Compound containing thiazolo ring structure

Abstract

The present disclosure belongs to the field of pharmaceutical chemistry. Provided are a compound containing a thiazolo ring structure or a pharmaceutically acceptable salt thereof, a preparation method therefor or a pharmaceutical composition thereof, and the use thereof in the preparation of a drug for treating or preventing tumor-associated diseases.

Description

Compounds containing thiazolocyclic structures

[0001] Cross-reference to Related Applications

[0002] This application claims priority to and the benefit of Chinese Patent Application No. 202411395608.9, filed September 30, 2024, in the China National Intellectual Property Office, the contents of which are incorporated herein in their entirety. TECHNICAL FIELD

[0003] The present disclosure belongs to the field of medicinal chemistry, and provides a compound containing a thiazolocyclic structure or a pharmaceutically acceptable salt thereof, a preparation method thereof or a pharmaceutical composition thereof, and a use thereof in the preparation of a drug for treating or preventing a tumor-related disease. BACKGROUND

[0004] Stable repair of DNA double-strand breaks (DSBs) is essential for maintaining genome stability and cell viability. DSBs can be repaired by one of three major pathways: homologous recombination (HR), non-homologous end joining (NHEJ), and alternative NHEJ (alt-NHEJ). Microhomology-mediated end joining (MMEJ) is the best characterized alt-NHEJ mechanism. MMEJ can function concurrently with HR and NHEJ pathways.

[0005] Unlike normal cells, the survival of cancer cells often depends on the misregulation of DNA damage response (DDR) pathways. Aberrant DDR can also sensitize cancer cells to specific types of DNA damage, and thus can exploit defective DDR to develop targeted cancer therapies. It is of critical importance that cancer cells with impaired or inactivated HR and NHEJ become hyperdependent on MMEJ-mediated DNA repair. PolQ (UniProtKB - O75417 (DPOLQ_HUMAN, or Polθ) is a key protein in MMEJ. Therapeutic inactivation of PolQ would incapacitate the ability of cells to perform MMEJ and provide a new targeting strategy in a range of defined tumor environments. First, PolQ has been shown to be critical for the survival of homologous recombination deficient (HRD) cells and is upregulated in HRD tumor cell lines. PolQ is largely repressed in normal tissues but has been shown to be upregulated in matched cancer samples, thus linking elevated expression to disease. Second, its inhibition or blockade confers radiosensitivity to tumor cells. There is a need to provide potent PolQ inhibitors that have potential to treat cancer.

[0006] DETAILED DESCRIPTION

[0007] The present disclosure relates to a compound of Formula I or a pharmaceutically acceptable salt thereof,

[0008] wherein,

[0009] R 1 is selected from H, D, CN, NH2, OH, CHO, COOH, halogen, or the following groups optionally substituted with one or more substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;

[0010] X 1 , X 2 , X 3 and X 4 are each independently selected from CH or N;

[0011] each R 2 , R 3 , R 4 , R 5 is independently selected from D, CN, halogen or the following groups optionally substituted with one or more substituents: C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 5-12 membered heteroaryl, C 6-12 aryl, -OR a , -NR a R b , -SR a , -S(O)R a , -SO2R a , -SO2NR a R b , -N(R a )SO2R b , -C(O)R a , -CO2R a , -OC(O)R a , -C(O)NR a R b or -N(R a )C(O)R b ;

[0012] n is selected from 0, 1 or 2;

[0013] m is selected from 0, 1, 2, 3, 4 or 5;

[0014] q is selected from 0, 1, 2 or 3;

[0015] p is selected from 0, 1, 2, 3, 4 or 5;

[0016] each R aand R b each independently selected from H, D, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, 5-10 membered heteroaryl, or C 6-10 aryl, said C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, 5-10 membered heteroaryl, or C 6-10 aryl is optionally substituted with one or more groups selected from D, OH, NH2, CN, or halogen;

[0017] -L- is selected from C 2-6 alkynylene, or OC 1-4 alkylene;

[0018] Ring A is selected from C 3-15 cycloalkyl, C 6-15 aryl, 3-15 membered heterocycloalkyl, 3-15 membered heterocycloalkenyl, or 5-10 membered heteroaryl;

[0019] Ring B is selected from C 6-15 aryl or 5-10 membered heteroaryl;

[0020] Ring C is selected from C 6-15 aryl or 5-10 membered heteroaryl.

[0021] In some embodiments, when -L- is selected from C 2-6 alkynylene (e.g. ), X 1 and X 4 are selected from N, X 2 and X 3 are selected from CH, Ring A is selected from C 3-15 cycloalkyl 3-15 membered heterocycloalkyl, 3-15 membered heterocycloalkenyl, or 5-10 membered heteroaryl.

[0022] In some embodiments, when -L- is selected from C 2-6 alkynylene (e.g. ), Ring A is selected from C 3-15 cycloalkyl, 3-15 membered heterocycloalkyl, or 5-10 membered heteroaryl.

[0023] In some embodiments, when -L- is selected from C 2-6 alkynylene (e.g. ), Ring A is selected from C 3-15 cycloalkyl or 3-15 membered heterocycloalkyl.

[0024] In some embodiments, when -L- is selected from C 2-6 alkenylene (e.g. ) X 1 and X 4 are selected from N, X 2 and X 3 are selected from CH. In some embodiments, when -L- is selected from -OC 1-4 alkylene- ring A is selected from C 6-15 aryl or 5-10 membered heteroaryl.

[0025] In some embodiments, when -L- is selected from C 2-6 alkenylene (e.g. ) X 1 and X 4 are selected from N, X 2 and X 3 are selected from CH, ring A is selected from C 3-15 cycloalkyl.

[0026] In some embodiments, X 4 is selected from N.

[0027] In some embodiments, X 1 is selected from N.

[0028] In some embodiments, when X 1 is selected from N, X 2 , X 3 and X 4 are selected from CH, ring C is selected from C 7-15 aryl or 5-10 membered heteroaryl.

[0029] In some embodiments, R 4 is selected from the following groups optionally substituted with one or more substituents: C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 5-12 membered heteroaryl, or C 6-12 aryl.

[0030] In some embodiments, the compound is not the following compound:

[0031] In some embodiments, the compound is not the following compound:

[0032] In some embodiments, R 1 is selected from H, D, CN, NH2, OH, CHO, COOH, halogen, or the following groups optionally substituted with one or more substituents: C 1-3 alkyl, C2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0033] In some implementation schemes, R 1 Selected from H, D, CN, NH2, OH, CHO, COOH, halogen, or optionally substituted with one or more substituents: methyl, ethyl, propyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or 3-6 membered heterocyclic groups.

[0034] In some implementation schemes, R 1 Selected from H.

[0035] In some implementation schemes, X 1 and X 4 Selected from N, X 2 and X 3 Selected from CH.

[0036] In some implementation schemes, X 3 Selected from N, X 1 X 2 and X 4 Selected from CH.

[0037] In some implementation schemes, X 1 Selected from N, X 2 X 3 and X 4 Selected from CH.

[0038] In some implementation schemes, R 1 R 2 R 3 R 4 and R 5 The "substituents" mentioned herein are each independently selected from R'.

[0039] Each R' is independently selected from CN, halogen, cyano, =O, or optionally substituted by one or more of the following groups selected from halogen (e.g., F, Cl, Br, or I), OH, NH2, or CN: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, 5-10 membered heteroaryl, C 6-10 Aryl, -OR e R e R f NH-, R e S-、-S(O)R e -SO2Re -SO2NR e R f -NR e SO2R f R e C(O)-, -CO2R e -OC(O)R e R e R f NC(O)- or R f C(O)NR e -,

[0040] each R e and R f is independently selected from H, D, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, 5-10 membered heteroaryl, or C 6-10 aryl.

[0041] In some embodiments, each R 2 , R 3 , R 4 , R 5 is independently selected from CN, halogen, or the following groups optionally substituted with one or more R' substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, C 6-9 aryl, -S(O)R a , -SO2R a , -SO2NR a R b , -N(R a )SO2R b , -C(O)R a , -CO2R a , -OC(O)R a , -C(O)NR a R b , or -N(R a )C(O)R b .

[0042] In some embodiments, each R 2 , R 3 , R 4 , R 5The following groups are selected independently from CN, halogens, or optionally substituted by one or more R' substituents: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, C 6-9 Aryl, -NR a R b -S(O)R a -SO2R a -SO2NR a R b -N(R) a SO2R b -C(O)R a -CO2R a -OC(O)R a -C(O)NR a R b or -N(R) a )C(O)R b .

[0043] In some implementations, each R 2 R 3 R 4 R 5 The following groups are selected independently from CN, halogen, OH, NH2, or optionally substituted by one or more R' substituents: C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkyl O-, (C 1-3 Alkyl)2N-, C 3-4 Cycloalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl or 5-6 membered heteroaryl.

[0044] In some implementations, each R 2 R 3 R 4 R 5 The following groups are selected independently from CN, halogen, OH, NH2, or optionally substituted by one or more R' substituents: C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkyl O-, C 1-3 Alkyl-NH-, (C 1-3 Alkyl)2N-, C 3-4 Cycloalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl or 5-6 membered heteroaryl.

[0045] In some embodiments, each R 2 , R 3 , R 4 , R 5 is independently selected from F, Cl, or the following groups optionally substituted with one or more R' substituents: methyl, propynyl, CH3O-, (C 1-2 alkyl)2N-, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, dihydropyridinyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, or pyridazinyl.

