Platinum compound and use thereof

Abstract

The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, and a pharmaceutical composition comprising same and a use thereof as a radiosensitizing drug.

Description

Platinum compounds and their applications Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and in particular relates to a new platinum compound and its use as a radiosensitizing drug. Background Art

[0002] Radiotherapy (radiotherapy, radiotherapy) is one of the important methods in the comprehensive treatment of malignant tumors. Neoadjuvant therapy based on conventional long-term radiotherapy has become the standard treatment for a variety of malignant tumors. However, long-term clinical studies have found that the response of patients with malignant tumors to radiotherapy varies greatly. Although some patients can achieve complete pathological remission at the end of the treatment cycle, some patients cannot benefit from long-term treatment, and even a small number of patients experience worsening and progression. In addition, the side effects of radiotherapy cannot be ignored in clinical practice. Therefore, how to improve the effect of radiotherapy, increase the patient benefit rate, and reduce the dose of radioactivity have become issues of concern in the clinical treatment of tumors.

[0003] The use of radiosensitizing drugs is one of the main ways to solve the above problems. Radiosensitizing drugs are also called radiation sensitizers or radiosensitizers, which can increase the sensitivity of tumor cells to radiotherapy. Generally speaking, radiosensitizing drugs are a chemical or pharmaceutical preparation that, when used simultaneously with radiotherapy, can change the responsiveness of tumor cells to radiation, thereby increasing the killing effect on tumor cells. Radiosensitization refers to the process of using some drugs or physical methods to increase the sensitivity of tumor cells to radiation in order to enhance the killing effect of radiation on tumor cells and improve the control rate and cure rate of tumors. Radiosensitizers do not affect normal tissue cells, but selectively enhance the killing effect of radiation on tumor cells.

[0004] Radiosensitizers should meet the following conditions simultaneously: ① The therapeutic dose is non-toxic or has very low toxicity to normal cells, and has little or no sensitizing effect on normal cells; ② It is easily soluble in water, not easy to react with other substances, and has stable properties; ③ It has strong permeability and can penetrate cells in areas without capillaries; ④ It has an appropriately long biological half-life to ensure the concentration of the drug in the body and can reach tumor tissue; ⑤ It has a strong sensitizing effect on proliferating and dormant tumor cells, especially hypoxic tumor cells; ⑥ It is effective within the commonly used radiotherapy fractionated doses.

[0005] Currently used radiosensitizers are primarily compounds that relieve tumor hypoxia, such as the clinical drug CMNA. However, these drugs have drawbacks such as low activity, high dosage, and significant toxic side effects.

[0006] Therefore, the development of new and highly effective radiosensitizing drugs is an urgent clinical need. Summary of the Invention

[0007] In one aspect, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0008] in,

[0009] R 1 and R 2 Each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from R;

[0010] or R 1 、R 2 Together with the nitrogen atom to which they are attached, they form a 3-8 membered heterocyclic group, which is optionally substituted by p R S replace;

[0011] L is selected from chemical bonds, C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkynylidene;

[0012] Each ring A is independently selected from C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from R;

[0013] R is selected from halogen, -CN, -NO2, -OR a 、-SR a 、-N(R b )(R c )、-C(O)-R a 、-OC(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c )、-N(R b )C(O)-R c 、-S(O)R a 、-S(O)2-R a 、-S(O)2NR b R c 、C 1-6 Alkyl and C 1-6 alkyl halide;

[0014] R a 、R b and R c Each independently selected from -H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; or R b 、R c Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic group;

[0015] p is an integer selected from 0, 1, 2, 3, 4 and 5;

[0016] R S Each independently selected from halogen, -CN, -NO2, -OR a 、-SR a 、-N(R b )(R c )、-C(O)-R a 、-OC(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c )、-N(R b )C(O)-R c 、-S(O)R a 、-S(O)2-R a 、-S(O)2NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl;

[0017] Provided that the compound of formula (I) is not the following compound:

[0018] In another aspect, the present invention relates to the use of a compound in the preparation of a radiosensitizing drug, wherein the compound is a compound of formula (I) or (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0019] The definitions of the groups are as described in this application. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 shows the inhibitory effect of the compound combined with radiotherapy on tumor growth in mice.

[0021] Figure 2 shows the inhibitory effect of the compound combined with radiotherapy on remote tumors in mice.

[0022] Detailed Description of the Invention

[0023] Chemical definition

[0024] definition

[0025] Definitions of specific functional groups and chemical terms are described in more detail below.

[0026] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1- 6 alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2- 5. C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0027] “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl is preferred. In some embodiments, C 1-2 Alkyl groups are preferred. 1- Examples of 6-alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "C6" refers to a group consisting of a methyl (C1), an ethyl (C2), an n-propyl (C3), an isopropyl (C3), an n-butyl (C4), a tert-butyl (C4), a sec-butyl (C4), an isobutyl (C4), a n-pentyl (C5), a 3-pentyl (C5), a pentyl (C5), a neopentyl (C5), a 3-methyl-2-butyl (C5), a 1-6"Alkyl" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen (O), sulfur (S), nitrogen (N), boron (B), silicon (Si), phosphorus (P)). The alkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0028] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0029] Therefore, “C 1-6 "Haloalkyl" refers to the above-mentioned "C 1-6 Alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-3 Halogenated alkyl is particularly preferred, more preferably C 1-2 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. The haloalkyl group can be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0030] “C 2-6 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). In some embodiments, C 2-4 Alkenyl is particularly preferred. Examples of the alkenyl include, but are not limited to, vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Regardless of whether the alkenyl is modified with "substituted", each of the alkenyl groups is independently optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, and suitable substituents are defined below.

[0031] “C 2-6"Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, or 3 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). In some embodiments, C 2-4 Alkynyl is particularly preferred. In some embodiments, alkynyl does not contain any double bond. One or more carbon triple bonds can be internal (e.g., in 2-butynyl) or end (e.g., in 1-butynyl). Examples of the alkynyl include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. Regardless of whether "substituted" is modified before the alkynyl, each of the alkynyl groups is optionally substituted independently, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, and suitable substituents are defined as follows.

[0032] “C 1-6 Alkylene", "C 2-6 Alkenylene" and "C 2-6 "Alkynylidene" refers to the group with "C 1-6 Alkyl", "C 2-6 Alkenyl" and "C 2-6 The other hydrogen atom of the "alkynyl" forms a divalent group.

[0033] “C 3-7 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-6 Cycloalkyl is preferred, C 4-6 Cycloalkyl is particularly preferred, more preferably C 5-6 Cycloalkyl. Cycloalkyl also includes ring systems in which the above-mentioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyls include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodec ... 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10), bornyl, adamantyl, etc. Regardless of whether the cycloalkyl group is preceded by "substituted", each of the cycloalkyl groups is independently optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, and suitable substituents are defined below.

[0034] "3-8 membered heterocyclyl" refers to a radical of a 3- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. In some embodiments, a 3- to 7-membered heterocyclyl is preferred, which is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, a 3- to 6-membered heterocyclyl is particularly preferred, which is a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably, a 5- to 6-membered heterocyclyl is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems in which the above-mentioned heterocyclyl ring is fused to one or more cycloalkyl, aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Regardless of whether the heterocyclyl group is preceded by "substituted", each of the heterocyclyl groups is independently optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent, suitable substituents being defined below.

[0035] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetane, and thietidinyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolane, oxasulfuranyl, disulfuranyl, and Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithian ... Alkyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl (triazinanyl). Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxepanyl, and thiecanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to, dihydroindole, isoindole, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzo Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclyl groups) fused to a C6 aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0036] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 "aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, C 6-10 Aryl is particularly preferred, with C6 aryl being more preferred. Aryl also includes ring systems in which the aforementioned aryl ring is fused to one or more cycloalkyl or heterocyclic groups, with the point of attachment being on the aryl ring. In this case, the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Regardless of whether the aryl group is preceded by "substituted," each aryl group is independently optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Suitable substituents are defined below.

[0037] "5-10 membered heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-6 membered heteroaryl is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-membered heteroaryl is particularly preferred, which is a 5-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. Regardless of whether the heteroaryl group is preceded by "substituted", each of the heteroaryl groups is independently optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, and suitable substituents are defined below.

