Compound containing fused tricyclic structure

Abstract

The present disclosure belongs to the field of pharmaceutical chemistry. Provided is a compound containing a fused tricyclic structure. Specifically, the present disclosure relates to a compound of formula I, 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-related diseases.

Description

Compounds containing a tri-pericyclic structure

[0001] Cross-reference to Related Applications

[0002] This disclosure claims the benefit of and priority to the following two Chinese patent applications, the contents of which are hereby incorporated by reference in their entirety: Chinese Patent Application No. CN 202410445278.3, filed on April 13, 2024, and Chinese Patent Application No. CN 202410591345.2, filed on May 13, 2024. TECHNICAL FIELD

[0003] The present disclosure belongs to the field of medicinal chemistry, and provides a compound containing a tri-pericyclic structure or a pharmaceutically acceptable salt thereof, a preparation method thereof or a pharmaceutical composition thereof, and the 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 the 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 hyper-dependent on MMEJ-mediated DNA repair.

[0006] PolQ (UniProtKB - 075417 (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 suppressed 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.

[0007] DETAILED DESCRIPTION

[0008] The present application relates to a compound of Formula I, or a pharmaceutically acceptable salt thereof:

[0009] wherein,

[0010] each ring A, ring B, and ring C is independently selected from a 3-20 membered ring;

[0011] each R 1 is independently selected from halogen, -CN, =O, or the following groups optionally substituted with one or more R’: C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, -OR a , -SR a , -NR a R b , -COR a , -COOR a , -OCOR a , -CONR a R b , -NR a COR b , -SOR a , -SONR a R b , -NR a SOR b , -SO2R a , -SO2R a R b , -NR a SO2R b , -OC(O)NR a R b , -NR a C(O)OR b , -NR a C(O)NR a R b , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, or 5-12 membered heteroaryl;

[0012] each R 2 is independently selected from halogen, CN, =O, or the following groups optionally substituted with one or more R”: C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, -OR a , -SR a , -NR a Rb , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;

[0013] each R 3 is independently selected from halogen, CN, =0, or the following groups optionally substituted with one or more R”’: 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, -OR a , -SR a , -NR a R b , -COR a , -COOR a , -OCOR a , -CONR a R b , -NR a COR b , -SOR a , -SONR a R b , -NR a SOR b , -SO2R a , -SO2NR a R b , -NR a SO2R b , -OC(O)NR a R b , -NR a C(O)OR b , -NR a C(O)NR a R b , C 3-12 cycloalkyl, C 6-12 aryl, 5-12 membered heteroaryl or 3-12 membered heterocyclyl;

[0014] each R a and R b is independently selected from hydrogen, C 1-12 alkyl, C 1-12 heteroalkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;

[0015] each R’, R” or R”’ is independently selected from halogen, CN, OH, SH, NH2, CHO, COOH, or the following groups optionally substituted with one or more Rd Substituted with the following groups: -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl;

[0016] m, n and p are independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0017] Each X is independently selected from -CH2-, -NH-, -O- or -S-;

[0018] k is selected from 0, 1, 2, 3 or 4;

[0019] L is selected from a bond, or optionally replaced by one or more R e Substituted with the following groups: -C 1-12 Alkylene-, -C 1-12 Alkylene O-, -C 1-12 Alkylene NH- or -C 1-12 Alkylene S-;

[0020] L 1 Selected from optionally one or more R f Substituted with the following groups: -COO-R c1 -、-OCO-R c1 -、-CONR c -R c1 -、-NR c CO-R c1 -、-SONR c -R c1 -、-NR c SO-R c1 -, -SO2NR c -R c1 -、-NR c SO2-R c1 -、C 1-12 Alkylene, C 2-12 Alkenylene, C 2-12 Alkynylidene, C 1-12 Heteroalkylene, C 2-12 Heteroalkenylene or C 2-12 heteroalkynylene;

[0021] R c1 Selected from bond, C 1-12 Alkylene, C1-12 Ethylene, C 1-12 Alkynylidene, C 1-12 Heteroalkylene, C 2-12 Heteroalkenylene or C 2-12 heteroalkynylene;

[0022] R c Selected from hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl;

[0023] R d 、R e and R f are independently selected from halogen, CN, OH, SH, NH2, CHO, COOH, or the following groups optionally substituted with one or more R: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -C 1-12 Alkyl-C 3-12 Cycloalkyl, -C 1-12 Alkyl-3-12 membered heterocyclic group, -C 1-12 Alkyl-C 6-12 Aryl, -C 1-12 Alkyl-5-12 membered heteroaryl, -C 1-12 Heteroalkyl-C 3-12 Cycloalkyl, -C 1-12 Heteroalkyl-3-12 membered heterocyclic group, -C 1-12 Heteroalkyl-C 6-12 Aryl or -C 1-12 heteroalkyl-5-12 membered heteroaryl;

[0024] R is selected from oxo, halogen, CN, OH, SH, NH2, CHO, COOH, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 3-12cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl, 5-12 membered heteroaryl, C 1-12 alkyl-L 2 -, C 2-12 alkenyl-L 2 -, C 2-12 alkynyl-L 2 -, C 3-12 cycloalkyl-L 2 -, 3-12 membered heterocyclyl-L 2 -, C 6-12 aryl-L 2 - or 5-12 membered heteroaryl-L 2 -; L 2 is selected from C(O), OC(O), C(O)O, C(O)NH, NHC(O), OC(O)NH or NHC(O)O;

[0025] said C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, -OC 1-12 alkyl, -SC 1-12 alkyl, -NHC 1-12 alkyl, -N(C 1-12 alkyl)2, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl, 5-12 membered heteroaryl, C 1-12 alkyl-L 2 -, C 2-12 alkenyl-L 2 -, C 2-12 alkynyl-L 2 -, C 3-12 cycloalkyl-L 2 -, 3-12 membered heterocyclyl-L 2 -, C 6-12 aryl-L 2 - or 5-12 membered heteroaryl-L 2 - is optionally substituted by one or more halogen, CN, OH, SH, NH2, CHO, COOH, C 1-12 alkyl-C(O)-, C 2-12 alkenyl-C(O)-, C 2-12 alkynyl-C(O)-, C 3-12 cycloalkyl-C(O)-, 3-12 membered heterocyclyl-C(O)-, C 6-12 aryl-C(O)- or 5-12 membered heteroaryl-C(O)-.

[0026] In some embodiments, ring A is selected from a 5-12 membered ring.

[0027] In some embodiments, ring A is selected from a 5-6 membered ring. In some embodiments, ring A is selected from a 5 membered ring.

[0028] In some embodiments, ring A is selected from a C5 cycloalkenyl, a 5 membered heterocyclyl, or a 5 membered heteroaryl.

[0029] In some embodiments, ring A is selected from a cyclopentenyl, a dihydrofuranyl, a furanyl, a thienyl, a pyrrolyl, a thiazolyl, an oxazolyl, an isoxazolyl, or a pyrazolyl. In some embodiments, ring A is selected from a thienyl.

[0030] In some embodiments, ring C is selected from a 5-12 membered monocyclic ring, or a 5-6 membered monocyclic ring.

[0031] In some embodiments, ring C is selected from a 5-10 membered heteroaryl.

[0032] In some embodiments, ring C is selected from a 5-6 membered heteroaryl.

[0033] In some embodiments, ring C is selected from a 6 membered heteroaryl.

[0034] In some embodiments, ring C is selected from a pyridyl.

[0035] In some embodiments, ring A and ring C are each independently a monocyclic ring.

[0036] In some embodiments, ring A is selected from a 5-12 membered monocyclic ring, or a 5-6 membered monocyclic ring.

[0037] In some embodiments, ring B is selected from a 5-12 membered ring. In some embodiments, ring B is selected from a 5-10 membered ring. In some embodiments, ring B is selected from a 5-6 membered monocyclic ring or a 7-10 membered bicyclic ring structure.

[0038] In some embodiments, ring B is selected from a 5-6 membered ring. In some embodiments, ring B is selected from a phenyl, a 9 membered heterocyclyl, or a 9 membered heteroaryl.

[0039] In some embodiments, ring B is selected from a phenyl. In some embodiments, ring B is selected from

[0040] In some embodiments, the "ring" is selected from a cycloalkyl, a partially non- containing carbocyclic ring, an aromatic ring, a heterocycloalkyl, a heterocyclic ring, or a heteroaryl; optionally a 5-, 6-, or 7-membered monocyclic ring, or an 8-15 membered polycyclic ring, such as a bicyclic, tricyclic ring structure.

[0041] In one embodiment, the structural unit is selected from In one embodiment, the structural unit selected from and In one embodiment, the structural unit is selected from

[0042] In some embodiments, each R 1 is independently selected from halogen, -CN, =0, or the following groups optionally substituted with one or more R ’ groups: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR a , -SR a , -NR a R b , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, or 5-6 membered heteroaryl.

[0043] In some embodiments, R 1 is selected from C 1-6 alkyl optionally substituted with one or more groups selected from halogen, CN, OH, or NH2.

[0044] In some embodiments, R 1 is selected from C 1-4 alkyl optionally substituted with one or more halogens.

[0045] In some embodiments, R 1 is selected from C 1-3 alkyl optionally substituted with one or more atoms selected from F, CI, or Br.

[0046] In some embodiments, R 1 is selected from methyl optionally substituted with one or more atoms selected from F, CI, or Br.

[0047] In some embodiments, R 1 is selected from trifluoromethyl or methyl.

[0048] In some embodiments, each R 2 is independently selected from halogen, -CN, =0, or the following groups optionally substituted with one or more R 1-6 groups: C 2-6 alkyl, C 2-6 alkenyl, C a alkynyl, -OR a , -SR a , -NR b R 3-6cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl.

[0049] In some embodiments, each R 2 is independently selected from carbonyl or OH.

[0050] In some embodiments, each R 2 is independently selected from carbonyl.

[0051] In some embodiments, each R 3 is independently selected from halogen, CN, =0, or the following groups optionally substituted with one or more R ’ : C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR a , -SR a , -NR a R b , C 3-6 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl.

[0052] In some embodiments, R 3 is selected from halogen, CN, OH, NH2or C 1-4 alkyl.

[0053] In some embodiments, R 3 is selected from halogen or C 1-3 alkyl.

[0054] In some embodiments, R 3 is selected from halogen (e.g., F, CI, Br or I) or methyl.

[0055] In some embodiments, each R a and R b is independently selected from hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl or 5-6 membered heteroaryl.

[0056] In some embodiments, each R a and R b is independently selected from hydrogen or C 1-4 alkyl.

[0057] In some embodiments, each R', R", or R'" is independently selected from halogen, CN, OH, SH, NH2, CHO, COOH, or the following groups optionally substituted with one or more R d substituted -OC 1-6 alkyl, -SC 1-6 alkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, or 5-6 membered heteroaryl.

[0058] In some embodiments, each R', R", or R'" is independently selected from halogen, CN, OH, SH, or NH2.

[0059] In some embodiments, each R', R", or R'" is independently selected from halogen (e.g., F, Cl, Br, or I).

[0060] In some embodiments, each R'" is selected from halogen (e.g., F, Cl, Br, or I).

[0061] In some embodiments, m is selected from 0, 1, or 2.

[0062] In some embodiments, n is selected from 1 or 2.

[0063] In some embodiments, p is selected from 0, 1, or 2.

[0064] In some embodiments, each X is independently selected from -CH2-.

[0065] In some embodiments, k is selected from 1.

[0066] In some embodiments, L is selected from a bond, or the following groups optionally substituted with one or more R e substituted -C 1-6 alkylene-, -C 1-6 alkylene O-, -C 1-6 alkylene NH-, or -C 1-6 alkylene S-.

[0067] In some embodiments, L is selected from the following groups optionally substituted with one or more R e substituted -C 1-6 alkylene NH-.

[0068] In some embodiments, L is selected from the following groups optionally substituted with one or more R e substituted -C1-3 Alkylene NH-.

[0069] In some embodiments, L is selected from the group consisting of e Substituted -CH2NH-.

[0070] In some embodiments, L 1 Selected from optionally one or more R f Substituted with the following groups: -COO-, -OCO-, -CONR c -、-NR c CO-、-SONR c -、-NR c SO-, -SO2NR c -、-NR c SO2-、C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 1-6 Heteroalkylene, C 2-6 Heteroalkenylene or C 2-6 Heteroalkynylene.

