Pyrimidine PLK1 inhibitor as well as preparation method and application thereof

Abstract

The invention provides a novel PLK1 inhibitor which can be used for preventing and / or treating diseases related to PLK1, such as tumors.

Description

Technical Field

[0001] The present invention relates to the field of biochemistry, and in particular to a pyrimidine PLK1 inhibitor, a preparation method and use thereof. Background Art

[0002] PLK1 belongs to the Polo-like kinases (PLKs) family (including PLK1 / 2 / 3 / 4) and is a highly conserved Ser / Thr protein kinase that plays an important role in the normal operation of the cell cycle, centrosome maturation, and cytoplasmic separation. PLK1 regulates the G2 / M transition by phosphorylating downstream cell cycle proteins such as WEE1 / CDK1; PLK1 inhibition causes cell mitosis to arrest in the G2 phase and induces apoptosis (Sci Signal. 2018 Aug 14; 11(543): eaar4195). In addition, PLK1 also has regulatory effects on cellular functions other than mitosis, such as repairing damaged DNA and promoting tumor cell proliferation (Mol Cell. 2021 Mar 4; 81(5): 1084-1099.e6.). PLK1 is overexpressed in most malignant tumors, including colorectal cancer, breast cancer, lung cancer, prostate cancer, leukemia, and pancreatic cancer, mediating poor prognosis in patients (Genes 2019, 10, 208; World J Gastroenterol 2005; 11(36): 5644-5650). In addition, PLK1 is highly associated with multiple tumor-related targets and pathways. RAS mutations cause cell mitotic stress, making tumor cells more dependent on PLK1 for mitosis. Interference with the mitotic process can promote synthetic lethality of tumor cells. PLK1 knockout or inhibition of PLK1 kinase activity causes mitosis of RAS mutant cells to arrest at the G2 / M phase (Cell 137, 835–848, May 29, 2009). PLK1 can directly phosphorylate p53 protein, mediating p53 instability, or indirectly promote TOPORS and GTSE1 phosphorylation, degrading p53 and causing it to lose its tumor suppressor function. PLK1 directly stabilizes or promotes the expression of the oncogenic protein Myc, promoting the occurrence and development of tumors. PLK1 can also inhibit PTEN phosphorylation and activate the PI3K signaling pathway.

[0003] Therefore, small molecules targeting the enzymatic activity of PLK1 have broad therapeutic potential for PLK1-related tumors. Summary of the Invention

[0004] The present invention provides a new PLK1 inhibitor, which can be used to prevent and / or treat PLK1-related diseases, such as tumors.

[0005] According to one aspect of the present invention, the present invention provides a compound represented by formula (I) or an isomer, deuterated substance, or pharmaceutically acceptable salt thereof, or a polymorph or solvate thereof or a salt thereof:

[0006]

[0007] in:

[0008] G is a bond or -CH2-;

[0009] Ring A is selected from phenyl, 5-6 membered heteroaryl containing 1-2 ring heteroatoms independently selected from N and S;

[0010] When ring A is a heteroaryl group, ring A and its fused ring share a ring carbon and / or ring nitrogen atom, and ring B is connected to a ring carbon atom or a ring nitrogen atom of ring A;

[0011] X and Y are independently selected from N and CH;

[0012] R 1a and R 1b independently selected from H, F, Cl, Br, OH, CN, -NR8R9, C 1-4 Straight-chain or branched alkyl, C 2-4 Straight-chain or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 Straight-chain or branched alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S connected to the proximal group through C or N on the ring, or, R 1a and R 1b Together with the ring C atoms to which they are connected, they form C=O, C=CH2, C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, and S, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted by one or more independently selected from F, Cl, Br, OH, SH, CN, -C(O)R8, -C(O)N(R8)R9, -S(O)2R8, -S(O)2N(R8)R9, -N(R8)R9, -N(R8)C(O)R9, -N(R8)S(O)2R9, -P(O)(R8)R9, C 1-4 Straight-chain or branched alkyl, C 2-4 Straight-chain or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 linear or branched alkoxy group substitution;

[0013] R2, R3 are independently selected from H, F, Cl, Br, OH, CN, NO2, C 1-4Straight-chain or branched alkyl, C 2-4 Straight-chain or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 Straight-chain or branched alkoxy, C 3-7 Cycloalkyl, C 3-7 Cycloalkyloxy, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, and S, which is connected to the proximal group through C or N on the ring, 3-7 membered heterocycloalkyloxy containing 1-3 ring heteroatoms independently selected from N, O, and S, which is connected to oxygen through C or N on the ring, 5-11 membered heteroaryl containing 1-3 ring heteroatoms independently selected from N, O, and S, which is connected to the proximal group through C or N on the ring, phenyl, -C(O)R8, -C(O)OR8, -C(O)N(R8)R9, -S(O)2R8, -S(O)2N(R8)R9, -N(R8)R9, -N(R8)C(O)R9, -N(R8)S(O)2R9, -P(O)(R8)R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocyclyloxy, heteroaryl, phenyl are optionally substituted by one or more independently selected from F, Cl, Br, OH, CN, NO2, -C(O)R8, -C(O)OR8, -C(O)N(R8)R9, -S(O)2R8, -S(O)2N(R8)R9, -N(R8)R9, -N(R8)C(O)R9, -N(R8)S(O)2R9, -P(O)(R8)R9, C 1-4 Straight-chain or branched alkyl, C 2-4 Straight-chain or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 Straight-chain or branched alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, and S, which is connected to the proximal group through C or N on the ring, 5-11 membered heteroaryl containing 1-3 ring heteroatoms independently selected from N, O, and S, which is connected to the proximal group through C or N on the ring, and phenyl;

[0014] R4 is selected from H, F, Cl, Br, OH, CN, NH2, C 1-4 Straight-chain or branched alkyl, C 2-4 Straight-chain or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 Straight chain alkoxy, C 3-7 Cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, OH, CN, NH2, C 1-4 Straight-chain or branched alkyl, C 2-4Straight-chain or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 linear or branched alkoxy group substitution;

[0015] R5 is selected from F, Cl, Br, -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0016] R6 is selected from H, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S connected to the proximal group through C or N on the ring, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, OH, CN, NH2, =O, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0017] R7 is independently selected from H, F, Cl, Br, OH, CN, =O, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S connected to the proximal group through C or N on the ring, or two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S; or, two R7 located on two non-adjacent ring C atoms are connected to form a C between the two non-adjacent ring C atoms. 1-2 Alkylene, the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkylene are optionally substituted by one or more independently selected from F, Cl, Br, OH, CN, NH2, =O, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0018] R8 and R9 are independently selected from H, OH, CN, NH2, C 1-4 Straight-chain or branched alkyl, C 2-4 Straight-chain or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 Straight-chain or branched alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, and S connected to the proximal group through C or N on the ring, 5-11 membered heteroaryl containing 1-3 ring heteroatoms independently selected from N, O, and S connected to the proximal group through C or N on the ring, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl are optionally substituted by one or more selected from F, Cl, Br, OH, CN, NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0019] Alternatively, R8 and R9 together with the atoms to which they are attached form a 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S, which is optionally substituted with one or more ring heteroatoms independently selected from F, Cl, Br, OH, CN, NH2, C 1-4 Straight-chain or branched alkyl, C 2-4 Straight-chain or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 A linear or branched alkoxy group is substituted, wherein the alkyl, alkenyl, alkynyl, alkoxy group is optionally substituted by one or more independently selected from F, Cl, Br, OH, CN, NH2, C 1-4 Straight-chain or branched alkyl, C 2-4 Straight-chain or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 linear or branched alkoxy group substitution;

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

[0021] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0022] In one embodiment of the present invention, in formula (I):

[0023] Ring A is selected from phenyl, 5-6 membered heteroaryl containing one ring heteroatom selected from N, S;

[0024] When ring A is a heteroaryl group, ring A and its fused ring share a ring carbon and / or ring nitrogen atom, and ring B is connected to a ring carbon atom or a ring nitrogen atom of ring A;

[0025] X and Y are independently selected from N and CH;

[0026] R 1a 、R 1b Independently selected from H, F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, or R 1a and R 1b Together with the ring C atoms to which they are connected, they form C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0027] R2 is selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, -S(O)2R8, -S(O)2N(R8)R9, -P(O)(R8)R9, The alkyl and alkoxy groups are optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0028] R3 is selected from H, F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0029] R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight chain alkoxy, C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0030] R5 is selected from F, Cl, Br, -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0031] R6 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0032] R7 is independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 A straight or branched alkoxy group, or two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group, or two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 Alkylene, the alkyl, alkoxy, cyclopropane is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0033] R8, R9 are independently selected from H, C 1-4 Straight or branched alkyl, the alkyl group is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0034] m is selected from 0, 1, and 2;

[0035] n is selected from 0, 1, 2, 3, 4.

[0036] According to one embodiment of the present invention, the present invention provides a compound represented by the following formula (II) or its isomer, deuterated substance, or pharmaceutically acceptable salt thereof, or polymorph or solvate thereof or its salt:

[0037]

[0038] In formula (II):

[0039] Q and T are independently selected from N and CH;

[0040] R 1a 、R 1b Independently selected from H, F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, or R 1a and R 1b Together with the ring C atoms to which they are connected, they form C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0041] R2 is selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, -S(O)2R8, -S(O)2N(R8)R9, -P(O)(R8)R9, The alkyl and alkoxy groups are optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0042] R3 is selected from H, F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0043] R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight chain alkoxy, C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0044] R5 is selected from F, Cl, Br, -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0045] R6 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0046] R7 is independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 A straight or branched alkoxy group, or two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group, or two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 Alkylene, the alkyl, alkoxy, cyclopropane is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0047] R8, R9 are independently selected from H, C 1-4 Straight or branched alkyl, the alkyl group is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0048] m is selected from 0 and 1;

[0049] n is selected from 0, 1, and 2.

[0050] According to one embodiment of the present invention, in formula (II):

[0051] Q and T are CH;

[0052] R 1a 、R1b Independently selected from H, -OH, C 1-4 Straight-chain or branched alkyl; or, R 1a and R 1b Together with the ring C atom to which they are attached, they form a cyclopropane group;

[0053] R2 is selected from C 1-4 Straight or branched alkyl, -CH2OCH3, -S(O)2CH3, -S(O)2NH2, -P(O)(CH3)2,

[0054] R3 is selected from F, Cl, Br; preferably, R3 is F;

[0055] R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain alkoxy, cyclopropane, wherein the alkyl, alkoxy, and cyclopropane are optionally substituted by one or more groups independently selected from F, Cl, Br, and -CN;

[0056] R5 is selected from -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, wherein the alkyl or alkoxy group is optionally substituted by a group selected from -OH or -NH2;

[0057] R6 is C 1-4 Straight or branched alkyl; preferably, R6 is -CH3;

[0058] R7 is independently selected from C 1-4 A straight or branched alkyl group, wherein the alkyl group is optionally substituted by one or more groups selected from F, Cl, and Br; or, two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group; or, two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 alkylene;

[0059] R8, R9 are independently selected from H, C 1-4 a straight or branched chain alkyl group, said alkyl group being optionally substituted with one -OH group;

[0060] m is selected from 0 and 1;

[0061] n is selected from 0, 1, and 2.

[0062] According to one embodiment of the present invention, in formula (II):

[0063] Q and T are CH;

[0064] R 1a and R 1b Together with the ring C atom to which they are attached, they form a cyclopropane group;

[0065] R3 is selected from F, Cl, Br;

[0066] R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain alkoxy, wherein the alkyl and alkoxy groups are optionally substituted by one or more groups independently selected from F, Cl, and Br;

[0067] R5 is selected from -OH, -CN, -COOH, -CONH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, the alkyl group being optionally substituted with one -OH;

[0068] R6 is C 1-4 Straight-chain or branched alkyl group;

[0069] m and n are 0.

[0070] According to one embodiment of the present invention, in formula (II):

[0071] Q and T are CH;

[0072] R 1a and R 1b Together with the ring C atom to which they are attached, they form a cyclopropane group;

[0073] R3 is F;

[0074] R4 is selected from -CH3, -OCH3, -OCF3;

[0075] R5 is selected from -OH, -CN, -COOH, -CONH2, -OCH3, -CH2OH;

[0076] R6 is -CH3;

[0077] m and n are 0.

[0078] According to one embodiment of the present invention, the present invention provides a compound represented by the following formula (III) or its isomer, deuterated substance, or pharmaceutically acceptable salt thereof, or polymorph or solvate thereof or its salt:

[0079]

[0080] In formula (III):

[0081] R 1a 、R 1bIndependently selected from H, F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, or R 1a and R 1b Together with the ring C atoms to which they are connected, they form C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0082] R2 is selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, -S(O)2R8, -S(O)2N(R8)R9, -P(O)(R8)R9, The alkyl and alkoxy groups are optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0083] R3 is selected from H, F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0084] R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight chain alkoxy, C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0085] R5 is selected from F, Cl, Br, -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0086] R6 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0087] R7 is independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 A straight or branched alkoxy group, or two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group, or two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 Alkylene, the alkyl, alkoxy, cyclopropane is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0088] R8, R9 are independently selected from H, C 1-4 Straight or branched alkyl, the alkyl group is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0089] m is selected from 0 and 1;

[0090] n is selected from 0, 1, 2, 3, 4.

[0091] According to one embodiment of the present invention, in formula (III):

[0092] R 1a 、R 1b Independently selected from H, -OH, C 1-4 Straight-chain or branched alkyl; or, R 1a and R 1b Together with the ring C atom to which they are attached, they form a cyclopropane group;

[0093] R2 is selected from C 1-4 Straight or branched alkyl, -CH2OCH3, -S(O)2CH3, -S(O)2NH2, -P(O)(CH3)2,

[0094] R3 is selected from F, Cl, Br; preferably, R3 is F;

[0095] R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain alkoxy, cyclopropane, wherein the alkyl, alkoxy, and cyclopropane are optionally substituted by one or more groups independently selected from F, Cl, Br, and -CN;

[0096] R5 is selected from -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, wherein the alkyl or alkoxy group is optionally substituted by a group selected from -OH or -NH2;

[0097] R6 is C 1-4 Straight or branched alkyl; preferably, R6 is -CH3;

[0098] R7 is independently selected from C 1-4 A straight or branched alkyl group, wherein the alkyl group is optionally substituted by one or more groups selected from F, Cl, and Br; or, two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group; or, two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 alkylene;

[0099] R8, R9 are independently selected from H, C 1-4 a straight or branched chain alkyl group, said alkyl group being optionally substituted with one -OH group;

[0100] m is selected from 0 and 1;

[0101] n is selected from 0, 1, and 2.

[0102] According to one embodiment of the present invention, in formula (III):

[0103] R 1a 、R 1b Independently selected from C 1-4 Straight-chain or branched alkyl; or, R 1a and R 1b Together with the ring C atom to which they are attached, they form a cyclopropane group;

[0104] R3 is selected from F, Cl, Br; preferably, R3 is F;

[0105] R4 is selected from -OCH3, -OCF3;

[0106] R5 is -OH;

[0107] R6 is -CH3;

[0108] m and n are 0.

[0109] According to one embodiment of the present invention, the present invention provides a compound represented by the following formula (IV) or its isomer, deuterated substance, or pharmaceutically acceptable salt thereof, or polymorph or solvate thereof or its salt:

[0110]

[0111] In formula (IV):

[0112] R 1a 、R 1b Independently selected from H, F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, or R 1a and R 1b Together with the ring C atoms to which they are connected, they form C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0113] R2 is selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, -S(O)2R8, -S(O)2N(R8)R9, -P(O)(R8)R9, The alkyl and alkoxy groups are optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0114] R3 is selected from H, F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0115] R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight chain alkoxy, C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0116] R5 is selected from F, Cl, Br, -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0117] R6 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0118] R7 is independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 A straight or branched alkoxy group, or two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group, or two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 Alkylene, the alkyl, alkoxy, cyclopropane is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0119] R8, R9 are independently selected from H, C 1-4 Straight or branched alkyl, the alkyl group is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0120] m is selected from 0, 1, and 2;

[0121] n is selected from 0, 1, 2, 3, 4.

