Pyrazolopyrimidine compounds as ATR kinase inhibitors

Abstract

Compounds of general formula (I) are disclosed, which can be used to treat ATR kinase-mediated diseases, such as proliferative diseases, such as cancer. Methods for preparing compounds of general formula (I), pharmaceutical compositions, and the use of said pharmaceutical compositions for treating ATR kinase-mediated diseases are also disclosed.

Description

Invention Field

[0001] This invention relates to pyrazolopyrimidine compounds as inhibitors of ATR kinases. More specifically, the compounds of this invention are effective for the treatment of ATR kinase-mediated diseases, such as proliferative diseases, such as cancer. This invention also provides pharmaceutical compositions of said compounds, their use in treating ATR kinase-mediated diseases, and their preparation. Background Technology

[0002] ATR (Ataxia telangiectasia and Rad3-related protein) is a protein kinase involved in genome stability and DNA damage repair, belonging to the PIKK family. ATR activation can be triggered by stalled replication forks or single-strand DNA damage (SSB). Activated ATRs recruit repair proteins or factors to repair damaged sites, delaying mitosis (especially during the G2 / M phase), thus stabilizing replication forks and ensuring genome stability.

[0003] Furthermore, most tumor cells have abnormal DNA damage repair systems, often lacking certain repair pathways (such as mutations in p53 or ATM), making them more dependent on ATR for survival. In normal cells, however, due to their intact repair pathways, inhibiting ATR kinase alone has little effect. Therefore, inhibiting ATR may have a more significant therapeutic effect on cancer, while producing less toxic side effects on normal cells.

[0004] Furthermore, ATR inhibition can be used in combination with radiotherapy or chemotherapy drugs to synergistically enhance their effects. Widely used chemotherapy drugs include antimetabolites (such as gemcitabine), DNA cross-linking agents (such as cisplatin and carboplatin), alkylating agents (such as temozolomide), and topoisomerase inhibitors (such as topotecan and irinotecan). When tumor cells are subjected to chemotherapy or radiotherapy, they significantly activate the ATR signaling pathway to repair damaged DNA. Therefore, inhibiting ATR while treating cancer with radiotherapy or chemotherapy drugs can greatly enhance the therapeutic effect.

[0005] To date, no ATR inhibitors have been marketed, making it essential to discover more effective and safer ATR inhibitors. Summary of the Invention

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

[0007] In one aspect, the present invention provides compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof:

[0008]

[0009] in,

[0010] X is CR X Or N;

[0011] Y is CR Y Or N;

[0012] R1, R2, R3, R4 and R Y Independently selected from H, D, halogens, and C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkyne group, or R1 and R2, R3 and R4 connected to form a bond, C 1-6 Alkylene, C 2-6 imide or C 2-6 Alynyl group; wherein the group may be substituted with one or more D or halogens, up to complete substitution;

[0013] Where R X H, D, halogen, -CN, -NRR', -OR, -SR, or C 1-6 Alkyl groups, wherein the group may be substituted with one or more D or halogens, up to complete substitution;

[0014] When Y is CR Y When, R Y R1, together with the atoms they are attached to, forms C. 3-5 Cycloalkyl or 3-5 membered heterocyclic groups, wherein the group may be substituted with one or more D or halogens, up to complete substitution;

[0015] Ring A is C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Aryl or 5-10 membered heteroaryl; or ring A is absent, therefore one R a Connect to L; or (R) a ) m -The AL ring does not exist;

[0016] R aIndependently selected from H, D, halogens, -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 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the group may be substituted with one or more D or halogens, up to complete substitution;

[0017] m = 0, 1, 2, 3, 4 or 5;

[0018] Ring B is a 5-6 membered heteroaryl group;

[0019] R b Independently selected from H, D, halogens, -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 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the group may be substituted with one or more D or halogens, up to complete substitution;

[0020] n = 0, 1, 2, 3, 4 or 5;

[0021] Ring C is C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups;

[0022] L represents a bond, -O-, -S-, -N(R)-, -C(O)-, C 1-6 Alkylene, C 2-6 imide or C 2-6 Ethyne group;

[0023] R5 represents H, D, halogen, -CN, -NRR', -OR, -SR, and C. 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkynyl group, wherein the group may be substituted with one or more D or halogens, up to complete substitution;

[0024] R6 represents H, D, halogen, -CN, -NRR', -OR, -SR, and C.1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkynyl group, wherein the group may be substituted with one or more D or halogens, up to complete substitution;

[0025] R* is 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 heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups, wherein the group may be substituted by one or more D or halogens, up to complete substitution;

[0026] R and R' are independently selected from H and C. 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group, or R, R', and the nitrogen atom attached to them form a 4-8 membered heterocyclic group; wherein the group may be substituted by one or more D or halogens, up to complete substitution;

[0027] p = 1 or 2.

[0028] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention and optionally a pharmaceutically acceptable excipient.

[0029] In another aspect, the present invention provides pharmaceutical compositions comprising the compounds of the present invention and pharmaceutically acceptable excipients, and further comprising other therapeutic agents.

[0030] In another aspect, the present invention provides a kit comprising the compounds of the present invention, and other therapeutic agents, as well as pharmaceutically acceptable carriers, adjuvants, or mediators.

[0031] In another aspect, the present invention provides the use of the compounds of the present invention in the preparation of medicaments for treating and / or preventing ATR kinase-mediated diseases.

[0032] In another aspect, the present invention provides a method for treating and / or preventing ATR kinase-mediated diseases in a subject, comprising administering the subject a compound or composition of the present invention.

[0033] In another aspect, the present invention provides compounds or compositions thereof for the treatment and / or prevention of ATR kinase-mediated diseases.

[0034] In specific implementation schemes, the diseases include proliferative diseases (such as cancer), especially solid tumors (such as carcinoma and sarcoma), and leukemia and lymphoma, particularly for example, breast cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioloalveolar carcinoma) and 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 [including acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), etc.], multiple myeloma and lymphoma.

[0035] Other objects and advantages of the invention will become apparent to those skilled in the art from the following detailed embodiments, examples and claims.

[0036] definition

[0037] Chemical definition

[0038] The definitions of specific functional groups and chemical terms are described in more detail below.

[0039] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0040] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl groups are preferred. 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). The term "C" is used in conjunction with the preceding text. 1-6"Alkyl" also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3) or i-Bu(-CH2CH(CH3)2).

[0041] “C 2-6 "Alkenyl" refers to a straight-chain 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 groups are preferred. C 2-6 Examples of alkenyl groups include: vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and so on. The term "C" is used in conjunction with these groups. 2-6 "Alkenyl" also includes heteroalkenyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0042] “C 2-6 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 Alkyne groups are preferred. C 2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentyynyl (C5), hexynyl (C6), etc. The term "C" is used in conjunction with other alkynyl groups. 2-6 "Alkyne" also includes heteroyne, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0043] “C 1-6 Alkylene, C 2-6 imide or C 2-6 "Nyneylyl" refers to the "C" group defined above. 1-6 Alkyl, C 2-6 alkenyl or C 2-6The divalent group of "alkynyl".

[0044] “C 1-6 "Alkylene" refers to the removal of C 1-6 The alkyl group is a divalent group formed by the other hydrogen atom of the alkyl group, and can be a substituted or unsubstituted alkylene group. In some embodiments, C 1-4 Alkylenes are particularly preferred. Unsubstituted alkylenes include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylenes, for example, those substituted with one or more alkyl (methyl) groups, 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 propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0045] “C 2-6 "Alkenyl" refers to the group that has been de-carbonied. 2-6 The other hydrogen atom of the alkenyl group forms a divalent group, and it can be a substituted or unsubstituted alkenyl group. In some embodiments, C 2-4 Alkenyl groups are particularly preferred. Exemplary unsubstituted alkenyl groups include, but are not limited to, vinylidene (-CH=CH-) and propenylidene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenyl groups, such as alkenyl groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylidene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylidene (-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.

[0046] “C 2-6 "Iso-ynyl group" refers to the group with the C group removed. 2-6The other hydrogen atom of the alkynyl group forms a divalent group, and it can be a substituted or unsubstituted alkynyl group. In some embodiments, C 2-4 The ethynyl group is particularly preferred. Exemplary ethynyl groups include, but are not limited to: ethynyl group (-C≡C-), substituted or unsubstituted propynyl group (-C≡CCH2-), etc.

[0047] “C 1-6 "Alkoxy" refers to the group -OR, where R is a substituted or unsubstituted carbon group. 1-6 Alkyl group. In some embodiments, C 1-4 Alkoxy groups are particularly preferred. Specific alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy. The alkoxy group may be optionally substituted with one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0048] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0049] Therefore, "C" 1-6 "Halogenated alkyl" and "C" 1-6 "Haloalkoxy" refers to the above "C" 1-6 "alkyl" and "C" 1-6 "Alkoxy" is substituted with one or more halogen groups. In some embodiments, C 1-4 Haloalkyl groups are particularly preferred, and C4 groups are more preferred. 1-2 Halogenated alkyl groups. In some embodiments, C 1-4 Halogenated alkoxy groups are particularly preferred, and C4 is more preferred. 1-2 Haloalkoxy groups. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. Exemplary haloalkoxy groups include, but are not limited to: -OCH2F, -OCHF2, -OCF3, etc. The haloalkyl and haloalkoxy groups can be substituted at any available connection point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0050] “C 3-7 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-5 Cycloalkyl groups are preferred. In other embodiments, C 3-6 Cycloalkyl groups are preferred. In other embodiments, C5-6 Cycloalkyl groups are preferred. Cycloalkyl groups also include ring systems in which the aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the linkage is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups 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), cyclohepttrienyl (C7), etc. The cycloalkyl group may optionally be substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0051] "3-11 membered heterocyclic groups" refer to groups with 3 to 11 membered non-aromatic ring systems having a ring carbon atom and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclic groups containing one or more nitrogen atoms, the linkage can be a carbon or nitrogen atom, provided that the valence allows. In some embodiments, a 3-9 membered heterocyclic group is preferred, which is a 3-9 membered non-aromatic ring system having a cyclic carbon atom and 1 to 5 cyclic heteroatoms; in some embodiments, a 3-8 membered heterocyclic group is preferred, which is a 3-8 membered non-aromatic ring system having a cyclic carbon atom and 1 to 4 cyclic heteroatoms; a 3-6 membered heterocyclic group is preferred, which is a 3-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; a 3-5 membered heterocyclic group is preferred, which is a 3-5 membered non-aromatic ring system having a cyclic carbon atom and 1 to 2 cyclic heteroatoms; a 4-8 membered heterocyclic group is preferred, which is a 4-8 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; a 4-7 membered heterocyclic group is preferred, which is a 4-7 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms; and a 5-6 membered heterocyclic group is preferred, which is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1 to 3 cyclic heteroatoms. Heterocyclic groups also include ring systems in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl groups, wherein the linking point is on the cycloalkyl ring, or ring systems in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the linking point is on the heterocyclic ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirropropyl, oxetane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirrobutyl, oxetane, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, disulfuranyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxasulfuranyl, and thioheptanyl.Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. The heterocyclic group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0052] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the connection point is 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 group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0053] "5-10-membered heteroaryl" refers to a group comprising a 4n+2 aromatic ring system of a 5-10-membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms (e.g., having 6 or 10 shared π electrons arranged in a ring), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the bonding point is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-6-membered heteroaryl is particularly preferred, which is a 4n+2 aromatic ring system of a 5-6-membered monocyclic or bicyclic ring having a ring carbon atom and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azirheptatrienyl, oxaheptatrienyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinel. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, zenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0054] Preferred examples of heteroaryl groups include: pyrrole, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, pyranyl, 2-furanyl, 3-furan, etc., 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).

[0055] The carbonyl group, whether used alone or in combination with other terms (such as aminocarbonyl), is represented as -C(O)-.

[0056] "Oxyto" means =O.

[0057] "Thio" means =S.

[0058] The alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups defined in this article are optional substituted groups.

[0059] Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa -NR bb CO2R aa -NR bb C(=O)N(R bb )2、-C(=NR bb )R aa -C(=NR) bb ORaa 、-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(Rcc )2、-OP(R cc )3、-B(R aa 2. -B(OR) cc )2、-BR aa (OR cc ), alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0060] Or the two hydrogen-bearing groups on the carbon atom: =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc replace;

[0061] R aa Each of them is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R aa Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0062] R bb Each is independently selected from: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc-P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R bb Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0063] R cc Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R groups. cc Groups are combined to form heterocyclic or heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0064] R dd Each is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2,、-N(R ff )3 + X - -N(OR) ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee -OCO2R ee -C(=O)N(R) ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee -NR ff CO2R ee -NR ff C(=O)N(R ff )2、-C(=NR ff OR ee -OC(=NR) ff )R ee -OC(=NR) ffOR ee -C(=NR) ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee -SO2N(R) ff )2、-SO2R ee -SO2OR ee -OSO2R ee -S(=O)R ee 、-Si(R ee )3、-OSi(R ee 3. -C(=S)N(R) ff )2、-C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0065] R ee Each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, aryl, heterocyclic, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0066] R ff Each is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R groups. ff The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0067] R ggEach 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 groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -OC(NH)NH2, -NHC(NH)N(C 1-6Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -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 group, -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 ynyl, C3-C7 carbocyclic, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0068] Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2R aa -C(=NR) bb )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SORaa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc 2. Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. cc The groups combine to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa R bb R cc and R dd As stated above.