[0071] In some embodiments, L 1 Selected from optionally one or more R f Substituted with the following groups: -CONR c -or-NR c CO-.

[0072] In some embodiments, L 1 Selected from -CONR c -or-NR c CO-.

[0073] In some embodiments, L 1 Selected from -CON(CH3)-.

[0074] In some embodiments, R c1 Select from bond or C 1-6 In some embodiments, R c1 Select from keys.

[0075] In some embodiments, R c Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl or 5-6 membered heteroaryl.

[0076] In some embodiments, R c Selected from hydrogen, C1-4 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl.

[0077] In some embodiments, R c is selected from hydrogen, C 1-3 alkyl, C 3-4 cycloalkyl or 3-4 membered heterocyclyl. In some embodiments, R c is selected from hydrogen or C 1-3 alkyl. In some embodiments, R c is selected from methyl.

[0078] In some embodiments, R d , R e and R f are each independently selected from halogen, CN, OH, SH, NH2, CHO, COOH, or the following groups optionally substituted with one or more R: C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, -OC 1-12 alkyl, -SC 1-12 alkyl, -NHC 1-12 alkyl, -N(C 1-12 alkyl)2, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, -C 1-12 alkyl-C 3-12 cycloalkyl, -C 1-12 alkyl-3-12 membered heterocyclyl, -C 1-12 alkyl-C 6-12 aryl, -C 1-12 alkyl-5-12 membered heteroaryl, -C 1-12 heteroalkyl-C 3-12 cycloalkyl, -C 1-12 heteroalkyl-3-12 membered heterocyclyl, -C 1-12 heteroalkyl-C 6-12 aryl or -C 1-12 heteroalkyl-5-12 membered heteroaryl.

[0079] In some embodiments, R d , R e and R f are each independently selected from halogen, CN, OH, SH, NH2, CHO, COOH, or the following groups optionally substituted with one or more R: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NHC1-6 alkyl, -N(C 1-6 alkyl)2, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -C 1-6 alkyl-C 3-6 cycloalkyl, -C 1-6 alkyl-3-6 membered heterocyclyl, -C 1-6 alkyl-C 6-10 aryl, -C 1-6 alkyl-5-6 membered heteroaryl, -C 1-6 heteroalkyl-C 3-6 cycloalkyl, -C 1-6 heteroalkyl-3-6 membered heterocyclyl, -C 1-6 heteroalkyl-C 6-10 aryl or -C 1-6 heteroalkyl-5-6 membered heteroaryl.

[0080] In some embodiments, R d and R f are each independently selected from halogen, CN, OH, SH, NH2, CHO, COOH, or the following groups optionally substituted with one or more R: 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NHC 1-6 alkyl or -N(C 1-6 alkyl)2.

[0081] In some embodiments, R d and R f are each independently selected from halogen, CN, OH, SH, NH2, CHO, COOH, C 1-6 alkyl or halogenated C 1-6 alkyl.

[0082] In some embodiments, R e is selected from the following groups optionally substituted with one or more R: 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6 alkyl-3-10 membered heterocyclyl, -C 1-6 alkyl-C 6-10 aryl, -C 1-6alkyl-5-10 membered heteroaryl, -C 1-6 heteroalkyl-C 3-10 cycloalkyl, -C 1-6 heteroalkyl-3-10 membered heterocyclyl, -C 1-6 heteroalkyl-C 6-10 aryl or -C 1-6 heteroalkyl-5-10 membered heteroaryl.

[0083] In yet some embodiments, R e is selected from the following groups optionally substituted with one or more R: C 1-3 alkyl, C 2-3 alkenyl, -C 1-3 alkyl-C 6-9 cycloalkyl, -C 1-3 alkyl-6-9 membered heterocycloalkyl, -C 1-3 heteroalkyl-6-9 membered heterocycloalkyl or -C 1-3 heteroalkyl-C 6-9 cycloalkyl, said -C 1-3 alkyl-6-9 membered heterocycloalkyl or -C 1-3 the 6-9 membered heterocycloalkyl in heteroalkyl-6-9 membered heterocycloalkyl is selected from piperazinyl, piperidinyl, morpholinyl, diazepinyl, diazabicycloheptanyl, diazabicyclooctanyl, diazaspiro nonanyl, oxazepinyl or diazepinyl; said -C 1-3 alkyl-C 6-9 cycloalkyl or -C 1-3 heteroalkyl-C 6-9 the 6-9 membered cycloalkyl in cycloalkyl is selected from cyclohexyl, cycloheptyl, cyclooctyl or cyclononyl.

[0084] In yet some embodiments, R e is selected from the following groups optionally substituted with one or more R: C 1-3 alkyl, C 2-3 alkenyl, -C 1-3 alkyl 6 membered heterocycloalkyl, -C 1-3 alkyl 7 membered heterocycloalkyl, -C 1-3 alkyl 8 membered heterocycloalkyl, -C 1-3 alkyl 9 membered heterocycloalkyl, -C 1-3 heteroalkyl 6 membered heterocycloalkyl, -C 1-3 heteroalkyl 7 membered heterocycloalkyl, -C 1-3 heteroalkyl 8 membered heterocycloalkyl, -C 1-3 alkyl-NH-6 membered heterocycloalkyl or -C 1-3 alkyl NH-C6 cycloalkyl.

[0085] In yet some embodiments, R eselected from the following groups optionally substituted with one or more R: C 1-3 alkyl, C 2-3 alkenyl, -C 1-3 alkyl-C 6-9 cycloalkyl or -C 1-3 alkyl-6-9 membered heterocyclyl, said -C 1-3 6-9 membered heterocyclyl in alkyl-6-9 membered heterocyclyl is selected from piperazinyl, piperidinyl, morpholinyl, diazabicyclooctanyl, diazaspiro nonanyl, oxazaspiroheptanyl or diazaspiroheptanyl.

[0086] In some embodiments, R e selected from the following groups optionally substituted with one or more R: C 1-3 alkyl, C 2-3 alkenyl, -C 1-3 alkyl 6 membered heterocyclyl, -C 1-3 alkyl 7 membered heterocyclyl, -C 1-3 alkyl 8 membered heterocyclyl or -C 1-3 alkyl 9 membered heterocyclyl.

[0087] In some embodiments, R e selected from the following groups optionally substituted with one or more R: methyl, propenyl,

[0088] In some embodiments, R e selected from the following groups optionally substituted with one or more R: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -C 1-6 alkyl-C 3-6 cycloalkyl, -C 1-6 alkyl-3-6 membered heterocyclyl, -C 1-6 alkyl-C 6-10 aryl, -C 1-6 alkyl-5-6 membered heteroaryl, -C 1-6 heteroalkyl-C 3-6 cycloalkyl, -C 1-6 heteroalkyl-3-6 membered heterocyclyl, -C 1-6 heteroalkyl-C 6-10 aryl or -C 1-6 heteroalkyl-5-6 membered heteroaryl.

[0089] In some embodiments, R e selected from the following groups optionally substituted with one or more R: C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 1-4 Alkyl-C 3-6 Cycloalkyl, -C 1-4 Alkyl-3-6 membered heterocyclic group, -C 1-4 Alkyl-C 6-10 Aryl or -C 1-4 Alkyl-5-6 membered heteroaryl.

[0090] In other embodiments, R e Selected from the following groups optionally substituted with one or more R: C 1-3 Alkyl, C 2-3 Alkenyl, -C 1-3 Alkyl-C 3-6 Cycloalkyl or -C 1-3 Alkyl-3-6 membered heterocyclic group.

[0091] In other embodiments, R e Selected from the following groups optionally substituted with one or more R: C 1-3 Alkyl, C 2-3 Alkenyl, or -C 1-3 Alkyl 6-membered heterocyclic group (for example, piperazinyl or morpholinyl).

[0092] In other embodiments, R e Selected from the following groups optionally substituted with one or more R: -C 1-4 Alkyl-C 3-6 Cycloalkyl, -C 1-4 Alkyl-3-6 membered heterocyclic group, -C 1-4 Alkyl-C 6-10 Aryl or -C 1-4 Alkyl-5-6 membered heteroaryl.

[0093] In other embodiments, R e Selected from the following groups optionally substituted with one or more R: -C 1-3 Alkyl-C 5-6 Cycloalkyl.

[0094] In other embodiments, R e Selected from the following groups optionally substituted with one or more R: -C 1-3 Alkyl-piperazinyl or -C 1-3 Alkyl-morpholinyl.

[0095] In other embodiments, R e is selected from the following groups optionally substituted with one or more R: -CH2CH2-piperazinyl, -CH2CH2-morpholinyl or -CH2-morpholinyl.

[0096] In some embodiments, R is selected from halogen, CN, OH, SH, NH2, CHO, COOH, C e is selected from the following groups optionally substituted with one or more R:

[0097] In some embodiments, R is selected from halogen, CN, OH, SH, NH2, CHO, COOH, C e is selected from the following groups optionally substituted with one or more R:

[0098] In some embodiments, R is selected from halogen, CN, OH, SH, NH2, CHO, COOH, C 1-12 alkyl, C 1-12 haloalkyl, C 2-12 alkenyl, C 2-12 alkynyl, -OC 1-12 alkyl, -SC 1-12 alkyl, -NHC 1-12 alkyl or -N(C 1-12 alkyl)2.

[0099] In some embodiments, R is selected from halogen, CN, OH, SH, NH2, CHO, COOH, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, -OC 1-12 alkyl, -SC 1-12 alkyl, -NHC 1-12 alkyl, -N(C 1-12 alkyl)2, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl, 5-12 membered heteroaryl, C 1-12 alkyl-L 2 -, C 2-12 alkenyl-L 2 -, C 2-12 alkynyl-L 2 -, C 3-12 cycloalkyl-L 2 -, 3-12 membered heterocyclyl-L 2 -, C 6-12 aryl-L 2 - or 5-12 membered heteroaryl-L 2 -; L 2 is selected from C(O), OC(O), C(O)O, C(O)NH, NHC(O), OC(O)NH or NHC(O)O;

[0100] said C 1-12 alkyl, C 2-12alkenyl, -OC 2-12 alkynyl, -OC 1-12 alkyl, -SC 1-12 alkyl, -NHC 1-12 alkyl, -N(C 1-12 alkyl)2, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C10 aryl, 5-12 membered heteroaryl, 6-12 alkyl, -SC 1-12 alkenyl, -OC 2 alkyl, -SC 2-12 alkenyl, -OC 2 alkyl, -SC 2-12 alkynyl, -OC 2 alkyl, -SC 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C10 aryl, 5-12 membered heteroaryl, 2 alkyl, -SC 2 alkenyl, -OC 6-12 alkyl, -SC 2 alkenyl, -OC 2 alkyl, -SC 1-12 alkyl, -SC 2-12 alkenyl, -OC 2-12 alkynyl, -OC 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C10 aryl, 5-12 membered heteroaryl, 6-12 alkyl, -SC

[0101] In some embodiments, R is selected from oxo, halogen, CN, OH, SH, NH2, CHO, COOH, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, -OC1-C6 alkyl, -SC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, 1-6 alkyl, -SC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, C 3-10 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, 1-6 alkyl, -SC 2 alkenyl, -OC 2-6 alkyl, -SC 2 alkenyl, -OC 2-6 alkynyl, -OC 2 alkyl, -SC 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, 2 alkyl, -SC 2 alkenyl, -OC 2 alkynyl, -OC2 -;L 2 is selected from C(O), OC(O) or C(O)O;

[0102] The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, C 1-6 Alkyl-L 2 -、C 2-6 Alkenyl-L 2 -、C 2-6 Alkynyl-L 2 -、C 3-6 Cycloalkyl-L 2 -, 3-6 membered heterocyclic group-L 2 -, C6 aryl-L 2 - or 5-6 membered heteroaryl-L 2 - optionally substituted with one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, COOH, C 1-6 Alkyl-C(O)-, C 2-6 Alkenyl-C(O)-, C 2-6 Alkynyl-C(O)-, C 3-6 Cycloalkyl-C(O)-, 3-6 membered heterocyclyl-C(O)-, C6 aryl-C(O)- or 5-6 membered heteroaryl-C(O)-.

