Compound, pharmaceutical composition comprising same, and use thereof

Abstract

Provided in the present application are a compound, a pharmaceutical composition comprising same, and a use thereof. The compound has a structure as represented by formula I.

Description

A compound, a pharmaceutical composition comprising the same and uses thereof

[0001] REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese patent application CN202411303182.X filed on September 18, 2024, the contents of which are incorporated by reference in their entirety and for all purposes. TECHNICAL FIELD

[0003] The present application relates to the field of biological medicine, in particular to a compound, a pharmaceutical composition comprising the same and uses thereof. BACKGROUND

[0004] DNA strands are negatively charged, and nucleosomes are composed of charged histones, which are usually combined together due to charge attraction, and the interaction needs to be disengaged in the process of DNA replication and transcription, which requires the function of chromatin remodeling complexes. SWI / SNF complex is a kind of chromatin remodeling complex, which can use the energy of ATP hydrolysis to realize the coordinated mobilization of nucleosomes and DNA.

[0005] The SWI / SNF complex of mammals is powered by two closely related paralog ATPase subunits, SMARCA4 (BRG1) and SMARCA2 (BRM), which assemble into the complex in mutually exclusive form and are co-expressed and localized in the nucleus in most tissue types. Studies have shown that the level of SMARCA2 increases after SMARCA4 inactivation. At the same time, in SMARCA4 wild-type cells, the knockout of SMARCA2 leads to the increase of SMARCA4 expression and the increase of SMARCA4 assembly into SWI / SNF complex, which indicates that SMARCA2 and SMARCA4 can complementarily express each other. Since SMARCA2 and SMARCA4 play a complementary role, and the activity of SMARCA2 or SMARCA4 is essential for chromatin remodeling to occur, cancer cells lacking SMARCA4 become highly dependent on SMARCA2 for survival, and the two will produce synthetic lethality by inhibiting SMARCA2. As early as 2014, the synthetic lethal interaction between SMARCA4 and SMARCA2 has been independently confirmed by two studies using unbiased (only random error without systematic error) shRNA screening.

[0006] SMARCA4 is aberrantly expressed in about 4% of human malignancies. Among them, lung cancer, ovarian clear cell carcinoma, colorectal cancer, oral cancer, melanoma, etc. have different frequencies of abnormalities. Therefore, SMARCA2 inhibitors have the potential to treat these cancers, and since SMARCA4 / 2 proteins have certain homology, selective SMARCA2 inhibitors are expected to further enhance safety, and currently there is a need for selective SMARCA2 inhibitors to fill the gap. SUMMARY

[0007] The present application provides a compound, a pharmaceutical composition comprising the same and uses thereof, the strategy of amide inversion of the present application significantly improves the activity of the compound, such as enzyme activity and cell activity, improves the drugability and pharmacokinetic properties, etc.

[0008] The first aspect of the present application provides a compound represented by Formula I, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof:

[0009] wherein,

[0010] A ring is selected from 5-10 membered heteroaryl, C 6-10 aryl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;

[0011] each R a is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, -NR A1 R A2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -O(C 3-6 cycloalkyl), 4-8 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, -C(O)C 1-6 alkyl, or two R a on the same carbon atom are taken together with the carbon atom to which they are attached to form C=T; said C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -O(C 3-6 cycloalkyl), 4-8 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 membered heteroaryl, -C(O)C1-6 alkyl is optionally each independently substituted with one or more R a ’;

[0012] R A1 and R A2 are each independently selected from H, deuterium, C 1-6 alkyl or -C(O)C 1-6 alkyl;

[0013] T is selected from CR e R f , R e and R f are each independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl;

[0014] R a ’ is selected from deuterium, halogen, cyano, amino, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2 or C 3-6 cycloalkyl;

[0015] t is 0, 1, 2, 3 or 4;

[0016] B ring is selected from 5-10 membered heteroaryl;

[0017] each R b is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 3-6 cycloalkyl;

[0018] s is 0, 1, 2, 3 or 4;

[0019] R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl or -C 1-6 alkylene-OC 1-6 alkyl;

[0020] m is 0, 1, 2 or 3;

[0021] R 3 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 deuteroalkyl;

[0022] X1is selected from CR X1or N;

[0023] X2is selected from CR X2 or N;

[0024] X3is selected from CR X3 or N;

[0025] R X1 , R X2 , R X3 each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0026] C ring is selected from 5-7 membered heterocyclyl or C 5-7 cycloalkyl, the heteroatoms in said 5-7 membered heterocyclyl being selected from one or both of nitrogen or oxygen;

[0027] each R c is independently selected from hydrogen, deuterium, hydroxyl, oxo, -S(O) n C 1-6 alkyl;

[0028] n is selected from 1 or 2;

[0029] q is selected from 0, 1, 2 or 3.

[0030] In some embodiments of the first aspect of the application,

[0031] A ring is selected from 5-10 membered heteroaryl, C 6-10 aryl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;

[0032] R a each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, -NR A1 R A2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -O(C 3-6 cycloalkyl), 4-8 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, -C(O)C 1-6 alkyl, or two R a together with the carbon atom to which they are attached form C=T; said C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C2-6 alkynyl, C 3-6 cycloalkyl, -0(C 3-6 cycloalkyl), 4-8 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, -C(O)C 1-6 alkyl optionally substituted with R a ’;

[0033] R A1 and R A2 are each independently selected from H, deuterium, C 1-6 alkyl or -C(O)C 1-6 alkyl;

[0034] T is selected from CR e R f , R e and R f are each independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl;

[0035] R a ’ is selected from deuterium, halogen, cyano, amino, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2 or C 3-6 cycloalkyl;

[0036] t is 0, 1, 2, 3 or 4;

[0037] B ring is selected from 5-10 membered heteroaryl;

[0038] R b are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 3-6 cycloalkyl;

[0039] s is 0, 1, 2, 3 or 4;

[0040] R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl or -C 1-6 alkylene-OC 1-6 alkyl;

[0041] m is 0, 1, 2 or 3;

[0042] R 3 is selected from hydrogen, deuterium, C 1-6alkyl, C 1-6 haloalkyl or C 1-6 deuteroalkyl;

[0043] X1is selected from CR X1 or N;

[0044] X2is selected from CR X2 or N;

[0045] X3is selected from CR X3 or N;

[0046] R X1 , R X2 , R X3 are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0047] C ring is selected from 5-7 membered heterocyclyl or C 5-7 cycloalkyl, the heteroatoms in the 5-7 membered heterocyclyl being selected from one or both of nitrogen or oxygen;

[0048] R c is selected from hydrogen, deuterium, hydroxyl, oxo, -S(O) n C 1-6 alkyl;

[0049] n is selected from 1 or 2;

[0050] q is selected from 0, 1, 2 or 3.

[0051] In some embodiments of the first aspect of the application, each R c is independently selected from hydrogen, hydroxyl, oxo or -S(O)2C 1-6 alkyl; preferably, each R c is independently selected from hydrogen, hydroxyl, oxo or -S(O)2CH3.

[0052] In some embodiments of the first aspect of the application, q is selected from 0 or 1; preferably, q is 1.

[0053] In some embodiments of the first aspect of the application, structural unit is selected from wherein Z1, Z2, Z3are each independently selected from CH2, O or NH, and at least one of Z1, Z2is selected from CH2; v is selected from 0, 1 or 2.

[0054] In some embodiments of the first aspect of the application, Z1is selected from CH2or O; Z2is selected from NH or CH2; Z3is selected from O, CH2or NH.

[0055] In some embodiments of the first aspect of the application, the structural unit is selected from

[0056] In some embodiments of the first aspect of the application, the structural unit is selected from

[0057] In some embodiments of the first aspect of the application, the structural unit is selected from

[0058] In some embodiments of the first aspect of the application, the structural unit is not

[0059] In some embodiments of the first aspect of the application, X1is selected from CR X1 ; X2is selected from CR X2 ; X3is selected from CR X3 .

[0060] In some embodiments of the first aspect of the application, R X1 , R X2 , R X3 are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy; preferably, R X1 , R X2 , R X3 are each independently selected from hydrogen, F, Cl, Br, methyl, ethyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2, or -OCF3; preferably, R X1 , R X2 , R X3 are each independently selected from hydrogen or halogen (e.g. F); preferably, R X1 , R X2 , R X3 one of which is halogen (e.g. F) and the others are hydrogen; preferably, R X1 , R X2 are both hydrogen, R X3 is halogen (e.g. F), or, R X1 is halogen (e.g. F) and R X2 , R X3 are both hydrogen; more preferably, R X1 , R X2 , RX3 are each hydrogen.

[0061] In some embodiments of the first aspect of the application, the structural unit is selected from wherein j is selected from 0, 1, 2, 3, 4 or 5, preferably j is selected from 0, 1 or 2, more preferably 0, and Z1, Z2, Z3are defined as in any of the preceding embodiments.