[0069] Other definitions

[0070] The term "cancer" includes, but is not limited to, the following cancers: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal cavity and pharynx (mouth), lip, tongue, oral cavity, pharynx, small intestine, colorectal, large intestine, rectum, brain and central nervous system cancers, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid 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, pilocarcinoma, and leukemia.

[0071] As used herein, the term “treatment” refers to reversing, alleviating, inhibiting, or preventing the progression of an obstacle or condition to which the term applies, or one or more symptoms of such an obstacle or condition. The noun “treatment” as used herein also refers to the action of the verb “to treat,” as defined above.

[0072] As used herein, the term "pharmaceutically acceptable salt" refers to carboxylates and amino acid addition salts of the compounds of the present invention that are suitable for contact with patient tissues within the limits of reliable medical judgment, without producing undue toxicity, irritation, allergic reactions, etc., and are effective for their intended use in proportion to a reasonable benefit / risk ratio, including (where possible) zwitterionic forms of the compounds of the present invention.

[0073] Pharmaceutically acceptable base addition salts are those formed with 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 amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucosamine, and procaine.

[0074] The base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the required base in a conventional manner to form a salt. The free acid can be regenerated by contacting the salt form with an acid in a conventional manner and then separating the free acid. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents; however, for the purposes of this invention, the salts are equivalent to their respective free acids.

[0075] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides prepared from inorganic acids, such as 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, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, gluconate, lactobionate, laurylsulfonate, and hydroxyethanesulfonate. Salts can also be prepared from organic acids, such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl diacids, aromatic acids, and aliphatic and aromatic sulfonic acids. Representative salts include acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, naphthates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates. Pharmaceutically acceptable salts may include alkali metal and alkaline earth metal-based cations, such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. It also covers salts of amino acids, such as arginine salts, gluconates, galacturons, etc. (see, for example, Berge S. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0076] Examples of pharmaceutically acceptable non-toxic amides of the compounds of this invention include those from Cl -C6 alkyl esters, wherein the alkyl group is straight-chain or branched. Acceptable esters also include C5-C7 cycloalkyl esters and arylalkyl esters, such as, but not limited to, benzyl esters. C1-C4 alkyl esters are preferred. The esters of the compounds of the present invention can be prepared by conventional methods, for example: March's Advanced Organic Chemistry, 5th Edition, MB Smith & J. March, John Wiley & Sons, 2001.

[0077] Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C1-C6 alkylamines, and secondary C1-C6 dialkylamines, wherein the alkyl group is straight-chain 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 preferred. The amides of the compounds of this invention can be prepared by conventional methods, for example: March's Advanced Organic Chemistry, 5th Edition, MB Smith & J. March, John Wiley & Sons, 2001.

[0078] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0079] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0080] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0081] Generally, the "effective amount" of a compound refers to the amount sufficient to elicit a target biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include therapeutic effective amounts and prophylactic effective amounts.

[0082] Unless otherwise stated, the term "therapeuticly effective amount" of a compound as used herein is an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. Therapeuticly effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" may include amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic effects of other therapeutic agents.

[0083] Unless otherwise stated, the “preventively effective amount” of a compound as used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount sufficient to prevent recurrence of a disease, disorder, or condition. The preventively effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other agents, that provides preventive benefit in the prevention of a disease, disorder, or condition. The term “preventively effective amount” may include amounts that improve overall prevention or enhance the preventive effect of other preventive agents.

[0084] The term "combination" and related terms refer to the simultaneous or sequential administration of the compounds of the present invention and other therapeutic agents. For example, the compounds of the present invention 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. Detailed Implementation Plan

[0085] In this document, “compounds of the present invention” refers to compounds of formulas (I) to (III) (including sub-formulas, such as (I-1), (II-2), (III-3) etc.), their pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof.

[0086] In this document, compounds are named using standard nomenclature. For compounds with asymmetric centers, it should be understood (unless otherwise stated) that all optical isomers and mixtures thereof are included. Furthermore, unless otherwise specified, all isomers included in this invention may have carbon-carbon double bonds in the forms of Z and E. For compounds existing in different tautomeric forms, a said compound is not limited to any particular tautomer, but is intended to encompass all tautomeric forms. General formulas used for certain compounds include descriptions and variables. Unless otherwise specified, each variable in such a formula is defined independently of any other variable and, in each occurrence, independently defines multiple variables of any one variable in a formula.

[0087] In one embodiment, the present invention relates to compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof:

[0088]

[0089] in,

[0090] X is CR X Or N;

[0091] Y is CR Y Or N;

[0092] R1, R2, R3, R4 and R Y Independently selected from H, D, halogens, and C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkyne group, or R1 and R2, R3 and R4 connected to form a bond, C 1-6 Alkylene, C 2-6 imide or C 2-6 Alynyl group; wherein the group may be substituted with one or more D or halogens, up to complete substitution;

[0093] Where R X H, D, halogen, -CN, -NRR', -OR, -SR, or C 1-6 Alkyl groups, wherein the group may be substituted with one or more D or halogens, up to complete substitution;

[0094] When Y is CR Y When, R Y R1, together with the atoms they are attached to, forms C. 3-5 Cycloalkyl or 3-5 membered heterocyclic groups, wherein the group may be substituted with one or more D or halogens, up to complete substitution;

[0095] Ring A is C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Aryl or 5-10 membered heteroaryl; or ring A is absent, therefore one R a Connect to L; or (R) a ) m -The AL ring does not exist;

[0096] R a Independently selected from H, D, halogens, -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 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the group may be substituted with one or more D or halogens, up to complete substitution;

[0097] m = 0, 1, 2, 3, 4 or 5;

[0098] Ring B is a 5-6 membered heteroaryl group;

[0099] R b Independently selected from H, D, halogens, -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 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the group may be substituted with one or more D or halogens, up to complete substitution;

[0100] n = 0, 1, 2, 3, 4 or 5;

[0101] Ring C is C 3-7 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups;

[0102] L represents a bond, -O-, -S-, -N(R)-, -C(O)-, C 1-6 Alkylene, C 2-6 imide or C 2-6 Ethyne group;

[0103] R5 represents H, D, halogen, -CN, -NRR', -OR, -SR, and C. 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkynyl group, wherein the group may be substituted with one or more D or halogens, up to complete substitution;

[0104] R6 represents H, D, halogen, -CN, -NRR', -OR, -SR, and C. 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkynyl group, wherein the group may be substituted with one or more D or halogens, up to complete substitution;

[0105] R* is 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 heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups, wherein the group may be substituted by one or more D or halogens, up to complete substitution;

[0106] R and R' are independently selected from H and C. 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group, or R, R', and the nitrogen atom attached to them form a 4-8 membered heterocyclic group; wherein the group may be substituted by one or more D or halogens, up to complete substitution;

[0107] p = 1 or 2.

[0108] X and Y

[0109] In one specific implementation scheme, X is CR X In another specific implementation, X is CH; in another specific implementation, X is N.

[0110] In one specific implementation scheme, Y is CR Y In another specific implementation, Y is N.

[0111] R1, R2, R3, R4 and R Y

[0112] In one specific embodiment, R1 is H; in another specific embodiment, R1 is D; in yet another specific embodiment, R1 is a halogen; in yet another specific embodiment, R1 is C. 1-6 Alkyl groups, such as (R)-C 1-6Alkyl, such as (R)-methyl; in another specific embodiment, R1 is C 1-6 Haloalkyl, such as (R)-C 1-6 Halogenated alkyl; in another specific embodiment, R1 is C 2-6 Alkenyl; in another specific embodiment, R1 is C 2-6 Alkyne group.

[0113] In one specific embodiment, R2 is H; in another specific embodiment, R2 is D; in yet another specific embodiment, R2 is a halogen; in yet another specific embodiment, R2 is C. 1-6 Alkyl groups, such as (R)-C 1-6 Alkyl, such as (R)-methyl; in another specific embodiment, R2 is C 1-6 Haloalkyl, such as (R)-C 1-6 Halogenated alkyl; in another specific embodiment, R2 is C 2-6 Alkenyl; in another specific embodiment, R2 is C 2-6 Alkyne group.

[0114] In one specific embodiment, R3 is H; in another specific embodiment, R3 is D; in yet another specific embodiment, R3 is a halogen; in yet another specific embodiment, R3 is C. 1-6 Alkyl groups, such as (R)-C 1-6 Alkyl, such as (R)-methyl; in another specific embodiment, R3 is C 1-6 Haloalkyl, such as (R)-C 1-6 Halogenated alkyl; in another specific embodiment, R3 is C 2-6 Alkenyl; in another specific embodiment, R3 is C 2-6 Alkyne group.

[0115] In one embodiment, R4 is H; in another embodiment, R4 is D; in yet another embodiment, R4 is a halogen; in yet another embodiment, R4 is C. 1-6 Alkyl groups, such as (R)-C 1-6 Alkyl, such as (R)-methyl; in another specific embodiment, R4 is C 1-6 Haloalkyl, such as (R)-C 1-6 Halogenated alkyl; in another specific embodiment, R4 is C 2-6 Alkenyl; in another specific embodiment, R4 is C 2-6 Alkyne group.

[0116] In one specific implementation plan, R Y For H; in another specific implementation, RY For D; in another specific implementation, R Y For halogen; in another specific implementation, R Y C 1-6 Alkyl groups, such as (R)-C 1-6 Alkyl, such as (R)-methyl; in another specific embodiment, R Y C 1-6 Haloalkyl, such as (R)-C 1-6 Halogenated alkyl; in another specific embodiment, R Y C 2-6 alkenyl; in another specific embodiment, R Y C 2-6 Alkyne group.

[0117] In another specific implementation, at least one of R1 and R2 is C 1-6 Alkyl groups, such as (R)-C 1-6 Alkyl, such as (R)-methyl.

[0118] In another specific embodiment, R1 and R2, or R3 and R4, are connected to form a bond; in another specific embodiment, R1 and R2, or R3 and R4, are connected to form a C 1-6 Alkylene, such as methylene, ethylene, or propylene; in another specific embodiment, R1 is connected with R2, or R3 with R4, to form C 2-6 alkenyl group; in another specific embodiment, R1 is connected with R2, or R3 with R4 to form C 2-6 Alynyl group.

[0119] In another specific embodiment, the above-mentioned group may be replaced by one or more D or halogens, up to complete substitution.

[0120] In another specific implementation, when Y is CR Y When, R Y R1, together with the atoms they are attached to, forms C. 3-5 cycloalkyl; in another specific embodiment, the C 3-5 The cycloalkyl group is cyclopropyl; in another specific embodiment, the C 3-5 The cycloalkyl group is cyclobutyl; in another specific embodiment, the C 3-5 The cycloalkyl group is cyclopentyl; in another specific embodiment, when Y is CR Y When, R YR1 and the atoms they are connected to form a 3-5 membered heterocyclic group; in another embodiment, the 3-5 membered heterocyclic group is oxetanepropyl, azironepropyl, or thioheteropropyl; in another embodiment, the 3-5 membered heterocyclic group is oxetanebutyl, azironebutyl, or thioheterobutyl; in another embodiment, the 3-5 membered heterocyclic group is tetrahydrofuranyl, pyrrolidinyl, or thioheteropentyl. In another embodiment, the C... 3-5 Memberally cycloalkanes and 3-5-membered heterocyclic groups can be substituted with one or more D or halogens, up to complete substitution.

[0121] Ring A

[0122] In one specific implementation, ring A does not exist; in another specific implementation, ring A is C. 3-7 Cycloalkyl; in another specific embodiment, ring A is a 4-7 membered heterocyclic group; in another specific embodiment, ring A is a C 6-10 Aryl; in another specific embodiment, ring A is a 5-10 membered heteroaryl.

[0123] In another embodiment, ring A is a 5-6 membered heteroaryl group. In yet another embodiment, ring A is a 4-7 membered heterocyclic group, preferably selected from piperazinyl or piperidinyl.

[0124] In another specific implementation, ring A is selected from... Where 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 As mentioned above regarding R a Defined.

