Heterocyclic compound, pharmaceutical composition thereof, and use thereof

Abstract

The present invention relates to a heterocyclic compound, a pharmaceutical composition thereof, and a use thereof. Specifically, the present invention relates to a compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a pharmaceutically acceptable salt of the atropisomer thereof, a pharmaceutically acceptable salt of the deuterated derivative thereof, or a solvate of any one of the foregoing. The compound exhibits significantly high inhibitory activity against KYSE70 cancer cells and has good pharmacokinetic properties.

Description

Heterocyclic compounds, pharmaceutical compositions thereof and uses thereof

[0001] This application claims priority to the following international applications:

[0002] International application PCT / CN2024 / 086596 with a filing date of April 8, 2024;

[0003] International application PCT / CN2024 / 099373 with a filing date of June 14, 2024;

[0004] International application PCT / CN2024 / 108011 with a filing date of July 27, 2024.

[0005] This application incorporates the entire contents of the above-mentioned international applications by reference. TECHNICAL FIELD

[0006] The present application belongs to the field of medicinal chemistry, and relates to a heterocyclic compound, a pharmaceutical composition thereof and uses thereof. BACKGROUND

[0007] Nrf2 is an important transcription factor that plays a key role in regulating cellular redox balance and antioxidant stress. However, in cancer, Nrf2 is often found to be abnormally activated, which can play an important role in tumor development.

[0008] Studies have shown that the abnormal activation of Nrf2 in various cancers is closely related to the occurrence, development and treatment resistance of tumors. For example, Shibata et al. found that overactivation of Nrf2 in tumors is closely related to malignant transformation and increased tumor invasion. This phenomenon can be because Nrf2 activation can promote the survival, proliferation and migration of tumor cells, while reducing sensitivity to oxidative stress and chemotherapy drugs (Tatsuhiro Shibata et al. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy, Proc Natl Acad Sci U S A. 2008 Sep 9; 105(36): 13568-73).

[0009] Another study showed that in head and neck squamous cell carcinoma, abnormal activation of Nrf2 is associated with poor prognosis, which suggests that the role of Nrf2 in tumor progression can be negative (Melba C Jaramillo et al. The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev. 2013 Oct 15; 27(20): 2179-91).

[0010] Data provided by The Cancer Genome Atlas database and data publicly available on Bioporta1 show that Nrf2 mutations are prevalent in primary tumors of about 20 organs (Gao J, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013; 6: p11.), and these mutations have been found to be associated with their enhanced transcriptional activity (Kim YR, et al. Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin. J Pathol 2010; 220: 446-51.). Among them, lung squamous cell carcinoma carries the highest frequency of Nrf2 mutations (about 19%), followed by head and neck squamous cell carcinoma (about 10%) and esophageal adenocarcinoma (about 8.5%). Therefore, the abnormal activation of Nrf2 in cancer can be both a driving factor for tumor development and a new therapeutic target for tumor treatment. It is very challenging to develop inhibitors that directly target Nrf2, and some indirect therapies have been reported, such as KARS inhibitors targeting Nrf2 (WO2021005586A1). There is no approved anti-tumor therapy that selectively targets the NRF2 / KEAP1 pathway, and this remains an unmet clinical need. SUMMARY

[0011] In one aspect, the present application provides a heterocyclic compound, specifically as follows:

[0012] The compound of the following formula (I), stereoisomer thereof, atropisomer thereof, deuterated derivative thereof, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of a stereoisomer thereof, pharmaceutically acceptable salt of an atropisomer thereof, pharmaceutically acceptable salt of a deuterated derivative thereof, or solvate of any of the foregoing:

[0013] wherein

[0014] Ring A is aryl, heteroaryl, or heterocyclyl;

[0015] each R1is independently H, halogen, -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C1-C6alkoxy, or -C(=O)N(R 1a )2, or two R1together with the atom to which they are attached form an optionally substituted C3-C8cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl; each R 1a is independently H, C1-C6alkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein C1-C6alkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three -OH, C1-C6alkyl, or C1-C6haloalkyl; or two R 1a together with the nitrogen atom to which they are attached form heterocycloalkyl, which is optionally substituted with one, two, or three C1-C6alkyl or C1-C6haloalkyl;

[0016] each R2is independently H, halogen, -CN, -OH, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, or optionally substituted C1-C6alkoxy;

[0017] each R3is independently H, halogen, -NH2, -NHR 3a , -N(R 3a )2, oxo (=O), thioxo (=S), -CN, -OH, -OR 3a , -SH, -SR 3a , -S(=O)R 3a , -S(=O)(=NH)R 3a , -SH(=O)(=NH), -NO2, -S(=O)2R 3a , -NHS(=O)2R 3a , -S(=O)2N(R 3a )2, -C(=O)R 3a , -C(=O)OR 3a , -C(=O)NH2, -C(=O)NHR 3a , -OC(=O)N(R 3a )2, -N(R 3a )C(=O)N(R 3a )2, -N(R 3a )C(=O)R 3a , -N(R 3a )C(=O)OR 3a, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C1-C6alkoxy, optionally substituted C3-C8cycloalkyl, or optionally substituted 4- to 8-membered heterocycloalkyl; or two R3are taken together with the atoms to which they are attached to form an optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl; each R 3a independently C1-C6alkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-C6alkylaryl, -C1-C6alkylheteroaryl, -C1-C6alkylcycloalkyl, or -C1-C6alkylheterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three -OH, C1-C6alkyl, or C1-C6haloalkyl; R3is H represents that ring A is not substituted;

[0018] R4is and R 4a is H, D, halogen, or C1-C6haloalkyl;

[0019] p and q are each independently 0, 1, 2, or 3; m is an integer from 1-12; n is an integer from 1-10;

[0020] X1is N or CR2;

[0021] X2is -O-, -S(=O)2-, -C(R1)2-, or -NR5; R5is H, -C(=O)R 5a , -S(=O)R 5a , or -S(=O)2R 5a ; wherein R 5a is H, optionally substituted C1-C6alkyl, or optionally substituted C3-C7cycloalkyl.

[0022] wherein m can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, and n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0023] In some embodiments, the compound has the structure of Formula (I-1) or (I-2) as follows:

[0024] In some embodiments, p and q are each independently 0, 1, or 2.

[0025] In some embodiments, the compound has the structure of Formula (I-1-1) or (I-1-2) as follows:

[0026] In some embodiments, ring A is: a 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms that are N, preferably ring A is: a 6 membered monocyclic heteroaryl having 2 heteroatoms that are N.

[0027] In some embodiments, ring A is the following structure:

[0028] In some embodiments, ring A is the following structure:

[0029] one end marked "#" indicates attachment to in formula (I).

[0030] In some embodiments, ring A is one end marked "#" indicates attachment to in formula (I).

[0031] In some embodiments, each R1is independently H, halogen, -OH, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or -C(=O)N(R 1a )2, or two R1together with the atom to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; each R 1a is independently H, C1-C6alkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, 3- to 6- membered heterocycloalkyl, C6-C8aryl, or C5-C8heteroaryl, or two R 1a together with the nitrogen atom to which they are attached form a 3- to 6- membered heterocycloalkyl, optionally substituted with one, two, or three C1-C6alkyl or C1-C6haloalkyl; wherein the C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C(=O)N(R 1a )2in the R1option is independently optionally substituted with one, two, or three -OH, halogen, or C1-C3alkoxy.

[0032] In some embodiments, each R1is independently H, F, Br, Cl, C1-C3alkyl, or -C(=O)N(R 1a )2, C1-C3alkyl is optionally substituted with one, two, or three F, Br, Cl, or C1-C3alkyl, each R 1a is independently H or C1-C6alkyl.

[0033] In some embodiments, each R1is independently H, F, -CH3, or -CHF2, preferably H.

[0034] In some embodiments, each R2is independently F, Br, or Cl, preferably Cl.