[0103] In some embodiments, R is selected from oxo, halogen, CN, OH, NH2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, C 1-3 Alkyl-C(O)-, C 2-3 Alkenyl-C(O)-, or C 2-3 Alkynyl-C(O)-;

[0104] The C 1-3alkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more halogen, CN, OH, SH, NH2, CHO, COOH, C 1-3 alkyl-C(O)-, C 2-3 alkenyl-C(O)-, or C 2-3 alkynyl-C(O)-.

[0105] In some embodiments, R is selected from oxo, halogen (F, CI, Br, or I), C 1-3 alkyl, -N(C 1-3 alkyl)2, 4 membered heterocycloalkyl, or C 2-3 alkenyl-C(O)-;

[0106] said C 1-3 alkyl or 4 membered heterocycloalkyl is optionally substituted with one or more OH or C 2-3 alkenyl-C(O)-.

[0107] In some embodiments, R is selected from halogen, CN, OH, SH, NH2, CHO, COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkyl-L 2 -, C 2-6 alkenyl-L 2 or C 2-6 alkynyl-L 2 -; L 2 is selected from C(O);

[0108] said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkyl-L 2 -, C 2-6 alkenyl-L 2 or C 2-6 alkynyl-L 2 - optionally substituted with one or more halogen, CN, OH, SH, NH2, CHO, COOH, C 1-6 alkyl-C(O)- or C 2-6 alkenyl-C(O)-.

[0109] In some embodiments, R is selected from halogen, C 1-3 alkyl, C 2-4 alkenyl-CO-, optionally substituted with C 1-3alkyl-CO- or C 2-4 alkenyl-CO-substituted 4-6 membered heterocycloalkyl.

[0110] In some embodiments, R is selected from oxo, F, methyl, ethyl, -CH2OH, -N(CH3)2,

[0111] In some other embodiments, R is selected from halogen, CN, OH, SH, NH2, CHO, COOH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NHC 1-6 alkyl or -N(C 1-6 alkyl)2.

[0112] In some other embodiments, R is selected from halogen, CN, OH, SH, NH2, CHO, COOH, C 1-4 alkyl or C 1-4 haloalkyl.

[0113] In some other embodiments, R is selected from CHO, COOH or C 1-3 alkyl.

[0114] In some other embodiments, R is selected from C 1-3 alkyl.

[0115] In some other embodiments, R is selected from CHO or methyl.

[0116] In some other embodiments, R is selected from methyl.

[0117] In some embodiments, R e is selected from

[0118] In some other embodiments, R e is selected from

[0119] In some other embodiments, R e is selected from

[0120] In some embodiments, the halo is selected from fluoro, chloro or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo is selected from fluoro.

[0121] In some embodiments, the C 1-10selected from C 1-9 , C 1-8 , C 1-7 , C 1-6 , C 1-4 , C 1-3 , or C 1-2 . In some embodiments, the C 1-6 is selected from C 1-4 , C 1-3 , or C 1-2 . In some embodiments, the C 1-4 is selected from C4, C3, C2, or C1. In some embodiments, the C 1-3 is selected from C3, C2, or C1.

[0122] In some embodiments, the C 2-10 is selected from C 2-8 , C 2-6 , C 2-5 , C 2-4 , C 2-3 . In some embodiments, the C 2-6 is selected from C 2-4 , or C 2-3 . In some embodiments, the C 2-4 is selected from C4, C3, or C2.

[0123] In some embodiments, the C 3-6 is selected from C 3-5 , C 3-4 , C 4-6 , C 4-5 , or C 5-6 . In some embodiments, the C 6-10 is selected from C 6-9 , C 6-8 , C 6-7 , C 7-10 , C 7-9 , C 7-8 , C 8-10 , C 8-9 , or C 9-10 . In some embodiments, the C 3-10 is selected from C 3-9 , C 3-8 , C 3-7 , C 3-6 , C 3-5 , C 3-4 , C 4-10 , C 4-9 , C 4-8 , C 4-7 , C 4-6 , C 4-5 , C 5-10 , C 5-9 , C5-8 , C 5-7 , C 5-6 , C 6-10 , C 6-9 , C 6-8 , C 6-7 , C 7-12 , C 7-10 , C 7-9 , C 7-8 , C 8-12 , C 8-10 , C 8-9 , C 9-12 or C 9-10 . In some embodiments, the C 3-15 is selected from C 3-12 or C 3-10 . In some embodiments, the C 3-12 is selected from C 3-10 . In some embodiments, the C 6-12 is selected from C 6-10 .

[0124] In some embodiments, the 3-6 membered is selected from 3-5 membered, 3-4 membered, 4-6 membered, 4-5 membered, or 5-6 membered. In some embodiments, the 5-10 membered is selected from 5-8 membered, 5-7 membered, 5-6 membered, 6-10 membered, 6-9 membered, 6-8 membered, 6-7 membered, 7-10 membered, 7-9 membered, 7-8 membered, 8-10 membered, 8-9 membered, 9-10 membered. In some embodiments, the 3-10 membered is selected from 3-9 membered, 3-8 membered, 3-7 membered, 3-6 membered, 3-5 membered, 3-4 membered, 4-10 membered, 4-9 membered, 4-8 membered, 4-7 membered, 4-6 membered, 4-5 membered, 5-10 membered, 5-9 membered, 5-8 membered, 5-7 membered, 5-6 membered, 6-10 membered, 6-9 membered, 6-8 membered, 6-7 membered, 7-10 membered, 7-9 membered, 7-8 membered, 8-10 membered, 8-9 membered, 9-10 membered. In some embodiments, the 3-15 membered is selected from 3-12 membered or 3-10 membered. In some embodiments, the 3-12 membered is selected from 3-10 membered. In some embodiments, the 5-12 membered is selected from 5-10 membered.

[0125] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from a compound of Formula II, III, IV, IA, IIA, IIIA, or IVA, or a pharmaceutically acceptable salt thereof:

[0126] wherein, ring A, ring B, ring C, X, R 1 , R 2 , R 3 , R e , R fm, n, p, k, L and L 1 are as described herein;

[0127] q and r are each independently selected from 0, 1 or 2.

[0128] In some embodiments, the structural unit as described herein.

[0129] In some embodiments, the structural unit is selected from

[0130] The present application provides the following compounds, or a pharmaceutically acceptable salt thereof:

[0131] In another aspect, the present disclosure also provides a pharmaceutical composition comprising the above-mentioned 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.

[0132] 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 above-mentioned compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0133] In another aspect, the present disclosure also provides the use of the above-mentioned 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.

[0134] In another aspect, the present disclosure also provides the use of the above-mentioned compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment or prevention of a disease.

[0135] In another aspect, the present disclosure also provides a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment or prevention of a disease.

[0136] In some embodiments, the disease is selected from cancer.

[0137] In some embodiments, the disease is selected from a Pol Q-related disease (e.g., cancer).

[0138] In some embodiments, the disease is selected from a Pol Q-related cancer.

[0139] Technical effects

[0140] The compounds of the present disclosure have good in vitro and in vivo inhibitory activity related to Pol Q (e.g., Pol Q in vitro enzyme inhibitory activity, in vitro cell inhibitory activity, and in vivo efficacy) and metabolic stability (e.g., liver microsomal metabolic stability and in vivo pharmacokinetics in mice).

[0141] Definitions

[0142] The following terms used in the present disclosure have the following meanings unless otherwise indicated. A particular term should not be construed as indefinite or unclear if 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 the corresponding product or its active ingredient.

[0143] When a covalent bond in a certain structural unit or group in the present disclosure is not connected to a specific atom, it means that the covalent bond can be connected to any atom in the structural unit or group, as long as the valence connection rule is not violated.

[0144] The term "substituted" means that any one or more hydrogen atoms on the specified atom are replaced with a substituent, provided that the valence of the specified atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo cannot occur on an aromatic group.

[0145] The term "optionally" or "optionally" means that the event or circumstance described thereafter can occur or not occur, and the description includes the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, ethyl "optionally" substituted with halogen means that ethyl can be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or completely substituted (CF2CF3). Those skilled in the art can understand that for any group containing one or more substituents, no substitution or substitution pattern that is not spatially possible and / or cannot be synthesized will be introduced.

[0146] "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 groups, which are 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.

[0147] C in this document m-n is an integer number of carbon atoms in the moiety that has the 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.

[0148] 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, C 1-12 amido, ureido, epoxy, C 2-12 ester and oxo, said substituent is optionally substituted with one or more substituents selected from oxo, hydroxy, 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, carboxy, -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.

[0149] When any variable (e.g., R) occurs more than one time in a compound or substituent, its definition in each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is substituted with two R’s, then each R is selected independently of the other.

[0150] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a covalent bond.

[0151] 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.

[0152] When a substituent is attached to two atoms of a ring, it can be bonded to any atom of the ring. For example, When m is selected from 1, the substitution R1can occur at any position of the ring, including but not limited to

[0153] The term “halo” or “halogen” means fluoro, chloro, bromo, and iodo.

[0154] The term “alkyl” means a hydrocarbon group of formula C n H 2n+1 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 chain, 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 having from 1 to 12 carbon atoms, including C1, C2, C3, C4, C5, C6, C7, C8, C9, C10 , C 11 , and C 12 alkyl and any range of combinations thereof. For example, the term "C 1-6 alkyl" refers to an alkyl group containing from 1 to 6 carbon atoms (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, and the like). Similarly, the alkyl portions of alkoxyl, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio have the same definition as alkyl. For another example, the term "C 1-3 alkyl" refers to an alkyl group containing from 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, and isopropyl).

[0155] The term "alkenyl" refers to a straight or branched chain, unsaturated aliphatic hydrocarbon group having at least one double bond and consisting of carbon and hydrogen atoms, 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" and the like. Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3- butadienyl, and the like.

[0156] The term "alkynyl" refers to a straight or branched chain, unsaturated aliphatic hydrocarbon group having at least one triple bond and consisting of carbon and hydrogen atoms, 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" and the like. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), 1,3- butynadiynyl (-C≡C-C≡CH), and the like.

[0157] The term "alkoxy" refers to -O-alkyl.

[0158] The term "alkylthio" refers to -S-alkyl.

[0159] The term "cycloalkoxy" refers to -O-cycloalkyl.

[0160] 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.

[0161] 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, dicyclo[1.1.1]pent-1-yl, and the like. For example, C 3-4 Cycloalkyl includes cyclopropyl and cyclobutyl.

[0162] 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.

[0163] 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.

[0164] The term "carbocyclic ring" 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.

[0165] 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) containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron (preferably 1 or 2 heteroatoms), a 4- to 8-membered ring, a 5- to 8-membered ring, or a 5- to 6-membered ring. 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.

[0166] 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 1-6heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, etc. Unless otherwise indicated, the heteroalkyl groups contain 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N, or NH. For example, the term "C1-C6heteroalkyl" means a heteroalkyl group having from 1 to 6 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed in any position (e.g., internal or terminal position) of the heteroalkyl group, including the position that links the alkyl group to the rest 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, etc. 1-6 heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, etc. Unless otherwise indicated, the heteroalkyl groups contain 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N, or NH. For example, the term "C1-C6heteroalkyl" means a heteroalkyl group having from 1 to 6 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed in any position (e.g., internal or terminal position) of the heteroalkyl group, including the position that links the alkyl group to the rest 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, etc.