[0062] In some embodiments of the first aspect of the application, the structural unit is selected from more preferably

[0063] In some embodiments of the first aspect of the application, m is 1.

[0064] In some embodiments of the first aspect of the application, preferably the compound of general formula (I) is selected from the group consisting of compounds of general formula (II):

[0065] wherein R c , q, Z1, Z2, Z3, v, X1, X2, X3, R 3 , R 2 , R 1 , B ring, R b , s, A ring, R a , t are defined as in any of the preceding embodiments.

[0066] In some embodiments of the first aspect of the application, R 3 is selected from H.

[0067] In some embodiments of the first aspect of the application, R 1 and R 2 are each independently selected from hydrogen, C 1-4 alkyl or -C 1-4 alkylene-OC 1-4 alkyl; preferably one of R 1 and R 2 is selected from hydrogen, and the other is selected from hydrogen, -CH3or -CH2OCH3; more preferably R 1 and R 2 are each selected from hydrogen.

[0068] In some embodiments of the first aspect of the application, ring B is selected from 9-10 membered bicyclic fused heteroaryl; preferably ring B is selected from wherein E 1 , E 2 , E 3, E 4 , E 5 and E 6 are each independently selected from N or CH, and at least one is N, preferably both are N, preferably E 1 and E 5 is N; preferably, ring B is selected from wherein the bond marked with "#" is connected to CR 1 R 2 when m is not 0, or C(=0) when m is 0, the bond marked with "#A" is connected to the A ring, E 1 , E 2 , E 3 , E 4 , E 5 and E 6 are each independently selected from N or CH, and at least one is N, preferably both are N, preferably E 1 and E 5 is N; preferably, ring B is selected from preferably, ring B is selected from wherein the bond marked with "#" is connected to CR 1 R 2 when m is not 0, or C(=0) when m is 0, the bond marked with "#A" is connected to the A ring; preferably, ring B is selected from preferably, ring B is selected from wherein the bond marked with "#" is connected to CR 1 R 2 when m is not 0, or C(=0) when m is 0, the bond marked with "#A" is connected to the A ring.

[0069] In some embodiments of the first aspect of the application, each R b is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl.

[0070] In some embodiments of the first aspect of the application, s is selected from 0 or 1 ; preferably, s is 0.

[0071] In some embodiments of the first aspect of the application, the A ring is selected from 5-10 membered heteroaryl, C 6-10 aryl, 5-10 membered heterocyclyl; preferably, the A ring is selected from 5-10 membered heteroaryl, C 6-10 aryl; preferably, the A ring is selected from 5-6 membered heteroaryl, phenyl, or 9-10 membered heterocyclyl; preferably, the A ring is selected from 5-6 membered heteroaryl, phenyl, or 9-10 membered partially unsaturated heterocyclyl.

[0072] In some embodiments of the first aspect of the application, the A ring is selected from wherein each of G1, G2, G3, G4, G5is independently selected from CH or N; preferably, each of G1, G2, G3, G4, G5is CH; preferably, one or two of G1, G2, G3, G4, G5is N and the rest are CH; preferably, G1is N and each of G2, G3, G4, G5is CH; G 1’ is selected from O, NH, S or CH2, preferably, G 1’ is selected from O, NH or CH2, more preferably, G 1’ is selected from O; denotes the connection site to the B ring; preferably, the A ring is selected from wherein, denotes the connection site to the B ring; preferably, the A ring is selected from wherein, denotes the connection site to the B ring.

[0073] In some embodiments of the first aspect of the application, each R a is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, -C(O)C 1-6 alkyl, -NHC(O)C 1-6 alkyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, -O(C 3-6 cycloalkyl), 4-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl; said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, -O(C 3-6 cycloalkyl), 4-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl are optionally each independently substituted with one or more R a ’; preferably, each R a is independently selected from halogen, cyano, -C(O)C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 saturated cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heteroaryl; said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 saturated cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heteroaryl are optionally each independently substituted with one or more R a ’; preferably, each R a is independently selected from C 3-6 saturated cycloalkyl, 4-7 membered saturated heterocyclyl, said C3-6 saturated cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heterocyclyl; said C a ; preferably each R a is independently selected from cyclobutyl, said cyclobutyl, optionally each independently substituted with one or more (e.g. 1, 2 or 3) R a ; preferably each R

[0074] In some embodiments of the first aspect of the application, R a is each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, -C(O)C 1-6 alkyl, -NHC(O)C 1-6 alkyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, -O(C 3-6 cycloalkyl), 4-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl; said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, -O(C 3-6 cycloalkyl), 4-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl optionally substituted with R a ; preferably R a is each independently selected from halogen, cyano, -C(O)C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 saturated cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heterocyclyl; said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 saturated cycloalkyl, 4-7 membered saturated heterocyclyl, 5-6 membered heterocyclyl optionally substituted with R a ; preferably R a is selected from C 3-6 saturated cycloalkyl, 4-7 membered saturated heterocyclyl, said C 3-6 saturated cycloalkyl, 4-7 membered saturated heterocyclyl optionally substituted with R a ; preferably R a is selected from cyclobutyl, said cyclobutyl, optionally substituted with R a .

[0075] In some embodiments of the first aspect of the application, R a is selected from halogen, C 1-6 alkyl, C1-6 alkoxy or C 3-6 saturated cycloalkyl; preferably, R a ' is selected from halogen or C 1-6 alkyl.

[0076] In some embodiments of the first aspect of the application, each R a is independently selected from cyclobutyl or (preferably ).

[0077] In some embodiments of the first aspect of the application, t is selected from 0, 1, 2 or 3, preferably t is selected from 0, 1 or 2; preferably t is 1.

[0078] In some embodiments of the first aspect of the application, preferably the compound of general formula (I) is selected from any one of the following general formula (III):

[0079] wherein R c , q, Z1, Z2, Z3, v, X1, X2, X3, R 3 , R 2 , R 1 , E 1 , E 2 , E 3 , E 4 , E 5 , E 6 , R b , s, A ring, R a , t are as defined in any of the preceding embodiments.

[0080] In some embodiments of the first aspect of the application, preferably the compound of general formula (III) is selected from any one of the following general formula (III-0):

[0081] wherein R c , q, Z1, Z2, Z3, v, X1, X2, X3, R 3 , R 2 , R 1 , R b , s, A ring, R a , t are as defined in any of the preceding embodiments.

[0082] In some embodiments of the first aspect of the application, the compound of general formula (I) is selected from any one of the following general formula (III-1), (III-2), (III-3) or (III-4):

[0083] wherein Z1, Z2, Z3, j, X1, X2, X3, R3 , R 2 , R 1 , E 1 , E 2 , E 3 , E 4 , E 5 , E 6 , R b , s, A ring, R a , t are as defined in any of the above embodiments.

[0084] In some embodiments of the first aspect of the application, the compound of general formula (I) is selected from any of the structures represented by general formulae (IV-1), (IV-2), (IV-3), (IV-4), (IV-5) or (IV-6):

[0085] wherein X1, X2, X3, R 3 , R 2 , R 1 , E 1 , E 2 , E 3 , E 4 , E 5 , E 6 , E b , R a , s, A ring, R 3 , t are as defined in any of the above embodiments.

[0086] In some embodiments of the first aspect of the application, the compound of general formula (I) is selected from any of the structures represented by general formulae (V-1), (V-2), (V-3), (V-4), (V-5), (V-6), (V-7), (V-8), (V-9), (V-10), (V-11) or (V-12):

[0087] wherein X1, X2, X3, R 3 , R 2 , R 1 , E 1 , E 2 , E 3 , E 4 , E 5 , E 6 , R b , s, G1, G2, G3, G4, G5, G1 ’ , R a , t are as defined in any of the above embodiments.

[0088] In some embodiments of the first aspect of the application, the compound of general formula (I) is selected from any one of the following general formulae (VI-1), (VI-2), (VI-3), (VI-4), (VI-5), (VI-6), (VI-7), (VI-8), (VI-9), (VI-10), (VI-11) or (VI-12):

[0089] wherein X1, X2, X3, R 3 , R 2 , R 1 , E 1 , E 2 , E 3 , E 4 , E 5 , E 6 , G1, G3, G4, G5, G1 ’ , R a are as defined in any of the embodiments above.

[0090] In some embodiments of the first aspect of the application, the compound of general formula (I) is selected from any one of the following compounds:

[0091] In some embodiments of the first aspect of the application, the compound of general formula (I) is selected from any one of the following compounds:

[0092] In some embodiments of the first aspect of the application, the compound of general formula (I) is selected from any one of the following compounds:

[0093] In some embodiments of the first aspect of the application, the compound of general formula (I) is selected from any one of the following compounds:

[0094] In some embodiments of the first aspect of the application, the compound of general formula (I) is selected from any one of the following compounds:

[0095] In some embodiments of the first aspect of the application, the compound of general formula (I) is selected from any one of the following compounds:

[0096] In some embodiments of the first aspect of the application, the compound of general formula (I) is selected from any one of the following compounds:

[0097] The second aspect of the present application provides a pharmaceutical composition comprising the compound provided by any of the embodiments of the first aspect above, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. The above compound, etc. serves as a pharmaceutical active ingredient (API) (or a therapeutic agent).