[0122] According to one embodiment of the present invention, in formula (IV):

[0123] R 1a 、R 1b Independently selected from H, -OH, C 1-4 Straight-chain or branched alkyl; or, R 1a and R 1b Together with the ring C atom to which they are attached, they form a cyclopropane group;

[0124] R2 is selected from C 1-4 Straight or branched alkyl, -CH2OCH3, -S(O)2CH3, -S(O)2NH2, -P(O)(CH3)2,

[0125] R3 is selected from F, Cl, Br; preferably, R3 is F;

[0126] R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain alkoxy, cyclopropane, wherein the alkyl, alkoxy, and cyclopropane are optionally substituted by one or more groups independently selected from F, Cl, Br, and -CN;

[0127] R5 is selected from -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, wherein the alkyl or alkoxy group is optionally substituted by a group selected from -OH or -NH2;

[0128] R6 is C 1-4 Straight or branched alkyl; preferably, R6 is -CH3;

[0129] R7 is independently selected from C 1-4A straight or branched alkyl group, wherein the alkyl group is optionally substituted by one or more groups selected from F, Cl, and Br; or, two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group; or, two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 alkylene;

[0130] R8, R9 are independently selected from H, C 1-4 a straight or branched chain alkyl group, said alkyl group being optionally substituted with one -OH group;

[0131] m is selected from 0 and 1;

[0132] n is selected from 0, 1, and 2.

[0133] According to one embodiment of the present invention, in formula (IV):

[0134] R 1a 、R 1b Independently selected from H, C 1-4 Straight-chain or branched alkyl; or, R 1a and R 1b Together with the ring C atoms to which they are attached, they form a cyclopropane group; preferably, R 1a 、R 1b is H;

[0135] R3 is selected from F, Cl, Br; preferably, R3 is F;

[0136] R4 is selected from -OCH3, -OCF3;

[0137] R5 is -OH;

[0138] R6 is -CH3;

[0139] m and n are 0.

[0140] According to one embodiment of the present invention, the present invention provides a compound represented by the following formula (V) or its isomer, deuterated substance, or pharmaceutically acceptable salt thereof, or polymorph or solvate thereof or its salt:

[0141]

[0142] In formula (V):

[0143] R 1a 、R 1b Independently selected from H, F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, or R1a and R 1b Together with the ring C atoms to which they are connected, they form C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0144] R2 is selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, -S(O)2R8, -S(O)2N(R8)R9, -P(O)(R8)R9, The alkyl and alkoxy groups are optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0145] R3 is selected from H, F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0146] R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight chain alkoxy, C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0147] R5 is selected from F, Cl, Br, -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4linear or branched alkoxy group substitution;

[0148] R6 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0149] R7 is independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 A straight or branched alkoxy group, or two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group, or two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 Alkylene, the alkyl, alkoxy, cyclopropane is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0150] R8, R9 are independently selected from H, C 1-4 Straight or branched alkyl, the alkyl group is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0151] m is selected from 0, 1, and 2;

[0152] n is selected from 0, 1, 2, 3, 4.

[0153] According to one embodiment of the present invention, in formula (V):

[0154] R 1a 、R 1b Independently selected from H, -OH, C 1-4 Straight-chain or branched alkyl; or, R 1a and R 1b Together with the ring C atom to which they are attached, they form a cyclopropane group;

[0155] R2 is selected from C 1-4 Straight or branched alkyl, -CH2OCH3, -S(O)2CH3, -S(O)2NH2, -P(O)(CH3)2,

[0156] R3 is selected from F, Cl, Br; preferably, R3 is F;

[0157] R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain alkoxy, cyclopropane, wherein the alkyl, alkoxy, and cyclopropane are optionally substituted by one or more groups independently selected from F, Cl, Br, and -CN;

[0158] R5 is selected from -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, wherein the alkyl or alkoxy group is optionally substituted by a group selected from -OH or -NH2;

[0159] R6 is C 1-4 Straight or branched alkyl; preferably, R6 is -CH3;

[0160] R7 is independently selected from C 1-4 A straight or branched alkyl group, wherein the alkyl group is optionally substituted by one or more groups selected from F, Cl, and Br; or, two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group; or, two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 alkylene;

[0161] R8, R9 are independently selected from H, C 1-4 a straight or branched chain alkyl group, said alkyl group being optionally substituted with one -OH group;

[0162] m is selected from 0 and 1;

[0163] n is selected from 0, 1, and 2.

[0164] According to one embodiment of the present invention, in formula (V):

[0165] R 1a 、R 1b Independently selected from H, C 1-4 Straight-chain or branched alkyl; or, R 1a and R 1b Together with the ring C atoms to which they are attached, they form a cyclopropane group; preferably, R 1a 、R 1b is H;

[0166] R3 is selected from F, Cl, Br; preferably, R3 is F;

[0167] R4 is selected from -OCH3, -OCF3;

[0168] R5 is -OH;

[0169] R6 is -CH3;

[0170] m and n are 0.

[0171] According to one embodiment of the present invention, the present invention provides a compound represented by the following formula (VI) or its isomer, deuterated substance, or pharmaceutically acceptable salt thereof, or polymorph or solvate thereof or its salt:

[0172]

[0173] In formula (VI):

[0174] R 1a 、R 1b Independently selected from H, F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, or R 1a and R 1b Together with the ring C atoms to which they are connected, they form C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0175] R2 is selected from H, C 1-4 Straight or branched alkyl, the alkyl group is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0176] R3 is selected from H, F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0177] R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight chain alkoxy, C3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0178] R5 is selected from F, Cl, Br, -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0179] R6 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0180] R7 is independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 A straight or branched alkoxy group, or two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group, or two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 Alkylene, the alkyl, alkoxy, cyclopropane is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0181] R8, R9 are independently selected from H, C 1-4 Straight or branched alkyl, the alkyl group is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 linear or branched alkoxy group substitution;

[0182] n is selected from 0, 1, 2, 3, 4.

[0183] According to one embodiment of the present invention, in formula (VI):

[0184] R 1a 、R 1b Independently selected from H, -OH, C 1-4 Straight-chain or branched alkyl; or, R 1a and R 1b Together with the ring C atom to which they are attached, they form a cyclopropane group;

[0185] R2 is C 1-4 Straight-chain or branched alkyl group;

[0186] R3 is selected from F, Cl, Br; preferably, R3 is F;

[0187] R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain alkoxy, cyclopropane, wherein the alkyl, alkoxy, and cyclopropane are optionally substituted by one or more groups independently selected from F, Cl, Br, and -CN;

[0188] R5 is selected from -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, wherein the alkyl or alkoxy group is optionally substituted by a group selected from -OH or -NH2;

[0189] R6 is C 1-4 Straight or branched alkyl; preferably, R6 is -CH3;

[0190] R7 is independently selected from C 1-4 A straight or branched alkyl group, wherein the alkyl group is optionally substituted by one or more groups selected from F, Cl, and Br; or, two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group; or, two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 alkylene;

[0191] R8, R9 are independently selected from H, C 1-4 a straight or branched chain alkyl group, said alkyl group being optionally substituted with one -OH group;

[0192] n is selected from 0, 1, and 2.

[0193] According to one embodiment of the present invention, in formula (VI):

[0194] R 1a 、R 1bIndependently selected from H, C 1-4 Straight-chain or branched alkyl; or, R 1a and R 1b Together with the ring C atoms to which they are attached, they form a cyclopropane group; preferably, R 1a 、R 1b is H;

[0195] R2 is C 1-4 Straight or branched alkyl; preferably, R2 is -CH3;

[0196] R3 is selected from F, Cl, Br; preferably, R3 is F;

[0197] R4 is selected from -CH3, -CF3, -OCH3, -OCF3, -CHF2, -OCHF2;

[0198] R5 is -OH;

[0199] R6 is -CH3;

[0200] n is 0.

[0201] In a preferred embodiment, the compound of the present invention is selected from the following compounds or their isomers, deuterated substances, or pharmaceutically acceptable salts thereof, or polymorphs or solvates thereof or their salts:

[0202]

[0203]

[0204] In the present invention, although substituents are disclosed in groups or ranges, the groups or ranges of the present invention specifically refer to each specific group they cover. For example, the term "C 1-4 The term "alkyl" specifically refers to the independently disclosed methyl (ie, C1 alkyl), ethyl (ie, C2 alkyl), propyl (ie, C3 alkyl), and butyl (ie, C4 alkyl).

[0205] In the present invention, examples of "5-6 membered heteroaryl containing one ring heteroatom selected from N and S" include, but are not limited to, pyrrole, thiophene, and pyridine.

[0206] In the present invention, examples of “5-6 membered heteroaryl containing 1-2 ring heteroatoms independently selected from N and S” include, but are not limited to, imidazole, pyrazole, thiazole, isothiazole, pyrimidine, pyrazine, and pyridazine in addition to the above.

[0207] In the present invention, examples of “5-11 membered heteroaryl containing 1-3 ring heteroatoms independently selected from N, O and S” include, but are not limited to, furan, oxazole, isoxazole, 1,2,3-triazole, 1,2,4-triazole, oxadiazole, thiadiazole, pyridone, triazine, benzazetidine, benzoβ-lactam ring, benzoβ-lactone, benzoxazoline, benzofuran, benzothiophene, benzopyrrole, benzopyrazole, benzimidazole, benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, benzotriazole, benzoxadiazole, benzothiadiazole, benzodioxane, benzomorpholine, benzopiperidine, benzopyran, benzo Pyridine, benzopyrimidine, benzotriazine, benzopiperidone, benzomorpholinone, benzazepine, benzazepine, pyridoazetidine, pyridoβ-lactam ring, pyridoβ-lactone, pyridoxadiazole, pyridofuran, pyridothiophene, pyridopyrrole, pyridopyrazole, pyridoimidazole, pyridothiazole, pyridoisothiazole, pyridoxazole, pyridoisoxazole, pyridotriazole, pyridoxadiazole, pyridothiadiazole, pyridodioxane, pyridomorpholine, pyridopiperidine, pyridopyran, pyridopyridine, pyridopyrimidine, pyridotriazine, pyridopiperidone, pyridomorpholinone, pyridoazepine.

[0208] In the present invention, "C 3-7 Examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

[0209] In the present invention, examples of “3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O and S” include but are not limited to oxirane, thiol, aziridine, oxetane, N-heterocyclobutane, α-lactam ring, β-lactam ring, β-lactone, tetrahydrofuran, thiolane, pyrrolidine, pyrrolidone, pyrroline, dioxolane, oxazolidine, oxazolidinone, oxazoline, isoxazolidine, thiazolidine, isothiazolidine, thiazoline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, tetrahydropyran, dihydropyran, pyran, piperidine, piperidone, 1,4-dioxane, morpholine, morpholinone, piperazine, piperazinone, azepane, oxirane, thipane, 1,4-oxazepane, 1,4-thiazepane.

[0210] The compounds of the present invention may be asymmetric, for example, having one or more stereocenters. All stereoisomers, such as enantiomers and diastereomers, are included within the scope of the present invention unless otherwise indicated. In the present invention, compounds containing asymmetrically substituted carbon atoms can be isolated in either optically active or racemic forms. Various methods for preparing optically active forms are known in the art, for example, by resolving a racemic mixture or by stereoselective synthesis.

[0211] The present invention also includes pharmaceutically acceptable salts of the compounds. Pharmaceutically acceptable salts of the compounds of the present invention can be prepared by reacting with non-toxic inorganic or organic acids. Inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, hydrogen sulfate, boric acid, and hemisulfuric acid; organic acids include formic acid, acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, heptanoic acid, undecanoic acid, palmitic acid, stearic acid, oleic acid, oxalic acid, malonic acid, adipic acid, lactic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphorsulfonic acid, citric acid, fumaric acid, and gluconic acid; and various amino acids.

[0212] The present invention also includes hydrates and solvates of the compounds.

[0213] The present invention also includes all forms of the compounds wherein the atoms are isotopes. Isotopes include all atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium.

[0214] The present invention also includes prodrugs of the compounds. "Prodrugs" refer to compounds obtained by structural modification of the compounds that are inactive or less active outside the patient's body, but release the compound through enzymatic or non-enzymatic conversion in the patient's body to exert its pharmacological effect.

[0215] It will be appreciated by those skilled in the art that the compounds of the present invention can be prepared by various methods disclosed in the literature. The compounds of the present invention can be prepared by reacting in a suitable solvent. A person skilled in the art of organic synthesis can easily select a suitable solvent that does not substantially react with the reactants, intermediates, or products. The reaction can be carried out in a solvent or in a mixture of more than one solvent. The compounds of the present invention can be prepared by reacting at a suitable temperature, for example, between the freezing temperature of the solvent and the boiling temperature of the solvent. The method for preparing the compounds of the present invention involves protecting and deprotecting various chemical groups. A person skilled in the art of organic synthesis can easily determine whether chemical groups need to be protected and deprotected and select suitable protecting groups. The reaction to prepare the compounds of the present invention can be monitored using any method known in the art, such as nuclear magnetic resonance spectroscopy, infrared spectroscopy, mass spectrometry, chromatography, etc.

[0216] The compounds of the present invention can be prepared, for example, by the following method:

[0217] Method I:

[0218]

[0219] The groups in the respective formulae are as defined above.

[0220] The synthesis of Ib can be carried out in a solvent in the presence of a base, a ligand and a catalyst. The solvent can be selected from tetrahydrofuran, 1,4-dioxane, toluene, xylene, ethylene glycol dimethyl ether, etc. or any mixture thereof; the base can be selected from cesium carbonate, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilylamine), potassium phosphate, etc.; the ligand can be selected from BINAP, S-Phos, DPPF, Xantphos, CyJohnPhos, X-Phos, 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride, etc.; the catalyst can be selected from Pd2(dba)3, Pd(OAc)2, Pd(PPh3)4, Pd(dppf)Cl2, Pd(PPh3)2Cl2, RuPhos Pd G3, BrettPhosPd G3, AlPhos Pd G3, AdBrettPhos Pd G3, Pd(t-Bu3P)2, etc.

[0221] The synthesis of Ic can be carried out in the presence of an acid in a solvent. The solvent can be selected from tetrahydrofuran, methanol, dichloromethane, 1,4-dioxane, or any mixture thereof; and the acid can be selected from hydrochloric acid, trifluoroacetic acid, acetic acid, sulfuric acid, citric acid, or the like.

[0222] The synthesis of compound I can be carried out in a solvent in the presence of a base, a ligand and a catalyst. The solvent can be selected from tetrahydrofuran, 1,4-dioxane, tert-butanol, toluene, xylene, ethylene glycol dimethyl ether, dimethyl sulfoxide, N,N-dimethylformamide, etc. or any mixture thereof; the base can be selected from cesium carbonate, potassium carbonate, sodium carbonate, lithium bis(trimethylsilyl)amide, potassium tert-butoxide, sodium tert-butoxide, potassium phosphate, potassium hydroxide, etc.; the ligand can be selected from BINAP, Davephos, X-Phos, Xantphos, S-Phos, RuPhos, BrettPhos, JohnPhos, t-BuXPhos, etc.; the catalyst can be selected from Pd2(dba)3, Pd(OAc)2, Pd(PPh3)4, Pd(dppf)Cl2, Pd(PPh3)2Cl2, RuPhos Pd G3, BrettPhos Pd G3, AlPhos Pd G3, AdBrettPhos Pd G3, Pd(t-Bu3P)2, etc.