[0167] 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 heterocycloalkyl group is typically a 3- to 20-membered, 3- to 15-membered, 3- to 10-membered, 5- to 10-membered, 3- to 7-membered, 4- to 8-membered, 5- to 8-membered, 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). 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 definitions of the terms "heteroalkenyl," "heteroalkynyl" are analogous, wherein one or more carbon atoms (and the hydrogen atoms attached thereto) of an alkenyl or alkynyl group, respectively, are each independently replaced with the same or different heteroatom groups. 2-12 heteroalkenyl, heteroalkynyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, etc. Unless otherwise indicated, the heteroalkyl groups contain 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N, or NH. For example, the term "C1-C6heteroalkyl" means a heteroalkyl group having from 1 to 6 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed in any position (e.g., internal or terminal position) of the heteroalkyl group, including the position that links the alkyl group to the rest 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, etc. 2-6 heteroalkenyl, heteroalkynyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, etc. Unless otherwise indicated, the heteroalkyl groups contain 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N, or NH. For example, the term "C1-C6heteroalkyl" means a heteroalkyl group having from 1 to 6 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed in any position (e.g., internal or terminal position) of the heteroalkyl group, including the position that links the alkyl group to the rest 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, etc. 2-12 heteroalkenyl, heteroalkynyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, etc. Unless otherwise indicated, the heteroalkyl groups contain 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N, or NH. For example, the term "C1-C6heteroalkyl" means a heteroalkyl group having from 1 to 6 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed in any position (e.g., internal or terminal position) of the heteroalkyl group, including the position that links the alkyl group to the rest 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, etc. 2-6 heteroalkenyl, heteroalkynyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, etc. Unless otherwise indicated, the heteroalkyl groups contain 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N, or NH. For example, the term "C1-C6heteroalkyl" means a heteroalkyl group having from 1 to 6 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed in any position (e.g., internal or terminal position) of the heteroalkyl group, including the position that links the alkyl group to the rest 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, etc.

[0168] The terms "aryl," "aromatic ring group,"

[0169] 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.

[0170] 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

[0171] 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.

[0172] 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.

[0173] The term "tricyclic" refers to a cyclic group containing three rings, which can be fully saturated, partially saturated, or aromatic. The tricyclic ring can consist entirely of C atoms, can contain one or more heteroatoms, e.g., selected from N, O, or S. Any two adjacent single rings of the tricyclic ring can be a fused ring, a bridged ring, or a spirocyclic ring.

[0174] 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.

[0175] Unless otherwise indicated, the use of a wavy line indicates the absolute configuration of a stereocenter, the use of a straight line indicates the relative configuration of a stereocenter, the use of a wavy line indicates a straight line indicates a straight line indicates a wavy line or a wavy line or a wavy line indicates a straight line and a straight line

[0176] 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 the (Z) isomer, the (E) isomer, or a mixture of isomers of the compound is indicated.

[0177] 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:

[0178] (i) inhibiting the disease or condition, i.e., arresting its development;

[0179] (ii) relieving the disease or condition, i.e., causing regression of the disease or condition.

[0180] 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.

[0181] The term "therapeutically or prophylactically effective amount" means an amount of a compound of the present 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 present 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.

[0182] 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.

[0183] 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.

[0184] The term "pharmaceutical composition" means a mixture of one or more compounds of the present disclosure or salts thereof with a pharmaceutically acceptable excipient. The objective of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to an organism.

[0185] 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 part of the mechanism of action of the composition.

[0186] 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".

[0187] The compounds and intermediates of the present disclosure can also exist in different tautomeric forms and all such forms are embraced within the scope of the present 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.

[0188] 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.

[0189] Certain isotopically-labeled compounds of the present disclosure (for example, those labeled with3H and14C) are useful in compound and / or substrate tissue distribution analysis. Tritiated (i.e., 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 are useful in positron emission tomography (PET) studies for measurement of substrate occupancy. Isotopically-labeled compounds of the present disclosure can generally be prepared by substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent in a procedure similar to those disclosed in the schemes and / or examples below.

[0190] 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 substitutions can be partial or total, partial deuterium substitution referring to replacement of at least one hydrogen by at least one deuterium, all such forms of compounds being included within the scope of the present disclosure.

[0191] 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.

[0192] The pharmaceutical compositions of the present disclosure can be prepared by combining a compound of the present disclosure with suitable pharmaceutically acceptable excipients.

[0193] The pharmaceutical compositions of the present disclosure can be manufactured in a manner appropriate for the route of administration, e.g., by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, or lyophilizing processes.

[0194] The therapeutic dosage of a compound of the present disclosure can be determined by, e.g., the particular use for which the treatment is made, the manner of administration of the compound, 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 route of administration. 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 kind and extent 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.

[0195] 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 the other chemical 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.

[0196] 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.

[0197] One important consideration in the planning of synthetic routes in the art is the selection of appropriate protecting groups for reactive functional groups, such as the amino group 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.

[0198] 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:

[0199] wherein, ring A, R 1 , R 2 , R 3 , R e , R f , m, p, q and r are defined as described herein;

[0200] R 4 is selected from C 1-6 alkyl (e.g., methyl or ethyl).

[0201] The following abbreviations are used in the present disclosure:

[0202] Boc represents tert-butyloxycarbonyl; EDCI represents l-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride; DMEDA represents N,N'-dimethylethylenediamine; DMF represents N,N-dimethylformamide; NMP represents N-methylpyrrolidinone; K2Os04-2H20 represents osmium potassium dioxide hydrate; NMO represents 4-methylmorpholine-N-oxide; T3P / DMF represents l-propylphosphonic acid cyclic anhydride in N,N-dimethylformamide.

[0203] For the sake of clarity, the present disclosure is further illustrated by examples, which are not intended to limit the scope of the present disclosure. All reagents used in the present disclosure are commercially available and used without further purification. DETAILED DESCRIPTION

[0204] Example 1: Compound 1

[0205] 1) Preparation method of compound 1-b:

[0206] To 2-methyl-6-nitroaniline (4.86 g), triethylamine (6.5 g), 4-dimethylamino pyridine (1.95 g) in dichloromethane (50 mL), di-tert-butyl dicarbonate (16.7 g) was added dropwise slowly, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, 40 mL of saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness. The residue was purified by column chromatography to give compound 1-b (10.1 g).

[0207] 2) Preparation method of compound 1-c:

[0208] Compound 1-b (10.1 g) was added to anhydrous methanol (50 mL), and 10% Pt / C (1 g) was added thereto. The mixture was stirred under hydrogen replacement at room temperature overnight. After the reaction was completed, the reaction mixture was filtered, the filter cake was washed with anhydrous methanol, and the filtrate was concentrated under reduced pressure to dryness to give compound 1-c (9.6 g).

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

[0210] Cyclopentanone (9.2 g), ethyl trifluoroacetylacetate (20.13 g), 4A molecular sieves (0.5 g), and ammonium acetate (8.44 g) were added to a 250 mL single-neck flask, and the mixture was heated to 130°C and reacted for 14 hours. After cooling to room temperature, the mixture was stirred for another 6 hours. The mixture was filtered, the filter cake was washed with petroleum ether, and the filter cake was slurried with methyl tert-butyl ether (20 mL) for another 30 minutes to give 1-d (4.5 g).

[0211] 4) Preparation method of compound 1-e:

[0212] Compound 1-d (1 g) was added to phosphorus tribromide (10 mL), and the mixture was heated to 100°C and stirred for 14 hours. After the reaction was completed, the reaction mixture was slowly added to ice water, and the pH of the system was adjusted to alkaline with saturated aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate, and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 1-e (340 mg). ESI-MS: m / z = 265.94 [M+H] +

[0213] 5) Preparation method of compound 1-f:

[0214] 1-a (700 mg), 1-c (1.2 g), and EDCI (1.4 g) were added to pyridine (20 mL), and the mixture was allowed to react at room temperature overnight. After the reaction was completed, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC to give compound 1-f (470 mg).

[0215] 6) Preparation method of compound 1-g:

[0216] Compound 1-f (235 mg), 1-e (127 mg), cuprous iodide (18 mg), DMEDA (8 mg), potassium carbonate (132 mg) were added into dioxane (10 mL), nitrogen substitution, the reaction was stirred at 60 °C for 12 hours, the reaction was completed. The reaction liquid was filtered, the filtrate was concentrated under reduced pressure to no liquid flow to obtain compound 1-g (330 mg).

[0217] 7) Preparation method of compound 1-h:

[0218] Compound 1-g (330 mg), cesium carbonate (1.6 g) was added to DMF (10 mL), iodomethane (680 mg) was added, and the reaction was stirred at room temperature for 2 hours, and the reaction was completed. Water (15 mL) was added to the reaction liquid, stirred well, extracted with ethyl acetate, combined organic phase, washed with water, dried with anhydrous sodium sulfate. Concentrated under reduced pressure to no liquid flow, compound 1-h (350 mg) was obtained. ESI-MS: m / z = 691.29 [M+H] + .

[0219] 8) Preparation method of compound 1-i:

[0220] Compound 1-h (350 mg), trifluoroacetic acid (20 drops) was added to dichloromethane (5 mL), stirred at room temperature for 2 hours, and the reaction was completed. Slowly add saturated aqueous sodium bicarbonate solution, adjust the pH value of the system to basic, dichloromethane extraction, combined organic phase, dried with anhydrous sodium sulfate, concentrated under reduced pressure, purified by column chromatography to obtain compound 1-i (280 mg). ESI-MS: m / z = 591.28 [M+H] + .

[0221] 9) Preparation method of compound 1-j:

[0222] Compound 1-i (280 mg) was added to anhydrous methanol (10 mL), and sodium borohydride (90 mg) was slowly added. After addition, it was stirred at room temperature for 1 hour, and the reaction was completed. Add saturated aqueous ammonium chloride solution to quench, stirred well, extracted with ethyl acetate, combined organic phase, dried with anhydrous sodium sulfate. Concentrated under reduced pressure to no liquid flow, compound 1-j (150 mg) was obtained. ESI-MS: m / z = 563.23 [M+H] + .

[0223] 10) Preparation method of compound 1-k:

[0224] Compound 1-j (150 mg), triethylamine (81 mg) were added into dichloromethane (10 mL), and methanesulfonic anhydride (232 mg) was added slowly. The reaction was stirred at room temperature for 14 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution. After stirring well, the organic phase was extracted with dichloromethane, and the combined organic phase was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product 1-k (90 mg) was purified by column chromatography. ESI-MS: m / z = 641.27 [M+H] + .

[0225] 11) Preparation method of compound 1-l:

[0226] Compound 1-k (90 mg), potassium phosphate (90 mg) were added into NMP (3 mL). The reaction was stirred at 60 °C for 14 hours. The reaction was cooled to room temperature, and 10 mL of water was added. After stirring well, the organic phase was extracted with ethyl acetate, and the combined organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain compound 1-l (80 mg). ESI-MS: m / z = 545.17 [M+H] + .

[0227] 12) Preparation method of compound 1:

[0228] Compound 1-l (20 mg) was added into 4N HCl / 1,4-dioxane (5 mL). The reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure to obtain compound 1 (2 mg) by HPLC purification.

[0229] ESI-MS: m / z = 445.23 [M+H] + .

[0230] Example 2: Compound 2

[0231] 1) Preparation method of compound 2-a:

[0232] Compound 1 (65 mg), 3-bromopropene (0.5 mL), and cesium carbonate (458 mg) were added into DMF (5 mL). The reaction was stirred at 60 °C for 16 hours. The reaction was cooled to room temperature, and 10 mL of water was added. The organic phase was extracted with ethyl acetate, and the combined organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 2-a (70 mg). ESI-MS: m / z = 485.21 [M+H] + .

[0233] 2) Preparation method of compound 2-b:

[0234] Compound 2-a (70 mg), K2OsO4·2H2O (5 mg), and NMO (84 mg) were added to tetrahydrofuran (5 mL) and water (5 mL) and stirred at room temperature for 2 hours. The reaction was completed. Sodium periodate (154 mg) was added to the reaction solution and stirred at room temperature for 1 hour. The reaction was completed. Saturated aqueous sodium sulfite solution (10 mL) was added to the reaction solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure until no liquid outflowed to obtain compound 2-b (76 mg).

[0235] 3) Preparation method of compound 2:

[0236] Compound 2-b (76 mg), N-methylpiperazine (22 mg), and acetic acid (1 drop) were added to anhydrous methanol (10 mL). The mixture was stirred at room temperature for half an hour. Sodium cyanoborohydride (91 mg) was added and stirred at room temperature for 1 hour. The reaction was completed. Saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction solution, stirred thoroughly, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure until no liquid outflowed. Compound 2 (8 mg) was purified by HPLC.

[0237] ESI-MS: m / z = 571.33 [M+H] + .

[0238] 1 H NMR (500MHz, Methanol-d4) δ8.37(s,1H),8.24(s,1H),7.29(d,J=3.2Hz,2H),4.72(d,J=8.4Hz,1H),3.62(d,J =10.8Hz,1H),3.35(s,3H),3.20–2.85(m,11H),2.84–2.56(m,8H),2.45(d,J=33.9Hz,5H),2.38–2.13(m,4H).