[0035] In some embodiments, each R3is independently H, halogen, -NH2, -NHR 3a , -N(R 3a )2, -C(=O)NH2, -C(=O)NH(C1-C3alkyl), -C(=O)N(C1-C3alkyl)2, -SH(=O)(=NH), or -S(=O)(=NH)R 3a , each R 3a is independently C1-C6alkyl.

[0036] In some embodiments, each R3is independently H, F, -NH2, -C(=O)NH2, -S(=O)(=NH)CH3, -S(=O)(=NH)CH2CH3, -S(=O)(=NH)CH2CH2CH3, or -S(=O)(=NH)CH(CH3)2, preferably -NH2or -C(=O)NH2.

[0037] In some embodiments, ring A and R2are located at any two of the 1-, 3-, or 5-positions of the ring on which they are located.

[0038] In some embodiments,

[0039] In some embodiments, when the compound has a chiral carbon, it is in the R or S configuration.

[0040] In some embodiments, the compound is any one of the following:

[0041] The present application also provides a compound of Formula (II) or (III), a stereoisomer thereof, an atropisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of an atropisomer thereof, a pharmaceutically acceptable salt of a deuterated derivative thereof, or a solvate of any of the foregoing:

[0042] wherein X a is N or CH;

[0043] each R a is independently H, F, Br, Cl, C1-C3alkyl, or -C(=O)N(R 1a )2, C1-C3alkyl optionally substituted with one, two, or three F, Br, Cl, or C1-C3alkyl, and each R​1a independently H or C1-C6 alkyl; each e is independently 0, 1, 2, 3, or 4;

[0044] each R b independently F, Br, or Cl;

[0045] each R c independently -S(=O)(=NH)CH3, F, Br, or Cl;

[0046] Ring A is the following structure:

[0047] In some embodiments, the compound has any one of the following structures:

[0048] In some embodiments, each atom in any compound, stereoisomer thereof, atropisomer thereof, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of a stereoisomer thereof, pharmaceutically acceptable salt of an atropisomer thereof, or solvate of any of the foregoing, of any of the preceding embodiments is at natural abundance.

[0049] In another aspect, the present application provides a pharmaceutical composition comprising any compound, stereoisomer thereof, atropisomer thereof, deuterated derivative thereof, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of a stereoisomer thereof, pharmaceutically acceptable salt of an atropisomer thereof, pharmaceutically acceptable salt of a deuterated derivative thereof, or solvate of any of the foregoing, of any of the preceding embodiments; and at least one pharmaceutically acceptable excipient.

[0050] In another aspect, the present application provides use of any compound, stereoisomer thereof, atropisomer thereof, deuterated derivative thereof, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of a stereoisomer thereof, pharmaceutically acceptable salt of an atropisomer thereof, pharmaceutically acceptable salt of a deuterated derivative thereof, or solvate of any of the foregoing, of any of the preceding embodiments; or a pharmaceutical composition according to the present application, in the manufacture of a medicament for mediating KEAP1 activation to inhibit Nrf2.

[0051] In another aspect, the present application provides any one of the compounds, stereoisomer thereof, atropisomer thereof, deuterated derivative thereof, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of a stereoisomer thereof, pharmaceutically acceptable salt of an atropisomer thereof, pharmaceutically acceptable salt of a deuterated derivative thereof, or solvate of any one of them as described in any of the preceding aspects, or use of the composition described previously in the manufacture of a medicament for the treatment of a disease or disorder that is cancer; preferably, the cancer is non-small cell lung cancer (NSCLC), liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, prostate cancer, lymphoma, leukemia, or myelodysplastic syndrome (MDS), for example, esophageal squamous carcinoma.

[0052] In another aspect, the present application provides a method of treating a subject having a disease or disorder with abnormal activation of Nrf2, the method comprising administering to the subject a therapeutically effective amount of any one of the compounds, stereoisomer thereof, atropisomer thereof, deuterated derivative thereof, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of a stereoisomer thereof, pharmaceutically acceptable salt of an atropisomer thereof, pharmaceutically acceptable salt of a deuterated derivative thereof, or solvate of any one of them as described in any of the preceding aspects; or the pharmaceutical composition described previously; wherein the disease or disorder is cancer; preferably, the cancer is non-small cell lung cancer (NSCLC), liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, prostate cancer, lymphoma, leukemia, or myelodysplastic syndrome (MDS), for example, esophageal squamous carcinoma.

[0053] In another aspect, the present application provides a method of treating a subject having a disease or disorder with abnormal activation of Nrf2, the method comprising administering to the subject a therapeutically effective amount of any one of the compounds, stereoisomer thereof, atropisomer thereof, deuterated derivative thereof, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of a stereoisomer thereof, pharmaceutically acceptable salt of an atropisomer thereof, pharmaceutically acceptable salt of a deuterated derivative thereof, or solvate of any one of them as described in any of the preceding aspects; or the pharmaceutical composition described previously; wherein the disease or disorder is cancer; preferably, the cancer is non-small cell lung cancer (NSCLC), liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, prostate cancer, lymphoma, leukemia, or myelodysplastic syndrome (MDS), for example, esophageal squamous carcinoma.

[0054] Definitions

[0055] The term "halogen" as used interchangeably herein, unless otherwise indicated, refers to fluorine, chlorine, bromine, or iodine. Preferred halogen groups include -F, -Cl, and -Br.

[0056] The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon groups having straight or branched chains. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl. Similarly, C1-6alkyl is defined to identify groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a straight or branched chain. Conventional alkyl abbreviations include: Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0057] The term "haloalkyl" as used herein, unless otherwise indicated, refers to an alkyl group as defined above substituted with one or more (1, 2, 3, 4, 5, or 6) halogen (-F, -Cl, or -Br). In some embodiments, haloalkyl is interchangeable with -C 1-6 haloalkyl or haloC 1-6 alkyl, wherein -C 1-6 haloalkyl or haloC 1-6 alkyl, wherein -C 1-6 represents the total number of carbon atoms in the alkyl group is 1 to 6. In some embodiments, -C 1-6 haloalkyl is -CF3. 1-3 haloalkyl. In some embodiments, -C 1-3 haloalkyl is -CF3. 1-3 haloalkyl is -CF3.

[0058] The term "alkylene" refers to a bifunctional group obtained by removing an additional hydrogen atom from an alkyl group as defined above. For example, methylene (i.e., -CH2-), ethylene (i.e., -CH2-CH2- or -CH(CH3)-), and propylene (i.e., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, or -CH2-CH(CH3)-).

[0059] The term "alkenyl" refers to straight chain or branched hydrocarbon groups containing one or more double bonds, typically 2 to 20 carbon atoms in length. For example, "-C 2-6 alkenyl" contains 2 to 6 carbon atoms. For example, alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0060] The term "alkynyl" refers to straight-chain or branched hydrocarbon groups containing one or more triple bonds, typically 2 to 20 carbon atoms in length. For example, "-C 2-6 alkynyl" contains 2 to 6 carbon atoms. For example, representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0061] The term "alkoxy" refers to an oxygen ether formed from the aforementioned alkyl groups, including, but not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CH2OCH3, -CH2CH2OCH3.

[0062] The term "haloalkoxy" as used herein, unless otherwise indicated, refers to the aforementioned alkoxy groups substituted with one or more (1, 2, 3, 4, 5, or 6) halogen (-F, -Cl, or -Br). In certain embodiments, haloalkoxy is interchangeable with -C 1-6 haloalkoxy or halo-C 1-6 alkoxy, wherein -C 1-6 haloalkoxy or halo-C 1-6 alkoxy, wherein -C 1-6 indicates that the total carbon atoms of the alkoxy group is 1 to 6. In certain embodiments, -C 1-6 haloalkoxy is -C 1-3 haloalkoxy. In certain embodiments, -C 1-6 haloalkoxy is (methoxy, ethoxy, propoxy, or isopropoxy) substituted with 1, 2, 3, 4, 5, or 6 -F; preferred -C 1-3 haloalkoxy is -OCF3.