[0223] The compounds of the present invention can inhibit PLK1. Therefore, according to another aspect of the present invention, the present invention provides a method for inhibiting PLK1, using the compounds of the present invention.

[0224] According to another aspect, the present invention provides a method for preventing and / or treating a PLK1-related disease, comprising administering a therapeutically and / or preventatively effective amount of a compound of the present invention or a pharmaceutical composition containing the compound of the present invention to a subject in need thereof. PLK1-related diseases include any disease directly and / or indirectly related to PLK1 expression and / or activity, such as diseases associated with PLK1 overexpression; diseases that can be prevented and / or treated by modulating, for example, inhibiting, PLK1 activity; and the like.

[0225] PLK1-related diseases include solid tumors, hematologic tumors, and the like. Examples of solid tumors include, but are not limited to, colorectal cancer, lung cancer, breast cancer, prostate cancer, pancreatic cancer, gastric cancer, head and neck cancer, ovarian cancer, uterine cancer, glioma, liver cancer, esophageal cancer, bladder cancer, kidney cancer, lymphoma, melanoma, and osteosarcoma; examples of hematologic tumors include, but are not limited to, leukemia and myelodysplastic syndrome.

[0226] According to another aspect of the present invention, the present invention provides use of the compound of the present invention in preparing a PLK1 inhibitor.

[0227] According to another aspect of the present invention, the present invention provides use of the compound of the present invention in preparing a method for preventing and / or treating PLK1-related diseases.

[0228] When the compound of the present invention is used to prevent and / or treat PLK1-related diseases, the compound of the present invention can be administered in the form of a pharmaceutical composition. Therefore, according to another aspect of the present invention, the present invention provides a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier.

[0229] It will be appreciated by those skilled in the art that the pharmaceutical compositions of the present invention can be prepared by various methods disclosed in the literature. The compounds or pharmaceutical compositions of the present invention can be administered by a variety of routes, depending on the area where local or systemic treatment is needed and the area where treatment is needed. For example, the compositions can be administered orally, parenterally (e.g., intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly or by infusion), intracranially, e.g., intrathecally or intraventricularly, transdermally, ophthalmically, nasally, vaginally, rectally, or pulmonary (e.g., by inhalation or insufflation of a powder or aerosol).

[0230] For oral administration, the pharmaceutical compositions of the present invention are typically provided in the form of tablets, capsules, or solutions. Tablets may comprise a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The carrier includes, but is not limited to, a diluent, a disintegrant, a binder, a lubricant, a colorant, or a preservative. Capsules include hard capsules and soft capsules. For parenteral administration, the pharmaceutical compositions of the present invention may be administered by intravenous, intramuscular, or subcutaneous injection. They are typically provided as sterile aqueous solutions or suspensions or lyophilized powders, and are adjusted for appropriate pH and isotonicity.

[0231] The effective amount of the compounds of the present invention can be determined based on the specific use of the treatment, the mode of administration, and the condition of the individual in need, such as the patient. Those skilled in the art are capable of determining the effective amount of the compounds of the present invention. Typical dosage ranges are, for example, 1 μg / kg / day to 1000 mg / kg / day.

[0232] When preventing and / or treating PLK1-related diseases, the compounds of the present invention may be used in combination with one or more other drugs, such as immune checkpoint drugs, targeted drugs, and chemotherapy drugs. DETAILED DESCRIPTION

[0233] Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiments are only used to illustrate the present invention and are not used in limiting the scope of the present invention.In addition, should be understood that after reading the content of the present invention being recorded, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall within the limited scope of the present invention equally.

[0234] Preparation Example 1. Synthesis of common intermediate common int-1

[0235]

[0236] Synthesis of Spiro[cyclopropane-1,1'-isoindole]-3'-one (2):

[0237] Dissolve ethyl 2-cyanobenzoate (2.4 g, 13.70 mmol) in diethyl ether, and add tetraisopropyl titanate (4.3 g, 15.07 mmol) dropwise to the reaction mixture, followed by a solution of ethylmagnesium bromide in tetrahydrofuran (13.7 mL, 2 mol / L). The reaction mixture was stirred at room temperature for 16 hours. LCMS confirmed the reaction was complete. Dilute hydrochloric acid (20 mL, 1 mol / L) was added to the reaction mixture, followed by extraction with dichloromethane (40 mL x 3). The organic phase was washed with saturated brine (30 mL), separated, dried, filtered, concentrated, and then purified by column chromatography (methanol:dichloromethane = 10%, Rf = 0.5) to afford the product as a white solid (800.0 mg). LCMS: [M+H] + :160.2.

[0238] Synthesis of 5'-bromospiro[cyclopropane-1,1'-isoindole]-3'-one (3):

[0239] Anhydrous aluminum trichloride (1.3 g, 9.42 mmol) was placed in a three-necked flask under nitrogen. Spiro[cyclopropane-1,1'-isoindol]-3'-one (600.0 mg, 3.77 mmol) dissolved in 1,2-dichloroethane was added, followed by the dropwise addition of liquid bromine (783.0 mg, 4.90 mmol). After the addition was complete, the reaction mixture was heated to 80°C and stirred for 16 hours. LCMS indicated the reaction was complete. The reaction was quenched with saturated sodium thiosulfate (15 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined and washed once with saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 0-100%, ethyl acetate:petroleum ether = 1:1, Rf = 0.5) to afford a light yellow solid (400.0 mg). LCMS: [M+H] + :238.1,240.1.

[0240] Synthesis of 5'-boronic acid pinacol ester spiro[cyclopropane-1,1'-isoindole]-3'-one (4):

[0241] 5'-Bromospiro[cyclopropane-1,1'-isoindol]-3'-one (400.0 mg, 1.68 mmol), potassium acetate (495.0 mg, 5.04 mmol), pinacol diboron (512.0 mg, 2.02 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (137.2 mg, 0.17 mmol) were dissolved in 1,4-dioxane (20 mL) and water (3 mL). The reaction mixture was stirred at 100°C under nitrogen for 16 hours. LCMS indicated the reaction was complete. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed once with saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product as a brown solid (300.0 mg). The crude product was used directly in the next reaction. LCMS: [M+H] + :286.3. Synthesis of 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindole]-3'-one (common int-1):

[0242] The compound 5'-boronic acid pinacol ester spiro[cyclopropane-1,1'-isoindole]-3'-one (200.0 mg, 0.70 mmol), cesium carbonate (455.0 mg, 1.40 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (56.7 mg, 0.07 mmol), and 2,4-dichloro-5-fluoropyrimidine (117.1 mg, 0.70 mmol) were suspended in 1,4-dioxane and water (10 mL, 5:1) and reacted at 100°C under nitrogen for 6 hours. The reaction solution was cooled to room temperature, poured into water (20 mL), and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 2:1, Rf = 0.6) to give a yellow solid (150.0 mg). LC-MS: [M+H] + :290.2.

[0243] Preparation Example 2. Synthesis of common intermediate common int-3

[0244]

[0245] Synthesis of 2-chloro-N-(2-chloroethyl)-N-methylethane-1-amine hydrochloride (2):

[0246] N-Methyldiethanolamine (5.0 g, 41.96 mmol) was dissolved in dichloromethane (20 mL), and thionyl chloride (16.7 g, 140.38 mmol) was slowly added under ice bath. The mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated, slurried with ether (30 mL), filtered, and the filter cake was dried to obtain a white solid (6.0 g). 1 H NMR (400MHz, MeOD) δ4.02 (t, J = 6.1 Hz, 4H), 3.68 (d, J = 6.1 Hz, 4H), 3.03 (s, 3H).

[0247] Synthesis of 4-(3-bromo-4-methoxyphenyl)-1-methylpiperidine-4-carbonitrile (common int-3):

[0248] 3-Bromo-4-methoxybenzeneacetonitrile (2.3 g, 10.17 mmol) and 2-chloro-N-(2-chloroethyl)-N-methylethane-1-amine hydrochloride (1.9 g, 9.87 mmol) were dissolved in N,N-dimethylformamide (35 mL). Under nitrogen protection, sodium hydroxide (1.6 g, 40.00 mmol, 60% w / w) was added at 0°C, and the temperature was raised to 60°C and stirred for 2 hours. The reaction was quenched with ice water (60 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with water (50 mL × 3) and saturated sodium chloride (60 mL), dried, and spin-dried. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to obtain a brown oil (2.8 g). 1 H NMR (400MHz, DMSO-d6) δ7.69(d,J=2.4Hz,1H),7.52(dd,J=8.8,2.4Hz,1H),7.16(d,J=8.8H z,1H),3.86(s,3H),2.94–2.78(m,2H),2.26–2.08(m,7H),2.01–1.93(m,2H); LC-MS:[M+H] + :309.2,311.2.

[0249] Preparation Example 3. Synthesis of common intermediate common int-4

[0250]

[0251] Synthesis of 4-(3-((diphenylmethylene)amino)-4-methoxyphenyl)-1-methylpiperidine-4-carbonitrile (common int-4):

[0252] Dissolve 4-(3-bromo-4-methoxyphenyl)-1-methylpiperidine-4-carbonitrile (500.0 mg, 1.62 mmol), benzophenone imine (351.7 mg, 1.94 mmol), cesium carbonate (1.6 g, 4.91 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (201.4 mg, 0.32 mmol), and tris(dibenzylideneacetone)dipalladium (148.1 mg, 0.16 mmol) in dioxane (10 mL). Under nitrogen, react at 100°C for 18 hours. Once the reaction is complete, dilute the reaction solution with water (40 mL) and extract with ethyl acetate (50 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product is subjected to acidic purification to obtain a yellow solid (650.0 mg). LC-MS: [M+H] + :410.3.

[0253] Preparation Example 4. Synthesis of common intermediate common int-5

[0254]

[0255] Synthesis of 2-chloro-4-iodo-1-(trifluoromethoxy)benzene (2):

[0256] Compound 3-chloro-4-(trifluoromethoxy)aniline (5.0 g, 23.63 mmol) was added to a cold mixed solution of 98% H2SO4 (3.8 mL) and H2O (11.3 mL). A solution of sodium nitrite (1.8 g, 26.08 mmol) in 5.0 mL of water was added at 0°C and stirred for 10 minutes. A solution of urea (0.27 g, 4.50 mmol) in 1.3 mL of water was added and stirred for 5 minutes. A solution of potassium iodide (8.3 g, 50.0 mmol) in 9 mL of water was then slowly added dropwise. The mixture was returned to room temperature and heated to 52°C for 2 hours. The mixture was cooled to room temperature, diluted with 50 mL of cold water, and extracted with dichloromethane (25 mL × 4). The organic phases were combined, 0.5% sodium thiosulfate (30 mL) was added and stirred for ten minutes. The organic phase was separated, dried, concentrated, and purified by column chromatography (100% petroleum ether) (R f =0.9, petroleum ether:ethyl acetate=20:1) to give a light yellow oily compound (3.2 g). 1 H NMR (400MHz, CDCl3) δ7.82 (d, J = 2.0 Hz, 1H), 7.61 (dd, J = 8.8, 2.0 Hz, 1H), 7.05 (dd, J = 8.8, 1.2 Hz, 1H).

[0257] Synthesis of 4-(3-chloro-4-(trifluoromethoxy)phenyl)-1-methylpiperidin-4-ol (3):

[0258] Dissolve 2-chloro-4-iodo-1-(trifluoromethoxy)benzene (2.0 g, 6.20 mmol) in anhydrous tetrahydrofuran (10 mL). Add 2.5 M n-butyllithium (3.23 mL, 8.06 mmol) dropwise at -65°C under nitrogen and stir for 1 hour. Then add 1-methylpiperidin-4-one (0.91 g, 8.06 mmol) dropwise. React at -65°C under nitrogen for 2 hours. Quench with saturated ammonium chloride solution (10 mL) and extract with ethyl acetate (10 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (DCM:MeOH = 10:1) to obtain a white solid (0.75 g). LC-MS: [M+H] + :310.1.

[0259] Synthesis of 4-(3-((diphenylmethylene)amino)-4-(trifluoromethoxy)phenyl)-1-methylpiperidin-4-ol (4):

[0260] The compound 4-(3-chloro-4-(trifluoromethoxy)phenyl)-1-methylpiperidin-4-ol (700.0 mg, 2.26 mmol), benzophenone imine (409.6 mg, 2.26 mmol), cesium carbonate (2.2 g, 6.75 mmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (185.6 mg, 0.45 mmol), and tris(dibenzylideneacetone)dipalladium (207.0 mg, 0.23 mmol) were added to anhydrous 1,4-dioxane (5 mL) and reacted at 100°C under nitrogen for 16 hours. The mixture was cooled to room temperature, diluted with 10 mL of water, and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH = 20:1) and preparative purification to yield a white solid (480.0 mg). LC-MS: [M+H] + :455.3.

[0261] Synthesis of 4-(3-amino-4-(trifluoromethoxy)phenyl)-1-methylpiperidin-4-ol (common int-5):

[0262] Dissolve the compound 4-(3-((diphenylmethylene)amino)-4-(trifluoromethoxy)phenyl)-1-methylpiperidin-4-ol (300.0 mg, 0.66 mmol) in dioxane (3.0 mL). Add 4M hydrochloric acid solution in dioxane (3 mL) dropwise at room temperature and stir at room temperature for 2 hours. Filter and slurry with dichloromethane and petroleum ether (dichloromethane:petroleum ether = 5:1) to obtain the crude compound (100.0 mg). The crude product was used directly in the next reaction. LC-MS: [M+H] + :291.1.

[0263] Preparation Example 5. Synthesis of common intermediate common int-6

[0264]

[0265] Synthesis of methyl 2-cyanothiophene-3-carboxylate (2):

[0266] Methyl 2-bromothiophene-3-carboxylate (25.0 g, 113.09 mmol) was dissolved in N-methylpyrrolidone (150 mL) and cuprous cyanide (20.2 g, 225.55 mmol) was added. The reaction was stirred at 120°C under nitrogen for 18 hours. LCMS monitored the reaction to be complete. After cooling the reaction solution to room temperature, it was diluted with water (1000 mL) and extracted with ethyl acetate (500 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain a light yellow solid product (12.0 g). LC-MS: [M+H]+ :168.1.

[0267] Synthesis of spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-4'(5'H)-one (3):

[0268] Methyl 2-cyanothiophene-3-carboxylate (10.0 g, 59.82 mmol) was dissolved in diethyl ether (600 mL). Tetraisopropyl titanate (18.7 g, 65.79 mmol) was added at room temperature, followed by a solution of ethylmagnesium bromide in tetrahydrofuran (65.8 mL, 2 mol / L, 131.60 mmol). The reaction mixture was stirred at room temperature for two hours. LCMS confirmed the reaction was complete. Dilute aqueous hydrochloric acid (100 mL, 1 mol / L) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (400 mL x 3). The combined organic phases were washed with saturated brine (300 mL), the separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 1:1) to obtain a brown solid (2.2 g). LCMS: [M+H] + :166.2.

[0269] Synthesis of 2'-bromospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-4'(5'H)-one (4):

[0270] Spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one (2.2 g, 13.32 mmol) was dissolved in acetic acid / water (1.2:1) (20 mL) and cooled in an ice bath. Bromine (2.3 g, 14.39 mmol) was then slowly added dropwise. After the addition, the reaction mixture was stirred for 0.5 hours. LCMS indicated the reaction was complete. Saturated aqueous sodium thiosulfate (30 mL) was poured into the reaction mixture to quench the reaction, followed by extraction with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 1:1) to obtain a brown-yellow solid (1.5 g). LCMS: [M+H] + :244.2,246.2.