[0046] In some embodiments, each R 2 , R 3 , R 4 , R 5 is independently selected from F, Cl, or the following groups optionally substituted with one or more R' substituents: methyl, ethyl, propynyl, CH3O-, C 1-2 alkyl-NH-, (C 1-2 alkyl)2N-, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, dihydropyridinyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, or pyridazinyl.

[0047] In some embodiments, each R' is selected from CN, halogen (e.g., F, Cl, Br, or I), OH, NH2, =0, CHO, COOH, NH2C(O)-, or the following groups optionally substituted with one or more substituents selected from halogen (e.g., F, Cl, Br, or I), OH, NH2, or CN: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkylO-, C 1-3 alkylNH-, (C 1-3 alkyl)2N-, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, C 6-9 aryl, -S(O)C 1-3 alkyl, -SO2C 1-3 alkyl, -SO2NHC 1-3 alkyl, -NHSO2C 1-3 alkyl, C 3-6 cycloalkylC(O)-, 3-6 membered heterocycloalkylC(O)-, (C 1-3 alkyl)2NC(O)-, C 1-3 alkylC(O)-, C 1-3 alkylCO2-, C 1-3 alkylOC(O)-, -C(O)NHC 1-3 alkyl, or -NHC(O)C 1-3 alkyl.

[0048] In some embodiments, each R' is selected from CN, halogen (e.g., F, Cl, Br, or I), OH, NH2, =0, CHO, COOH, NH2C(O)-, or, optionally substituted with one or more groups selected from halogen (e.g., F, Cl, Br, or I), OH, NH2, or CN: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkylO-, C 1-3 alkylNH-, (C 1-3 alkyl)2N-, C 3-6 cycloalkyl, 6-10 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, C 6-9 aryl, -S(O)C 1-3 alkyl, -SO2C 1-3 alkyl, -SO2NHC 1-3 alkyl, -NHSO2C 1-3 alkyl, C 3-6 cycloalkylC(O)-, 3-6 membered heterocycloalkylC(O)-, (C 1-3 alkyl)2NC(O)-, C 1-3 alkylC(O)-, C 1-3 alkylCO2-, C 1-3 alkylOC(O)-, -C(O)NHC 1-3 alkyl or -NHC(O)C 1-3 alkyl.

[0049] In some embodiments, each R e and R f are each independently selected from H, D, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, or C 6-10 aryl.

[0050] In some embodiments, each R e and R f are each independently selected from H, D, C 1-3 alkyl or 3-4 membered heterocycloalkyl.

[0051] In some embodiments, each R' is selected from CN, halogen (e.g., F, Cl, Br, or I), OH, NH2, =0, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3alkyl O-, C 1-3 alkyl NH-, (C 1-3 alkyl)2N-, C 3-6 cycloalkyl C(O)-, 3-6 membered heterocycloalkyl C(O)-, NH2C(O)-, or (C 1-3 alkyl)2NC(O)-, said C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkyl O-, C 1-3 alkyl NH-, (C 1-3 alkyl)2N-, C 3-6 cycloalkyl C(O)-, 3-6 membered heterocycloalkyl C(O)-, or (C 1-3 alkyl)2NC(O)- optionally substituted with one or more groups selected from halogen (e.g., F, Cl, Br, or I), OH, NH2, or CN.

[0052] In some embodiments, each R' is selected from CN, halogen (e.g., F, Cl, Br, or I), OH, NH2, =O, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkyl O-, C 1-3 alkyl NH-, (C 1-3 alkyl)2N-, 7-10 membered heterocycloalkyl, C 3-6 cycloalkyl C(O)-, 3-6 membered heterocycloalkyl C(O)-, NH2C(O)-, or (C 1-3 alkyl)2NC(O)-, said C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkyl O-, C 1-3 alkyl NH-, (C 1-3 alkyl)2N-, C 3-6 cycloalkyl C(O)-, 3-6 membered heterocycloalkyl C(O)-, or (C 1-3 alkyl)2NC(O)- optionally substituted with one or more groups selected from halogen (e.g., F, Cl, Br, or I), OH, NH2, or CN.

[0053] In some embodiments, each R' is selected from CN, F, =O, methyl, (C 1-2 alkyl)2N-, (C 1-2 alkyl)2NC(O)-, or azetidinyl C(O)-, said methyl, (C 1-2 alkyl)2N-, (C 1-2alkyl)2NC(O)-, or azetidinyl C(O)-, said methyl, (C

[0054] In some embodiments, each R' is independently selected from F, Cl, CH3, 1-2 alkyl)2N-, (C 1-2 alkyl)2NC(O)-, or azetidinyl C(O)-, said methyl, (C 1-2 alkyl)2N-, (C 1-2 alkyl)2NC(O)-, or azetidinyl C(O)-, optionally substituted with one or more groups selected from halogen (e.g., F, Cl, Br, or I), OH, NH2, or CN.

[0055] In some embodiments, each R 2 , R 3 , R 4 , R 5 are each independently selected from F, Cl, CH3, -CH2CN, cyclopropyl, or

[0056] In some embodiments, each R 2 , R 3 , R 4 , R 5 are each independently selected from F, Cl, CH3, -CH2CN, cyclopropyl,

[0057] In some embodiments, each R 2 are each independently selected from F.

[0058] In some embodiments, each R 3 are each independently selected from Cl.

[0059] In some embodiments, each R 4 are each independently selected from CH3, -CH2CN, cyclopropyl, or

[0060] In some embodiments, each R 4 is independently selected from CH3.

[0061] In some embodiments, each R 4 is independently selected from CH3, -CH2CN, cyclopropyl,

[0062] In some embodiments, each R 5 is independently selected from F, Cl, CHF2, CF3, or -OCH3.

[0063] In some embodiments, each R 5 is independently selected from Cl or -OCH3.

[0064] In some embodiments, each R 5 is independently selected from F, Cl, CH3, CH2CH3, CHF2, CF3, -OCH3, or

[0065] In some embodiments, n is selected from 0 or 1. In some embodiments, m is selected from 0 or 1. In some embodiments, q is selected from 1. In some embodiments, p is selected from 2 or 3. In some embodiments, m is selected from 0.

[0066] In some embodiments, each R a and R b are each independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, or C 6-10 aryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, or C 6-10 aryl is optionally substituted with one or more groups selected from D, OH, NH2, CN, or halogen.

[0067] In some embodiments, each R a and R b are each independently selected from H, D, C 1-3 alkyl, C 2-3alkenyl or C 2-3 alkynyl.

[0068] In some embodiments, each R a and R b are each independently selected from H or C 1-6 alkyl.

[0069] In some embodiments, each R a and R b are each independently selected from H, methyl or ethyl.

[0070] In some embodiments, -L- is selected from or -OCH2-. In some embodiments, -L- is selected from In some embodiments, -L- is selected from -OCH2-.

[0071] In some embodiments, when ring A is selected from cycloalkyl, the cycloalkyl is a 3 to 10 membered ring, a 4 to 8 membered ring, a 5 to 8 membered ring, or a 5 to 6 membered ring.

[0072] In some embodiments, when ring A is selected from cycloalkyl, the cycloalkyl is a 5 to 6 membered ring.

[0073] In some embodiments, ring A is selected from C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, or 5-10 membered heteroaryl.

[0074] In some embodiments, ring A is selected from C 3-6 cycloalkyl, 6-membered aryl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, or 5-6 membered heteroaryl.

[0075] In some embodiments, ring A is selected from C 3-6 cycloalkyl.

[0076] In some embodiments, ring A is selected from C 4-8 cycloalkyl.

[0077] In some embodiments, ring A is selected from C 5-8 cycloalkyl.

[0078] In some embodiments, ring A is selected from C 5-6 cycloalkyl.

[0079] In some embodiments, ring A is selected from cyclopropyl or phenyl.

[0080] In some embodiments, ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, or bicyclo[1.1.1]pent-1-yl.

[0081] In some embodiments, ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0082] In some embodiments, ring A is selected from cyclopentyl or cyclohexyl.

[0083] In some embodiments, ring A is selected from cyclopropyl, phenyl, oxetanyl, piperidinyl, tetrahydropyranyl, cyclobutyl, cyclopentyl, azetidinyl, or cyclohexyl.

[0084] In some embodiments, ring B is selected from C 6-10 aryl or 5-10 membered heteroaryl.

[0085] In some embodiments, ring B is selected from phenyl or 5-6 membered heteroaryl.

[0086] In some embodiments, ring B is selected from phenyl or pyridinyl.

[0087] In some embodiments, ring B is selected from pyridinyl.

[0088] In some embodiments, ring C is selected from C 6-10 aryl or 5-10 membered heteroaryl.

[0089] In some embodiments, ring C is selected from phenyl or 5-6 membered heteroaryl.

[0090] In some embodiments, ring C is selected from phenyl or pyridinyl.

[0091] In some embodiments, ring C is selected from pyridinyl.

[0092] In some embodiments, ring B is selected from phenyl or 5-10 membered heteroaryl; ring C is selected from phenyl or 5-10 membered heteroaryl.

[0093] In some embodiments, ring B is selected from pyridinyl; ring C is selected from pyridinyl.