[0038] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepine, oxepinyl, and thiepine. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0039] In this application, the term "optional" or "optionally" generally means that the subsequently described event or circumstance can but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group can but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0040] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2, -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa 、-NR bb SO2Raa 、-SO2N(R bb )2, -SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2, -C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa )2、-B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0041] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN(R bb )2, =NNR bbC(=O)R aa 、=NNR bb C(=O)OR aa 、=NNR bb S(=O)2R aa 、=NR bb or = NOR cc replace;

[0042] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0043] R bb Each of the following is independently selected from: hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0044] R ccEach of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0045] R dd Each of the is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee 、-ON(R ff )2、-N(R ff )2,、-N(R ff )3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2, -SO2R ee 、-SO2OR ee 、-OSO2R ee、-S(=O)R ee 、-Si(R ee )3、-OSi(R ee )3、-C(=S)N(R ff )2, -C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)2R ee 、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0046] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0047] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0048] R gg Each of the independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3+ X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1- 6 alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1- 6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1- 6-alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2、C(=S)NH(C 1-6alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 carbocyclic group, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0049] Exemplary substituents on nitrogen atoms include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom ccThe groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd Group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0050] As used herein, the term "compound of the present application" refers to the compound of the present application. The term also includes various pharmaceutically acceptable salts, stereoisomers, enantiomers, diastereomers, meso-racemates, racemates or tautomers of the compound of the present application.

[0051] Other definitions

[0052] In this application, the term "comprising" generally refers to including the features specified but not excluding other elements. The terms "above" and "below" generally refer to including the number.

[0053] In this application, the term "about" generally refers to a variation within a range of 0.5%-10% above or below the specified value, for example, a variation within a range of 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% above or below the specified value.

[0054] As used herein, the term "pharmaceutically acceptable salt" means an acid addition salt or a base addition salt of the compounds of the invention which are suitable for use in contact with the tissues of patients, within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, or the like, commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, including, where possible, zwitterionic forms of the compounds of the invention.

[0055] Pharmaceutically acceptable salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, borates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, and the like, prepared from inorganic acids. Representative salts include hydrobromides, hydrochlorides, sulfates, bisulfates, nitrates, borates, and phosphates. Salts can also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Representative salts include acetate, propionate, valerate, oleate, palmitate, stearate, laurate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, glucoheptonate, lactobionate, laurylsulfonate, and isethionate, etc. Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also contemplated are salts of amino acids, such as argininate, gluconate, galacturonate, and the like (see, e.g., Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0056] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those of the general formulae or specific compounds described herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36Cl. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. In addition, heavier isotopes such as deuterium (i.e. 2 H) substitution may be preferred in some cases because greater metabolic stability may provide therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when performing the processes disclosed in the following schemes and / or the Examples and Preparations.

[0057] The compounds of the present invention include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0058] "Tautomer" refers to a functional group in certain compounds that changes its structure to become another functional group isomer, and can rapidly convert into each other, forming two isomers in dynamic equilibrium, and these two isomers are called tautomers.

[0059] The term "solvate" refers to a form of a compound or its salt that is combined with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in a crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in the solution state and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0060] The term "hydrate" refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, the hydrate of a compound can be represented by the general formula R·x H2O, for example, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrate (R·0.5H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R·2H2O) and hexahydrates (R·6H2O)).

[0061] The compounds of the present invention may be in amorphous or crystalline form (crystal form or polymorph). In addition, each component compound of the present invention may exist in one or more crystalline forms. Therefore, the present invention includes within its scope all amorphous or crystalline forms of each component compound of the present invention. The term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate or solvate) with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors may cause one crystalline form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0062] In addition, prodrugs are also included in the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo, for example by hydrolysis in the blood, into its active form that has a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra, "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each of which is incorporated herein by reference.

[0063] A prodrug is any covalently bonded compound of the present invention that releases the parent compound in vivo when such a prodrug is administered to a patient. Prodrugs are typically prepared by modifying functional groups in such a way that the modification can be cleaved to produce the parent compound by conventional manipulation or in vivo. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, can cleave to form a hydroxyl, amino, or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate / amide, formate / amide, and benzoate / amide derivatives of the hydroxyl, sulfhydryl, and amino functional groups of compounds of formula (I). Additionally, in the case of carboxylic acids (-C(O)OH), esters such as methyl esters, ethyl esters, and the like can be used. Esters themselves can be active and / or can be hydrolyzed under human in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily decompose in the human body to release the parent acid or a salt thereof.

[0064] As used herein, the term "pharmaceutical composition" generally refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. Pharmaceutical compositions can facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity. Conventional pharmaceutical compositions can be prepared using techniques commonly used in the art.

[0065] In this application, the term "pharmaceutically acceptable carrier" generally refers to a carrier for administering therapeutic agents, such as antibodies or polypeptides, genes and other therapeutic agents. The term refers to any pharmaceutical carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition and can be administered without excessive toxicity. For example, a pharmaceutically acceptable carrier can be distinguished from a nucleic acid vector used to contain a gene in genetic engineering. Suitable carriers can be large, slowly metabolized macromolecules, such as proteins, polysaccharides, polylactic acid, polyglycolic acid, polyamino acids, amino acid copolymers, lipid aggregates and inactivated viral particles. These carriers are well known to those skilled in the art. Pharmaceutically acceptable carriers in therapeutic compositions may include liquids, such as water, saline, glycerol and ethanol. Auxiliary substances, such as wetting agents or emulsifiers, pH buffer substances, etc., may also be present in these carriers.

[0066] As used herein, the term "effective amount" generally refers to an amount of a therapeutic agent that treats, alleviates, or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or preventive effect. The precise effective amount for a given subject depends on the subject's size and health, the nature and extent of the condition, and the therapeutic agent and / or combination of therapeutic agents selected for administration. Therefore, it is not useful to specify an exact effective amount in advance. However, for a given condition, the effective amount can be determined by routine experimentation, which is within the judgment of the clinician.

[0067] The term "patient" includes both mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs, and including unborn mammals. Examples of non-mammals include, but are not limited to, birds, fish, and the like.

[0068] The term "patient" includes confirmed patients, but the "patient" does not need to have any special identity with respect to the hospital, clinic or research facility (such as being a confirmed patient, research participant, etc.). Specific implementation plan

[0069] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0070] in,

[0071] R 1 and R 2 Each independently selected from C 1-6 Alkyl, C1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from R;

[0072] or R 1 、R 2 Together with the nitrogen atom to which they are attached, they form a 3-8 membered heterocyclic group, which is optionally substituted by p R S replace;

[0073] L is selected from chemical bonds, C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkynylidene;

[0074] Each ring A is independently selected from C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from R;

[0075] R is selected from halogen, -CN, -NO2, -OR a 、-SR a 、-N(R b )(R c )、-C(O)-R a 、-OC(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c )、-N(R b )C(O)-R c 、-S(O)R a 、-S(O)2-R a 、-S(O)2NR b R c 、C 1-6 Alkyl and C 1-6 alkyl halide;

[0076] R a 、R b and R c Each independently selected from -H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; or Rb 、R c Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic group;

[0077] p is an integer selected from 0, 1, 2, 3, 4 and 5;

[0078] R S Each independently selected from halogen, -CN, -NO2, -OR a 、-SR a 、-N(R b )(R c )、-C(O)-R a 、-OC(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c )、-N(R b )C(O)-R c 、-S(O)R a 、-S(O)2-R a 、-S(O)2NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl;

[0079] Provided that the compound of formula (I) is not the following compound:

[0080] R 1 and R 2

[0081] In one embodiment, R 1 C 1-6 Alkyl; in another embodiment, R 1 C 1-6 haloalkyl; in another embodiment, R 1 C 2-6 alkenyl; in another embodiment, R 1 C 2-6 Alkynyl; in another embodiment, R 1 for

[0082] In one embodiment, R 2 C 1-6 Alkyl; in another embodiment, R2 C 1-6 haloalkyl; in another embodiment, R 2 C 2-6 alkenyl; in another embodiment, R 2 C 2-6 Alkynyl; in another embodiment, R 2 for

[0083] In a more specific embodiment of the above embodiment, wherein the group is unsubstituted; in other more specific embodiments of the above embodiment, wherein the group is substituted with 1, 2, 3, 4 or 5 substituents independently selected from R.