[0098] The term "pharmaceutical composition" refers to a composition that can be used as a medicine, which in some embodiments further comprises a pharmaceutically acceptable carrier, adjuvant, vehicle. The term "pharmaceutically acceptable carrier" refers to an adjuvant that is administered together with a therapeutic agent, and which is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. The above pharmaceutical composition can act systemically and / or locally, which can be achieved by a suitable dosage form. The dosage form includes, but is not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups. The above pharmaceutical composition can contain 0.01 mg to 1000 mg of at least one compound of the present application, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0099] The third aspect of the present application provides use of the compound, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof provided by any of the embodiments of the first aspect, or the pharmaceutical composition provided by any of the embodiments of the second aspect, in the preparation of a medicament for preventing and / or treating a cancer, which is non-small cell lung cancer, colorectal cancer, bladder cancer, primary cancer of unknown origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal cancer, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastroenteric neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenal cortical cancer, appendix cancer, small intestine cancer, or penile cancer.

[0100] The fourth aspect of the present application provides use of the compound, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof provided by any of the embodiments of the first aspect, or the pharmaceutical composition provided by any of the embodiments of the second aspect, in the preparation of a medicament for preventing and / or treating a disease or disorder of BRG1 (SMARCA4) loss-of-function mutation.

[0101] The disease or disorder of BRG1 (SMARCA4) loss-of-function mutation in the fourth aspect of the present application is selected from a cancer or a tumor, which includes but is not limited to non-small cell lung cancer, colorectal cancer, bladder cancer, primary cancer of unknown origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal cancer, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastroenteric neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenal cortical cancer, appendix cancer, small intestine cancer, or penile cancer.

[0102] The fifth aspect of the present application also provides a method for preventing and / or treating cancer, comprising the step of administering to an individual in need thereof a therapeutically effective amount of the compound of any of the embodiments of the first aspect, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the second aspect. The cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, primary cancer of unknown origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal cancer, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenal cortex cancer, appendix cancer, small intestine cancer, or penile cancer.

[0103] The sixth aspect of the present application also provides a method for preventing and / or treating a disease or disorder of BRG1 (SMARCA4) loss-of-function or mutation, the method comprising administering to an individual in need thereof a prophylactically and / or therapeutically effective amount of the compound of any of the embodiments of the first aspect described above, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the second aspect. Preferably, the disease or disorder of BRG1 (SMARCA4) loss-of-function or mutation is a cancer or a tumor; preferably, the cancer or tumor is selected from non-small cell lung cancer, colorectal cancer, bladder cancer, primary cancer of unknown origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal cancer, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastroenteropancreatic neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenocortical carcinoma, appendix cancer, small intestine cancer, or penile cancer. The term "effective amount" means an amount that is capable of eliciting a biological or medical response of a cell, tissue, organ, or organism (e.g., an individual), and is sufficient to achieve the desired prophylactic and / or therapeutic effect. The dosage regimen can be adjusted to provide the optimum desired response. For example, several divided doses can be administered daily, doses can be proportionally reduced or increased, or drugs can be administered, as local circumstances demand. It will be appreciated that the specific dose level and frequency of dosage for any particular individual can be adjusted by the attending physician in accordance with the dosage teaching and uniquely individual circumstances. The amount of the compound of the present application to be administered will depend on the individual circumstances, the severity of the disease or disorder, the rate of administration, the disposition of the compound and the judgment of the prescribing physician. In general, an effective amount is from about 0.001 to 10000 mg / kg body weight of the subject per day. In appropriate cases, an effective amount is from about 0.01 to 1000 mg / kg body weight of the subject per day. Administration can be from about 0.01 to 1000 mg / kg body weight of the subject per day, typically from about 0.1 to 500 mg / kg body weight of the subject per day, either daily, every second day or every third day. An exemplary dosage regimen is one or more times per day, or one or more times per week, or one or more times per month. When multiple doses are administered, the intervals between successive doses will generally be daily, weekly, monthly or yearly. Alternatively, administration can be by sustained release formulation, in which case less frequent administration is required. The dosage and frequency of administration will vary depending on the half-life of the drug in the subject and whether the application is prophylactic or therapeutic.In prophylactic applications, relatively low doses are administered at long intervals; in therapeutic applications, relatively high doses are sometimes administered at short intervals, until progression of the disease is slowed, or halted, preferably until the individual shows partial or complete amelioration of symptoms associated with the disease.

[0104] The term "treatment" refers to the reduction or elimination of the disease or condition being addressed. A subject is successfully "treated" if, after receiving a therapeutic amount of a compound of the application or a pharmaceutically acceptable form thereof or a pharmaceutical composition of the application, at least one indicator and symptom of the subject exhibits an observable and / or detectable alleviation and / or improvement. It is understood that treatment includes not only complete treatment, but also treatment that fails to achieve complete treatment, but that achieves some biologically or medically relevant result. The terms "administrate," "administrating," "administration" (or "administering") refer to the process of applying a pharmaceutically active ingredient (such as a compound of the application) or a pharmaceutical composition comprising a pharmaceutically active ingredient (such as a pharmaceutical composition of the application) to a site of the individual or its cells, tissues, organs, biological fluids, etc., so as to make the pharmaceutically active ingredient or the pharmaceutical composition contact the individual or its cells, tissues, organs, biological fluids, etc. at the site. Common modes of administration include, but are not limited to, oral administration, subcutaneous administration, intramuscular administration, intraperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, etc.

[0105] The term "in need thereof or "in need" refers to the judgment of a physician or other care provider that an individual needs or will benefit from a prophylactic and / or therapeutic process, which judgment is made based on various factors within the purview of the physician or other care provider. The term "individual" (or subject) refers to a human or non-human animal. Individuals of the present application include individuals (patients) having a disease and / or condition and normal individuals. Non-human animals of the present application include all vertebrates, e.g., non-mammals, such as birds, amphibians, reptiles, etc., and mammals, e.g., non-human primates, domestic animals, and / or laboratory animals, e.g., sheep, dogs, cats, cows, pigs, etc.

[0106] The seventh aspect of the present application also provides the compound of any of the above embodiments of the first aspect, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any of the above embodiments of the second aspect, for use in the prevention and / or treatment of cancer; preferably, the cancer is selected from non-small cell lung cancer, colorectal cancer, bladder cancer, primary cancer of unknown origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal cancer, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastroenteropancreatic neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenal cortex cancer, appendix cancer, small intestine cancer, or penile cancer.

[0107] The eighth aspect of the present application also provides the compound of any of the above embodiments of the first aspect, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an enantiomer thereof, or a diastereomer thereof, or a racemate thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any of the above embodiments of the second aspect, for use in the prevention and / or treatment of a disease or disorder of BRG1 (SMARCA4) loss-of-function or mutation; preferably, the disease or disorder of BRG1 (SMARCA4) loss-of-function or mutation is cancer or tumor; preferably, the cancer or tumor is selected from non-small cell lung cancer, colorectal cancer, bladder cancer, primary cancer of unknown origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal cancer, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastroenteropancreatic neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenal cortex cancer, appendix cancer, small intestine cancer, or penile cancer.

[0108] The compounds and derivatives provided in the present application can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstract Service, Columbus, OH) nomenclature system.

[0109] Definitions of terms used in the present application: Unless otherwise indicated, the initial definition of a group or term provided herein applies to that group or term throughout the specification; for terms not specifically defined herein, a meaning that is consistent with the disclosure and context will be given by those of ordinary skill in the art.

[0110] The term "substituted" or "is substituted" means that any one or more hydrogen atoms on the designated atom is / are replaced with a substituent, as long as the valency of the designated atom is properly satisfied and the resulting compound is stable. When the substituent is oxo (i.e., =0) or thioxo (=S), it means that two hydrogen atoms are replaced. Oxidation and / or thioxo groups do not occur on aromatic groups.

[0111] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs and instances where it does not. For example, 3-7 membered heterocycle optionally substituted with one or more substituents selected from deuterium substitution means that the 3-7 membered heterocycle group can be unsubstituted, mono-substituted, poly-substituted, or fully substituted. One of skill in the art will understand that for any group comprising one or more substituents, no substitution or substitution pattern will be introduced that is not spatially possible and / or synthetically feasible.