[0239] Example 3: Compound 3

[0240] 1) Preparation method of intermediate 3-a:

[0241] Referring to the preparation method of compound 1-d in Example 1, the reactant cyclopentanone was replaced with dihydro-3(2H)-furanone to obtain compound 3-a.

[0242] 2) Preparation method of intermediate 3-b:

[0243] Referring to the preparation method of compound 1-e in Example 1, compound 1-d was replaced with compound 3-a to obtain compound 3-b.

[0244] 3) Preparation method of compound 3-c:

[0245] The preparation method of compound 1-g in Reference Example 1 is referred to, and compound 1-e is replaced by compound 3-b to obtain compound 3-c.

[0246] 4) Preparation method of compound 3-d:

[0247] The preparation method of compound 1-h in Reference Example 1 is referred to, and compound 1-g is replaced by compound 3-c to obtain compound 3-d.

[0248] 5) Preparation method of compound 3-e:

[0249] The preparation method of compound 1-i in Reference Example 1 is referred to, and compound 1-h is replaced by compound 3-d to obtain compound 3-e.

[0250] 6) Preparation method of compound 3-f:

[0251] The preparation method of compound 1-j in Reference Example 1 is referred to, and compound 1-i is replaced by compound 3-e to obtain compound 3-f.

[0252] 7) Preparation method of compound 3-g:

[0253] The preparation method of compound 1-k in Reference Example 1 is referred to, and compound 1-j is replaced by compound 3-f to obtain compound 3-g.

[0254] 8) Preparation method of compound 3-h:

[0255] The preparation method of compound 1-l in Reference Example 1 is referred to, and compound 1-k is replaced by compound 3-g to obtain compound 3-h.

[0256] 9) Preparation method of compound 3:

[0257] The preparation method of compound 1 in Reference Example 1 is referred to, and compound 1-l is replaced by compound 3-h to obtain compound 3.

[0258] ESI-MS: m / z = 447.18 [M+H] + .

[0259] 1H NMR(500MHz, Methanol-d4)δ8.42–8.38(m,1H),7.30–7.22(m,2H),7.20–7.16(m,1H),5.22(s,2H),5.06–5.00(m,1H),4.97–4.91(m,1 H),4.82(s,1H),3.67(dd,J=12.8,3.9Hz,1H),3.29(s,3H),2.78–2.71(m,2H),2.42(s,3H),2.39–2.32(m,1H),2.19(t,J=7.6Hz,1H).

[0260] Example 4: Compound 4

[0261] 1) Preparation method of intermediate 4-a:

[0262] Referring to the preparation method of compound 2-a in Example 2, compound 1 was replaced by compound 3 to obtain compound 4-a.

[0263] 2) Preparation method of intermediate 4-b:

[0264] Referring to the preparation method of compound 2-b in Example 2, compound 2-a was replaced with compound 4-a to obtain compound 4-b.

[0265] 3) Preparation method of compound 4:

[0266] Referring to the preparation method of compound 2 in Example 2, compound 4 was obtained by replacing compound 2-b with compound 4-b.

[0267] ESI-MS: m / z = 573.31 [M+H] + .

[0268] 1 H NMR (500MHz, Methanol-d4) δ8.40 (s, 1H), 7.32–7.24 (m, 3H), 5.22 (s, 2H), 5.03 (d, J = 13. 6Hz,1H),4.94(d,J=13.9Hz,1H),4.75–4.70(m,1H),3.63(d,J=9.8Hz,1H),3.34(s,3H), 3.11(dq,J=14.2,7.2Hz,4H),3.01–2.88(m,4H),2.83(s,3H),2.70(q,J=8.1Hz,2H),2.5 7–2.46(m,3H),2.42(d,J=3.7Hz,3H),2.36(dd,J=16.9,11.1Hz,2H),2.23–2.16(m,1H).

[0269] Example 5: Preparation of compound 5

[0270] 1) Preparation method of compound 5-b:

[0271] 5-a (1.0 g) was added into ethyl trifluoroacetylacetate (10 mL). After nitrogen replacement, it was stirred at 110 °C for 10 hours. Water (20 mL) was added into the reaction solution. The organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with n-hexane, filtered, and dried to obtain 5-b (1.5 g). ESI-MS: m / z = 220.1 [M+H] + .

[0272] 2) Preparation method of compound 5-c:

[0273] 5-b (1.5 g) was added into phosphorus tribromide (20 mL). After nitrogen replacement, it was stirred at 100 °C for 10 hours. The reaction solution was cooled to 0 °C and added into saturated sodium bicarbonate aqueous solution. The organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: PE:EA = 4:1) to obtain 5-c (700 mg). ESI-MS: m / z = 281.9 [M+H] + .

[0274] 3) Preparation method of compound 5-d:

[0275] Referring to the preparation method of compound 1-g in Example 1, compound 1-e was replaced by compound 5-c to obtain compound 5-d.

[0276] 4) Preparation method of compound 5-e:

[0277] Referring to the preparation method of compound 1-h in Example 1, compound 1-g was replaced by compound 5-d to obtain compound 5-e.

[0278] 5) Preparation method of compound 5-f:

[0279] Referring to the preparation method of compound 1-i in Example 1, compound 1-h was replaced by compound 5-e to obtain compound 5-f.

[0280] 6) Preparation method of compound 5-g:

[0281] Referring to the preparation method of compound 1-j in Example 1, compound 1-i was replaced by compound 5-f to obtain compound 5-g.

[0282] 7) Preparation method of compound 5-h:

[0283] Reference is made to the preparation method of compound 1-k in Reference Example 1, and compound 1-j is replaced by compound 5-g to obtain compound 5-h.

[0284] 8) Preparation method of compound 5-i:

[0285] Reference is made to the preparation method of compound 1-l in Reference Example 1, and compound 1-k is replaced by compound 5-h to obtain compound 5-i.

[0286] 9) Preparation method of compound 5-j:

[0287] Reference is made to the preparation method of compound 1 in Reference Example 1, and compound 1-l is replaced by compound 5-i to obtain compound 5-j.

[0288] 10) Preparation method of compound 5-k:

[0289] Reference is made to the preparation method of compound 2-a in Reference Example 2, and compound 1 is replaced by compound 5-j to obtain compound 5-k.

[0290] 11) Preparation method of intermediate 5-l:

[0291] Reference is made to the preparation method of compound 2-b in Reference Example 2, and compound 2-a is replaced by compound 5-k to obtain compound 5-l.

[0292] 12) Preparation method of compound 5:

[0293] Reference is made to the preparation method of compound 2 in Reference Example 2, and compound 2-b is replaced by compound 5-l to obtain compound 5.

[0294] ESI-MS: m / z = 587.22 [M+H] + .

[0295] 1 H NMR (500 MHz, CDC13-d) δ 8.58 (s, 1H), 7.81 (d, J = 5.5 Hz, 1H), 7.33 (d, J = 5.5 Hz, 1H), 7.29 (s, 1H), 4.83 (d, J = 9.5 Hz, 1H), 4.12 (q, J = 7.2 Hz, 1H), 3.36 (s, 3H), 3.06 (s, 5H), 2.87 - 2.72 (m, 4H), 2.40 (s, 7H), 2.24 - 2.19 (m, 2H), 2.05 - 1.99 (m, 4H).

[0296] Example 6: Compound 6

[0297] 1) Preparation method of intermediate 6-a:

[0298] Furan-3-tert-butylamine (1.0 g), ethyl trifluoroacetylacetate (2.5 g) were added into acetic acid (15 mL). After nitrogen replacement, the reaction was stirred at 100 °C for 16 hours. The reaction was completed. The reaction solution was concentrated to dryness, and purified by column chromatography to obtain 6-a (1.1 g). ESI-MS: m / z = 203.97 [M+H] + .

[0299] 2) Preparation method of compound 6-b:

[0300] Referring to the preparation method of compound 1-e in Reference Example 1, compound 1-d was replaced by compound 6-a to obtain compound 6-b.

[0301] 3) Preparation method of compound 6-c:

[0302] Referring to the preparation method of compound 1-g in Reference Example 1, compound 1-e was replaced by compound 6-b to obtain compound 6-c.

[0303] 4) Preparation method of compound 6-d:

[0304] Referring to the preparation method of compound 1-h in Reference Example 1, compound 1-g was replaced by compound 6-c to obtain compound 6-d.

[0305] 5) Preparation method of compound 6-e:

[0306] Referring to the preparation method of compound 1-i in Reference Example 1, compound 1-h was replaced by compound 6-d to obtain compound 6-e.

[0307] 6) Preparation method of compound 6-f:

[0308] Referring to the preparation method of compound 1-j in Reference Example 1, compound 1-i was replaced by compound 6-e to obtain compound 6-f.

[0309] 7) Preparation method of compound 6-g:

[0310] Referring to the preparation method of compound 1-k in Reference Example 1, compound 1-j was replaced by compound 6-f to obtain compound 6-g.

[0311] 8) Preparation method of compound 6-h:

[0312] Referring to the preparation method of compound 1-l in Reference Example 1, compound 1-k was replaced by compound 6-g to obtain compound 6-h.

[0313] 9) Preparation method of compound 6-i:

[0314] Reference is made to the preparation method of compound 1 in Reference Example 1, replacing compound 1-l with compound 6-h to obtain compound 6-i.

[0315] 10) Preparation method of compound 6-j:

[0316] Reference is made to the preparation method of compound 2-a in Reference Example 2, replacing compound 1 with compound 6-i to obtain compound 6-j.

[0317] 11) Preparation method of intermediate 6-k:

[0318] Reference is made to the preparation method of compound 2-b in Reference Example 2, replacing compound 2-a with compound 6-j to obtain compound 6-k.

[0319] 12) Preparation method of compound 5:

[0320] Reference is made to the preparation method of compound 2 in Reference Example 2, replacing compound 2-b with compound 5-l to obtain compound 4.

[0321] ESI-MS: m / z = 571.26 [M+H] + .

[0322] 1 H NMR (500 MHz, CDCl3-d) δ 8.47 (s, 1H), 8.25 (s, 1H), 7.91 (t, J = 1.8 Hz, 1H), 7.31 - 7.26 (m, 2H), 6.80 (t, J = 1.7 Hz, 1H), 4.81 (d, J = 9.7 Hz, 1H), 3.60 (dd, J = 14.7, 4.6 Hz, 1H), 3.34 (d, J = 1.2 Hz, 3H), 3.15 - 2.69 (m, 12H), 2.57 (d, J = 1.3 Hz, 3H), 2.46 (ddq, J = 19.7, 12.7, 7.0 Hz, 3H), 2.38 (s, 3H), 2.22 (d, J = 5.3 Hz, 1H).

[0323] Example 7: Compound 7

[0324] Preparation method of compound 7:

[0325] Reference is made to the preparation method of compound 2 in Reference Example 2, replacing N-methylpiperazine with morpholine and replacing compound 2-b with compound 6-k to obtain compound 7.

[0326] ESI-MS: m / z = 558.29 [M+H] + .

[0327] 1 H NMR (500 MHz, MeOD-d4) δ 8.48 (s, 1H), 8.20 (d, J = 2.3 Hz, 1H), 7.46 (dd, J = 6.4, 3.2 Hz, 1H), 7.35 - 7.30 (m, 2H), 7.09 (d, J = 2.3 Hz, 1H), 4.83 (s, 1H), 3.74 - 3.63 (m, 5H), 3.37 (s, 3H), 3.18 (dtd, J = 27.5, 13.5, 7.1 Hz, 2H), 3.04 - 2.89 (m, 2H), 2.72 (dd, J = 16.8, 7.7 Hz, 1H), 2.60 (s, 6H), 2.43 (s, 4H).

[0328] Example 8: Compound 8

[0329] Preparation method of compound 8:

[0330] Reference to the preparation method of compound 2 in Example 2, replace N- methylpiperazine with (R)-1,2-dimethylpiperazine, and replace compound 2-b with compound 6-k to obtain compound 8.

[0331] ESI-MS: m / z = 585.33 [M+H] + .