[0084] In one embodiment, R 1 、R 2 Together with the nitrogen atom to which they are attached, they form a 3-8 membered heterocyclic group, which is optionally substituted by p R S replace.

[0085] L

[0086] In one embodiment, L is a chemical bond; in another embodiment, L is C 1-6 Alkylene; in another embodiment, L is C 2-6 Alkenylene; in another embodiment, L is C 2- 6 alkynylene groups.

[0087] Ring A

[0088] In one embodiment, Ring A is C 3-7 Cycloalkyl; in another embodiment, ring A is a 3-7 membered heterocyclic group; in another embodiment, ring A is C 6-10 Aryl; In another embodiment, Ring A is a 5-10 membered heteroaryl.

[0089] In a more specific embodiment of the above embodiment, wherein the group is unsubstituted; in other more specific embodiments of the above embodiment, wherein the group is substituted with 1, 2, 3, 4 or 5 substituents independently selected from R.

[0090] R

[0091] In one embodiment, R is halogen; in another embodiment, R is -CN; in another embodiment, R is -NO2; in another embodiment, R is -OR a In another embodiment, R is -SR a In another embodiment, R is -N(R b )(R c); In another embodiment, R is -C(O)-R a In another embodiment, R is -OC(O)-R a In another embodiment, R is -C(O)OR a In another embodiment, R is -C(O)-N(R b )(R c ); In another embodiment, R is -N(R b )C(O)-R c In another embodiment, R is -S(O)R a In another embodiment, R is -S(O)2-R a In another embodiment, R is -S(O)2NR b R c In another embodiment, R is C 1-6 Alkyl; in another embodiment, R is C 1-6 Halogenated alkyl.

[0092] p

[0093] In one embodiment, p is 0; in another embodiment, p is 1; in another embodiment, p is 2; in another embodiment, p is 3; in another embodiment, p is 4; in another embodiment, p is 5.

[0094] R S

[0095] In one embodiment, R S is halogen; in another embodiment, R S is -CN; in another embodiment, R S is -NO2; in another embodiment, R S For-OR a In another embodiment, R S For-SR a In another embodiment, R S -N(R b )(R c ); In another embodiment, R S -C(O)-R a In another embodiment, R S -OC(O)-R a In another embodiment, R S -C(O)OR a In another embodiment, R S -C(O)-N(R b)(R c ); In another embodiment, R S -N(R b )C(O)-R c In another embodiment, R S -S(O)R a In another embodiment, R S -S(O)2-R a In another embodiment, R S -S(O)2NR b R c In another embodiment, R S C 1-6 Alkyl; in another embodiment, R S C 1-6 haloalkyl; in another embodiment, R S C 2-6 alkenyl; in another embodiment, R S C 2-6 Alkynyl; in another embodiment, R S C 3-7 Cycloalkyl; in another embodiment, R S is a 3-7 membered heterocyclic group; in another embodiment, R S C 6-10 Aryl; In another embodiment, R S It is a 5-10 membered heteroaryl group.

[0096] R a 、R b and R c

[0097] In one embodiment, R a is -H; in another embodiment, R a C 1-6 Alkyl; in another embodiment, R a C 1-6 haloalkyl; in another embodiment, R a C 2-6 alkenyl; in another embodiment, R a C 2-6 Alkynyl; in another embodiment, R a C 3-7 Cycloalkyl; in another embodiment, R a is a 3-7 membered heterocyclic group; in another embodiment, R a C 6-10 Aryl; In another embodiment, R a It is a 5-10 membered heteroaryl group.

[0098] In one embodiment, R b is -H; in another embodiment, R b C 1-6 Alkyl; in another embodiment, R b C 1-6 haloalkyl; in another embodiment, R b C 2-6 alkenyl; in another embodiment, R b C 2-6 Alkynyl; in another embodiment, R b C 3-7 Cycloalkyl; in another embodiment, R b is a 3-7 membered heterocyclic group; in another embodiment, R b C 6-10 Aryl; In another embodiment, R b It is a 5-10 membered heteroaryl group.

[0099] In one embodiment, R c is -H; in another embodiment, R c C 1-6 Alkyl; in another embodiment, R c C 1-6 haloalkyl; in another embodiment, R c C 2-6 alkenyl; in another embodiment, R c C 2-6 Alkynyl; in another embodiment, R c C 3-7 Cycloalkyl; in another embodiment, R c is a 3-7 membered heterocyclic group; in another embodiment, R c C 6-10 Aryl; In another embodiment, R c It is a 5-10 membered heteroaryl group.

[0100] In one embodiment, R b 、R c Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic group.

[0101] In another aspect, the present invention provides the following specific technical solutions:

[0102] Technical Solution 1. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0103] in,

[0104] R 1 and R 2 Each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from R;

[0105] or R 1 、R 2 Together with the nitrogen atom to which they are attached, they form a 3-8 membered heterocyclic group, which is optionally substituted by p R S replace;

[0106] L is selected from chemical bonds, C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkynylidene;

[0107] Each ring A is independently selected from C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from R;

[0108] R is selected from halogen, -CN, -NO2, -OR a 、-SR a 、-N(R b )(R c )、-C(O)-R a 、-OC(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c )、-N(R b )C(O)-R c 、-S(O)R a 、-S(O)2-R a 、-S(O)2NR b R c 、C 1-6 Alkyl and C 1-6 alkyl halide;

[0109] R a 、R b and R c Each independently selected from -H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; or R b 、R c Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic group;

[0110] p is an integer selected from 0, 1, 2, 3, 4 and 5;

[0111] R S Each independently selected from halogen, -CN, -NO2, -OR a 、-SR a 、-N(R b )(R c )、-C(O)-R a 、-OC(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c )、-N(R b )C(O)-R c 、-S(O)R a 、-S(O)2-R a 、-S(O)2NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl;

[0112] Provided that the compound of formula (I) is not the following compound:

[0113] Technical Solution 2. The compound of Technical Solution 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0114] R 1 and R 2 Each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and wherein said above groups are optionally unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents independently selected from R;

[0115] R is selected from halogen, -CN, -NO2, -OR a 、-C(O)-R a 、-C(O)OR a 、-N(R b )(R c )、-N(R b )C(O)-R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl.

[0116] Technical Solution 3. The compound of formula (I) of Technical Solution 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0117] in,

[0118] R 1 and R 2 Each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from R;

[0119] R is selected from halogen, -CN, -NO2, -OR a 、-SR a 、-N(R b )(R c )、-C(O)-R a 、-OC(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c )、-N(R b )C(O)-R c 、-S(O)R a 、-S(O)2-R a 、-S(O)2NR b R c 、C 1-6 Alkyl and C 1-6 alkyl halide;

[0120] R a 、R b and R c Each independently selected from -H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; or R b 、R c Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic group.

[0121] Technical Solution 4. The compound of Technical Solution 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0122] R 1 and R 2 Each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from R;

[0123] R is selected from halogen, -CN, -NO2, -OR a 、-C(O)-R a 、-C(O)OR a 、-N(R b )(R c )、-N(R b )C(O)-R c 、C 1-6 Alkyl and C 1-6 haloalkyl; and

[0124] R a 、R b and R c are each independently selected from -H and C 1-6 alkyl.

[0125] Technical Solution 5. The compound of Technical Solution 3 or 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0126] R 1 and R 2 Each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6Alkynyl, wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, -CN, -NO2, -C(O)OH, -C(O)CH3, -OH, -O-CH3, -C(O)OCH3, -NH2, -NHCH3, -N(CH3)2 and -NHC(O)CH3.

[0127] Technical Solution 6. The compound of any one of Technical Solutions 3-5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0128] R 1 and R 2 Each independently is C 1-6 Alkyl, which is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, -CN, -NO2, -C(O)OH, -C(O)CH3, -OH, -O-CH3, -C(O)OCH3, -NH2, -NHCH3, -N(CH3)2 and -NHC(O)CH3.

