Pyrazolopyrimidine compounds used as ATR kinase inhibitors

Abstract

Disclosed are compounds of general formula (I) that can be used to treat diseases mediated by ATR kinase, e.g., proliferative diseases such as cancer. Also disclosed are methods for preparing compounds of general formula (I), pharmaceutical compositions, and the use of pharmaceutical compositions to treat diseases mediated by ATR kinase. TIFF2023534676000064.tif37144

Description

[Technical Field]

[0001] This disclosure relates to pyrazolopyrimidine compounds as ATR kinase inhibitors. More specifically, the compounds of this disclosure are effective in treating ATR kinase-mediated diseases, such as proliferative disorders like cancer. This disclosure also provides pharmaceutical compositions of the compounds, the use of the compounds for treating ATR kinase-mediated diseases, and the manufacture of the compounds. [Background technology]

[0002] ATR (Ataxia telangiectasia and Rad)3-related proteins are a group of protein kinases involved in genome stability and DNA damage repair. They belong to the PIKK family. ATR activation is triggered by replication fork stalling or DNA single-strand breaks (SSBs). ATR activation will ensure genome stability by recruiting repair proteins or repair factors, repairing damaged sites, slowing the mitotic process (particularly the process in the G2 / M phase of mitosis), and stabilizing the replication fork.

[0003] In addition, the DNA damage repair system in most tumor cells is abnormal, usually lacking specific repair pathways (such as p53 or ATM mutations), and becoming dependent on ATR for survival. In normal cells, because of their robust and complete repair pathways, inhibiting ATR kinase alone would likely have little impact. Therefore, inhibiting ATR may have a more significant effect on cancer treatment without causing major toxic side effects in normal cells.

[0004] Furthermore, inhibition of ATR can be combined with radiotherapy or chemotherapeutic agents to synergistically enhance their effects. Commonly used chemotherapeutic agents include antimetabolites (such as gemcitabine), DNA crosslinking agents (such as cisplatin and carboplatin), and alkylating agents (such as temozolomide), topoisomerase inhibitors (such as topotecan and irinotecan), etc. When tumor cells are affected by chemotherapy or radiotherapy, the ATR signaling pathway is activated to a greater extent to repair damaged DNA. Therefore, when treating cancer using radiotherapy or chemotherapy, simultaneously inhibiting ATR can greatly improve the therapeutic effect against cancer.

[0005] So far, ATR inhibitors have not yet been on the market, and there is still a need to find more effective and safe ATR inhibitors.

Summary of the Invention

[0006] The present disclosure provides compounds of general formula (I) that can be used to treat diseases mediated by ATR kinase, such as proliferative diseases such as cancer.

[0007] In one aspect, the present disclosure relates to general formula (I):

Chemical formula

[0008] In yet another embodiment, the present disclosure provides a pharmaceutical composition which may comprise the compounds disclosed herein and optionally pharmaceutically acceptable excipients.

[0009] In yet another embodiment, the present disclosure provides a pharmaceutical composition comprising the compounds disclosed herein and pharmaceutically acceptable excipients, and further comprising other therapeutic agents.

[0010] In yet another embodiment, the Disclosure provides a kit comprising the compounds disclosed herein, other therapeutic agents, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0011] In yet another embodiment, the Disclosure provides the use of the compounds disclosed herein in the manufacture of pharmaceuticals for the treatment and / or prevention of ATR kinase-mediated diseases.

[0012] In yet another embodiment, the present disclosure provides a method for treating and / or preventing an ATR kinase-mediated disease in a subject, comprising administering to the subject a compound or composition disclosed herein.

[0013] In yet another embodiment, the present disclosure provides compounds or compositions disclosed herein for use in the treatment and / or prevention of ATR kinase-mediated diseases.

[0014] In certain embodiments, the diseases include proliferative disorders (such as cancer), particularly solid tumors (such as carcinomas and sarcomas), leukemias and lymphomas, in particular, for example, breast cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchoalveolar cancer), prostate cancer and biliary tract cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer, as well as leukemia [including acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), etc.], multiple myeloma and lymphoma.

[0015] Other purposes and advantages of this disclosure will be apparent to those skilled in the art from the specific embodiments, examples and claims disclosed herein.

[0016] definition chemistry definition The definitions of specific functional groups and chemical terms are explained in more detail below.

[0017] When values ​​are listed as a range, it shall encompass each value within that range and its sub-ranges. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 It shall include alkyl groups.

[0018] "C 1-6 "Alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl can be used as a substitute. C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). 1-6 The term "alkyl" also includes heteroalkyls, where one or more (e.g., 1, 2, 3, or 4) carbon atoms are substituted with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkyl alkyl groups can be optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional abbreviations for alkyl include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0019] "C 2-6 An "alkenyl" is a linear or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl can be used as a substitute. C 2-6Examples of alkenyls include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. 2-6 The term "alkenyl" also encompasses heteroalkenyls, where one or more (e.g., 1, 2, 3, or 4) carbon atoms are substituted with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0020] "C 2-6 "Alkynyl" refers to a linear or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more double bonds. In some embodiments, C 2-4 Alkinyl can be used as a substitute. C 2-6 Examples of alkynyls include, but are not limited to, ethinyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), etc. 2-6 The term "alkynyl" also encompasses heteroalkynyl, where one or more (e.g., 1, 2, 3, or 4) carbon atoms are substituted with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0021] "C 1-6 Alkilen, C 2-6 Alkenylene or C 2-6 "Alkinylene" is the same as the above-mentioned "C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 This refers to the divalent group of "alkynyl".

[0022] "C 1-6 "Alkilen" is C 1-6A divalent group formed by removing another hydrogen of an alkyl, which can be a substituted or unsubstituted alkylene. In some embodiments, C 1-4 The alkylene is further alternative. Examples of unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), etc. Examples of substituted alkylene groups such as groups substituted with one or more alkyls (methyl) include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0023] “C 2-6 Alkenylene” refers to a C 2-6 alkenyl group from which another hydrogen is removed to provide a divalent group of alkenylene, which may be a substituted or unsubstituted alkenylene. In some embodiments, C 2-4 The alkenylene is further alternative. Examples of unsubstituted alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Examples of substituted alkenylene groups substituted with one or more alkyls (methyl) include, but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), etc.

[0024] "C 2-6 "alkynylene" refers to a divalent group of alkynylene formed by the removal of another hydrogen from C 2-6 "alkynyl" group, which may be a substituted or unsubstituted alkynylene. In some embodiments, C 2-4 "alkynylene" is further alternative. Examples of alkynylene groups include, but are not limited to, ethynylene (-C≡C-), substituted or unsubstituted propynylene (-C≡CCH2-), etc.

[0025] "C 1-6 "alkoxy" refers to the group -OR where R is a substituted or unsubstituted C 1-6 "alkyl". In some embodiments, C 1-4 "alkoxy" group is further alternative. Specific alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy and 1,2-dimethylbutoxy. The alkoxy may be substituted, if desired, with one or more substituents, such as 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0026] "halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0027] Thus, "C 1-6 "haloalkyl" and "C 1-6 "haloalkoxy" refer to the above-mentioned "C 1-6 "alkyl" and "C 1-6 "alkoxy" which are substituted with one or more halogens. In some embodiments, C 1-4 "haloalkyl" is further alternative, and alternatively still is C 1-2 "haloalkyl". In some embodiments, C 1-4 "haloalkoxy" group is further alternative, and alternatively still is C 1-2These are haloalkoxy groups. Examples of haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, and 2,2,2-trifluoro-1,1-dimethylethyl. Examples of haloalkoxy groups include, but are not limited to, -OCH2F, -OCHF2, and -OCF3. Haloalkyl and haloalkoxy groups can be substituted at any available bond site with, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0028] "C 3-7 A "cycloalkyl" is a non-aromatic cyclic hydrocarbon group having 3 to 7 carbon ring atoms and 0 heteroatoms. In some embodiments, C 3-5 Cycloalkyls can be used as a substitute. In other embodiments, C 3-6 Cycloalkyls can be used as a substitute. In other embodiments, C 5-6 Cycloalkyls are alternatives. Cycloalkyls also include ring systems in which the cycloalkyls described herein are fused with one or more aryl or heteroaryl groups, in which case the bonding site is on the cycloalkyl ring, and even in such cases the number of carbon atoms still represents the number of carbon atoms in the cycloalkyl system. Examples of cycloalkyls include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), etc. Cycloalkyls may be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0029] A "3- to 11-membered heterocyclil" refers to a 3- to 11-membered non-aromatic ring system group having a carbocyclic atom and 1 to 5 heterocyclic atoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclils containing one or more nitrogen atoms, the bond sites can be carbon or nitrogen atoms, as long as the valence allows. In some embodiments, a 3- to 9-membered heterocyclil is substituted, which is a 3- to 9-membered non-aromatic ring system group having a carbocyclic atom and 1 to 5 heterocyclic atoms. In some embodiments, a 3- to 8-membered heterocyclil is substituted, which is a 3- to 8-membered non-aromatic ring group having a carboelectric atom and 1 to 4 heterocyclic atoms; a 3- to 6-membered heterocyclil is substituted, which is a 3- to 6-membered non-aromatic ring group having a carboelectric atom and 1 to 3 heterocyclic atoms; a 3- to 5-membered heterocyclil is substituted, which is a 3- to 5-membered non-aromatic ring group having a carboelectric atom and 1 to 2 heterocyclic atoms; a 4- to 8-membered heterocyclil is substituted, which is a 4- to 8-membered non-aromatic ring group having a carboelectric atom and 1 to 3 heterocyclic atoms; a 4- to 7-membered heterocyclil is substituted, which is a 4- to 7-membered non-aromatic ring group having a carboelectric atom and 1 to 3 heterocyclic atoms; and a 5- to 6-membered heterocyclil is further substituted, which is a 5- to 6-membered non-aromatic ring group having a carboelectric atom and 1 to 3 heterocyclic atoms. Heterocyclyl also includes ring systems in which the heterocyclyl described above is fused with one or more cycloalkyl groups, where the bond site is on the cycloalkyl ring, or ring systems in which the heterocyclyl described above is fused with one or more aryl or heteroaryl groups, where the bond site is on the cycloalkyl ring; in such cases, the number of ring members still represents the number of ring members in the heterocyclyl ring system. Examples of three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridiyl, oxyranil, and thiranil. Examples of four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanil, and thietanil.Examples of five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranil, dihydrofuranil, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanil, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Examples of five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidyl, tetrahydropyranil, dihydropyridyl, and thianyl. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanil. Examples of six-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Examples of seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Examples of five-membered heterocyclyl groups condensed with a C6 aryl (also referred to herein as 5,6-bicyclic heterocyclyls) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinol, etc. Examples of six-membered heterocyclyl groups condensed with a C6 aryl (also referred to herein as 6,6-bicyclic heterocyclyls) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. Heterocyclyls may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0030] "C 6-10"Aryl" refers to a 4n+2 aromatic ring system group having 6 to 10 carbocyclic atoms and zero heteroatoms, either monocyclic or polycyclic (e.g., bicyclic) (e.g., having 6 or 10 shared π electrons in a cyclic arrangement). In some embodiments, the aryl group has 6 carbocyclic atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has 10 carbocyclic atoms ("C6 aryl"). 10 "Aryl" (e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). The aryl group also includes ring systems in which one or more cycloalkyl or heterocyclyl groups are fused to the aryl ring, with the bonding site located on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl can be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0031] A "5-10 membered heteroaryl" refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons in the ring arrangement) having a carbon ring atom and 1-4 hetero ring atoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the bond site can be carbon or nitrogen, as long as the valence allows. A bicyclic heteroaryl ring system may contain one or more heteroatoms in one or two rings. Heteroaryls also include ring systems in which the above heteroaryl ring is fused with one or more heteroalkyl or heterocyclyl groups, with the bond site located on the heteroaryl ring. In such cases, the number of carbon atoms represents the number of carbon atoms continuously present in the heteroaryl ring system. In some embodiments, a further substitution is a 5- to 6-membered heteroaryl group, which is a monocyclic or bicyclic 4n+2 aromatic ring system having a carbon ring atom and 1 to 4 hetero ring atoms. Examples of 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Examples of 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Examples of 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl. Examples of six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl, respectively. Examples of seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl.Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolinyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolidinyl, and prinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthylidinyl, pteridinyl, quinolyl, isoquinolyl, sinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Heteroaryls can be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0032] Specific examples of alternative heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, triazolyl (4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, oxazolyl, isoxazolyl, oxazolyl (1,2,4-oxazolyl, 1,3,4-oxazolyl, 1,2,5-oxazolyl, thiazolyl, thiadiazolyl (1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl).

[0033] The term "carbonyl" is represented as -C(O)-, whether used alone or in combination with other terms (e.g., aminocarbonyl).

[0034] "Oxo" represents =O.

[0035] "Thioxo" represents S.

[0036] Alkyl, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are groups that may be optionally substituted.

[0037] Exemplary substituents on carbon atoms include, but are not limited to, halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR cc )2, -CO2R aa -OC(=O)R aa , -OCO2R aa -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa -C(=NR bb )OR aa -OC(=NR bb )R aa -OC(=NR bb )OR aa -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa -S(=O)R aa-OS(=O)R aa , -Si(R aa )3, -OSi(R aa )3, -C(=S)N(R bb )2, -C(=O)SR aa -C(=S)SR aa -SC(=S)SR aa -SC(=O)SR aa -OC(=O)SR aa , -SC(=O)OR aa -SC(=O)R aa -P(=O)2R aa -OP(=O)2R aa -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl and heteroaryl, where each of the alkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl and heteroaryl independently contains 0, 1, 2, 3, 4 or 5 R dd Substituted with the base;

[0038] Alternatively, the two geminal hydrogens on a carbon atom are =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa ,=NNRbb C(=O)OR aa ,=NNR bb S(=O)2R aa ,=NR bb or =NOR cc Replace with the base;

[0039] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl, or two R aa The groups combine to form a heterocyclyl or heteroaryl ring, where each of alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base;

[0040] R bb Each of these is independently hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl and heteroaryl, or two R bbThe groups combine to form a heterocyclyl or heteroaryl ring, where each of alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base;

[0041] R cc Each of them is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocykryl, heterocyclyl, aryl, and heteroaryl, or two R cc The groups combine to form a heterocyclyl or heteroaryl ring, where each of alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base;

[0042] R dd Each of these is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee , -OCO2R ee -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff )OR ee -OC(=NR ff )R ee-OC(=NR ff )OR ee -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl, where each of alkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg Substituted by or two Geminal R dd Substituents can combine to form =O or =S;

[0043] R ee Each of these is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocykrill, aryl, heterocyclyl, and heteroaryl, where each of alkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg Substituted with the base;

[0044] R ff Each of them is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocykryl, heterocyclyl, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclyl or heteroaryl ring, where each of alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. gg Substituted with the base;

[0045] R gg Each of these is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2,-N(C 1-6 Alkyl)2,-N(C 1-6 Alkyl)3 + X - , -NH(C 1-6 Alkyl)2 + X - , -NH2(C 1-6 Alkyl) + X - , -NH3 + X - , -N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -CO2H, -CO2(C 1-6 Alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl), -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2,-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 Alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2,-NHC(=O)NH(C 1-6 Alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC(=NH)(C 1-6 Alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2,-C(=NH)NH(C 1-6 Alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2,-OC(NH)NH(C 1-6 Alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2,-NHC(=NH)NH2,-NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2,-SO2NH(C 1-6 Alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 Alkyl)3,-OSi(C 1-6 Alkyl)3,-C(=S)N(C 1-6 Alkyl)2, C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2, -OP(=O)(C 1-6 Alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 carbocyclyl, C6-C 10 Aryl, C3-C7 heterocyclyl, and C5-C 10Selected from heteroaryls; or two geminal Rs gg The substituents may combine to form =O or =S; where X - It is a counterion.

[0046] Examples of substituents on the nitrogen atom include, but are not limited to, hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR bb )R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl and heteroaryl, or two R atoms bonded to a nitrogen atom cc The groups combine to form a heterocyclyl or heteroaryl ring, where each of alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base, where R aa , R bb , R cc and R dd This is as described herein.

