to 5, and optionally, one or more pharmaceutically acceptable carriers or excipients.

7. Use of the substituted oxazolo six-membered ring compound according to any one of claims 1 to 5 in the preparation of a drug for inhibiting ULK1.

8. Use of the substituted oxazolo six-membered ring compound according to any one of claims 1 to 5 in the preparation of anti-tumor drugs.

9. The use according to claim 8, characterized in that: The tumor is liver cancer.

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