[0129] Technical Solution 7. The compound of formula (I) according to Technical Solution 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0130] in,

[0131] R 1 for

[0132] R 2 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and

[0133] L is selected from chemical bonds, C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkynylidene;

[0134] Each ring A is independently selected from C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from R;

[0135] R is selected from halogen, -CN, -NO2, -ORa 、-SR a 、-N(R b )(R c )、-C(O)-R a 、-OC(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c )、-N(R b )C(O)-R c 、-S(O)R a 、-S(O)2-R a 、-S(O)2NR b R c 、C 1-6 Alkyl and C 1-6 alkyl halide;

[0136] R a 、R b and R c Each independently selected from -H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; or R b 、R c Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic group.

[0137] Technical Solution 8. The compound of Technical Solution 7, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 1 for

[0138] R 2 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and

[0139] L is selected from chemical bonds and C 1-6 an alkylene group; and

[0140] Each ring A is independently selected from C 3-7 cycloalkyl, phenyl and 5-6 membered heteroaryl.

[0141] Technical Solution 9. The compound of Technical Solution 7 or 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0142] R 1 for And R 2 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0143] Technical Solution 10. The compound of Technical Solution 7 or 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0144] R 1 for And R 2 for

[0145] Technical Solution 11. The compound of any one of Technical Solutions 7-10, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0146] L is a chemical bond or C 1-3 alkylene, and each ring A is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thienyl and pyridyl.

[0147] Technical Solution 12. The compound of Technical Solution 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has a structure of Formula (II):

[0148] in,

[0149] Ring B is

[0150] Z is a chemical bond, -C(R A )(R B )-、-NR D -, -O-, or -S-;

[0151] m is an integer selected from 1, 2 and 3;

[0152] n is an integer selected from 1, 2 and 3;

[0153] p is an integer selected from 0, 1, 2, 3, 4 and 5;

[0154] R A 、R B and R S Each independently selected from -H, halogen, -CN, -NO2, -OR a 、-SR a 、-N(R b )(R c )、-C(O)-R a 、-OC(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c )、-N(R b )C(O)-R c 、-S(O)R a 、-S(O)2-R a 、-S(O)2NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl;

[0155] R D Selected from -H, -C(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c ),-S(O)R a 、-S(O)2-R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl;

[0156] R a 、R b and R c Each independently selected from -H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C6-10 Aryl and 5-10 membered heteroaryl; or R b 、R c Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic group.

[0157] Technical Solution 13. The compound of Technical Solution 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0158] Ring B is

[0159] Z is a chemical bond, -C(R A )(R B )-、-NR D -or-O-;

[0160] m is an integer selected from 1, 2 and 3;

[0161] n is an integer selected from 1, 2 and 3;

[0162] p is an integer selected from 0, 1, 2 and 3;

[0163] R A 、R B and R S are each independently selected from -H, halogen and C 1-6 alkyl;

[0164] R D -H, C 1-6 Alkyl or -C(O)-R a ;

[0165] R a Selected from -H, C 1-6 Halogenated alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0166] Technical Solution 14. The compound of Technical Solution 12 or 13, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0167] Ring B is selected from and the ring B is optionally substituted by 1, 2 or 3 R S replace;

[0168] R S are each independently selected from halogen and C 1-6 alkyl.

[0169] Technical Solution 15. The compound of any one of Technical Solutions 12-14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0170] The R S is F or -CH3.

[0171] Technical Solution 16. The compound of formula (I) according to Technical Solution 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein the compound is selected from the following:

[0172] Technical solution 17. A pharmaceutical composition comprising a compound of any one of Technical Solutions 1-16, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, optionally other drugs.

[0173] Technical Solution 18. Use of a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof in the preparation of a radiosensitizing drug:

[0174] in,

[0175] R 1 and R 2 Each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from R;

[0176] or R 1 、R 2 Together with the nitrogen atom to which they are attached, they form a 3-8 membered heterocyclic group, which is optionally substituted by p R S replace;

[0177] L is selected from chemical bonds, C 1-6 Alkylene, C 2-6 Alkenylene and C2-6 Alkynylidene;

[0178] Each ring A is independently selected from C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from R;

[0179] R is selected from halogen, -CN, -NO2, -OR a 、-SR a 、-N(R b )(R c )、-C(O)-R a 、-OC(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c )、-N(R b )C(O)-R c 、-S(O)R a 、-S(O)2-R a 、-S(O)2NR b R c 、C 1-6 Alkyl and C 1-6 alkyl halide;

[0180] R a 、R b and R c Each independently selected from -H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; or R b 、R c Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic group;

[0181] p is an integer selected from 0, 1, 2, 3, 4 and 5;

[0182] R S Each independently selected from halogen, -CN, -NO2, -OR a 、-SR a 、-N(R b )(R c )、-C(O)-R a 、-OC(O)-R a 、-C(O)ORa 、-C(O)-N(R b )(R c )、-N(R b )C(O)-R c 、-S(O)R a 、-S(O)2-R a 、-S(O)2NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl.

[0183] Technical Solution 19. The use of Technical Solution 18, wherein:

[0184] R 1 and R 2 Each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and wherein said above groups are optionally unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents independently selected from R;

[0185] R is selected from halogen, -CN, -NO2, -OR a 、-C(O)-R a 、-C(O)OR a 、-N(R b )(R c )、-N(R b )C(O)-R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl.

[0186] Technical Solution 20. The use of Technical Solution 18, wherein:

[0187] in,

[0188] R 1 and R 2 Each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from R;

[0189] R is selected from halogen, -CN, -NO2, -OR a 、-SR a 、-N(R b )(R c )、-C(O)-R a 、-OC(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c )、-N(R b )C(O)-R c 、-S(O)R a 、-S(O)2-R a 、-S(O)2NR b R c 、C 1-6 Alkyl and C 1-6 alkyl halide;

[0190] R a 、R b and R c Each independently selected from -H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; or R b 、R c Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic group.

[0191] Technical Solution 21. The use of Technical Solution 20, wherein:

[0192] R 1 and R 2 Each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from R;

[0193] R is selected from halogen, -CN, -NO2, -OR a 、-C(O)-R a 、-C(O)OR a 、-N(R b )(R c )、-N(R b )C(O)-Rc 、C 1-6 Alkyl and C 1-6 haloalkyl; and

[0194] R a 、R b and R c are each independently selected from -H and C 1-6 alkyl.

[0195] Technical Solution 22. The use of Technical Solution 20 or 21, wherein:

[0196] R 1 and R 2 Each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, -CN, -NO2, -C(O)OH, -C(O)CH3, -OH, -O-CH3, -C(O)OCH3, -NH2, -NHCH3, -N(CH3)2 and -NHC(O)CH3.

[0197] Technical Solution 23. The use of any one of Technical Solutions 20-22, wherein:

[0198] R 1 and R 2 Each independently is C 1-6 Alkyl, which is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, -CN, -NO2, -C(O)OH, -C(O)CH3, -OH, -O-CH3, -C(O)OCH3, -NH2, -NHCH3, -N(CH3)2 and -NHC(O)CH3.

[0199] Technical Solution 24. The use of Technical Solution 18, wherein:

[0200] in,

[0201] R 1 for

[0202] R 2 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and

[0203] L is selected from chemical bonds, C 1-6 Alkylene, C2-6 Alkenylene and C 2-6 Alkynylidene;

[0204] Each ring A is independently selected from C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from R;

[0205] R is selected from halogen, -CN, -NO2, -OR a 、-SR a 、-N(R b )(R c )、-C(O)-R a 、-OC(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c )、-N(R b )C(O)-R c 、-S(O)R a 、-S(O)2-R a 、-S(O)2NR b R c 、C 1-6 Alkyl and C 1-6 alkyl halide;

[0206] R a 、R b and R c Each independently selected from -H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; or R b 、R c Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic group.