[0047] Other definitions The term "cancer" is not limited to but includes cancers of the breast, ovaries, cervix, prostate, testes, esophagus, stomach, skin, lungs, bones, colon, pancreas, thyroid, biliary tract, cheek cavity and pharynx (mouth), lips, tongue, oral cavity, pharynx, small intestine, rectum, large intestine, colon, cancers of the brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermal carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, bone marrow disorders, lymphatic disorders, Hodgkin's disease, hairy cell carcinoma, and leukemia.

[0048] As used herein, the term “to treat” refers to the disorder or symptom to which the term applies, or to the reversal, alleviation, inhibition of progression, or prevention of one or more signs of such disorder or symptom. As used herein, the noun “treatment” refers to the verb action of treating, the latter being precisely as defined.

[0049] As used herein, the term “pharmaceutically acceptable salt” means the carboxylate and amino acid addition salts of the compounds disclosed herein that are suitable for contact with patient tissue within the bounds of reliable medical judgment and do not cause inappropriate toxicity, irritation, allergy, etc. They are commensurate with a reasonable ratio of benefits and risks and are effective for their intended use. The term encompasses, where possible, the zwitterionic forms of the compounds disclosed.

[0050] Medicinally acceptable base addition salts are formed using metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, and calcium. Suitable examples of amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0051] Base addition salts of acidic compounds can be prepared by contacting the free acid with a sufficient amount of base in a conventional manner to form a salt. The free acid can be regenerated by contacting the salt with the acid in a conventional manner and then isolating the free acid. The free acid may differ somewhat from the salt in terms of its physical properties, such as solubility in polar solvents. However, for the purposes of this disclosure, the salt is still equivalent to its respective free acid.

[0052] Salts can be produced from inorganic acids and include sulfates, pyrosulfates, bisulfates, sulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides. Examples of acids include hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, methanesulfonate, glucoheptanoate, lactobionate, lauryl sulfate, and isethionate. Salts can also be produced from organic acids, including aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanos, hydroxyalkanoics, alkanedioics, aromatic acids, and aliphatic and aromatic sulfonic acids. Typical salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberinate, sebacinate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, besilate, tosilate, phenylacetate, citrate, lactate, maleate, tartrate, and methanesulfonate. Medicinally acceptable salts include, but are not limited to, cations based on alkali metals and alkaline earth metals such as sodium, lithium, potassium, calcium, and magnesium, as well as ammonium, tetramethylammonium, triethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine, and may also include non-toxic ammonium, quaternary ammonium, and amine cations. Salts of amino acids such as alginates, glucons, and galacturons are also included (see, for example, Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19).

[0053] Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this disclosure include C1-C6 alkyl esters, where the alkyl group is either linear or branched. Acceptable esters also include, but are not limited to, C5-C7 cycloalkyl esters, as well as arylalkyl esters such as benzyl esters. C1-C4 alkyl esters are alternatives. Esters of the compounds of this disclosure can be prepared by conventional methods, e.g., according to March's Advanced Organic Chemistry, 5th Edition, MB Smith & J. March, John Wiley & Sons, 2001.

[0054] Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this disclosure include amides derived from ammonia, primary C1-C6 alkylamines, and secondary C1-C6 dialkylamines, where the alkyl group is linear or branched. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amines, and C1-C2 dialkyl secondary amines are alternatives. Amides of the compounds of this disclosure can be prepared by conventional methods, e.g., according to March's Advanced Organic Chemistry, 5th Edition, MB Smith & J. March, John Wiley & Sons, 2001.

[0055] The “subjects” to which administration is planned include, but are not limited to, humans, for example, men or women of any age group, for example, pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young, middle-aged, or elderly adults), and / or non-human animals such as mammals, for example, primates (e.g., crab-eating macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is human. In some embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” may be used interchangeably herein.

[0056] The terms "disease," "disorder," and "symptom" may be used interchangeably in this specification.

[0057] Unless otherwise specified, the term “treatment” as used herein includes effects on an object suffering from a particular disease, disorder, or condition that reduce the severity of the disease, disorder, or condition, or that delay or slow the progression of the disease, disorder, or condition (“therapeutic treatment”). The term also includes effects that occur before the object begins to suffer from a particular disease, disorder, or condition (“preventive treatment”).

[0058] Generally, the “effective amount” of a compound refers to the amount sufficient to elicit a targeted biological response. As will be understood by those skilled in the art, the effective amount of a compound in this disclosure may vary depending on the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the method of administration, and factors such as the age, health status, and symptoms of the subject. The effective amount includes both a therapeutically effective amount and a prophylactically effective amount.

[0059] Unless otherwise specified, the “therapeutically effective amount” of a compound as used herein is an amount sufficient to provide a therapeutic benefit in the course of treating a disease, disorder, or symptom, or to delay or minimize one or more signs associated with said disease, disorder, or symptom. The therapeutically effective amount of a compound means the amount of the therapeutic agent that, when used alone or in combination with other therapeutic agents, provides a therapeutic benefit in treating a disease, disorder, or symptom. The term “therapeutically effective amount” may include an amount that improves the overall treatment, an amount that reduces or avoids the signs or etiology of a disease or symptom, or an amount that enhances the therapeutic effect of other therapeutic agents.

[0060] Unless otherwise specified, as used herein, “prophylactically effective amount” of a compound means an amount sufficient to prevent a disease, disorder or symptom, or one or more signs associated with a disease, disorder or symptom, or a amount sufficient to prevent recurrence of a disease, disorder or symptom. The prophylactically effective amount of a compound means the amount of the therapeutic agent that, when used alone or in combination with other therapeutic agents, provides a prophylactic benefit in preventing a disease, disorder or symptom. The term “prophylactically effective amount” may include an amount that improves the overall treatment or enhances the prophylactic effect of other therapeutic agents.

[0061] "Combination" and related terms refer to the simultaneous or sequential administration of the compounds of this disclosure with other therapeutic agents. For example, the compounds of this disclosure may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form. [Modes for carrying out the invention]

[0062] As used herein, the terms “compounds disclosed herein” or “compounds of the disclosure” mean the compounds of the following formulas (I) to (III) (including subformulas such as (I-1), (II-2), (III-3), etc.), or their pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants, or mixtures thereof.

[0063] In this disclosure, compounds are named using standard nomenclature. For compounds with chiral centers, it should be understood that all optical isomers and mixtures thereof are included unless otherwise specified. Furthermore, unless otherwise specified, all isomer compounds and carbon-carbon double bonds included in this disclosure may arise in Z and E forms. For compounds existing in different tautomer forms, one of the compounds is not limited to a specific tautomer, but covers all tautomer forms. General formulas, including descriptions and variable groups, are used for specific compounds. Unless otherwise specified, each variable group in such formula is defined independently of any other variable group, and any multiple variable groups, with any one variable group independently defined in each occurrence.

[0064] In one embodiment, the disclosure relates to general formula (I): [ka] [In formula: X is CR X or N; Y is CR Y or N; R1, R2, R3, R4 and R Y These are independently H, D, halogen, and C. 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from alkynyls, or R1 and R2, R3 and R4 are linked to form a bond, C 1-6 Alkilen, C 2-6 Alkenylene or C 2-6 It forms an alkynylene; where the group may be substituted with one or more D or halogens until it is completely replaced; Here, R X H, D, halogen, -CN, -NRR', -OR, -SR or C 1-6 It is an alkyl group, where the group may be substituted with one or more D or halogens until it is completely substituted; Y is CR Y If R YAnd R1, together with the atoms they bond to, C 3-5 Forming a cycloalkyl or 3- to 5-membered heterocycline, where the group may be substituted with one or more D or halogens until completely replaced; Ring A is C 3-7 Cycloalkyl, 4-7 membered heterocyclyl, C 6-10 It is either an aryl or a 5-10 member heteroaryl; or ring A is absent, so there is 1 R a is linked to L; or (R a ) m -Ring AL- does not even exist; R a These are independently H, D, halogen, -CN, -NRR', -OR, -SR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) p R, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Selected from cycloalkyls and 3- to 8-membered heterocyclines, each of which optionally includes R * It may be replaced by, where the group may be replaced by one or more D or halogens until it is completely replaced; m is 0, 1, 2, 3, 4, or 5; Ring B is a 5- or 6-membered heteroaryl; R b These are independently H, D, halogen, -CN, -NRR', -OR, -SR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) p R, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Selected from cycloalkyl and 3- to 8-membered heterocyclines, each of which may optionally be R *It may be replaced by, where the group may be replaced by one or more D or halogens until it is completely replaced; n is 0, 1, 2, 3, 4, or 5; Ring C is C 3-7 Cycloalkyl, 4-7 membered heterocyclyl, C 6-10 It is an aryl or a 5- to 10-membered heteroaryl; L represents a bond, -O-, -S-, -N(R)-, -C(O)-, C 1-6 Alkilen, C 2-6 Alkenylene or C 2-6 It is alkynylene; R5 stands for H, D, Halogen, -CN, -NRR', -OR, -SR, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 It is an alkynyl group, where the group may be substituted with one or more D or halogens until it is completely substituted; R6 stands for H, D, Halogen, -CN, -NRR', -OR, -SR, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 It is an alkynyl group, where the group may be substituted with one or more D or halogens until it is completely substituted; R * H, halogen, -CN, -NRR', -OR, -SR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) p R, C 3-7 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 An aryl or 5- to 10-membered heteroaryl group, where the group may be substituted with one or more D or halogens until completely replaced; R and R' are independent of H and C. 1-6 Alkyl, C 2-6 Alkenyl and C 2-6Selected from alkynyl groups, or R and R' together with their bonded nitrogen atoms, form a 4- to 8-membered heterocycline; where the group may be substituted with one or more D or halogens until completely replaced; p is either 1 or 2. This relates to the compounds represented by [the specified symbol], or their pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants, or mixtures thereof.

[0065] X and Y In a particular embodiment, X is CR X And; in yet another specific embodiment, X is CH; and in yet another specific embodiment, X is N.

[0066] In a particular embodiment, Y is CR Y And; in another specific embodiment, Y is N.

[0067] R1, R2, R3, R4 and R Y In one particular embodiment, R1 is H; in yet another particular embodiment, R1 is D; in yet another particular embodiment, R1 is a halogen; and in yet another particular embodiment, R1 is (R)-C 1-6 Alkyl, for example, (R)-methyl C 1-6 It is alkyl; in another specific embodiment, R1 is (R)-C 1-6 C such as haloalkyl 1-6 It is a haloalkyl; in yet another specific embodiment, R1 is C 2-6 It is an alkenyl; in another specific embodiment, R1 is C 2-6 It is alkinyl.

[0068] In one particular embodiment, R2 is H; in yet another particular embodiment, R2 is D; in yet another particular embodiment, R2 is halogen; and in yet another particular embodiment, R2 is (R)-C 1-6 Alkyl, for example, (R)-methyl C 1-6 It is alkyl; in another specific embodiment, R2 is (R)-C 1-6 C such as haloalkyl 1-6 It is a haloalkyl; in yet another specific embodiment, R2 is C 2-6 It is an alkenil; in another specific embodiment, R2 is C 2-6 It is alkinyl.

[0069] In one particular embodiment, R3 is H; in yet another particular embodiment, R3 is D; in yet another particular embodiment, R3 is halogen; in yet another particular embodiment, R3 is (R)-C 1-6 Alkyl, for example, (R)-methyl C 1-6 It is alkyl; in another specific embodiment, R3 is (R)-C 1-6 C such as haloalkyl 1-6 It is a haloalkyl; in yet another specific embodiment, R3 is C 2-6 It is an alkenyl; in another specific embodiment, R3 is C 2-6 It is alkinyl.

[0070] In one particular embodiment, R4 is H; in yet another particular embodiment, R4 is D; in yet another particular embodiment, R4 is halogen; in yet another particular embodiment, R4 is (R)-C 1-6 Alkyl, for example, (R)-methyl C 1-6 It is alkyl; in another specific embodiment, R4 is (R)-C 1-6 C such as haloalkyl 1-6 It is a haloalkyl; in yet another specific embodiment, R4 is C 2-6 It is an alkenyl; in yet another specific embodiment, R4 is C2-6 It is alkinyl.

[0071] In this particular embodiment, R Y is H; in another specific embodiment, R Y is D; and in another specific embodiment, R Y is a halogen; in another specific embodiment, R Y is (R)-C 1-6 Alkyl, for example, (R)-methyl C 1-6 It is alkyl; in another specific embodiment, R Y is (R)-C 1-6 C such as haloalkyl 1-6 It is a haloalkyl; in yet another specific embodiment, R Y is C 2-6 It is an alkenyl; in yet another specific embodiment, R Y is C 2-6 It is alkinyl.

[0072] In yet another specific embodiment, at least one of R1 and R2 is (R)-C 1-6 Alkyl, for example, (R)-methyl C 1-6 It is alkyl.

[0073] In yet another specific embodiment, R1 and R2, or R3 and R4 are linked to form a bond; and in yet another specific embodiment, R1 and R2, or R3 and R4 are linked to form a bond such as methylene, ethylene, or propylene. 1-6 Forming an alkylene; in another specific embodiment, R1 and R2, or R3 and R4 are linked together, C 2-6 Forming an alkenylene; in another specific embodiment, R1 and R2, or R3 and R4 are linked to C 2-6 Forms alkynylenes.

[0074] In yet another specific embodiment, the above group may be substituted with one or more D or halogens until completely replaced.

[0075] In yet another specific embodiment, Y is CR Y If R Y And R1, together with the atoms they bond to, C 3-5 Forming a cycloalkyl group; in another specific embodiment, C 3-5 The cycloalkyl is cyclopropyl; in another specific embodiment, C 3-5 The cycloalkyl is cyclobutyl; in another specific embodiment, C 3-5 The cycloalkyl is cyclopentyl; in yet another specific embodiment, Y is CR Y If R Y R1 and R1, together with their bonding atoms, form a 3-5 member heterocycline; in yet another specific embodiment, the 3-5 member heterocycline is oxyranyl, aziridiyl, or thiranyl; in yet another specific embodiment, the 3-5 member heterocycline is oxetanyl, azetidinyl, or thietanyl; in yet another specific embodiment, the 3-5 member heterocycline is tetrahydrofuranyl, pyrrolidinyl, or thiolanyl. In yet another specific embodiment, C 3-5 Cycloalkyls and 3- to 5-membered heterocyclines may be substituted with one or more D or halogens until they are completely substituted.

[0076] Ring A In one particular embodiment, ring A is absent; in another particular embodiment, ring A is C 3-7 It is a cycloalkyl group; in another specific embodiment, ring A is a 4- to 7-membered heterocycline group; in yet another specific embodiment, ring A is C 6-10 It is an aryl group; in another specific embodiment, ring A is a 5- to 10-membered heteroaryl group.

[0077] In yet another specific embodiment, ring A is a 5- to 6-membered heteroaryl. In yet another specific embodiment, ring A is a 4- to 7-membered heterocyclyl, or is selected from piperazinyl and piperidinyl.

[0078] In another specific embodiment, ring A is [ka] More selected, here A1 is CR a1 or N; A2 is CR a2 or N; A3 is CR a3 or N; A4 is CR a4 or N; A5 is CR a5 or N; R a1 , R a2 , R a3 , R a4 and R a5 is R a The above is true.

[0079] In another specific manner, (R a ) m -Ring AL- is, [ka] More likely to be selected.