[0112] As used herein, the term "one or more" means 1 or more than 1, e.g., 2, 3, 4, 5, or 10, under reasonable conditions. Wherein, when a group is substituted with "one or more" substituents, it means that one or more than one hydrogen on the group is replaced with one or more than one substituent from the indicated group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., substituents, provided that the normal valency of the atom in question under the current circumstances is not exceeded and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0113] If substituents are described as being "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent can be the same as or different from the other substituent(s).

[0114] Unless specified, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent.

[0115] When a bond of a substituent is shown as a dashed line ("dashed bond") extending through the middle of a ring ("floating bond"), then such substituent can be bonded to any atom in the ring that can be substituted, unless otherwise specified. Where a useable ring member carries a substitutable hydrogen atom, when the floating bond is bonded to that useable ring member, the substitutable hydrogen atom is essentially substituted (i.e., not present). For example represents R a may be bound to the 1, 2, or 3 position, while represents R a may be bound to the 1, 2, 3, 4, or 5 position.

[0116] As used herein, the term "alkyl" defines a straight-chain or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 6, for example, "C 1-6 "alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, or n-hexyl).

[0117] As used herein, the term "alkylene" means a divalent straight-chain or branched saturated aliphatic hydrocarbon radical, which is obtained after removal of one H from an alkyl group as defined above. In some embodiments, the alkylene group has 1 to 6, for example, "C 1-6 "alkylene" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, t-butylene, n-pentylene, or n-hexylene).

[0118] As used herein, the term "alkoxy" refers to -O-alkyl, wherein the alkyl group is as defined above. The term "C 1-6 "alkoxy" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, i-propoxy, t-butoxy, n-pentoxy, or n-hexoxy).

[0119] As used herein, the term "alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one double bond. For example "C 2-6 "alkenyl" can be understood to mean a straight-chain or branched unsaturated hydrocarbon group comprising one or more double bonds and having 2, 3, 4, 5, or 6 carbon atoms. It can be understood that in case the alkenyl group comprises more than one double bond, the double bonds can be separated from each other or conjugated. Specific examples of the alkenyl group include, but are not limited to, ethenyl, allyl, (E)-2-methylethenyl, (Z)-2-methylethenyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, or (Z)-1-methylprop-1-enyl, and the like.

[0120] As used herein, the term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one triple bond. For example "C 2-6"Alkynyl" can be understood to mean a straight-chain or branched unsaturated hydrocarbon group, which contains one or more triple bonds and has 2, 3, 4, 5, or 6 carbon atoms. Examples include, but are not limited to, ethynyl, propynyl, but-1-ynyl, but-2-ynyl, or but-3-ynyl, and the like.

[0121] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused, or bridged systems (such as bicyclo[l.l.l]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or bicyclo[5.2.0]nonyl, decahydronaphthyl, and the like). For example, "C 3-6 "Cycloalkyl" refers to a saturated or partially saturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0122] As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, fused ring, spiro, or bridged ring radical having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and one or more (e.g., one, two, three, or four) heteroatoms selected from nitrogen, oxygen, or sulfur in the ring. The heterocyclyl group can be attached to the rest of the molecule through any one of the carbon atoms or the nitrogen atom, if present. The "heterocyclyl" can be a monocyclic or a polycyclic ring system (polycyclic ring systems include, but are not limited to, bicyclic, tricyclic, tetracyclic, or pentacyclic ring system radicals). For example, a 3-10 membered heterocyclyl is a ring having 3-10 (e.g., 3-7, 4-6, 4-7, 4-8, or 5-6) ring atoms in the ring, which ring atoms include carbon atoms and heteroatoms, such as, but not limited to, oxetanyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl. In some embodiments, heterocyclyl also includes heteroaryl-fused heterocyclyl, heteroaryl-fused cycloalkyl, and aryl-fused heterocyclyl, as long as the overall ring system is non-aromatic. For example

[0123] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused ring polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, the term "C 6-10 "Aryl" means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl.

[0124] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which can be the same or different (the heteroatom is, for example, oxygen, nitrogen or sulfur), and, in addition, can in each case be benzo-fused. In particular, heteroaryl is selected from the group consisting of thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl), thiadiazolyl and the like, and benzo derivatives thereof; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and benzo derivatives thereof.

[0125] "Halogen" as used herein refers to fluorine, chlorine, bromine or iodine.

[0126] "Stereoisomers" as used herein refer to compounds which have the same chemical constitution, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like. Unless otherwise specified, all stereoisomers and mixtures thereof of the structure formulae described herein are within the scope of the application. The term "enantiomers" as used herein refers to stereoisomers which are mirror images of one another and are not superimposable. "Diastereomers" refer to stereoisomers which have two or more chiral centers and which are not mirror images of one another.

[0127] The term "geometric isomers" as used herein includes: cis / trans isomers, homotactic and heterotactic stereoisomer polymers, atropisomers, and the like caused by steric hindrance.

[0128] The stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0129] The term "tautomer" as used herein refers to structural isomers that can interconvert by a low energy barrier. For example, prototonic tautomers (also known as prototropic tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0130] The term "polymorph" as used herein refers to crystalline forms of a compound (or salt, hydrate or solvate thereof) that are arranged in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystal forms often have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. The recrystallization solvent, rate of crystallization, storage temperature, and other factors can cause one crystal form to dominate.

[0131] The term "solvate" as used herein refers to a mixture of a compound with solvent.

[0132] The term "N-oxide" as used herein refers to a class of organic compounds with the general formula R3N+-O- (also written as R3N=O or R3N→O).

[0133] The term "isotopically-labeled compound" as used herein refers to a compound in which one or more atoms are replaced by an isotope of that atom, such as a hydrogen atom replaced by a deuterium atom, wherein the deuterium atom is present in an amount greater than the natural abundance of deuterium; or a 12C atom replaced by a 13C atom.

[0134] The term "metabolite" as used herein refers to a substance resulting from a chemical transformation of a drug molecule in the body.

[0135] The term "ester" as used herein refers to esters derived from compounds of the various formulae herein, including physiologically hydrolysable esters (which can be hydrolyzed in vivo to release the free acid or alcohol form of the compound of the application). The compounds of the application can themselves be esters.

[0136] The term "prodrug" as used herein refers to a compound that is inactive or less active in vitro, but is converted in vivo by enzymatic or non-enzymatic processes to release an active drug.

[0137] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, adjuvant, and / or salt formed is generally compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically tolerable by a recipient thereof.

[0138] The terms "salt" and "pharmaceutically acceptable salt" refer to the acid and / or base salts of the above compounds or stereoisomers thereof, with inorganic and / or organic acids and bases, and also include zwitterions, and also include quaternary ammonium salts, such as alkyl ammonium salts. These salts can be formed during the final isolation and purification of the compounds, or by further treatment of the compounds or stereoisomers thereof after isolation and purification. The salts can be formed in solution or in solid, and can be recovered by filtration or by evaporation of the solvent.

[0139] The term "prevention" includes inhibition and delay of the onset of a disease, and includes not only prevention before the development of a disease, but also prevention of recurrence of a disease after treatment.

[0140] The term "treatment" means reversing, alleviating, or inhibiting the progress of the disease or condition to which such term applies, or one or more symptoms thereof.

[0141] In certain embodiments, one or more compounds of the present application can be used in conjunction with each other. It can also be desirable to use a compound of the present application in combination with any other active agents for the preparation of a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a combination of compounds is used, the compounds can be administered simultaneously, separately or sequentially.

[0142] Obviously, great changes in form and detail can be made to the above-described embodiments without departing from the spirit and scope of the present application as defined in the appended claims.

[0143] The above-described subject matter of the present application will be further illustrated by way of specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above-described subject matter of the present application to the following examples. Any technology realized based on the above-described subject matter of the present application falls within the scope of the present application. DETAILED DESCRIPTION

[0144] The present application will be further illustrated by way of specific preparation examples and biological experiments below, but it should be understood that these examples and biological experiments are merely for the purpose of specific illustration, and should not be construed as limiting the present application in any form.

[0145] It is clear to the person skilled in the art that, in the following, if not specified otherwise, the materials used are known in the art, can be purchased on the market or can be obtained by the person skilled in the art according to the already published literature or according to the usual methods. Unless otherwise specified, all the reactions of the present application are carried out under continuous magnetic stirring, under a dry nitrogen or argon atmosphere, with dry solvents, in which: (i) the temperatures are expressed in degrees Celsius (°C) and the operations are carried out at room temperature, which generally means 15-35 °C, preferably 20-30 °C, more preferably 20-25 °C; (ii) the removal of the solvent is carried out by evaporation under reduced pressure using a rotary evaporator, generally at a bath temperature not higher than 60 °C; (iii) the progress of the reaction is followed by thin layer chromatography (TLC); (iv) the end products have satisfactory proton nuclear magnetic resonance spectrum (H-NMR) and / or mass spectrum (MS) data. 1 H-NMR) and / or mass spectrum (MS) data.