[0207] Technical Solution 25. The use of Technical Solution 24, wherein:

[0208] R 1 for

[0209] R 2 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and

[0210] L is selected from chemical bonds and C 1-6 an alkylene group; and

[0211] Each ring A is independently selected from C 3-7 cycloalkyl, phenyl and 5-6 membered heteroaryl.

[0212] Technical Solution 26. The use of Technical Solution 24 or 25, wherein:

[0213] R 1 for And R 2 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0214] Technical Solution 27. The use of Technical Solution 24 or 25, wherein:

[0215] R 1 for And R 2 for

[0216] Technical Solution 28. The use of any one of Technical Solutions 24-27, wherein:

[0217] L is a chemical bond or C 1-3 alkylene, and each ring A is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thienyl and pyridyl.

[0218] Technical Solution 29. Use of a compound of formula (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof in the preparation of a radiosensitizing drug:

[0219] in,

[0220] Ring B is

[0221] Z is a chemical bond, -C(R A )(R B )-、-NR D -, -O-, or -S-;

[0222] m is an integer selected from 1, 2 and 3;

[0223] n is an integer selected from 1, 2 and 3;

[0224] p is an integer selected from 0, 1, 2, 3, 4 and 5;

[0225] R A 、R B and R S Each independently selected from -H, halogen, -CN, -NO2, -OR a 、-SR a 、-N(R b )(R c )、-C(O)-R a 、-OC(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c )、-N(R b )C(O)-R c 、-S(O)R a 、-S(O)2-R a 、-S(O)2NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl;

[0226] R D Selected from -H, -C(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c ),-S(O)R a 、-S(O)2-R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl;

[0227] R a 、R b and R c Each independently selected from -H, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C6-10 Aryl and 5-10 membered heteroaryl; or R b 、R c Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic group.

[0228] Technical Solution 30. The use of Technical Solution 29, wherein:

[0229] Ring B is

[0230] Z is a chemical bond, -C(R A )(R B )-、-NR D -or-O-;

[0231] m is an integer selected from 1, 2 and 3;

[0232] n is an integer selected from 1, 2 and 3;

[0233] p is an integer selected from 0, 1, 2 and 3;

[0234] R A 、R B and R S are each independently selected from -H, halogen and C 1-6 alkyl;

[0235] R D -H, C 1-6 Alkyl or -C(O)-R a ;

[0236] R a Selected from -H, C 1-6 Halogenated alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0237] Technical solution 31. The use of technical solution 29 or 30, wherein:

[0238] Ring B is selected from and the ring B is optionally substituted by 1, 2 or 3 R S replace;

[0239] R S are each independently selected from halogen and C 1-6 alkyl.

[0240] Technical solution 32. The use of any one of technical solutions 29-31, wherein:

[0241] The R S is F or -CH3.

[0242] Technical Solution 33. Use of a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in the preparation of a radiosensitizing drug, wherein the compound is selected from the following:

[0243] Technical Solution 34. The use according to any one of Technical Solutions 18-33, wherein the radiosensitizing drug is a tumor radiotherapy sensitizing drug.

[0244] Technical Solution 35. The use described in Technical Solution 34, wherein the tumor radiotherapy sensitizing drug can be applied to tumors selected from the following: reproductive system tumors, digestive system tumors, respiratory system tumors, nervous system tumors, urinary system tumors, skin tumors, bone and soft tissue sarcoma, breast cancer, thyroid cancer and pituitary tumors.

[0245] Technical Solution 36. The use described in Technical Solution 35, wherein the tumor is cervical cancer, endometrial epithelial cancer, ovarian cancer, prostate cancer, gastric cancer, liver cancer, colorectal cancer, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, nasopharyngeal cancer, hypopharyngeal cancer, astrocytoma, neuroblastoma, medulloblastoma, bladder cancer, skin squamous cell carcinoma, melanoma, osteosarcoma, soft tissue sarcoma, breast cancer, thyroid cancer, pituitary tumor or renal cell carcinoma.

[0246] Technical solution 37. The use according to any one of claims 18 to 36, wherein the radiosensitizing drug is used in combination with radiotherapy.

[0247] Example

[0248] In order to make the technical solution of the present application clearer and more specific, the present application is further described in detail by the following examples. The following examples are only used to illustrate the specific embodiments of the present application so that those skilled in the art can understand the present application, but are not intended to limit the scope of protection of the present application. In the specific embodiments of the present application, the technical means or methods not specifically described are conventional technical means or methods in the art. The materials, reagents, etc. used in the examples, unless otherwise specified, can be obtained from commercial sources.

[0249] Example 1: Synthesis of Compound 1

[0250] In a 50 mL round-bottom flask, diethylamine (0.73 g, 10 mmol, 1.0 eq) and carbon disulfide (0.76 g, 10 mmol, 1.0 eq) were dissolved in 8 mL of methanol and stirred at 25°C for 4 h. Column chromatography was used to obtain 0.28 g of 1-IM1.

[0251] Dissolve 1-IM1 (0.28 g, 1.87 mmol, 3 eq) and PtCl4 (0.21 g, 0.63 mmol, 1 eq) in 8 mL of methanol. Add anhydrous K2CO3 (0.26 g, 1.87 mmol, 3 eq) to adjust the pH to approximately 8-9. Stir the reaction at 25°C. The reaction is complete by TLC. Column chromatography yields 68 mg of a reddish-brown solid. 1 H NMR (400MHz, MeOD) δ3.70 (q, J=7.2Hz, 12H), 1.33 (t, J=7.2Hz, 18H); m / z (ESI): 640.0485[M] + .

[0252] Example 2: Synthesis of Compound 2

[0253] PtCl4 (0.5 g, 1.48 mmol), 2-IM1 (0.64 g, 4.47 mmol) and 50 mL of methanol were added to a single-necked bottle, replaced with nitrogen, and stirred at 10-15°C for 4 h to obtain a suspension.

[0254] Post-treatment: The mother liquor was filtered and desolvated under reduced pressure in a 30°C water bath to dryness to obtain the crude product, which was purified by column chromatography using a methanol / DCM = 1:20 eluent to obtain 120 mg of the pure product with a liquid phase purity of 98.0%; 1 H NMR (400MHz, CDCl3) δ3.39 (18H, s); m / z (ESI): 555.8[M] + .

[0255] Example 3: Synthesis of Compound 3

[0256] In a 50 mL round-bottom flask, dipropylamine (1.03 g, 10 mmol, 1.0 eq) and carbon disulfide (0.76 g, 10 mmol, 1.0 eq) were dissolved in 8 mL of methanol and stirred at 25°C with TLC monitoring. After 4 h, PtCl₄ (0.17 g, 0.50 mmol, 1 eq) was added, followed by anhydrous K₂CO₃ (0.20 g, 1.5 mmol, 3 eq) to adjust the pH to approximately 8-9. The reaction was continued with stirring at 25°C. TLC monitoring and column chromatography yielded 28 mg of a pale yellow solid. 1H NMR(400MHz,MeOD)δ3.61(dt,J=9.1,3.9Hz,6H),3.03–2.78(m,6H),1.80(p,J=7.6Hz,6 H),1.70(dt,J=15.1,7.7Hz,6H),1.00(dt,J=15.3,7.4Hz,18H); m / z(ESI):723.1346[M] + .

[0257] Example 4: Synthesis of Compound 5

[0258] Add methylethylamine (10.00g, 0.1692mol) to a 500mL three-necked flask and stir to dissolve with 300mL of isopropyl ether. Under nitrogen protection, control the temperature at 0-10°C, add flake KOH (9.47g, 0.1692mol), stir for 10 minutes, and then add carbon disulfide (12.88g, 0.1692mol) dropwise. A large amount of white insoluble material will form in the reaction solution. Stir for 10 minutes, then raise the temperature to 10-15°C and react for 12 hours.

[0259] Post-treatment: filtration, rinsing the filter cake with 40 mL of isopropyl ether, drying the filter cake by suction, and drying it in a vacuum drying oven at 35° C. for 6 h to obtain 19.8 g of white powder (5-IM1) with a yield of 74%.