[0332] 1 H NMR (500 MHz, MeOD-d4) δ 8.48 (s, 1H), 8.20 (d, J = 2.3 Hz, 1H), 7.46 (dd, J = 6.4, 3.2 Hz, 1H), 7.35 - 7.30 (m, 2H), 7.09 (d, J = 2.3 Hz, 1H), 4.83 (s, 1H), 3.74 - 3.63 (m, 5H), 3.37 (s, 3H), 3.18 (dtd, J = 27.5, 13.5, 7.1 Hz, 2H), 3.04 - 2.89 (m, 2H), 2.72 (dd, J = 16.8, 7.7 Hz, 1H), 2.60 (s, 6H), 2.43 (s, 4H).

[0333] Example 9: Compound 9

[0334] Preparation method of compound 9:

[0335] Reference to the preparation method of compound 2 in Example 2, replace N- methylpiperazine with (S)-1,2-dimethylpiperazine, and replace compound 2-b with compound 6-k to obtain compound 9.

[0336] ESI-MS: m / z = 585.37 [M+H] + .

[0337] 1 H NMR (500 MHz, MeOD-d4) δ 8.48 (s, 1H), 8.20 (d, J = 2.3 Hz, 1H), 7.45 (dd, J = 6.2, 3.4 Hz, 1H), 7.34 - 7.29 (m, 2H), 7.08 (d, J = 2.3 Hz, 1H), 4.82 (d, J = 2.3 Hz, 1H), 3.69 - 3.60 (m, 1H), 3.36 (s, 3H), 3.18 - 3.07 (m, 2H), 3.01 - 2.88 (m, 4H), 2.81 (dd, J = 27.0, 11.6 Hz, 2H), 2.71 (dd, J = 16.8, 7.9 Hz, 1H), 2.49 - 2.34 (m, 12H), 1.11 (d, J = 6.3 Hz, 3H).

[0338] Example 10: Compound 10

[0339] Preparation method of compound 10:

[0340] Reference to the preparation method of compound 2 in Example 2, replace N- methylpiperazine with 2-oxa-6-azaspiro[3.3]heptane, and replace compound 2-b with compound 6-k to obtain compound 10.

[0341] ESI-MS: m / z = 570.30 [M+H] + .

[0342] 1H NMR (500 MHz, MeOD-d4) δ 8.50 (s, 1H), 8.21 (d, J = 2.2 Hz, 1H), 7.47 (dd, J = 6.8, 2.7 Hz, 1H), 7.39 - 7.27 (m, 2H), 7.10 (d, J = 2.2 Hz, 1H), 4.83 (s, 1H), 4.73 (s, 4H), 3.63 (d, J = 10.2 Hz, 1H), 3.49 (s, 4H), 3.37 (s, 3H), 3.03 - 2.85 (m, 4H), 2.73 (dd, J = 16.8, 7.4 Hz, 1H), 2.57 (ddd, J = 28.4, 10.5, 5.6 Hz, 2H), 2.42 - 2.34 (m, 2H), 1.96 (d, J = 6.6 Hz, 2H).

[0343] Example 11: Compound 11

[0344] 1) Preparation method of compound 11-a:

[0345] Referring to the preparation method of compound 2 in Reference Example 2, replace N- methylpiperazine with 1-(tert-butoxycarbonyl)piperazine, and replace compound 2-b with compound 6-k to obtain compound 11-a.

[0346] 2) Preparation method of compound 11:

[0347] Compound 11-a (30 mg) was added to 4N HC1 / 1,4-dioxane (5 mL). After stirring at room temperature for 2 hours, the reaction was monitored by LC-MS. The reaction solution was concentrated under reduced pressure until no liquid flowed out, and then purified by HPLC to obtain compound 11 (4 mg).

[0348] ESI-MS: m / z = 557.33 [M+H] + .

[0349] 1 H NMR (500 MHz, CDCl3-d) δ 8.47 (s, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.25 (dd, J = 7.3, 2.6 Hz, 2H), 6.80 (d, J = 2.1 Hz, 1H), 4.81 (d, J = 9.6 Hz, 1H), 3.61 (dd, J = 14.3, 4.6 Hz, 1H), 3.34 (s, 3H), 3.15 - 2.98 (m, 4H), 2.78 (ddd, J = 29.9, 15.7, 10.2 Hz, 3H), 2.43 (d, J = 45.2 Hz, 8H), 2.31 - 2.16 (m, 2H), 2.01 (d, J = 2.4 Hz, 3H).

[0350] Example 12: Compound 12

[0351] Preparation method of Compound 12:

[0352] Reference to the preparation method of Compound 2 in Reference Example 2, replace N- methylpiperazine with (S)-1,3-dimethylpiperazine, and replace Compound 2-b with Compound 6-k to obtain Compound 12.

[0353] ESI-MS: m / z = 585.39 [M+H] + .

[0354] 1 H NMR (500 MHz, MeOD-d4) δ 8.50 (s, 1H), 8.22 (d, J = 2.3 Hz, 1H), 7.48 (dd, J = 6.5, 2.9 Hz, 1H), 7.34 (p, J = 2.8 Hz, 2H), 7.11 (d, J = 2.2 Hz, 1H), 4.84 (s, 1H), 3.75 - 3.61 (m, 2H), 3.39 (d, J = 2.1 Hz, 3H), 3.24 - 3.10 (m, 5H), 3.01 - 2.88 (m, 4H), 2.72 (s, 3H), 2.65 (d, J = 9.5 Hz, 1H), 2.46 (d, J = 2.0 Hz, 3H), 2.43 - 2.36 (m, 1H), 2.31 (d, J = 5.9 Hz, 1H), 2.21 (t, J = 7.6 Hz, 1H), 2.11 - 2.01 (m, 1H), 1.04 (d, J = 5.8 Hz, 3H).

[0355] Example 13: Compound 13

[0356] Preparation method of Compound 13:

[0357] Reference to the preparation method of Compound 2 in Reference Example 2, replace N- methylpiperazine with (S)-3-methylmorpholine, and replace Compound 2-b with Compound 6-k to obtain Compound 13.

[0358] ESI-MS: m / z = 572.33 [M+H] + .

[0359] 1H NMR (500 MHz, MeOD-d4) δ 8.49 (s, 1H), 8.20 (d, J = 2.3 Hz, 1H), 7.49 (dd, J = 7.1, 2.5 Hz, 1H), 7.38 - 7.32 (m, 2H), 7.09 (d, J = 2.3 Hz, 1H), 4.83 (d, J = 1.5 Hz, 1H), 3.89 - 3.79 (m, 2H), 3.74 - 3.66 (m, 2H), 3.39 (s, 3H), 3.30 - 3.24 (m, 2H), 3.17 (dp, J = 9.3, 4.1 Hz, 2H), 2.96 (qd, J = 12.0, 8.5 Hz, 3H), 2.83 (t, J = 10.6 Hz, 1H), 2.74 (ddd, J = 16.7, 9.9, 6.9 Hz, 2H), 2.46 - 2.37 (m, 4H), 1.13 (d, J = 6.5 Hz, 2H).

[0360] Example 14: Compound 14

[0361] Preparation method of compound 14:

[0362] The preparation method of compound 2 in Reference Example 2 was referred to, 1- methyl-1, 4-diazepane was used to replace N-methylpiperazine, and compound 6-k was used to replace compound 2-b, to obtain compound 14.

[0363] ESI-MS: m / z = 585.31 [M+H] + .

[0364] 1 H NMR (500 MHz, MeOD-d4) δ 8.51 (s, 1H), 8.23 (d, J = 2.3 Hz, 1H), 7.48 (dd, J = 5.8, 3.7 Hz, 1H), 7.35 - 7.34 (m, 2H), 7.11 (d, J = 2.3 Hz, 1H), 4.85 (s, 1H), 3.67 (d, J = 10.0 Hz, 1H), 3.39 (s, 3H), 3.16 - 3.08 (m, 4H), 2.98 - 2.95 (m, 2H), 2.86 (s, 2H), 2.80 - 2.78 (m, 2H), 2.73 - 2.70 (m, 3H), 2.66 - 2.60 (m, 2H), 2.45 (s, 3H), 2.45 - 2.38 (m, 1H), 2.22 (t, J = 7.5 Hz, 1H), 1.96 (s, 1H), 1.95 (s, 3H).

[0365] Example 15: Compound 15

[0366] Method for preparing compound 15:

[0367] Reference is made to the method for preparing compound 2 in Reference Example 2, replacing N-methylpiperazine with (S)-2-ethyl-l-methylpiperazine and compound 2-b with compound 6-k to obtain compound 15.

[0368] ESI-MS: m / z = 599.34 [M+H] + .

[0369] 1 H NMR (500 MHz, MeOD-d4) δ 8.38 (s, 1H), 8.10 (d, J = 2.3 Hz, 1H), 7.36 (dd, J = 6.1, 3.5 Hz, 1H), 7.27 - 7.18 (m, 2H), 6.99 (d, J = 2.3 Hz, 1H), 4.72 (s, 1H), 3.56 (s, 2H), 3.29 - 3.24 (m, 4H), 3.22 (d, J = 1.7 Hz, 3H), 2.84 (d, J = 10.2 Hz, 6H), 2.53 (s, 1H), 2.39 (s, 3H), 2.34 (s, 3H), 2.09 (t, J = 7.6 Hz, 2H), 1.23 (s, 3H), 0.80 (t, J = 6.8 Hz, 2H).

[0370] Example 16: Compound 16

[0371] Method for preparing compound 16:

[0372] Reference is made to the method for preparing compound 2 in Reference Example 2, replacing N-methylpiperazine with (R)-2-ethyl-l-methylpiperazine and compound 2-b with compound 6-k to obtain compound 16.

[0373] ESI-MS: m / z = 599.36 [M+H] + .

[0374] 1H NMR (500 MHz, CDCI3-d) 8.47 (s, 1 H), 7.90 (s, 1 H), 7.28 (s, 1 H), 7.25 (d, J = 5.3 Hz, 2 H), 6.85 - 6.77 (m, 1 H), 4.82 (d, J = 9.5 Hz, 1 H), 3.63 (d, J = 13.0 Hz, 1 H), 3.34 (s, 3 H), 3.07 (d, J = 41.2 Hz, 3 H), 2.76 (dd, J = 53.1, 20.9 Hz, 6 H), 2.39 (s, 3 H), 2.31 (s, 3 H), 2.22 (t, J = 7.7 Hz, 4 H), 2.05 (d, J = 5.2 Hz, 2 H), 0.88 (t, J = 6.2 Hz, 5 H).

[0375] Example 17: Compound 17

[0376] Process for the preparation of Compound 17:

[0377] The process for the preparation of Compound 17 was carried out according to the process for the preparation of Compound 2 in Reference Example 2, replacing N-methylpiperazine with 1-methylpiperazine-2-one and Compound 2-b with Compound 6-k.

[0378] ESI-MS: m / z = 585.26 [M+H] + .

[0379] 1 H NMR (500 MHz, CDCI3-d) 8.47 (s, 1 H), 7.90 (s, 1 H), 7.28 (s, 1 H), 7.25 (d, J = 5.3 Hz, 2 H), 6.85 - 6.77 (m, 1 H), 4.82 (d, J = 9.5 Hz, 1 H), 3.63 (d, J = 13.0 Hz, 1 H), 3.34 (s, 3 H), 3.07 (d, J = 41.2 Hz, 3 H), 2.76 (dd, J = 53.1, 20.9 Hz, 6 H), 2.39 (s, 3 H), 2.31 (s, 3 H), 2.22 (t, J = 7.7 Hz, 4 H), 2.05 (d, J = 5.2 Hz, 2 H), 0.88 (t, J = 6.2 Hz, 5 H).

[0380] Example 18: Compound 18

[0381] Process for the preparation of Compound 18:

[0382] The process for the preparation of Compound 18 was carried out according to the process for the preparation of Compound 2 in Reference Example 2, replacing N-methylpiperazine with 3-methyl-3,8-diazabicyclo[3.2.1]octane and Compound 2-b with Compound 6-k.

[0383] ESI-MS: m / z = 597.30 [M+H] + .