[0094] In some embodiments, the structural moiety is selected from

[0095] In some embodiments, the structural moiety is selected from

[0096] In some embodiments, the structural moiety is selected from

[0097] In some embodiments, the structural moiety selected from

[0098] In some embodiments, the structural moiety selected from

[0099] In some embodiments, the structural moiety selected from the structural moiety selected from

[0100] In some embodiments, the structural unit selected from In some embodiments, the structural unit selected from

[0101] In some embodiments, the structural unit selected from

[0102] In some embodiments, the structural unit selected from

[0103] In some embodiments, the structural unit selected from

[0104] In some embodiments, the structural unit selected from

[0105] In some embodiments, the structural unit selected from

[0106] In some embodiments, the structural unit selected from

[0107] In some embodiments, the structural unit selected from

[0108] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from a compound of Formula II, a compound of Formula III, a compound of Formula IV, a compound of Formula V, or a pharmaceutically acceptable salt thereof,

[0109] wherein X 5 , X 6 and X7 are each independently selected from CH or N, R 1 , R 2 , n, X 1 , X 3 , X 4 , L, ring A, ring C, R 3 , m, R 4 , q, R 5 , p are as described herein.

[0110] In some embodiments, the moiety is as described herein. In some embodiments, the moiety is selected from In some embodiments, the moiety is selected from In some embodiments, the moiety is selected from

[0111] In another aspect, the present disclosure relates to the following compounds, or a pharmaceutically acceptable salt thereof:

[0112] In another aspect, the present disclosure also provides a pharmaceutical composition comprising the compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

[0113] In some embodiments of the present disclosure, the pharmaceutical composition contains 0.01 mg to 1000 mg (calculated as the free form of the compound) of the above-mentioned compound, or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments of the present disclosure, the pharmaceutical composition contains a single dose of 0.01 mg to 1000 mg (calculated as the free form of the compound) of the above-mentioned compound, or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments of the present disclosure, the single dose of 0.01 mg to 1000 mg is further selected from 0.1 mg to 1000 mg, 0.1 mg to 500 mg, 1 mg to 1000 mg, or 1 mg to 500 mg.

[0116] In some embodiments of the present disclosure, the subject to which the pharmaceutical composition is administered is selected from a mammal, for example, a human.

[0117] In some embodiments of the present disclosure, the pharmaceutical composition is selected from a solid pharmaceutical composition.

[0118] In some embodiments of the present disclosure, the pharmaceutical composition is selected from a liquid pharmaceutical composition.

[0119] In some embodiments of the present disclosure, the pharmaceutical composition is selected from a pharmaceutical composition in oral form or in injectable form. In another aspect, the present disclosure also provides a method for treating or preventing a disease, comprising administering to a mammal, preferably a human, in need of such treatment, a therapeutically or prophylactically effective amount of the compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0120] In another aspect, the present disclosure also provides the use of the compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for treating or preventing a disease.

[0121] In another aspect, the present disclosure also provides the use of the compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in treating or preventing a disease.

[0122] In another aspect, the present disclosure also provides the compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating or preventing a disease.

[0123] In some embodiments, the disease is selected from a cancer.

[0124] In some embodiments, the disease is selected from a Pol Q-related disease (e.g., a cancer).

[0125] In some embodiments, the disease is selected from a Pol Q-related cancer (e.g., breast cancer).

[0126] Technical effects

[0127] The compound of the present disclosure has good Pol Q protein inhibitory activity and cell proliferation inhibitory effect, good proliferation inhibitory activity relative to MDA-MB-436 (SHLD2- / -) cells, good selective inhibitory effect relative to MDA-MB-436 WT cells, good in vivo efficacy, good in vitro metabolic stability such as liver microsomal metabolic stability, and good in vivo pharmacokinetic properties.

[0128] Definitions

[0129] Unless otherwise indicated, the following terms used in the present disclosure have the following meanings. A particular term should not be construed as indefinite or unclear if it is not specifically defined, but should be understood according to the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0130] When a covalent bond in certain structural units or groups in the present disclosure is not attached to a specific atom, it means that the covalent bond can be attached to any atom in the structural unit or group as long as the valence bond connection rule is not violated.

[0131] The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent group, as long as the valence of the particular atom is properly satisfied and the resulting compound is stable. When the substituent is oxo (i.e., =0), it means that two hydrogen atoms are replaced, and oxo cannot occur on an aromatic group.

[0132] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs and instances where it does not. For example, an ethyl group "optionally" substituted with a halogen means that the ethyl group can be unsubstituted (CH2CH3), mono-substituted (such as CH2CH2F), poly-substituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). One skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern will be introduced that is not spatially possible and / or synthetically feasible.

[0133] "substituents" include, but are not limited to, the terms "alkyl," "alkoxy," "alkylthio," "cycloalkoxy," "heteroalkyl," "alkenyl," "alkynyl," "cycloalkenyl," "cycloalkyl," "cycloalkynyl," "heterocycloalkyl," "heterocycloalkenyl," "heterocyclyl," "aryl," "heteroaryl," "alkylene," and the like, and corresponding non-limiting or exemplary groups, where some non-limiting examples of the "substituents" include -OH, -SH, halogen, -NH2, nitro, nitroso, -CN, azido, sulfoxide, sulfone, sulfonamide, carboxy, carboxaldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy, aralkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroaralkoxy, heteroaralkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate, amide, ureido, epoxy, and ester, and the like, optionally substituted with one or more substituents selected from oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, aryl, aralkyl, or aryloxy.

[0134] C in this document m-n is an integer number of carbon atoms in the moiety having a given range. For example, "C 1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. For example, C 1-3 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms.

[0135] In some embodiments herein, the substituents are selected from hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azido, sulfoxide, sulfone, sulfonamide, carboxy, aldehyde, imine, C 1-12alkyl, halo-C 1-12 alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 alkenyl, halo-C 2-12 alkenyl, 3-12 membered cycloalkenyl, halo-3-12 membered cycloalkenyl, C 2-12 alkynyl, halo-C 2-12 alkynyl, 8-12 membered cycloalkynyl, halo-8-12 membered cycloalkynyl, C 1-12 heteroalkyl, halo-C 1-12 heteroalkyl, C 1-12 alkoxy, C 1-12 alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered aryl C 1-12 alkylene, 6-10 membered aryl C 1-12 alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclyl C 1-12 alkylene, 3-12 membered heterocyclyl C 1-12 alkoxy, 3-12 membered heterocyclyl C 1-12 alkylthio, C 1-12 acyl, C 1-12 acyloxy, carbamate group, C 1-12 amido, ureido, epoxy group, C 2-12 ester group and oxo, said substituent is optionally substituted with one or more substituents selected from oxo, hydroxyl, amino, nitro, halogen, cyano, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, halo C 1-12 alkoxy, C 1-12 alkylamino, di C 1-12 alkylamino, halo C 1-12 alkylamino, halo di C 1-12 alkylamino, carboxyl, -C(O)O-C 1-12 alkyl, -OC(O)-C 1-12 alkyl, -C(O)NH2, -C(O)NH-C 1-12 alkyl, -C(O)N(C 1-12 alkyl)2, -NHC(O)-C 1-12 alkyl, -C(O)-C 1-12 alkyl, -S(O)-C 1-12alkyl, -S(O)2-C 1-12 alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 alkyl, -S(O)2N(C 1-12 alkyl)2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyl C 1-12 alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl C 1-12 alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryl C 1-12 alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered aryl C 1-12 alkylene, or 6-10 membered aryloxy.

[0136] When any variable (e.g. R 2 ) occurs more than one time in a compound or substituent, its definition in each occurrence is independent of its definition at every other occurrence. 2 Thus, for example, if a group is substituted with 2 R 2 groups, then each R n is selected independently.

[0137] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a covalent bond.

[0138] When one of the variables is selected from a covalent bond, it indicates that the two groups to which it is attached are directly connected, such as L' represents a covalent bond in A-L'-Z indicates that the structure is actually A-Z.

[0139] The term "halo" or "halogen" means fluoro, chloro, bromo, and iodo.

[0140] The term "alkyl" means a hydrocarbon group of formula C n H 2n+1 , typically having from 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The alkyl group can be straight or branched, such as "C 1-12 alkyl" or "C 1-6 alkyl" and the like. For example, the term "C 1-12 alkyl" means an alkyl group containing from 1 to 12 carbon atoms, including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 alkyl groups and any range of combinations thereof. For example, the term "C 1-6"Alkyl" refers to an alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.) containing from 1 to 6 carbon atoms. Similarly, the alkyl portions of alkoxyl, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups (i.e., alkyl) have the same definition. For example, the term "C 1-3 "Alkyl" refers to an alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.) containing from 1 to 6 carbon atoms. Similarly, the alkyl portions of alkoxyl, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups (i.e., alkyl) have the same definition. For example, the term "C

[0141] The term "alkenyl" refers to a straight or branched chain, unsaturated aliphatic hydrocarbon group having at least one double bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms, for example, can be "C 2-12 "Alkenyl" or "C 2-6 "Alkenyl" or "C

[0142] The term "alkynyl" refers to a straight or branched chain, unsaturated aliphatic hydrocarbon group having at least one triple bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms, for example, can be "C 2-12 "Alkynyl" or "C 2-6 "Alkynyl" or "C

[0143] The term "alkoxy" refers to -O-alkyl.

[0144] The term "ring" refers to a carbocyclic or heteroatom-containing ring, including cycloalkyl, partially unsaturated carbocyclic ring, aromatic ring group, heterocycloalkyl, heterocyclic group, or heteroaromatic group.

[0145] The term "cycloalkyl" refers to a carbocyclic ring that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 20 membered ring, 3 to 15 membered ring, 3 to 10 membered ring, 4 to 8 membered ring, 5 to 8 membered ring, or 5 to 6 membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, bicyclo[1.1.1]pent-1-yl, etc. For example, C 3-4 Cycloalkyl includes cyclopropyl and cyclobutyl.