[0146] Test instruments:

[0147] The structure of the compounds of the present application is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shifts (δ) are given in parts per million (ppm). The NMR measurements are carried out using a Bruker Neo 400M or a Bruker Ascend 400 nuclear magnetic instrument, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and / or deuterated chloroform (CDCl3) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.

[0148] The liquid chromatography-mass spectrometry (LC-MS) measurements are carried out using a Shimadzu 2030Plus-LCMS2020 mass spectrometer, an Agilent 1260-6125B single quadrupole mass spectrometer or a Shimadzu LCMS-2020 mass spectrometer. The HPLC measurements are carried out using a Shimadzu LCMS-2020 or an Agilent 1260 high-performance liquid chromatograph.

[0149] The preparative high-performance liquid chromatography is carried out using a Shimadzu FRC-40 equipped with LC-20AP and PDA-20A (chromatographic column: Synergi Max-RP, 150 x 30 mm, 4 m) or a GILSON Trilution LC (chromatographic column: SunFire Prep C18, 10 pm, 19 x 250 mm XBridge Prep C18, 10 pm, 19 x 250 mm).

[0150] The microwave synthesis instrument is a Biotage Initiator+.

[0151] Examples:

[0152] Synthesis of intermediate Int H

[0153] Step one: at 25 °C, compound H-1 (10.00 g, 39.30 mmol) and (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (8.88 g, 39.30 mmol) were added to dioxane-water (80.0 mL), under nitrogen atmosphere, sodium carbonate (8.32 g, 78.60 mmol) and dichloro[1,1’-bis(diphenylphosphino)ferrocene] palladium (2.88 g, 3.93 mmol) were added, stirred at 90 °C for 12 h. The reaction was filtered, the filtrate was poured into water (100 mL), then extracted with ethyl acetate (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 99 / 1 ~ 60 / 40) to give compound H-2.

[0154] Step two: at 25 °C, compound H-2 (8.50 g, 37.50 mmol) was added to ethanol (60 mL), sodium thiomethoxide (6.83 g, 97.50 mmol) was added, the temperature was raised to 60 °C, stirred for 2 h, the reaction was quenched with sodium hypochlorite aqueous solution (50 mL, 5% mass fraction), filtered to give compound H-3. LCMS: m / z = 181.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 12.14 (br s, 1H), 8.69 (s, 1H), 8.00 (d, J = 9.5 Hz, 1H), 7.22 (s, 1H), 6.60 (d, J = 9.6 Hz, 1H).

[0155] Step three: at 25 °C, compound H-3 (1.00 g, 5.54 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (1.30 g, 6.66 mmol) were added to dimethyl sulfoxide-water (20.0 mL), under nitrogen atmosphere, potassium fluoride (964 mg, 16.62 mmol) and dichloro[1,1’-bis(diphenylphosphino)ferrocene] palladium (404 mg, 0.56 mmol) were added, stirred at 120 °C for 12 h. The reaction was filtered and concentrated. The crude product was purified by flash silica gel column chromatography (methanol / dichloromethane = 1 / 99 ~ 15 / 85), then purified by preparative high performance liquid chromatography column to give compound Int G. LCMS: m / z = 186.0 [M+H] + .

[0156] Step four: Compound Int G (350 mg, 1.89 mmol) was added to acetonitrile (10 mL) at 25 °C, and phosphorus oxychloride (350 μL, 3.78 mmol) was added. The temperature was raised to 80 °C, and the reaction was stirred for 12 h. The reaction was quenched by dropwise addition to a saturated solution of sodium bicarbonate in ice (20 mL), followed by extraction with ethyl acetate (40 mL), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate. Purification by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 99 / 1 to 50 / 50) gave compound Int H. LCMS: m / z = 244.9 [M+42] + .

[0157] Synthesis of intermediate Int 1

[0158] Step one: To a solution of compound J-1 (1.00 g, 5.68 mmol) and cis-2,6-dimethylmorpholine (0.70 mL, 5.68 mmol) in dimethyl sulfoxide (15 mL) was added N,N-diisopropylethylamine (1.88 mL, 11.4 mmol) at 25 °C, and the reaction was stirred at 120 °C for 12 h. The reaction was diluted with water (120 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 99 to 10 / 90) to give compound J-2.

[0159] Step two: Compound J-2 (900 mg, 3.32 mmol), lithium chloride (703.48 mg, 16.60 mmol), tricyclohexylphosphine (93.08 mg, 0.33 mmol), and tris(dibenzylideneacetone)dipalladium (151.97 mg, 0.17 mmol) were added to dioxane (40 mL) at 25 °C, and hexabutyldistannane (2.01 mL, 3.98 mmol) was added. The reaction was stirred at 100 °C for 3 h. The reaction was added to a saturated aqueous potassium fluoride solution (100 mL) and stirred for 2 h. The reaction was extracted with ethyl acetate (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 99 / 1 to 90 / 10) to give compound J-3. LCMS: m / z = 483.0 [M+H]+.

[0160] Step three: Compound J-3 (756.67 mg, 1.57 mmol), cuprous iodide (56.12 mg, 0.29 mmol), tetrakis(triphenylphosphine)palladium (170.25 mg, 0.15 mmol) and compound Int H (300 mg, 1.47 mmol) were added into dioxane (20 mL) at 25 °C. The reaction was stirred at 100 °C for 3 h. The reaction was added into saturated potassium fluoride aqueous solution (100 mL) and stirred for 2 h. The reaction was extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by flash column chromatography on silica gel (dichloromethane / ethyl acetate = 99 / 1 ~ 50 / 50) to give compound J-4. LCMS: m / z = 360.2 [M+H]+.

[0161] Step four: Compound J-4 (266 mg, 0.74 mmol) and barium hydroxide (240 mg, 1.4 mmol) were added into isopropanol (15 mL) and water (10 mL) at 25 °C. The reaction was stirred at 100 °C for 4 h. The reaction was adjusted to acidic by dropwise adding hydrogen chloride aqueous solution (1 M). The reaction was purified by C18 reverse-phase silica gel chromatography (water / acetonitrile = 99 / 1 ~ 60 / 40) after adding methanol to give compound Int 1. LCMS: m / z = 379.2 [M+H]+.

[0162] Example 1: Synthesis of compound 1

[0163] Compound Int 1 (25 mg, 0.066 mmol) and compound 2 (14 mg, 0.079 mmol) were dissolved in N,N-dimethylformamide (0.5 mL). Diisopropylethylamine (35 μL, 0.20 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (38 mg, 0.10 mmol) in N,N-dimethylformamide (0.5 mL) were added to the mixture. The reaction mixture was stirred at 25 °C for 16 h. The reaction was filtered and the filtrate was purified by preparative high performance liquid chromatography (0.1% formic acid, acetonitrile-water) to give compound 1. LCMS: m / z = 539.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.37 (s, 1H), 8.70 - 8.60 (m, 2H), 8.32 (t, J = 5.4 Hz, 1H), 8.00 - 7.92 (m, 3H), 7.83 - 7.72 (m, 2H), 7.05 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.33 (dd, J = 12.9, 2.4 Hz, 2H), 4.23 (t, J = 4.9 Hz, 2H), 4.06 (s, 2H), 3.74 - 3.64 (m, 2H), 3.29 (q, J = 6.0, 5.2 Hz, 2H), 2.53 (m, 2H), 1.23 (d, J = 6.3 Hz, 6H).

[0164] Using a similar synthetic procedure as Example 1, the following example compounds were obtained by condensing Int 1 with the following commercially available starting material fragments:

[0165] Other compounds of the application can be prepared by analogy with the methods described in the Examples above, mutatis mutandis.

[0166] Bioactivity testing:

[0167] Experimental Example 1: Assay of ATPase catalytic activity of BRM (or SMARCA2) and BRG 1 (or SMARCA4)

[0168] The present application uses an in vitro biochemical assay of ADP-Glo to measure the ATPase catalytic activity of BRM or BRG1, which detects kinase activity by quantifying the amount of ADP generated during the kinase reaction. When the reaction is complete, the ADP-Glo kinase detection process is divided into 2 steps. The first step is to stop the kinase reaction and deplete the remaining ATP in the reaction system. The second step is to convert the reaction product ADP to ATP, and the newly synthesized ATP is detected by the light signal generated by the luciferase / luciferin reaction, and the light signal generated is measured by the luminescence detector Envision.