[0080] R a In this particular embodiment, R a These are independently H, D, halogen, -CN, -NRR', -OR, -SR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) p R, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Selected from cycloalkyl and 3- to 8-membered heterocyclines, each of which may optionally be R *It may be replaced by, where the group may be replaced by one or more D or halogens until it is completely replaced; in another specific embodiment, R a One of them is H; in another specific embodiment, R a One of them is D; in another specific embodiment, R a One of them is a halogen; in another specific embodiment, R a One of them is -CN; in another specific embodiment, R a One of them is -NRR'; in another specific embodiment, R a One of them is -OR; in another specific embodiment, R a One of them is -SR; in another specific embodiment, R a One of them is -C(O)R; in another specific embodiment, R a One of them is -C(O)OR; in another specific embodiment, R a One of them is -C(O)NRR'; in another specific embodiment, R a One of them is -OC(O)R'; in another specific embodiment, R a One of them is -NRC(O)R'; in another specific embodiment, R a One of them is -OC(O)NRR'; in another specific embodiment, R a One of them is -NRC(O)NRR'; in another specific embodiment, R a One of them is -S(O) p R is; and in yet another specific embodiment, R a One of them is C 1-6 It is alkyl; in another specific embodiment, R a One of them is C 2-6 It is an alkenyl; in yet another specific embodiment, R a One of them is C 2-6 It is an alkynyl; in another specific embodiment, R a One of them is C 3-7It is cycloalkyl; in another specific embodiment, R a One of them is a 3- to 8-membered heterocyclyl; another, in a different specific embodiment, R a One of them has 1, 2, or 3 R * It is replaced by; in another specific embodiment, the group may be replaced by one or more D or halogens until it is completely replaced.

[0081] In another specific embodiment, R a These are independently H, D, halogen, -CN, -NRR', -OR, -SR, -C(O)R, -C(O)OR, -C(O)NRR', C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Selected from alkynyl groups, the group may be substituted with one or more D groups until it is completely replaced.

[0082] m In one particular embodiment, m is 0; in yet another particular embodiment, m is 1; in yet another particular embodiment, m is 2; in yet another particular embodiment, m is 3; in yet another particular embodiment, m is 4; and in yet another particular embodiment, m is 5.

[0083] Ring B In certain embodiments, ring B is a 5- to 6-membered heteroaryl, such as pyrrolyl, furanil, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl, or pyrazinyl; or it is pyrrolyl, furanil, thienyl, pyrazolyl, or pyridyl; or it is pyrazolyl.

[0084] R b

[0085] In this particular embodiment, R bThese are independently H, D, halogen, -CN, -NRR', -OR, -SR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) p R, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Selected from cycloalkyl and 3- to 8-membered heterocyclines, each of which may optionally be R * It may be replaced by, where the group may be replaced by one or more D or halogens until it is completely replaced; in another specific embodiment, R b One of them is H; in another specific embodiment, R b One of them is D; in another specific embodiment, R b One of them is a halogen; in another specific embodiment, R b One of them is -CN; in another specific embodiment, R b One of them is -NRR'; in another specific embodiment, R b One of them is -OR; in another specific embodiment, R b One of them is -SR; in another specific embodiment, R b One of them is -C(O)R; in another specific embodiment, R b One of them is -C(O)OR; in another specific embodiment, R b One of them is -C(O)NRR'; in another specific embodiment, R b One of them is -OC(O)R'; in another specific embodiment, R b One of them is -NRC(O)R'; in another specific embodiment, R b One of them is -OC(O)NRR'; in another specific embodiment, R b One of them is -NRC(O)NRR'; in another specific embodiment, R b One of them is -S(O) pR is; and in yet another specific embodiment, R b One of them is C 1-6 It is alkyl; in another specific embodiment, R b One of them is C 2-6 It is an alkenyl; in yet another specific embodiment, R b One of them is C 2-6 It is an alkynyl; in another specific embodiment, R b One of them is C 3-7 It is cycloalkyl; in another specific embodiment, R b One of them is a 3- to 8-membered heterocyclyl; another, in a different specific embodiment, R b One of them has 1, 2, or 3 R * It is replaced by; in another specific embodiment, the group may be replaced by one or more D or halogens until it is completely replaced.

[0086] In another specific embodiment, R b These are independently H, D, halogen, -CN, -NRR', -OR, -SR, C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups, each of which may optionally be R * It may be replaced with.

[0087] n In one particular embodiment, n is 0; in another particular embodiment, n is 1; in yet another particular embodiment, n is 2; in yet another particular embodiment, n is 3; in yet another particular embodiment, n is 4; in yet another particular embodiment, n is 5.

[0088] Ring C In a particular embodiment, the ring C is C 3-7 It is a cycloalkyl group; in another specific embodiment, ring C is a 4- to 7-membered heterocycline group; in yet another specific embodiment, ring C is C 6-10It is an aryl group; in another specific embodiment, ring C is a 5- to 10-membered heteroaryl group.

[0089] In yet another specific embodiment, ring C is a 5- to 6-membered heteroaryl or phenyl; or it is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl or pyrazinyl; or it is pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or triazolyl; or it is pyrazolyl.

[0090] In yet another specific embodiment, the ring C is C 3-7 It is either a cycloalkyl or a 4- to 7-membered heterocyclyl, or it may also be cyclopentyl or tetrahydropyranyl.

[0091] L In one particular embodiment, L is a joint; in yet another particular embodiment, L is -O-; in yet another particular embodiment, L is -S-; in yet another particular embodiment, L is -N(R)-; in yet another particular embodiment, L is -C(O)-; in yet another particular embodiment, L is C 1-6 It is an alkylene; in yet another specific embodiment, L is C 2-6 It is an alkenylene; in yet another specific embodiment, L is C 2-6 It is alkynylene.

[0092] In yet another specific embodiment, L is a bond, -C(O)- or C 1-6 It is alkylene.

[0093] R5 In one particular embodiment, R5 is H; in yet another particular embodiment, R5 is D; in yet another particular embodiment, R5 is halogen; in yet another particular embodiment, R5 is -CN; in yet another particular embodiment, R5 is -NRR'; in yet another particular embodiment, R5 is -OR; in yet another particular embodiment, R5 is -SR; in yet another particular embodiment, R5 is C 1-6 It is alkyl; in another specific embodiment, R5 is C 2-6 It is an alkenyl; in yet another specific embodiment, R5 is C 2-6 It is an alkynyl; in another specific embodiment, R5 may be substituted with one or more D or halogens until it is completely replaced.

[0094] R6 In one particular embodiment, R6 is H; in yet another particular embodiment, R6 is D; in yet another particular embodiment, R6 is halogen; in yet another particular embodiment, R6 is -CN; in yet another particular embodiment, R6 is -NRR'; in yet another particular embodiment, R6 is -OR; in yet another particular embodiment, R6 is -SR; in yet another particular embodiment, R6 is C 1-6 It is alkyl; in another specific embodiment, R6 is C 2-6 It is an alkenil; in yet another specific embodiment, R6 is C 2-6 It is an alkynyl; in another specific embodiment, R6 may be substituted with one or more D or halogens until it is completely replaced.

[0095] R * In this particular embodiment, R * is H; in another specific embodiment, R * is a halogen; in another specific embodiment, R *is -CN; in another specific embodiment, R * is -NRR'; in another specific embodiment, R * is -OR; in another specific embodiment, R * is -SR; in another specific embodiment, R * is -C(O)R; in another specific embodiment, R * is -C(O)OR; in another specific embodiment, R * is -C(O)NRR'; in another specific embodiment, R * is -OC(O)R'; in another specific embodiment, R * is -NRC(O)R'; in another specific embodiment, R * is -OC(O)NRR'; in another specific embodiment, R * is -NRC(O)NRR'; in another specific embodiment, R * is -S(O) p R is; and in yet another specific embodiment, R * is C 3-7 It is cycloalkyl; in another specific embodiment, R * R is a 3- to 8-membered heterocycline; in another specific embodiment, R * is C 6-10 It is aryl; and in another specific embodiment, R * is a 5-10 member heteroaryl; in another specific embodiment, R * It may be replaced with one or more D or halogens until it is completely replaced.

[0096] R and R' In a particular embodiment, R and R' are independently H; in yet another particular embodiment, R and R' are independently C 1-6 It is alkyl; in another specific embodiment, R and R' are independently C 2-6It is an alkenyl; in another specific embodiment, R and R' are independently C 2-6 They are alkynyls; in yet another specific embodiment, R and R' together with their bonding nitrogen atoms form a 4- to 8-membered heterocycline; in yet another specific embodiment, R and R' may be substituted with one or more D or halogens until completely substituted.

[0097] p In one particular embodiment, p is 1; in another particular embodiment, p is 2.

[0098] Any technical solution or any combination thereof in any one of the particular embodiments described above may be combined with any technical solution or any combination thereof in any other particular embodiment. For example, any technical solution or any combination thereof of X may be combined with Y, R1-R6, ring A, ring B, ring C, R a , R b , R * This may be combined with any of the technical solutions of m, n, p, R, and R', or any combination thereof. For the sake of saving space, this disclosure shall encompass all combinations of such technical solutions that are not exhaustively listed herein.

[0099] In a more specific embodiment, the present disclosure relates to a general formula (I) having the following general structure: [ka] [In the formula: Each unit is defined as it is in its context.] The present invention provides compounds represented by, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, or mixtures thereof.

[0100] In a more specific embodiment, this disclosure relates to general formula (I-1) or (I-2): [ka] [In formula: Ring C is C 3-7 It is a cycloalkyl or a 4- to 7-membered heterocycline; or it is cyclopentyl or tetrahydropyranyl; Ring B is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl, or pyrazinyl; or it is pyrrolyl, furanyl, thienyl, pyrazolyl, or pyridyl; R5 is also H, D, halogen, -CN, -NRR', -OR, or -SR, where the group may be substituted with one or more D or halogens until completely substituted; or the ring C is located on a C atom bonded to the parent nucleus; Other bases are defined as they are in their respective contexts. The present invention provides compounds represented by, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, or mixtures thereof.

[0101] In a more specific embodiment, this disclosure relates to general formula (I-1): [ka] [In formula: Ring C is a 5- or 6-membered heteroaryl or phenyl; or it is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl or pyrazinyl; or it is pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or triazolyl; or it is pyrazolyl; Other bases are defined as they are in their respective contexts. The present invention provides compounds represented by, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, or mixtures thereof.

[0102] In yet another, more specific embodiment, the present disclosure relates to a compound of the general formula (I-1) above, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof, wherein Ring B is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl, or pyrazinyl; or it is pyrrolyl, furanyl, thienyl, pyrazolyl, or pyridyl; Other bases are defined in their respective contexts. The present invention provides compounds, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, or mixtures thereof.

[0103] In a more specific embodiment, this disclosure relates to general formula (II) or (II-1): [ka] [In formula: Ring A is absent, C 3-7 It is a cycloalkyl or a 4- to 7-membered heterocycline; Other bases are defined as they are in their respective contexts. The present invention provides compounds represented by, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, or mixtures thereof.

[0104] In yet another, more specific embodiment, the present disclosure relates to a compound of general formula (II) or (II-1), or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof, wherein Ring A is either absent or a 4- to 7-membered heterocycline; or it is either piperidyl or piperazinyl; Ring B is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl, or pyrazinyl; or it is pyrrolyl, furanyl, thienyl, pyrazolyl, or pyridyl; L is a bond, -O-, -S-, -N(R)-, -C(O)- or C 1-6 It is alkylene; R5 and R6 are independent of C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 It is an alkynyl group, where the group may be substituted with one or more D until it is completely deuterated; Other bases are defined in their respective contexts. The present invention provides compounds, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, or mixtures thereof.

[0105] In a more specific embodiment, this disclosure relates to general formula (III) or (III-1): [ka] [In formula: Ring C is a 5- or 6-membered heteroaryl or phenyl; or it is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl or pyrazinyl; or it is pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or triazolyl; or it is pyrazolyl; Other bases are defined as they are in their respective contexts. The present invention provides compounds represented by, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, or mixtures thereof.

[0106] In yet another, more specific embodiment, the present disclosure relates to a compound of general formula (III) or (III-1), or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof, wherein Ring B is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl, or pyrazinyl; or it is pyrrolyl, furanyl, thienyl, pyrazolyl, or pyridyl; Other bases are defined in their respective contexts. The present invention provides compounds, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, or mixtures thereof.

[0107] In a more specific embodiment, this disclosure relates to general formula (III-2) or (III-3): [ka] [In formula: A1 is CR a1 or N; A2 is CR a2or N; A5 is CR a5 or N; Other bases are defined as they are in their respective contexts. The present invention provides compounds represented by, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, or mixtures thereof.

[0108] In yet another, more specific embodiment, the present disclosure relates to a compound of general formula (III-3), or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof, wherein A3 is CR a3 or N; R a1 , R a2 , R a3 , R a5 R5 and R6 are independently H, D, halogen, -CN, -OR, -SR, -NRR', -C(O)R, -C(O)OR, -C(O)NRR', or C 1-6 It is an alkyl group, where the group may be substituted with one or more D or halogens until it is completely substituted; Other bases are defined in their respective contexts. The present invention provides compounds, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, or mixtures thereof.

[0109] In yet another, more specific embodiment, the present disclosure relates to a compound of general formula (III-3), or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof, wherein A3 is CR a3 or N; R a1 , R a2 , R a3 and R a5However, independently, H, D, halogen, -CN, -OH, -C(O)NH2, C 1-6 Alkyl and C 1-6 A haloalkyl group is selected, where the group may be substituted with one or more D atoms until it is completely deuterated; R5 and R6 are independent of C 1-6 Alkyl or C 1-6 It is a haloalkyl group, where the group may be substituted with one or more D until it is completely deuterated. The present invention provides compounds, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, or mixtures thereof.

[0110] In yet another, more specific embodiment, the present disclosure relates to a compound of general formula (III-3), or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof, wherein A3 is CR a3 or N; R a1 is H or D; R a2 H, D, halogen, -CN, -OH, -C(O)NH2, C 1-6 Alkyl or C 1-6 It is a haloalkyl; R a3 is H, D, or -OH; R a5 is H or D; R5 is C 1-6 Alkyl or C 1-6 It is a haloalkyl; or it is methyl; R6 is C 1-6 Alkyl or C 1-6 It is a haloalkyl; or it is also methyl. The present invention provides compounds, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, or mixtures thereof.

[0111] In a more specific embodiment, this disclosure relates to general formula (III-3): [ka] [In formula: A3 is CR a3 or N; R a1 , R a2 , R a3 , R a5 R5 and R6 are independently H, D, halogen, -OR, -SR, -NRR', C 1-6 Alkyl or C 1-6 It is a haloalkyl group, where the group may be substituted with one or more D atoms until it is completely deuterated; R and R' are independent of H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Selected from alkynyl groups, or R and R' together with their bonded nitrogen atoms, form a 4- to 8-membered heterocycline; where the group may be substituted with one or more D atoms until fully deuterated. The present invention provides compounds represented by, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, or mixtures thereof.

[0112] In yet another, more specific embodiment, the present disclosure relates to a compound of general formula (III-3), or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof, wherein A3 is CR a3 or N; Ra1 , R a2 , R a3 and R a5 However, independently, H, D, halogen, -OH, C 1-6 Alkyl and C 1-6 Selected from a haloalkyl group, where the group may be substituted with one or more D until it is completely deuterated; R5 and R6 are independent of C 1-6 Alkyl or C 1-6 It is a haloalkyl group, where the group may be substituted with one or more D until it is completely deuterated. The present invention provides compounds, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, or mixtures thereof.

[0113] In yet another, more specific embodiment, the present disclosure relates to a compound of general formula (III-3), or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof, wherein A3 is CR a3 or N; R a1 is H or D; R a2 H, D, halogen, C 1-6 Alkyl or C 1-6 It is a haloalkyl; R a3 is H, D, or -OH; R a5 is H or D; R5 is C 1-6 Alkyl or C 1-6 It is a haloalkyl; or it is methyl; R6 is C 1-6 Alkyl or C 1-6 It is a haloalkyl; or it is methyl. The present invention provides compounds, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, or mixtures thereof.

[0114] In a more specific embodiment, this disclosure relates to general formula (III-4): [ka] [In formula: A4 is CR a4 or N; R a1 , R a2 , R a4 , R a5 R5 and R6 are independently H, D, halogen, -CN, -OR, -SR, -NRR', -C(O)R, -C(O)OR, -C(O)NRR', or C 1-6 It is an alkyl group, where the group may be substituted with one or more D or halogens until it is completely substituted; Other bases are defined as they are in their respective contexts. The present invention provides compounds represented by, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, or mixtures thereof.