[0271] Synthesis of tert-butyl 2'-bromo-4'-oxospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4'H)-carboxylate (5):

[0272] 2'-Bromospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one (1.5 g, 6.14 mmol) was dissolved in dichloromethane (20 mL) and cooled in an ice bath. Di-tert-butyl dicarbonate (2.7 g, 12.37 mmol) and triethylamine (1.2 g, 11.86 mmol) were then added, followed by 4-dimethylaminopyridine (80.0 mg, 0.65 mmol). The reaction mixture was stirred at room temperature for 1 hour. LCMS indicated that the reaction was complete. The reaction mixture was directly concentrated to obtain the crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to afford a light yellow solid (930.0 mg). LCMS: [M+H-tBu] + :288.1,290.1.

[0273] Synthesis of tert-butyl 4'-oxo-2'-boronic acid pinacol ester spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4'H)-carboxylate (6):

[0274] Dissolve tert-butyl 2'-bromo-4'-oxospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4'H)-carboxylate (800.0 mg, 2.32 mmol), potassium acetate (684.0 mg, 6.97 mmol), biboronic acid pinacol ester (708.0 mg, 2.79 mmol), and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (170.0 mg, 0.23 mmol) in anhydrous 1,4-dioxane (8 mL). The reaction solution was stirred at 80°C under nitrogen protection for 0.5 hours. LCMS showed that the reaction was complete. The reaction solution was used directly in the next reaction. LCMS: [M+H- t Bu] + :336.2.

[0275] Synthesis of tert-butyl 2'-(2-chloro-5-fluoropyrimidin-4-yl)-4'-oxospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4'H)-carboxylate (common int-6):

[0276] Under nitrogen, tert-butyl 4'-oxo-2'-boronic acid pinacol ester spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4'H)-carboxylate (300.0 mg, 0.77 mmol), potassium phosphate (489.0 mg, 2.30 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (56.1 mg, 0.077 mmol), and 2,4-dichloro-5-fluoropyrimidine (128.0 mg, 0.77 mmol) were placed in 1,4-dioxane and water (8 mL, 5:1 ratio). The reaction solution was heated to 80°C and stirred for 2 hours. LCMS monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 2:1) to give a white solid (150.0 mg). LCMS: [M+H-tBu] + :340.3.

[0277] Preparation Example 6. Synthesis of common intermediate common int-7

[0278]

[0279] Synthesis of 4-(3-chloro-4-methoxyphenyl)-1-methylpiperidin-4-ol (2):

[0280] Dissolve 2-chloro-4-iodo-1-methoxybenzene (3.3 g, 12.29 mmol) in tetrahydrofuran (20 mL). After cooling to -78°C, slowly add 2.5 M n-butyllithium solution (4.9 mL, 12.25 mmol) dropwise. After complete addition, stir the reaction mixture at -78°C for 30 minutes. Then, slowly add a solution of 1-methylpiperidin-4-one (1.5 g, 13.25 mmol) in tetrahydrofuran (20 mL) dropwise to the solution, maintaining stirring at -78°C for 1 hour. The reaction mixture is quenched with saturated ammonium chloride (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phases are washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product is purified by silica gel column chromatography (methanol:dichloromethane = 0-6%) to afford a white solid (856.0 mg). LC-MS: [M+H] + :256.1,258.1.

[0281] Synthesis of 4-(3-((diphenylmethylene)amino)-4-methoxyphenyl)-1-methylpiperidin-4-ol (3):

[0282] Under nitrogen, 4-(3-chloro-4-methoxyphenyl)-1-methylpiperidin-4-ol (240.0 mg, 0.94 mmol), benzophenone imine (340.2 mg, 1.88 mmol), cesium carbonate (611.5 mg, 1.88 mmol), 2-dicyclohexylphosphine-2′,6′-dimethoxy-biphenyl (77.1 mg, 0.19 mmol), and tris(dibenzylideneacetone)dipalladium (85.9 mg, 0.094 mmol) were placed in 1,4-dioxane (4 mL) and stirred at 110°C for 18 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 0%-8%) to obtain an orange oil (150.0 mg). LC-MS: [M+H] + :401.5.

[0283] Synthesis of 4-(3-amino-4-methoxyphenyl)-1-methylpiperidin-4-ol (common int-7):

[0284] The compound 4-(3-((diphenylmethylene)amino)-4-methoxyphenyl)-1-methylpiperidin-4-ol (150.0 mg, 0.38 mmol) was dissolved in 1,4-dioxane (2 mL), and a 4M hydrochloric acid solution in dioxane (2 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours. LCMS confirmed that the reaction was complete. The solvent was dried by rotary evaporation, and saturated sodium bicarbonate was added to adjust the pH to 8. The mixture was extracted with ethyl acetate (20 mL x 3), dried by rotary evaporation, and purified by reverse phase column chromatography (acetonitrile:water (ammonia) = 0-30%) to obtain a yellow solid (80.0 mg). LC-MS: [M+H] + :237.1.

[0285] Example 1. Synthesis of compound DP-01-195

[0286]

[0287] Synthesis of 2-chloro-4-iodo-1-(trifluoromethoxy)benzene (2):

[0288] Compound 3-chloro-4-(trifluoromethoxy)aniline (5.0 g, 23.63 mmol) was added to a cold mixed solution of 98% H2SO4 (3.8 mL) and H2O (11.3 mL). A solution of sodium nitrite (1.8 g, 26.09 mmol) in 5.0 mL of water was added at 0°C and stirred for 10 minutes. A solution of urea (0.27 g, 4.50 mmol) in 1.3 mL of water was added and stirred for 5 minutes. A solution of potassium iodide (8.3 g, 50.0 mmol) in 9 mL of water was then slowly added dropwise. The mixture was returned to room temperature and stirred for 10 minutes. The mixture was heated to 52°C and reacted for 2 hours. The mixture was cooled to room temperature, diluted with 50 mL of cold water, and extracted with dichloromethane (4×25 mL). The organic phases were combined, 0.5% sodium thiosulfate (30 mL) was added, and stirred for ten minutes. The organic phases were separated, dried, concentrated, and purified by column chromatography (100% petroleum ether) (R f =0.9, petroleum ether:ethyl acetate=20:1) to give a light yellow oily compound (3.2 g). 1 H NMR (400MHz, CDCl3) δ7.82 (d, J = 2.0 Hz, 1H), 7.61 (dd, J = 8.8, 2.0 Hz, 1H), 7.05 (dd, J = 8.8, 1.2 Hz, 1H).

[0289] Synthesis of 4-(3-chloro-4-(trifluoromethoxy)phenyl)-1-methylpiperidin-4-ol (3):

[0290] 2-Chloro-4-iodo-1-(trifluoromethoxy)benzene (2.0 g, 6.20 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). 2.5 M n-butyllithium (3.23 mL, 8.08 mmol) was added dropwise at -65°C under nitrogen and stirred for 1 hour. 1-Methylpiperidin-4-one (0.91 g, 8.04 mmol) was then added dropwise. The reaction was continued at -65°C under nitrogen for 2 hours. The mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH = 80:1-20:1) (DCM:MeOH = 10:1, Rf = 0.2) to afford a white solid (0.75 g). LC-MS: [M+H] + :310.1.

[0291] Synthesis of 4-(3-((diphenylmethylene)amino)-4-(trifluoromethoxy)phenyl)-1-methylpiperidin-4-ol (4):

[0292] Compound 4-(3-chloro-4-(trifluoromethoxy)phenyl)-1-methylpiperidin-4-ol (700.0 mg, 2.26 mmol), benzophenone imine (409.6 mg, 2.26 mmol), cesium carbonate (2.2 g, 6.75 mmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (185.6 mg, 0.45 mmol), tris(dibenzylideneacetone)dipalladium (207.0 mg, 0.23 mmol) were added to anhydrous dioxane (5 mL) and reacted at 100°C under nitrogen for 16 hours. The mixture was cooled to room temperature, diluted with 10 mL of water, extracted with ethyl acetate (3×10 mL), and the organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH=50:1-20:1) (DCM:MeOH=10:1, R f =0.2) and preparative purification to give a white solid (480.0 mg). LC-MS: [M+H] + :455.3.

[0293] Synthesis of 4-(3-amino-4-(trifluoromethoxy)phenyl)-1-methylpiperidin-4-ol (5):

[0294] Dissolve the compound 4-(3-((diphenylmethylene)amino)-4-(trifluoromethoxy)phenyl)-1-methylpiperidin-4-ol (300.0 mg, 0.66 mmol) in dioxane (3.0 mL). Add 4M hydrochloric acid solution in dioxane (3 mL) dropwise at room temperature and stir at room temperature for 2 hours. Filter and slurry with dichloromethane and petroleum ether (dichloromethane:petroleum ether = 5:1) to obtain the crude compound (100.0 mg). The crude product was used directly in the next reaction. LC-MS: [M+H] + :291.1.

[0295] Synthesis of 5'-(5-fluoro-2-((5-(4-hydroxy-1-methylpiperidin-4-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (DP-01-195):

[0296] The compound 4-(3-amino-4-(trifluoromethoxy)phenyl)-1-methylpiperidin-4-ol (130.0 mg, 0.45 mmol), 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (142.7 mg, 0.49 mmol), cesium carbonate (291.8 mg, 0.90 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (31.2 mg, 0.05 mmol), and tris(dibenzylideneacetone)dipalladium (41.0 mg, 0.045 mmol) were added to anhydrous dioxane (5 mL) and reacted at 90°C under nitrogen for 6 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (3×10 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative separation to give a light yellow solid (22.3 mg). 1 H NMR(400MHz, DMSO-d6)δ9.29(s,1H),8.92(s,1H),8.64(d,J=3.6Hz,1H),8.35(s,1H),8.26–8.18(m,2H),8.09(s,1H),7.47(d,J=8.4Hz,1H), 7.37–7.28(m,2H),2.82–2.73(m,2H),2.65–2.55(m,2H),2.36(s,3H), 2.10–1.99(m,2H),1.74–1.64(m,2H),1.59–1.46(m,4H); LC-MS:[M+H] + :544.2.

[0297] Example 2. Synthesis of compound DP-01-231

[0298]

[0299] Synthesis of 4-(3-chloro-4-methoxyphenyl)-1-methylpiperidin-4-ol (2):

[0300] Dissolve 2-chloro-4-iodo-1-methoxybenzene (3.3 g, 12.29 mmol) in tetrahydrofuran (20 mL). After cooling to -78°C, slowly add 2.5 M n-butyllithium solution (4.9 mL, 12.25 mmol) dropwise. After the addition is complete, stir the reaction mixture at -78°C for 30 minutes. Then, slowly add a solution of 1-methylpiperidin-4-one (1.5 g, 13.26 mmol) in tetrahydrofuran (20 mL) dropwise to the solution, maintaining stirring at -78°C for 1 hour. The reaction mixture is quenched with saturated ammonium chloride (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phases are washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 0-6%, dichloromethane / methanol = 10:1, Rf = 0.3) to give a white solid (856.0 mg). LC-MS: [M+H] + :256.1,258.1.

[0301] Synthesis of 4-(3-((diphenylmethylene)amino)-4-methoxyphenyl)-1-methylpiperidin-4-ol (3):

[0302] Under nitrogen, 4-(3-chloro-4-methoxyphenyl)-1-methylpiperidin-4-ol (240.0 mg, 0.94 mmol), benzophenone imine (340.2 mg, 1.88 mmol), cesium carbonate (611.5 mg, 1.88 mmol), 2-dicyclohexylphosphine-2′,6′-dimethoxy-biphenyl (77.1 mg, 0.19 mmol), and tris(dibenzylideneacetone)dipalladium (85.9 mg, 0.094 mmol) were placed in 1,4-dioxane (4 mL) and stirred at 110°C for 18 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 0-8%, dichloromethane / methanol = 10:1, Rf = 0.2) to give 4-(3-((diphenylmethylene)amino)-4-methoxyphenyl)-1-methylpiperidin-4-ol (150.0 mg) as an orange oil. LC-MS: [M+H] + :401.5. Synthesis of 4-(3-amino-4-methoxyphenyl)-1-methylpiperidin-4-ol (4):

[0303] The compound 4-(3-((diphenylmethylene)amino)-4-methoxyphenyl)-1-methylpiperidin-4-ol (150.0 mg, 0.37 mmol) was dissolved in 1,4-dioxane (2 mL), and a 4M hydrochloric acid solution in dioxane (2 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours. LCMS confirmed that the reaction was complete. The solvent was dried by rotary evaporation, and saturated sodium bicarbonate was added to adjust the pH to 8. The mixture was extracted with ethyl acetate (20 mL x 3), dried by rotary evaporation, and purified by reverse phase column chromatography (acetonitrile:water (ammonia) = 0-30%) to obtain a yellow solid (80.0 mg). LC-MS: [M+H] + :237.1.

[0304] Synthesis of 5'-(5-fluoro-2-((5-(4-hydroxy-1-methylpiperidin-4-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (DP-01-231):

[0305] 4-(3-Amino-4-methoxyphenyl)-1-methylpiperidin-4-ol (80.0 mg, 0.34 mmol), 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (117.7 mg, 0.41 mmol), cesium carbonate (220.6 mg, 0.68 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (42.2 mg, 0.068 mmol), and tris(dibenzylideneacetone)dipalladium (31.0 mg, 0.034 mmol) were placed in dioxane (3 mL). The atmosphere was replaced with nitrogen and the mixture was heated to 100°C and stirred for 6 hours. LCMS monitoring indicated that the starting material had reacted completely. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by preparative purification to obtain a light yellow solid (39.5 mg). 1 H NMR (400MHz, DMSO-d6) δ8.93 (s, 1H), 8.65 (d, J = 4.0Hz, 1H), 8.38 (s, 1H), 8.35 –8.30(m,3H),8.22(s,1H),7.50(d,J=8.0Hz,1H),7.17(dd,J=8.8,2.4Hz,1H), 7.01(d,J=8.8Hz,1H),3.85(s,3H),2.71–2.67(m,2H),2.55–2.51(m,2H),2.31 (s,3H),2.03–1.96(m,2H),1.69–1.65(m,2H),1.56–1.54(m,4H); LC-MS:[M+H] + :490.7.

[0306] Example 3. Synthesis of compound DP-01-232

[0307]

[0308] Synthesis of tert-butyl 4-(3-chloro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate (2):

[0309] The compound 2-chloro-4-iodo-1-methoxybenzene (2.0 g, 7.45 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to -78 ° C under nitrogen protection, and n-butyl lithium (4.0 mL, 2.5 M, 10.00 mmol) was slowly added dropwise. The reaction solution was stirred at -78 ° C for 30 minutes. 4-Oxopiperidine-1-carboxylic acid tert-butyl ester (1.5 g, 7.53 mmol) was dissolved in 20 mL of tetrahydrofuran and slowly added dropwise to the above solution. Stirring was continued at -78 ° C for 1.5 hours. Saturated aqueous ammonium chloride solution (40 mL) was added to the reaction solution to quench the reaction, and ethyl acetate was added for extraction (100 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain a white solid (2.2 g). LC-MS: [M- t Bu-H2O+H] + :268.1,270.1.

[0310] Synthesis of tert-butyl 4-(3-chloro-4-methoxyphenyl)-4-methoxypiperidine-1-carboxylate (3):

[0311] tert-Butyl 4-(3-chloro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate (1.0 g, 2.93 mmol) and sodium hydride (117.3 mg, 2.93 mmol, 60%) were added to N,N-dimethylformamide (20 mL) and stirred at 0°C for 0.5 hours. Methyl iodide (498.2 mg, 3.51 mmol) was then added and stirred at room temperature for 0.5 hours. The reaction solution was diluted with water (100 mL) and then extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain a yellow oil (670.0 mg). LC-MS: [M- t Bu-H2O+H] + :282.1.