[0169] The reaction mixture contains 30 nM BRM (636-1331 aa, sf9 insect expression system) or 60 nM BRG1 (658-1361 aa, sf9 insect expression system), 40 nM salmon sperm DNA (Invitrogen, UltraPure Salmon Sperm DNA Solution, Cat# 15632011) and 200 mM ATP (Promega, Cat# V915B) in ATPase assay buffer containing 20 mM Tris (pH 8), 20 mM MgCl2, 0.1% Triton-X100, 1 mM fresh DTT (Pierce, Cat# 20290) and 0.1% BSA. The reaction is initiated by adding 2.5 pL ATPase solution to a white Proxiplate-384 plate (PerkinElmer, Cat# 6007290) containing a serial dilution of the test compound (maximal concentration of 10 pM, 3-fold serial dilution, 10 points), followed by 2.5 pL ATP / DNA solution and incubated for 1 hour at room temperature. Then, 5 pL ADP-Glo reagent provided in the ADP-Glo kit (Promega, V9102) is added and the reaction is incubated for 40 minutes at room temperature. Then, 10 pL kinase detection reagent provided in the kit is added to convert ADP to ATP and the reaction is incubated for 1 hour at room temperature. Finally, luminescence measurements are taken using Envision. Compound A is used as positive control and DMSO as negative control. The compound concentration at which the enzyme activity is inhibited by 50% (IC 50 ) is calculated using Graphpad Prism.

[0170] Compound A:

[0171] Inhibition % = 100% - (Avg. PC - Avg. compound) / (Avg. PC - Avg. NC) x 100%

[0172] wherein:

[0173] Avg. PC: average luminescence measurement of the positive control,

[0174] Avg. NC: average luminescence measurement of the negative control.

[0175] Enzyme selectivity factor = IC 50 (SMARCA4) / IC 50 (SMARCA2)

[0176] The test results show that the compound of the application can strongly inhibit the ATPase catalytic activity of SMARCA2, and the inhibition of the ATPase catalytic activity of SMARCA4 is relatively weak. Most of the compounds show strong selectivity. Part of the test results are shown in Table 1.

[0177] For SMARCA2 (or BRM) IC50, A≤1uM; 1uM<B≤3uM; C>3uM;

[0178] For SMARCA4 (or BRG1) IC50, A≤5uM; 5uM<B≤10uM; C>10uM;

[0179] For enzyme selectivity fold, A≤2, B>2.

[0180] Experimental Example 2: Inhibition of BRG1 / BRM ATPase on the proliferation of non-small cell lung cancer cell line A549

[0181] The BRG1 / BRM ATPase inhibitor compound is dissolved in DMSO and added to a 384-well cell culture plate by Echo at a concentration gradient of 0 to 10 micromoles, and then a non-small cell lung cancer cell line A549 (cells purchased from ATCC, item number CRM-CCL-185) containing growth medium (F12K+10% FBS, F12K purchased from ATCC, item number 30-20024, FBS purchased from Corning, item number 35-081-CV) is plated at 200 cells per well. The cells are incubated at 37 degrees Celsius in 5% carbon dioxide for 7 days. The relative cell growth is measured by adding CellTiter-Glo (Promega, G7573), and the luminescence is measured on an Envision plate reader (Perkin Elmer). The blank complete medium is used as a positive control group, and DMSO is used as a negative control group. The concentration at which the proliferation of each cell line is inhibited by 50% (IC 50 ) is calculated using Graphpad Prism, and a graph is drawn.

[0182] Inhibition% = 100%-(Avg.PC-Avg.compound) / (Avg.PC-Avg.NC) x 100%

[0183] Wherein:

[0184] Avg.PC: the average luminescence measurement value of the positive control group,

[0185] Avg.NC: the average luminescence measurement value of the negative control group.

[0186] The test results show that the compound has proliferation inhibition activity on A549 cells (BGR1 mutation), and some compounds have strong proliferation inhibition activity on A549 cells (BGR1 mutation).

[0187] Experimental Example 3: Inhibition of BRG1 / BRM ATPase on the proliferation of HT1080 BRG1 WT and BRG1 KO cell lines

[0188] Construction of BRG1 KO HT1080 cell line: The designed BRG1 sgRNA sequence is constructed into a virus vector to obtain a knockout plasmid, and then the knockout plasmid is delivered to HT1080 cells (cells purchased from ATCC, item number CBP60492) for drug screening; After drug screening, the pool gene editing efficiency is detected to obtain the genotype contained in the pool cells and the proportion of each genotype. The cells after drug screening are prepared into a single cell suspension, inoculated into a multi-well plate for single clone amplification and single clone genotype identification, and the PCR product prepared from the cell lysate is sent for detection, and according to the sequencing results and Western blot, the single clone cells meeting the knockout standard are selected: sequencing shows insertion or deletion at the gene level, and Western blot shows that the target protein band cannot be detected. HT1080 BRG1 WT is a single clone cell without detection of editing, and HT1080 BRG1 KO is a single clone cell with detection of BRG1 knockout.

[0189] Cell growth inhibition experiment: The BRG1 / BRM ATPase inhibitor compound is dissolved in DMSO and added to a 384-well cell culture plate by Echo at a concentration gradient of 0 to 10 micromoles, and then HT1080 BRG1 WT and BRG1 KO cells containing growth medium (EMEM+10% FBS, EMEM purchased from ATCC, item number 30-2003, FBS purchased from Corning, item number 35-081-CV) are inoculated, 75 cells per well. The cells are incubated at 37 degrees Celsius, 5% carbon dioxide for 7 days. The relative cell growth is measured by adding CellTiter-Glo (Promega), and the luminescence is measured on an Envision plate reader (Perkin Elmer). The concentration of each cell line that inhibits 50% of proliferation (IC 50 ) is calculated using Graphpad Prism.

[0190] Inhibition%=100%-(Avg.compound-Avg.PC) / (Avg.NC-Avg.PC)×100%

[0191] Wherein:

[0192] Avg.PC: average luminescence measurement of positive control group,

[0193] Avg.NC: average luminescence measurement of negative control group.

[0194] Cell selectivity fold = IC 50 (HT1080 BRG1 WT) / IC 50 (HT1080 BRG1 KO)

[0195] The test results show that at least part of the compounds of the present application have stronger proliferation inhibition activity on HT1080 BRG1 KO (BRG1 knockout) monoclonal cells, relatively weaker proliferation inhibition activity on HT1080 BRG1 WT (no editing detected) monoclonal cells, and better selectivity.

[0196] Experimental Example 4: Liver microsomal stability test (LMS)

[0197] Take acetonitrile solutions of various genus liver microsomes and compounds to prepare reaction mother liquor with 100 mM phosphate buffer (pH 7.4), so that the final concentration of the compound in the reaction system is 1 μM. The genus abbreviation is H for human and M for mouse. After mixing, 30 μL of each is dispensed into a new 96-deep well plate to set up 0, 5, 15, 30 and 45 min reaction groups (n = 2) containing NADPH, and 0 and 45 min control groups (n = 1) without NADPH.

[0198] After pre-incubating the above sample at 37°C water bath for 5 min, 15 μL of NADPH was added to start the reaction, so that the final concentration of NADPH was 1 mM. The control group without NADPH was added with 15 μL of phosphate buffer solution, and after mixing, the corresponding incubation time was continued. The reaction was terminated with 200 μL of ice acetonitrile containing an internal standard. After vortex mixing, centrifugation was performed at 4°C and 4000 rpm for 50 min, and the supernatant was diluted with ultrapure water and then subjected to UPLC-MS / MS detection and analysis.

[0199] The logarithmic value of the remaining percentage of the test substance was plotted against the incubation time, and T 1 / 2 = 0.693 / K to calculate the elimination half-life of the test substance.

[0200] Conclusion: At least part of the compounds of the present application have good liver microsomal stability.

[0201] Experimental Example 5: Caco-2 permeability experiment

[0202] Remove the Transwell plates from the incubator. Rinse the cell monolayer membrane twice with HBSS (10 mM HEPES, pH 7.4) buffer and incubate at 37 °C for 30 minutes.

[0203] Determine the rate of compound transport from apical to basolateral. Add 125 μL of the donor solution to the upper chamber (apical) per well, then transfer 50 μL of sample to 400 μL of acetonitrile containing internal standard as a 0 minute dosing sample across the apical side of the Transwell plate. Add 235 μL of the receiver solution to the lower chamber (basolateral) per well.

[0204] Determine the rate of compound transport from basolateral to apical. Add 75 μL of the receiver solution to the upper chamber (apical) per well and 285 μL of the donor solution to the lower chamber (basolateral) per well. Then transfer 50 μL of sample to 400 μL of acetonitrile containing internal standard as a 0 minute dosing sample across the basolateral side of the Transwell plate.

[0205] Combine the upper and lower transport apparatus and incubate at 37 °C for 2 hours.

[0206] Transfer 50 μL of sample from the work solution preparation plate to 400 μL of acetonitrile containing internal standard as a 0 minute dosing sample for analysis.