[0125] In another specific implementation scheme, (R a ) m -Cyclic AL-Selected from

[0126] R a

[0127] In one specific implementation plan, R aIndependently selected from H, D, halogens, -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 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the groups may be substituted with one or more D or halogens up to complete substitution; in another specific embodiment, one of the R... a For H; in another specific implementation, one of R a For D; in another specific implementation, one of R a For halogen; in another specific embodiment, one of the R a For -CN; in another specific implementation, one of the R a For -NRR'; in another specific implementation, one of the R a For -OR; in another specific implementation, one of the R a For -SR; in another specific implementation, one of the R a For -C(O)R; in another specific implementation, one of the R a For -C(O)OR; in another specific implementation, one of the R a For -C(O)NRR'; in another specific implementation, one of the R a For -OC(O)R'; in another specific implementation, one of the R a For -NRC(O)R'; in another specific implementation, one of the R a For -OC(O)NRR'; in another specific implementation, one of the R a For -NRC(O)NRR'; in another specific implementation, one of the R a For -S(O) p R; in another specific implementation, one of R a C 1-6 Alkyl; in another specific embodiment, one of the R a C 2-6 alkenyl; in another specific embodiment, one of the R a C 2-6 Alkyne group; in another specific embodiment, one of the R groups is... a C 3-7cycloalkyl; in another specific embodiment, one of the R a It is a 3-8 membered heterocyclic group; in another specific embodiment, one of the R a It may be replaced by one, two, or three R*; in another specific embodiment, the group may be replaced by one or more D or halogens, up to complete substitution.

[0128] In another specific implementation scheme, R a Independently selected from H, D, halogens, -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 or C 2-6 Alkyne group, wherein the group may be substituted with one or more D atoms up to complete deuteration.

[0129] m

[0130] In one specific implementation, m = 0; in another specific implementation, m = 1; in another specific implementation, m = 2; in another specific implementation, m = 3; in another specific implementation, m = 4; in another specific implementation, m = 5.

[0131] Ring B

[0132] In one specific embodiment, ring B is a 5-6 membered heteroaryl group, such as pyrrole, furanyl, thiophene, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl; preferably pyrrole, furanyl, thiophene, pyrazolyl, or pyridinyl; preferably pyrazolyl.

[0133] R b

[0134] In one specific implementation plan, R b Independently selected from H, D, halogens, -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 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the groups may be substituted with one or more D or halogens up to complete substitution; in another specific embodiment, one of the R... bFor H; in another specific implementation, one of R b For D; in another specific implementation, one of R b For halogen; in another specific embodiment, one of the R b For -CN; in another specific implementation, one of the R b For -NRR'; in another specific implementation, one of the R b For -OR; in another specific implementation, one of the R b For -SR; in another specific implementation, one of the R b For -C(O)R; in another specific implementation, one of the R b For -C(O)OR; in another specific implementation, one of the R b For -C(O)NRR'; in another specific implementation, one of the R b For -OC(O)R'; in another specific implementation, one of the R b For -NRC(O)R'; in another specific implementation, one of the R b For -OC(O)NRR'; in another specific implementation, one of the R b For -NRC(O)NRR'; in another specific implementation, one of the R b For -S(O) p R; in another specific implementation, one of R b C 1-6 Alkyl; in another specific embodiment, one of the R b C 2-6 alkenyl; in another specific embodiment, one of the R b C 2-6 Alkyne group; in another specific embodiment, one of the R groups is... b C 3-7 cycloalkyl; in another specific embodiment, one of the R b It is a 3-8 membered heterocyclic group; in another specific embodiment, one of the R b It may be replaced by one, two, or three R*; in another specific embodiment, the group may be replaced by one or more D or halogens, up to complete substitution.

[0135] In another specific implementation scheme, R b Independently selected from H, D, halogens, -CN, -NRR', -OR, -SR, C, which are arbitrarily substituted with R*. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0136] n

[0137] In one specific implementation, n = 0; in another specific implementation, n = 1; in another specific implementation, n = 2; in another specific implementation, n = 3; in another specific implementation, n = 4; in another specific implementation, n = 5.

[0138] Ring C

[0139] In one specific implementation, ring C is C 3-7 Cycloalkyl; in another specific embodiment, the ring C is a 4-7 membered heterocyclic group; in another specific embodiment, the ring C is C 6-10 Aryl; in another specific embodiment, the ring C is a 5-10 membered heteroaryl.

[0140] In another specific embodiment, the ring C is a 5-6 membered heteroaryl or phenyl group; preferably pyrroleyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyrimidinyl, or pyrazinyl; preferably pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or triazolyl; pyrazolyl is the most preferred.

[0141] In another specific implementation, ring C is C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups, preferably cyclopentyl or tetrahydropyranyl.

[0142] L

[0143] In one specific embodiment, L is a key; in another specific embodiment, L is -O-; in yet another specific embodiment, L is -S-; in yet another specific embodiment, L is -N(R)-; in yet another specific embodiment, L is -C(O)-; in yet another specific embodiment, L is C 1-6 Alkylene; in another specific embodiment, L is C 2-6 Ideonyl; in another specific embodiment, L is C 2-6 Alynyl group.

[0144] In another specific implementation, L is a bond, -C(O)-, or C. 1-6 Alkylene.

[0145] R5

[0146] In one embodiment, R5 is H; in another embodiment, R5 is D; in another embodiment, R5 is a halogen; in another embodiment, R5 is -CN; in another embodiment, R5 is -NRR'; in another embodiment, R5 is -OR; in another embodiment, R5 is -SR; in another embodiment, R5 is C 1-6 Alkyl; in another specific embodiment, R5 is C 2-6 Alkenyl; in another specific embodiment, R5 is C 2-6 Alkyne group; in another specific embodiment, R5 may be substituted with one or more D or halogens, up to complete substitution.

[0147] R6

[0148] In one embodiment, R6 is H; in another embodiment, R6 is D; in another embodiment, R6 is a halogen; in another embodiment, R6 is -CN; in another embodiment, R6 is -NRR'; in another embodiment, R6 is -OR; in another embodiment, R6 is -SR; in another embodiment, R6 is C 1-6 Alkyl; in another specific embodiment, R6 is C 2-6 Alkenyl; in another specific embodiment, R6 is C 2-6 Alkyne group; in another specific embodiment, R6 may be substituted with one or more D or halogens, up to complete substitution.

[0149] R*

[0150] In one embodiment, R* is H; in another embodiment, R* is halogen; in another embodiment, R* is -CN; in another embodiment, R* is -NRR'; in another embodiment, R* is -OR; in another embodiment, R* is -SR; in another embodiment, R* is -C(O)R; in another embodiment, R* is -C(O)OR; in another embodiment, R* is -C(O)NRR'; in another embodiment, R* is -OC(O)R'; in another embodiment, R* is -NRC(O)R'; in another embodiment, R* is -OC(O)NRR'; in another embodiment, R* is -NRC(O)NRR'; in another embodiment, R* is -S(O) p R; In another specific implementation, R* is C 3-7Cycloalkyl; in another specific embodiment, R* is a 3-8 membered heterocyclic group; in another specific embodiment, R* is a C 6-10 Aryl; in another embodiment, R* is a 5-10 membered heteroaryl; in another embodiment, R* may be substituted by one or more D or halogens, up to complete substitution.

[0151] R and R'

[0152] In one specific implementation, R and R' are independently H; in another specific implementation, R and R' are independently C. 1-6 Alkyl; in another specific embodiment, R and R' are independently C 2-6 Alkenyl; in another specific embodiment, R and R' are independently C 2-6 Alkyne group; in another specific embodiment, R, R' form a 4-8 membered heterocyclic group with the nitrogen atom to which they are attached; in another specific embodiment, R and R' may be substituted with one or more D or halogens, up to complete substitution.

[0153] p

[0154] In one specific implementation, p = 1; in another specific implementation, p = 2.

[0155] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof of X can be combined with Y, R1-R6, ring A, ring B, ring C, R a R b This invention relates to any technical solution or any combination thereof, such as R*, m, n, p, R, and R'. The invention aims to include combinations of all these technical solutions; however, due to space limitations, they are not listed individually.

[0156] In more specific embodiments, the present invention provides compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, having the following general formula structure:

[0157]

[0158] Each group is defined as in the context.

[0159] In more specific embodiments, the present invention provides compounds of general formula (I-1) or (I-2), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof:

[0160]

[0161] in,

[0162] Ring C is C 3-7 Cycloalkyl or 4-7 membered heterocyclic groups; preferably cyclopentyl or tetrahydropyranyl;

[0163] Ring B is pyrrole, furanyl, thiophene, pyrazolyl, imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl; preferably pyrrole, furanyl, thiophene, pyrazolyl, or pyridinyl.

[0164] R5 is preferably H, D, halogen, -CN, -NRR', -OR, or -SR, wherein the group can be substituted by one or more D or halogens until completely substituted; preferably, R5 is located on the C atom of the ring C connected to the parent nucleus;

[0165] Other groups are as defined in the context.

[0166] In more specific embodiments, the present invention provides compounds of general formula (I-1), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof:

[0167]

[0168] in,

[0169] The ring C is a 5-6 membered heteroaryl or phenyl group; preferably pyrrole, furanyl, thiophene, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl; preferably pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or triazolyl; preferably pyrazolyl.

[0170] Other groups are as defined in the context.

[0171] In another, more specific embodiment, the present invention provides compounds of the above general formula (I-1), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein,

[0172] Ring B is pyrrole, furanyl, thiophene, pyrazolyl, imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl; preferably pyrrole, furanyl, thiophene, pyrazolyl, or pyridinyl.

[0173] Other groups are as defined in the context.

[0174] In more specific embodiments, the present invention provides compounds of general formula (II) or (II-1), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof:

[0175]

[0176] in,

[0177] Ring A does not exist, C 3-7 cycloalkyl or 4-7 membered heterocyclic groups;

[0178] Other groups are as defined in the context.

[0179] In another, more specific embodiment, the present invention provides compounds of the above general formula (II) or (II-1), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein,

[0180] Ring A is absent or is a 4-7 membered heterocyclic group; preferably piperidinyl or piperazine;

[0181] Ring B is pyrrole, furanyl, thiophene, pyrazolyl, imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl; preferably pyrrole, furanyl, thiophene, pyrazolyl, or pyridinyl.

[0182] L represents a bond, -O-, -S-, -N(R)-, -C(O)-, or C. 1-6 Alkylene;

[0183] R5 and R6 are independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6 Alkyne group, wherein the group may be substituted with one or more D atoms until fully deuterated;

[0184] Other groups are as defined in the context.

[0185] In more specific embodiments, the present invention provides compounds of general formula (III) or (III-1), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof:

[0186]

[0187] in,

[0188] The ring C is a 5-6 membered heteroaryl or phenyl group; preferably pyrrole, furanyl, thiophene, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl; preferably pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or triazolyl; preferably pyrazolyl.

[0189] Other groups are as defined in the context.

[0190] In another, more specific embodiment, the present invention provides compounds of the above general formula (III) or (III-1), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein,

[0191] Ring B is pyrrole, furanyl, thiophene, pyrazolyl, imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl; preferably pyrrole, furanyl, thiophene, pyrazolyl, or pyridinyl.

[0192] Other groups are as defined in the context.

[0193] In more specific embodiments, the present invention provides compounds of general formula (III-2) or (III-3), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof:

[0194]

[0195] in,

[0196] A1 is CR a1 Or N; A2 is CR a2 Or N; A5 is CR a5 Or N;

[0197] Other groups are as defined in the context.

[0198] In another, more specific embodiment, the present invention provides compounds of the above general formula (III-3), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein,

[0199] A3 is CR a3 Or N;

[0200] R a1 R a2 R a3R 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 Alkyl groups, wherein the group may be substituted with one or more D or halogens, up to complete substitution;

[0201] Other groups are as defined in the context.

[0202] In another, more specific embodiment, the present invention provides compounds of the above general formula (III-3), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein,

[0203] A3 is CR a3 Or N;

[0204] R a1 R a2 R a3 and R a5 Independently selected from H, D, halogens, -CN, -OH, -C(O)NH2, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the group may be substituted with one or more D groups up to complete deuteration;

[0205] R5 and R6 are independently C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the groups may be substituted with one or more D groups up to complete deuteration.

[0206] In another, more specific embodiment, the present invention provides compounds of the above general formula (III-3), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein,

[0207] A3 is CR a3 Or N;

[0208] R a1 For H or D;

[0209] R a2 For H, D, halogens, -CN, -OH, -C(O)NH2, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0210] R a3 It can be H, D, or -OH;

[0211] Ra5 For H or D;

[0212] R5 is C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably methyl;

[0213] R6 is C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably methyl.

[0214] In more specific embodiments, the present invention provides compounds of general formula (III-3), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof:

[0215]

[0216] in,

[0217] A3 is CR a3 Or N;

[0218] 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 Halogenated alkyl groups, wherein the group may be substituted with one or more D groups up to complete deuteration;

[0219] R and R' are independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl or C 2-6 The alkynyl group, or R, R', and the nitrogen atom to which they are attached form a 4-8 membered heterocyclic group; wherein the group may be substituted by one or more D atoms, up to complete deuteration.

[0220] In another, more specific embodiment, the present invention provides compounds of the above general formula (III-3), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein,

[0221] A3 is CR a3 Or N;

[0222] R a1 R a2 R a3 and R a5 Independently selected from H, D, halogens, -OH, C1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the group may be substituted with one or more D groups up to complete deuteration;

[0223] R5 and R6 are independently C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the groups may be substituted with one or more D groups up to complete deuteration.