[0146] The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and has at least one double bond and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 5- to 20-membered ring, 5- to 15-membered ring, 5- to 10-membered ring, or 5- to 8-membered ring. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.

[0147] The term "cycloalkynyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and has at least one triple bond and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 5- to 20-membered ring, 5- to 15-membered ring, 5- to 10-membered ring, or 5- to 8-membered ring.

[0148] The term "carbocyclic" refers to a ring composed of carbon atoms only, with no involvement of heteroatoms, including aromatic rings, partially unsaturated carbocyclic rings, fully saturated carbocyclic rings (i.e., cycloalkyl), and the like.

[0149] The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not a fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 20-membered ring or 3- to 15-membered ring (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered), 4- to 8-membered ring, 5- to 8-membered ring, or 5- to 6-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron (preferably 1 or 2 heteroatoms). Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, and the like.

[0150] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and the hydrogen atoms attached thereto) are each independently replaced with the same or different heteroatom group, and can be "C 1-12 heteroalkyl" or "C 1-6 heteroalkyl" and the like. Unless otherwise indicated, the heteroalkyl group contains 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N, or NH. For example, the term "C 1-6 heteroalkyl" refers to a heteroalkyl group containing 1 to 6 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed at any position in the heteroalkyl group (e.g., internal or terminal positions), including the position that connects the alkyl group to the remainder of the molecule. Typically, where more than one heteroatom group is present, the heteroatoms are not adjacent to one another. Exemplary heteroalkyl groups include alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, and the like.

[0151] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged (including annelated), or spirocyclic ring. Unless otherwise indicated, the heterocycle typically contains 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron (preferably 1 or 2 heteroatoms), in a 3- to 20-membered ring, 3- to 15-membered ring, 3- to 10-membered ring, 5- to 10-membered ring, 3- to 7-membered ring, 4- to 8-membered ring, 5- to 8-membered ring, or 5- to 6-membered ring. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thiiranyl, aziridinyl, non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxinanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl. Preferred are monocyclic heterocycloalkyl groups having 5 or 6 ring atoms. The terms "heteroalkenyl", "heteroalkynyl" are defined analogously, wherein one or more carbon atoms (and the hydrogen atoms attached thereto) are each independently replaced with the same or different heteroatom group, can be "C 2-12 heteroalkenyl" or "C 2-6 heteroalkenyl" or "C 2-12 heteroalkenyl" or "C 2-6 heteroalkenyl" or "C

[0152] The term "heterocycloalkenyl" includes a cycloalkenyl group in which up to 3 carbon atoms, or up to 2 carbon atoms, or 1 carbon atom, is each independently replaced with boron, oxygen, S(O), or nitrogen, provided that at least one cycloalkenyl carbon-carbon double bond is preserved. The cyclic group can exist as a monocyclic, bridged, or spirocyclic ring, can be a 3- to 13-membered ring (e.g., 5- to 13-membered ring, 5- to 8-membered ring).

[0153] The terms "aryl", "aromatic ring group", "aromatic group", or "aromatic ring" refer to a fully carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi-electron system. For example, the aryl group or "aromatic ring" can have 6-20 carbon atoms, 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, and 1,2,3,4-tetrahydronaphthyl, and the like.

[0154] The term "heteroaryl" or "heteroaromatic" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 5- to 8-membered ring (e.g., 5-, 6-, 7-, or 8-membered), or multiple fused rings comprising 6 to 20, 6 to 14, and especially 6 to 10 ring atoms (e.g., 6, 7, 8, 9, or 10 ring atoms). Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, pyridopyrrolyl, and the like.

[0155] The term "alkylene" refers to a divalent radical resulting from the removal of one hydrogen from an alkyl group, e.g., the term "C 1-6 The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms; the term "C 1-4 The term "alkylene" refers to a divalent radical resulting from the removal of one hydrogen from an alkyl group, e.g., the term "C

[0156] The term "monocyclic" refers to a cyclic group containing one ring, which can be fully saturated, partially saturated, or aromatic. The monocyclic ring can consist entirely of C atoms, can contain one or more heteroatoms, e.g., selected from N, O, or S.

[0157] The term "bicyclic" or "bi-cyclic" refers to a cyclic group containing two rings, which can be fully saturated, partially saturated, or aromatic. The bicyclic ring can consist entirely of C atoms, can contain one or more heteroatoms, e.g., selected from N, O, or S. The bicyclic ring can be a fused ring, a bridged ring, or a spirocyclic ring.

[0158] The compounds of the disclosure can exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as racemic mixtures and other mixtures thereof, e.g., mixtures of enantiomers or diastereomers, all of which are intended to be within the scope of the present disclosure. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are included within the scope of the present disclosure.

[0159] Unless otherwise indicated, the use of a wavy line indicates an absolute configuration of a stereocenter, the use of a straight line bond and a dashed line bond indicates a relative configuration of a stereocenter, the use of a wavy line indicates a wavy line bond or a dashed line bond or a wavy line indicates a straight line bond and a dashed line bond

[0160] Unless otherwise indicated, when a compound contains a double bond, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom of the double bond is attached to two different substituents (in the case of a double bond involving a nitrogen atom, a pair of lone electrons on the nitrogen atom is considered to be a substituent), if the atoms of the double bond and their substituents are connected by a wavy line , then the (Z) isomer, the (E) isomer, or a mixture of the two isomers of the compound is indicated.

[0161] The term "treatment" means the administration of a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0162] (i) inhibiting the disease or condition, i.e., arresting its development;

[0163] (ii) relieving the disease or condition, i.e., causing regression of the disease or condition.

[0164] The term "prevention" means the administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes: preventing the disease or condition from occurring in a subject that is predisposed to the disease or condition, but has not yet been diagnosed with the disease or condition.

[0165] The term "therapeutically or prophylactically effective amount" means an amount of a compound of the disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of the disclosure that will constitute a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by the skilled practitioner as an initial guess of an appropriate amount of the compound to be administered.

[0166] The term "pharmaceutically acceptable" pertains to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0167] As the pharmaceutically acceptable salt, for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like can be mentioned.

[0168] The term "pharmaceutical composition" means a mixture of one or more compounds of the disclosure or salts thereof with a pharmaceutically acceptable excipient. The objective of a pharmaceutical composition is to facilitate administration of a compound of the disclosure to an organism.

[0169] The term "pharmaceutically acceptable excipient" means an excipient that is not biologically or otherwise undesirable, i.e., the excipient can be administered to an organism without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The presence of an excipient in a composition does not imply that the excipient is intended to be in any way therapeutic or prophylactic.

[0170] The words "comprise" or "comprising" and variations thereof such as "comprises" or "comprising", when used in relation to a list of items or steps, are to be interpreted as "including but not limited to".

[0171] The compounds and intermediates of the disclosure can also exist in different tautomeric forms and all such forms are embraced within the scope of the disclosure. The term "tautomer" or "tautomeric forms" refers to different energy structures that can interconvert via a low energy barrier. For example, prototropic tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of prototropic tautomers is the imidazole moiety, wherein a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0172] The present disclosure also includes isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl, and the like. For example, it is understood that compounds of the present disclosure wherein one or more hydrogen atoms are replaced by deuterium atoms are within the scope of the present disclosure.

[0173] Certain isotopically-labeled compounds of the present disclosure, for example those 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Generally, isotopically-labeled compounds of the present disclosure can be prepared by substituting isotopically-labeled reagents for non-isotopically labeled reagents in the procedures disclosed in the Schemes and / or Examples set forth below.

[0174] Moreover, substitution with heavier isotopes such as deuterium (i.e. 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence can be preferred in some circumstances. Deuterium substitution can be partial or total. Partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium. All such forms of compounds are included within the scope of the present disclosure.

[0175] The compounds of the present disclosure can be asymmetric, e.g., having one or more stereocenters. Unless otherwise indicated, all stereoisomers, including enantiomers and diastereomers, are included within the scope of the present disclosure. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically active form or as racemic mixtures. Optically active forms can be obtained, for example, by resolution of a racemic mixture or by synthesis from an optically active starting material or reagent.

[0176] The pharmaceutical compositions of the present disclosure can be prepared by combining a compound of the present disclosure with suitable pharmaceutically acceptable excipients.

[0177] The pharmaceutical compositions of the present disclosure can be manufactured in a manner appropriate to the type of composition by methods known to those skilled in the art, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing processes, and the like.

[0178] The therapeutic dosage of a compound of the present disclosure can be determined by, for example, the particular use for which the treatment is made, the manner and route of administration, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present disclosure in a pharmaceutical composition can not be fixed, but can vary with a variety of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the type of delivery. For example, a compound of the present disclosure can be provided in an aqueous physiological buffer at concentrations from about 0.1 to 10% w / v for parenteral injection. Some typical dosages range from about 1 μg / kg to about 1 g / kg body weight / day. In certain embodiments, the dosage ranges from about 0.001 mg / kg to about 1000 mg / kg body weight / day. The dosage will likely depend on such variables as the type and extent of progression of the disease or disorder, the general health and age of the particular patient, the relative biological efficacy of the compound selected, the excipient formulation employed, and the route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0179] The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining other synthetic methods with the embodiments set forth below, and equivalents thereof as appreciated by those skilled in the art, preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0180] The chemical reactions of the specific embodiments of the present disclosure are performed in solvents appropriate to the reagents and materials employed and suitable for the chemical changes being effected. In the synthetic schemes and examples described below, all substituents unless otherwise indicated are as previously defined. Further, the skilled worker will appreciate that the application is not limited by the method of synthesis or the specific conditions employed in the schemes and examples, but rather the scope of the application extends to the total family of compounds disclosed and to all methods and conditions described in the art for the preparation of such compounds.