[0115] In yet another, more specific embodiment, the present disclosure relates to a compound of general formula (III-4), or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof, wherein A4 is CR a4 or N; R a1 , R a2 , R a4 and R a5 However, independently, H, D, halogen, -CN, -OH, -C(O)NH2, C 1-6 Alkyl and C 1-6Selected from a haloalkyl group, where the group may be substituted with one or more D until it is completely deuterated; R5 and R6 are independent of C 1-6 Alkyl or C 1-6 It is a haloalkyl group, where the group may be substituted with one or more D until it is completely deuterated. The present invention provides compounds, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, or mixtures thereof.

[0116] In yet another, more specific embodiment, the present disclosure relates to a compound of general formula (III-4), or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant thereof, or a mixture thereof, wherein A4 is CR a4 or N; R a1 is H, D, or halogen; R a2 H, D, halogen, -CN, -OH, -C(O)NH2, C 1-6 Alkyl or C 1-6 It is a haloalkyl; R a4 is H, D, or -OH; R a5 is H or D; R5 is C 1-6 Alkyl or C 1-6 It is a haloalkyl; or it is methyl; R6 is C 1-6 Alkyl or C 1-6 It is a haloalkyl; or it is methyl. The present invention provides compounds, or pharmaceutically acceptable salts thereof, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, or mixtures thereof.

[0117] Alternative compounds to those described herein include, but are not limited to, the compounds listed below, or their pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants, or mixtures thereof: [ka] [ka]

[0118] The compounds of the present disclosure may contain one or more chiral centers and thus may exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds of the present disclosure may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or in the form of a mixture of stereoisomers, including a racemic mixture and a mixture rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or they can also be produced by asymmetric synthesis.

[0119] Those skilled in the art will understand that organic compounds can form complexes with the solvents in which they react, or that they may precipitate or crystallize from the solvent. These complexes are known as “solvates.” When the solvent is water, the complex is known as a “hydrate.” This disclosure encompasses all solvates of the compounds herein.

[0120] The term "solvate" usually refers to a compound or a salt thereof that has associated with a solvent through solvolysis. This physical bonding may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein may be prepared, for example, in crystalline form and solvated. Suitable solvates include pharmaceutically acceptable solvates, which further encompass both stoichiometric and non-stoichiometric solvates. In some cases, solvates may be isolateable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvates" include both solution phases and isolateable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0121] The term "hydrate" refers to a compound that is bound to water. Generally, the number of water molecules contained in a compound hydrate is in a constant ratio to the number of compounds in the hydrate. Therefore, a compound hydrate can be represented, for example, by the general formula R·xH₂O (where R is the compound and x is a number greater than 0). A given compound can form multiple types of hydrates, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R·0.5H₂O)) and polyhydrate (x is a number greater than 1, for example, dihydrate (R·2H₂O) and hexahydrate (R·6H₂O)).

[0122] The compounds of this disclosure may be amorphous or in crystalline form (polymorphs). Furthermore, the compounds of this disclosure may exist in one or more crystalline forms. Accordingly, this disclosure encompasses all amorphous or crystalline forms of the compounds of this disclosure. The term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate, or solvate) in a particular crystalline packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally differ in X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to dominate. Various polymorphs of a compound can be produced by crystallization under different conditions.

[0123] The disclosure also includes isotope-labeled compounds that are equivalent to the compound represented by formula (I), but in which one or more atoms are replaced with atoms having atomic weights or mass numbers different from those of atoms common in nature. Examples of isotopes that can be introduced into the compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, individually. 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Contains Cl. All compounds of the Disclosure, their prodrugs, and pharmaceutically acceptable salts of such compounds or prodrugs, including the above-mentioned isotopes and / or other isotopes of other atoms, are within the scope of the Disclosure. Compounds of specific isotope labeling in the Disclosure, e.g., radioactive isotopes (e.g., 3 H and 14 Compounds incorporating C) can be used to measure the distribution of drugs and / or substrates in tissues. 3 Tritium, which is H, and 14The carbon-14 isotope is another viable alternative, because it is easy to manufacture and detect. Furthermore, 2 When H is replaced with a heavier isotope such as deuterium, therapeutic benefits may be obtained because metabolic stability is increased, such as by extending the in vivo half-life or reducing the required dose, and thus it may be a substitute in some cases. The isotope-labeled compounds of formula (I) of this disclosure and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of unisotope-labeled reagents in the operations disclosed in the following scheme and / or examples and preparations.

[0124] In addition, prodrugs are also included in the context of this disclosure. The term “prodrug” as used herein refers to a compound that is converted in vivo into an active form with therapeutic effects by hydrolysis in the blood, for example. Medicinalally acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACS Symposium Series, Vol. 14, Edward B. Roche (ed.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra, “Improved oral drug delivery: solubility limitations overcome by the use of prodrugs,” Advanced Drug Delivery Reviews (1996) 19 (2) 115-130 (each of which is incorporated herein by attribution).

[0125] A prodrug is any of the covalently bonded compounds of the Disclosure that, upon administration to a patient, releases the parent compound in vivo. Prodrugs are typically produced by modifying a functional group such that the modification is either cleaved by a routine operation or can be degraded in vivo to produce the parent compound. Prodrugs include, for example, compounds of the Disclosure in which a hydroxyl, amino, or sulfhydryl group is bonded to any group and, upon administration to a patient, is cleaved to form the hydroxyl, amino, or sulfhydryl group. Thus, representative examples of prodrugs include (but are not limited to) acetate / acetamide, formate / formamide, and benzoate / benzamide derivatives of the hydroxyl, amino, or sulfhydryl functional group of the compound of formula (I). Furthermore, in the case of carboxylic acids (-COOH), esters such as methyl esters and ethyl esters may be used. The ester itself may be active in itself and / or hydrolyzable under in vivo conditions in the body. Appropriately pharmaceutically acceptable in vivo hydrolyzable ester groups include those that can be readily decomposed in the human body to release the parent compound or a salt thereof.

[0126] The disclosure also provides pharmaceutical formulations comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carriers, diluents, or excipients thereof. All of these forms belong to the disclosure.

[0127] Pharmaceutical compositions, formulations, and kits In yet another embodiment, the Disclosure provides a pharmaceutical composition comprising the Compound of the Disclosure (also referred to as the “Active Ingredient”) and a pharmaceutically acceptable excipient. In a particular embodiment, the pharmaceutical composition comprises an effective amount of the Compound of the Disclosure. In a particular embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the Compound of the Disclosure. In a particular embodiment, the pharmaceutical composition comprises a preventively effective amount of the Compound of the Disclosure.

[0128] pharmaceutically acceptable excipients for use in this disclosure mean non-toxic carriers, adjuvants, or vehicles that do not impair the pharmacological activity of the compounds they are formulated with. pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts, or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulosic materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0129] This disclosure also encompasses kits (e.g., pharmaceutical packs). The kits provided may include the compounds disclosed herein, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packages or other materials) containing the compounds disclosed herein or other therapeutic agents. In some embodiments, the kits provided may also optionally include a third container containing pharmaceutically acceptable excipients for diluting or suspending the compounds disclosed herein and / or other therapeutic agents. In some embodiments, the compounds disclosed herein provided in the first container and other therapeutic agents provided in the second container are combined to form unit dosage forms.

[0130] Administration The pharmaceutical compositions provided herein may be administered by various routes, including, but are not limited to, oral, parenteral, inhalation, topical, rectal, nasal, oral, vaginal, implantation, or other means of administration. For example, parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-arterial, intra-articular, intra-articular, intra-sternal, intrasternal, intraventricular, intrafocal, and intracranial injection or infusion techniques.

[0131] Generally, the compounds provided herein are administered in effective doses. The actual amount of compound administered will typically be determined by a physician, taking into account relevant circumstances, including the symptoms to be treated, the chosen route of administration, the actual compound administered, the individual patient's age, weight and response, and the severity of the patient's symptoms.

[0132] When used to prevent the disorders disclosed herein, the compounds provided herein would be administered to subjects at risk of developing the symptoms, typically under the advice and supervision of a physician, at the dosage levels described above. Subjects at risk of developing specific symptoms generally include those with a family history of the symptoms, or those identified as particularly susceptible to the symptoms through genetic testing or screening.

[0133] The pharmaceutical compositions provided herein may also be administered chronically ("chronic administration"). Chronic administration means administering the compound or the pharmaceutical composition over a long period of time, for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue without limitation, for example, for the remainder of the patient's life. In certain embodiments, chronic administration provides a constant blood level of the compound, for example, within the therapeutic concentration range over a long period of time.

[0134] The pharmaceutical compositions of this disclosure may be further delivered by various administration methods. For example, in certain embodiments, the pharmaceutical composition may be administered as a bolus, for example, to raise the blood concentration of the compound to an effective level. The arrangement of bolus administration depends on the desired systemic level of the active ingredient throughout the body; for example, intramuscular or subcutaneous bolus administration allows for slow release of the active ingredient, while a bolus delivered directly to a vein (e.g., a bolus via IV infusion) allows for much faster delivery, rapidly raising the blood concentration of the active ingredient to an effective level. In other embodiments, the pharmaceutical composition may be administered by continuous infusion, for example, by IV infusion, to maintain a steady level of the concentration of the active ingredient in the target body. Furthermore, in yet another embodiment, the pharmaceutical composition may be administered first as a bolus and then by continuous infusion.

[0135] Compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders. However, more commonly, the composition is taken in unit dosage forms to facilitate the administration of precise doses. The term "unit dosage form" refers to a physically separate unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect in combination with appropriate pharmaceutical excipients. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes for liquid compositions, or pills, tablets, capsules, etc., for solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, or also about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids that help form the desired dosage form.

[0136] For oral administration, a typical dosing regimen involves 1 to 5 doses per day, particularly 2 to 4 doses, and usually 3 doses. Using these dosing patterns, each dose ferments approximately 0.01 to 20 mg / kg of the compound provided herein, while alternative doses ferment approximately 0.1 to 10 mg / kg, particularly 1 to 5 mg / kg of the compound.

[0137] Transdermal doses are generally selected to provide blood concentrations equivalent to or lower than those achieved by injection, and are typically in the range of about 0.01 to about 20% by weight, or about 0.1 to about 20% by weight, or about 0.1 to about 10% by weight, or even about 0.5 to about 15% by weight.

[0138] The injection dose level ranges from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour, with administration times ranging from approximately 1 to 120 hours, particularly 24 to 96 hours. Alternatively, preloaded bolus doses of approximately 0.1 mg / kg to 10 mg / kg or higher may be administered to achieve an appropriate steady-state level. The maximum total dose is considered to be no more than approximately 2 g / day for patients weighing 40-80 kg.

[0139] Liquid forms suitable for oral administration may include appropriate aqueous or non-aqueous vehicles containing buffers, anti-precipitation agents and dispensing agents, colorants, flavorings, etc. Solid forms may include, for example, the following components: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; lubricants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavoring, or compounds having similar properties.

[0140] The injectable compositions are typically based on sterile selenium for injection or phosphate-buffered selenium or other injectable excipients known in the art. As described above, the active compound in such compositions is typically a minor component, often amounting to about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0141] Transdermal compositions are typically formulated as topical ointments or creams containing an active ingredient. When formulated as an ointment, the active ingredient will typically be combined with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated into a cream using, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additives to enhance the transdermal penetration and stability of the active ingredient or formulation. All such known transdermal formulations and components are provided herein.

[0142] The compounds provided herein can also be administered by transdermal devices. Therefore, transdermal administration can be achieved using a reservoir, a porous membrane, or a patch of various solid matrices.

[0143] The above-mentioned components for orally administered, injectable, or topically administered compositions are representative only. Other materials and processing techniques are described in Remington's Pharmaceutical Sciences, Part 8, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, and are incorporated herein by appropriate attribution.

[0144] The compounds of this disclosure may also be administered in sustained-release form or through sustained-release drug delivery systems. Representative sustained-release materials can be found in the descriptions in Remington's Pharmaceutical Sciences.

[0145] This disclosure also relates to pharmaceutically acceptable formulations of the compounds of this disclosure. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, each consisting of 6, 7, and 8 α-1,4-linked glucose units, and optionally comprising one or more substituents on the linked sugar portion, including, but not limited to, methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin (also known as captisol). See, for example, U.S. Patent No. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0146] treatment As described herein, ATR kinase is known to play a role in tumorigenesis and many other diseases. The inventors have found that the compound of formula (I) has potent antitumor activity, which is thought to be obtained by inhibiting ATR kinase.

[0147] The compounds of this disclosure have value as antitumor agents. In particular, the compounds of this disclosure have value as antiproliferative, apoptotic, and / or anti-invasive agents in containing and / or treating solid and / or liquid tumor diseases. In particular, the compounds of this disclosure are considered useful in the prevention or treatment of tumors that are sensitive to ATR inhibition. Furthermore, the compounds of this disclosure are considered useful in the prevention or treatment of tumors in which ATR is alone or partially mediated. Thus, the compounds may be used to induce ATR enzyme inhibitory activity in warm-blooded animals that require such treatment.

[0148] As described herein, ATR kinase inhibitors should have therapeutic value in treating proliferative disorders such as cancer, particularly solid tumors such as carcinomas and sarcomas, and leukemias and lymphoid malignancies, especially cancers of the breast, colorectal, lung (including small cell lung cancer, non-small cell lung cancer and bronchoalveolar cancer) and prostate, and cancers of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovaries, pancreas, skin, testes, thyroid, uterus, cervix and vulva, as well as leukemia [including acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), etc.], multiple myeloma and lymphoma.

[0149] Therefore, the anti-cancer effects useful in treating a patient's cancer include, but are not limited to, antitumor effects, response rates, time to disease progression, and improved survival rates. The antitumor effects of the therapeutic methods disclosed herein include, but are not limited to, inhibition of tumor growth, delay of tumor growth, tumor regression, tumor reduction, increased time to tumor regrowth after discontinuation of treatment, and slower disease progression. The anti-cancer effects encompass both prophylactic treatment and treatment of existing disease.

[0150] ATR kinase inhibitors or their pharmaceutically acceptable salts also, but are not limited to, hematological malignancies such as leukemia, multiple myeloma, Hodgkin's disease and other lymphomas, non-Hodgkin lymphomas (including mantle cell lymphoma), and myelodysplastic syndromes, as well as tumors of the central nervous system such as breast cancer, lung cancer (non-small cell lung cancer (NSCL), small cell lung cancer (SCLC), squamous cell carcinoma), endometrial cancer, glioma, dysplastic neuroepithelial tumor, glioblastoma multiforme, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor and teratoma, gastric cancer, esophageal cancer, hepatocellular (liver) cancer, biliary cancer. It may also be useful in treating patients with solid tumors and their metastases, including gastrointestinal cancers such as ductal cancer, colorectal cancer, and small intestine cancer; skin cancers such as pancreatic cancer and melanoma (especially metastatic melanoma); thyroid cancer; head and neck cancer; and solid tumors and their metastases, such as those of the salivary glands, prostate, testes, ovaries, cervix, uterus, clitoris, bladder, kidneys (including renal cell carcinoma, clear cell carcinoma, and renal pluricytoma), squamous cell carcinoma, osteosarcoma, chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma, gastrointestinal stromal sarcoma (GIST), Kaposi's sarcoma, and childhood cancers such as rhabdomyosarcoma and neuroblastoma.

[0151] Therapeutic methods comprising the administration or use of the compounds of this disclosure and ATR kinase inhibitors or pharmaceutically acceptable salts thereof are considered to be particularly useful in the treatment of patients with lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcoma, head and neck cancer, central nervous system tumors, and their metastases, as well as in the treatment of patients with acute myeloid leukemia.