[0312] Synthesis of 4-(3-chloro-4-methoxyphenyl)-4-methoxypiperidine (4):

[0313] Dissolve tert-butyl 4-(3-chloro-4-methoxyphenyl)-4-methoxypiperidine-1-carboxylate (780.0 mg, 2.19 mmol) in methanol (10 mL), add oxalyl chloride (321.0 mg, 2.53 mmol) at room temperature, and stir the mixture for 16 hours. After the reaction is complete, the reaction mixture is concentrated in vacuo to yield a white solid (550.0 mg). LC-MS: [M+H] + :256.2.

[0314] Synthesis of 4-(3-chloro-4-methoxyphenyl)-4-methoxy-1-methylpiperidine (5):

[0315] 4-(3-chloro-4-methoxyphenyl)-4-methoxypiperidine (550.0 mg, 2.15 mmol) was dissolved in methanol (10 mL). 37% aqueous formaldehyde solution (0.5 mL) and acetic acid (30.0 mg, 0.50 mmol) were then added to the reaction mixture. After stirring for 1 hour, sodium triacetoxyborohydride (694.9 mg, 3.28 mmol) was added. The suspension was then stirred for 2 hours, quenched with saturated aqueous sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (0-10% methanol / dichloromethane) to obtain a yellow solid (500.0 mg). LC-MS: [M+H] + :270.2.

[0316] Synthesis of N-(2-methoxy-5-(4-methoxy-1-methylpiperidin-4-yl)phenyl)-1,1-diphenylmethanimine (6):

[0317] To a solution of 4-(3-chloro-4-methoxyphenyl)-4-methoxy-1-methylpiperidine (500.0 mg, 1.85 mmol) in 1,4-dioxane (3 mL) were added benzophenone imine (413.2 mg, 2.28 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (141.6 mg, 0.23 mmol), tris(dibenzylideneacetone)dipalladium (208.4 mg, 0.23 mmol), and cesium carbonate (1.8 g, 5.52 mmol). The mixture was heated to 100°C and stirred under nitrogen for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by silica gel column chromatography (0-10% methanol / dichloromethane) to afford a yellow solid (340.0 mg). LC-MS: [M+H] + :415.2.

[0318] Synthesis of 2-methoxy-5-(4-methoxy-1-methylpiperidin-4-yl)aniline (7):

[0319] To a solution of N-(2-methoxy-5-(4-methoxy-1-methylpiperidin-4-yl)phenyl)-1,1-diphenylcarbamethane (240.0 mg, 0.58 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL), and the reaction was stirred at room temperature for 1 hour. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was purified by silica gel column chromatography (0-20% methanol / dichloromethane) to afford a yellow oil (100.0 mg). LC-MS: [M+H] + :251.2.

[0320] Synthesis of 5'-(5-fluoro-2-((2-methoxy-5-(4-methoxy-1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (DP-01-232):

[0321] To a solution of 2-methoxy-5-(4-methoxy-1-methylpiperidin-4-yl)aniline (100.0 mg, 0.40 mmol) in 1,4-dioxane (10 mL) were added 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (171.0 mg, 0.59 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (40.8 mg, 0.065 mmol), tris(dibenzylideneacetone)dipalladium (45.0 mg, 0.05 mmol), and cesium carbonate (390.0 mg, 1.20 mmol), followed by heating to 100°C and stirring for 6 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude product was purified by preparative purification to give a yellow solid (6.3 mg). 1 HNMR(400MHz,DMSO-d6)δ8.89(s,1H),8.67(d,J=3.6Hz,1H),8.31–8.29(m ,3H),8.23(s,2H),7.48(d,J=8.0Hz,1H),7.11–7.02(m,2H),3.88(s,3H), 2.88(s,3H),2.59(d,J=10.3Hz,2H),2.32(t,J=10.7Hz,2H),2.22(s,3H), 2.00(d,J=12.8Hz,2H),1.88(t,J=12.0Hz,2H),1.55(s,4H).LC-MS:[M+H] + :504.5.

[0322] Example 4. Synthesis of Compound DP-01-244

[0323]

[0324] Synthesis of 4-(3-bromo-4-methoxyphenyl)-1-methylpiperidine-4-carboxaldehyde (1):

[0325] The compound 4-(3-bromo-4-methoxyphenyl)-1-methylpiperidine-4-carbonitrile (2.0 g, 6.47 mmol) was dissolved in toluene (30 mL). Diisobutylaluminum hydride (3.90 mL, 7.8 mmol, 2 M) was slowly added dropwise at -65°C. The mixture was allowed to react at the same temperature for 2 hours. Aqueous hydrochloric acid (10 mL, 1 M) was slowly added to the reaction mixture to quench the reaction. The mixture was then diluted with 150 mL of water and extracted with ethyl acetate (150 mL x 2). The combined organic phases were washed with saturated sodium chloride (200 mL x 1), dried over anhydrous sodium sulfate, and concentrated to obtain a colorless crude oil. The crude product was purified by column chromatography (0-15% methanol / dichloromethane) to obtain a yellow oil (210.0 mg). LC-MS: [M+H] + :312.1,314.1.

[0326] Synthesis of (4-(3-bromo-4-methoxyphenyl)-1-methylpiperidin-4-yl)methanol (2):

[0327] The compound 4-(3-bromo-4-methoxyphenyl)-1-methylpiperidine-4-carbaldehyde (200.0 mg, 0.64 mmol) was dissolved in methanol (5 mL). Sodium borohydride (36.5 mg, 0.96 mmol) was slowly added at room temperature and allowed to react for 2 hours. The reaction solution was diluted with 40 mL of aqueous solution and extracted with ethyl acetate (40 mL x 2). The ethyl acetate layer was washed once with saturated sodium chloride solution (60 mL). The organic phase was dried over anhydrous sodium sulfate and the ethyl acetate was evaporated to dryness to obtain a colorless crude oil. The crude product was purified by column chromatography (0-12% methanol / dichloromethane) to obtain a brown solid (95.0 mg). LC-MS: [M+H] + :314.1,316.1.

[0328] Synthesis of (4-(3-((diphenylmethylene)amino)-4-methoxyphenyl)-1-methylpiperidin-4-yl)methanol (3):

[0329] Compound (4-(3-bromo-4-methoxyphenyl)-1-methylpiperidin-4-yl)methanol (90.0 mg, 0.29 mmol), benzophenone imine (77.5 mg, 0.43 mmol), tris(dibenzylideneacetone)dipalladium (27.5 mg, 0.03 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (37.3 mg, 0.06 mmol), cesium carbonate (273.0 mg, 0.84 mmol) ) was dissolved in 1,4-dioxane (1 mL) and reacted at 100°C for 4 hours. After cooling, the reaction solution was diluted with 20 mL of aqueous solution and extracted with ethyl acetate (20 mL x 2). The ethyl acetate layer was washed once with saturated sodium chloride solution (40 mL). The organic phase was dried over anhydrous sodium sulfate and the ethyl acetate was evaporated to dryness to obtain a colorless oily crude product. The crude product was purified by column chromatography (0-20% methanol / dichloromethane) to obtain a brown solid (80.0 mg). LC-MS: [M+H] + :415.1.

[0330] Synthesis of (4-(3-amino-4-methoxyphenyl)-1-methylpiperidin-4-yl)methanol (4):

[0331] The compound (4-(3-((diphenylmethylene)amino)-4-methoxyphenyl)-1-methylpiperidin-4-yl)methanol (70.0 mg, 0.17 mmol) and a 2M hydrochloric acid solution in 1,4-dioxane (0.3 mL) were dissolved in methanol (1 mL) and reacted at room temperature for 1 hour. The reaction solution was concentrated to obtain a white solid (40.0 mg). LC-MS: [M+H] + :251.1.

[0332] Synthesis of 5'-(5-fluoro-2-((5-(4-(hydroxymethyl)-1-methylpiperidin-4-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (DP-01-244):

[0333] The compound (4-(3-amino-4-methoxyphenyl)-1-methylpiperidin-4-yl)methanol (35.0 mg, 0.14 mmol), 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (48.5 mg, 0.17 mmol), tris(dibenzylideneacetone)dipalladium (18.3 mg, 0.02 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (18.7 mg, 0.03 mmol), and cesium carbonate (136.5 mg, 0.42 mmol) were placed in 1,4-dioxane (1 mL) and heated to 100°C under nitrogen for 6 hours. After cooling to room temperature, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed twice with saturated sodium chloride solution (80 mL x 2), dried over sodium sulfate, filtered and concentrated to obtain a black solid crude product. The crude product was purified by preparative method to obtain a white solid (13.7 mg). 1 H NMR(400MHz,MeOD)δ8.73(s,1H),8.61(s,1H),8.52(d,J=3.2Hz,1H),8.35–8.31(m,1H),7.46–7.41(m,1H),7.10–7.04(m,2H),3.9 6(s,3H),3.51–3.48(m,4H),2.94(s,2H),2.75(s,3H),2.52(d,J=14.8Hz,2H),2.15–2.10(m,2H),1.70–1.60(m,4H); LC-MS:[M+H] + :504.8.

[0334] Example 5. Synthesis of compound DP-01-244-01

[0335]

[0336] Synthesis of 4-(3-bromo-4-methoxyphenyl)-1-methylpiperidine-4-carboxylic acid (1):

[0337] Dissolve the compound 4-(3-bromo-4-methoxyphenyl)-1-methylpiperidine-4-carbonitrile (1.0 g, 3.23 mmol) in concentrated hydrochloric acid (10 mL) and heat to 100°C for 18 hours. Concentrate to obtain a yellow oil (1.0 g). LC-MS: [MH] - :326.1,328.1.

[0338] Synthesis of ethyl 4-(3-bromo-4-methoxyphenyl)-1-methylpiperidine-4-carboxylate (2):

[0339] The compound 4-(3-bromo-4-methoxyphenyl)-1-methylpiperidine-4-carboxylic acid (1.0 g, 3.05 mmol), thionyl chloride (3.6 g, 30.26 mmol), and N,N-dimethylformamide (0.3 mL) were dissolved in ethanol (10 mL) and heated to 80°C for 2 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (80 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a colorless oily crude product. The crude product was purified by silica gel column chromatography (0-50% ethyl acetate / petroleum ether) to obtain a yellow oil (240.0 mg). LC-MS: [M+H] + :356.1,358.1.

[0340] Synthesis of ethyl 4-(3-((diphenylmethylene)amino)-4-methoxyphenyl)-1-methylpiperidine-4-carboxylate (3):

[0341] The compound ethyl 4-(3-bromo-4-methoxyphenyl)-1-methylpiperidine-4-carboxylate (220.0 mg, 0.62 mmol), benzophenone imine (128.4 mg, 0.71 mmol), tris(dibenzylideneacetone)dipalladium (59.4 mg, 0.065 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (80.8 mg, 0.13 mmol), and cesium carbonate (528.1 mg, 1.62 mmol) were placed in 1,4-dioxane (5 mL) and reacted at 100°C for 4 hours. The reaction solution was cooled, diluted with water (40 mL), and extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (0-10% methanol / dichloromethane) to obtain a brown solid (250.0 mg). LC-MS: [M+H] + :457.1.

[0342] Synthesis of ethyl 4-(3-amino-4-methoxyphenyl)-1-methylpiperidine-4-carboxylate (4):

[0343] To a solution of ethyl 4-(3-((diphenylmethylene)amino)-4-methoxyphenyl)-1-methylpiperidine-4-carboxylate (230.0 mg, 0.50 mmol) in dichloromethane (3 mL) was added a 2M hydrochloric acid / 1,4-dioxane solution (1 mL) and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was concentrated to obtain a gray crude product (130.0 mg), which was used directly in the next reaction. LC-MS: [M+H] + :293.1.

[0344] Synthesis of 4-(3-amino-4-methoxyphenyl)-1-methylpiperidine-4-carboxylic acid (5):

[0345] Dissolve ethyl 4-(3-amino-4-methoxyphenyl)-1-methylpiperidine-4-carboxylate (120.0 mg, 0.41 mmol) and sodium hydroxide (164.0 mg, 4.10 mmol) in tetrahydrofuran (2 mL) and water (1 mL). Heat to 90°C and react for 16 hours. After cooling, the reaction solution was adjusted to pH 5 with 1M aqueous hydrochloric acid, concentrated, and purified by reverse-phase column chromatography to yield a white solid (100.0 mg). LC-MS: [MH] - :263.1.

[0346] Synthesis of 4-(3-((5-fluoro-4-(3'-oxospiro[cyclopropane-1,1'-isoindoline]-5'-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)-1-methylpiperidine-4-carboxylic acid (DP-01-244-01):

[0347] Compound 4-(3-amino-4-methoxyphenyl)-1-methylpiperidine-4-carboxylic acid (90.0 mg, 0.34 mmol), 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (108.1 mg, 0.37 mmol), tris(dibenzylideneacetone)dipalladium (31.1 mg, 0.03 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (43.5 mg, 0.07 mmol), and cesium carbonate (276.2 mg, 0.85 mmol) were dissolved in 1,4-dioxane (1 mL). The mixture was heated to 100 ° C under nitrogen protection and reacted for 5 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated sodium chloride solution (80 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a black solid crude product, which was purified by preparative high performance liquid chromatography to obtain a white solid (7.0 mg). 1 H NMR (400MHz, DMSO) δ8.98(s,1H),8.65(d,J=3.6Hz,1H),8.32–8.29(m,3H),8.23(d,J=1.6Hz,1H),7.48(d,J=8.8Hz,1H),7.08–6 .98(m,2H),3.86(s,3H),2.67(s,2H),2.41(d,J=14.0Hz,2H),2.16–2.11(m,5H),1.80(s,2H),1.55(d,J=6.0Hz,4H); LC-MS:[MH] - :516.4.

[0348] Example 6. Synthesis of compound DP-01-244-02

[0349]

[0350] Synthesis of 4-(3-((diphenylmethylene)amino)-4-methoxyphenyl)-1-methylpiperidine-4-carboxamide (1):

[0351] The compound 4-(3-((diphenylmethylene)amino)-4-methoxyphenyl)-1-methylpiperidine-4-carbonitrile (350.0 mg, 0.85 mmol) and potassium carbonate (354.3 mg, 2.56 mmol) were suspended in anhydrous dimethyl sulfoxide (2 mL) and 30% hydrogen peroxide (0.4 mL) was added dropwise at room temperature. After the addition was complete, the reaction solution was heated to 65°C and reacted for 5 hours. The reaction solution was cooled and quenched with saturated sodium sulfite (10 mL) aqueous solution. The mixture was extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated brine (10 mL), dried, and spin-dried. The crude product was purified by alkaline reverse phase chromatography to obtain a white solid (90.0 mg). LC-MS: [M+H] + :428.2.

[0352] Synthesis of 4-(3-amino-4-methoxyphenyl)-1-methylpiperidine-4-carboxamide (2):

[0353] Dissolve 4-(3-((diphenylmethylene)amino)-4-methoxyphenyl)-1-methylpiperidine-4-carboxamide (80.0 mg, 0.19 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL) dropwise, and react at room temperature for 18 hours. The reaction mixture is dried and the crude product is purified by reverse phase alkaline treatment to obtain a white solid (45.0 mg). LC-MS: [M+H] + :264.0.