[0224] In another, more specific embodiment, the present invention provides compounds of the above general formula (III-3), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein,

[0225] A3 is CR a3 Or N;

[0226] R a1 For H or D;

[0227] R a2 For H, D, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0228] R a3 It can be H, D, or -OH;

[0229] R a5 For H or D;

[0230] R5 is C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably methyl;

[0231] R6 is C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably methyl.

[0232] In more specific embodiments, the present invention provides compounds of general formula (III-4), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof:

[0233]

[0234] in,

[0235] A4 is CR a4 Or N;

[0236] R a1 R a2 R a4 R a5R5 and R6 are independently H, D, halogen, -CN, -OR, -SR, -NRR', -C(O)R, -C(O)OR, -C(O)NRR', or C 1-6 Alkyl groups, wherein the group may be substituted with one or more D or halogens, up to complete substitution;

[0237] Other groups are as defined in the context.

[0238] In another, more specific embodiment, the present invention provides compounds of the above general formula (III-4), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein,

[0239] A4 is CR a4 Or N;

[0240] R a1 R a2 R a4 and R a5 Independently selected from H, D, halogens, -CN, -OH, -C(O)NH2, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the group may be substituted with one or more D groups up to complete deuteration;

[0241] R5 and R6 are independently C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the groups may be substituted with one or more D groups up to complete deuteration.

[0242] In another, more specific embodiment, the present invention provides compounds of the above general formula (III-4), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof, wherein,

[0243] A4 is CR a4 Or N;

[0244] R a1 It is H, D or halogen;

[0245] R a2 For H, D, halogens, -CN, -OH, -C(O)NH2, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0246] R a4 It can be H, D, or -OH;

[0247] R a5 For H or D;

[0248] R5 is C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably methyl;

[0249] R6 is C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably methyl.

[0250] Preferred compounds of the present invention include, but are not limited to, the compounds listed below, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopic variants thereof, and mixtures thereof:

[0251]

[0252]

[0253] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures 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-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0254] Those skilled in the art will understand that organic compounds can form complexes with solvents, react in the solvent, or precipitate or crystallize out of the solvent. These complexes are called "solvates." When the solvent is water, the complex is called a "hydrate." This invention covers all solvates of the compounds of this invention.

[0255] The term "solvent" refers to a compound or its salt that is bound to a solvent and formed typically by a solvent decomposition reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be separable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvent" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0256] The term "hydrate" refers to a compound that is bound to water. Typically, it is determined by the ratio of the number of water molecules contained in the hydrate to the number of molecules of the compound in the hydrate. Therefore, a hydrate of a compound 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 more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, e.g., hemihydrates (R×0.5H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R×2H₂O) and hexahydrates (R·6H₂O)).

[0257] The compounds of this invention can be in amorphous or crystalline forms (polymorphs). Furthermore, the compounds of this invention can exist in one or more crystalline forms. Therefore, this invention encompasses all amorphous or crystalline forms of the compounds of this invention within its scope. The term "polymorph" refers to the crystalline form of a compound (or its salts, hydrates, or solvates) with a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to the dominance of one crystalline form. Various polymorphs of the compounds can be prepared by crystallization under different conditions.

[0258] The present invention also includes isotopically labeled compounds that are equivalent to those described in formula (I), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents when performing the processes described below and / or the techniques disclosed in the examples and preparation examples.

[0259] Furthermore, prodrugs are also included in the context of this invention. As used herein, the term "prodrug" refers to a compound which is converted in vivo, for example, by hydrolysis in the blood, into its active form having a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium 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 reference.

[0260] A prodrug is any covalently bonded compound of the present invention that, when administered to a patient, releases the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in a manner that allows the modification to produce the parent compound through conventional operation or in vivo cleavage. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or thiol group is bonded to any group, which, when administered to a patient, can cleave to form a hydroxyl, amino, or thiol group. Thus, representative examples of prodrugs include (but are not limited to) acetate / amide, formate / amide, and benzoate / amide derivatives of formula (I) with hydroxyl, thiol, and amino functional groups. Additionally, in the case of carboxylic acids (-COOH), esters, such as methyl esters, ethyl esters, etc., can be used. The ester itself may be active and / or hydrolyzable under in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups that readily decompose in the body to release the parent acid or its salt.

[0261] The present invention also provides pharmaceutical formulations comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, or excipient thereof. All such forms are subject to the present invention.

[0262] Pharmaceutical compositions, formulations and kits

[0263] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as the "active component") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a preventatively effective amount of the compound of the present invention.

[0264] Pharmaceutically acceptable excipients used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0265] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the compounds of the present invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compounds of the present invention and other therapeutic agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the present invention and / or other therapeutic agents. In some embodiments, the compounds of the present invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0266] Dosage

[0267] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0268] Typically, an effective amount of the compound described herein is administered. The actual amount of compound administered may be determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0269] When used to prevent the conditions described in this invention, the compounds provided herein are administered to subjects at risk of developing the conditions, typically based on a physician's advice and under physician supervision, at the dosage levels described above. Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[0270] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof over a prolonged period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be administered indefinitely, such as for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of said compound in the blood over a prolonged period of time, such as within a therapeutic window.

[0271] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for instance, to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active component through the body; for example, an intramuscular or subcutaneous bolus dose results in a slow release of the active component, while a bolus dose delivered directly to a vein (e.g., via IV intravenous infusion) allows for a more rapid delivery, causing the concentration of the active component in the blood to rapidly increase to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, via IV intravenous infusion, thereby providing a steady-state concentration of the active component in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0272] Oral compositions may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, more commonly, the compositions are provided in unit dose form for the purpose of precise dosing. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined quantity of active substance and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect. Typical unit dose forms include pre-filled, pre-measured ampoules or syringes for liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is typically a smaller component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients useful for forming the desired dosage form, as well as processing aids.

[0273] For oral dosage, a typical regimen is one to five oral doses daily, particularly two to four oral doses, typically three oral doses. Using these dosage regimens, each dose provides approximately 0.01 to approximately 20 mg / kg of the compound of the invention, with preferred doses each providing approximately 0.1 to approximately 10 mg / kg, particularly approximately 1 to approximately 5 mg / kg.

[0274] To provide blood levels similar to or lower than those achieved with an injection dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight.

[0275] From approximately 1 to approximately 120 hours, especially 24 to 96 hours, the injection dose level ranges from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour. To obtain adequate steady-state levels, a preload bolus of approximately 0.1 mg / kg to approximately 10 mg / kg or more may also be administered. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g / day.

[0276] Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers, as well as buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components, or compounds with similar properties: 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; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavorings.

[0277] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As previously described, in such compositions, the active compound is typically a smaller component, often about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0278] Transdermal compositions are typically formulated as topical ointments or creams containing an active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water emulsion base. Such transdermal formulations are well known in the art and generally include other components to enhance stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of this invention.

[0279] The compounds of this invention can also be administered via transdermal devices. Therefore, transdermal drug delivery can be achieved using reservoirs or porous membrane types, or patches with various solid matrices.

[0280] The above-described components for oral, injectable, or topical administration are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0281] The compounds of this invention can also be administered in a sustained-release form or from a sustained-release drug delivery system. Descriptions of representative sustained-release materials can be found at Remington's Pharmaceutical Sciences.

[0282] This invention also relates to pharmaceutically acceptable formulations of the compounds of this invention. 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, respectively, composed of 6, 7, and 8 α-1,4-linked glucose units, optionally including one or more substituents on the linked sugar moieties, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfonyl ether substituted groups. In some embodiments, the cyclodextrin is a sulfonyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0283] treat

[0284] As described in this article, ATR kinases are known to play a role in tumorigenesis and many other diseases. We have discovered that compounds of formula (I) possess potent antitumor activity, which is believed to be obtained by inhibiting ATR kinases.

[0285] Therefore, the compounds of the present invention have value as antitumor agents. In particular, the compounds of the present invention have value as antiproliferative, anti-apoptotic, and / or anti-invasive agents in the suppression and / or treatment of solid and / or liquid tumor diseases. In particular, the compounds of the present invention are intended for the prevention or treatment of those tumors sensitive to ATR inhibition. Furthermore, the compounds of the present invention are intended for the prevention or treatment of those tumors mediated solely or partially by ATR. Thus, the compounds can be used to induce ATR enzyme inhibition in warm-blooded animals requiring such treatment.

[0286] As described in this article, ATR kinase inhibitors are valuable for the treatment of proliferative diseases (such as cancers), especially solid tumors (such as carcinomas and sarcomas), as well as leukemia and lymphoma. They are particularly valuable for the treatment of breast cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, and bronchioloalveolar carcinoma), prostate cancer, 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 [including acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML)], multiple myeloma, and lymphoma.

[0287] The anticancer effects of this invention in treating cancer patients include, but are not limited to, antitumor effects, response rates, time to disease progression, and survival rates. The antitumor effects of the treatment method of this invention include, but are not limited to, inhibition of tumor growth, delay of tumor growth, tumor regression, tumor shrinkage, prolongation of the duration of tumor regeneration after treatment cessation, and slowing of disease progression. The anticancer effects include both preventative treatment and treatment of existing diseases.

[0288] ATR kinase inhibitors or pharmaceutically acceptable salts thereof are also used to treat patients with cancer, including but not limited to blood cancers such as leukemia and multiple myeloma; lymphomas such as Hodgkin's disease, non-Hodgkin's lymphoma (including mantle cell lymphoma), and myelodysplastic syndromes; and solid tumors and their metastases such as breast cancer, lung cancer (non-small cell lung cancer (NSCL), small cell lung cancer (SCLC), squamous cell carcinoma), endometrial cancer, and central nervous system tumors (such as gliomas, dysplastic neuroepithelial tumors, glioblastoma multiforme, mixed gliomas, medulloblastoma, and stromal tumors). Omental cell tumors, neuroblastomas, germ cell tumors and teratomas, gastrointestinal cancers (such as stomach cancer), esophageal cancer, hepatocellular carcinoma, bile duct cancer, colon and rectal cancer, small bowel cancer, pancreatic cancer, skin cancers such as melanoma (especially metastatic melanoma), thyroid cancer, head and neck cancers and salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, uterine cancer, vulvar cancer, bladder cancer, kidney cancer (including renal cell carcinoma, leukocyte carcinoma and renal eosinophilic tumor), squamous cell carcinoma, sarcomas such as osteosarcoma, chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing sarcoma, gastrointestinal stromal tumors (GIST), Kaposi's sarcoma, and pediatric cancers such as rhabdomyosarcoma and neuroblastoma.

[0289] The compounds of the present invention, as well as treatment methods including the administration or use of ATR kinase inhibitors or pharmaceutically acceptable salts thereof, are intended particularly for 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, tumors of the central nervous system and their metastases, and also for the treatment of patients with acute myeloid leukemia.

[0290] The effective amount of the compounds of the present invention is generally from an average daily dose of 0.01 mg to 50 mg of compound per kilogram of patient body weight, preferably from 0.1 mg to 25 mg of compound per kilogram of patient body weight, administered once or multiple times. Typically, the compounds of the present invention can be administered to patients requiring this treatment at a daily dose range of about 1 mg to about 3500 mg per patient, preferably from 10 mg to 1000 mg. For example, the daily dose per patient can 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 can be administered once or multiple times daily, weekly (or every few days), or on an intermittent schedule. For example, the compound can be given once or multiple times daily on a weekly basis (e.g., every Monday), indefinitely or for several weeks, for example, 4-10 weeks. Alternatively, the compound may be administered daily for several days (e.g., 2-10 days), followed by several days without administration (e.g., 1-30 days), and this cycle may be repeated indefinitely or for a given number of times, such as 4-10 cycles. For example, the compound of the present invention may be administered daily for 5 days, then intermittently for 9 days, then administered daily for 5 days again, then intermittently for 9 days, and so on, repeating this cycle indefinitely or for a total of 4-10 times.

[0291] Combination therapy

[0292] The treatments defined herein may be used as a single treatment, or in addition to the compounds of the present invention, may include conventional surgery, radiation therapy, or chemotherapy. Therefore, the compounds of the present invention may also be used in combination with existing therapeutic agents for treating cancer.

[0293] Suitable agents for combined use include:

[0294] (i) Antiproliferative / antitumor drugs and combinations thereof used in medical oncology, such as alkylating agents (e.g., cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, and nitrosourea); antimetabolites (e.g., antifolate agents such as fluorouracil (e.g., 5-fluorouracil and tegafur), raltitrexed, methotrexate, cytarabine, hydroxyurea, and gemcitabine); and antitumor antibiotics (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, and idarubicin). Actinomycin C, mitomycin-C, dactinomycin D, and mithramycin; antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vinorelbine, and vinorelbine; and taxanes such as paclitaxel and docetaxel); topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, and camptothecin); and DNA damage repair inhibitors (e.g., olaparib, rucaparib, and niraparib).