[0260] PtCl4 (0.5 g, 1.48 mmol), 5-IM1 (0.70 g, 4.45 mmol) and 50 mL of methanol were added to a single-necked bottle, replaced with nitrogen, and stirred at 10-15°C for 4 h to obtain a suspension.

[0261] Post-treatment: The mother liquor was filtered and desolventized to dryness in a 30°C water bath. 30 mL of acetonitrile was added to dissolve the solid, followed by 30 mL of water. Solid precipitated and the mother liquor was filtered and desolventized to dryness in a 30°C water bath to obtain 300 mg of crude product. 30 mg of pure product was obtained by reverse phase preparation with a liquid phase purity of 97.1%. 1 H NMR (400MHz, CDCl3) δ3.75 (q, J=7.3Hz, 6H), 3.33 (s, 9H), 1.37 (t, J=7.2Hz, 9H); m / z (ESI): 597.8[M] + .

[0262] Example 5: Synthesis of Compound 52

[0263] Add diethanolamine (10.00 g, 0.0951 mol) to a 500 mL three-necked flask and stir to dissolve in 200 mL of methanol. Under nitrogen protection and at a temperature of 0-10°C, add powdered NaOH solid (3.81 g, 0.0951 mol) and stir for 10 minutes. Then, add carbon disulfide (7.24 g, 0.0951 mol) dropwise and stir for 10 minutes. Then, raise the temperature to 10-15°C and react for 5 hours.

[0264] Post-treatment: The reaction solution was desolvated to dryness under reduced pressure in a 30°C water bath. Ethanol (100 mL x 2) was added to the mixture until an oil formed. 70 mL of ethanol was added and stirred to dissolve the oil. After stirring for 10 minutes, a white solid gradually precipitated. Stirring was continued for 30 minutes. 280 mL of isopropyl ether was then added dropwise to the suspension, causing a large amount of white solid to precipitate. Stirring was continued for 30 minutes. The suspension was filtered, and the filter cake was rinsed with 40 mL of isopropyl ether. The filter cake was then dried in a vacuum oven at 35°C for 6 hours to obtain 16.2 g of a white powder (52-IM1), with a yield of 83.8%.

[0265] PtCl4 (0.5 g, 1.48 mmol), 52-IM1 (0.82 g, 4.43 mmol) and 50 mL of methanol were added to a single-necked bottle, replaced with nitrogen, and stirred at 10-15°C for 4 h to obtain a suspension.

[0266] Post-treatment: The mother liquor was filtered and desolventized to dryness in a 30°C water bath. 30 mL of acetonitrile was added to dissolve the solid, followed by 30 mL of water. Solid precipitated and the mother liquor was filtered and desolventized to dryness in a 30°C water bath to obtain 300 mg of crude product. 35 mg of the pure product was obtained by reverse phase preparation with a liquid phase purity of 98.1%. 1 H NMR (400MHz, CD3OD) δ3.88 (s, 18H), 3.31 (s, 12H); m / z (ESI): 734.8[M] + .

[0267] Example 6: Synthesis of Compound 71

[0268] Piperidine (71-SM, 10.00 g, 0.1174 mol) was added to a 500 mL three-necked flask, followed by 200 mL of methanol and stirring to dissolve. Under nitrogen protection and at a temperature of 0-10°C, 2M aqueous NaOH (58.7 mL, 0.1174 mol) was added and stirred for 10 minutes. Then, carbon disulfide (10.73 g, 0.1409 mol) was added dropwise. Stir for 10 minutes, and the temperature was raised to 10-15°C for 8 hours.

[0269] Post-treatment: The reaction mixture was desolvated to dryness under reduced pressure in a 30°C water bath. Methanol (100 mL x 2) was added and evaporated until a paste formed. 100 mL of isopropyl ether was added and evaporated once. An additional 100 mL of isopropyl ether was added and the mixture was slurried at 10-15°C for 12 h. The mixture was filtered, and the filter cake was rinsed with 40 mL of isopropyl ether. The filter cake was then dried in a vacuum oven at 35°C for 6 h to obtain 20.0 g of a white powder (71-IM1), with a yield of 93%.

[0270] PtCl4 (0.5 g, 1.48 mmol), 71-IM1 (0.82 g, 4.47 mmol) and 50 mL of methanol were added to a single-necked bottle, replaced with nitrogen, and stirred at 10-15°C for 4 h to obtain a suspension.

[0271] Post-treatment: The mother liquor was filtered and desolventized to dryness in a 30°C water bath under reduced pressure. 30 mL of acetonitrile was added to dissolve the solid, followed by 30 mL of water. Solid precipitated and the mother liquor was filtered and desolventized to dryness in a 30°C water bath to obtain 300 mg of crude product. 80 mg of the pure product was obtained by reverse phase preparation with a liquid phase purity of 95.0%; 1 H NMR (400MHz, CDCl3) δ3.80 (s, 12H), 1.91-1.72 (m, 18H); m / z (ESI): 675.0 [M] + .

[0272] Example 7: Synthesis of Compound 88

[0273] In a 50 mL round-bottom flask, dissolve azetidine (0.57 g, 10 mmol, 1.0 eq) in 8 mL of ethanol. Slowly add 30% NaOH solution dropwise under ice until the pH reaches approximately 8-10. Then slowly add carbon disulfide (0.76 g, 10 mmol, 1.0 eq) dropwise. Reaction was continued under ice for 1 h, monitored by TLC. A small amount of white solid precipitated in the reaction system. Ethyl acetate was added, and the reaction was allowed to stand for a large amount of solid to precipitate. Filter the mixture to obtain 88-IM1.

[0274] 88-IM1 (0.28 g, 1.80 mmol, 3 eq) and PtCl4 (0.20 g, 0.60 mmol, 1 eq) were dissolved in 8 mL of methanol and stirred at 25°C. The reaction was complete as determined by TLC, and 7 mg of an orange-red solid was obtained by column chromatography. 1 H NMR (400MHz, MeOD) δ4.44 (t, J=7.8Hz, 12H), 2.55 (p, J=7.8Hz, 6H); m / z (ESI): 590.9467[M] + .

[0275] Example 8: Synthesis of Compound 90

[0276] Morpholine (90-SM, 10.00 g, 0.1148 mol) was added to a 500 mL three-necked flask, followed by 200 mL of methanol and stirring to dissolve. Under nitrogen, at a temperature of 0-10°C, 2M aqueous NaOH (58.4 mL, 0.1148 mol) was added and stirred for 10 minutes. Carbon disulfide (10.49 g, 0.1378 mol) was then added dropwise. Stir for 10 minutes, and the mixture was heated to 10-15°C for 8 hours.

[0277] Post-treatment: The reaction mixture was desolvated to dryness under reduced pressure in a 30°C water bath. Methanol (100 mL x 2) was added and evaporated until a paste formed. 100 mL of isopropyl ether was added and evaporated once. An additional 100 mL of isopropyl ether was added and the mixture was slurried at 10-15°C for 12 h. The mixture was filtered, and the filter cake was rinsed with 40 mL of isopropyl ether. The filter cake was then dried in a vacuum oven at 35°C for 6 h to obtain 18.4 g of a white powder (90-IM1), with a yield of 86.5%.

[0278] PtCl4 (0.5 g, 1.48 mmol), 90-IM1 (0.82 g, 4.43 mmol) and 50 mL of methanol were added to a single-necked bottle, replaced with nitrogen, and stirred at 10-15°C for 4 h to obtain a suspension.

[0279] Post-treatment: The mother liquor was filtered and desolventized to dryness in a 30°C water bath. 30 mL of acetonitrile was added to dissolve the solid, followed by 30 mL of water. Solid precipitated and the mother liquor was filtered and desolventized to dryness in a 30°C water bath to obtain 400 mg of crude product. 70 mg of the pure product was obtained by reverse phase preparation with a liquid phase purity of 99.2%. 1 H NMR (400MHz, CDCl3) δ3.89 (s, 24H); m / z (ESI): 681.0[M] + .

[0280] Example 9: Synthesis of Compound 91

[0281] In a 50 mL round-bottom flask, 1-methylpiperazine (1.0 g, 10 mmol, 1.0 eq) was dissolved in 8 mL of ethanol. Carbon disulfide (0.76 g, 10 mmol, 1.0 eq) was slowly added dropwise under ice-cooling. White turbidity was observed. After reacting for 10 min, the solid was filtered, washed with ethanol, and air-dried to obtain 91-IM1.