[0207] After the incubation is complete, take 50 μL from each well of the upper and lower chambers of the Transwell plate and add to a new sample tube. Add 400 μL of acetonitrile containing internal standard to the sample tube, vortex for 10 minutes, and centrifuge at 4000 rpm for 30 minutes. Take 150 μL of the supernatant and dilute with an equal volume of water before analysis by LC-MS / MS. All samples are prepared in duplicate.

[0208] Evaluate the integrity of the cell monolayer membrane after 2 hours of incubation using a fluorescent yellow leakage assay. Dilute the fluorescent yellow stock solution with HBSS (10 mM HEPES, pH 7.4) to a final concentration of 100 μM. Add 100 μL of the fluorescent yellow solution to each well of the upper Transwell insert plate and 300 μL of HBSS (10 mM HEPES, pH 7.4) to each well of the lower receiver plate. After incubation at 37 °C for 30 minutes, remove 80 μL of the solution from each well of the upper and lower chambers into a new 96-well plate. Measure the fluorescence using a microplate reader at an excitation wavelength of 485 nm and an emission wavelength of 530 nm.

[0209] Calculate the apparent permeability coefficient (Papp) of the compound in Caco-2 cells by specific concentrations of the receiver and donor sides. app , units: cm / s) is calculated using the following equation:

[0210] In the formula, V A The volume of the receiving end solution (0.235 mL from the top end to the base end, and 0.075 mL from the base end to the top end), Area is the Transwell-96 well plate membrane area (0.143 cm 2 ); time is the incubation time (unit: s).

[0211] The efflux rate is calculated using the following formula:

[0212] In the formula, P app(B-A) is the apparent permeability coefficient from the base end to the top end;

[0213] P app(A-B) is the apparent permeability coefficient from the top end to the base end.

[0214] Conclusion: At least part of the compounds have better permeability and efflux ratio.

[0215] Experimental Example 6: In vivo pharmacokinetic experiment

[0216] The pharmacokinetic characteristics of the test compound under oral administration and intravenous injection of CD-1 (ICR) male mice are tested.

[0217] The compound is dissolved in 5% DMSO / 10% Solutol / 85% saline, ultrasonically dissolved to obtain a clear solution, and then filtered through a microporous filter for standby. CD-1 (ICR) male mice are selected, and the candidate compound solution is administered intravenously or orally. Whole blood is collected at a certain time, and plasma is prepared. The drug concentration is analyzed by LC-MS / MS method, and the data is processed by Phoenix WinNonlin software to calculate the pharmacokinetic parameters. The blood collection time points of the IV group are 0.033 h, 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration; the blood collection time points of the PO group are 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration.

[0218] Conclusion: At least part of the compounds have good pharmacokinetic properties.

[0219] Note that the present application is not limited to the above-described embodiments. The above-described embodiments are merely examples, and embodiments having substantially the same configuration, function, and effect as the technical idea of the present application are included in the technical scope of the present application. Furthermore, other modes constructed by applying various modifications to the embodiments, or by combining part of the configurations of the embodiments, which can be conceived by those skilled in the art, without departing from the spirit of the present application, are also included in the scope of the present application.

Claims

1. A compound of Formula I, or a stereoisomer thereof, a tautomer thereof, a polymorph thereof, a solvate thereof, a hydrate thereof, an N-oxide thereof, an isotopically labeled compound thereof, a metabolite thereof, an ester thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof: wherein, A ring is selected from 5-10 membered heteroaryl, C 6-10 aryl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; Each R a Independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, -NR A1 R A2 , Oxide group, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -O(C) 3-6 cycloalkyl), 4-8 membered heterocyclic groups, 5-10 membered heteroaryl groups, C 6-10 Aryl, -C(O)C 1-6 Alkyl groups, or two R atoms attached to the same carbon atom a Together with the carbon atoms they are attached to, they form C=T; the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, -O(C) 3-6 cycloalkyl), 4-8 membered heterocyclic groups, 5-10 membered heteroaryl groups, C 6-10 Yuanfangji, -C(O)C 1-6 Alkyl groups are optionally each independently bound by one or more R a 'replace; R A1 and R A2 each independently is selected from H, deuterium, C 1-6 alkyl or -C(O)C 1-6 alkyl; T is selected from CR e R f , R e and R f are each independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl; R a ’ is selected from deuterium, halogen, cyano, amino, hydroxyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, or C 3-6 cycloalkyl; t is 0, 1, 2, 3 or 4; B ring is selected from 5-10 membered heteroaryl; Each R b Independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl; s is 0, 1, 2, 3 or 4; R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl or -C 1-6 alkylene-OC 1-6 alkyl; m is 0, 1, 2 or 3; R 3 selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 deuterated alkyl; X1is selected from CR X1 or N; X2is selected from CR X2 or N; X3is selected from CR X3 or N; R X1 , R X2 , R X3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; C ring is selected from a 5-7 membered heterocyclyl or C 5-7 cycloalkyl, the heteroatom in the 5-7 membered heterocyclyl is selected from one or both of nitrogen or oxygen; Each R c Independently selected from hydrogen, deuterium, hydroxyl, oxo group, and -S(O). n C 1-6 alkyl; n is selected from 1 or 2; q is selected from 0, 1, 2 or 3.

2. The compound as claimed in claim 1, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotopically-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, wherein, Each R c Independently selected from hydrogen, hydroxyl, oxo group or -S(O)2C 1-6 alkyl; Preferably, each R c is independently selected from hydrogen, hydroxyl, oxo, or -S(O)2CH3; and / or q is selected from 0 or 1; Preferably, q is 1.

3. The compound according to claim 1 or 2, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that, Structural unit selected from the group consisting of wherein, Z1, Z2, Z3are each independently selected from CH2, O or NH, and at least one of Z1, Z2is selected from CH2; v is selected from 0, 1 or 2; Preferably, Z1is selected from CH2or O; Z2is selected from NH or CH2; Z3is selected from O, CH2or NH; Preferably, the structural unit selected from the group consisting of Preferably, the structural unit selected from the group consisting of More preferably, the structural unit selected from the group consisting of 4. The compound according to any one of claims 1 to 3, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that, X1is selected from CR X1 ; X2is selected from CR X2 ; X3is selected from CR X3 ; and / or R X1 , R X2 , R X3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy; Preferably, R X1 R X2 R X3 Each is independently selected from hydrogen, F, Cl, Br, methyl, ethyl, -OCH3, -OCH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, -OCH2F, -OCHF2 or -OCF3; Preferably, R X1 , R X2 , R X3 are each independently selected from hydrogen or halogen (e.g. F); Preferably, R X1 , R X2 , R X3 one of which is halogen (e.g. F) and the others are hydrogen; Preferably, R X1 , R X2 are each hydrogen, and R X3 is halogen (e.g., F), or, R X1 is halogen (e.g., F), R X2 , R X3 are each hydrogen; Preferably, R X1 , R X2 , R X3 are each hydrogen.

5. The compound according to any one of claims 1 to 4, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that, Structural unit selected from the group consisting of wherein j is selected from 0, 1, 2, 3, 4 or 5, preferably j is selected from 0, 1 or 2, more preferably 0, Z1, Z2, Z3are defined as in claim 3; Preferably, the structural unit selected from the group consisting of more preferably 6. The compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that, m is 1.

7. The compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is as shown in formula (II): wherein R c , q, Z1, Z2, Z3, v, X1, X2, X3, R 3 , R 2 , R 1 , B ring, R b , s, A ring, R a , t are as defined in any one of claims 1 to 6.

8. The compound according to any one of claims 1 to 7, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that, R 3 selected from H; and / or Preferably, R 1 and R 2 Each is independently selected from hydrogen and C. 1-4 Alkyl or -C 1-4 Alkylene-OC 1-4 alkyl; Preferably, R 1 and R 2 wherein one is selected from hydrogen, the other is selected from hydrogen, -CH3or -CH2OCH3; More preferably, R 1 and R 2 are both selected from hydrogen.

9. The compound according to any one of claims 1 to 8, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that, ring B is selected from 9-10 membered bicyclic fused heteroaryl; Preferably, ring B is selected from wherein E 1 , E 2 , E 3 , E 4 , E 5 , and E 6 are each independently selected from N or CH, and at least one is N, preferably both are N, preferably E 1 and E 5 are N; Preferably, ring B is selected from wherein the bond marked "#" is connected to CR 1 R 2 (when m is not 0) or C(=0) (when m is 0), the bond marked "#A" is connected to ring A, E 1 , E 2 , E 3 , E 4 , E 5 and E 6 are each independently selected from N or CH, and at least one is N, preferably both are N, preferably E 1 and E 5 are N; Preferably, ring B is selected from Preferably, ring B is selected from wherein the bond identified with "#" is connected to CR 1 R 2 (when m is other than 0) or C(=0) (when m is 0), the bond identified with "#A" is connected to the A ring; Preferably, ring B is selected from Preferably, ring B is selected from wherein the bond identified with "#" is connected to CR 1 R 2 (when m is other than 0) or C(=0) (when m is 0), the bond identified with "#A" is connected to the A ring.