[0384] 1 H NMR (500 MHz, MeOD-d4) δ 8.48 (s, 1H), 8.20 (d, J = 2.4 Hz, 1H), 7.46 (dd, J = 6.2, 3.4 Hz, 1H), 7.39 - 7.25 (m, 2H), 7.08 (d, J = 2.3 Hz, 1H), 4.82 (s, 1H), 4.56 (s, 1H), 3.67 (d, J = 9.6 Hz, 1H), 3.37 (s, 3H), 3.28 (s, 1H), 3.24 - 3.06 (m, 3H), 3.00 - 2.87 (m, 2H), 2.79 - 2.67 (m, 3H), 2.54 (dd, J = 15.0, 6.3 Hz, 2H), 2.43 (s, 3H), 2.38 (dd, J = 16.7, 10.9 Hz, 2H), 2.29 (s, 3H), 1.99 - 1.93 (m, 2H), 1.84 (d, J = 8.5 Hz, 2H).

[0385] Example 19: Compound 19

[0386] Preparation method of compound 19:

[0387] Reference to the preparation method of compound 2 in Reference Example 2, replace N- methylpiperazine with (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane, and replace compound 2-b with compound 6-k to obtain compound 19.

[0388] ESI-MS: m / z = 583.29 [M+H] + .

[0389] 1H NMR (500 MHz, MeOD-d4) δ 8.48 (s, 1H), 8.20 (d, J = 2.3 Hz, 1H), 7.46 (dd, J = 6.1, 3.5 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.09 (d, J = 2.4 Hz, 1H), 4.82 (s, 1H), 3.85 (s, 1H), 3.67 - 3.61 (m, 1H), 3.56 (s, 1H), 3.36 (s, 3H), 3.11 - 3.02 (m, 2H), 2.98 - 2.79 (m, 5H), 2.71 (d, J = 15.1 Hz, 5H), 2.61 - 2.51 (m, 1H), 2.43 (s, 3H), 2.41 - 2.33 (m, 1H), 1.92 (s, 3H).

[0390] Example 20: Compound 20

[0391] Preparation method of compound 20:

[0392] The preparation method of compound 2 in Reference Example 2 was referred to, N- methylpiperazine was replaced by (1R, 4R)-2-methyl-2, 5-diazabicyclo [2.2.1] heptane, and compound 2-b was replaced by compound 6-k to obtain compound 20.

[0393] ESI-MS: m / z = 583.36 [M+H] + .

[0394] 1 H NMR (500 MHz, MeOD-d4) δ 8.48 (s, 1H), 8.20 (d, J = 2.3 Hz, 1H), 7.46 (dd, J = 6.1, 3.5 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.09 (d, J = 2.4 Hz, 1H), 4.82 (s, 1H), 3.85 (s, 1H), 3.67 - 3.61 (m, 1H), 3.56 (s, 1H), 3.36 (s, 3H), 3.11 - 3.02 (m, 2H), 2.98 - 2.79 (m, 5H), 2.71 (d, J = 15.1 Hz, 5H), 2.61 - 2.51 (m, 1H), 2.43 (s, 3H), 2.41 - 2.33 (m, 1H), 1.92 (s, 3H).

[0395] Example 21: Compound 21

[0396] Method for preparing compound 21:

[0397] Reference is made to the method for preparing compound 2 in Reference Example 2, replacing N-methylpiperazine with 4-dimethylaminopiperidine, and replacing compound 2-b with compound 6-k to obtain compound 21.

[0398] ESI-MS: m / z = 599.32 [M+H] + .

[0399] 1 H NMR (500 MHz, CDC13-d) δ 8.47 (s, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.26 - 7.17 (m, 3H), 6.80 (d, J = 2.3 Hz, 1H), 4.81 (d, J = 9.5 Hz, 1H), 3.62 (dd, J = 14.3, 4.6 Hz, 1H), 3.34 (s, 3H), 3.14 - 2.88 (m, 5H), 2.78 (ddd, J = 29.6, 15.7, 10.2 Hz, 3H), 2.45 (s, 6H), 2.42 - 2.32 (m, 5H), 2.27 - 2.13 (m, 2H), 1.87 (ddt, J = 12.3, 5.8, 3.1 Hz, 2H), 1.70 - 1.48 (m, 3H).

[0400] Example 22: Compound 22

[0401] Method for preparing compound 22:

[0402] Reference is made to the method for preparing compound 2 in Reference Example 2, replacing N-methylpiperazine with 4-dimethylaminopiperidine, and replacing compound 2-b with compound 6-k to obtain compound 21.

[0403] ESI-MS: m / z = 599.32 [M+H] + .

[0404] 1H NMR (500 MHz, MeOD-d4) δ 8.35 (s, 1H), 8.08 (d, J = 2.3 Hz, 1H), 7.37 (dd, J = 7.3, 2.4 Hz, 1H), 7.26 - 7.17 (m, 2H), 6.97 (d, J = 2.3 Hz, 1H), 4.70 (s, 1H), 3.51 (dd, J = 14.3, 4.5 Hz, 1H), 3.25 (s, 3H), 3.07 (td, J = 13.3, 6.1 Hz, 4H), 2.79 - 2.66 (m, 4H), 2.47 (d, J = 12.8 Hz, 5H), 2.31 (s, 3H), 1.94 (d, J = 13.4 Hz, 2H), 1.80 (d, J = 4.3 Hz, 3H), 1.46 (d, J = 12.6 Hz, 2H).

[0405] Example 23: Compound 23

[0406] Process for preparing compound 23:

[0407] Reference to the preparation method of compound 2 in example 2, replace N- methylpiperazine with N,N-dimethyl-1,4-cyclohexanediamine, replace compound 2-b with compound 6-k, reaction was completed, purified by HPLC (preparative liquid phase) (YMC AQ C18, specification 30*250mm, 10μm, mobile phase: A: 0.05% trifluoroacetic acid, B: acetonitrile; gradient: 15%-50% B 0-70min, wavelength 254nm, v = 30ml / min, rt 50min to get 23 and rt 53min to get 24.

[0408] Compound 23: ESI-MS: m / z = 613.36 [M+H] + .

[0409] Compound 24: ESI-MS: m / z = 613.36 [M+H] + .

[0410] Experimental Example 1: POLQ protein inhibitory activity assay

[0411] POLQ protein solution (concentration 4 nM) was added to the detection hole at 6 μL per hole, and different compounds dissolved in DMSO were added to the detection hole by means of nanoliter sample injector, so that the final concentration of the compound was 2000 nM-0.488 nM, 2 duplicate holes, and controls were set. After mixing 100 nM PolQ substrate and 40 μM dNTP, 6 μL per hole was added to the detection hole, and the above system was incubated for 60 minutes. PicoGreen dye (manufacturer: Thermo) was diluted 1:80 with termination buffer and added to the detection hole at 8 μL per hole; after reaction at room temperature for 90 min; PerkinElmer Envision multifunctional enzyme label instrument was used for detection (excitation 485 nm, emission 520 nm), and four-parameter fitting was used to calculate IC 50 The experimental results are shown in Table 1.

[0412] Table 1

[0413] Test Example 2: In vitro liver microsomal stability evaluation

[0414] The liver microsomal incubation sample was prepared by mixing PBS buffer (PH 7.4), liver microsomal solution (0.5 mg / ml), test compound and NADPH+MgCl2 solution 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 acetonitrile solution containing an internal standard, and the supernatant was prepared by protein precipitation. After dilution, it was used for LC / MS / MS determination. The test results show that the compound of the application has liver microsomal metabolic stability.

[0415] Test Example 3: In vivo pharmacokinetics

[0416] ICR mice, weighing 18-22 g, were randomly divided into groups after 3-5 days of adaptation, 9 mice per group, and the compound solution was administered by intravenous injection at a dose of 1 mg / kg and by gavage at a dose of 10 mg / kg.

[0417] The blood sampling time points for intravenous injection were 0, 0.083 (5 min), 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, 10, 24 h, and the blood was taken from the orbit to prepare the test plasma sample.

[0418] The blood sampling time points for gavage were 0, 0.25 (15 min), 0.5 (30 min), 1, 2, 4, 6, 8, 10, 24 h, and the blood was taken from the orbit to prepare the test plasma sample.

[0419] 30 μL of the test plasma sample and the standard sample were taken, acetonitrile containing an internal standard was added, and the supernatant was obtained by protein precipitation. After dilution, it was used for LC / MS / MS determination. Non-compartmental model fitting was used.

[0420] The test results show that the test compounds of the present application have good in vivo metabolic kinetics.

[0421] Test Example 4: Cell activity test

[0422] 1.1 MDA-MB-436WT cell proliferation inhibition activity determination

[0423] Take the MDA-MB-436WT cells in good growth state, collect into centrifuge tubes, adjust the cell density to 5x10 3 6nM, 2 replicate wells, and set controls at the same time. After 7 days of continuous culture in the cell incubator, add detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well), incubate in the cell incubator for 2 hours, then detect the absorbance value at 450 nm by Envision enzyme label instrument, analyze by four parameters, fit the dose-effect curve, and calculate the IC 50 . The results are shown in Table 2.

[0424] Table 2

[0425] 1.2 MDA-MB-436(SHLD2- / -) cell proliferation inhibition activity determination

[0426] Take the MDA-MB-436(SHLD2- / -) cells in good growth state, collect into centrifuge tubes, adjust the cell density to 5x10 3 6nM, 2 replicate wells, and set controls at the same time. After 7 days of continuous culture in the cell incubator, add detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well), incubate in the cell incubator for 2 hours, then detect the absorbance value at 450 nm by Envision enzyme label instrument, analyze by four parameters, fit the dose-effect curve, and calculate the IC 50 . The results are shown in Table 3.