[0152] The effective dose of the compounds disclosed herein is typically 0.01 mg to 50 mg of the compound per kg of patient body weight, or 0.1 mg to 25 mg of the compound per kg of patient body weight, in a single or multiple doses, with an average daily dose. Generally, the compounds disclosed herein may be administered to patients requiring this treatment in a daily dose range of approximately 1 mg to approximately 3500 mg per patient, or also in a daily dose range of 10 mg to 1000 mg. For example, the daily dose per patient may be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 900, or 1000 mg. It may be administered once or multiple times daily, weekly (or at intervals of several days), or on an intermittent schedule. For example, the compound may be administered once or more times a day on a weekly basis (e.g., every Monday) for a variable period of several weeks, for example, 4 to 10 weeks. Alternatively, the compound may be administered daily for several days (e.g., 2 to 10 days), followed by several days (e.g., 1 to 30 days), with the cycle being arbitrarily repeated, or repeated a predetermined number of times, for example, 4 to 10 cycles. For example, the compound of the Disclosure may be administered daily for 5 days, followed by a 9-day break, then administered for 5 days, followed by a 9-day break, and so on, with the cycle being arbitrarily repeated, or repeated a total of 4 to 10 times.

[0153] Combination therapy The treatments defined herein may be applied as monotherapy, or they may include conventional surgery or radiotherapy or chemotherapy in addition to the compounds disclosed herein. Accordingly, the compounds disclosed herein may also be used in combination with existing therapeutic agents for the treatment of cancer.

[0154] Suitable drugs for use in combination include: (i) Antiproliferative / antitemogenic drugs and combinations thereof, such as alkylating agents (e.g., cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, and nitrosourea), used in oncology; antimetabolites (e.g., fluoropyrimidines such as 5-fluorouracil and tegafur, antifolic acid agents such as larcitrexed, methotrexate, cytosine arabinoside, hydroxyurea, and gemcitabine); antitumor antibiotics (e.g., adriamycin, bleomycin, doxorubicin, daunomycin) Anthracyclines such as epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin; antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, as well as taxoids such as paclitaxel and taxotere); topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, ansacrin, topotecan, and camptothecin); and DNA damage repair inhibitors (e.g., olaparib such as lucaparib and niraparib);

[0155] (ii) Cell proliferation inhibitors, such as anti-estrogens (e.g., tamoxifen, toremifene, raloxifene, doroxifene, and iodoxifene), estrogen receptor downregulators (e.g., fulvestrant), anti-androgens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, borazole, and exemestane), and 5α-reductase inhibitors such as finasteride;

[0156] (iii) Anti-infiltration agents (e.g., c-Src kinase family inhibitors such as AZD0530 and dasatinib), and metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasminogen activator receptor function;

[0157] (iv) Inhibitors of growth factor function: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin (registered trademark)] and anti-erbBl antibody cetuximab [C225]); such inhibitors also include, for example, tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib and CI 1033; and erbB2 tyrosine kinase inhibitors such as lapatinib), inhibitors of the hepatocyte growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib, serine / threonine kinase inhibitors (e.g., Ras / Raf signaling inhibitors such as farnesyltransferase inhibitors, e.g., sorafenib (BAY 43-9006)), and inhibitors of cell signaling mediated by MEK and / or Akt kinases;

[0158] (v) Agents that inhibit the action of vascular endothelial growth factor, such as the anti-vascular endothelial growth factor antibody bevacizumab (Avastin®) and VEGF receptor tyrosine kinase inhibitors such as ZD6474, AZD2171, batalanib and sunitinib, as well as anti-angioplastic agents such as compounds that act by other mechanisms (e.g., linamide, inhibitors of integral αvβ3 function, and angiostatin);

[0159] (vi) Vascular damage agents such as combretastatin;

[0160] (vii) Antisense agents, such as those targeted at the above-listed targets including ISIS 2503;

[0161] (viii) Gene therapy, including methods for replacing abnormal genes such as abnormal p53 or abnormal BRCAl or BRCA2, methods for using cytosine deaminase, thymidine kinase or bacterial nitroreductase enzymes, etc., GDEPT methods (gene-directed enzyme prodrug therapy), and methods for increasing a patient's resistance to chemotherapy or radiotherapy, such as multidrug resistance gene therapy; and

[0162] (ix) Immunotherapy methods including ex vivo and in vivo methods to enhance the immunogenicity of a patient's tumor cells, such as transfection with cytokines like interleukin-2, interleukin-4, or granulocyte-macrophage colony-stimulating factor; methods to reduce T cell anergy; methods using transfected immune cells such as cytokine-transduced dendritic cells; methods using cytokine-transduced tumor cell lines; and methods using anti-idiotic antibodies. It includes.

[0163] Examples The materials or reagents used herein are commercially available or produced by synthetic methods commonly known in the art. The following reaction pathways illustrate specific methods for synthesizing the compounds of this disclosure.

[0164] Details are as follows: Production of important intermediates a1-a4: [ka]

[0165] The starting material, 5,7-dichloropyrazolo[1,5-a]pyrimidine a1-1 (53.2 mmol, 10 g), was dissolved in 30 mL of 1 N NaOH aqueous solution. The mixture was heated to 90°C and reacted for 0.5 hours. The reaction was stopped. The mixture was cooled to room temperature, and 1 N hydrochloric acid solution was slowly added to adjust the pH to 7. The mixture was extracted with dichloromethane and dried on anhydrous Na2SO4 to obtain intermediate a1-2 (9 g, quantitative yield). LC-MS: [M+H] + :170

[0166] Intermediate a1-2 (47.3 mmol, 8 g) and (R)-2-methylmorpholine (94.6 mmol, 9.56 g) were added to a microwave reaction flask and dissolved by adding 30 mL of N-methylpyrrolidone NMP. The mixture was then heated to 190°C using a microwave and reacted for 6 hours. The reaction was stopped. The solvent was evaporated under reduced pressure, and the residue was separated by flash column chromatography to obtain intermediate a1-3 (6.4 g, yield: 58%). LC-MS: [M+H] + :235

[0167] Intermediate a1-3 (27.4 mmol, 6.4 g) and triethylamine (54.8 mmol, 5.55 g) were added to a reaction flask, and the mixture was dissolved with 20 mL of phosphorus oxychloride. The mixture was heated to 80°C and stirred for 2 hours. The reaction was stopped. The reaction mixture was quenched by slowly adding 100 mL of ice water, and then the pH was adjusted to 8 by dropwise adding 1N NaOH aqueous solution. The mixture was extracted with dichloromethane, dried over anhydrous Na2SO4, and separated by flash column chromatography to obtain intermediate a1 (4.4 g, yield: 64%). LC-MS: [M+H] + :253 [ka]

[0168] Intermediate a1 (15.9 mmol, 4.0 g) and intermediate 3,5-dimethyl-1H-pyrazole-4-boronic acid pinacol ester a2-1 (24.0 mmol, 5.3 g) were dissolved under nitrogen in 50 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1). Sodium carbonate (32 mmol, 3.39 g) and Pd(dppf)Cl2 (1.6 mmol, 1.17 g) were added, and the mixture was heated under reflux and reacted for 10 hours. The reaction was stopped. The mixture was filtered, and the solvent was evaporated under reduced pressure. 50 mL of water was added to the residue. The mixture was extracted with ethyl acetate and separated by flash column chromatography to obtain intermediate a2 (3.2 g, yield: 65%). LC-MS: [M+H] + :313 [ka]

[0169] Intermediate a2 (10.25 mmol, 3.2 g) was dissolved in 15 mL of anhydrous dichloromethane in an ice bath, and N-bromosuccinimide NBS (10.3 mmol, 1.8 g) was slowly added in batches. The mixture was stirred for a further 2 hours. The reaction was stopped, and 50 mL of saturated aqueous ammonium chloride was added. The mixture was extracted with dichloromethane, dried on anhydrous sodium sulfate, and separated by flash column chromatography to obtain intermediate a3-1 (3.9 g, yield: 98%). LC-MS: [M+H] + :392

[0170] Intermediate a3-1 (3.32 mmol, 1.3 g) and starting material a3-2 (4.98 mmol, 1.38 g) were dissolved under nitrogen in 20 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1), and sodium carbonate (6.64 mmol, 704 mg) and Pd(dppf)Cl2 (0.33 mmol, 241 mg) were added. The mixture was heated to 100°C by microwave and reacted for 1 hour. The reaction was stopped. The mixture was filtered, and 40 mL of water was added to the system. The mixture was extracted with ethyl acetate, dried on anhydrous sodium sulfate, and separated by flash column chromatography to obtain intermediate a3 (400 mg, yield: 26%). LC-MS: [M+H] + :463 [ka]

[0171] Intermediate a1 (1.63 mmol, 410 mg) was dissolved in 15 mL of anhydrous dichloromethane in an ice bath, and N-iodosuccinimide NIS (1.79 mmol, 403 mg) was slowly added in batches. The mixture was stirred for a further 2 hours. The reaction was stopped, and 50 mL of saturated aqueous ammonium chloride was added. The mixture was extracted with dichloromethane and dried on anhydrous sodium sulfate to obtain intermediate a4-1 (700 mg, crude). LC-MS: [M+H] + :379

[0172] Intermediate a4-1 (700 mg) and starting material a3-2 (2.44 mmol, 678 mg) were dissolved under nitrogen in 20 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1), and potassium carbonate (3.26 mmol, 451 mg) and Pd(dppf)Cl2 (0.16 mmol, 117 mg) were added. The mixture was heated to 100°C by microwave and reacted for 1 hour. The reaction was stopped. The mixture was filtered, and 40 mL of water was added to the system. The mixture was extracted with ethyl acetate, dried on anhydrous sodium sulfate, and separated by flash column chromatography to obtain intermediate a4 (220 mg, total yield for 2 steps: 34%). LC-MS: [M+H]+ :403

[0173] Production of important intermediates b1-b7: [ka]

[0174] In a reaction flask, starting materials b1-1 (36.7 mmol, 7 g) and cesium carbonate (92.1 mmol, 30.03 g) were added, and the mixture was dissolved in 100 mL of DMF. Starting material b1-2 (36.8 mmol, 8.43 g) was slowly added. The mixture was heated to 80°C and reacted for 4 hours. The reaction was then stopped. 300 mL of water was slowly added. The mixture was extracted with ethyl acetate, dried on anhydrous Na2SO4, and separated by flash column chromatography to obtain intermediate b1-3 (3.4 g, yield: 23%) and intermediate b1-4 (7.0 g, yield: 47%). LC-MS: [M+H] + :413 [ka]

[0175] Intermediate b1-3 (6.3 mmol, 2.6 g) was dissolved in 60 mL of anhydrous THF at -78°C. Butyllithium (3.0 mL, 2.5 M) was added dropwise. After 30 minutes, isopropoxyboronic acid pinacol ester (9.5 mmol, 1.88 mL) was added. The mixture was reacted at -78°C for a further 3 hours. The reaction mixture was quenched by adding 150 mL of saturated aqueous ammonium chloride solution, extracted with dichloromethane, and dried on anhydrous sodium sulfate to obtain the crude intermediate b1, which was used directly in the next reaction step. LC-MS: [M+H] + :460

[0176] Referring to the synthesis route of intermediate b1, b1-4 were used as raw materials to obtain the crude intermediate b2. LC-MS:[M+H] + :460 [ka]

[0177] Under nitrogen in an ice bath, starting material a2-1 (2.25 mmol, 500 mg) was dissolved in 15 mL of DMF, and NaH (4.5 mmol, 180 mg) was added in batches. The mixture was stirred for 30 minutes, and then tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (3.37 mmol, 943 mg) was slowly added. The mixture was heated to 90°C and reacted for a further 2 hours. The reaction was stopped. The system was quenched by slowly adding 50 mL of ice water, extracted with ethyl acetate, and dried on anhydrous sodium sulfate to obtain the crude intermediate b3, which was used directly in the next reaction step. LC-MS: [M+H] + :406 [ka]

[0178] Starting material b4-1 (1.54 mmol, 150 mg) was dissolved in 10 mL of anhydrous THF at -78°C under nitrogen, and n-butyllithium (1.0 mL, 2.5 M) was added dropwise. After 30 minutes, trimethyltin chloride (2.31 mmol, 462 mg) was added. The mixture was reacted at -78°C for a further 3 hours. The reaction was stopped. The reaction mixture was quenched by adding 40 mL of saturated aqueous solution of ammonium chloride, extracted with dichloromethane, and dried on anhydrous sodium sulfate to obtain the crude intermediate b4, which was used directly in the next reaction step. LC-MS: [M+H] + :260 [ka]

[0179] Starting materials a2-1 (2.0 mmol, 444 mg), tert-butylpiperazine-1-carboxylate (3.0 mmol, 559 mg), and DIEA (5.0 mmol, 645 mg) were dissolved in 15 mL of tetrahydrofuran in an ice bath. The mixture was stirred for 5 minutes, and then triphosgene (4.0 mmol, 1.08 g) was slowly added to the system. The mixture was stirred in an ice bath for 2 hours, and then the reaction was stopped. 40 mL of water was added to the reaction solution. The mixture was extracted with dichloromethane and separated by flash column chromatography to obtain intermediate b5 (180 mg, yield: 21%). LC-MS: [M+H] + :435 [ka]

[0180] Starting materials b6-1 (9.2 mmol, 2.0 g) and N-Boc-hydrazine (10.1 mmol, 1.33 g) were dissolved in 30 mL of acetic acid. The mixture was stirred for 5 minutes, and then NaBH3CN (27.6 mmol, 1.7 g) was slowly added. The mixture was reacted at room temperature for 10 hours. The reaction was stopped. 80 mL of ice water was added to the system to quench the reaction mixture, and the solvent was evaporated under reduced pressure. The pH of the system was adjusted to approximately 9 using a saturated aqueous solution of NaHCO3, extracted with dichloromethane, and dried on anhydrous sodium sulfate to obtain the crude intermediate b6-2 (a pair of diastereoisomers).

[0181] Intermediate b6-2 (crude product) and acetylacetone (10.6 mmol, 1.1 mL) were added to a reaction flask and dissolved in 30 mL of acetic acid. 3 mL of hydrobromic acid (45%) was slowly added to the mixture, and the mixture was reacted at room temperature for 2 hours. The reaction was stopped, and the solvent was evaporated under reduced pressure to obtain crude intermediate b6-3 (3.0 g, crude product). LC-MS: [M+H] + :198

[0182] Crude intermediate b6-3 (3.0 g), anhydrous Boc (11.7 mmol, 2.5 g), triethylamine (23.4 mmol, 3.4 mL), and DMAP (0.78 mmol, 95 mg) were dissolved in 20 mL of tetrahydrofuran, and the mixture was reacted at room temperature for 12 hours. The reaction was stopped, and 100 mL of water was added. The mixture was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried on anhydrous sodium sulfate to obtain the product (2.4 g) as a yellow oil. The yellow oil was dissolved in 10 mL of DMF, and the mixture was placed in an ice bath. NBS (8.88 mmol, 1.58 g) was slowly added in batches, and the mixture was reacted at room temperature for 8 hours. Next, 50 mL of ice water was added. The mixture was extracted with ethyl acetate, dried on anhydrous sodium sulfate, and separated by flash column chromatography to obtain intermediate b6-4 (1.2 g, total yield for 3 steps: 35%) and intermediate b6-5 (600 mg, total yield for 3 steps: 17%). LC-MS: [M+H] + :377

[0183] Intermediate b6-4 (1.25 mmol, 470 mg), bis(pinacolato)diborone (2.34 mmol, 595 mg), DIEA (2.5 mmol, 323 mg), and Pd(Amphos)Cl2 (0.13 mmol, 90 mg) were added to a microwave reaction flask under nitrogen and dissolved in 16 mL of a mixture of 2-methyltetrahydrofuran and methanol (v / v, 1 / 1). The mixture was heated to 100°C by microwave and reacted for 1 hour, after which the reaction was stopped. The mixture was filtered and 30 mL of water was added. The mixture was extracted with ethyl acetate and separated by flash column chromatography to obtain intermediate b6 (120 mg, yield: 23%). LC-MS: [M+H] + :424

[0184] Referring to the synthesis of intermediate b6, intermediate b7 was synthesized using b6-5 as a starting material. LC-MS:[M+H] + :424

[0185] Example 1: [ka]