[0354] Synthesis of 4-(3-((5-fluoro-4-(3'-oxospiro[cyclopropane-1,1'-isoindoline]-5'-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)-1-methylpiperidine-4-carboxamide (DP-01-244-02):

[0355] 4-(3-Amino-4-methoxyphenyl)-1-methylpiperidine-4-carboxamide (40.0 mg, 0.15 mmol), 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (44.0 mg, 0.15 mmol), cesium carbonate (148.5 mg, 0.46 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (18.9 mg, 0.03 mmol) and palladium acetate (3.4 mg, 0.015 mmol) were dissolved in toluene (5 mL) and reacted at 100 ° C for 18 hours under nitrogen protection. The reaction solution was spin-dried and the crude product was subjected to reverse-phase alkaline treatment to obtain a brown solid (2.7 mg). 1 H NMR(400MHz, DMSO-d6)δ8.91(s,1H),8.64(d,J=3.6Hz,1H),8.34–8.30(m,3H),8.18(s,1H),7.49(d,J=8.0Hz,1H),7.11–6.96( m,4H),3.84(s,3H),2.60–2.54(s,2H),2.43–2.36(m,3H),2.16(s,4H),1.90–1.82(m,2H),1.54(d,J=4.4Hz,4H); LC-MS:[M+H] + :517.3.

[0356] Example 7. Synthesis of compound DP-01-244-03

[0357]

[0358] Synthesis of 4-(3-amino-4-methoxyphenyl)-1-methylpiperidine-4-carbonitrile (3):

[0359] The compound 4-(3-((diphenylmethylene)amino)-4-methoxyphenyl)-1-methylpiperidine-4-carbonitrile (200.0 mg, 0.49 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was slowly added, and the reaction solution was stirred at room temperature for 4 hours. The reaction solution was directly concentrated and purified by silica gel column chromatography (dichloromethane:methanol:aqueous ammonia = 100:10:1) to obtain a white solid (110.0 mg). LC-MS: [M+H] + :246.2.

[0360] Synthesis of 4-(3-((5-fluoro-4-(3'-oxospiro[cyclopropane-1,1'-isoindoline]-5'-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)-1-methylpiperidine-4-carbonitrile (DP-01-244-03):

[0361] The compound 4-(3-amino-4-methoxyphenyl)-1-methylpiperidine-4-carbonitrile (100.0 mg, 0.41 mmol), 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindol]-3'-one (118.1 mg, 0.41 mmol), tris(dibenzylideneacetone)dipalladium (37.3 mg, 0.04 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (50.8 mg, 0.08 mmol) were dissolved in anhydrous 1,4-dioxane (3 mL). Cesium carbonate (398.4 mg, 1.22 mmol) was added under nitrogen. The reaction solution was heated to 100°C and stirred for 4 hours. After the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The product was purified by preparative separation to give a white solid (36.0 mg). 1 H NMR(400MHz, CDCl3)δ8.85(d,J=2.4Hz,1H),8.69(s,1H),8.48–8.46(m,2H),8.30(s,1H),7 .92(s,1H),7.26(d,J=8.0Hz,1H),7.15(dd,J=8.4,2.4Hz,1H),6.94(d,J=8.4Hz,1H),6.85 (s,1H),3.98(s,3H),3.21(d,J=12.0Hz,2H),2.78(d,J=12.0Hz,2H),2.56(s,3H),2.40(t, J=11.6Hz,2H),2.27(d,J=12.4Hz,2H),1.68–1.66(m,2H),1.63–1.56(m,2H); LC-MS:[M+H] + :499.4.

[0362] Example 8. Synthesis of Compound DP-01-281

[0363]

[0364] Synthesis of 4-(3-chloro-4-methylphenyl)-1-methylpiperidin-4-ol (2):

[0365] Dissolve 2-chloro-4-iodo-1-methylbenzene (2.0 g, 7.92 mmol) in tetrahydrofuran (10 mL), cool the temperature to -65°C, and slowly add a 2.5 M solution of n-butyllithium (4.2 mL, 10.50 mmol) in tetrahydrofuran. Stir at -65°C for 1 hour. Dissolve 1-methylpiperidin-4-one (1.0 g, 8.84 mmol) in tetrahydrofuran (10 mL) and add it dropwise to the solution at -65°C. Maintain stirring at -65°C for 2 hours. Quench the reaction mixture with saturated ammonium chloride (40 mL). Collect the organic phase, extract the aqueous phase with ethyl acetate (50 mL x 3). The combined organic phases are washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product. Purify the crude product on a silica gel column (dichloromethane:methanol = 0-8%) to obtain a white solid (1.04 g). LC-MS: [M+H] + :240.1,242.1.

[0366] Synthesis of 4-(3-((diphenylmethylene)amino)-4-methylphenyl)-1-methylpiperidin-4-ol (3):

[0367] The compound 4-(3-chloro-4-methylphenyl)-1-methylpiperidin-4-ol (400.0 mg, 1.67 mmol), dibenzophenone imine (453.6 mg, 2.50 mmol), cesium carbonate (1.09 g, 3.34 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (141.8 mg, 0.33 mmol) and tris(dibenzylideneacetone)dipalladium (229.2 mg, 0.25 mmol) were dissolved in dioxane (8 mL), replaced with nitrogen three times, heated to 110 ° C, and reacted for 12 hours. LCMS monitoring showed that the main peak was the product, and the raw material reaction was complete. Water (30 mL) was added to the reaction mixture to dilute it. The organic phase was collected and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The product was purified by silica gel column chromatography (dichloromethane:methanol = 0-8%) to obtain a red solid (360.0 mg). LC-MS: [M+H] + :385.2.

[0368] Synthesis of 4-(3-amino-4-methylphenyl)-1-methylpiperidin-4-ol (4):

[0369] The compound 4-(3-((diphenylmethylene)amino)-4-methylphenyl)-1-methylpiperidin-4-ol (360.0 mg, 0.94 mmol) was dissolved in dioxane (4 mL) and methanol (3 mL). A 4M hydrochloric acid solution in dioxane (3 mL) and methanol (3 mL) was added at room temperature and stirred at room temperature for 2 hours. LCMS monitoring showed that the main peak was the product peak. The reaction solution was dried by rotary evaporation, the solid was dissolved in water, and extracted with ethyl acetate (30 mL × 3). The aqueous phase was collected. The pH was adjusted to 8 with saturated sodium bicarbonate, and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and dried to obtain a white solid (120.0 mg). LC-MS: [M+H] + :221.2.

[0370] Synthesis of 5'-(5-fluoro-2-((5-(4-hydroxy-1-methylpiperidin-4-yl)-2-methylphenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (DP-01-281)

[0371] Compound 4-(3-amino-4-methylphenyl)-1-methylpiperidin-4-ol 4 (60.0 mg, 0.27 mmol), 5'-(2-chloro-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (94.7 mg, 0.33 mmol), cesium carbonate (177.5 mg, 0.54 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (33.9 mg, 0.05 mmol) and tris(dibenzylideneacetone)dipalladium (24.9 mg, 0.03 mmol) were dissolved in dioxane (2 mL), nitrogen was replaced, the temperature was raised to 100 ° C, and stirred for 6 hours. LCMS monitoring showed that the raw material had reacted completely and the product was the main peak. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL×3), and the combined organic phases were washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product, which was then prepared into a yellow solid (14.4 mg). 1 H NMR (400MHz, DMSO) δ8.94 (s, 1H), 8.88 (s, 1H), 8.56 (d, J = 4.0Hz, 1H), 8.32 (s,1H),8.22(s,1H),7.70(s,1H),7.44(d,J=8.0Hz,1H),7.17(s,2H),4.8 1(s,1H),2.68-2.61(m,2H),2.47-2.42(m,2H),2.26(s,3H),2.22(s,3H), 2.00-1.92(m,2H),1.66-1.58(m,2H),1.52(d,J=3.2Hz,4H).LC-MS:[M+H] +:474.3.

[0372] Example 9. Synthesis of Compound DP-01-280

[0373]

[0374] Synthesis of 5'-(2-((5-(4-azido-1-methylpiperidin-4-yl)-2-methoxyphenyl)amino)-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (1):

[0375] The compound 5'-(5-fluoro-2-((5-(4-hydroxy-1-methylpiperidin-4-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (50 mg, 0.10 mmol) and trimethylsilyl azide (34.5 mg, 0.30 mmol) were dissolved in dichloromethane (3 mL). Boron trifluoride etherate (0.2 mL) was added under nitrogen protection and reacted at room temperature for 4 hours. The solution was concentrated and purified by column chromatography (dichloromethane:methanol = 10:1) to obtain a yellow solid compound (35 mg). LC-MS: [M+H] + :515.2.

[0376] Synthesis of 5'-(2-((5-(4-amino-1-methylpiperidin-4-yl)-2-methoxyphenyl)amino)-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (DP-01-280):

[0377] Compound 5'-(2-((5-(4-azido-1-methylpiperidin-4-yl)-2-methoxyphenyl)amino)-5-fluoropyrimidin-4-yl)spiro[cyclopropane-1,1'-isoindolin]-3'-one (35 mg, 0.07 mmol) and triphenylphosphine (55 mg, 0.21 mmol) were dissolved in tetrahydrofuran (2 mL) and water (0.2 mL), reacted at room temperature for 3 hours, and purified by preparative separation to give a white solid (2.1 mg). 1H NMR (400MHz, DMSO) δ8.89(s,1H),8.65(d,J=3.6Hz,1H),8.39(d,J=2.4Hz,1H ),8.31(dd,J=11.6,7.2Hz,3H),7.50(d,J=8.4Hz,1H),7.23(dd,J=8.4,2.4H z,1H),7.04(d,J=8.4Hz,1H),3.86(s,3H),2.58–2.51(m,4H),2.21(s,3H),2 .15–2.08(m,2H),1.71(d,J=12.4Hz,2H),1.54(d,J=4.8Hz,4H).LC-MS:[M+H] + :489.2.

[0378] Example 10. Synthesis of compound DP-01-295

[0379]

[0380] Synthesis of tert-butyl 2'-(5-fluoro-2-((5-(4-hydroxy-1-methylpiperidin-4-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-4'-oxospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4'H)-carboxylate (1):

[0381] Compound 4-(3-amino-4-(trifluoromethoxy)phenyl)-1-methylpiperidin-4-ol (50.0 mg, 0.17 mmol), tert-butyl 2'-(2-chloro-5-fluoropyrimidin-4-yl)-4'-oxospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4'H)-carboxylate (67.0 mg, 0.17 mmol), cesium carbonate (168.0 mg, 0.52 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (21.0 mg, 0.034 mmol) and tris(dibenzylideneacetone)dipalladium (16.0 mg, 0.017 mmol) were dissolved in 1,4-dioxane (1 mL), the atmosphere was replaced with nitrogen, the temperature was raised to 100°C, and the mixture was stirred for 6 hours. LCMS monitoring showed that the raw material had reacted completely and the product was the main peak. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed once with saturated brine (15 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was purified on a silica gel column (methanol:dichloromethane = 0-22%) to obtain a white solid (55.0 mg). LC-MS: [M+H] + :650.3.

[0382] Synthesis of 2'-(5-fluoro-2-((5-(4-hydroxy-1-methylpiperidin-4-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-4'(5'H)-one (DP-01-295):

[0383] Tert-butyl 2'-(5-fluoro-2-((5-(4-hydroxy-1-methylpiperidin-4-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-4'-oxospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4'H)-carboxylate (55.0 mg, 0.085 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (0.3 mL) was added and stirred at room temperature for 1 hour. LCMS monitoring indicated that the starting material had reacted completely, with the product being the main peak. The reaction solution was concentrated and purified to obtain a white solid (7.3 mg). 1 H NMR (400MHz, DMSO) δ9.21(s,1H),8.69(s,1H),8.64(d,J=3.2Hz,1H),8.03(s,1H),7.79(d,J=1.6Hz,1H),7.37(s,2H),5.03(s ,1H),2.72(s,2H),2.59–2.51(s,2H),2.33(s,3H),2.06(t,J=11.2Hz,2H),1.72–1.62(m,4H),1.54–1.51(m,2H).LC-MS:[M+H] + :550.4.

[0384] Example 11. Synthesis of Compound DP-01-299

[0385]

[0386] Synthesis of tert-butyl 2'-(5-fluoro-2-((5-(4-hydroxy-1-methylpiperidin-4-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)-4'-oxospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4'H)-carboxylate (1):

[0387] To a solution of 4-(3-amino-4-methoxyphenyl)-1-methylpiperidin-4-ol (100.0 mg, 0.42 mmol) in 1,4-dioxane (5 mL) was added tert-butyl 2'-(2-chloro-5-fluoropyrimidin-4-yl)-4'-oxospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4'H)-carboxylate (165.9 mg, 0.42 mmol), tris(dibenzylideneacetone)palladium (38.8 mg, 0.042 mmol), cesium carbonate (275.8 mg, 0.85 mmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (26.4 mg, 0.042 mmol). The reaction mixture was stirred at 100°C under nitrogen for 6 hours. LCMS confirmed the reaction was complete. The reaction mixture was purified by silica gel flash column chromatography to obtain a white solid compound (200.0 mg). LC-MS: [M+H] + :596.4.

[0388] Synthesis of 2'-(5-fluoro-2-((5-(4-hydroxy-1-methylpiperidin-4-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-4'(5'H)-one (DP-01-299):

[0389] To tert-butyl 2'-(5-fluoro-2-((5-(4-hydroxy-1-methylpiperidin-4-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)-4'-oxospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-5'(4'H)-carboxylate (180.0 mg, 0.30 mmol) was added formic acid (2 mL). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. LCMS indicated that the reaction was complete. The residue was purified by column chromatography and reverse preparative method to give a yellow solid (80.0 mg). 1 HNMR (400MHz, DMSO) δ8.70(s,1H),8.63(d,J=3.2Hz,1H),8.23–8.21(m,1H),8.17(s,1H),7.79(d,J=1.2Hz,1H),7.23(dd,J=8.4,2.0Hz,1H),7.01(d ,J=8.6Hz,1H),3.85(s,3H),2.68(d,J=9.6Hz,2H),2.51(s,2H),2.29(s,3 H),2.12–2.04(m,2H),1.74–1.61(m,4H),1.54–1.51(m,2H).LC-MS:[M+H] + :496.2.

[0390] Example 12. Synthesis of Compound DP-01-298

[0391]

[0392] Synthesis of di-tert-butyl 4-oxo-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-1,5(4H)-dicarboxylate (2):

[0393] Dissolve 1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (3.20 g, 23.50 mmol), triethylamine (9.50 g, 93.88 mmol), and 4-dimethylaminopyridine (287.1 mg, 2.35 mmol) in acetonitrile (50 mL). Slowly add di-tert-butyl dicarbonate (19.00 g, 87.06 mmol) dropwise. React at room temperature under nitrogen for 16 hours. After concentration, add 50 mL of water and extract with ethyl acetate (20 mL x 3). The organic phases are combined, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford the compound (3.20 g) as a white solid. 1 H NMR (400MHz, DMSO) δ7.24 (d, J = 3.6 Hz, 1H), 6.49 (d, J = 4.0 Hz, 1H), 3.95 (t, J = 6.4 Hz, 2H), 3.15 (t, J = 6.4 Hz, 2H), 1.56 (s, 9H), 1.46 (s, 9H).

[0394] Synthesis of tert-butyl 4-oxo-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (3):

[0395] The compound 4-oxo-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-1,5(4H)-dicarboxylic acid di-tert-butyl ester (3.20 g, 9.51 mmol) was dissolved in methanol (15 mL), and aqueous ammonia (5 mL) was added. The reaction was allowed to proceed at 75°C for 5 hours. The mixture was concentrated, 15 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain a white solid compound (1.9 g). 1 HNMR (400MHz, DMSO) δ11.35(s,1H),6.77–6.70(m,1H),6.31(t,J=2.4Hz,1H),3.91(t,J=6.0Hz,2H),2.83(t,J=6.4Hz,2H),1.45(s,9H).