[0427] Table 3

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, in, Ring A, Ring B and Ring C are each independently selected from a 3-20 membered ring; Every R 1 are independently selected from halogen, -CN, =O, or the following groups optionally substituted with one or more R': C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a 、-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2R a R b 、-NR a SO2R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; Every R 2 are independently selected from halogen, CN, =O, or the following groups optionally substituted with one or more R": C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, -OR a 、-SR a 、-NR a R b 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; Every R 3 are independently selected from halogen, CN, =O, or the following groups optionally substituted with one or more R'': C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, -OR a 、-SR a 、-NR a R b 、-COR a 、-COOR a 、-OCOR a 、-CONR a R b 、-NR a COR b 、-SOR a 、-SONR a R b 、-NR a SOR b 、-SO2R a 、-SO2NR a R b 、-NR a SO2R b 、-OC(O)NR a R b 、-NR a C(O)OR b 、-NR a C(O)NR a R b 、C 3-12 Cycloalkyl, C 6-12 aryl, 5-12 membered heteroaryl or 3-12 membered heterocyclyl; Every R a and R b are independently selected from hydrogen, C 1-12 Alkyl, C 1-12 Heteroalkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; Each R', R" or R'" is independently selected from halogen, CN, OH, SH, NH2, CHO, COOH, or optionally substituted by one or more R d Substituted with the following groups: -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; m, n and p are independently selected from 0, 1, 2, 3, 4, 5 or 6; Each X is independently selected from -CH2-, -NH-, -O- or -S-; k is selected from 0, 1, 2, 3 or 4; L is selected from a bond, or optionally replaced by one or more R e Substituted with the following groups: -C 1-12 Alkylene-, -C 1-12 Alkylene O-, -C 1-12 Alkylene NH- or -C 1-12 Alkylene S-; L 1 Selected from optionally one or more R f Substituted with the following groups: -COO-R c1 -、-OCO-R c1 -、-CONR c -R c1 -、-NR c CO-R c1 -、-SONR c -R c1 -、-NR c SO-R c1 -, -SO2NR c -R c1 -、-NR c SO2-R c1 -、C 1-12 Alkylene, C 2-12 Alkenylene, C 2-12 Alkynylidene, C 1-12 Heteroalkylene, C 2-12 Heteroalkenylene or C 2-12 heteroalkynylene; R c1 Selected from bond, C 1-12 Alkylene, C 1-12 Ethylene, C 1-12 Alkynylidene, C 1-12 Heteroalkylene, C 2-12 Heteroalkenylene or C 2-12 heteroalkynylene; R c Selected from hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl; R d 、R e and R f are independently selected from halogen, CN, OH, SH, NH2, CHO, COOH, or the following groups optionally substituted with one or more R: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -C 1-12 Alkyl-C 3-12 Cycloalkyl, -C 1-12 Alkyl-3-12 membered heterocyclic group, -C 1-12 Alkyl-C 6-12 Aryl, -C 1-12 Alkyl-5-12 membered heteroaryl, -C 1-12 Heteroalkyl-C 3-12 Cycloalkyl, -C 1-12 Heteroalkyl-3-12 membered heterocyclic group, -C 1-12 Heteroalkyl-C 6-12 Aryl or -C 1-12 heteroalkyl-5-12 membered heteroaryl; R is selected from oxo, halogen, CN, OH, SH, NH2, CHO, COOH, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkanyl, C 6-12 Aryl, 5-12 membered heteroaryl, C 1-12 Alkyl-L 2 -、C 2-12 Alkenyl-L 2 、C 2-12 Alkynyl-L 2 -、C 3-12 Cycloalkyl-L 2 -, 3-12 membered heterocyclic group-L 2 -、C 6-12 Aryl-L 2 - or 5-12 membered heteroaryl-L 2 -;L 2 is selected from C(O), OC(O), C(O)O, C(O)NH, NHC(O), OC(O)NH or NHC(O)O; The C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkanyl, C 6-12 Aryl, 5-12 membered heteroaryl, C 1-12 Alkyl-L 2 -、C 2-12 Alkenyl-L 2 、C 2-12 Alkynyl-L 2 -、C 3-12 Cycloalkyl-L 2 -, 3-12 membered heterocyclic group-L 2 -、C 6-12 Aryl-L 2 - or 5-12 membered heteroaryl-L 2 - optionally substituted with one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, COOH, C 1-12 Alkyl-C(O)-, C 2-12 Alkenyl-C(O)-, C 2-12 Alkynyl-C(O)-, C 3-12 Cycloalkyl-C(O)-, 3-12 membered heterocyclyl-C(O)-, C 6-12 Aryl-C(O)- or 5-12 membered heteroaryl-C(O)-.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from a 5-12 membered ring; or, Ring A is selected from a 5-6 membered ring; Alternatively, Ring A is selected from a C5 cycloalkenyl, a 5-membered heterocyclyl, or a 5-membered heteroaryl; Alternatively, Ring A is selected from a cyclopentenyl, a dihydrofuranyl, a furanyl, a thienyl, a pyrrolyl, a thiazolyl, an oxazolyl, an isoxazolyl, or a pyrazolyl; Alternatively, Ring A is selected from a thienyl; Alternatively, ring C is selected from a 5-12 membered monocyclic ring, or a 5-6 membered monocyclic ring; Alternatively, ring C is selected from a 5-6 membered heteroaryl group; Alternatively, ring C is selected from a 6 membered heteroaryl group; Alternatively, ring C is selected from a pyridyl group; Alternatively, Ring A and Ring C are each independently a monocyclic structure; Alternatively, Ring A is selected from a 5-12 membered monocyclic ring, or a 5-6 membered monocyclic ring; Alternatively, ring B is selected from a 5-12 membered ring; alternatively, ring B is selected from a 5-10 membered ring; alternatively, ring B is selected from a 5-6 membered ring; alternatively, ring B is selected from a phenyl group, a 9-membered heterocyclyl group or a 9-membered heteroaryl group; alternatively, ring B is selected from a phenyl group.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each R 1 are independently selected from halogen, -CN, =O, or optionally substituted by one or more R ’ Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR a 、-SR a 、-NR a R b 、C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl; Or, R 1 is selected from C optionally substituted by one or more halogens 1-4 alkyl; Or, R 1 is selected from methyl optionally substituted by one or more atoms selected from F, Cl or Br; Or, R 1 Selected from trifluoromethyl or methyl; Optionally, each R 2 are independently selected from halogen, CN, =O, or the following groups optionally substituted with one or more R": C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR a 、-SR a 、-NR a R b 、C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl; Or, each R 2 are independently selected from carbonyl or OH; Or, each R 2 are each independently selected from a carbonyl group; Optionally, each R 3 are independently selected from halogen, CN, =O, or optionally substituted by one or more R" ’ Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OR a 、-SR a 、-NR a R b 、C 3-6 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group; Or, R 3 Selected from halogen or C 1-3 alkyl; Or, R 3 is selected from halogen (e.g., F, Cl, Br, or I) or methyl; Optionally, each R a and R b are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl; Or, each R a and R b are independently selected from hydrogen or C 1-4 alkyl; Optionally, each R', R" or R'" is independently selected from halogen, CN, OH, SH, NH2, CHO, COOH, or optionally substituted by one or more R d Substituted with the following groups: -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl; Alternatively, each R''' is selected from halogen (eg, F, Cl, Br, or I).

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein m is selected from 0, 1 or 2; optionally, n is selected from 1 or 2; optionally, p is selected from 0, 1 or 2; optionally, k is selected from 1; optionally, each X is independently selected from -CH2-.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein each X is independently selected from -CH2- or -NH-; Alternatively, each X is independently selected from -O- or -S-; alternatively, X is selected from -CH2-; alternatively, X is selected from -NH-.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein L is selected from a bond, or is optionally replaced by one or more R e Substituted with the following groups: -C 1-6 Alkylene-, -C 1-6 Alkylene O-, -C 1-6 Alkylene NH- or -C 1-6 Alkylene S-; Alternatively, L is selected from optionally one or more R e Substituted -C 1-3 Alkylene NH-; Alternatively, L is selected from optionally one or more R e substituted -CH2NH-; Optionally, L 1 Selected from optionally one or more R f Substituted with the following groups: -COO-, -OCO-, -CONR c -、-NR c CO-、-SONR c -、-NR c SO-, -SO2NR c -、-NR c SO2-、C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 1-6 Heteroalkylene, C 2-6 Heteroalkenylene or C 2-6 heteroalkynylene; Or, L 1 Selected from -CONR c -or-NR c CO-; Or, L 1 Selected from -CON(CH3)-; Optionally, R c1 Select from bond or C 1-6 Alkylene; or, R c1 Select from keys; Optionally, R c Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl; Or, R c Selected from hydrogen, C 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group; or, R c Selected from methyl.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R d 、R e and R f are independently selected from halogen, CN, OH, SH, NH2, CHO, COOH, or the following groups optionally substituted with one or more R: C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -C 1-12 Alkyl-C 3-12 Cycloalkyl, -C 1-12 Alkyl-3-12 membered heterocyclic group, -C 1-12 Alkyl-C 6-12 Aryl, -C 1-12 Alkyl-5-12 membered heteroaryl, -C 1-12 Heteroalkyl-C 3-12 Cycloalkyl, -C 1-12 Heteroalkyl-3-12 membered heterocyclic group, -C 1-12 Heteroalkyl-C 6-12 Aryl or -C 1-12 heteroalkyl-5-12 membered heteroaryl; Or, R d and R f are independently selected from halogen, CN, OH, SH, NH2, CHO, COOH, C 1-6 Alkyl or halogenated C 1-6 alkyl; Optionally, R e Selected from the following groups optionally substituted with one or more R: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-3-10 membered heterocyclic group, -C 1-6 Alkyl-C 6-10 Aryl, -C 1-6 Alkyl-5-10 membered heteroaryl, -C 1-6 Heteroalkyl-C 3-10 Cycloalkyl, -C 1-6 Heteroalkyl-3-10 membered heterocyclic group, -C 1-6 Heteroalkyl-C 6-10 Aryl or -C 1-6 heteroalkyl-5-10 membered heteroaryl; Or, R e Selected from the following groups optionally substituted with one or more R: C 1-3 Alkyl, C 2-3 Alkenyl, -C 1-3 Alkyl 6-membered heterocycloalkyl, -C 1-3 Alkyl 7-membered heterocycloalkyl, -C 1-3 Alkyl 8-membered heterocycloalkyl, -C 1-3 Alkyl 9-membered heterocycloalkyl, -C 1-3 Heteroalkyl 6-membered heterocycloalkyl, -C 1-3 Heteroalkyl 7-membered heterocycloalkyl, -C 1-3 Heteroalkyl 8-membered heterocycloalkyl, -C 1-3 Alkyl-NH-6-membered heterocycloalkyl or -C 1-3 AlkylNH-C6cycloalkyl; Or, R e Selected from the following groups optionally substituted by one or more R: methyl, propenyl, Or, R e Selected from the following groups optionally substituted with one or more R: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-3-6 membered heterocyclic group, -C 1-6 Alkyl-C 6-10 Aryl, -C 1-6 Alkyl-5-6 membered heteroaryl, -C 1-6 Heteroalkyl-C 3-6 Cycloalkyl, -C 1-6 Heteroalkyl-3-6 membered heterocyclic group, -C 1-6 Heteroalkyl-C 6-10 Aryl or -C 1-6 Heteroalkyl-5-6 membered heteroaryl; Or, R e Selected from the following groups optionally substituted with one or more R: -C 1-4 Alkyl-C 3-6 Cycloalkyl, -C 1-4 Alkyl-3-6 membered heterocyclic group, -C 1-4 Alkyl-C 6-10 Aryl or -C 1-4 Alkyl-5-6 membered heteroaryl; Or, R e Selected from the following groups optionally substituted with one or more R: -C 1-3 Alkyl-piperazinyl or -C 1-3 Alkyl-morpholinyl; Or, R e is selected from the following groups optionally substituted with one or more R: Optionally, R is selected from halogen, CN, OH, SH, NH2, CHO, COOH, C 1-12 Alkyl, C 1-12 Halogenated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl or -N(C 1-12 Alkyl)2; Alternatively, R is selected from halogen, CN, OH, SH, NH2, CHO, COOH, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, -OC 1-12 Alkyl, -SC 1-12 Alkyl, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkanyl, C 6-12 Aryl, 5-12 membered heteroaryl, C 1-12 Alkyl-L 2 -、C 2-12 Alkenyl-L 2 、C 2-12 Alkynyl-L 2 -、C 3-12 Cycloalkyl-L 2 -, 3-12 membered heterocyclic group-L 2 -、C 6-12 Aryl-L 2 - or 5-12 membered heteroaryl-L 2 -;L 2 is selected from C(O), OC(O), C(O)O, C(O)NH, NHC(O), OC(O)NH or NHC(O)O; Alternatively, R is selected from oxo, halogen, CN, OH, SH, NH2, CHO, COOH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, C 1-6 Alkyl-L 2 -、C 2-6 Alkenyl-L 2 、C 2-6 Alkynyl-L 2 -、C 3-6 Cycloalkyl-L 2 -, 3-6 membered heterocyclic group-L 2 -, C6 aryl-L 2 - or 5-6 membered heteroaryl-L 2 -;L 2 is selected from C(O), OC(O) or C(O)O; The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, C 1-6 Alkyl-L 2 -、C 2-6 Alkenyl-L 2 -、C 2-6 Alkynyl-L 2 -、C 3-6 Cycloalkyl-L 2 -, 3-6 membered heterocyclic group-L 2 -, C6 aryl-L 2 - or 5-6 membered heteroaryl-L 2 - optionally substituted with one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, COOH, C 1-6 Alkyl-C(O)-, C 2-6 Alkenyl-C(O)-, C 2-6 Alkynyl-C(O)-, C 3-6 Cycloalkyl-C(O)-, 3-6 membered heterocyclyl-C(O)-, C6 aryl-C(O)- or 5-6 membered heteroaryl-C(O)-; Alternatively, R is selected from oxo, halogen, CN, OH, NH2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, -OC 1-3 Alkyl, -SC 1-3 Alkyl, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, C 1-3 Alkyl-C(O)-, C 2-3 Alkenyl-C(O)-, or C 2-3 Alkynyl-C(O)-; The C 1-3 Alkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, CN, OH, SH, NH2, CHO, COOH, C 1-3 Alkyl-C(O)-, C 2-3 Alkenyl-C(O)- or C 2-3 Alkynyl-C(O)-; Alternatively, R is selected from oxo, F, methyl, ethyl, -CH2OH, -N(CH3)2, Alternatively, R is selected from methyl; Or, R e Selected from 8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is selected from a compound of formula II, III, IV, IA, IIA, IIIA or IVA or a pharmaceutically acceptable salt thereof: in, Ring A, Ring B, Ring C, X, R 1 、R 2 、R 3 、R e 、R f , m, n, p, k, L and L 1 The definition as described in any one of claims 1 to 7; q and r are each independently selected from 0, 1 or 2.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof:

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and optionally further comprising a pharmaceutically acceptable excipient.

11. Use of the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 10 in the preparation of a medicament for preventing or treating cancer.

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