[0186] Starting material a1-1 (1.06 mmol, 200 mg) and intermediate b1 (1.59 mmol, 730 mg) were dissolved under nitrogen in 10 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1). Sodium carbonate (2.12 mmol, 225 mg) and Pd(dppf)Cl2 (0.1 mmol, 73 mg) were added. The mixture was heated to 95°C and reacted for 3 hours. The reaction was stopped. The mixture was filtered, and 40 mL of water was added to the system. The mixture was extracted with ethyl acetate, dried on anhydrous sodium sulfate, and separated by flash column chromatography to obtain compound A1-1 (330 mg, yield: 64%). LC-MS: [M+H] + :485

[0187] Intermediate A1-1 (0.68 mmol, 330 mg) and (R)-2-methylmorpholine (1.36 mmol, 138 mg) were dissolved in 5 mL of DMSO, and KF (2.04 mmol, 118 mg) was added. The mixture was heated to 150°C by microwave and reacted for 2 hours. The reaction was stopped, and 30 mL of water was added. The mixture was extracted with dichloromethane, dried on anhydrous sodium sulfate, and separated by flash column chromatography to obtain compound A1-2 (220 mg, yield: 59%). LC-MS: [M+H] + :550

[0188] Intermediate A1-2 (0.40 mmol, 220 mg) was dissolved in 5 mL of anhydrous dichloromethane in an ice bath, and N-bromosuccinimide NBS (0.40 mmol, 72 mg) was slowly added in batches. The mixture was stirred for a further 2 hours. The reaction was stopped, and 20 mL of saturated aqueous ammonium chloride was added. The mixture was extracted with dichloromethane, dried on anhydrous sodium sulfate, and separated by flash column chromatography to obtain compound A1-3 (140 mg, yield: 56%). LC-MS: [M+H] + :629

[0189] Intermediate A1-3 (0.22 mmol, 140 mg) and starting material a3-2 (0.33 mmol, 92 mg) were dissolved under nitrogen in 5 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1). Potassium carbonate (0.44 mmol, 61 mg) and Pd(dppf)Cl2 (0.02 mmol, 15 mg) were added. The mixture was heated to 95°C and reacted for 2 hours. The reaction was stopped. The mixture was filtered, and 20 mL of water was added to the system. The mixture was extracted with ethyl acetate, dried on anhydrous sodium sulfate, and separated by flash column chromatography to obtain intermediate A1-4 (45 mg, yield: 29%). LC-MS: [M+H] + :700

[0190] Intermediate A1-4 (45 mg) was dissolved in 5 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 2 hours. The reaction was stopped, and the solvent was evaporated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to adjust the pH to 10. The mixture was extracted with dichloromethane and separated by preparative chromatography to obtain the target compound A1 (8 mg, yield: 24%). LC-MS: [M+H] + :516

[0191] The following compounds were synthesized following the route of Example 1: [Table 1]

[0192] Example 2: [ka]

[0193] Intermediate a1 (0.79 mmol, 200 mg) and intermediate b3 (1.19 mmol, crude) were dissolved under nitrogen in 10 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1), and sodium carbonate (1.60 mmol, 170 mg) and Pd(dppf)Cl2 (0.08 mmol, 59 mg) were added. The mixture was heated to 95°C and reacted for 10 hours. The reaction was stopped. The mixture was filtered, and 40 mL of water was added to the system. The mixture was extracted with ethyl acetate, dried on anhydrous sodium sulfate, and separated by flash column chromatography to obtain compound A3-1 (230 mg, yield: 59%). LC-MS: [M+H] + :496

[0194] Intermediate A3-1 (0.46 mmol, 230 mg) was dissolved in 15 mL of anhydrous dichloromethane in an ice bath, and N-bromosuccinimide NBS (0.51 mmol, 90 mg) was slowly added in batches. The mixture was stirred for a further 2 hours. The reaction was stopped, and 30 mL of saturated aqueous ammonium chloride was added. The mixture was extracted with dichloromethane, dried on anhydrous sodium sulfate, and separated by flash column chromatography to obtain compound A3-2 (220 mg, yield: 83%). LC-MS: [M+H] + :575

[0195] Intermediate A3-2 (0.38 mmol, 220 mg) and starting material a3-2 (0.76 mmol, 211 mg) were dissolved under nitrogen in 10 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1). Potassium carbonate (0.76 mmol, 105 mg) and Pd(dppf)Cl2 (0.038 mmol, 28 mg) were added. The mixture was heated to 100°C by microwave and reacted for 2 hours. The reaction was stopped. The mixture was filtered, and 30 mL of water was added to the system. The mixture was extracted with ethyl acetate, dried on anhydrous sodium sulfate, and separated by flash column chromatography to obtain compound A3-3 (100 mg, yield: 41%). LC-MS: [M+H] + :646

[0196] Intermediate A3-3 (100 mg) was dissolved in 6 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 2 hours. The reaction was stopped, and the solvent was evaporated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to adjust the pH to 10. The mixture was extracted with dichloromethane and separated by preparative chromatography to obtain the target compound A3 (25 mg, yield: 35%). LC-MS: [M+H] + :462

[0197] The following compounds were synthesized following the route of Example 2: [Table 1]

[0198] Example 3: [ka]

[0199] Intermediate A1-3 (0.32 mmol, 200 mg) and starting material tetrahydroxydiborone (0.64 mmol, 58 mg) were dissolved in 10 mL of anhydrous tetrahydrofuran under nitrogen, and DIEA (0.64 mmol, 83 mg) and Pd(Amphos)Cl2 (0.03 mmol, 21 mg) were added. The mixture was heated to 95°C by microwave and reacted for 2 hours. The reaction was stopped. The mixture was filtered, and 30 mL of water was added to the system. The mixture was extracted with ethyl acetate and dried on anhydrous sodium sulfate to obtain the crude compound A5-1, which was used directly in the next step. LC-MS:[M+H] + :594

[0200] The crude intermediate A5-1 (150 mg, crude) and 2-bromoimidazole A5-2 (0.25 mmol, 37 mg) derived from the above process were dissolved under nitrogen in 10 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1), and potassium carbonate (0.5 mmol, 69 mg) and Pd(dppf)Cl2 (0.025 mmol, 19 mg) were added. The mixture was heated to 110°C by microwave and reacted for 2 hours. The reaction was stopped. The mixture was filtered, and 30 mL of water was added to the system. The mixture was extracted with ethyl acetate, dried on anhydrous sodium sulfate, and separated by flash column chromatography to obtain compound A5-3 (70 mg, total yield for 2 steps: 36%). LC-MS: [M+H] + :616

[0201] Intermediate A5-3 (70 mg) was dissolved in 4 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 2 hours. The reaction was stopped, and the solvent was evaporated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to adjust the pH to 10. The mixture was extracted with dichloromethane and separated by preparative chromatography to obtain the target compound A5 (30 mg, yield: 53%). LC-MS: [M+H] + :516

[0202] The following compounds were synthesized referring to the route in Example 3: [Table 1]

[0203] Example 4: [ka]

[0204] Intermediate A1-3 (0.29 mmol, 180 mg) and thiophene-2-boronic acid pinacol ester A7-1 (0.58 mmol, 121 mg) were dissolved under nitrogen in 10 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1). Potassium carbonate (0.87 mmol, 120 mg) and Pd(dppf)Cl2 (0.03 mmol, 22 mg) were added. The mixture was heated to 95°C and reacted for 2 hours. The reaction was stopped. The mixture was filtered, and the solvent was evaporated under reduced pressure. 30 mL of water was added. The mixture was extracted with ethyl acetate and separated by flash column chromatography to obtain compound A7-2 (100 mg, yield: 55%). LC-MS: [M+H] + :632

[0205] Intermediate A7-2 (100 mg) was dissolved in 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 2 hours. The reaction was stopped, and the solvent was evaporated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to adjust the pH to 10. The mixture was extracted with dichloromethane and separated by preparative chromatography to obtain compound A7 (20 mg, yield: 25%). LC-MS: [M+H] + :532

[0206] (TFA salt); 1 H NMR (600MHz, DMSO-d6) δ 8.83(s,1H), 8.44(s,1H), 8.27(d,J=11.8Hz,1H), 7.44(t,J=7.4Hz,1H), 7.35( m,1H), 7.08(m,1H), 6.94(m,1H), 4.73(s,1H), 4.54(s,1H), 4.25(d,J=13.8Hz,1 H), 4.01(m,1H), 3.78(m,1H), 3.68(s,1H), 3.59-3.53(m,1H), 3.45(d,J=12.5H) z,2H), 3.26(m,3H), 2.42-2.30(m,2H), 2.23-1.97(m,5H), 1.28(d,J=6.9Hz,3H)

[0207] Example 5: [ka]

[0208] Intermediate a1 (0.59 mmol, 150 mg) and intermediate b4 (1.54 mmol, crude) were dissolved in 10 mL of toluene under nitrogen, and triethylamine (1.19 mmol, 120 mg) and Pd(PPh3)2Cl2 (0.12 mmol, 84 mg) were added. The mixture was heated to 100°C and reacted for 3 hours. The reaction was stopped. The mixture was filtered, and 30 mL of water was added to the system. The mixture was extracted with ethyl acetate, dried on anhydrous sodium sulfate, and separated by TLC chromatography to obtain compound A8-1 (120 mg, yield: 65%). LC-MS: [M+H] + :314

[0209] Intermediate A8-1 (0.38 mmol, 120 mg) was dissolved in 8 mL of anhydrous dichloromethane in an ice bath, and N-bromosuccinimide NBS (0.42 mmol, 75 mg) was slowly added in batches. The mixture was stirred at room temperature for 2 hours. The reaction was stopped, and 20 mL of saturated aqueous ammonium chloride was added. The mixture was extracted with dichloromethane and dried on anhydrous sodium sulfate to obtain compound A8-2 (200 mg, crude). LC-MS: [M+H] + :393

[0210] The crude intermediate A8-2 (200 mg) and starting material a3-2 (0.57 mmol, 158 mg) derived from the above process were dissolved in 10 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1) under nitrogen, and potassium carbonate (0.76 mmol, 105 mg) and Pd(dppf)Cl2 (0.04 mmol, 29 mg) were added. The mixture was heated to 100°C by microwave and reacted for 2 hours. The reaction was stopped. The mixture was filtered, and 40 mL of water was added to the system. The mixture was extracted with ethyl acetate, dried on anhydrous sodium sulfate, and separated by TLC chromatography to obtain compound A8-3 (80 mg, total yield for 2 steps: 46%). LC-MS: [M+H] + :464

[0211] Intermediate A8-3 (80 mg) was dissolved in 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 2 hours. The reaction was stopped, and the solvent was evaporated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to adjust the pH to 10. The mixture was extracted with dichloromethane and separated by preparative chromatography to obtain the target compound A8 (27 mg, yield: 42%). LC-MS: [M+H] + :380

[0212] (TFA salt); 1 1H NMR (400MHz, DMSO-d6) δ 8.30(s,1H), 7.67(d,J=1.8Hz,1H), 7.05(s,1H), 6.79(d,J=2.0Hz,1H), 4 .57(d,J=6.6Hz,1H), 4.28(d,J=13.2Hz,1H), 4.02(d,J=3.4Hz,1H), 3.99 (s,3H), 3.79(d,J=11.4Hz,1H), 3.67(dd,J=11.8, 2.9Hz,1H), 3.52(td,J =11.8, 2.9Hz,1H), 3.33-3.23(m,1H), 2.27(s,3H), 1.29(d,J=6.7Hz,3H)

[0213] Example 6: [ka]

[0214] Intermediate a3 (0.17 mmol, 80 mg), 3-bromo-5-fluoropyridine A9-1 (0.34 mmol, 60 mg), potassium phosphate (0.34 mmol, 72 mg), and CuI (0.034 mmol, 7 mg) were added to a microwave reaction flask under nitrogen and dissolved in 5 mL of DMF. The mixture was stirred for 5 minutes, and then N,N-dimethyl-1,2-cyclohexanediamine (0.07 mmol, 10 mg) was slowly added. The mixture was heated to 110°C by microwave and reacted for 1.5 hours. The reaction was stopped. 40 mL of water was added. The mixture was extracted with ethyl acetate, dried on anhydrous Na2SO4, and separated by flash column chromatography to obtain compound A9-2 (50 mg, yield: 53%). LC-MS: [M+H] + :558

[0215] Intermediate A9-2 (50 mg) was dissolved in 4 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 2 hours. The reaction was stopped, and the solvent was evaporated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to adjust the pH to 10. The mixture was extracted with dichloromethane and separated by preparative chromatography to obtain the target compound A9 (28 mg, yield: 67%). LC-MS: [M+H] + :474

[0216] The following compounds were synthesized referring to the route in Example 6: [Table 1] [Table 1] [Table 1]

[0217] Example 7: [ka]

[0218] Intermediate a3 (0.15 mmol, 70 mg), 3-bromo-6-benzyloxypyridine A14-1 (0.30 mmol, 79 mg), potassium phosphate (0.45 mmol, 95 mg), and CuI (0.02 mmol, 4 mg) were added to a microwave reaction flask under nitrogen and dissolved in 5 mL of N-methylpyrrolidone. The mixture was stirred for 5 minutes, and then N,N-dimethyl-1,2-cyclohexanediamine (0.03 mmol, 4.3 mg) was slowly added. The mixture was heated to 110°C by microwave and reacted for 10 hours. The reaction was then stopped. 20 mL of water was added. The mixture was extracted with ethyl acetate, dried on anhydrous sodium sulfate, and separated by TLC chromatography to obtain compound A14-2 (70 mg, yield: 73%). LC-MS: [M+H] + :646

[0219] Intermediate A14-2 (70 mg) was dissolved in 5 mL of methanol, and 3 mL of concentrated hydrochloric acid was added. The mixture was heated to 65°C and reacted for 2 hours. The reaction was stopped. The reaction solution was placed in an ice bath, and a saturated aqueous solution of NaHCO3 was slowly added to the system. The mixture was extracted with ethyl acetate, dried on anhydrous sodium sulfate, and separated by preparative chromatography to obtain the target compound A14 (20 mg, yield: 39%). LC-MS: [M+H] + :472

[0220] (free base); 1 H NMR (400MHz, DMSO-d6) δ 8.27(s,1H), 7.74(d,J=2.9Hz,1H), 7.62(dd,J=9.5, 3.0Hz,2H), 6.77(d,J=1.9 Hz,1H), 6.69(s,1H), 6.49(d,J=9.6Hz,1H), 4.54(s,1H), 4.26(d,J=13.5Hz,1H) , 4.03-3.98(m,1H), 3.78(d,J=11.4Hz,1H), 3.68(dd,J=11.6, 3.1Hz,1H), 3.57- 3.49(m,1H), 3.30-3.22(m,1H), 2.24(s,3H), 2.20(s,3H), 1.28(d,J=6.6Hz,3H)

[0221] Example 8: [ka]

[0222] Intermediate a1 (0.79 mmol, 200 mg) and intermediate b5 (1.19 mmol, 516 mg) were dissolved under nitrogen in 15 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1), and potassium carbonate (1.60 mmol, 221 mg) and Pd(dppf)Cl2 (0.08 mmol, 59 mg) were added. The mixture was heated to 95°C and reacted for 10 hours. The reaction was stopped. The mixture was filtered, and 40 mL of water was added to the system. The mixture was extracted with ethyl acetate, dried on anhydrous sodium sulfate, and separated by flash column chromatography to obtain compound A15-1 (170 mg, yield: 41%). LC-MS: [M+H] + :525

[0223] Intermediate A15-1 (0.32 mmol, 170 mg) was dissolved in 10 mL of anhydrous dichloromethane in an ice bath, and N-bromosuccinimide NBS (0.35 mmol, 63 mg) was slowly added in batches. The mixture was stirred at room temperature for 2 hours. The reaction was stopped, and 20 mL of saturated aqueous ammonium chloride was added. The mixture was extracted with dichloromethane and dried on anhydrous sodium sulfate to obtain compound A15-2 (200 mg, crude). LC-MS: [M+H] + :604

[0224] Intermediate A15-2 (200 mg) and starting material a3-2 (0.64 mmol, 178 mg) derived from the above process were dissolved in 10 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1) under nitrogen, and potassium carbonate (0.64 mmol, 89 mg) and Pd(dppf)Cl2 (0.03 mmol, 22 mg) were added. The mixture was heated to 100°C by microwave and reacted for 2 hours. The reaction was stopped. The mixture was filtered, and 20 mL of water was added to the system. The mixture was extracted with ethyl acetate, dried on anhydrous sodium sulfate, and separated by TLC chromatography to obtain compound A15-3 (45 mg, total yield for 2 steps: 21%). LC-MS: [M+H] + :675