[0396] Synthesis of tert-butyl 1-methyl-4-oxo-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (4):

[0397] 4-Oxo-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (1.90 g, 8.04 mmol) and cesium carbonate (3.90 g, 11.97 mmol) were added to N,N-dimethylformamide (15 mL), followed by slow dropwise addition of iodomethane (1.70 g, 11.98 mmol). The mixture was allowed to react at room temperature for 2 hours. 15 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography (petroleum ether:ethyl acetate = 2:1) to afford the compound as a white solid (1.6 g). 1 H NMR (400MHz, DMSO) δ6.75 (d, J = 2.8 Hz, 1H), 6.32 (d, J = 3.2 Hz, 1H), 3.92 (t, J = 6.4 Hz, 2H), 3.53 (d, J = 3.2 Hz, 3H), 2.83 (t, J = 6.0 Hz, 2H), 1.45 (s, 9H).

[0398] Synthesis of tert-butyl 2-bromo-1-methyl-4-oxo-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (5):

[0399] The compound tert-butyl 1-methyl-4-oxo-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (1.60 g, 6.39 mmol) was dissolved in anhydrous tetrahydrofuran (18 mL) and methanol (6 mL). N-bromosuccinimide (1.16 g, 6.52 mmol) was slowly added at -65°C under nitrogen protection. The reaction was allowed to proceed for 4 hours. The mixture was concentrated, 15 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain the compound as a white solid (1.3 g). 1 H NMR (400MHz, DMSO) δ6.49(s,1H),3.93(t,J=6.4Hz,2H),3.49(s,3H),2.88(t,J=6.4Hz,2H),1.45(s,9H)

[0400] Synthesis of tert-butyl 1-methyl-4-oxo-2-boronic acid pinacol ester-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (6):

[0401] Dissolve tert-butyl 2-bromo-1-methyl-4-oxo-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (400.0 mg, 1.215 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (87.8 mg, 0.12 mmol), pinacol diboron (401.4 mg, 1.58 mmol), and potassium acetate (358.0 mg, 3.65 mmol) in 1,4-dioxane (5.0 mL). The reaction system was incubated at 80°C under nitrogen for 0.5 hours. After the reaction was complete, the excess solvent was removed under vacuum to obtain a black solid (459.1 mg). LC-MS: [M+H-tBu] + :321.2.

[0402] Synthesis of tert-butyl 2-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-4-oxo-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (7):

[0403] Tert-butyl 1-methyl-4-oxo-2-boronic acid pinacol ester-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (459.1 mg, 1.22 mmol), 2,4-dichloro-5-fluoropyrimidine (243.6 mg, 1.46 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (87.8 mg, 0.12 mmol), and potassium phosphate (774.4 mg, 3.65 mmol) were dissolved in a mixture of 1,4-dioxane and water (5.5 mL, 1,4-dioxane:water = 10:1). The reaction system was reacted at 90°C under nitrogen for 3 hours. After the reaction was complete, water (10.0 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Column chromatography (dichloromethane:methanol = 10:1) afforded a yellow solid (65.0 mg). LC-MS: [M+H-tBu] + :325.1,327.1.

[0404] Synthesis of tert-butyl 2-(5-fluoro-2-((5-(4-hydroxy-1-methylpiperidin-4-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-1-methyl-4-oxo-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (8):

[0405] The compound tert-butyl 2-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-4-oxo-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (30.0 mg, 0.079 mmol), 4-(3-amino-4-(trifluoromethoxy)phenyl)-1-methylpiperidin-4-ol (23.0 mg, 0.079 mmol), cesium carbonate (77.0 mg, 0.24 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (10.0 mg, 0.016 mmol) and tris(dibenzylideneacetone)dipalladium (7.0 mg, 0.0076 mmol) were dissolved in dioxane (1 mL), replaced with nitrogen, heated to 100°C and stirred for 6 hours. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic phases were washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product, which was purified by column chromatography (methanol:dichloromethane = 0%-9%) to obtain a yellow solid (18.0 mg). LC-MS: [M+H] + :635.3.

[0406] Synthesis of 2-(5-fluoro-2-((5-(4-hydroxy-1-methylpiperidin-4-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-1-methyl-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (DP-01-298):

[0407] Tert-butyl 2-(5-fluoro-2-((5-(4-hydroxy-1-methylpiperidin-4-yl)-2-(trifluoromethoxy)phenyl)amino)pyrimidin-4-yl)-1-methyl-4-oxo-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (18.0 mg, 0.028 mmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (0.3 mL) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain a white solid (9.8 mg). 1 H NMR (400MHz, MeOD) δ8.53(s,1H),8.30(d,J=3.6Hz,1H),8.21(d,J=1.6Hz,1H),7.39–7.31(m,2H),7.28(d,J=3.6Hz,1H),3.82(s, 3H), 3.59 (t, J=7.2Hz, 2H), 3.34 (d, J=7.6Hz, 4H), 2.93 (t, J=7.2Hz, 2H), 2.85 (s, 3H), 2.38–2.26 (m, 2H), 1.96 (d, J=13.6Hz, 2H). LC-MS:[M+H] + :535.1.

[0408] Example 13. The following molecules were synthesized according to the method of Method I:

[0409]

[0410]

[0411] Example 14. Test of the PLK1 Inhibitory Activity of Compounds

[0412] Prepare a 3-fold serial dilution of the test compound in DMSO in a 384-well dilution plate. Transfer 25 nL of the diluted compound to a 384-well reaction plate using an echophoresis tube, ensuring a DMSO concentration of 0.5%. Transfer 2.5 μL of 2× PLK1 enzyme solution to a 384-well reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 10 minutes. Transfer 2.5 μL of 2× ATP & PLK tide mixed solution to a 384-well reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 60 minutes. Transfer 4 μL of ADP-Glo ​​Reagent to a 384-well reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes. Transfer 8 μL of ADP-Glo ​​Detection Reagent to a 384-well reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes. Read the RLU (Relative Luminescence Unit) signal using a BMG microplate reader. Signal intensity is used to indicate kinase activity. The IC of positive drugs was calculated using the nonlinear fitting formula (1) of GraphPad software. 50 :

[0413] Y=Bottom + (Top-Bottom) / (1+10^((LogIC50-X) ×HillSlope)) (1)

[0414] Wherein, X represents the log value of compound concentration, and Y represents the inhibition rate (%inhibition).

[0415] The results showed that the compounds of the present invention have good PLK1 inhibitory activity, IC 50 The IC values ​​of representative compounds are less than 100 nM, preferably less than 10 nM, and more preferably less than 1 nM. 50 As shown in Table 1 below:

[0416] Table 1. Inhibitory activity against PLK1, proliferation inhibition activity against HCT116 cells, and solubility of representative compounds

[0417] Compound number <![CDATA[PLK1 IC 50 (nM)]]> <![CDATA[HCT116 IC 50 (nM)]]> Solubility (μM) pH 7.4 DP-01-195 0.19 7.8 DP-01-231 0.10 5.8 50.4 DP-01-232 0.18 DP-01-244 2.14 DP-01-244-01 1.32 DP-01-244-02 9.35 DP-01-244-03 0.12 18.2 DP-01-281 0.09 8.3 318.8 DP-01-280 76.0 DP-01-295 0.19 22.9 DP-01-299 0.15 7.4 DP-01-298 1.6

[0418] Example 15. HCT116 cell proliferation inhibitory activity test

[0419] HCT116 cells were revived in complete culture medium (M'5AMedium + 10% FBS + 1% P / S). After approximately two passages, cells in logarithmic growth phase were selected and counted. Cells were resuspended and seeded into 384-well plates, with 500 cells / 40 μL of cell suspension added to each well. The cells were cultured overnight. Test compounds were prepared as stock solutions in DMSO and diluted three-fold in DMSO, starting at 1 μM, to create a nine-point concentration gradient. 40 nL of compound was added to each well, and the plates were incubated in a 37°C, 100% relative humidity, 5% CO2 incubator for 3 days. 40 μL of CellCounting-Lite 2.0 Luminescent Cell Viability Assay was added to each well, shaken for 2 minutes, and incubated at room temperature for 30 minutes. Fluorescence readings (RLU) were then read in a BMG microscope. Inhibition rate data were calculated using the following formula:

[0420] Inhibition Rate(Inh%)=100-(RLUCpd-RLUMin) / (RLUMax-RLUMin)*100%;

[0421] Where RLUCpd represents the mean fluorescence value of the wells containing compound at each concentration, RLUMax represents the mean fluorescence value of the wells containing DMSO, and RLUMin represents the mean fluorescence value of the blank wells.

[0422] The inhibition rates corresponding to different concentrations of compounds were calculated in EXCEL, and then the inhibition rate curves were fitted using GraphPad Prism software to calculate the IC 50 Values, IC values ​​of representative compounds 50 As shown in Table 1 above.

[0423] The results showed that the compounds of the present invention have good HCT116 tumor cell inhibitory activity, IC 50 The IC values ​​of representative compounds are less than 100 nM, preferably less than 20 nM, and more preferably less than 10 nM. 50 As shown in Table 1 above.

[0424] Example 16. Solubility test

[0425] (1) Solution Preparation: Prepare the test compound into a 10 mM stock solution in DMSO. Prepare the test buffer solution: Weigh 7.098 g of Na₂HPO₄ and dissolve it in 500 mL of ultrapure water by sonication. Weigh 3.40 g of KH₂PO₄ and dissolve it in 250 mL of ultrapure water by sonication. Mix the buffer solutions and adjust the pH to 7.40.

[0426] (2) Test operation

[0427] a) Add 30 μL of compound stock solution to the wells of a 96-well solubility plate in duplicate.

[0428] b) Add 970 μL of test solution to the above compound wells.

[0429] c) Place a PTFE-encapsulated stainless steel rod stirrer into each well, and then seal the well with a PTDE / SIL silicone plug;

[0430] d) Transfer the solubility sample plate to a Thermomixer Comfort plate shaker and shake at 1100 rpm at 25°C for 2 hours.

[0431] e) After 2 hours, remove the stirring bar using a magnet;

[0432] f) Pipette 200 μL of sample into a filter plate, filter, and collect the filtrate;

[0433] g) 10 μL of the filtered sample and 10 μL of DMSO were added to 980 μL of methanol, and the mixture was further diluted 5-fold with methanol:water (1:1) to prepare the filtered sample for LC-MS / MS analysis;

[0434] h) For standard samples, dilute the 10 mM DMSO stock solution to 300 μM;

[0435] i) 10 μL of 300 μM DMSO sample and 10 μL of buffer were added to 980 μL of methanol, and then diluted 5-fold with methanol:water (1:1) to prepare a standard sample for LC-MS / MS analysis.

[0436] (3) Data Analysis

[0437] Solubility was calculated using Microsoft Excel.

[0438]

[0439] Where DF represents the dilution factor, Area is the area under the curve, and std is the standard

[0440] The results show that the compounds of the present invention have good solubility. The solubility of representative compounds is shown in Table 1 above.

[0441] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A compound represented by formula (I) or an isomer, deuterated form thereof, or a pharmaceutically acceptable salt thereof, or a polymorph or solvate thereof or a salt thereof: in: G is a bond or -CH2-; Ring A is selected from phenyl, 5-6 membered heteroaryl containing 1-2 ring heteroatoms independently selected from N and S; When ring A is a heteroaryl group, ring A and its fused ring share a ring carbon and / or ring nitrogen atom, and ring B is connected to a ring carbon atom or a ring nitrogen atom of ring A; X and Y are independently selected from N and CH; R 1a and R 1b independently selected from H, F, Cl, Br, OH, CN, -NR8R9, C 1-4 Straight-chain or branched alkyl, C 2-4 Straight-chain or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 Straight-chain or branched alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S connected to the proximal group through C or N on the ring, or, R 1a and R 1b Together with the ring C atoms to which they are connected, they form C=O, C=CH2, C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, and S, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted by one or more independently selected from F, Cl, Br, OH, SH, CN, -C(O)R8, -C(O)N(R8)R9, -S(O)2R8, -S(O)2N(R8)R9, -N(R8)R9, -N(R8)C(O)R9, -N(R8)S(O)2R9, -P(O)(R8)R9, C 1-4 Straight-chain or branched alkyl, C 2-4 Straight-chain or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R2, R3 are independently selected from H, F, Cl, Br, OH, CN, NO2, C 1-4 Straight-chain or branched alkyl, C 2-4 Straight-chain or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 Straight-chain or branched alkoxy, C 3-7 Cycloalkyl, C 3-7 Cycloalkyloxy, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, and S, which is connected to the proximal group through C or N on the ring, 3-7 membered heterocycloalkyloxy containing 1-3 ring heteroatoms independently selected from N, O, and S, which is connected to oxygen through C or N on the ring, 5-11 membered heteroaryl containing 1-3 ring heteroatoms independently selected from N, O, and S, which is connected to the proximal group through C or N on the ring, phenyl, -C(O)R8, -C(O)OR8, -C(O)N(R8)R9, -S(O)2R8, -S(O)2N(R8)R9, -N(R8)R9, -N(R8)C(O)R9, -N(R8)S(O)2R9, -P(O)(R8)R9, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocyclyloxy, heteroaryl, phenyl are optionally substituted by one or more independently selected from F, Cl, Br, OH, CN, NO2, -C(O)R8, -C(O)OR8, -C(O)N(R8)R9, -S(O)2R8, -S(O)2N(R8)R9, -N(R8)R9, -N(R8)C(O)R9, -N(R8)S(O)2R9, -P(O)(R8)R9, C 1-4 Straight-chain or branched alkyl, C 2-4 Straight-chain or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 Straight-chain or branched alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, and S, which is connected to the proximal group through C or N on the ring, 5-11 membered heteroaryl containing 1-3 ring heteroatoms independently selected from N, O, and S, which is connected to the proximal group through C or N on the ring, and phenyl; R4 is selected from H, F, Cl, Br, OH, CN, NH2, C 1-4 Straight-chain or branched alkyl, C 2-4 Straight-chain or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 Straight chain alkoxy, C 3-7 Cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, OH, CN, NH2, C 1-4 Straight-chain or branched alkyl, C 2-4 Straight-chain or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R5 is selected from F, Cl, Br, -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R6 is selected from H, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S connected to the proximal group through C or N on the ring, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, OH, CN, NH2, =O, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R7 is independently selected from H, F, Cl, Br, OH, CN, =O, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S connected to the proximal group through C or N on the ring, or two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S; or, two R7 located on two non-adjacent ring C atoms are connected to form a C between the two non-adjacent ring C atoms. 1-2 Alkylene, the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkylene are optionally substituted by one or more independently selected from F, Cl, Br, OH, CN, NH2, =O, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R8 and R9 are independently selected from H, OH, CN, NH2, C 1-4 Straight-chain or branched alkyl, C 2-4 Straight-chain or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 Straight-chain or branched alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, and S connected to the proximal group through C or N on the ring, 5-11 membered heteroaryl containing 1-3 ring heteroatoms independently selected from N, O, and S connected to the proximal group through C or N on the ring, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl are optionally substituted by one or more selected from F, Cl, Br, OH, CN, NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; Alternatively, R8 and R9 together with the atoms to which they are attached form a 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms independently selected from N, O, S, which is optionally substituted with one or more ring heteroatoms independently selected from F, Cl, Br, OH, CN, NH2, C 1-4 Straight-chain or branched alkyl, C 2-4 Straight-chain or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 A linear or branched alkoxy group is substituted, wherein the alkyl, alkenyl, alkynyl, alkoxy group is optionally substituted by one or more independently selected from F, Cl, Br, OH, CN, NH2, C 1-4 Straight-chain or branched alkyl, C 2-4 Straight-chain or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, 4, 5, 6, 7 or 8. Preferably: Ring A is selected from phenyl, 5-6 membered heteroaryl containing one ring heteroatom selected from N, S; When ring A is a heteroaryl group, ring A and its fused ring share a ring carbon and / or ring nitrogen atom, and ring B is connected to a ring carbon atom or a ring nitrogen atom of ring A; X and Y are independently selected from N and CH; R 1a 、R 1b Independently selected from H, F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, or R 1a and R 1b Together with the ring C atoms to which they are connected, they form C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R2 is selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, -S(O)2R8, -S(O)2N(R8)R9, -P(O)(R8)R9, The alkyl and alkoxy groups are optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R3 is selected from H, F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight chain alkoxy, C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R5 is selected from F, Cl, Br, -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R6 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R7 is independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 A straight or branched alkoxy group, or two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group, or two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 Alkylene, the alkyl, alkoxy, cyclopropane is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R8, R9 are independently selected from H, C 1-4 Straight or branched alkyl, the alkyl group is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; m is selected from 0, 1, and 2; n is selected from 0, 1, 2, 3, 4.