[0063] The term "aryl" or "aromatic ring" as used herein, unless otherwise indicated, refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing only carbon ring atoms. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. For example, phenyl, naphthyl, and the like.

[0064] The term "heterocyclyl" or "heterocycle" as used herein, unless otherwise indicated, refers to a saturated or unsaturated non-aromatic ring system having ring carbon atoms and 1 or more ring heteroatoms, wherein each heteroatom is independently selected from one or more of nitrogen, oxygen, sulfur, boron, phosphorus and silicon, wherein optionally contains 0, 1, 2 or 3 double or triple bonds, which includes monocyclic heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl and spirocyclic heterocyclyl. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. In some embodiments, 4-8 membered heterocyclyl groups are preferred, which are 4 to 8 membered non-aromatic ring systems having ring carbon atoms and 1 or more ring heteroatoms; heterocyclyl also includes ring systems in which the above-mentioned heterocyclyl ring is fused with one or more cycloalkyl rings, wherein the point of attachment is on the heterocyclyl ring, or in which the above-mentioned heterocyclyl ring is fused with one or more aryl or heteroaryl rings, wherein the point of attachment is on the heterocyclyl ring; and in such cases the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. Heterocyclyl also includes ring systems in which the above-mentioned heterocyclyl ring, wherein any non-adjacent carbon or nitrogen atoms on which substituents are attached form a bridge ring, together form a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclyl also includes ring systems in which the above-mentioned heterocyclyl ring, wherein substituents on the same carbon atom are connected to form a ring, together form a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: aziridinyl, oxiranyl, thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to: pyrrolidinyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolinyl and pyrrol-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: pyrazolidinyl, dioxolanyl, oxathiolanyl, dithiolanyl and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: hexahydrotriazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azepinyl, oxepinyl and thiepinyl.

[0065] The term "heterocycloalkyl" as used herein, unless otherwise indicated, refers to a cyclic group having the specified number of ring atoms (e.g., 3-6 membered), the specified number of heteroatoms (e.g., 1, 2, or 3), the specified type of heteroatoms (1, 2, or 3 of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon), which is monocyclic, bridged cyclic, or spirocyclic, and each ring is saturated. Heterocycloalkyl groups include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, and piperidinyl, among others.

[0066] The term "heteroaryl" as used herein, unless otherwise indicated, denotes an aromatic ring system containing carbon and at least one heteroatom. The heteroatoms therein can be nitrogen, oxygen, or sulfur. The heteroaryl or heteroaromatic ring can be monocyclic or polycyclic, substituted or unsubstituted. Monocyclic heteroaryls can have from 1 to 4 heteroatoms in its ring, while polycyclic heteroaryls can include from 1 to 10 heteroatoms. The polycyclic heteroaryl ring can contain fused rings, for example, a bicyclic heteroaryl is a polycyclic heteroaryl. The bicyclic heteroaryl ring can contain from 8 to 12 ring atoms. The monocyclic heteroaryl ring can contain from 5 to 8 ring atoms (carbon atoms and heteroatoms). In some embodiments, the "heteroaryl" is monocyclic or bicyclic, and the heteroatoms are selected from one or more of nitrogen, oxygen, or sulfur, and the number of heteroatoms is 1, 2, 3, or 4. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adeninyl, quinolinyl, or isoquinolinyl.

[0067] The term "carbocyclyl" refers to a substituted or unsubstituted monocyclic, bicyclic, bridged cyclic, fused ring, spirocyclic non-aromatic ring system containing only carbon atoms. Preferably, the ring is three to ten membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two, or three, are included within the present definition. Carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0068] The term "cycloalkyl" refers to a saturated cyclic group having the specified number of ring carbon atoms (e.g., C3-C12, e.g., C3-C6), the ring atoms consisting only of carbon atoms.

[0069] The term "one or more" means one or more. In some embodiments, "one or more" means 1, 2, 3, 4, 5, or 6. In some embodiments, "one or more" means 1, 2, 3, or 4. In some embodiments, "one or more" means 1, 2, or 3. In some embodiments, "one or more" means 1 or 2. In some embodiments, "one or more" means 1. In some embodiments, "one or more" means 2. In some embodiments, "one or more" means 3. In some embodiments, "one or more" means 4. In some embodiments, "one or more" means 5. In some embodiments, "one or more" means up to 6.

[0070] In the present application, when a ring is substituted with one or more substituents, it means that each substituent can be independently substituted on each ring atom of the ring, including but not limited to a ring carbon atom or a ring nitrogen atom, respectively. In addition, when the ring is a polycyclic ring, such as a fused ring, a bridged ring, or a spiro ring, each substituent can be independently substituted on each ring atom of the polycyclic ring, respectively.

[0071] The term "oxo" means an oxygen and the carbon atom to which it is attached collectively form a group.

[0072] In the present application, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Thus, pharmaceutical compositions containing the compounds of the present application as an active ingredient, as well as methods of preparing the compounds of the present application, are part of the present application. Furthermore, some crystalline forms of the compounds can exist as polymorphs and are intended to be included in the present application. In addition, some of the compounds can form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are included within the scope of the present application.

[0073] The term "pharmaceutically acceptable salt" means a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the present application is acidic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic base, including inorganic bases and organic bases. When the compound of the present application is basic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic acid, including inorganic acids and organic acids. Since the compounds in the present application are intended for pharmaceutical use, they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% by weight).

[0074] The definition of any substituent or variable at a particular location in a molecule herein includes not only the explicit definition of such substituent or variable, but also includes all geometric and stereoisomers of the molecule. The definition of any substituent or variable at a particular location in a molecule herein also includes not only the explicit definition of such substituent or variable, but also includes the definition of any of its sub-variables. The definition of any substituent or variable at a particular location in a molecule herein is intended to independently represent any of its sub-variables and is independent of its definition at another position in the molecule. It is understood that one of ordinary skill in the art can select substituents and substitution patterns on the compounds of the application in order to produce compounds that are chemically stable, and can readily synthesize such compounds by techniques known in the art and as exemplified herein.

[0075] The compounds described herein can contain one or more asymmetric centers and can thus give rise to enantiomers and optical isomers. The present application includes all such possible enantiomers and optical isomers and racemic mixtures thereof. Isomers can be separated from mixtures of isomers by known techniques, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers can be prepared by asymmetric synthesis.

[0076] The present application includes all stereoisomers of the compounds and their pharmaceutically acceptable salts. In addition, mixtures of stereoisomers and isolated individual stereoisomers are also included. The products of the synthetic steps of the processes described herein can be in the form of a mixture of stereoisomers, or can be isolated to provide an individual stereoisomer.

[0077] The term "stereoisomers" as used herein means isomers that have the same sequence of atoms but differ in the spatial arrangement of their atoms. This term includes geometric isomers and optical isomers (also known as enantiomers and diastereomers). The present application includes all possible stereoisomers of the compounds.

[0078] Some of the compounds provided herein can exist as atropisomers, which are conformational stereoisomers that occur when rotation about a single bond in the molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule. The compounds provided herein include all atropisomers, including pure individual atropisomers, atropisomers enriched in each, or non-specific mixtures of atropisomers. Isolation of atropisomers can be permitted if the barrier to rotation about the single bond is sufficiently high and the interconversion between conformations is sufficiently slow.

[0079] The present application is intended to include all atom isotopes of the compounds of the present application. Isotopes are atoms with the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of hydrogen can be denoted as 1 H (hydrogen), 2 H (deuterium), and 3H (tritium). They are also commonly denoted as D (deuterium) and T (tritium). In the present application, CD3 means a methyl group in which all hydrogen atoms are deuterium. Isotopes of carbon include 13 C and 14 C. The isotopically-labeled compounds of the application can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.