[0181] One important consideration in the synthetic route planning in the art is the selection of appropriate protecting groups for reactive functional groups, such as amino groups in the present disclosure, for example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0182] In some embodiments, the compounds of the present disclosure can be prepared by one skilled in the art of organic synthesis with reference to the following routes:

[0183] wherein, P is selected from H or common protecting groups such as Boc and the like; X a are each independently selected from halogen and the like; alkyl represents C 1-10 alkyl (e.g. C 1-6 alkyl);

[0184] R 1 , R 2 , n, X 1 , X 2 , X 3 , X 4 , L, ring A, ring B, ring C, R 3 , m, R 4 , q, R 5 , p are as described herein.

[0185] The following abbreviations are used in the present application:

[0186] DMF stands for N,N-dimethylformamide; DMAP stands for 4-dimethylaminopyridine; DCM stands for dichloromethane, TFA stands for trifluoroacetic acid.

[0187] For the purpose of clarity, the present application is further illustrated by examples, but the examples are not intended to limit the scope of the present application. All reagents used in the present application are commercially available and used without further purification. DETAILED DESCRIPTION

[0188] Example 1: Compound 1

[0189] 1) Preparation method of compound 1-a:

[0190] Compound 1-a-1 (200 mg), di-tert-butyl dicarbonate (208 mg), DMAP (11 mg), triethylamine (175 mg) and DCM (10 mL) were added to a reaction bottle, and the reaction was stirred at room temperature for 8 h. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to obtain compound 1-a (280 mg). ESI-MS: m / z = 330.84 [M+H] + .

[0191] 2) Preparation method of compound 1-b:

[0192] Compound 1-a (280 mg), cyclopropylacetylene (464 mg), tetraphenylphosphonium palladium (203 mg), cuprous iodide (2.5 mg), triethylamine (144 mg) and DMF (10 mL) were added to a reaction bottle, and the reaction was stirred at 50°C under nitrogen protection for 16 h. The reaction solution was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain compound 1-b (240 mg). ESI-MS: m / z = 317.07 [M+H] + .

[0193] 3) Preparation method of compound 1-c:

[0194] Compound 1-b (240 mg), DCM (20 mg), TFA (10 mL) were added to a reaction bottle, and the reaction was stirred at room temperature for 8 h. The reaction solution was concentrated under reduced pressure, and the concentrate was slurried with ethyl acetate (5 mL) to obtain compound 1-d (100 mg). ESI-MS: m / z = 217.10 [M+H] + .

[0195] 4) Preparation method of compound 1-d:

[0196] The preparation method of compound 1-d can be prepared according to the method of Intermediate G in document WO2022259204A1.

[0197] 5) Preparation method of compound 1:

[0198] Compound 1-c (30 mg), compound 1-d (40 mg), pyridine (5 mL) were added to a reaction bottle, and phosphorus oxychloride (100 mg) was added under stirring at -10°C, and the reaction was carried out for 1 h, and then heated to room temperature for 3 h. The reaction solution was quenched by adding water (1 mL), concentrated under reduced pressure, and purified by HPLC to obtain compound 1 (3 mg).

[0199] ESI-MS: m / z = 477.14 [M+H] + .

[0200] 1 H NMR (500 MHz, MeOD) δ 8.90 (s, 1H), 8.51 (s, 1H), 8.08 (s, 1H), 7.53 (s, 1H), 7.44 (s, 1H), 3.72 (s, 3H), 2.70 (s, 3H), 1.60 (tt, J = 8.2, 5.0 Hz, 1H), 1.05 - 0.97 (m, 2H), 0.92 - 0.83 (m, 2H).

[0201] Example 2: Compound 2

[0202] 1) Preparation method of compound 2-b:

[0203] Compound 2-a (100 mg), anhydrous dichloromethane (10 mL), oxalyl chloride (1 mL) and 1 drop of DMF were added to a reaction bottle, the reaction was stirred at room temperature for 3 h until the reaction was complete, and the reaction solution was concentrated under reduced pressure. The concentrate was added to 5 mL of anhydrous dichloromethane and concentrated under reduced pressure to obtain compound 2-b (100 mg).

[0204] 2) Preparation method of compound 2:

[0205] Compound 1-c (72 mg), anhydrous dichloromethane (5 mL) and triethylamine (0.5 mL) were added to a reaction bottle, and a solution of compound 2-b (100 mg) in anhydrous dichloromethane (10 mL) was added dropwise to the reaction system at room temperature. After dropping, it was moved to 38°C and stirred for 12 h. The reaction solution was concentrated under reduced pressure, and the concentrate was purified by HPLC to obtain compound 2 (20 mg).

[0206] ESI-MS: m / z = 559.21 [M+H] + .

[0207] 1 H NMR (500 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.65 (s, 1H), 8.50 (s, 1H), 7.96 (s, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.82 (s, 1H), 7.15 - 6.90 (m, 2H), 3.96 (s, 3H), 3.73 (s, 3H), 1.66 (ddd, J = 8.3, 5.0, 3.3 Hz, 1H), 1.04 - 0.95 (m, 2H), 0.91 - 0.79 (m, 2H).

[0208] Example 3: Compound 3

[0209] 1) Preparation method of compound 3-a:

[0210] To a flask, 5-amino-2-bromo-3-fluoropyridine (3 g), di-tert-butyl dicarbonate (3.766 g), DMAP (192 mg) and triethylamine (3.17 g) were added in anhydrous dichloromethane (100 mL), and the reaction was stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and purified by column chromatography to obtain compound 1-a (3.4 g). ESI-MS: m / z = 291.00 [M+H] + .

[0211] 2) Preparation method of compound 3-b:

[0212] To a flask, compound 3-a (200 mg), cyclopropylacetylene (0.45 mL), tetraphenylphosphonium palladium (159 mg), cuprous iodide (26 mg), triethylamine (485 mg) and DMF (10 mL) were added, and the reaction was stirred at 50°C under nitrogen protection for 12 hours. The reaction solution was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain compound 3-b (200 mg). ESI-MS: m / z = 277.11 [M+H] + .

[0213] 3) Preparation method of compound 3-c:

[0214] To a flask, compound 3-b (350 mg), tetramethylethylenediamine (441 mg), anhydrous tetrahydrofuran were added, and the reaction solution was cooled to -65°C under nitrogen protection, and n-butyllithium (1.6 M, 1.52 mL) was added dropwise. After the dropwise addition was completed, the temperature was slowly increased to -20°C, and the reaction was allowed to proceed for 1.5 hours. The temperature was lowered to -65°C, 1,2-dibromotetrafluoroethane (989 mg) was added dropwise, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched by adding 1 M aqueous hydrochloric acid solution, and the pH of the system was adjusted to neutral with saturated sodium bicarbonate solution. The reaction solution was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and purified by column chromatography to obtain compound 3-c (100 mg). ESI-MS: m / z = 355.10 [M+H] + .

[0215] 4) Preparation method of compound 3-d:

[0216] Compound 3-c (200 mg), dichloromethane (10 mL) and trifluoroacetic acid (5 mL) were added to a reaction bottle, and the reaction was stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, dissolved with ethyl acetate, and the pH of the system was adjusted to neutral with saturated aqueous sodium bicarbonate solution. The organic phase was combined after being washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. Compound 3-d (90 mg) was obtained by trituration. ESI-MS: m / z = 254.90 [M+H] + .

[0217] 5) Preparation method of compound 3-e:

[0218] Compound 3-d (90 mg) and 9-fluorenylmethoxycarbonyl isothiocyanate (190 mg) were added to acetone (20 mL), and the reaction was stirred at 50°C for 4 hours. Filtration and concentration to dryness of the filter cake gave compound 3-e (120 mg). ESI-MS: m / z = 456.19 [M+H] + .

[0219] 6) Preparation method of compound 3-f:

[0220] Compound 3-e (70 mg) and triethylamine (0.5 mL) were added to dioxane (5 mL) in a reaction bottle, and the reaction was stirred at 50°C for 4 hours. Filtration and concentration to dryness of the filter cake gave compound 3-f (30 mg). ESI-MS: m / z = 234.00 [M+H] + .

[0221] 7) Preparation method of compound 3:

[0222] Referring to Example 1, Step 5), compound 3-f was used instead of 1-c to obtain compound 3.

[0223] ESI-MS: m / z = 494.10 [M+H] + .

[0224] 1 H NMR (500 MHz, MeOD-d4) δ 8.86 (s, 1H), 8.75 (d, J = 1.5 Hz, 1H), 8.09 (s, 1H), 7.55 (s, 1H), 7.48 (s, 1H), 3.70 (s, 3H), 2.71 (s, 3H), 1.62 (dt, J = 8.3, 3.6 Hz, 1H), 1.06-0.97 (m, 2H), 0.90-0.85 (m, 2H).

[0225] Example 4: Compound 4

[0226] Preparation method of compound 2-a:

[0227] Reference Example 1, step 5) using compound 2-a instead of 1-d and 3-f instead of 1-c to give compound 4.

[0228] ESI-MS: m / z = 576.17 [M+H] + .