[0295] (ii) Cell growth inhibitors, such as anti-estrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene, and iodoxyfene), estrogen receptor downregulators (e.g., fulvestrant), and anti-androgens (e.g., bicalutamide, flutamide, nilutamide, and...). Cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin and buserelin), progestins (e.g., medroxyprogesterone acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole and exemestane), and 5α-reductase inhibitors, such as finasteride;

[0296] (iii) Anti-invasive agents (e.g., c-Src kinase family inhibitors, such as AZD0530 and dasatinib) and metalloproteinase inhibitors, such as marimastat; and inhibitors of urokinase-type plasminogen activator receptor function);

[0297] (iv) Growth factor function inhibitors: such as growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin]). TM [and anti-erbB1 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; inhibitors of serine / threonine kinases (e.g. Ras / Raf signaling inhibitors, such as farnesyltransferase inhibitors, such as sorafenib (BAY43-9006)); and inhibitors of cell signaling via MEK and / or Akt kinases;

[0298] (v) Anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor (VEGF) [e.g., the anti-VEGF antibody bevacizumab (Avastin)]. TM ); and VEGF receptor tyrosine kinase inhibitors, such as ZD6474, AZD2171, vatalanib and sunitinib, and compounds that act through other mechanisms (such as linomide, integrin αvβ3 function inhibitors and angiogenesis inhibitors)];

[0299] (vi) Vasodilators, such as cobretastatin;

[0300] (vii) Antisense therapies, such as those targeting the targets listed above, such as ISIS 2503;

[0301] (viii) Gene therapy methods, including methods that replace abnormal genes (such as abnormal p53 or abnormal BRCA1 or BRCA2); GDEPT (gene-directed enzyme prodrug therapy) methods, such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase; and methods to improve patient tolerance to chemotherapy or radiotherapy, such as gene therapy for multidrug resistance; and

[0302] (ix) Immunotherapy methods, including in vitro and in vivo methods to enhance the immunogenicity of a patient’s tumor cells, such as transfection with cytokines (e.g., interleukin-2, interleukin-4, or granulocyte-macrophage colony-stimulating factor); methods to reduce T-cell anergy; methods using transfected immune cells (e.g., dendritic cells transfected with cytokines); methods using tumor cell lines transfected with cytokines; and methods using anti-idiotype antibodies.

[0303] Example

[0304] The materials or reagents used herein are commercially available or prepared by synthetic methods commonly known in the art. The following reaction routes illustrate specific synthetic methods for the compounds of this invention.

[0305] Specifically as follows:

[0306] Preparation of key intermediates a1-a4:

[0307]

[0308] 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 h, after which the reaction was stopped. The mixture was cooled to room temperature, and the pH was adjusted to 7 by slowly adding 1 N hydrochloric acid solution. The mixture was extracted with dichloromethane and dried over anhydrous Na₂SO₄ to give intermediate a1-2 (9 g, quantitative yield). LC-MS: [M+H] + :170.

[0309] Intermediate a1-2 (47.3 mmol, 8 g) and (R)-2-methylmorpholine (94.6 mmol, 9.56 g) were added to a microwave-safe reaction flask. After dissolving in 30 mL of N-methylpyrrolidone (NMP), the mixture was microwave-treated at 190 °C for 6 hours. The reaction was then stopped, the solvent was removed under reduced pressure, and the mixture was separated by flash column chromatography to give intermediate a1-3 (6.4 g, yield: 58%). LC-MS: [M+H] + :235.

[0310] Intermediate a1-3 (27.4 mmol, 6.4 g) and triethylamine (54.8 mmol, 5.55 g) were added to a reaction flask and dissolved in 20 mL of phosphorus oxychloride. The mixture was heated to 80 °C and stirred for 2 hours, then the reaction was stopped. The reaction was quenched by slowly adding 100 mL of ice water, and the pH was adjusted to 8 by adding 1 N 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.

[0311]

[0312] Under nitrogen protection, 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 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 to reflux for 10 hours. The reaction was stopped, filtered, the solvent was removed under reduced pressure, 50 mL of water was added, and the mixture was extracted with ethyl acetate. The extract was separated by flash column chromatography to give intermediate a2 (3.2 g, yield: 65%). LC-MS: [M+H] + :313.

[0313]

[0314] Under ice bath conditions, intermediate a2 (10.25 mmol, 3.2 g) was dissolved in 15 mL of anhydrous dichloromethane. N-bromosuccinimide (NBS) (10.3 mmol, 1.8 g) was slowly added in portions, and the mixture was stirred for 2 hours. The reaction was then stopped, and 50 mL of saturated ammonium chloride aqueous solution was added. The mixture was extracted with dichloromethane. After drying over anhydrous sodium sulfate, the solution was separated by flash column chromatography to give intermediate a3-1 (3.9 g, yield: 98%). LC-MS: [M+H] + :392.

[0315] Under nitrogen protection, intermediate a3-1 (3.32 mmol, 1.3 g) and starting material a3-2 (4.98 mmol, 1.38 g) were dissolved in 20 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1). Sodium carbonate (6.64 mmol, 704 mg) and Pd(dppf)Cl2 (0.33 mmol, 241 mg) were added, and the mixture was heated in a microwave oven at 100 °C for 1 hour. The reaction was stopped, filtered, and 40 mL of water was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by flash column chromatography to give intermediate a3 (400 mg, yield: 26%). LC-MS: [M+H] + :463.

[0316]

[0317] Under ice bath conditions, intermediate a1 (1.63 mmol, 410 mg) was dissolved in 15 mL of anhydrous dichloromethane. N-iodosuccinimide (NIS) (1.79 mmol, 403 mg) was slowly added in portions, and stirring was continued for 2 hours. The reaction was stopped, and 50 mL of saturated ammonium chloride aqueous solution was added. Extraction was performed with dichloromethane. The extract was dried over anhydrous sodium sulfate to give intermediate a4-1 (700 mg, crude product). LC-MS: [M+H] + :379.

[0318] Under nitrogen protection, intermediate a4-1 (700 mg) and starting material a3-2 (2.44 mmol, 678 mg) were dissolved in 20 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1). Potassium carbonate (3.26 mmol, 451 mg) and Pd(dppf)Cl2 (0.16 mmol, 117 mg) were added, and the mixture was heated in a microwave oven at 100 °C for 1 hour. The reaction was stopped, filtered, and 40 mL of water was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by flash column chromatography to give intermediate a4 (220 mg, overall yield: 34%). LC-MS: [M+H] + :403.

[0319] Preparation of key intermediates b1-b7:

[0320]

[0321] In a reaction flask, starting material b1-1 (36.7 mmol, 7 g) and cesium carbonate (92.1 mmol, 30.03 g) were added and dissolved in 100 mL of DMF. Starting material b1-2 (36.8 mmol, 8.43 g) was slowly added. The reaction was heated to 80 °C and reacted for 4 hours. The reaction was then stopped, and 300 mL of water was slowly added. The mixture was extracted with ethyl acetate, dried over anhydrous Na₂SO₄, and separated by flash column chromatography to give intermediates b1-3 (3.4 g, yield: 23%) and b1-4 (7.0 g, yield: 47%). LC-MS: [M+H] + :413.

[0322]

[0323] 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, pinacol isopropoxyborate (9.5 mmol, 1.88 mL) was added. The reaction was continued at -78 °C for 3 hours. The reaction was quenched with 150 mL of saturated ammonium chloride aqueous solution, extracted with dichloromethane, and dried over anhydrous sodium sulfate to obtain crude intermediate b1. This was used directly in the next reaction. LC-MS: [M+H]+ :460.

[0324] Following the synthetic route of intermediate b1, using b1-4 as raw material, crude intermediate b2 was obtained. LC-MS: [M+H] + :460.

[0325]

[0326] Under nitrogen protection and in an ice bath, starting material a2-1 (2.25 mmol, 500 mg) was dissolved in 15 mL of DMF. NaH (4.5 mmol, 180 mg) was added in portions, and the mixture was stirred for 30 minutes. Then, tert-butyl 4-((methanesulfonyl)oxy)piperidine-1-carboxylate (3.37 mmol, 943 mg) was slowly added, and the mixture was heated to 90 °C and reacted for another 2 hours. The reaction was then stopped, and 50 mL of ice water was slowly added to quench the reaction. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate to obtain crude intermediate b3, which was used directly in the next reaction. LC-MS: [M+H] + :406.

[0327]

[0328] Under nitrogen protection and at -78°C, starting material b4-1 (1.54 mmol, 150 mg) was dissolved in 10 mL of anhydrous THF. Butyllithium (1.0 mL, 2.5 M) was added dropwise. After 30 minutes, trimethyltin chloride (2.31 mmol, 462 mg) was added. The reaction was continued at -78°C for 3 hours. The reaction was then stopped, quenched with 40 mL of saturated ammonium chloride aqueous solution, extracted with dichloromethane, and dried over anhydrous sodium sulfate to obtain crude intermediate b4. This was used directly in the next reaction. LC-MS: [M+H] + :260.

[0329]

[0330] Under ice bath conditions, starting material a2-1 (2.0 mmol, 444 mg), piperazine-1-carboxylic acid tert-butyl ester (3.0 mmol, 559 mg), and DIEA (5.0 mmol, 645 mg) were dissolved in 15 mL of tetrahydrofuran. After stirring for 5 minutes, triphosgene (4.0 mmol, 1.08 g) was slowly added to the system, and stirring was continued under ice bath conditions for 2 hours until the reaction was stopped. 40 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane and separated by flash column chromatography to give intermediate b5 (180 mg, yield: 21%). LC-MS: [M+H] + :435.

[0331]

[0332] The starting material 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. After stirring for 5 minutes, NaBH3CN (27.6 mmol, 1.7 g) was slowly added, and the reaction was carried out at room temperature for 10 hours. The reaction was stopped, and 80 mL of ice water was added to quench the reaction. The solvent was removed by vacuum distillation. The pH of the system was adjusted to about 9 with a saturated NaHCO3 aqueous solution, and the mixture was extracted with dichloromethane. After drying with anhydrous sodium sulfate, crude intermediate b6-2 (a pair of non-corresponding isomers) was obtained.

[0333] 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 reaction was carried out at room temperature for 2 hours. The reaction was stopped, and the solvent was removed under reduced pressure to give crude intermediate b6-3 (3.0 g, crude product). LC-MS: [M+H] + :198.

[0334] Crude intermediate b6-3 (3.0 g), Boc anhydride (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 reacted at room temperature for 12 hours. The reaction was stopped, 100 mL of water was added, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate to give a yellow oily product (2.4 g). This yellow oily product was dissolved in 10 mL of DMF and placed in an ice bath. NBS (8.88 mmol, 1.58 g) was slowly added in portions, and the mixture was reacted at room temperature for 8 hours. Then, 50 mL of ice water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by flash column chromatography to give intermediate b6-4 (1.2 g, total yield of three steps: 35%) and intermediate b6-5 (600 mg, total yield of three steps: 17%). LC-MS: [M+H] + :377.

[0335] Under nitrogen protection, intermediate b6-4 (1.25 mmol, 470 mg), pinacol diborate (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 and dissolved in 16 mL of a mixed solution of 2-methyltetrahydrofuran and methanol (v / v, 1 / 1). The reaction was heated to 100 °C and stopped after 1 hour. The mixture was filtered, extracted with 30 mL of water and ethyl acetate, and separated by flash column chromatography to give intermediate b6 (120 mg, yield: 23%). LC-MS: [M+H] + :424.

[0336] Following the synthesis of intermediate b6, intermediate b7 was synthesized using b6-5 as a starting material. LC-MS: [M+H] + :424.

[0337] Example 1:

[0338]

[0339] Under nitrogen protection, starting material a1-1 (1.06 mmol, 200 mg) and intermediate b1 (1.59 mmol, 730 mg) were dissolved 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 reaction was heated at 95 °C for 3 hours. The reaction was stopped, filtered, and 40 mL of water was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by flash column chromatography to give compound A1-1 (330 mg, yield: 64%). LC-MS: [M+H] + :485.

[0340] 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 microwaved to 150 °C and reacted for 2 hours. The reaction was stopped, and 30 mL of water was added. The mixture was extracted with dichloromethane. After drying with anhydrous sodium sulfate, the solution was separated by flash column chromatography to give compound A1-2 (220 mg, yield: 59%). LC-MS: [M+H] + :550.

[0341] Under ice bath conditions, intermediate A1-2 (0.40 mmol, 220 mg) was dissolved in 5 mL of anhydrous dichloromethane. N-bromosuccinimide (NBS) (0.40 mmol, 72 mg) was slowly added in portions, and stirring was continued for 2 hours. The reaction was stopped, and 20 mL of saturated ammonium chloride aqueous solution was added. Extraction was performed with dichloromethane. The solution was dried over anhydrous sodium sulfate, and separation was achieved by flash column chromatography to give compound A1-3 (140 mg, yield: 56%). LC-MS: [M+H] + :629.