[0080] The term "deuterated derivative" as used herein, unless otherwise indicated, means a compound having the same chemical structure as the reference compound, but with one or more hydrogen atoms replaced by deuterium atoms ("D"). It will be recognized that depending on the source of the chemical materials used in the synthesis, some variation in the natural isotopic abundance will occur in the synthesized compounds. The concentration of the naturally abundant stable hydrogen isotope, while small and insignificant, is compared to the degree of stable isotope substitution of the deuterated derivatives described herein. Thus, unless otherwise indicated, when reference is made to "deuterated derivatives" of the presently disclosed compounds, at least one hydrogen is replaced by deuterium in amounts substantially higher than its natural isotopic abundance (typically about 0.015%). In some embodiments, the presently disclosed deuterated derivatives have an isotopic enrichment factor of at least 3500 for each deuterium atom (containing 52.5% deuterium in each specified deuterium), at least 4500 (containing 67.5% deuterium), at least 5000 (containing 75% deuterium), at least 5500 (containing 82.5% deuterium), at least 6000 (containing 90% deuterium), at least 6333.3 (containing 95% deuterium), at least 6466.7 (containing 97% deuterium), or at least 6600 (containing 99% deuterium) for each deuterium atom.

[0081] When tautomers exist for the compounds of the application, the present application includes any and all tautomers, and pharmaceutically acceptable salts thereof, and mixtures thereof, unless otherwise indicated.

[0082] A "solvate" of a substance is a form of the substance that involves the attachment of one or more solvent molecules to the substance. Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.

[0083] The pharmaceutical compositions of the present application comprise a compound of the present application, a stereoisomer thereof, an atropisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of an atropisomer thereof, a pharmaceutically acceptable salt of a deuterated derivative thereof, or a solvate of any of the foregoing, as an active ingredient, together with a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the condition for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0084] In practice, the compounds of the present application, a stereoisomer thereof, an atropisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of an atropisomer thereof, a pharmaceutically acceptable salt of a deuterated derivative thereof, or a solvate of any of the foregoing, can be combined as active ingredients in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. Depending upon the particular route of administration, the pharmaceutical carrier can take a wide variety of forms, for instance, oral or parenteral (including intravenous) vehicle. Thus, the pharmaceutical compositions of the present application can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Alternatively, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil emulsion. In addition to the common dosage forms set out above, the compounds represented by Formula I, a stereoisomer thereof, an atropisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of an atropisomer thereof, a pharmaceutically acceptable salt of a deuterated derivative thereof, or a solvate of any of the foregoing, can be administered by controlled release means and / or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step wherein the active ingredient is in combination with the carrier or carriers which constitute one or more necessary ingredients. Generally, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. The compositions of the present application can be administered in a form suitable to

[0085] Accordingly, the pharmaceutical composition of the present application can include a compound, a stereoisomer thereof, an atropisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of an atropisomer thereof, a pharmaceutically acceptable salt of a deuterated derivative thereof, or a solvate of any of the foregoing, and a pharmaceutically acceptable carrier. The compound of Formula (I), (II), (III), (I-1), (I-2), (I-1-1), (I-1-2), or a stereoisomer thereof, an atropisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of an atropisomer thereof, a pharmaceutically acceptable salt of a deuterated derivative thereof, or a solvate of any of the foregoing, can also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0086] The pharmaceutical carrier used can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, or stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil, or water. Examples of gaseous carriers include carbon dioxide or nitrogen. In making a composition for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycol, oil, alcohol, flavoring agents, preservatives, coloring agents, and the like can be used to form oral liquid preparations such as suspensions, solutions, and elixirs; while starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules, and tablets. Because of their ease in administration, tablets and capsules are preferred oral dosage units, and the use of solid pharmaceutical carriers is preferred. Alternatively, the tablets can be coated by standard aqueous or nonaqueous techniques.

[0087] Tablets containing the compositions of the present application are made by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient. Each cachet or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient. For instance, a formulation for oral administration to humans can contain from about 0.5 mg to about 5 g of active agent mixed with appropriate and convenient amounts of carriers, solvents, fillers, buffers, diluents, surface active or dispersing agents, etc. The carriers, solvents, fillers, buffers, diluents, surface active agents, dispersants etc. can make up from about 0.05 to about 95% of the total composition, more typically from about 5 to 90%. Unit dosage forms will generally contain between about 0.01 mg and about 2 g, typically 0.01 mg, 0.02 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1500 mg or 2000 mg of the active ingredient.

[0088] Pharmaceutical compositions of the present application suitable for parenteral administration can be formulated as solutions or suspensions of the active compounds in water. Suitable surfactants such as hydroxypropylcellulose can be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Moreover, a preservative can be included to prevent the detrimental growth of microorganisms.

[0089] Pharmaceutical compositions of the present application suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy of syringeability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycols), vegetable oils, and

[0090] The pharmaceutical compositions of the present application can be in a form suitable for topical use, such as an aerosol, cream, ointment, lotion, powder, or the like. These formulations are prepared by combining the compounds of the present application or a pharmaceutically acceptable salt thereof with the conventional preparations used for topically administering drugs. For example, creams and ointments are prepared by mixing the active compound with the alcohol and water, in about 0.05 wt% to about 10 wt% of the compound, to produce a cream or ointment having the desired consistency.

[0091] The pharmaceutical compositions of this application can be in a form suitable for rectal administration wherein the carrier is a solid. Exemplary suitable carriers include cacao butter and other materials used in the manufacture of suppositories. A suppository is formed by mixing the composition with a non-irritating excipient which is solid at room temperature, but liquid at body temperature and therefore will melt in the rectum to release the active components. This formulation is then introduced into the rectum, for example, by means of a suppository. Examples of suitable excipients include cocoa butter and other glycerides.

[0092] In addition to the carrier ingredients, the pharmaceutical formulations described above can include one or more additional ingredients such as diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like. Further, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound, a stereoisomer thereof, a atropisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a atropisomer thereof, a pharmaceutically acceptable salt of a deuterated derivative thereof, or a solvate of any of the foregoing, can also be prepared in powder or liquid concentrate form.

[0093] Generally, dosage levels of the order of from about 0.001 mg to about 150 mg / kg of body weight per day are useful in the treatment of the above -indicated conditions, or about 0.05 mg to about 7 g per patient per day of the active therapeutic ingredient. For example, oral dosages of the compounds in the range of from about 0.001 to 50 mg per kilogram of body weight per day, or about 0.05 mg to about 3.5 g per kilogram of body weight per day, are useful in the treatment of diseases or conditions mediated by the inhibition of Nrf2 through the activation of KEAP1, such as, but not limited to, non-small cell lung cancer (NSCLC), liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, melanoma, stomach cancer, prostate cancer, lymphoma, leukemia, or myelodysplastic syndrome (MDS).

[0094] It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease being treated.

[0095] Unless otherwise indicated, when a value is expressed as "about" X or "approximately" X, the stated value of X will be understood to be accurate to ±10%, preferably ±5%, ±2%.

[0096] These and other aspects will become apparent from the following written description of the application. DETAILED DESCRIPTION

[0097] The compounds of the present application can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. The examples outlining specific synthetic routes are intended to provide guidance to synthetic chemists in the art who will readily appreciate that the solvents, concentrations, reagents, protecting groups, order of synthetic steps, times, temperatures, and the like, can be modified as is routine practice in the art, within the skill and judgment of the artisan. The abbreviations in the following table are used in the examples:

[0098] Examples 1 to 4

[0099] Compound 1, Compound 2, Compound 3 and Compound 4 were synthesized respectively, the specific process as follows.