[0282] Dissolve 91-IM1 (0.20 g, 1.13 mmol, 3 eq) and PtCl4 (0.13 g, 0.38 mmol, 1 eq) in 8 mL of methanol, then add anhydrous K2CO3 (0.15 g, 1.13 mmol, 3 eq) and stir at 25°C. The reaction is complete by TLC, and column chromatography yields 3.4 mg of a yellow solid.1 H NMR(400MHz,MeOD)δ3.84(t,J=5.2Hz,12H),2.58(t,J=5.2Hz,12H),2.36(s,9H); m / z(ESI):720.0733[M] + .

[0283] Experimental Example 1: Ability of each new platinum compound to enhance radiotherapy sensitivity (sensitization ratio calculated based on cell survival)

[0284] Representative tumor cell lines of each system were selected, including: 1. Reproductive system tumors including endometrial epithelial carcinoma (ESS-1), ovarian cancer (OVCAR-5) and prostate cancer (PC-3) cell lines; 2. Digestive system tumors including gastric cancer (AGS), liver cancer (Huh-7), colorectal cancer (HCT116) and pancreatic cancer (PANC1) cell lines; 3. Respiratory system tumors including non-small cell lung cancer (H1975) and small cell lung cancer (H378) cell lines; 4. Head and neck tumors including nasopharyngeal carcinoma (CNE2) and hypopharyngeal carcinoma (FaDu); 5. Nervous system tumors Including astrocytoma (U87), neuroblastoma (ACN) and medulloblastoma (PFSK-1) cell lines; 6. Urinary system tumors including human renal carcinoma cell line (A704) and bladder cancer (T24) cell lines; 7. Skin cancer including cutaneous squamous cell carcinoma (A431) and melanoma (COLO-829) cell lines; 8. Bone and soft tissue sarcoma including osteosarcoma (U2OS) and soft tissue sarcoma (HT-1080) cell lines; and 9. Breast cancer cell line (MCF-7), thyroid cancer (HTC-C3) and pituitary tumor (RC-4BC) cell lines.

[0285] Tumor cells of each strain in the logarithmic growth phase were seeded into 6-well plates. Twenty-four hours later, the cells were treated with 12 Gy of X-rays and / or 100 nM of a novel platinum compound (the selected compound had no effect on cell growth at this concentration). The group without compound treatment served as the control group, and the group treated with 25 μM sodium glycidylamine (CMNA) served as the reference group. After 48 hours of incubation, the CCK8 assay was used to assess tumor cell growth inhibition in each system. The fold change (FC) of synergistic effect was calculated as the percentage of cell death in the radiotherapy plus compound group divided by the percentage of cell death in the compound-only group. The fold change (FC0) of radiotherapy alone was calculated as the percentage of cell death in the radiotherapy-free group and the non-radiotherapy group. The compound sensitization ratio was calculated as FC / FC0. The results are shown in Table 1.

[0286] Table 1: Ability of various new platinum compounds to enhance radiosensitivity (sensitization ratio calculated based on cell survival)

[0287] Experimental Example 2: The ability of each new platinum compound to enhance the activation of tumor cell innate immunity after combination with radiotherapy (based on the expression level of type I interferon in the radiotherapy control group alone)

[0288] Tumor cells of each strain in the logarithmic growth phase were plated into six-well plates (the number of plates was determined based on cell growth status and size). After complete attachment, cells were treated with short-course, continuous, large-fractionated irradiation (4 Gy / day for 3 days). Specifically, the cells were irradiated using a cell radiotherapy device for the first time at a dose of 4 Gy. After irradiation, the cells were placed in an incubator for further culture. A second irradiation dose of 4 Gy was administered 24 hours after the first irradiation. After irradiation, the cells were placed in an incubator for further culture. After a second irradiation dose of 4 Gy was administered 24 hours after the first irradiation. After irradiation, the cells were placed in an incubator for further culture for 12 hours. Each platinum compound was then added and incubated for 2 hours. Cells were then harvested and mRNA extracted. A DMSO solvent group served as a blank control, and a group treated with 25 μM sodium glycidylamine (CMNA) served as a reference group. Interferon-β1 mRNA expression in the cells was determined by qPCR.

[0289] The results, shown in Table 2, show that radiotherapy alone barely activates the innate immune response (increased IFNβ1 expression), while combined use of platinum compounds can increase IFNβ1 mRNA levels to varying degrees compared to radiotherapy alone. Compounds 1, 3, and 71, in particular, performed exceptionally well across various tumor cell lines, significantly enhancing the innate immune response of tumor cells after radiotherapy.

[0290] Table 2: IFNβ1 mRNA expression in cells

[0291] Experimental Example 3: Ability of a novel platinum compound combined with radiotherapy to enhance tumor cell immunogenicity (based on the expression level of CXCL10 in the radiotherapy alone control group)

[0292] Tumor cells of each strain in the logarithmic growth phase were plated into six-well plates (the number of plates was determined based on cell growth status and size). After complete cell attachment, they were treated with short-course, continuous, large-fractionated irradiation (4 Gy / day for 3 days). Specifically, the cells were irradiated using a cell radiotherapy device for the first time at a dose of 4 Gy. Following irradiation, the cells were placed in an incubator for further culture. A second irradiation dose of 4 Gy was administered 24 hours after the first irradiation. After the second irradiation dose, the cells were placed in an incubator for further culture. After the second irradiation dose, the cells were placed in an incubator for further culture for 12 hours. Each platinum compound was then added and incubated for 6 hours. Cells were then harvested and mRNA extracted. A DMSO solvent group served as a blank control, and a group treated with 25 μM sodium glycidylamine (CMNA) served as a reference group. Interferon-β1 mRNA expression in the cells was determined by qPCR. The results are shown in Table 3.

[0293] Table 3: CXCL10 mRNA expression levels in cells

[0294] Experimental Example 4: In vivo experimental results in mice after the new platinum compound was combined with radiotherapy

[0295] Mouse colorectal cancer CT26 cells were used to evaluate the tumor killing effect of the selected molecules after combined radiotherapy in vivo. At the same time, the immune effect of the selected molecules on distant tumors after radiotherapy was evaluated. Specific implementation methods:

[0296] Establishment of mouse tumor model: BALB / C mice aged 4 to 5 weeks were selected, CT26 cells with logarithmic growth and good condition were counted and matched into 10 7 Each mouse was injected with 100 μL of a sterile PBS suspension of 100 cells per ml into the lymph node enrichment area under the right and left forelimb axilla. On the 5th day after injection, when the right tumor volume reached 50-100 mm 3Then they were randomly divided into groups, with 5 mice in each group. The groups were divided into the following groups: (1) control group (normal saline group): did not receive irradiation, and received an intraperitoneal injection of normal saline with the same volume as the drug group (0 Gy + NS); (2) single irradiation group: intervened according to the irradiation treatment plan, and received an intraperitoneal injection of normal saline with the same volume as the drug group (14 Gy + NS); (3) molecule No. 1 single drug group: did not receive irradiation, and intervened according to the drug regimen (0 Gy + 1); (4) molecule No. 3 single drug group: did not receive irradiation, and intervened according to the drug regimen (0 Gy + 3); (5) molecule No. 71 single drug group: did not receive irradiation, and intervened according to the drug regimen (0 Gy + 71); (6) CMNA single drug group: did not receive irradiation, and intervened according to the drug regimen (0 Gy + CMNA); (7) irradiation-molecule No. 1 combination group: intervened according to the drug regimen and irradiation treatment plan at the same time. If drug administration and irradiation operations are required within one day, drug administration should be performed 30 minutes first, and then irradiation intervention (the same below) (14 Gy + 1) should be performed. (8) Irradiation-3 molecule combination group: intervention was performed simultaneously according to the dosing regimen and the irradiation treatment regimen (14Gy+3). (9) Irradiation-71 molecule combination group: intervention was performed simultaneously according to the dosing regimen and the irradiation treatment regimen (14Gy+71). (10) Irradiation-CMNA combination group: intervention was performed simultaneously according to the dosing regimen and the irradiation treatment regimen (14Gy+CMNA).