[0342] Under nitrogen protection, intermediate A1-3 (0.22 mmol, 140 mg) and starting material a3-2 (0.33 mmol, 92 mg) were dissolved 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 reaction was heated at 95 °C for 2 hours. The reaction was stopped, filtered, and 20 mL of water was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by flash column chromatography to give intermediate A1-4 (45 mg, yield: 29%). LC-MS: [M+H] + 700.

[0343] Intermediate A1-4 (45 mg) was dissolved in 5 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 2 hours. The reaction was stopped, the solvent was removed under reduced pressure, and the pH was adjusted to 10 with saturated sodium bicarbonate aqueous solution. Extraction with dichloromethane was performed, followed by preparative chromatographic separation to obtain the target compound A1 (8 mg, yield: 24%). LC-MS: [M+H] + :516.

[0344] The following compound was synthesized following the route described in Example 1:

[0345]

[0346]

[0347] Example 2:

[0348]

[0349] Under nitrogen protection, intermediates a1 (0.79 mmol, 200 mg) and b3 (1.19 mmol, crude product) were dissolved 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 reaction was heated at 95 °C for 10 hours. The reaction was stopped, filtered, and 40 mL of water was added to the system. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by flash column chromatography to give compound A3-1 (230 mg, yield: 59%). LC-MS: [M+H] + :496.

[0350] Under ice bath conditions, intermediate A3-1 (0.46 mmol, 230 mg) was dissolved in 15 mL of anhydrous dichloromethane. N-bromosuccinimide (NBS) (0.51 mmol, 90 mg) was slowly added in portions, and stirring was continued for 2 hours. The reaction was stopped, and 30 mL of saturated ammonium chloride aqueous solution was added. Extraction was performed with dichloromethane. The solution was dried over anhydrous sodium sulfate, and separation was achieved by flash column chromatography to give compound A3-2 (220 mg, yield: 83%). LC-MS: [M+H] + :575.

[0351] Under nitrogen protection, intermediate A3-2 (0.38 mmol, 220 mg) and starting material a3-2 (0.76 mmol, 211 mg) were dissolved 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 reaction was heated in a microwave at 100 °C for 2 hours. The reaction was stopped, filtered, and 30 mL of water was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by flash column chromatography to give compound A3-3 (100 mg, yield: 41%). LC-MS: [M+H] + :646.

[0352] Intermediate A3-3 (100 mg) was dissolved in 6 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 2 hours. The reaction was stopped, the solvent was removed under reduced pressure, and the pH was adjusted to 10 with saturated sodium bicarbonate aqueous solution. Extraction with dichloromethane was performed, followed by preparative chromatographic separation to obtain the target compound A3 (25 mg, yield: 35%). LC-MS: [M+H] + :462.

[0353] The following compound was synthesized following the route in Example 2:

[0354]

[0355] Example 3:

[0356]

[0357] Under nitrogen protection, intermediate A1-3 (0.32 mmol, 200 mg) and starting material tetrahydroxydiboron (0.64 mmol, 58 mg) were dissolved in 10 mL of anhydrous tetrahydrofuran. DIEA (0.64 mmol, 83 mg) and Pd(Amphos)Cl2 (0.03 mmol, 21 mg) were added, and the mixture was heated in a microwave oven at 95 °C for 2 hours. The reaction was stopped, filtered, and 30 mL of water was added. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate to give crude compound A5-1. This was used directly in the next reaction. LC-MS: [M+H]+ :594.

[0358] Under nitrogen protection, the crude intermediate A5-1 (150 mg, crude product) and 2-bromoimidazole A5-2 (0.25 mmol, 37 mg) from the previous step were dissolved in 10 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1). Potassium carbonate (0.5 mmol, 69 mg) and Pd(dppf)Cl2 (0.025 mmol, 19 mg) were added. The reaction was heated in a microwave at 110 °C for 2 hours. The reaction was stopped, filtered, and 30 mL of water was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by flash column chromatography to give compound A5-3 (70 mg, overall yield of both steps: 36%). LC-MS: [M+H] + :616.

[0359] Intermediate A5-3 (70 mg) was dissolved in 4 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 2 hours. The reaction was stopped, the solvent was removed under reduced pressure, and the pH was adjusted to 10 with saturated sodium bicarbonate aqueous solution. Extraction with dichloromethane was performed, followed by preparative chromatographic separation to obtain the target compound A5 (30 mg, yield: 53%). LC-MS: [M+H] + :516.

[0360] The following compound was synthesized following the route described in Example 3:

[0361]

[0362] Example 4:

[0363]

[0364] Under nitrogen protection, intermediate A1-3 (0.29 mmol, 180 mg) and thiophene-2-boronic acid pinacol ester A7-1 (0.58 mmol, 121 mg) were dissolved 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, and the mixture was heated at 95 °C for 2 hours. The reaction was stopped, filtered, the solvent was removed under reduced pressure, 30 mL of water was added, and the mixture was extracted with ethyl acetate. The extract was separated by flash column chromatography to give compound A7-2 (100 mg, yield: 55%). LC-MS: [M+H] + :632.

[0365] Intermediate A7-2 (100 mg) was dissolved in 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 2 hours. The reaction was stopped, the solvent was removed under reduced pressure, and the pH was adjusted to 10 with saturated sodium bicarbonate aqueous solution. Extraction with dichloromethane was performed, followed by preparative chromatographic separation to obtain the target compound A7 (20 mg, yield: 25%). LC-MS: [M+H] + :532.

[0366] (TFA salt); 1 H NMR (600MHz, DMSO-d6) δ8.83(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,1H),4.01(m,1H),3.78(m,1H),3.68(s,1H),3.59–3.53(m,1H),3.45(d,J=1 2.5Hz,2H),3.26(m,3H),2.42–2.30(m,2H),2.23–1.97(m,5H),1.28(d,J=6.9Hz,3H).

[0367] Example 5:

[0368]

[0369] Under nitrogen protection, intermediates a1 (0.59 mmol, 150 mg) and b4 (1.54 mmol, crude product) were dissolved in 10 mL of toluene, and triethylamine (1.19 mmol, 120 mg) and Pd(PPh3)2Cl2 (0.12 mmol, 84 mg) were added. The reaction was heated at 100 °C for 3 hours. The reaction was stopped, filtered, and 30 mL of water was added to the system. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by TLC to give compound A8-1 (120 mg, yield: 65%). LC-MS: [M+H] + :314.

[0370] Under ice bath conditions, intermediate A8-1 (0.38 mmol, 120 mg) was dissolved in 8 mL of anhydrous dichloromethane. N-bromosuccinimide (NBS) (0.42 mmol, 75 mg) was slowly added in portions, and the mixture was stirred at room temperature for 2 hours. The reaction was then stopped, and 20 mL of saturated ammonium chloride aqueous solution was added. The mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate to give compound A8-2 (200 mg, crude product). LC-MS: [M+H] + :393.

[0371] Under nitrogen protection, the crude intermediate A8-2 (200 mg) and the starting material a3-2 (0.57 mmol, 158 mg) from the previous step were dissolved 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 (0.04 mmol, 29 mg) were added. The reaction was heated in a microwave at 100 °C for 2 hours. The reaction was stopped, filtered, and 40 mL of water was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by TLC to give compound A8-3 (80 mg, overall yield of both steps: 46%). LC-MS: [M+H] + :464.

[0372] Intermediate A8-3 (80 mg) was dissolved in 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 2 hours. The reaction was stopped, the solvent was removed under reduced pressure, and the pH was adjusted to 10 with saturated sodium bicarbonate aqueous solution. Extraction with dichloromethane was performed, followed by preparative chromatographic separation to obtain the target compound A8 (27 mg, yield: 42%). LC-MS: [M+H] + :380.

[0373] (TFA salt); 1 H NMR (400MHz, DMSO-d6) δ8.30 (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=3.4H z,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).

[0374] Example 6:

[0375]

[0376] Under nitrogen protection, 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-safe reaction flask and dissolved in 5 mL of DMF. After stirring for 5 minutes, N,N-dimethyl-1,2-cyclohexanediamine (0.07 mmol, 10 mg) was slowly added. The reaction was heated to 110 °C and stopped after 1.5 hours. 40 mL of water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous Na2SO4, and separated by flash column chromatography to give compound A9-2 (50 mg, yield: 53%). LC-MS: [M+H] + :558.

[0377] Intermediate A9-2 (50 mg) was dissolved in 4 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 2 hours. The reaction was stopped, the solvent was removed under reduced pressure, and the pH was adjusted to 10 with saturated sodium bicarbonate aqueous solution. Extraction with dichloromethane was performed, followed by preparative chromatographic separation to obtain the target compound A9 (28 mg, yield: 67%). LC-MS: [M+H] + :474.

[0378] The following compound was synthesized following the route in Example 6:

[0379]

[0380]

[0381] Example 7:

[0382]

[0383] Under nitrogen protection, intermediate a3 (0.15 mmol, 70 mg), 3-bromo-6-benzyloxy-pyridine 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-safe reaction flask and dissolved in 5 mL of N-methylpyrrolidone. After stirring for 5 minutes, N,N-dimethyl-1,2-cyclohexanediamine (0.03 mmol, 4.3 mg) was slowly added. The reaction was heated to 110 °C and carried out for 10 hours. The reaction was then stopped, and 20 mL of water was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by TLC to give compound A14-2 (70 mg, yield: 73%). LC-MS: [M+H] + :646.

[0384] 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 then stopped, and the reaction solution was placed in an ice bath. A saturated aqueous solution of NaHCO3 was slowly added to the system. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by preparative chromatography to obtain the target compound A14 (20 mg, yield: 39%). LC-MS: [M+H] + :472.

[0385] (Free base); 1 H NMR (400MHz, DMSO-d6) δ8.27(s,1H),7.74(d,J=2.9Hz,1H),7.62(dd,J=9.5,3.0Hz,2H ),6.77(d,J=1.9Hz,1H),6.69(s,1H),6.49(d,J=9.6Hz,1H),4.54(s,1H),4.26(d,J=1 3.5Hz,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).

[0386] Example 8:

[0387]

[0388] Under nitrogen protection, intermediates a1 (0.79 mmol, 200 mg) and b5 (1.19 mmol, 516 mg) were dissolved in 15 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1). Potassium carbonate (1.60 mmol, 221 mg) and Pd(dppf)Cl2 (0.08 mmol, 59 mg) were added, and the mixture was heated at 95 °C for 10 hours. The reaction was stopped, filtered, and 40 mL of water was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by flash column chromatography to give compound A15-1 (170 mg, yield: 41%). LC-MS: [M+H] + :525.

[0389] Under ice bath conditions, intermediate A15-1 (0.32 mmol, 170 mg) was dissolved in 10 mL of anhydrous dichloromethane, and N-bromosuccinimide (NBS) (0.35 mmol, 63 mg) was slowly added in portions. The reaction was stopped by stirring at room temperature for 2 hours. 20 mL of saturated ammonium chloride aqueous solution was added, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate to give compound A15-2 (200 mg, crude product). LC-MS: [M+H] + :604.

[0390] Under nitrogen protection, the crude intermediate A15-2 (200 mg) and the starting material a3-2 (0.64 mmol, 178 mg) from the previous step were dissolved in 10 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1). Potassium carbonate (0.64 mmol, 89 mg) and Pd(dppf)Cl2 (0.03 mmol, 22 mg) were added. The reaction was heated in a microwave at 100 °C for 2 hours. The reaction was stopped, filtered, and 20 mL of water was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by TLC to give compound A15-3 (45 mg, overall yield of both steps: 21%). LC-MS: [M+H] + :675.

[0391] 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, the solvent was removed under reduced pressure, and the pH was adjusted to 10 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane, and the final product was separated by preparative chromatography to obtain the target compound A15 (9 mg, yield: 30%). LC-MS: [M+H] + :491.

[0392] (Free base); 1 H NMR(400MHz,DMSO-d6)δ8.26(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,1H),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).

[0393] Example 9:

[0394]

[0395] Under nitrogen protection, intermediates a4 (0.25 mmol, 100 mg) and b6 (0.50 mmol, 211 mg) were dissolved 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 reaction was heated in a microwave at 100 °C for 2 hours. The reaction was stopped, filtered, and 20 mL of water was added to the system. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by TLC to give compound A16-1 (60 mg, yield: 36%). LC-MS: [M+H] + :664.

[0396] 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, the solvent was removed under reduced pressure, and the pH was adjusted to 10 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane, and the solution was separated by preparative chromatography to obtain the target compound A16-I (10 mg, yield: 23%). LC-MS: [M+H] + :480.

[0397] (Free base);

[0398] Following the synthetic route of compound A16-I, intermediate b6 was replaced with its non-corresponding isomer b7 to obtain the target compound A16-II.

[0399] (Free base); 1 H NMR(400MHz,DMSO-d6)δ8.24(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,1H),4.27(d,J=13.6Hz,1H),4.02–3.96(m,1H),3.76(d,J=11.4Hz,1H),3.66(dd,J=1 1.4,3.1Hz,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=12.5H z,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).