[0100] Preparation of Compound 1

[0101] First step

[0102] Compound 1-1 (26.6 g, 100 mmol) was added to 500 mL round bottom flask with 18% hydrochloric acid (200 mL) and cooled to 0 °C. NaNO2(8.3 g, 120 mmol) was dissolved in 100 mL water and slowly added to the above mixture, stirred at 0 °C for 1 hr. SnCl2(37.8 g, 200 mmol) was dissolved in 50 mL concentrated hydrochloric acid, the solution was added to the reaction liquid at 0 °C, and stirred at room temperature for 2 hrs. Filtration and drying gave brown solid 1-2 (17 g). LCMS [M+H] + = 221.1.

[0103] Second step

[0104] 1-2 (30 mmol, 7.74 g), Et3N (6.1 g, 60 mmol) and DCM (100 mL) were added to a 250 mL round bottom flask and cooled to 0 °C, (Boc)2O (13.1 g, 60 mmol) was slowly added, and stirred at room temperature overnight. The solvent was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain white solid 1-3 (7.8 g). LCMS [M+H-56] + = 266.1.

[0105] Third step:

[0106] 1-3 (6.4 g, 20 mmol) and DMF (100 mL) were added to a 250 mL round bottom flask, Cs2CO3(19.5 g, 60 mmol) was added, and stirred at room temperature overnight. 20 mL water was added to quench, and extracted three times with DCM (3 x 20 mL), the organic phase was dried with sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was separated by column chromatography to obtain yellow oil 1-4 (5.0 g). LCMS [M+H-56]+ = 319.2.

[0107] Fourth Step:

[0108] Compound 1-4 (2.8 g, 7.5 mmol) was dissolved in DCM (10 mL) and cooled to 0 °C, TFA (5 mL) was added slowly to the above solution, then warmed to room temperature and stirred for 30 mins. The volatile components were concentrated under reduced pressure, DCM (10 mL) and Et3N (2.2 g, 22.5 mmol) were added and cooled to 0 °C, acryloyl chloride (1.35 g, 15 mmol) was added, the temperature was restored to room temperature and stirred for 1 hr. H2O (20 mL) was added to the reaction, DCM (3 x 10 mL) was extracted, the organic phase was dried with sodium sulfate, and the resulting crude product was purified by column chromatography to obtain yellow oil 1-5 (1.5 g). LCMS [M+H] + = 329.6.

[0109] Fifth Step

[0110] 1-5 (2.1 g, 6.4 mmol), (Bpin)2 (2.4 g, 9.6 mmol), AcOK (1.25 g, 12.8 mmol) and Pd(dppf)Cl2·CH2Cl2(522 mg, 0.6 mmol) were added to a 25 mL flask, the flask was replaced with nitrogen three times, then 1,4-dioxane (10 mL) was added, and the temperature was raised to 100 °C and stirred overnight. The reaction was cooled to room temperature, 10 mL of water was added, and EtOAc (3 x 10 mL) was extracted three times, the organic phase was dried with sodium sulfate, and the resulting crude product was separated by column chromatography to obtain yellow solid 1-6 (1.5 g). LCMS [M+H] + = 377.5.

[0111] Sixth Step

[0112] 1-6 (189 mg, 0.5 mmol), 1a (65 mg, 0.5 mmol), Na2CO3 (106 mg, 1.0 mmol) and Pd(dppf)Cl2(41 mg, 0.05 mmol) were added to a 15 mL reaction tube, replaced with nitrogen three times, then 1,4-dioxane / H2O (2 mL / 0.4 mL) was added, and the temperature was raised to 100 °C and stirred overnight. The reaction was cooled to room temperature, 5 mL of water was added, and EtOAc (3 x 5 mL) was extracted three times, the organic phase was dried with sodium sulfate, and the resulting crude product was separated by column chromatography to obtain white solid 1 (55 mg). LCMS [M+H] + = 344.5. 1H NMR (400 MHz, CDC13) δ 8.26 (s, 2H), 7.86 (t, J = 1.6 Hz, 1H), 7.76 - 7.66 (m, 1H), 6.84 (t, J = 2.2 Hz, 1H), 6.76 (dd, J = 17.1, 10.3 Hz, 1H), 6.47 (dd, J = 17.1, 2.2 Hz, 1H), 5.70 (dd, J = 10.4, 2.2 Hz, 1H), 4.56 (dd, J = 12.5, 3.4 Hz, 1H), 4.34 - 4.10 (m, 1H), 3.84 (s, 2H), 3.27 (ddd, J = 14.8, 12.1, 2.7 Hz, 1H), 3.09 - 2.83 (m, 1H), 1.90 - 1.58 (m, 4H).

[0113] Preparation of compound 2

[0114] To a solution of 1-6 (189 mg, 0.5 mmol), 2a (99 mg, 0.5 mmol), Na2C03(106 mg, 1.0 mmol) and Pd(dppf)Cl2(41 mg, 0.05 mmol) in 15 mL reaction tube, 1,4-dioxane / H20 (2 mL / 0.4 mL) was added after purging with nitrogen for three times, and then the mixture was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature, 5 mL water was added, and the mixture was extracted with EtOAc (3 x 5 mL) three times. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was separated by column chromatography to give white solid 2 (50 mg). LCMS [M+H] + = 368.3. 1 H NMR (400 MHz, CDC13) δ 8.26 (s, 2H), 7.86 (t, J = 1.6 Hz, 1H), 7.76 - 7.66 (m, 1H), 6.84 (t, J = 2.2 Hz, 1H), 6.76 (dd, J = 17.1, 10.3 Hz, 1H), 6.47 (dd, J = 17.1, 2.2 Hz, 1H), 5.70 (dd, J = 10.4, 2.2 Hz, 1H), 4.56 (dd, J = 12.5, 3.4 Hz, 1H), 4.34 - 4.10 (m, 1H), 3.84 (s, 2H), 3.27 (ddd, J = 14.8, 12.1, 2.7 Hz, 1H), 3.09 - 2.83 (m, 1H), 1.90 - 1.58 (m, 4H).

[0115] Preparation of compound 3

[0116] To a solution of 1-6 (189 mg, 0.5 mmol), 3a (99 mg, 0.5 mmol), Na2C03(106 mg, 1.0 mmol) and Pd(dppf)Cl2(41 mg, 0.05 mmol) in 15 mL reaction tube, 1,4-dioxane / H20 (2 mL / 0.4 mL) was added after purging with nitrogen for three times, and the mixture was stirred at 100 °C overnight. The reaction was cooled to room temperature, 5 mL water was added, and the mixture was extracted with EtOAc (3 x 5 mL) three times. The organic phase was dried over Na2S04and concentrated under reduced pressure to give the crude product, which was separated by column chromatography to give white solid 3 (60 mg). LCMS [M+H] + = 371.5. 1 H NMR (400 MHz, CDC13) δ 8.82 (d, J = 5.0 Hz, 1H), 8.05 (s, 1H), 7.58 (dd, J = 5.0, 1.6 Hz, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 6.90 (s, 1H), 6.75 (dd, J = 17.1, 10.4 Hz, 1H), 6.48 (dd, J = 17.1, 2.1 Hz, 1H), 6.34 (s, 1H), 5.91 (s, 1H), 5.72 (dd, J = 10.3, 2.1 Hz, 1H), 4.63 - 4.51 (m, 1H), 4.32 - 4.12 (m, 1H), 3.33 - 3.18 (m, 1H), 3.04 - 2.81 (m, 1H), 1.93 - 1.65 (m, 4H).

[0117] Preparation of intermediate 4-3

[0118] First step:

[0119] To a solution of 4-1 (1.3 g, 10 mmol), MeSNa (700 mg, 10 mmol) and DMF (30 mL) in 50 mL reaction bottle, it was stirred at room temperature overnight. 30 mL water was added, and the mixture was extracted with EtOAc (3 x 30 mL) three times. The organic phase was dried over Na2S04and concentrated under reduced pressure to give the crude product, which was separated by column chromatography to give yellow oil 4-2 (1.1 g). LCMS [M+H] + = 160.2.