[0297] Treatment plan: From the 6th day onwards, the drug was administered by continuous intraperitoneal injection every day (24 hours apart). The above drug dosage was 2.5 mg / kg / day for a total of 8 days, with a cumulative injection of 20 mg / kg / mouse. The control group was injected with an equal volume of normal saline, and the injection method and time were exactly the same as those of the drug administration group. From the 7th day onwards, the right tumor was continuously irradiated with X-rays every day, and the rest of the area was protected with lead plates (24 hours apart). The irradiation dose was 2Gy each time, for a total of 7 days, with a total dose of 14Gy. From the 5th day onwards, the long and short diameters of the tumors on the left and right sides were measured every 2 days, and the diameter was calculated according to V = (long diameter * short diameter). 2 ) / 2. The changes in tumor volume of mice in each group are shown in the figure.

[0298] The results, shown in Figures 1 and 2, demonstrate that compounds 1, 3, and 71, when combined with radiotherapy, significantly enhance the tumor growth inhibition effect induced by radiotherapy. The biological effect of tumor growth inhibition was higher for compound 71 than for compound 3 and higher for compound 1. Compounds 1, 3, and 71, when combined with radiotherapy, reversed the ineffectiveness of radiotherapy on distant tumors, reducing the size of distant tumors to a smaller range. The biological effect of distant tumor control was higher for compound 71 than for compound 3 and higher for compound 1.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof: in, R 1 and R 2 Each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from R; or R 1 、R 2 Together with the nitrogen atom to which they are attached, they form a 3-8 membered heterocyclic group, which is optionally substituted by p R S replace; L is selected from chemical bonds, C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkynylidene; Each ring A is independently selected from C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from R; R is selected from halogen, -CN, -NO2, -OR a 、-SR a 、-N(R b )(R c )、-C(O)-R a 、-OC(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c )、-N(R b )C(O)-R c 、-S(O)R a 、-S(O)2-R a 、-S(O)2NR b R c 、C 1-6 Alkyl and C 1-6 alkyl halide; R a 、R b and R c Each independently selected from -H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; or R b 、R c Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic group; p is an integer selected from 0, 1, 2, 3, 4 and 5; R S Each independently selected from halogen, -CN, -NO2, -OR a 、-SR a 、-N(R b )(R c )、-C(O)-R a 、-OC(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c )、-N(R b )C(O)-R c 、-S(O)R a 、-S(O)2-R a 、-S(O)2NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; Provided that the compound of formula (I) is not the following compound:

2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 1 and R 2 Each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and wherein said above groups are optionally unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents independently selected from R; R is selected from halogen, -CN, -NO2, -OR a 、-C(O)-R a 、-C(O)OR a 、-N(R b )(R c )、-N(R b )C(O)-R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl.

3. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof: in, R 1 and R 2 Each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from R; R is selected from halogen, -CN, -NO2, -OR a 、-SR a 、-N(R b )(R c )、-C(O)-R a 、-OC(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c )、-N(R b )C(O)-R c 、-S(O)R a 、-S(O)2-R a 、S(O)2NR b R c 、C 1-6 Alkyl and C 1-6 alkyl halide; R a 、R b and R c Each independently selected from -H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; or R b 、R c Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic group.

4. The compound of claim 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 1 and R 2 Each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from R; R is selected from halogen, -CN, -NO2, -OR a 、-C(O)-R a 、-C(O)OR a 、-N(R b )(R c )、-N(R b )C(O)-R c 、C 1-6 Alkyl and C 1-6 haloalkyl; and R a 、R b and R c are each independently selected from -H and C 1-6 alkyl.

5. The compound of claim 3 or 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 1 and R 2 Each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, -CN, -NO2, -C(O)OH, -C(O)CH3, -OH, -O-CH3, -C(O)OCH3, -NH2, -NHCH3, -N(CH3)2 and -NHC(O)CH3.

6. The compound of any one of claims 3 to 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 1 and R 2 Each independently is C 1-6 Alkyl, which is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, -CN, -NO2, -C(O)OH, -C(O)CH3, -OH, -O-CH3, -C(O)OCH3, -NH2, -NHCH3, -N(CH3)2 and -NHC(O)CH3.

7. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof: in, R 1 for R 2 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and L is selected from chemical bonds, C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkynylidene; Each ring A is independently selected from C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, wherein the above groups are optionally unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from R; R is selected from halogen, -CN, -NO2, -OR a 、-SR a 、-N(R b )(R c )、-C(O)-R a 、-OC(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c )、-N(R b )C(O)-R c 、-S(O)R a 、-S(O)2-R a 、-S(O)2NR b R c 、C 1-6 Alkyl and C 1-6 alkyl halide; R a 、R b and R c Each independently selected from -H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; or R b 、R c Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic group.

8. The compound of claim 7, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 1 for R 2 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and L is selected from chemical bonds and C 1-6 an alkylene group; and Each ring A is independently selected from C 3-7 cycloalkyl, phenyl and 5-6 membered heteroaryl.

9. The compound of claim 7 or 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 1 for And R 2 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl.

10. The compound of claim 7 or 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 1 for And R 2 for 11. The compound of any one of claims 7 to 10, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L is a chemical bond or C 1-3 alkylene, and each ring A is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thienyl and pyridyl.

12. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, having the structure of formula (II): in, Ring B is Z is a chemical bond, -C(R A )(R B )-、-NR D -, -O-, or -S-; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2 and 3; p is an integer selected from 0, 1, 2, 3, 4 and 5; R A 、R B and R S Each independently selected from -H, halogen, -CN, -NO2, -OR a 、-SR a 、-N(R b )(R c )、-C(O)-R a 、-OC(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c )、-N(R b )C(O)-R c 、-S(O)R a 、-S(O)2-R a 、-S(O)2NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; R D Selected from -H, -C(O)-R a 、-C(O)OR a 、-C(O)-N(R b )(R c ),-S(O)R a 、-S(O)2-R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; R a 、R b and R c Each independently selected from -H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl; or R b 、R c Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic group.

13. The compound of claim 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Ring B is Z is a chemical bond, -C(R A )(R B )-、-NR D -or-O-; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2 and 3; p is an integer selected from 0, 1, 2 and 3; R A 、R B and R S are each independently selected from -H, halogen and C 1-6 alkyl; R D -H, C 1-6 Alkyl or -C(O)-R a ; R a Selected from -H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

14. The compound of claim 12 or 13, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Ring B is selected from and the ring B is optionally substituted by 1, 2 or 3 R S replace; R S are each independently selected from halogen and C 1-6 alkyl.

15. The compound of any one of claims 12 to 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein The R S is F or -CH3.

16. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein The compound is selected from the following:

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, optionally with other drugs.

18. Use of a compound in the preparation of a radiosensitizing drug, wherein the compound is a compound of formula (I) or (II), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof: The definitions of the groups are as described in any one of claims 1 to 17.

19. The use according to claim 18, wherein the radiosensitizing drug is a tumor radiotherapy sensitizing drug.

20. The use according to claim 19, wherein the tumor radiosensitization drug can be applied to tumors selected from the group consisting of reproductive system tumors, digestive system tumors, respiratory system tumors, nervous system tumors, urinary system tumors, skin tumors, bone and soft tissue sarcomas, breast cancer, thyroid cancer, and pituitary tumors.

21. The method of claim 20, wherein the tumor is cervical cancer, endometrial epithelial cancer, ovarian cancer, prostate cancer, gastric cancer, liver cancer, colorectal cancer, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, nasopharyngeal cancer, hypopharyngeal cancer, astrocytoma, neuroblastoma, medulloblastoma, bladder cancer, squamous cell carcinoma of the skin, melanoma, osteosarcoma, soft tissue sarcoma, breast cancer, thyroid cancer, pituitary tumor or renal cell carcinoma.

22. The use according to any one of claims 18 to 21, wherein the radiosensitizing drug is used in combination with radiotherapy.

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