[0229] 1 H NMR (500 MHz, DMSO-d6) δ 13.62 (s, 1H), 9.00 (s, 1H), 8.88 (d, J = 1.8 Hz, 1H), 8.49 (s, 1H), 7.96 (s, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.82 (s, 1H), 7.02 (t, J = 55.1 Hz, 1H), 6.98 (d, J = 2.3 Hz, 1H), 3.96 (s, 3H), 3.70 (s, 3H), 1.83 - 1.59 (m, 1H), 1.18 - 0.94 (m, 2H), 0.91 - 0.67 (m, 2H).

[0230] Example 5: Compound 5

[0231] 1) Preparation method of compound 5-a:

[0232] Compound 1-d (5 g), 2-amino-6-bromothiazolo[4,5-b]pyrazine (4.1 g), 1- methylimidazole (4.4 g) were added into acetonitrile (50 mL) and DMF (30 mL), and the temperature was raised to 70 °C. A solution of N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (5 g) in acetonitrile was added dropwise slowly. After the dropwise addition was completed, the reaction was stirred at 70 °C for 1 h. 1-Methylimidazole (4.4 g) was added, and a solution of N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (5 g) in acetonitrile was added dropwise slowly. After the dropwise addition was completed, the reaction was stirred at 70 °C for 1 h. The temperature was lowered to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was slurried to give compound 5-a (5 g). ESI-MS: m / z = 491.00 [M+H] + .

[0233] 2) Preparation method of compound 5:

[0234] Compound 5-a (60 mg), 4-chlorophenylacetylene (20 mg), tetrakis(triphenylphosphine)palladium (14 mg), cuprous iodide (5 mg), triethylamine (25 mg) and DMF (3 mL) were added into a reaction bottle, and the reaction was stirred at 50 °C for 12 h under nitrogen protection. The reaction solution was concentrated under reduced pressure, and purified by HPLC to give compound 5 (24 mg).

[0235] ESI-MS: m / z = 547.04 [M+H] + .

[0236] 1 H NMR (500 MHz, DMSO-d6) δ 13.63 (s, 1H), 8.89 (d, J = 8.4 Hz, 2H), 8.19 (s, 1H), 7.70 (d, J = 8.5 Hz, 2H), 7.62 (s, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.50 (s, 1H), 3.64 (s, 3H), 2.62 (s, 3H).

[0237] Example 6: Compound 6

[0238] 1) Preparation of compound 6-a:

[0239] Referring to Example 5, Step 1), replacing 1-d with compound 2-a, compound 6-a was obtained.

[0240] 2) Preparation of compound 6:

[0241] Referring to Example 5, Step 2), replacing 5-a with compound 6-a, compound 6 was obtained.

[0242] ESI-MS: m / z = 629.22 [M+H] + .

[0243] Example 7: Compound 7

[0244] Preparation of compound 7:

[0245] Referring to Example 5, Step 2), replacing 4-chlorophenylacetylene with rel-((1S,2R)-2-ethynylcyclopropyl)methanol, compound 7 was obtained.

[0246] ESI-MS: m / z = 507.16 [M+H] + .

[0247] 1 H NMR (500 MHz, DMSO-d6) δ 13.53 (s, 1H), 8.88 (s, 1H), 8.64 (s, 1H), 8.18 (s, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 4.72 (s, 1H), 3.62 (s, 3H), 3.48 (d, J = 9.3 Hz, 1H), 2.61 (s, 3H), 1.51 (ddt, J = 29.8, 10.2, 5.0 Hz, 2H), 1.04 - 0.90 (m, 2H).

[0248] Example 8: Compound 8

[0249] 1) Preparation method of compound 8-a:

[0250] Compound 7 (20 mg), triethylamine (8 mg), 4-dimethylaminopyridine (3 mg) were added into anhydrous dichloromethane (3 mL), and p-toluenesulfonyl chloride (10 mg) was slowly added. After addition, the reaction was stirred at room temperature for 2 hours. Water was added for quenching, dichloromethane was used for extraction, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give compound 8-a (22 mg). ESI-MS: m / z = 661.19 [M+H] + .

[0251] 2) Preparation method of compound 8:

[0252] Compound 8-a (22 mg) was added into dimethyl sulfoxide (3 mL), and sodium borohydride (20 mg) was added. The reaction was stirred at 80 °C under nitrogen protection for 10 minutes. After quenching with water, compound 8 (5 mg) was obtained by HPLC purification.

[0253] ESI-MS: m / z = 491.11 [M+H] + .

[0254] 1 H NMR (500 MHz, MeOD-d4) δ 8.86 (s, 1H), 8.51 (s, 1H), 8.07 (s, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 3.71 (s, 3H), 2.69 (s, 3H), 1.60 (t, J = 7.4 Hz, 1H), 1.28-1.25 (m, 1H), 1.16 (d, J = 5.7 Hz, 3H), 1.04 (dt, J = 8.1, 4.7 Hz, 1H), 0.77 (ddd, J = 8.3, 6.2, 4.3 Hz, 1H).

[0255] Example 9: Compound 9

[0256] Preparation method of compound 9:

[0257] Referring to Example 5, step 2), 1-ethyl-1-ethynylcyclopropane was used to replace 4-chlorophenylacetylene to give compound 9.

[0258] ESI-MS: m / z = 505.13 [M+H] + .

[0259] 1H NMR (500 MHz, MeOD-d4) δ 8.87 (s, 1H), 8.56 (s, 1H), 8.10 (s, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 3.73 (s, 3H), 2.71 (s, 3H), 1.54 (q, J = 7.3 Hz, 2H), 1.19 (t, J = 7.3 Hz, 3H), 1.08 (q, J = 4.2 Hz, 2H), 0.89 - 0.60 (m, 2H).

[0260] Example 10: Compound 10

[0261] Process for preparing compound 10:

[0262] Referring to Example 5, Step 2), replace 4-chlorophenylacetylene with 3- ethynyl-3-methyloxetane to obtain compound 10.

[0263] ESI-MS: m / z = 507.09 [M+H] + .

[0264] 1 H NMR (500 MHz, MeOD-d4) δ 8.87 (s, 1H), 8.56 (s, 1H), 8.10 (s, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 3.73 (s, 3H), 2.71 (s, 3H), 1.54 (q, J = 7.3 Hz, 2H), 1.19 (t, J = 7.3 Hz, 3H), 1.08 (q, J = 4.2 Hz, 2H), 0.89 - 0.60 (m, 2H).

[0265] Example 11: Compound 11

[0266] Process for preparing compound 11:

[0267] Referring to Example 5, Step 2), replace 4-chlorophenylacetylene with 4- ethynyl-1-methylpiperidine to obtain compound 11.

[0268] ESI-MS: m / z = 534.20 [M+H] + .

[0269] 1 H NMR (500 MHz, MeOD-d4) δ 8.87 (s, 1H), 8.56 (s, 1H), 8.10 (s, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 3.73 (s, 3H), 2.71 (s, 3H), 1.54 (q, J = 7.3 Hz, 2H), 1.19 (t, J = 7.3 Hz, 3H), 1.08 (q, J = 4.2 Hz, 2H), 0.89 - 0.60 (m, 2H).

[0270] Example 12: Compound 12

[0271] Preparation method of compound 12:

[0272] Reference Example 5, step 2), using 4-ethynyl-2,2-dimethyltetrahydro-2H-pyran instead of 4-chlorostyrene, to give compound 12.

[0273] ESI-MS: m / z = 549.12 [M+H] + .

[0274] 1 H NMR (500 MHz, CDCl3-d) δ 10.79 (s, 1H), 8.92 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.18 (d, J = 13.5 Hz, 2H), 3.86 - 3.75 (m, 3H), 3.77 - 3.51 (m, 3H), 2.97 (tt, J = 11.7, 3.9 Hz, 1H), 2.69 (s, 2H), 1.90 (dddd, J = 22.2, 13.3, 4.0, 1.9 Hz, 2H), 1.79 - 1.65 (m, 2H), 1.26 (d, J = 18.9 Hz, 6H).

[0275] Example 13: Compound 13

[0276] 1) Preparation method of compound 13-a:

[0277] Methyl 4-chloro-6-methoxynicotinate (500 mg), 2-chloro-5-methoxypyridine-4- boronic acid (463 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (362 mg), potassium carbonate (1.02 g) and dioxane (30 mL), water (3 mL) were added into a reaction flask, stirred at 100 °C for 3 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, extracted with ethyl acetate, the combined organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by column chromatography to give compound 13-a (210 mg). ESI-MS: m / z = 309.00 [M+H] + .

[0278] 2) Preparation method of compound 13-b:

[0279] Compound 13-a (210 mg), lithium hydroxide monohydrate (33 mg) and tetrahydrofuran (6 mL), water (2 mL) were added into a reaction bottle, the reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, purified by HPLC to obtain 13-b (150 mg). ESI-MS: m / z = 294.97 [M+H] + .

[0280] 3) Preparation method of compound 13:

[0281] Compound 13-b (100 mg), compound 1-c (73 mg), N-methyl imidazole (84 mg), acetonitrile (10 mL), DMF (2 mL) were added into a reaction bottle, and N,N,N',N'-tetramethylchloroformamidum hexafluorophosphate (95 mg) in acetonitrile was slowly added dropwise under stirring at 70°C, after dropping, the reaction was stirred at 70°C for 1 hour. The reaction solution was concentrated under reduced pressure, purified by HPLC to obtain compound 13 (15 mg).

[0282] ESI-MS: m / z = 493.08 [M+H] + .