[0400] The following compound was synthesized according to Example 9:

[0401]

[0402] Example 10:

[0403]

[0404] Compound A11 (0.063 mmol, 30 mg) was dissolved in 6 mL of a mixture of water and acetonitrile (v / v, 5 / 1), and manganese dioxide (0.115 mmol, 10 mg) was added. The reaction was heated at 90 °C for 10 hours. The reaction was stopped, filtered, and separated by flash column chromatography to give compound A17 (4 mg, yield: 13%). LC-MS: [M+H] + :499.

[0405] (Free base); 1 H NMR (400MHz, DMSO-d6) δ9.11(d,J=1.9Hz,1H),8.98(d,J=2.4Hz,1H),8.42(t,J=2.2H z,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).

[0406] Example 11:

[0407]

[0408] Under nitrogen protection, intermediate a3 (0.17 mmol, 80 mg), 2-bromoethanol A18-1 (0.34 mmol, 43 mg), and 5 mL of DMF were added to a reaction flask and dissolved. After stirring for 5 minutes, NaH (0.34 mmol, 14 mg) was slowly added. The reaction was stopped after heating to 50 °C for 2 hours, and 40 mL of water was added. The mixture was extracted with ethyl acetate, dried over anhydrous Na2SO4, and separated by TLC to give compound A18-2 (40 mg, yield: 47%). LC-MS: [M+H] + :507.

[0409] Intermediate A18-2 (60 mg) was dissolved in 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 2 hours. The reaction was stopped, the solvent was removed under reduced pressure, and the pH was adjusted to approximately 10 with saturated sodium bicarbonate aqueous solution. Extraction with dichloromethane was performed, followed by preparative chromatographic separation to obtain the target compound A18 (20 mg, yield: 40%). LC-MS: [M+H] + :423.

[0410] (Free base); 1 H NMR(400MHz,DMSO-d6)δ12.66(br,1H),8.23(s,1H),7.58(s,1H),6.74(s,1H),6.58(s,1 H),4.92(t,J=5.3Hz,1H),4.54(d,J=7.5Hz,1H),4.25(d,J=13.6Hz,1H),4.10(t,J=5.7H z,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).

[0411] Example 12:

[0412]

[0413] Under nitrogen protection, intermediate a3 (0.19 mmol, 90 mg), 3-bromo-5-benzyloxy-pyridine 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-safe reaction flask and dissolved in 5 mL of DMF. After stirring for 5 minutes, N,N-dimethyl-1,2-cyclohexanediamine (0.04 mmol, 5 mg) was slowly added. The reaction was heated to 110 °C and carried out for 10 hours. The mixture was then stopped, filtered, and extracted with 30 mL of water, dried over anhydrous sodium sulfate, and separated by TLC to give compound A19-2 (85 mg, yield: 70%). LC-MS: [M+H] + :646.

[0414] Intermediate A19-2 (0.13 mmol, 85 mg) and Pd / C (9 mg) were mixed in 4 mL of a mixture of methanol and ethyl acetate (v / v, 3 / 1), and hydrogen gas was introduced at 4 atm. The mixture was heated to 50 °C and reacted for 2 hours. The reaction was stopped, filtered, and the solvent was removed by vacuum distillation to obtain crude intermediate A19-3. LC-MS: [M+H]+ :556.

[0415] The crude intermediate A19-3 was dissolved in 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 2 hours, and then the reaction was stopped. The solvent was removed by vacuum distillation, and 10 mL of saturated NaHCO3 aqueous solution was slowly added to the system. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and separated by preparative chromatography to obtain the target compound A19 (38 mg, overall yield of two steps: 63%). LC-MS: [M+H] + :472.

[0416] (Free base); 1 H NMR(400MHz,DMSO-d6)δ8.32–8.24(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).

[0417] Example 13:

[0418]

[0419] Under nitrogen protection at -78°C, intermediate a1 (1.59 mmol, 400 mg) was dissolved in 15 mL of anhydrous tetrahydrofuran, and n-butyllithium (0.76 mL, 2.5 M) was added dropwise. After reacting for 30 minutes, tetrahydropyran-4-one A20-1 (1.75 mmol, 175 mg) was slowly added, and the reaction was stopped after stirring for 2 hours. 30 mL of saturated ammonium chloride aqueous solution was slowly added to the system, and the mixture was extracted with dichloromethane. The solution was dried over anhydrous sodium sulfate, and separated by TLC to give compound A20-2 (100 mg, yield: 20%). LC-MS: [M+H] + :319.

[0420] Under ice bath conditions, intermediate A20-2 (0.31 mmol, 100 mg) was dissolved in 10 mL of anhydrous dichloromethane, and N-iodosuccinimide (NIS) (0.35 mmol, 79 mg) was slowly added in portions. The reaction was stopped by stirring at room temperature for 2 hours. 20 mL of saturated ammonium chloride aqueous solution was added, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate to give compound A20-3 (170 mg, crude product). LC-MS: [M+H] + :445.

[0421] Under nitrogen protection, the crude intermediate A20-3 (170 mg) and the starting material a3-2 (0.62 mmol, 172 mg) from the previous step were dissolved in 10 mL of a mixture of 1,4-dioxane and water (v / v: 9 / 1). Potassium carbonate (0.64 mmol, 89 mg) and Pd(dppf)Cl2 (0.03 mmol, 22 mg) were added. The reaction was heated in a microwave at 100 °C for 2 hours. The reaction was stopped, filtered, and 20 mL of water was added. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by TLC to give compound A20-4 (120 mg, overall yield of both steps: 83%). LC-MS: [M+H] + :467.

[0422] 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, the solvent was removed under reduced pressure, and the pH was adjusted to 10 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane, and the solution was separated by preparative chromatography to obtain the target compound A20 (61 mg, yield: 61%). LC-MS: [M+H] + :383.

[0423] (Free base); 1 H NMR(400MHz,DMSO-d6)δ12.68(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=1 2.8, 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).

[0424] Example 14: ATR kinase activity assay:

[0425] Proteins derived from p53 biotinylated proteins were phosphorylated using ATR kinase (Eurofins, catalog number: 14-952). The amount of phosphorylated protein was determined using time-resolved fluorescence. The amount of phosphorylated protein was detected using an anti-p53-phospho-(serine 15)-K-specific antibody (Cisbio, catalog number: 61GSTDLA) and a d2-labeled anti-GST antibody (Cisbio, catalog number: 61P08KAE). Before starting the experiment, prepare the following working solutions as needed: 1× 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). Unless otherwise specified, all reagents used were purchased from Sigma or Invitrogen.

[0426] Perform the following operations:

[0427] Nine different concentrations of the compound were obtained by preparing 4× serially diluted compound solutions using 1× reaction buffer and adding 2.5 μL of each solution to a 384-well analytical plate (784075, Greiner). 4× p53 substrate working solution (40 nM) was prepared using 1× reaction buffer and added 2.5 μL to the wells. 4× ATR / ATRIP working solution (12.8 ng / μL) was prepared using dilution buffer and added 2.5 μL to the wells. 4× ATP working solution (2 mM) was prepared using deionized water and added 2.5 μL to the wells. The plates were incubated at room temperature in the dark for 30 minutes. 5 μL of stop solution was added to the wells. Finally, 5 μL of the detection mixture (0.084 ng / μL of Anti-phospho-p53(ser15)-K and 5 ng / μL of Anti-GST-d2) was added to a 384-well analytical plate. The plate was incubated overnight at room temperature, and 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 from the fluorescence intensity values: ER (Emission Ratio) = (fluorescence intensity at 665 nm / fluorescence intensity at 615 nm); Inhibition rate = (ER positive - ER of the test compound) / (ER positive - ER negative) × 100%. The IC50 of the compound was calculated using the parameter fitting standard software (GraphPad Prism 6.0). 50 Numerical value.

[0428] Kinase data results from the examples:

[0429]

[0430]

[0431] Example 15: In vitro cell proliferation inhibition experiment:

[0432] This experiment investigated the inhibitory effect of the compound on cell proliferation by examining its effects on in vitro cell activity in tumor cell lines TOV21G (ovarian cancer) and MV4-11 (leukemia).

[0433] Both TOV21G and MV4-11 cells were purchased from the American Type Culture Collection (ATCC).

[0434] TOV21G cells were cultured in MCDB105 / M199 medium (containing 15% FBS) until cell confluence reached 85% or higher, at which point they were used for experiments. Approximately 1000 cells were seeded per well in a 96-well plate and cultured for 24 hours. Different concentrations of the test compound (0-10 μM) were added to treat the cells, with three replicates per group. Blank wells (containing only culture medium) and control wells (seedled with cells, without drug treatment) were also included. After 120 hours of culture, 40 μL of Cell Titer-Glo solution (Promega, #G7573) was added to each well, and the plates were incubated for 20 minutes with shaking in the dark. 100 μL of the solution from each well was then transferred to a 96-well white plate (Corning, #3917), and the luminescence value was read using a Biotek Synergy H1 multi-mode microplate reader.

[0435] MV-4-11 cells were cultured in IMDM medium (containing 20% ​​FBS), with approximately 10,000 cells seeded per well in a 96-well plate. Different concentrations of the test compound (0-10 μM) were added to treat the cells, with three replicates per group. Blank wells (containing only culture medium) and control wells (cells seeded, no drug treatment) were also included. After 120 hours of culture, 40 μL of Cell Titer-Glo solution was added to each well, and the plates were incubated in the dark with shaking for 20 minutes. 100 μL of the solution was then transferred from each well to a 96-well plate, and the luminescence values ​​were read using a Biotek Synergy H1 multi-mode microplate reader.

[0436] Inhibition rate (%) = 100% × (control wells - test wells) / (control wells - blank wells)

[0437] Proliferation assays demonstrated the efficacy of the tested compound in the studied human tumor cells, with an IC50 concentration of [missing information]. 50 The value reflects (IC) 50 (This refers to the inhibition concentration at 50% of maximum efficacy).

[0438] CellTiter-Glo luminescence immunoassay results

[0439]

[0440] NT = Untested

[0441] Example 16: In vitro liver microsomal stability experiment of the compound:

[0442] Liver microsomal stability studies were conducted on the compounds of this invention. The test compounds (final concentration 2.0 nM) were co-incubated with human / mouse liver microsomes with or without the addition of NADPH, and the concentration of the compounds in the supernatant was measured within 60 minutes. Results for representative compounds are as follows:

[0443]

[0444] Example 17: In vivo pharmacokinetic experiments of the compound:

[0445] In vivo pharmacokinetic studies were conducted on the compounds of this invention.

[0446] Experimental methods:

[0447] Male ICR mice (n=3 per group) were administered the drug orally via gavage at a dose of 10 mg / kg. Plasma samples were collected before (0 h) and after (0.25, 0.5, 1, 2, 4, 6, 8, 24 h) administration. The collected samples were analyzed by LC / MS, and the data were collected. The relevant pharmacokinetic parameters were calculated using Analyst v1.6.2 (AB Applied Biosystems Company, USA) software.

[0448] The results for representative compounds are as follows:

[0449]

[0450] Example 18: Study on the selectivity of the compound for ATR kinase:

[0451] The compounds of this invention were subjected to family-specific (ATM, DNA-PK, PI3K, mTOR) inhibition assays:

[0452] Following the experimental method reported in the literature, the test compound was diluted 3-fold to 0.51 nM starting at 10 μM (a total of 10 concentrations), and its effect on kinase ATM was measured. 1 DNA-PK 2 ,PI3Kα 3 ,PI3Kδ 3 and mTOR 4 The inhibitory activity was observed, and the results are shown below:

[0453]

[0454] The above results indicate that the compound described in this invention is highly selective for ATR and has low inhibitory activity against other kinases in the family.

[0455] References:

[0456] [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;

[0457] [2]The Discovery of7-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-puri n-8-one(AZD7648), a Potent and Selective DNA-Dependent Protein Kinase(DNA-PK)Inhibitor,J.Med.Chem.2020,63,3461-3471;

[0458] [3]WO2012044641;

[0459] [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.

[0460] The above description, in conjunction with specific preferred embodiments, provides a further detailed explanation of the present invention. It should not be construed that the specific implementation of the present invention is limited to these descriptions. For those skilled in the art, various simple deductions or substitutions can be made without departing from the concept of the present invention, and all such modifications and substitutions should be considered within the scope of protection of the present invention.