2. The compound according to claim 1 or its isomer, deuterated substance, or pharmaceutically acceptable salt thereof, or polymorph or solvate thereof or its salt, wherein the compound has the following formula (II): In formula (II): Q and T are independently selected from N and CH; R 1a 、R 1b Independently selected from H, F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, or R 1a and R 1b Together with the ring C atoms to which they are connected, they form C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R2 is selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, -S(O)2R8, -S(O)2N(R8)R9, -P(O)(R8)R9, The alkyl and alkoxy groups are optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R3 is selected from H, F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight chain alkoxy, C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R5 is selected from F, Cl, Br, -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R6 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R7 is independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 A straight or branched alkoxy group, or two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group, or two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 Alkylene, the alkyl, alkoxy, cyclopropane is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R8, R9 are independently selected from H, C 1-4 Straight or branched alkyl, the alkyl group is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; m is selected from 0 and 1; n is selected from 0, 1, and 2. Preferably: Q and T are CH; R 1a 、R 1b Independently selected from H, -OH, C 1-4 Straight-chain or branched alkyl; or, R 1a and R 1b Together with the ring C atom to which they are attached, they form a cyclopropane group; R2 is selected from C 1-4 Straight or branched alkyl, -CH2OCH3, -S(O)2CH3, -S(O)2NH2, -P(O)(CH3)2, R3 is selected from F, Cl, Br; preferably, R3 is F; R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain alkoxy, cyclopropane, wherein the alkyl, alkoxy, and cyclopropane are optionally substituted by one or more groups independently selected from F, Cl, Br, and -CN; R5 is selected from -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, wherein the alkyl or alkoxy group is optionally substituted by a group selected from -OH or -NH2; R6 is C 1-4 Straight or branched alkyl; preferably, R6 is -CH3; R7 is independently selected from C 1-4 A straight or branched alkyl group, wherein the alkyl group is optionally substituted by one or more groups selected from F, Cl, and Br; or, two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group; or, two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 alkylene; R8, R9 are independently selected from H, C 1-4 a straight or branched chain alkyl group, said alkyl group being optionally substituted with one -OH group; m is selected from 0 and 1; n is selected from 0, 1, and 2. Preferably: Q and T are CH; R 1a and R 1b Together with the ring C atom to which they are attached, they form a cyclopropane group; R3 is selected from F, Cl, Br; R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain alkoxy, wherein the alkyl and alkoxy groups are optionally substituted by one or more groups independently selected from F, Cl, and Br; R5 is selected from -OH, -CN, -COOH, -CONH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, the alkyl group being optionally substituted with one -OH; R6 is C 1-4 Straight-chain or branched alkyl group; m and n are 0. Preferably: Q and T are CH; R 1a and R 1b Together with the ring C atom to which they are attached, they form a cyclopropane group; R3 is F; R4 is selected from -CH3, -OCH3, -OCF3; R5 is selected from -OH, -CN, -COOH, -CONH2, -OCH3, -CH2OH; R6 is -CH3; m and n are 0.

3. The compound according to claim 1 or its isomer, deuterated substance, or pharmaceutically acceptable salt thereof, or polymorph or solvate thereof or its salt, wherein the compound has the following formula (III): In formula (III): R 1a 、R 1b Independently selected from H, F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, or R 1a and R 1b Together with the ring C atoms to which they are connected, they form C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R2 is selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, -S(O)2R8, -S(O)2N(R8)R9, -P(O)(R8)R9, The alkyl and alkoxy groups are optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R3 is selected from H, F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight chain alkoxy, C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R5 is selected from F, Cl, Br, -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R6 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R7 is independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 A straight or branched alkoxy group, or two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group, or two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 Alkylene, the alkyl, alkoxy, cyclopropane is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R8, R9 are independently selected from H, C 1-4 Straight or branched alkyl, the alkyl group is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; m is selected from 0 and 1; n is selected from 0, 1, 2, 3, 4. Preferably: R 1a 、R 1b Independently selected from H, -OH, C 1-4 Straight-chain or branched alkyl; or, R 1a and R 1b Together with the ring C atom to which they are attached, they form a cyclopropane group; R2 is selected from C 1-4 Straight or branched alkyl, -CH2OCH3, -S(O)2CH3, -S(O)2NH2, -P(O)(CH3)2, R3 is selected from F, Cl, Br; preferably, R3 is F; R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain alkoxy, cyclopropane, wherein the alkyl, alkoxy, and cyclopropane are optionally substituted by one or more groups independently selected from F, Cl, Br, and -CN; R5 is selected from -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, wherein the alkyl or alkoxy group is optionally substituted by a group selected from -OH or -NH2; R6 is C 1-4 Straight or branched alkyl; preferably, R6 is -CH3; R7 is independently selected from C 1-4 A straight or branched alkyl group, wherein the alkyl group is optionally substituted by one or more groups selected from F, Cl, and Br; or, two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group; or, two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 alkylene; R8, R9 are independently selected from H, C 1-4 a straight or branched chain alkyl group, said alkyl group being optionally substituted with one -OH group; m is selected from 0 and 1; n is selected from 0, 1, and 2. Preferably: R 1a 、R 1b Independently selected from C 1-4 Straight-chain or branched alkyl; or, R 1a and R 1b Together with the ring C atom to which they are attached, they form a cyclopropane group; R3 is selected from F, Cl, Br; preferably, R3 is F; R4 is selected from -OCH3, -OCF3; R5 is -OH; R6 is -CH3; m and n are 0.

4. The compound according to claim 1 or its isomer, deuterated substance, or pharmaceutically acceptable salt thereof, or polymorph or solvate thereof or its salt, wherein the compound has the following formula (IV): In formula (IV): R 1a 、R 1b Independently selected from H, F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, or R 1a and R 1b Together with the ring C atoms to which they are connected, they form C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R2 is selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, -S(O)2R8, -S(O)2N(R8)R9, -P(O)(R8)R9, The alkyl and alkoxy groups are optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R3 is selected from H, F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight chain alkoxy, C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R5 is selected from F, Cl, Br, -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R6 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R7 is independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 A straight or branched alkoxy group, or two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group, or two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 Alkylene, the alkyl, alkoxy, cyclopropane is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R8, R9 are independently selected from H, C 1-4 Straight or branched alkyl, the alkyl group is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; m is selected from 0, 1, and 2; n is selected from 0, 1, 2, 3, 4. Preferably: R 1a 、R 1b Independently selected from H, -OH, C 1-4 Straight-chain or branched alkyl; or, R 1a and R 1b Together with the ring C atom to which they are attached, they form a cyclopropane group; R2 is selected from C 1-4 Straight or branched alkyl, -CH2OCH3, -S(O)2CH3, -S(O)2NH2, -P(O)(CH3)2, R3 is selected from F, Cl, Br; preferably, R3 is F; R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain alkoxy, cyclopropane, wherein the alkyl, alkoxy, and cyclopropane are optionally substituted by one or more groups independently selected from F, Cl, Br, and -CN; R5 is selected from -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, wherein the alkyl or alkoxy group is optionally substituted by a group selected from -OH or -NH2; R6 is C 1-4 Straight or branched alkyl; preferably, R6 is -CH3; R7 is independently selected from C 1-4 A straight or branched alkyl group, wherein the alkyl group is optionally substituted by one or more groups selected from F, Cl, and Br; or, two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group; or, two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 alkylene; R8, R9 are independently selected from H, C 1-4 a straight or branched chain alkyl group, said alkyl group being optionally substituted with one -OH group; m is selected from 0 and 1; n is selected from 0, 1, and 2. Preferably: R 1a 、R 1b Independently selected from H, C 1-4 Straight-chain or branched alkyl; or, R 1a and R 1b Together with the ring C atoms to which they are attached, they form a cyclopropane group; preferably, R 1a 、R 1b is H; R3 is selected from F, Cl, Br; preferably, R3 is F; R4 is selected from -OCH3, -OCF3; R5 is -OH; R6 is -CH3; m and n are 0.

5. The compound according to claim 1 or its isomer, deuterated substance, or pharmaceutically acceptable salt thereof, or polymorph or solvate thereof or its salt, wherein the compound has the following formula (V): In formula (V): R 1a 、R 1b Independently selected from H, F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, or R 1a and R 1b Together with the ring C atoms to which they are connected, they form C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R2 is selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, -S(O)2R8, -S(O)2N(R8)R9, -P(O)(R8)R9, The alkyl and alkoxy groups are optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R3 is selected from H, F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight chain alkoxy, C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R5 is selected from F, Cl, Br, -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R6 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R7 is independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 A straight or branched alkoxy group, or two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group, or two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 Alkylene, the alkyl, alkoxy, cyclopropane is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R8, R9 are independently selected from H, C 1-4 Straight or branched alkyl, the alkyl group is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; m is selected from 0, 1, and 2; n is selected from 0, 1, 2, 3, 4. Preferably: R 1a 、R 1b Independently selected from H, -OH, C 1-4 Straight-chain or branched alkyl; or, R 1a and R 1b Together with the ring C atom to which they are attached, they form a cyclopropane group; R2 is selected from C 1-4 Straight or branched alkyl, -CH2OCH3, -S(O)2CH3, -S(O)2NH2, -P(O)(CH3)2, R3 is selected from F, Cl, Br; preferably, R3 is F; R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain alkoxy, cyclopropane, wherein the alkyl, alkoxy, and cyclopropane are optionally substituted by one or more groups independently selected from F, Cl, Br, and -CN; R5 is selected from -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, wherein the alkyl or alkoxy group is optionally substituted by a group selected from -OH or -NH2; R6 is C 1-4 Straight or branched alkyl; preferably, R6 is -CH3; R7 is independently selected from C 1-4 A straight or branched alkyl group, wherein the alkyl group is optionally substituted by one or more groups selected from F, Cl, and Br; or, two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group; or, two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 alkylene; R8, R9 are independently selected from H, C 1-4 a straight or branched chain alkyl group, said alkyl group being optionally substituted with one -OH group; m is selected from 0 and 1; n is selected from 0, 1, and 2. Preferably: R 1a 、R 1b Independently selected from H, C 1-4 Straight-chain or branched alkyl; or, R 1a and R 1b Together with the ring C atoms to which they are attached, they form a cyclopropane group; preferably, R 1a 、R 1b is H; R3 is selected from F, Cl, Br; preferably, R3 is F; R4 is selected from -OCH3, -OCF3; R5 is -OH; R6 is -CH3; m and n are 0.

6. The compound according to claim 1 or its isomer, deuterated substance, or pharmaceutically acceptable salt thereof, or polymorph or solvate thereof or its salt, wherein the compound has the following formula (VI): In formula (VI): R 1a 、R 1b Independently selected from H, F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, or R 1a and R 1b Together with the ring C atoms to which they are connected, they form C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R2 is selected from H, C 1-4 Straight or branched alkyl, the alkyl group is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R3 is selected from H, F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, -NO2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight chain alkoxy, C 3-7 Cycloalkyl, the alkyl, alkoxy, cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R5 is selected from F, Cl, Br, -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R6 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight or branched alkoxy, the alkyl, alkoxy is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R7 is independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 A straight or branched alkoxy group, or two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group, or two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 Alkylene, the alkyl, alkoxy, cyclopropane is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; R8, R9 are independently selected from H, C 1-4 Straight or branched alkyl, the alkyl group is optionally substituted by one or more independently selected from F, Cl, Br, -OH, -CN, -NH2, C 1-4 Straight-chain or branched alkyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; n is selected from 0, 1, 2, 3, 4. Preferably: R 1a 、R 1b Independently selected from H, -OH, C 1-4 Straight-chain or branched alkyl; or, R 1a and R 1b Together with the ring C atom to which they are attached, they form a cyclopropane group; R2 is C 1-4 Straight-chain or branched alkyl group; R3 is selected from F, Cl, Br; preferably, R3 is F; R4 is selected from C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain alkoxy, cyclopropane, wherein the alkyl, alkoxy, and cyclopropane are optionally substituted by one or more groups independently selected from F, Cl, Br, and -CN; R5 is selected from -OH, -CN, -N(R8)R9, -COOH, -CON(R8)R9, C 1-4 Straight-chain or branched alkyl, C 1-4 Straight-chain or branched alkoxy, wherein the alkyl or alkoxy group is optionally substituted by a group selected from -OH or -NH2; R6 is C 1-4 Straight or branched alkyl; preferably, R6 is -CH3; R7 is independently selected from C 1-4 A straight or branched alkyl group, wherein the alkyl group is optionally substituted by one or more groups selected from F, Cl, and Br; or, two R7 located on two adjacent ring C atoms together with the two ring C atoms to which they are respectively connected form a cyclopropane group; or, two R7 located on two non-adjacent ring C atoms are connected to form a C group between the two non-adjacent ring C atoms. 1-2 alkylene; R8, R9 are independently selected from H, C 1-4 a straight or branched chain alkyl group, said alkyl group being optionally substituted with one -OH group; n is selected from 0, 1, and 2. Preferably: R 1a 、R 1b Independently selected from H, C 1-4 Straight-chain or branched alkyl; or, R 1a and R 1b Together with the ring C atoms to which they are attached, they form a cyclopropane group; preferably, R 1a 、R 1b is H; R2 is C 1-4 Straight or branched alkyl; preferably, R2 is -CH3; R3 is selected from F, Cl, Br; preferably, R3 is F; R4 is selected from -CH3, -CF3, -OCH3, -OCF3, -CHF2, -OCHF2; R5 is -OH; R6 is -CH3; n is 0.

7. The compound according to claim 1 or its isomer, deuterated substance, or pharmaceutically acceptable salt thereof, or polymorph or solvate thereof or its salt, wherein the compound is selected from the following structures:

8. Use of the compound according to any one of claims 1 to 7 in the preparation of a PLK1 inhibitor.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier.

10. Use of the compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing and / or treating PLK1-related diseases; Preferably, the PLK1-related diseases include solid tumors, hematological tumors, etc. Examples of solid tumors include, but are not limited to, colorectal cancer, lung cancer, breast cancer, prostate cancer, pancreatic cancer, gastric cancer, head and neck cancer, ovarian cancer, uterine cancer, glioma, liver cancer, esophageal cancer, bladder cancer, kidney cancer, lymphoma, melanoma, osteosarcoma, etc.; examples of hematological tumors include, but are not limited to, leukemia, myelodysplastic syndrome, etc.

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