[0283] 1 H NMR (500 MHz, DMSO-d6) δ 13.45 (s, 1H), 8.65 (d, J = 18.6 Hz, 2H), 8.17 (s, 1H), 7.59 (s, 1H), 7.02 (s, 1H), 3.99 (s, 3H), 3.63 (s, 3H), 1.66 (s, 1H), 1.03-0.95 (m, 2H), 0.89-0.79 (m, 2H).

[0284] Example 14: Compound 14

[0285] Preparation method of compound 14:

[0286] Referring to Example 13 step 3), compound 3-f was used to replace compound 1-c to obtain compound 14.

[0287] ESI-MS: m / z = 510.08 [M+H] + .

[0288] Example 15: Compound 15

[0289] 1) Preparation method of compound 15-a:

[0290] Compound 5-a (50 mg), N-bromosuccinimide (20 mg), benzoyl peroxide (5 mg) and acetonitrile (5 mL) were added to a reaction bottle, stirred at 75 °C for 3 hours under the condition of nitrogen protection. Slowly add aqueous ammonium chloride solution, extract with ethyl acetate, combine the organic phase, wash with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to obtain compound 15-a (52 mg). ESI-MS: m / z = 568.81 [M+H] + .

[0291] 2) Preparation method of compound 15-b:

[0292] Compound 15-a (52 mg), 7-oxo-2-azaspiro[3.5]nonane (25 mg), cesium carbonate (100 mg) and DMF (3 mL) were added to a reaction bottle, stirred at room temperature for 4 hours, extracted with ethyl acetate, combined the organic phase, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated the filtrate to obtain compound 15-b (45 mg). ESI-MS: m / z = 616.02 [M+H] + .

[0293] 3) Preparation method of compound 15:

[0294] Compound 15-b (45 mg), cyclopropylacetylene (48 mg), tetraphenylphosphonium palladium (24 mg), cuprous iodide (4 mg), triethylamine (72 mg) and DMF (5 mL) were added to a reaction bottle, stirred at 50 °C for 16 hours under the condition of nitrogen protection. The reaction solution was concentrated under reduced pressure, purified by HPLC to obtain compound 15 (5 mg).

[0295] ESI-MS: m / z = 602.14 [M+H] + .

[0296] Example 16: Compound 16

[0297] 1) Preparation method of compound 16-a:

[0298] Referring to Example 15 step 2), replace 7-oxo-2-azaspiro[3.5]nonane with 8-oxa-2-azaspiro[4.5]decane to obtain compound 16-a. ESI-MS: m / z = 632.09 [M+H] + .

[0299] 2) Preparation method of compound 16:

[0300] Referring to Example 15 step 3), replace compound 15-b with compound 16-a to obtain compound 16.

[0301] ESI-MS: m / z = 616.19 [M+H] + .

[0302] Example 17: Compound 17

[0303] 1) Preparation method of compound 17-a:

[0304] Reference Example 15, step 2), replace 7-oxo-2-azaspiro[3.5]nonane with 2- azaspiro[3.3]heptane to obtain compound 17-a. ESI-MS: m / z = 585.99 [M+H] + .

[0305] 2) Preparation method of compound 17:

[0306] Reference Example 15, step 3), replace compound 15-b with compound 17-a to obtain compound 17.

[0307] ESI-MS: m / z = 572.20 [M+H] + .

[0308] Example 18: Compound 18

[0309] 1) Preparation method of compound 18-a:

[0310] Potassium carbonate (491.3 mg), molecular sieve (500 mg) were added to the reaction bottle, replaced with nitrogen for three times, stirred at 0 °C, added dropwise 1- methylcyclopentane-1-carboxaldehyde (200 mg) in methanol (30 mL), after dropwise, slowly added (1-diazo-2-oxopropyl) dimethyl phosphonate (410.3 mg), slowly increased to room temperature, stirred for 12 hours. Filtered, extracted with ethyl acetate and water, washed with saturated aqueous sodium chloride solution, combined the organic phase, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-a.

[0311] 2) Preparation method of compound 18:

[0312] Reference Example 5, step 2), replace 4-chlorophenylacetylene with compound 18-a to obtain compound 18.

[0313] ESI-MS: m / z = 519.16 [M+H] + .

[0314] Experimental Example 1: POLQ protein inhibitory activity assay

[0315] PolQ ssDNA configuration: 2 uL of 100 mM Oligonucleotide 1 and 2 uL of 100 mM Oligonucleotide 2 with 2 uL of 100 mM Oligonucleotide 3 in annealing buffer. 10 uL aliquot was heated to 95 °C in a heat block for 5 min, then the heat block was turned off and the reaction was allowed to cool to room temperature.

[0316] Oligonucleotide 1: 5'-GCACTGGCCGTCGTTTTACGGTCGTGACTGGGAAAACCCTGGCG-3'

[0317] Oligonucleotide 2: 5'-TTTTTTTTTTTTTTTTTTTTTTCCAAGTAAAACGACGGCCAGTGC-3'

[0318] Oligonucleotide 3: 5'-TTGGAAAAAAAAAAAAAAAAAAAAAA-3'

[0319] POLQ (1-894) protein solution (concentration 1 nM) was added to the detection hole at 5 uL per hole, and different compounds dissolved in DMSO were added to the detection hole by nanoliter injector, so that the final concentration of the compound was 1000 nM-0.244 nM, 2 duplicate holes, and controls were set, and incubated at room temperature for 15 minutes. After mixing 400 nM ATP and 80 nM ssDNA, 5 uL per hole was added to the detection hole, and the above system was incubated for 180 minutes. ADP-Glo reagent (manufacturer: Promega) was added to the detection hole at 5 uL per hole, and incubated at room temperature for 60 min. Kinase Detection reagent (manufacturer: Promega) was added to each hole at 10 uL, and incubated at room temperature for 60 min. Envision multifunctional enzyme label instrument was used for luminescence module detection, four-parameter fitting was used, and IC50 was calculated. The test results are shown in Table 1.

[0320] Table 1

[0321] Experimental Example 2 In vitro cell proliferation inhibition activity

[0322] 2.1 MDA-MB-436 WT cell proliferation inhibition activity determination

[0323] MDA-MB-436WT cells in good growth state were collected into centrifuge tubes, the cell density was adjusted to 5 x 103 / mL, inoculated into 96-well plates (100 μL / well), and cultured in a cell incubator overnight. Compound addition was performed using a nanoliter injector, DMSO was used as a solvent, the final concentration of the compound was 10000 nM-0.6 nM, two duplicate wells were set up, and controls were set up at the same time. After 7 days of continuous culture in a cell incubator, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added, and the cells were incubated in a cell incubator for 2 hours. The absorbance was detected at 450 nm by Envision microplate reader. Four-parameter analysis was performed, the dose-effect curve was fitted, and the IC50 was calculated. 50 The test results are shown in Table 2.

[0324] Table 2

[0325] 2.2 MDA-MB-436(SHLD2- / -) cell proliferation inhibition activity determination

[0326] MDA-MB-436(SHLD2- / -) cells in good growth state were collected into centrifuge tubes, the cell density was adjusted to 5 x 103 / mL, inoculated into 96-well plates (100 μL / well), and cultured in a cell incubator overnight. Compound addition was performed using a nanoliter injector, DMSO was used as a solvent, the final concentration of the compound was 10000 nM-0.6 nM, two duplicate wells were set up, and controls were set up at the same time. After 7 days of continuous culture in a cell incubator, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added, and the cells were incubated in a cell incubator for 2 hours. The absorbance was detected at 450 nm by Envision microplate reader. Four-parameter analysis was performed, the dose-effect curve was fitted, and the IC50 was calculated. 50 The test results are shown in Table 3.

[0327] Table 3

[0328] Example 3 In vitro liver microsomal stability evaluation

[0329] The liver microsomal incubation sample was prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / ml), and test compound and NADPH+MgCl2solution, and incubated at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / ml), and test compound. The sample was added to an internal standard acetonitrile solution, and the supernatant was prepared by protein precipitation. After dilution, it was used for LC / MS / MS determination.

[0330] The experimental results show that the compound of the present disclosure has good in vitro liver microsomal stability.

[0331] In vivo pharmacokinetics of Experimental Example 4

[0332] Mouse pharmacokinetics

[0333] ICR mice, weighing 18-22 g, were randomly divided into groups of 9 after 3-5 days of acclimation, and were administered intravenously at a dose of 1 mg / kg and orally at a dose of 3 mg / kg.

[0334] Blood was collected at time points of 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h, and orbital blood was prepared to obtain the test plasma samples.

[0335] 20 μL of the test plasma sample and the standard sample were taken, and acetonitrile solution was added to precipitate the proteins to obtain supernatant, which was diluted and used for LC / MS / MS determination.

[0336] Non-compartmental models were used to fit the pharmacokinetic parameters.

[0337] The experimental results show that the compound of the present disclosure has good in vivo pharmacokinetic properties.

[0338] In vivo efficacy evaluation of Experimental Example 5

[0339] SPF female nude mice (source: Huacheng Xinnuo) were inoculated subcutaneously with MDA-MB-436 SHLD- / - cells in the right axillary fossa at a dose of 1×10 7 / each. When the average tumor volume reached 100-200 mm 3 , the animals were grouped.

[0340] The day of grouping was day 0, and administration was performed once daily starting from day 0. The tumor volume was measured 2-3 times per week, and the mice were weighed, and the data were recorded; the general performance of the mice was observed and recorded daily. After the experiment, the tumors were stripped and weighed, and photographs were taken.

[0341] The detection indexes and calculation formulas are as follows:

[0342] Tumor volume, TV (mm 3 ) = 1 / 2 × (a × b 2 ); wherein a is the long diameter of the tumor, and b is the short diameter of the tumor.