[0225] Intermediate A15-3 (45 mg) was dissolved in 4 mL of dichloromethane, and 1.5 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 2 hours. The reaction was stopped, and the solvent was evaporated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to adjust the pH to 10. The mixture was extracted with dichloromethane and separated by preparative chromatography to obtain the target compound A15 (9 mg, yield: 30%). LC-MS: [M+H] + :491

[0226] (free base); 1 1H NMR (400MHz, DMSO-d6) δ 8.26(s,2H), 7.71(s,1H), 7.51(s,1H), 6.78(s,1H), 6.69(s,1H), 4.57 (s,1H), 4.27(s,1H), 4.00(dd,J=11.5, 3.6Hz,1H), 3.77(d,J=11.4Hz,1 H), 3.67(dd,J=11.3, 3.1Hz,1H), 3.56-3.37(m,5H), 3.23(dd,J=12.7, 3.9Hz,1H), 2.76(m,4H), 2.32(s,3H), 2.17(s,3H), 1.27(d,J=6.7Hz,3H)

[0227] Example 9: [ka]

[0228] Intermediate a4 (0.25 mmol, 100 mg) and intermediate b6 (0.50 mmol, 211 mg) were dissolved under nitrogen in 10 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1), and potassium carbonate (0.50 mmol, 69 mg) and Pd(dppf)Cl2 (0.03 mmol, 22 mg) were added. The mixture was heated to 100°C by microwave and reacted for 2 hours. The reaction was stopped. The mixture was filtered, and 20 mL of water was added to the system. The mixture was extracted with ethyl acetate, dried on anhydrous sodium sulfate, and separated by TLC chromatography to obtain compound A16-1 (60 mg, yield: 36%). LC-MS: [M+H] + :664

[0229] Intermediate A16-1 (60 mg) was dissolved in 4 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 2 hours. The reaction was stopped, and the solvent was evaporated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to adjust the pH to 10. The mixture was extracted with dichloromethane and separated by preparative chromatography to obtain the target compound A16-I (10 mg, yield: 23%). LC-MS: [M+H] + :480

[0230] By referring to the synthetic route of compound A16-I, and using its diastereoisomer b7 instead of intermediate b6, the target compound A16-II was obtained. (free base); 1H NMR (400MHz, DMSO-d6) δ 8.24(s,1H), 7.59(s,1H), 6.74(s,1H), 6.64(s,1H), 4.92-4.73(m,1H), 4.56(s,1H), 4.43(m,1 H), 4.27(d,J=13.6Hz,1H), 4.02-3.96(m,1H), 3.76(d,J=11.4Hz,1H), 3.66(dd,J=11.4, 3.1Hz ,1H), 3.55-3.49(m,1H), 3.44(dd,J=7.0, 5.0Hz,1H), 3.25-3.18(m,1H), 2.97(d,J=12.5Hz,1H) ), 2.68-2.61(m,2H), 2.25(s,3H), 2.16(s,3H), 2.08(m,1H), 1.92(m,1H), 1.27(d,J=6.7Hz,3H)

[0231] The following compounds were synthesized with reference to Example 9: [Table 1]

[0232] Example 10: [ka]

[0233] Compound A11 (0.063 mmol, 30 mg) was dissolved in a 6 mL mixture of water and acetonitrile (v / v, 5 / 1), and manganese dioxide (0.115 mmol, 10 mg) was added. The mixture was heated to 90°C and reacted for 10 hours. The reaction was stopped. The mixture was filtered and separated by flash column chromatography to obtain compound A17 (4 mg, yield: 13%). LC-MS: [M+H] + :499

[0234] (free base); 1H NMR (400MHz, DMSO-d6) δ 9.11(d,J=1.9Hz,1H), 8.98(d,J=2.4Hz,1H), 8.42(t,J=2.2Hz,1H), 8.35(s,1H) ), 8.28(s,1H), 7.78(s,1H), 7.60(s,1H), 6.77(s,2H), 4.56(d,J=7.4Hz,1H), 4 .28(d,J=13.4Hz,1H), 4.05-3.97(m,1H), 3.79(d,J=11.5Hz,1H), 3.69(m,1H), 3.54(m,1H), 3.28-3.22(m,1H), 2.38(s,3H), 2.26(s,3H), 1.29(d,J=6.7Hz,3H)

[0235] Example 11: [ka]

[0236] Intermediate a3 (0.17 mmol, 80 mg) and 2-bromoethanol A18-1 (0.34 mmol, 43 mg) were added to a reaction flask under nitrogen and dissolved in 5 mL of DMF. The mixture was stirred for 5 minutes, and then NaH (0.34 mmol, 14 mg) was slowly added. The mixture was heated to 50°C and reacted for 2 hours. The reaction was stopped. 40 mL of water was added. The mixture was extracted with ethyl acetate, dried on anhydrous Na2SO4, and separated by TLC chromatography to obtain compound A18-2 (40 mg, yield: 47%). LC-MS: [M+H] + :507

[0237] Intermediate A18-2 (60 mg) was dissolved in 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 2 hours. The reaction was stopped, and the solvent was evaporated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to adjust the pH to approximately 10. The mixture was extracted with dichloromethane and separated by preparative chromatography to obtain the target compound A18 (20 mg, yield: 40%). LC-MS: [M+H] + :423

[0238] (free base); 1 H NMR (400MHz, DMSO-d6) δ 12.66(br,1H), 8.23(s,1H), 7.58(s,1H), 6.74(s,1H), 6.58(s,1H), 4.92(t,J=5.3 Hz,1H), 4.54(d,J=7.5Hz,1H), 4.25(d,J=13.6Hz,1H), 4.10(t,J=5.7Hz,2H), 3.99 (dd,J=11.5, 3.6Hz,1H), 3.77(m,3H), 3.67(dd,J=11.5, 3.1Hz,1H), 3.52(td,J=11 .8, 3.0Hz,1H), 3.28-3.20(m,1H), 2.25(s,3H), 2.13(s,3H), 1.27(d,J=6.7Hz,3H)

[0239] Example 12: [ka]

[0240] Intermediate a3 (0.19 mmol, 90 mg), 3-bromo-5-benzyloxypyridine A19-1 (0.38 mmol, 100 mg), potassium phosphate (0.57 mmol, 120 mg), and CuI (0.04 mmol, 8 mg) were added to a microwave reaction flask under nitrogen and dissolved in 5 mL of DMF. The mixture was stirred for 5 minutes, and then N,N-dimethyl-1,2-cyclohexanediamine (0.04 mmol, 5 mg) was slowly added. The mixture was heated to 110°C and reacted for 10 hours. The reaction was then stopped, and the mixture was filtered. 30 mL of water was added. The mixture was extracted with ethyl acetate, dried on anhydrous sodium sulfate, and separated by TLC chromatography to obtain compound A19-2 (85 mg, yield: 70%). LC-MS: [M+H] + :646

[0241] Intermediate A19-2 (0.13 mmol, 85 mg) and Pd / C (9 mg) were mixed in 4 mL of a methanol-ethyl acetate mixture (v / v, 3 / 1), and the air was replaced with hydrogen (4 atm). The mixture was heated to 50°C and reacted for 2 hours. The reaction was stopped. The mixture was filtered, and the solvent was evaporated under reduced pressure to obtain the crude intermediate A19-3. LC-MS: [M+H] + :556

[0242] Crude intermediate A19-3 was dissolved in 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 2 hours. The reaction was stopped. The solvent was evaporated under reduced pressure, and 10 mL of saturated aqueous solution of NaHCO3 was slowly added to the system. The mixture was extracted with dichloromethane, dried on anhydrous sodium sulfate, and separated by preparative chromatography to obtain the target compound A19 (38 mg, total yield for 2 steps: 63%). LC-MS: [M+H] + :472

[0243] (free base); 1 1H NMR (400MHz, DMSO-d6) δ 8.32-8.24(m,2H), 8.22(d,J=2.5Hz,1H), 7.60(s,1H), 7.36(t,J=2.3Hz, 1H), 6.76(s,2H), 4.56(d,J=8.0Hz,1H), 4.27(d,J=13.5Hz,1H), 4.01(dd, J=11.4, 3.6Hz,1H), 3.79(d,J=11.4Hz,1H), 3.69(dd,J=11.5, 3.1Hz,1H), 3.54(m,1H), 3.27(m,1H), 2.33(s,3H), 2.23(s,3H), 1.29(d,J=6.7Hz,3H)

[0244] Example 13: [ka]

[0245] Intermediate a1 (1.59 mmol, 400 mg) was dissolved in 15 mL of anhydrous tetrahydrofuran under nitrogen at -78°C, and n-butyllithium (0.76 mL, 2.5 M) was added dropwise. The mixture was reacted for 30 minutes. Tetrahydropyran-4-one A20-1 (1.75 mmol, 175 mg) was then slowly added, and the mixture was stirred for a further 2 hours. The reaction was then stopped. 30 mL of saturated aqueous ammonium chloride was slowly added to the system. The mixture was extracted with dichloromethane, dried on anhydrous sodium sulfate, and separated by TLC chromatography to obtain compound A20-2 (100 mg, yield: 20%). LC-MS: [M+H] + :319

[0246] Intermediate A20-2 (0.31 mmol, 100 mg) was dissolved in 10 mL of anhydrous dichloromethane in an ice bath, and N-iodosuccinimide NIS (0.35 mmol, 79 mg) was slowly added in batches. The mixture was stirred at room temperature for 2 hours. The reaction was stopped, and 20 mL of saturated aqueous ammonium chloride solution was added. The mixture was extracted with dichloromethane and dried on anhydrous sodium sulfate to obtain compound A20-3 (170 mg, crude). LC-MS: [M+H] + :445

[0247] Intermediate A20-3 (170 mg) and starting material a3-2 (0.62 mmol, 172 mg) derived from the above process were dissolved in 10 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1) under nitrogen, and potassium carbonate (0.64 mmol, 89 mg) and Pd(dppf)Cl2 (0.03 mmol, 22 mg) were added. The mixture was heated to 100°C by microwave and reacted for 2 hours. The reaction was stopped. The mixture was filtered, and 20 mL of water was added to the system. The mixture was extracted with ethyl acetate, dried on anhydrous sodium sulfate, and separated by TLC chromatography to obtain compound A20-4 (120 mg, total yield for 2 steps: 83%). LC-MS: [M+H] + :467

[0248] Intermediate A20-4 (120 mg) was dissolved in 6 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 2 hours. The reaction was stopped, and the solvent was evaporated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to adjust the pH to 10. The mixture was extracted with dichloromethane and separated by preparative chromatography to obtain the target compound A20 (61 mg, yield: 61%). LC-MS: [M+H] + :383

[0249] (free base); 1 H NMR (400MHz, DMSO-d6) δ 12.68(br,1H), 8.33(s,1H), 7.70-7.52(m,1H), 6.81(s,1H), 6.73(s,1H), 5.87(s,1H) , 4.58-4.45(m,1H), 4.18(d,J=13.3Hz,1H), 4.01(dd,J=11.4, 3.6Hz,1H), 3.81(t,J=9. 7Hz,5H), 3.66(dd,J=11.5, 3.1Hz,1H), 3.51(td,J=11.8, 2.9Hz,1H), 3.25(dd,J=12.8, 3.8Hz,1H), 3.01(td,J=12.7, 5.8Hz,2H), 1.50(d,J=11.8Hz,2H), 1.28(d,J=6.6Hz,3H)

[0250] Example 14: Assay of ATR kinase activity: Biotinylated protein derived from p53 (Eurofins, product number: 14-952) was phosphorylated with ATR kinase. In this assay, the amount of phosphorylated protein was measured by time-resolved fluorescence. The amount of phosphorylated protein was detected by anti-p53-phospho-(serine 15)-K-specific antibody (Cisbio, product number: 61GSTDLA) and d2-labeled anti-GST antibody (Cisbio, product number: 61P08KAE). Prior to the assay, the following working solutions were prepared as needed: 1x reaction buffer (20mM HEPES pH 8.0, 1% glycerol, 0.01% Brij-35), dilution buffer (20mM HEPES pH 8.0, 1% glycerol, 0.01% Brij-35, 5mM DTT and 1% BSA), stop solution (20mM HEPES pH 8.0, 1% glycerol, 0.01% Brij-35, 250mM EDTA), and detection buffer (50mM HEPES pH 7.0, 150mM NaCl, 267mM KF, 0.1% sodium cholate, 0.01% Tween-20, 0.0125% sodium azide). The reagents used above were purchased from Sigma or Invitrogen, except where the manufacturer is specified.

[0251] The operation was as follows: Solutions of the compound were prepared using 1x reaction buffer in 4x serial dilutions, yielding solutions of nine compounds at different concentrations. 2.5 μL of each of these 4x serial dilution solutions was added to a 384-well analysis plate (784075, Greiner). A 4xp53 substrate working solution (40 nM) was prepared using 1x reaction buffer, and 2.5 μL of this working solution was added to the 384-well analysis plate. A 4x ATR / ATRIP working solution (12.8 ng / μL) was prepared using dilution buffer, and 2.5 μL of this 4xp ATR / ATRIP working solution was added to the 384-well analysis plate. A 4x ATP working solution (2 mM) was prepared using deionized water, and 2.5 μL of this 4x ATP working solution was added to the 384-well analysis plate. These plates were incubated in the dark at room temperature for 30 minutes. 5 μL of stop solution was added to the 384-well analysis plate. Finally, 5 μL of the assay mixture (0.084 ng / μL anti-phospho-p53(ser15)-K and 5 ng / μL anti-GST-d2) was added to a 384-well analysis plate and incubated overnight at room temperature. Fluorescence signals were detected using an ENVISION (Perkinelmer) instrument (excitation wavelength: 320 nm, emission wavelengths: 665 nm and 615 nm). The inhibition rate in each well was calculated using the fluorescence intensity value in each well: ER (Emission Rate) = (Fluorescence intensity at 665 nm / Fluorescence intensity at 615 nm); Inhibition Rate = (ER of positive compound - ER of assay compound) / (ER of positive compound - ER of negative compound) x 100%. IC of the compound 50 The values ​​were calculated using standard parameter fitting software (GraphPad Prism 6.0).

[0252] Results of kinase data for the compounds in the examples: [Table 1]

[0253] Example 15: In vitro assay of cell proliferation inhibition: This assay investigated the inhibitory effect of compounds on cell proliferation by detecting their in vitro effects on cell activity in tumor cell lines TOV21G (ovarian cancer) and MV4-11 (leukemia). TOV21G cells and MV4-11 cells were purchased from the American Type Culture Collection (ATCC).

[0254] TOV21G cells were cultured in MCDB105 / M199 medium (containing 15% FBS) and used in the assay when cell confluence reached 85% or higher. Approximately 1,000 cells were inoculated into each well of a 96-well culture plate and cultured for 24 hours. Cells were treated with assay compounds at different concentrations (0-10 μM). Each group was triple-dubbed in the assay. Blank wells (containing only culture medium) and control wells (cells inoculated without drug treatment) were set up. Cells were cultured for 120 hours. 40 μL of Cell Titer-Glo solution (Promega, no. G7573) was added to each well, and the cells were incubated in the dark for 20 minutes with shaking. 100 μL of solution from each well was transferred to a 96-well blank plate (Corning, number 3917), and the luminescence values ​​were read using a Biotek Synergy H1 multifunction microplate reader.

[0255] MV-4-11 cells were cultured in IMDM medium (containing 20% ​​FBS). Approximately 10,000 cells were inoculated into each well of a 96-well culture plate and treated with assay compounds at different concentrations (0-10 μM). Each group was triple-replicated in the assay. Blank wells (containing only culture medium) and control wells (cells inoculated without drug treatment) were prepared. Cells were cultured for 120 hours. 40 μL of Cell Titer-Glo solution was added to each well, and the cells were incubated in the dark for 20 minutes with shaking. 100 μL of solution derived from each well was transferred to a 96-well blank plate, and the luminescence values ​​were read using a Biotech Synergy H1 multifunction microplate reader. Inhibition rate (%) = 100% x (control well - assay well) / (control well - blank well)

[0256] The results of the proliferation assay showed that the assay compound was effective in the human tumor cells examined, and this is confirmed by IC 50 The value is reflected (IC 50 (This concentration inhibits the maximum effect by 50%).