[0120] Second step:

[0121] 4-2 (798 mg, 5 mmol) was taken in 5 mL reaction vial, Phl(OAc)2(4 g, 12.5 mmol) and (NH4)2CO3(720 mg, 7.5 mmol) were added, stirred at room temperature for 2 hrs. 3 mL water was added, extracted with DCM (3 x 3 mL) three times, organic phase was dried over sodium sulfate, concentrated under reduced pressure to get crude product which was separated by column chromatography to get yellow solid 4-3 (591 mg). LCMS [M+H] + = 191.3.

[0122] Preparation of compound 4

[0123] 1-6 (189 mg, 0.5 mmol), 4-3 (95 mg, 0.5 mmol), Na2CO3(106 mg, 1.0 mmol) and Pd(dppf)Cl2(41 mg, 0.05 mmol) were taken in 15 mL reaction tube, purged with nitrogen three times, 1,4-dioxane / H2O (2 mL / 0.4 mL) was added, temperature was raised to 100 °C and stirred overnight. The reaction was cooled to room temperature, 5 mL water was added, extracted with EtOAc (3 x 5 mL) three times, organic phase was dried over sodium sulfate, concentrated under reduced pressure to get crude product which was separated by column chromatography to get white solid 4 (35 mg). LCMS [M+H] + = 405.6. 1 H NMR (400 MHz, CDC13) δ 8.92 (d, J = 5.0 Hz, 1H), 8.24 - 8.17 (m, 1H), 7.82 (dd, J = 5.0, 1.6 Hz, 1H), 7.49 (dt, J = 9.2, 1.7 Hz, 2H), 6.93 (t, J = 2.1 Hz, 1H), 6.74 (dd, J = 17.1, 10.3 Hz, 1H), 6.49 (dd, J = 17.1, 2.1 Hz, 1H), 5.72 (dd, J = 10.4, 2.1 Hz, 1H), 4.65 - 4.52 (m, 1H), 4.33 - 4.09 (m, 1H), 3.43 - 3.24 (m, 1H), 3.17 (s, 3H), 3.03 - 2.83 (m, 1H), 1.91 - 1.61 (m, 4H).

[0124] Examples 5 to 8

[0125] Using similar procedure as in example 1, compounds 5 to 8 were synthesized using intermediate 1-6 and respective aryl halide, details are given in table 1.

[0126] Table 1: Synthesis of compounds 5-8

[0127] Example 9

[0128] Synthesis of compound 9

[0129] First step

[0130] Compound 2-1 (5 g, 18.26 mmol) was taken in 500 mL round bottom flask with EtOH (200 mL), 85% N2H4.H2O (5.38 g, 91.28 mmol) was added, warmed to 100 °C and refluxed overnight. The resulting crude product was concentrated under reduced pressure and purified by column chromatography to get brown solid 2-2 (1.01 g). LCMS [M+H] = 179.6. +

[0131] Second step

[0132] 2-2 (1 g, 5.62 mmol), Et3N (1.71 g, 16.85 mmol) was taken in 25 mL round bottom flask with THF (10 mL) and cooled to 0 °C, (Boc)2O (868.59 mg, 6.18 mmol) was added slowly and stirred at room temperature overnight. The solvent was concentrated under reduced pressure to get crude product which was purified by column chromatography to get white solid 2-3 (509 mg). LCMS [M+H] = 283.2. +

[0133] Third step:

[0134] 2-3 (500 mg, 1.80 mmol), dibromobutane (388.6 mg, 1.8 mmol) was taken in 25 mL round bottom flask with DMF (10 mL), Cs2CO3 (426.97 mg, 1.98 mmol) was added and stirred at room temperature for 2 hr. 10 mL saturated brine was added to quench, extracted with EtOAc (3 x 10 mL) three times, the organic phase was dried over sodium sulfate and concentrated under reduced pressure to get crude product which was separated by column chromatography to get yellow solid 2-4 (372 mg). LCMS [M+H] = 333.2. +

[0135] Fourth step:

[0136] ​​​Compound 2-4 (350 mg, 1.05 mmol) was dissolved in DCM (4 mL) and cooled to 0 °C, TFA (2 mL) was added slowly to above solution and then raised to room temperature and stirred for 1 hr. Volatile components were concentrated under reduced pressure, DCM (6 mL) and Et3N (544.97 mg, 5.39 mmol) were added and cooled to 0 °C, acryloyl chloride (194.97 mg, 2.15 mmol) was added, stirred at room temperature for 1 hr. H2O (20 mL) was added to the reaction, extracted with DCM (3 x 10 mL), organic phase was dried over sodium sulfate and concentrated under reduced pressure to get the crude product which was purified by column chromatography to get white solid 2-5 (120 mg). LCMS [M+H] + = 286.2.

[0137] Fifth step

[0138] Compound 2a (100 mg, 0.5 mmol), hexamethylditin (179.28 mg, 0.55 mmol) and Pd(PPh3)4 (114.97 mg, 0.1 mmol) were taken in 8 mL reaction tube, toluene (2 mL) was added and then purged with nitrogen and sealed, temperature was raised to 120 °C and stirred overnight. The reaction was cooled to room temperature, 5 mL of aqueous potassium fluoride solution was added, extracted with EtOAc (3 x 5 mL), organic phase was dried over sodium sulfate and concentrated to get the crude product which was taken in 2-5 (50 mg, 0.17 mmol), Pd(PPh3)4 (40.38 mg, 0.03 mmol) in 8 mL reaction tube, toluene (2 mL) was added and then purged with nitrogen, temperature was raised to 100 °C and stirred overnight. 5 mL of aqueous potassium fluoride solution was added, extracted with EtOAc (3 x 5 mL), organic phase was dried over sodium sulfate to get the crude product which was separated by HPLC to get white solid - compound 9 (11 mg), LCMS [M+H] + = 372.8. 1 H NMR (400 MHz, CDC13) δ 8.68 (d, J = 5.1 Hz, 1H), 8.62 (s, 1H), 8.16 (d, J = 4.4 Hz, 1H), 7.92 (s, 1H), 7.19 (d, J = 1.8 Hz, 1H), 6.78 (d, J = 1.9 Hz, 1H), 6.57 - 6.51 (m, 2H), 5.78 (dd, J = 7.5, 4.8 Hz, 1H), 5.67 (s, 1H), 4.64 (dd, J = 13.7, 3.1 Hz, 1H), 4.20 (d, J = 14.4 Hz, 1H), 3.43 - 3.22 (m, 1H), 3.01 - 2.79 (m, 1H), 1.39 - 1.13 (m, 4H).

[0139] Examples 10-13

[0140] Synthesized using a similar method to Example 9, using intermediate 2-5 coupled with the corresponding aryl stannane reagent, as detailed in Table 2.

[0141] Table 2. Synthesis of compounds 10-13

[0142] Example 14

[0143] Into a 15 mL reaction tube was added 1-6 (300 mg, 0.8 mmol), 5a (207 mg, 1.6 mmol), Na2CO3(170 mg, 1.6 mmol) and Pd(dppf)Cl2(59 mg, 0.08 mmol), after three nitrogen purges 1,4-dioxane / H2O (5 mL / 1 mL) was added and the reaction was stirred at 80 °C overnight. The reaction was cooled to room temperature, 10 mL water was added and the reaction was extracted with EtOAc (3 x 10 mL) three times, the organic phase was dried over sodium sulfate and the crude product was separated by HPLC to give 14 as a light yellow solid (48 mg). LCMS [M+H] = 344.2. + 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 5.8 Hz, 1H), 7.89 - 7.77 (m, 1H), 7.75 - 7.63 (m, 1H), 7.04 (t, J = 2.0 Hz, 1H), 6.98 (s, 2H), 6.69 (dd, J = 17.1, 10.3 Hz, 1H), 6.38 (d, J = 5.8 Hz, 1H), 6.29 (dd, J = 17.1, 2.3 Hz, 1H), 5.75 (dd, J = 10.4, 2.3 Hz, 1H), 4.34 (d, J = 12.9 Hz, 1H), 4.25 (d, J = 14.3 Hz, 1H), 3.22 - 3.13 (m, 1H), 2.84 - 2.75 (m, 1H), 1.74 - 1.51 (m, 4H).