[0343] Relative tumor volume, RTV = TV t / TV0; wherein TV0 is the tumor volume on day 0, and TV t is the tumor volume at each measurement.

[0344] Relative tumor proliferation rate, T / C (%) = T RTV / C RTV × 100%; wherein T RTVRTV; C RTV RTV for the vehicle control group.

[0345] Tumor growth inhibition rate, TGI (%) = (1-TW / TW0) x 100%; wherein, TW is the tumor weight of the treatment group, and TW0 is the tumor weight of the vehicle control group.

[0346] Body weight change rate, WCR (%) = (Wt t -Wt0) / Wt0 x 100%; wherein, Wt0 is the body weight of the mouse on day 0, and Wt t is the body weight of the mouse at each measurement.

[0347] The experimental results show that the compound of the present disclosure has good in vivo efficacy.

Claims

a compound of Formula I, or a pharmaceutically acceptable salt thereof: wherein, R 1 is selected from H, D, CN, NH2, OH, CHO, COOH, halogen, or the following groups optionally substituted with one or more substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; X 1 , X 2 , X 3 and X 4 are each independently selected from CH or N; each R 2 , R 3 , R 4 , R 5 is independently selected from D, CN, halogen or the following groups optionally substituted with one or more substituents: C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 5-12 membered heteroaryl, C 6-12 aryl, -OR a , -NR a R b , -SR a , -S(O)R a , -SO2R a , -SO2NR a R b , -N(R a )SO2R b , -C(O)R a , -CO2R a , -OC(O)R a , -C(O)NR a R b , or -N(R a )C(O)R b ; n is selected from 0, 1, or 2; m is selected from 0, 1, 2, 3, 4, or 5; q is selected from 0, 1, 2, or 3; p is selected from 0, 1, 2, 3, 4, or 5; each R a and R b are each independently selected from H, D, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, 5-10 membered heteroaryl, or C 6-10 aryl, said C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, 5-10 membered heteroaryl, or C 6-10 aryl is optionally substituted with one or more groups selected from D, OH, NH2, CN, or halogen; L is selected from C 2-6 alkylene or OC 1-4 alkylene; Ring A is selected from C 3-15 cycloalkyl, C 6-15 aryl, 3-15 membered heterocycloalkyl, 3-15 membered heterocycloalkenyl, or 5-10 membered heteroaryl; Ring B is selected from C 6-15 aryl or 5-10 membered heteroaryl; Ring C is selected from C 6-15 aryl or 5-10 membered heteroaryl. The compound of claim 1, or a pharmaceutically acceptable salt thereof, R 1 is selected from H, D, CN, NH2, OH, CHO, COOH, halogen, or the following groups optionally substituted with one or more substituents: C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; Or, R 1 Selected from H, D, CN, NH2, OH, CHO, COOH, halogen, or optionally substituted with one or more substituents: methyl, ethyl, propyl, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-6 membered heterocyclic groups. or R 1 selected from H. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, X 1 and X 4 is selected from N, X 2 and X 3 is selected from CH; or X 3 is selected from N, X 1 , X 2 and X 4 is selected from CH; or X 1 is selected from N, X 2 , X 3 and X 4 is selected from CH. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, R 1 , R 2 , R 3 , R 4 , and R 5 "substituents" described in R', each R' is independently selected from the group consisting of CN, halogen, cyano, =0, or, optionally substituted with one or more groups selected from halogen (e.g. F, Cl, Br or I), OH, NH2or CN: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, 5-10 membered heteroaryl, C 6-10 aryl, -OR e , R e R f NH-, R e S-, -S(O)R e , -SO2R e , -SO2NR e R f , -NR e SO2R f , R e C(O)-, -CO2R e , -OC(O)R e , R e R f NC(O)- or R f C(O)NR e -, each R e and R f are each independently selected from H, D, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, 5-10 membered heteroaryl, or C 6-10 aryl; or each R 2 , R 3 , R 4 , R 5 is independently selected from CN, halogen, or the following groups optionally substituted with one or more R' substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, C 6-9 aryl, -NR a R b , -S(O)R a , -SO2R a , -SO2NR a R b , -N(R a )SO2R b , -C(O)R a , -CO2R a , -OC(O)R a , -C(O)NR a R b , or -N(R a )C(O)R b ; or each R 2 , R 3 , R 4 , R 5 is independently selected from F, Cl, or the following groups optionally substituted with one or more R' substituents: methyl, ethyl, propynyl, CH3O-, C 1-2 alkyl-NH-, (C 1-2 alkyl)2N-, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, dihydropyridinyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, or pyridazinyl; or each R' is selected from CN, halogen (e.g., F, CI, Br, or I), OH, NH2, =0, CHO, COOH, NH2C(O)-, or, optionally substituted with one or more groups selected from halogen (e.g., F, CI, Br, or I), OH, NH2, or CN: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkylO-, C 1-3 alkylNH-, (C 1-3 alkyl)2N-, C 3-6 cycloalkyl, 6-10 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, C 6-9 aryl, -S(O)C 1-3 alkyl, -SO2C 1-3 alkyl, -SO2NHC 1-3 alkyl, -NHSO2C 1-3 alkyl, C 3-6 cycloalkylC(O)-, 3-6 membered heterocycloalkylC(O)-, (C 1-3 alkyl)2NC(O)-, C 1-3 alkylC(O)-, C 1-3 alkylCO2-, C 1-3 alkylOC(O)-, -C(O)NHC 1-3 alkyl or -NHC(O)C 1-3 alkyl; or each R e and R f are each independently selected from H, D, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, or C 6-10 aryl; or each R is independently selected from H, D, C e and R is independently selected from H, D, C f each independently selected from H, D, C 1-3 alkyl or 3-4 membered heterocycloalkyl; or each R' is selected from CN, OH, F, =0, methyl, 7-10 membered heterocycloalkyl, (C 1-2 alkyl)2N-, (C 1-2 alkyl)2NC(O)- or azetidinylC(O)-, said methyl, (C 1-2 alkyl)2N-, (C 1-2 alkyl)2NC(O)- or azetidinylC(O)- being optionally substituted with one or more groups selected from halogen (e.g. F, CI, Br or I), OH, NH2or CN; or each R 2 , R 3 , R 4 , R 5 is independently selected from F, CI, CH3, CH2CH3, CHF2, CF3, -OCH3, -CH2CN, cyclopropyl, or each R 2 are each independently selected from F; or each R 3 are each independently selected from the group consisting of Cl; or each R is independently selected from the group consisting of CH3, 4 are each independently selected from the group consisting of CH3, -CH2CN, cyclopropyl, or each R is independently selected from F, CI, CH3, CH2CH3, CHF2, CF3, -OCH3, or 5 are each independently selected from F, CI, CH3, CH2CH3, CHF2, CF3, -OCH3, or the compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, n is selected from 0 or 1; or, m is selected from 0 or 1; or, q is selected from 1; or, p is selected from 2 or 3; or, m is selected from 0. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, each R a and R b is each independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, or C 6-10 aryl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, or C 6-10 aryl is optionally substituted with one or more groups selected from D, OH, NH2, CN, or halogen; or each R a and R b are each independently selected from H, D, C 1-3 alkyl, C 2-3 alkenyl or C 2-3 alkynyl; or each R a and R b are each independently selected from H or C 1-6 alkyl; or each R is independently selected from H, methyl or ethyl. a and R is independently selected from H, methyl or ethyl. b each R is independently selected from H, methyl or ethyl. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, -L- is selected from or -OCH2-; or, -L- is selected from or, -L- is selected from -OCH2-. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, ring A is selected from C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, or 5-10 membered heteroaryl; or, ring A is selected from C 3-6 cycloalkyl, 6-membered aryl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, or 5-6 membered heteroaryl; or, ring A is selected from cyclopropyl, phenyl, oxetanyl, piperidinyl, tetrahydropyranyl, cyclobutyl, cyclopentyl, azetidinyl, or cyclohexyl; or, ring A is selected from cyclopropyl, phenyl, oxetanyl, piperidinyl, tetrahydropyranyl, cyclobutyl, cyclopentyl, azetidinyl, or cyclohexyl; or, ring A is selected from cyclopentyl or cyclohexyl. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, Ring B is selected from C 6-10 aryl or 5-10 membered heteroaryl; or, ring B is selected from phenyl or 5-6 membered heteroaryl; or, ring B is selected from phenyl or pyridinyl; or, ring B is selected from pyridinyl. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, ring C is selected from C 6-10 aryl or 5-10 membered heteroaryl; or, ring C is selected from phenyl or 5-6 membered heteroaryl; or, ring C is selected from phenyl or pyridinyl; or, ring C is selected from pyridinyl. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, having the structural element selected from the group consisting of or a structural unit selected from the group consisting of or a structural unit selected from the group consisting of or a structural unit selected from the group consisting of or a structural unit selected from the group consisting of or a structural unit of formula (II) selected from the structural units selected from the group consisting of or a structural unit selected from the group consisting of The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, selected from a compound of Formula II, a compound of Formula III, a compound of Formula IV, a compound of Formula V, or a pharmaceutically acceptable salt thereof, wherein X 5 , X 6 and X 7 are each independently selected from CH or N. The following compounds, or pharmaceutically acceptable salts thereof: A pharmaceutical composition comprising a compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof. Use of a compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 14, in the manufacture of a medicament for the treatment or prevention of a disease selected from cancer; or, the cancer is selected from breast cancer.

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