10. The compound according to any one of claims 1 to 9, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that, each R is independently selected from hydrogen, deuterium, halogen, C1-C4-alkyl; and / or b is independently selected from hydrogen, deuterium, halogen, C1-C4-alkyl; and / or 1-6 alkyl; and / or Preferably, s is selected from 0 or 1; More preferably, s is 0.

11. The compound according to any one of claims 1 to 10, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that, A ring is selected from 5-10 membered heteroaryl, C 6-10 aryl, 5-10 membered heterocyclyl; Preferably, ring A is selected from 5-6 membered heteroaryl, phenyl or 9-10 membered heterocyclyl; Preferably, ring A is selected from 5-6 membered heteroaryl, phenyl or 9-10 membered partially unsaturated heterocyclyl; Preferably, the A ring is selected from G1, G2, G3, G4, G5are each independently selected from CH or N; preferably, G1, G2, G3, G4, G5are all CH; preferably, one or two of G1, G2, G3, G4, G5are N and the others are CH; preferably, G1is N and G2, G3, G4, G5are all CH; G 1’ is selected from O, NH, S or CH2, preferably G 1’ is selected from O, NH or CH2, more preferably G 1’ is selected from O; represents the connecting site with ring B; Preferably, the A ring is selected from wherein, represents the connecting site with ring B; Preferably, the A ring is selected from wherein represents the connecting site with ring B.

12. The compound according to any one of claims 1 to 11, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that, each R is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, -C(O)C a alkyl, -NHC(O)C 1-6 alkyl, oxo, C 1-6 alkyl, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, -O(C 3-6 cycloalkyl), 4-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl; said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, -O(C 3-6 cycloalkyl), 4-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl are optionally each independently substituted with one or more R a’ substituents; Preferably, each R a Independently selected from halogens, cyano groups, and -C(O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Saturated cycloalkyl, 4-7 membered saturated heterocyclic groups, 5-6 membered heteroaryl groups; the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Saturated cycloalkyl, 4-7 saturated heterocyclic, and 5-6 heteroaryl groups are optionally each independently bound by one or more R groups. a 'replace; R is independently selected from C a R is independently selected from C 3-6 saturated cycloalkyl, 4-7 membered saturated heterocyclyl, optionally each independently substituted with one or more (e.g. 1, 2 or 3) R 3-6 saturated cycloalkyl, 4-7 membered saturated heterocyclyl, optionally each independently substituted with one or more (e.g. 1, 2 or 3) R a ’substituents; Preferably, each R a is independently selected from cyclobutyl, said cyclobutyl, optionally each independently substituted by one or more (e.g. 1, 2 or 3) R a substituted; and / or Preferably, R a is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 saturated cycloalkyl; Preferably, R a ' is selected from halogen or C 1-6 alkyl; Preferably, each R a is independently selected from cyclobutyl or (preferably ) and / or t is selected from 0, 1, 2 or 3; Preferably, t is selected from 0, 1 or 2; Preferably, t is 1.

13. The compound according to any one of claims 1 to 12, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is as shown in formula (III): wherein R c , q, Z1, Z2, Z3, v, X1, X2, X3, R 3 , R 2 , R 1 , E 1 , E 2 , E 3 , E 4 , E 5 , E 6 , R b , s, A ring, R a , t are as defined in any one of claims 1 to 12; Preferably, the compound is as shown in general formula (III-0): wherein R c , q, Z1, Z2, Z3, v, X1, X2, X3, R 3 , R 2 , R 1 , R b , s, A ring, R a , t are as defined in any one of claims 1 to 12.

14. The compound as claimed in claim 13, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotopically-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, wherein, The compound is represented by any one of formulae (III-1), (III-2), (III-3), or (III-4): wherein Z1, Z2, Z3, j, X1, X2, X3, R 3 , R 2 , R 1 , E 1 , E 2 , E 3 , E 4 , E 5 , E 6 , R b , s, A ring, R a , t are as defined in any one of claims 1 to 13.

15. The compound as claimed in claim 14, or its stereoisomer, or its tautomer, or its polymorph, or its solvate, or its hydrate, or its N-oxide, or its isotopically-labeled compound, or its metabolite, or its ester, or its prodrug, or its pharmaceutically acceptable salt, wherein, The compound is according to any one of formulae (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), or (IV-6): wherein X1, X2, X3, R 3 , R 2 , R 1 , E 1 , E 2 , E 3 , E 4 , E 5 , E 6 , R b , s, A ring, R a , t are as defined in any one of claims 1 to 14.

16. The compound of claim 15, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is represented by any one of formulae (V-1), (V-2), (V-3), (V-4), (V-5), (V-6), (V-7), (V-8), (V-9), (V-10), (V-11), or (V-12): wherein X1, X2, X3, R 3 , R 2 , R 1 , E 1 , E 2 , E 3 , E 4 , E 5 , E 6 , R b , s, G1, G2, G3, G4, G5, G1', R a , t are as defined in any one of claims 1 to 15.

17. The compound of claim 16, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that, said compound is according to any one of formulae (VI-1), (VI-2), (VI-3), (VI-4), (VI-5), (VI-6), (VI-7), (VI-8), (VI-9), (VI-10), (VI-11), or (VI-12): wherein X1, X2, X3, R 3 , R 2 , R 1 , E 1 , E 2 , E 3 , E 4 , E 5 , E 6 , G1, G3, G4, G5, G1', R a as defined in any one of claims 1-15.

18. The compound according to any one of claims 1 to 17, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from:

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

20. The pharmaceutical composition of claim 19, wherein, further comprising a pharmaceutically acceptable carrier, adjuvant, vehicle.

21. Use of a compound of any one of claims 1 to 18, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19 or 20, for the manufacture of a medicament for the prevention and / or treatment of a cancer, which is non-small cell lung cancer, colorectal cancer, bladder cancer, primary cancer of unknown origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal cancer, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastroenteropancreatic neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenocortical carcinoma, appendix cancer, small bowel cancer, or penile cancer.

22. Use of a compound of any one of claims 1 to 18, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19 or 20, for the manufacture of a medicament for the prevention and / or treatment of a disease or disorder of BRG1 (SMARCA4) loss-of-function or mutation.

23. Use according to claim 22, characterized in that, The disease or disorder of BRG1 (SMARCA4) loss-of-function or mutation is a cancer or a tumor.

24. Use according to claim 23, characterized in that, The cancer or tumor is selected from non-small cell lung cancer, colorectal cancer, bladder cancer, primary cancer of unknown origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal cancer, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastroenteropancreatic neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenocortical carcinoma, appendix cancer, small bowel cancer, or penile cancer.

25. A compound of any one of claims 1 to 18, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19 or 20, for use in the prevention and / or treatment of cancer; preferably, the cancer is selected from non-small cell lung cancer, colorectal cancer, bladder cancer, primary cancer of unknown origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal cancer, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastroenteropancreatic neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenocortical carcinoma, appendix cancer, small bowel cancer, or penile cancer.

26. A compound of any one of claims 1 to 18, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19 or 20, for use in the prevention and / or treatment of a disease or disorder of BRG1 (SMARCA4) loss-of-function or mutation; preferably, the disease or disorder of BRG1 (SMARCA4) loss-of-function or mutation is a cancer or a tumor; preferably, the cancer or tumor is selected from non-small cell lung cancer, colorectal cancer, bladder cancer, primary cancer of unknown origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal cancer, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastroenteropancreatic neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenocortical carcinoma, appendix cancer, small bowel cancer, or penile cancer.

27. A method of preventing and / or treating cancer, the method comprising administering to an individual in need thereof a prophylactically and / or therapeutically effective amount of a compound according to any one of claims 1 to 18, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19 or 20; preferably, the cancer is selected from non-small cell lung cancer, colorectal cancer, bladder cancer, primary cancer of unknown origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal cancer, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastroenteropancreatic neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenal cortex cancer, appendix cancer, small intestine cancer, or penile cancer.

28. A method of preventing and / or treating a disease or disorder of BRG1 (SMARCA4) loss-of-function or mutation, the method comprising administering to an individual in need thereof a prophylactically and / or therapeutically effective amount of a compound according to any one of claims 1 to 18, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or a hydrate thereof, or an N-oxide thereof, or an isotopically-labeled compound thereof, or a metabolite thereof, or an ester thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19 or 20; preferably, the disease or disorder of BRG1 (SMARCA4) loss-of-function or mutation is a cancer or a tumor; preferably, the cancer or tumor is selected from non-small cell lung cancer, colorectal cancer, bladder cancer, primary cancer of unknown origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal cancer, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastroenteropancreatic neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymoma, adrenal cortex cancer, appendix cancer, small intestine cancer, or penile cancer.

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