[0144] Activity test example

[0145] 1. Cell activity

[0146] Test method:

[0147] ​The KYSE70 cells in logarithmic growth phase were placed in each well at a cell number of 3000 per well, and 90 μL of cell suspension was used. After 24 h of culture, the compound was diluted with DMSO to 3 mM, 3-fold gradient dilution, 9 concentration points, and DMSO was used as a negative control. The above compound was further diluted 100 times with RPMI-1640 medium, and the compound molecules were added to the medium in the well at 10 μM per well, so that the final dilution effect was 1000 times. The final concentration of the compound was 3 μM, 3-fold dilution of 9 concentration points, and the cell group containing 0.1% DMSO was set as a solvent control group, and the blank control group only contained medium and 0.1% DMSO, and three replicates were set for each concentration of the compound and the control well. The cells were placed back into the cell incubator for about 1.5 h, and the OD value at 450 nm was read using an enzyme-labeled instrument. The inhibition rate was calculated according to the following formula, the inhibition curve was drawn by Graphpad Prism software, and the EC 50 .

[0148] The experimental result calculation formula: cell inhibition rate = [(solvent control well-test compound well) / (solvent control well-blank control well)] x 100%.

[0149] The results are shown in Table 3, A represents EC 50 <50 nM, B represents EC 50 = 50 nM-500 nM, C represents EC 50 > 500 nM.

[0150] Among them, the structures of Comparative Examples 1 to 3 are as follows, and the synthesis method refers to WO2024073587A1.

[0151] Table 3 KYSE70 cell activity data

[0152] The results show that the compound of the present application has significantly high inhibitory activity on KYSE70 Cell cancer cells.

[0153] 2. Mouse pharmacokinetic test

[0154] Test method:

[0155] Three ICR mice (male) were needed for each compound. The mice were treated with a single 10 mg / kg dose of compound (oral). For each mouse, blood samples were collected at time points of 0.5, 1, 2, 4 and 8 hours after administration. The whole blood sample was placed into a test tube containing EDTA-K2, inverted several times, and then centrifuged at 6000 rpm, 4°C for 15 minutes to obtain plasma. The concentration of the compound in the plasma sample was determined using the LC-MS / MS method.

[0156] Table 4 Pharmacokinetic data

[0157] The results are shown in Table 4, the absorption rate in vivo, the elimination rate in vivo and the total absorption amount of the compound of the present application are obviously higher than those of the comparative example.

[0158] 3. Liver microsomal stability

[0159] Test method:

[0160] Preparation of compound working solution: prepare 10 mM DMSO stock solution of test substance and control compound verapamil (i.e. Varapamil), dilute to 200 μM working solution with acetonitrile before test, the final concentration of test substance and verapamil is 1 μM.

[0161] Preparation of phosphate buffer: weigh 7.098 g of disodium hydrogen phosphate, add 500 mL of pure water and ultrasonically dissolve. Weigh 3.400 g of potassium dihydrogen phosphate, add 250 mL of pure water and ultrasonically dissolve. Adjust the pH to 7.4±0.2.

[0162] Preparation of 10 mM NADPH: weigh an appropriate amount of NADPH (reduced coenzyme II), freshly prepare a working solution with a concentration of 10 mM in phosphate buffer, and the final concentration is 1 mM.

[0163] Preparation of incubation system: prepare the suspension according to Table 5 into the incubation plate, pre-incubate in a 37°C water bath for 10 min.

[0164] Table 5 Configuration table of incubation system

[0165] Test: add 2 μL of positive control or test compound working solution to 358 μL of incubation system, vortex mix uniformly, all samples are prepared in duplicate. Add 40 μL of 10 mM NADPH to the system, vortex mix uniformly at low speed, start the reaction timing, take 50 μL of the above suspension at 0.5, 5, 10, 15, 30, 60 min, add 400 μL of acetonitrile (containing 100 ng / ml dexamethasone) termination solution, vortex mix uniformly. Centrifuge at 4700 rpm, 4°C for 15 min to precipitate the protein. Transfer 100 μL of supernatant to the injection plate, add 100 μL of pure water and mix, for UPLC-MS / MS analysis, the results are shown in Table 6.

[0166] Table 6 Liver microsomal stability results

[0167] The results show that the metabolic stability of most of the compounds of the present application is much higher than that of Comparative Example 2. In addition, the clearance of some of the compounds of the present application in human liver microsomes is less than 10 μL / min / mg, which has very good drug properties; while that of Comparative Example 2 is as high as 235 μL / min / mg, and is very metabolically unstable.

[0168] 4. Rat PK test

[0169] Test method

[0170] Three SD rats (male) were needed for each compound. The rats were treated with a single dose of 25 mg / kg (oral gavage). For each rat, blood samples were collected at time points of 0.083, 0.25, 0.5, 1, 2, 4, 8 hours after dosing. The whole blood samples were put into tubes containing EDTA-K2, inverted several times, and then centrifuged at 6000 rpm, 4°C for 15 minutes to obtain plasma. The concentration of the compound in the plasma sample was determined using the LC-MS / MS method.

[0171] Calculation formula

[0172] According to the bioanalysis data, the pharmacokinetic parameters were calculated by WinNonlin Phoenix (Pharsight Corporation) software using the method of non-compartment model analysis. The specific results are shown in Table 7.

[0173] Table 7 Rat PK results

[0174] .

[0175] It should be understood that, if the present application refers to any prior art publication; such reference does not constitute an admission that the publication forms part of the common general knowledge of the prior art in any country.

[0176] All publications, patents, patent applications and published patent applications referred to herein are hereby incorporated by reference in their entirety.

[0177] Although the foregoing application has been described in some detail by way of illustration and example for purposes of clarity and understanding, certain changes and modifications will be obvious to those skilled in the art. Therefore, the description and examples should not be construed as limiting the scope of the application.

Claims

1. A compound of formula (I), a stereoisomer thereof, an atropisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of an atropisomer thereof, a pharmaceutically acceptable salt of a deuterated derivative thereof, or a solvate of any of the foregoing: in, Ring A is an aryl group, a heteroaryl group or a heterocyclic group; Each R1 is independently H, halogen, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy, or -C(=O)N(R 1a )2, or two R1 together with the atoms to which they are attached form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 3 to 8 membered heterocycloalkyl; each R 1a are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently optionally substituted with one, two or three -OH, C1-C6 alkyl or C1-C6 haloalkyl; or two R 1a Together with the nitrogen atom to which they are attached, they form a heterocycloalkyl group, which is optionally substituted with one, two or three C1-C6 alkyl groups or C1-C6 haloalkyl groups; each R2 is independently H, halogen, -CN, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, or optionally substituted C1-C6 alkoxy; Each R3 is independently H, halogen, -NH2, -NHR 3a 、-N(R 3a )2, oxo (=O), thio (=S), -CN, -OH, -OR 3a 、-SH、-SR 3a 、-S(=O)R 3a 、-S(=O)(=NH)R 3a , -SH(=O)(=NH), -NO2, -S(=O)2R 3a 、-NHS(=O)2R 3a 、-S(=O)2N(R 3a )2, -C(=O)R 3a 、-C(=O)OR 3a 、-C(=O)NH2、-C(=O)NHR 3a 、-OC(=O)N(R 3a )2、-N(R 3a )C(=O)N(R 3a )2、-N(R 3a )C(=O)R 3a 、-N(R 3a )C(=O)OR 3a , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C8 cycloalkyl or optionally substituted 4- to 8-membered heterocycloalkyl; or two R3 are taken together with the atoms to which they are attached to form an optionally substituted aryl, an optionally substituted heteroaryl ring or an optionally substituted heterocycloalkyl; each R 3a R is independently C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C1-C6 alkylaryl, -C1-C6 alkylheteroaryl, -C1-C6 alkylcycloalkyl or -C1-C6 alkylheterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one, two or three -OH, C1-C6 alkyl or C1-C6 haloalkyl; when R3 is H, it means that ring A is not substituted; R4 is and R4a is H, D, halogen or C1-C6 haloalkyl; p and q are each independently 0, 1, 2 or 3; m is an integer from 1 to 12; n is an integer from 1 to 10; X1 is N or CR2; X2 is -O-, -S(=O)2-, -C(R1)2- or -NR5; R5 is H, -C(=O)R 5a 、-S(=O)R 5a or -S(=O)2R 5a ; where R 5a is H, optionally substituted C1-C6 alkyl or optionally substituted C3-C7 cycloalkyl.