[0257] Results of cell activity assays using the CellTiter-Glo luminescence method: [Table 1] NT=Not tested

[0258] Example 16: In vitro stability assay of a compound in liver microsomes The compounds disclosed herein were subjected to stability assays in liver microsomes. The assay compounds (final concentration 2.0 nM) were co-incubated with human / mouse liver microsomes, with or without the addition of NADPH. The concentration of the compounds in the supernatant was measured within 60 minutes after incubation. The results for representative compounds were as follows: [Table 1]

[0259] Example 17: In vivo pharmacokinetic assay of a compound In vivo pharmacokinetic studies were conducted on the compounds disclosed herein. Assay method: Male ICR mice (3 mice per group) were force-administered a dose of 10 mg / kg orally. Plasma samples were collected before administration (0 hours) and after administration (0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours). The collected samples were subjected to LC / MS analysis, and data were collected. The collected analysis data was used with Analyst v1.6.2 (Applied Biosystems Company, USA) software to calculate relevant pharmacokinetic parameters.

[0260] The results for representative compounds were as follows: [Table 1]

[0261] Example 18: Investigation of the selectivity of the compound for ATR kinase: The compounds disclosed herein were assayed for inhibition of the same family (ATM, DNA-PK, PI3K, mTOR): According to assay methods reported in the literature, the compounds to be assayed were subjected to sequential 3-fold dilutions starting from 10 μM and down to 0.51 nM (a total of 10 concentrations), and their inhibitory activity against kinases ATM1, DNA-PK2, PI3Kα3, PI3Kδ3, and mTOR4 was assayed. The results are shown below: [Table 1]

[0262] The results described above indicate that the compounds of this disclosure have high selectivity for ATR and low inhibitory activity against other kinases in the family.

[0263] References: [1]Discovery of Novel 3-Quinoline Carboxamides as Potent, Selective and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated(ATM)Kinase, J. Med. Chem. 2016, 56, 6281-6292; [2]The Discovery of 7-methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one(AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor, J. Med. Chem. 2020, 63, 3461-3471; [3]WO 2012044641; [4]Discovery and SAR exploration of a novel series of imidazo[4,5-b]pyrazin-2-ones as potent and selective mTOR kinase inhibitors. Bioorg. Med. Chem. Lett. 2011;21:6793-6799

[0264] The foregoing further describes the disclosure in relation to specific alternative embodiments, and the specific embodiments of the disclosure are not limited to that description. Those skilled in the art will be able to make some minor deductions or substitutions without departing from the spirit of the invention, all of which should be considered to be within the scope of the protection of the invention. Furthermore, the present invention includes the following embodiments. [Aspect 1] General formula (I): [ka] [In formula: X is CR X or N; Y is CR Y or N; R 1 、R 2 、R 3 、R 4 and R Y These are independently H, D, halogen, and C. 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from Alkinyl, or R 1 and R 2 、R 3 and R 4 and are connected to form a joint, C 1-6 Alkilen, C 2-6 Alkenylene or C 2-6 It forms an alkynylene; where the group may be substituted with one or more D or halogens until it is completely replaced; Here, R X H, D, halogen, -CN, -NRR', -OR, -SR or C 1-6 It is an alkyl group, where the group may be substituted with one or more D or halogens until it is completely substituted; Y is CR Y If R Y and R 1 This means that together with the atoms they bond to, C 3-5 Forming a cycloalkyl or 3- to 5-membered heterocycline, where the group may be substituted with one or more D or halogens until completely replaced; Ring A is C 3-7 Cycloalkyl, 4-7 membered heterocyclyl, C 6-10 It is either an aryl or a 5-10 member heteroaryl; or ring A is absent, so there is 1 R a is linked to L; or (R a ) m -Ring AL- does not even exist; R a These are independently H, D, halogen, -CN, -NRR', -OR, -SR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) p R, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Selected from cycloalkyls and 3- to 8-membered heterocyclines, each of which optionally includes R * It may be replaced by, where the group may be replaced by one or more D or halogens until it is completely replaced; m is 0, 1, 2, 3, 4, or 5; Ring B is a 5- or 6-membered heteroaryl; R b These are independently H, D, halogen, -CN, -NRR', -OR, -SR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) p R, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-7 Selected from cycloalkyls and 3- to 8-membered heterocyclines, each of which optionally includes R * It may be replaced by, where the group may be replaced by one or more D or halogens until it is completely replaced; n is 0, 1, 2, 3, 4, or 5; Ring C is C 3-7 Cycloalkyl, 4-7 membered heterocyclyl, C 6-10 It is an aryl or a 5- to 10-membered heteroaryl; L represents a bond, -O-, -S-, -N(R)-, -C(O)-, C 1-6 Alkilen, C 2-6 Alkenylene or C 2-6 It is alkynylene; R 5 H, D, Halogen, -CN, -NRR', -OR, -SR, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 It is an alkynyl group, where the group may be substituted with one or more D or halogens until it is completely replaced; R 6 H, D, Halogen, -CN, -NRR', -OR, -SR, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 It is an alkynyl group, where the group may be substituted with one or more D or halogens until it is completely substituted; R * H, halogen, -CN, -NRR', -OR, -SR, -C(O)R, -C(O)OR, -C(O)NRR', -OC(O)R', -NRC(O)R', -OC(O)NRR', -NRC(O)NRR', -S(O) p R, C 3-7 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 An aryl or 5- to 10-membered heteroaryl group, where the group may be substituted with one or more D or halogens until completely replaced; R and R' are independent of H and C. 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from alkynyl groups, or R and R' together with their bonded nitrogen atoms, form a 4- to 8-membered heterocycline; where the group may be substituted with one or more D or halogens until completely replaced; p is either 1 or 2. Compounds represented by, or their pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants, or mixtures thereof. [Aspect 2] R 1 C 1-6 It is alkyl, or (R)-C 1-6 The compounds described in Embodiment 1, which are alkyl or even (R)-methyl, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, or mixtures thereof. [Aspect 3] X is CR X And R 2 、R 3 、R 4 and R X A compound according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant, or mixture thereof, wherein is hydrogen or D. [Aspect 4] A compound according to any one of embodiments 1 to 3, wherein Y is N, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug, or isotopic variant, or mixture thereof. [Aspect 5] Ring A is the following group:

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Claims

1. General formula (I): 【Chemistry 1】 [In the formula: X is CR Ｘ And; Y is N; R １ , R ２ , R ３ and R ４ These are H, D, and C independently. １－６ Selected from alkyl groups; where C １－６ Alkyl can be substituted with one or more D or halogens until it is completely substituted; Here, R Ｘ is H or D; Ring A is a 5- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl; or Ring A is absent, and then one of R ａ is linked to L; or (R ａ ) ｍ -Ring A-L- does not even exist; R ａ These are independently H, D, halogen, -CN, -OR, -C(O)NRR' and C １－６ Selected from alkyl groups, C １－６ Alkyl can be substituted with one or more D or halogens until it is completely substituted; m is 0, 1, 2, 3, 4, or 5; Ring B is a 5-6 member heteroaryl; R ｂ These are independently H, D, halogen, -CN and C １－６ Selected from alkyl groups; n is 0, 1, 2, 3, 4 or 5; Ring C is a 5-6 member heterocyclyl or 5-6 member heteroaryl; L is a joint, -C(O)- or C １－６ It is alkylene; R ５ is H, D, -OR or C １－６ It is alkyl, and here, C １－６ Alkyl can be substituted with one or more D or halogens until it is completely substituted; R ６ is H, D, -OR or C １－６ It is alkyl, and here, C １－６ Alkyl can be substituted with one or more D or halogens until it is completely substituted; R and R' are H. A compound represented by, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound thereof, However, if the compound is 【Chemistry 2】 isn't it, Compounds, or their pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, or deuterium compounds.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound, wherein the compound has one or more of the following definitions: i) R １ (R)-C １－６ It is alkyl; ii) R ２ , R ３ and R ４ is hydrogen or D; iii) Ring A is the following group: 【Transformation 3】 More selected; Here A １ CR ａ１ or N; A ２ CR ａ２ or N; A ３ CR ａ３ or N; A ４ CR ａ４ or N; A ５ CR ａ５ or N; R ａ１ , R ａ２ , R ａ３ , R ａ４ and R ａ５ R of claim 1 ａ It is synonymous with; iv) Ring A is absent or selected from piperazinyl and piperidinyl; v) R ａ However, independently, H, D, halogen, -CN, -OR, -C(O)NRR' and C １－６ Selected from alkyl, where C １－６ Alkyl groups may be substituted with one or more D atoms until they are completely deuterated; vi) Ring B is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl, or pyrazinyl; vii) R ｂ However, it is H; vii) Ring C is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl, or pyrazinyl; ix) The ring C is a 5-6 member heterocycline; x) L is a joint; xi)R ５ and R ６ However, independently, H, D, or C １－６ It is alkyl, and here, C １－６ Alkyl may be substituted with one or more D or halogens until it is completely substituted. Compounds, or their pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, or deuterium compounds.

3. R １ is (R)-methyl, The compound described in claim 2, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

4. (R ａ ) ｍ The following group is formed by ring A-L: 【Chemistry 4】 More selected The compound described in claim 2, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

5. Ring B is pyrazolyl. The compound described in claim 2, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

6. The ring C is pyrazolyl. The compound described in claim 2, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

7. The following is a general structural formula: 【Transformation 5】 [Each group is defined in any one of claims 1 to 6.] A compound according to any one of claims 1 to 6 shown, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

8. General formula (I-1) or (I-2): 【Transformation 6】 [In the formula: Ring C is a 5-6 member heterocyclyl; Ring B is pyrrolyl, furanyl, thienyl, pyrazolyl, or pyridyl; R ５ is H, D, or -OR; The other groups are defined in the same way as in any one of claims 1 to 6. The compound described in claim 7, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

9. The C ring is tetrahydropyranyl. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

10. General formula (I-1): 【Transformation 7】 [In the formula: Ring C is pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or triazolyl; Ring B is pyrrolyl, furanyl, thienyl, pyrazolyl, or pyridyl; The other groups are defined in the same way as in any one of claims 1 to 6. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

11. General formula (II) or (II-1): 【Transformation 8】 [In the formula: Ring A is either absent or is piperidyl or piperazinyl; Ring B is pyrrolyl, furanyl, thienyl, pyrazolyl, or pyridyl; L is a joint, -C(O)- or C １－６ It is alkylene; R ５ and R ６ Independently, C １－６ Alkyl or C １－６ It is a haloalkyl; The other groups are defined in the same way as in any one of claims 1 to 6. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

12. General formula (III) or (III-1): 【Chemistry 9】 [In the formula: Ring C is pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or triazolyl; Ring B is pyrrolyl, furanyl, thienyl, pyrazolyl, or pyridyl; The other groups are defined in the same way as in any one of claims 1 to 6. The compound described in claim 7, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

13. General formula (III-2) or (III-3): 【Chemistry 10】 [In the formula: A １ CR ａ１ or N; A ２ CR ａ２ or N; A ５ CR ａ５ or N; The other groups are defined in the same way as in any one of claims 1 to 6. The compound described in claim 7, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

14. A ３ CR ａ３ or N; R ａ１ , R ａ２ , R ａ３ , R ａ５ , R ５ and R ６ However, independently, H, D, halogen, -CN, -OR, -C(O)NRR' or C １－６ It is alkyl, and here, C １－６ Alkyl can be substituted with one or more D or halogens until it is completely substituted; The other groups are defined in any one of claims 1 to 6, The compound according to claim 13, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

15. A ３ CR ａ３ or N; R ａ１ , R ａ２ , R ａ３ and R ａ５ However, independently, H, D, halogen, -CN, -OH, -C(O)NH ２ , C １－６ Alkyl and C １－６ A haloalkyl group is selected, where the group may be substituted with one or more D until it is completely deuterated; R ５ and R ６ are each, independently, C １－６ alkyl or C １－６ haloalkyl, where the group may be substituted with one or more D until it is fully deuterated The compound according to claim 13, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

16. A ３ CR ａ３ or N; R ａ１ is H or D; R ａ２ is H, D, halogen, -CN, -OH, -C(O)NH ２ , C １－６ alkyl or C １－６ haloalkyl; R ａ３ is H, D, or -OH; R ａ５ is H or D; R ５ C １－６ Alkyl or C １－６ It is a haloalkyl; R ６ C １－６ Alkyl or C １－６ It is a haloalkyl, The compound according to claim 13, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

17. R ５ is methyl, The compound according to claim 16, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

18. R ６ is methyl, The compound according to claim 16, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

19. General formula (III-3): 【Chemistry 11】 [In the formula: A ３ CR ａ３ or N; R ａ１ , R ａ２ , R ａ３ , R ａ５ , R ５ and R ６ These are independently H, D, halogen, -OR, and C. １－６ Alkyl or C １－６ It is a haloalkyl group, where the group may be substituted with one or more D until it is completely deuterated; R and R' are independently H. The compound described in claim 7, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

20. This is shown by the general formula (III-3), where A ３ CR ａ３ or N; R ａ１ , R ａ２ , R ａ３ and R ａ５ However, independently, H, D, halogen, -OH, C １－６ Alkyl and C １－６ A haloalkyl group is selected, where the group may be substituted with one or more D until it is completely deuterated; R ５ and R ６ However, independently, C １－６ Alkyl or C １－６ It is a haloalkyl group, where the group may be substituted with one or more D groups until it is completely deuterated. The compound according to claim 19, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

21. This is shown by the general formula (III-3), where A ３ CR ａ３ or N; R ａ１ is H or D; R ａ２ H, D, halogen, C １－６ Alkyl or C １－６ It is a haloalkyl; R ａ３ is H, D, or -OH; R ａ５ is H or D; R ５ C １－６ Alkyl or C １－６ It is a haloalkyl; R ６ C １－６ Alkyl or C １－６ It is a haloalkyl, The compound according to claim 19, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

22. This is shown by the general formula (III-3), where R ５ is methyl, The compound according to claim 21, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

23. This is shown by the general formula (III-3), where R ６ is methyl, The compound according to claim 21, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

24. General formula (III-4): 【Chemistry 12】 [In the formula: A ４ CR ａ４ or N; R ａ１ is H, D, or halogen; R ａ２ H, D, halogen, -CN, -OH, -C(O)NH ２ , C １－６ Alkyl or C １－６ It is a haloalkyl; R ａ４ is H, D, or -OH; R ａ５ is H or D; R ５ is methyl; R ６ [It is methyl] The compound described in claim 7, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound. 【Request Item 25】 【Chemistry 13】 【Chemistry 14】 More selected The compound described in claim 1, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound, or a mixture thereof, and a pharmaceutically acceptable excipient.

27. The pharmaceutical composition according to claim 26, further comprising other therapeutic agents.

28. A pharmaceutical composition for treating and / or preventing ATR kinase-mediated diseases, comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound, or a mixture thereof, A pharmaceutical composition in which the ATR kinase-mediated disease is selected from proliferative disorders, leukemia, and lymphoma.

29. A pharmaceutical composition for treating and / or preventing ATR kinase-mediated diseases, comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound, or a mixture thereof, A pharmaceutical composition in which the ATR kinase-mediated disease is selected from breast cancer, colorectal cancer, lung cancer, prostate cancer and bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer, as well as leukemia, multiple myeloma and lymphoma.

30. A pharmaceutical composition for treating and / or preventing ATR kinase-mediated diseases, comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, enantiomer, diastereomer, racemate, solvate, hydrate, or deuterium compound, or a mixture thereof, A pharmaceutical composition in which the ATR kinase-mediated disease is selected from small cell lung cancer, non-small cell lung cancer and bronchoalveolar cancer, acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML).

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