Claims

1. A compound of general formula (I), or a pharmaceutically acceptable salt thereof: (I) in, X is CR X ; Y is N; R1, R2, R3, and R4 are independently selected from H, D, and C. 1-6 alkyl; Where R X For H or D; Ring A is a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group; R a Independently selected from H, D, halogens, -CN, -OR, -C(O)NRR' and C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may be optionally substituted by one or more D or halogens, up to complete substitution; m = 0, 1, 2, 3, 4 or 5; Ring B is a 5-6 membered heteroaryl group; R b Independently selected from H, D, halogens, -CN and C 1-6 alkyl; n = 0, 1, 2, 3, 4 or 5; The ring C is a 5-6 membered heteroaryl group; L represents a bond, -C(O)-, or C. 1-6 Alkylene; R5 is H, D, -OR, or C. 1-6 Alkyl, wherein the C 1-6 Alkyl groups may be optionally substituted by one or more D or halogens, up to complete substitution; R6 is H, D, -OR, or C. 1-6 Alkyl, wherein the C 1-6 Alkyl groups may be optionally substituted by one or more D or halogens, up to complete substitution; R and R' are H.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, R1 is C 1-6 alkyl.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein, R1 is ( R )-C 1-6 alkyl.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein, R1 is ( R )-methyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, X is CR X And R2, R3, R4 and R X It is hydrogen or D.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from the following groups: or , Where A3 is CR a3 Or N; A4 is CR a4 Or N; R a1 R a2 R a3 R a4 and R a5 Having the same R as in claim 1 a Same definition.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, Ring A is: ， Where A1 is CR a1 Or N; A2 is CR a2 Or N; A3 is N; A4 is CR a4 Or N; A5 is CR a5 Or N; R a1 R a2 R a4 and R a5 Having the same R as in claim 1 a Same definition.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, Ring A is: ， Where A1 is CR a1 Or N; A2 is CR a2 Or N; A3 is CR a3 Or N; A4 is N; A5 is CR a5 Or N; R a1 R a2 R a3 and R a5 Having the same R as in claim 1 a Same definition.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, (R a ) m - Cyclic AL- is selected from the following groups: , , , , , , , , , , , , , , , , , , or .

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from piperazine or piperidinyl.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, Ring B is pyrrole, furanyl, thiophene, pyrazolyl, imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, Ring B is pyrrole, furanyl, thiophene, pyrazolyl or pyridinyl.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, Ring B is a pyrazol group.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, R b For H.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, The ring C is a 5-membered heteroaryl group.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, The ring C is pyrrole, furanyl, thiophene, pyrazolyl, imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, The ring C is pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or triazolyl.

18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, The ring C is a pyrazol group.

19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, R5 and R6 are independently H, D, or C. 1-6 Alkyl, wherein the C 1-6 Alkyl groups may be optionally substituted with one or more D or halogens, up to complete substitution.

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the following general formula: (I-1) where, Each group has the same definition as any one of claims 1-19.

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the following general formula: (II) Among them, Each group has the same definition as any one of claims 1-19.

22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the following general formula: (II-1) Wherein, Each group has the same definition as any one of claims 1-19.

23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the following general formula: (III) in, A1, A2, A3, A4, and A5 have the same definition as in claim 7 or 8, and the other groups have the same definition as in any one of claims 1-19.

24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the following general formula: (III-1) Wherein, A1, A2, A3, A4, and A5 have the same definition as in claim 7 or 8, and the other groups have the same definition as in any one of claims 1-19.

25. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the following general formula: (III-2) Wherein, A1, A2, A3, and A5 have the same definition as in claim 8, and the other groups have the same definition as in any one of claims 1-19.

26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the following general formula: (III-3) Among them, A3 is CR a3 ;R a1 R a2 R a3 and R a5 It has the same definition as claim 6, and the other groups have the same definition as any one of claims 1-19.

27. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the following general formula: (III-4) Among them, A4 is CR a4 ;R a1 R a2 R a4 and R a5 It has the same definition as claim 6, and the other groups have the same definition as any one of claims 1-19.

28. The compound of claim 20, or a pharmaceutically acceptable salt thereof: (I-1) in, The ring C is a 5-6 membered heteroaryl group.

29. The compound of general formula (I-1) of claim 28, or a pharmaceutically acceptable salt thereof, wherein, The ring C is pyrrole, furanyl, thiophene, pyrazolyl, imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.

30. The compound of general formula (I-1) of claim 28, or a pharmaceutically acceptable salt thereof, wherein, The ring C is pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or triazolyl.

31. The compound of general formula (I-1) of claim 28, or a pharmaceutically acceptable salt thereof, wherein, The ring C is a pyrazol group.

32. The compound of general formula (I-1) of claim 28, or a pharmaceutically acceptable salt thereof, wherein, Ring B is pyrrole, furanyl, thiophene, pyrazolyl, imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.

33. The compound of general formula (I-1) of claim 32, or a pharmaceutically acceptable salt thereof, wherein, Ring B is pyrrole, furanyl, thiophene, pyrazolyl or pyridinyl.

34. The compound of claim 21, or a pharmaceutically acceptable salt thereof: (II) in, Ring A is a 5-6 membered heterocyclic group.

35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein, Ring A is piperidinyl or piperazine.

36. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein, Ring B is pyrrole, furanyl, thiophene, pyrazolyl, imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl. R5 and R6 are independently C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein, Ring B is pyrrole, furanyl, thiophene, pyrazolyl or pyridinyl.

38. The compound of claim 22, or a pharmaceutically acceptable salt thereof: (II-1) in, Ring A is a 5-6 membered heterocyclic group.

39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein, Ring A is a 5-6 membered heterocyclic group; Ring B is pyrrole, furanyl, thiophene, pyrazolyl, imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl. R5 and R6 are independently C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein, Ring A is piperidinyl or piperazine.

41. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein, Ring B is pyrrole, furanyl, thiophene, pyrazolyl or pyridinyl.

42. The compound of claim 23, or a pharmaceutically acceptable salt thereof: (III) in, The ring C is a 5-6 membered heteroaryl group.

43. The compound of general formula (III) of claim 42, or a pharmaceutically acceptable salt thereof, wherein, The ring C is pyrrole, furanyl, thiophene, pyrazolyl, imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.

44. The compound of general formula (III) of claim 42, or a pharmaceutically acceptable salt thereof, wherein, The ring C is pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or triazolyl.

45. The compound of general formula (III) of claim 42, or a pharmaceutically acceptable salt thereof, wherein, The ring C is a pyrazol group.

46. ​​The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein, Ring B is pyrrole, furanyl, thiophene, pyrazolyl, imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.

47. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein, Ring B is pyrrole, furanyl, thiophene, pyrazolyl or pyridinyl.

48. The compound of claim 25, or a pharmaceutically acceptable salt thereof: (III-2) in, A1 is CR a1 Or N; A2 is CR a2 Or N; A3 is N; A5 is CR a5 Or N.

49. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of general formula (III-3): (III-3) in, A3 is CR a3 Or N; R5 is H, D, -OR, or C. 1-6 Alkyl, wherein the C 1-6 Alkyl groups may be optionally substituted by one or more D or halogens, up to complete substitution; R6 is H, D, -OR, or C. 1-6 Alkyl, wherein the C 1-6 Alkyl groups may be optionally substituted by one or more D or halogens, up to complete substitution; R a1 R a2 R a3 and R a5 Having the same R as in claim 1 a Same definition.

50. The compound of general formula (III-3) of claim 49, or a pharmaceutically acceptable salt thereof, wherein, A3 is N.

51. The compound of general formula (III-3) of claim 49, or a pharmaceutically acceptable salt thereof, wherein, A3 is CR a3 Or N; R a1 R a2 R a3 and R a5 Independently selected from H, D, halogens, -CN, -OH, -C(O)NH2, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl groups may be optionally substituted with one or more D atoms, up to complete deuteration; R5 and R6 are independently C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl groups may be optionally substituted with one or more D atoms, up to complete deuteration.

52. The compound of general formula (III-3) of claim 49, or a pharmaceutically acceptable salt thereof, wherein, A3 is CR a3 Or N; R a1 For H or D; R a2 For H, D, halogens, -CN, -OH, -C(O)NH2, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R a3 It can be H, D, or -OH; R a5 For H or D; R5 is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R6 is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

53. The compound of general formula (III-3) of claim 52, or a pharmaceutically acceptable salt thereof, wherein, R5 stands for methyl.

54. The compound of general formula (III-3) of claim 52, or a pharmaceutically acceptable salt thereof, wherein, R6 is a methyl group.

55. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of general formula (III-3): (III-3) in, A3 is CR a3 Or N; R a1 R a2 R a3 and R a5 Independently H, D, halogen, -OR, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl groups may be optionally substituted with one or more D atoms, up to complete deuteration; R5 is H, D, -OR, or C. 1-6 Alkyl, wherein the C 1-6 Alkyl groups may be optionally substituted by one or more D or halogens, up to complete substitution; R6 is H, D, -OR, or C. 1-6 Alkyl, wherein the C 1-6 Alkyl groups may be optionally substituted by one or more D or halogens, up to complete substitution; R is H.

56. The compound of general formula (III-3) of claim 55, or a pharmaceutically acceptable salt thereof, wherein, A3 is CR a3 Or N; R a1 R a2 R a3 and R a5 Independently selected from H, D, halogens, -OH, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl groups may be optionally substituted with one or more D atoms, up to complete deuteration; R5 and R6 are independently C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl groups may be optionally substituted with one or more D atoms, up to complete deuteration.

57. The compound of general formula (III-3) of claim 55, or a pharmaceutically acceptable salt thereof, wherein, A3 is CR a3 Or N; R a1 For H or D; R a2 For H, D, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R a3 It can be H, D, or -OH; R a5 For H or D; R5 is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R6 is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

58. The compound of general formula (III-3) of claim 57, or a pharmaceutically acceptable salt thereof, wherein, R5 stands for methyl.

59. The compound of general formula (III-3) of claim 57, or a pharmaceutically acceptable salt thereof, wherein, R6 is a methyl group.

60. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of general formula (III-4): (III-4) in, A4 is CR a4 Or N; R a1 R a2 R a4 and R a5 Independently H, D, halogen, -CN, -OR, -C(O)NRR' or C 1-6 Alkyl, wherein the C 1-6 The alkyl group may be optionally substituted with one or more D or halogens, up to complete substitution; R5 is H, D, -OR, or C. 1-6 Alkyl, wherein the C 1-6 Alkyl groups may be optionally substituted by one or more D or halogens, up to complete substitution; R6 is H, D, -OR, or C. 1-6 Alkyl, wherein the C 1-6 Alkyl groups may be optionally substituted with one or more D or halogens, up to complete substitution.

61. The compound of general formula (III-4) of claim 60, or a pharmaceutically acceptable salt thereof, wherein, A4 is CR a4 Or N; R a1 R a2 R a4 and R a5 Independently selected from H, D, halogens, -CN, -OH, -C(O)NH2, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl groups may be optionally substituted with one or more D atoms, up to complete deuteration; R5 and R6 are independently C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl groups may be optionally substituted with one or more D atoms, up to complete deuteration.

62. The compound of general formula (III-4) of claim 60, or a pharmaceutically acceptable salt thereof, wherein, A4 is CR a4 Or N; R a1 It can be H, D, or halogen; R a2 For H, D, halogens, -CN, -OH, -C(O)NH2, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R a4 It can be H, D, or -OH; R a5 For H or D; R5 is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R6 is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

63. The compound of general formula (III-4) of claim 62, or a pharmaceutically acceptable salt thereof, wherein, R5 stands for methyl.

64. The compound of general formula (III-4) of claim 62, or a pharmaceutically acceptable salt thereof, wherein, R6 is a methyl group.

65. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of general formula (III-3): (III-3) in, A3 is CR a3 Or N; R5 and R6 are independently C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may be optionally substituted with one or more D atoms, up to complete deuteration; R a1 R a2 R a3 and R a5 Independently selected from H, D, halogens, and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl groups may be optionally substituted with one or more D atoms, up to complete deuteration.

66. The compound of claim 65, or a pharmaceutically acceptable salt thereof: (III-3) in, A3 is CR a3 ; R5 and R6 are independently C 1-6 alkyl; R a1 For H or D; R a2 For H, D, halogens, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R a3 For H or D; R a5 It can be H or D.

67. The compound of general formula (III-3) of claim 66, or a pharmaceutically acceptable salt thereof, wherein, R5 and R6 are methyl groups independently.

68. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of general formula (III-4): (III-4) in, A4 is CR a4 Or N; R5 and R6 are independently C 1-6 Alkyl, wherein the C 1-6 Alkyl groups may be optionally substituted with one or more D atoms, up to complete deuteration; R a1 R a2 R a4 and R a5 Independently selected from H, D, halogens, and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl groups may be optionally substituted with one or more D atoms, up to complete deuteration.

69. A pharmaceutical composition comprising a compound of any one of claims 1-68, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

70. The pharmaceutical composition of claim 69, further comprising other therapeutic agents.

71. Use of a compound of any one of claims 1-68 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 69 or 70, in the preparation of a medicament for treating and / or preventing ATR kinase-mediated diseases.

72. The use of claim 71, wherein the ATR kinase-mediated disease is a proliferative disease.

73. The use of claim 71, wherein the ATR kinase-mediated disease is cancer.

74. The use of claim 71, wherein the ATR kinase-mediated diseases are selected from leukemia, breast cancer, colorectal cancer, lung cancer, prostate cancer, 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, vulvar cancer, multiple myeloma, and lymphoma.

75. The use of claim 71, wherein the ATR kinase-mediated disease is selected from small cell lung cancer, non-small cell lung cancer, bronchioloalveolar carcinoma, acute lymphoblastic leukemia, chronic myeloid leukemia, and acute myeloid leukemia.

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