2. The compound according to claim 1, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, its pharmaceutically acceptable salt of its atropisomer, its pharmaceutically acceptable salt of its deuterated derivative, or a solvate of any of the foregoing, characterized in that: The compound has the structure of the following formula (I-1) or (I-2):

3. The compound according to claim 1 or 2, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, its pharmaceutically acceptable salt of its atropisomer, its pharmaceutically acceptable salt of its deuterated derivative, or a solvate of any of the foregoing, characterized in that: p and q are each independently 0, 1 or 2.

4. The compound according to claim 1, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, its pharmaceutically acceptable salt of its atropisomer, its pharmaceutically acceptable salt of its deuterated derivative, or a solvate of any of the foregoing, characterized in that: The compound has the structure of the following formula (I-1-1) or formula (I-1-2):

5. The compound according to any one of claims 1 to 4, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of a stereoisomer, its pharmaceutically acceptable salt of an atropisomer, its pharmaceutically acceptable salt of a deuterated derivative, or a solvate thereof, characterized in that: Ring A is a 5-6 membered monocyclic heteroaryl group or an 8-10 membered bicyclic heteroaryl group, wherein the heteroatom is N and the number of heteroatoms is 1, 2 or 3; preferably, Ring A is a 6 membered monocyclic heteroaryl group, wherein the heteroatom is N and the number of heteroatoms is 2.

6. The compound according to any one of claims 1 to 4, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of a stereoisomer, its pharmaceutically acceptable salt of an atropisomer, its pharmaceutically acceptable salt of a deuterated derivative, or a solvate of any one of the foregoing, characterized in that: Ring A is the following structure:

7. The compound according to any one of claims 1 to 4, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, its pharmaceutically acceptable salt of its atropisomer, its pharmaceutically acceptable salt of its deuterated derivative, or a solvate of any one of the foregoing, characterized in that: Ring A is the following structure: The end marked with "#" indicates the connected; Ring A is preferably 8. The compound according to any one of claims 1 to 7, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of a stereoisomer, its pharmaceutically acceptable salt of an atropisomer, its pharmaceutically acceptable salt of a deuterated derivative, or a solvate of any one of the foregoing, characterized in that: Each R1 is independently H, halogen, -OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or -C(=O)N(R 1a )2, or two R1 together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl; each R 1a are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C6-C8 aryl, or C5-C8 heteroaryl, or two R 1a Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered heterocycloalkyl group, which is optionally substituted by one, two or three C1-C6 alkyl or C1-C6 haloalkyl; wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C(=O)N(R1a)2 in the R1 options are independently optionally substituted by one, two or three -OH, halogen or C1-C3 alkoxy.

9. The compound according to any one of claims 1 to 7, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of a stereoisomer, its pharmaceutically acceptable salt of an atropisomer, its pharmaceutically acceptable salt of a deuterated derivative, or a solvate of any one of the foregoing, characterized in that: Each R1 is independently H, F, Br, Cl, C1-C3 alkyl or -C(=O)N(R 1a )2, C1-C3 alkyl is optionally substituted by one, two or three F, Br, C1, C1-C3 alkyl, each R 1a are independently H, C1-C6 alkyl; Preferably, each R1 is independently H, F, -CH3 or -CHF2, preferably H.

10. The compound according to any one of claims 1 to 9, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of a stereoisomer, its pharmaceutically acceptable salt of an atropisomer, its pharmaceutically acceptable salt of a deuterated derivative, or a solvate thereof, characterized in that: Each R2 is independently F, Br or Cl, preferably Cl.

11. The compound according to any one of claims 1 to 9, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of a stereoisomer, its pharmaceutically acceptable salt of an atropisomer, its pharmaceutically acceptable salt of a deuterated derivative, or a solvate of any one of the foregoing, characterized in that: Each R3 is independently H, halogen, -NH2, -NHR 3a 、-N(R 3a )2, -C(=O)NH2, -C(=O)NH(C1-C3 alkyl), -C(=O)N(C1-C3 alkyl)2, -SH(=O)(=NH) or -S(=O)(=NH)R 3a , each R 3a are independently C1-C6 alkyl.

12. The compound according to any one of claims 1 to 9, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of a stereoisomer, its pharmaceutically acceptable salt of an atropisomer, its pharmaceutically acceptable salt of a deuterated derivative, or a solvate of any one of the foregoing, characterized in that: Each R3 is independently H, F, -NH2, -C(=O)NH2, -S(=O)(=NH)CH3, -S(=O)(=NH)CH2CH3, -S(=O)(=NH)CH2CH2CH3 or -S(=O)(=NH)CH(CH3)2, preferably -NH2 or -C(=O)NH2.

13. The compound according to any one of claims 1 to 12, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of a stereoisomer, its pharmaceutically acceptable salt of an atropisomer, its pharmaceutically acceptable salt of a deuterated derivative, or a solvate of any one of the foregoing, characterized in that: Ring A and R2 are located at any two positions of the 1st, 3rd or 5th position of the ring; Preferably, for 14. The compound according to any one of claims 1 to 12, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of a stereoisomer, its pharmaceutically acceptable salt of an atropisomer, its pharmaceutically acceptable salt of a deuterated derivative, or a solvate of any one of the foregoing, characterized in that: When there is chiral carbon in the compound, it is in R configuration or S configuration.

15. The compound according to any one of claims 1 to 14, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of a stereoisomer, its pharmaceutically acceptable salt of an atropisomer, its pharmaceutically acceptable salt of a deuterated derivative, or a solvate of any one of the foregoing, characterized in that: The compound has any of the following structures:

16. The compound according to any one of claims 1 to 15, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of a stereoisomer, its pharmaceutically acceptable salt of an atropisomer, its pharmaceutically acceptable salt of a deuterated derivative, or a solvate of any one of the foregoing, characterized in that: The atoms in the compound, its stereoisomers, its atropisomers, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts of its stereoisomers, its pharmaceutically acceptable salts of its atropisomers, or a solvate of any thereof are atoms at natural abundance.

17. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any one of claims 1 to 16, its stereoisomers, its atropisomers, its deuterated derivatives, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts of stereoisomers, its pharmaceutically acceptable salts of atropisomers, its pharmaceutically acceptable salts of deuterated derivatives, or a solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients.

18. Use of a compound according to any one of claims 1 to 16, a stereoisomer thereof, an atropisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of an atropisomer thereof, a pharmaceutically acceptable salt of a deuterated derivative thereof, or a solvate of any of the foregoing, or a pharmaceutical composition according to claim 17, in the preparation of a medicament for preventing and / or treating cancer; preferably, the cancer is non-small cell lung cancer, liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, prostate cancer, lymphoma, leukemia, or myelodysplastic syndrome; the esophageal cancer is, for example, esophageal squamous cell carcinoma.

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