Condensed ring compound, pharmaceutical composition and application thereof

Abstract

The invention provides a compound shown in a formula (I) or pharmaceutically acceptable salt, a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt and application of the compound or the pharmaceutically acceptable salt, and the compound or the pharmaceutically acceptable salt is particularly suitable for preparing drugs for treating or preventing abnormal cell proliferation diseases. # imgabs0 #

Description

A condensed ring compound, pharmaceutical composition and use thereof

[0001] This disclosure claims priority to a prior application filed with the State Intellectual Property Office of China on September 29, 2022, with patent application number 202211200084.4, entitled “A class of condensed ring compounds, pharmaceutical compositions and uses thereof”; a prior application filed with the State Intellectual Property Office of China on December 30, 2022, with patent application number 202211725524.8, entitled “A class of condensed ring compounds, pharmaceutical compositions and uses thereof”; and a prior application filed with the State Intellectual Property Office of China on June 21, 2023, with patent application number 202310747025.7, entitled “A class of condensed ring compounds, pharmaceutical compositions and uses thereof”. The entire text of the above-mentioned prior applications is incorporated into this disclosure by reference. Technical Field

[0002] The present disclosure belongs to the field of medical technology, and specifically relates to a small molecule compound capable of regulating CRBN and degrading specific proteins, or a pharmaceutically acceptable salt thereof. The compound has biological activities such as anti-proliferation of tumor cells and is used for the treatment of related diseases. Background Art

[0003] The ubiquitin-proteasome system (UPS) is a key protein degradation pathway in human cells, primarily involving ubiquitination of substrate proteins and degradation of ubiquitin-tagged proteins by the proteasome. Dysfunction of the UPS can affect cell cycle regulation, cell growth, proliferation, apoptosis, DNA repair, and other cellular signaling processes, and is closely associated with the development and progression of malignancies, cardiovascular disease, and neurodegenerative disorders. The use of small molecules to target specific proteins for degradation through the UPS has become a hot area in the treatment of related diseases. One approach is to bind to E3 ligases, alter their conformation, and thereby induce or stabilize protein-protein interactions between the E3 ligase and its substrate, leading to degradation of the target protein. For example, the immunomodulators thalidomide, lenalidomide, and pomalidomide, upon binding to CRBN, can induce the degradation of proteins such as IKZF1 / 3, CK1α, and GSPT1. These marketed drugs have shown good efficacy mainly in hematological tumors and are widely used, while small molecule compounds that can regulate CRBN and degrade specific proteins for the treatment of other types of tumors still need more development.

[0004] Summary of the Invention

[0005] The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0006] in,

[0007] Ring B is selected from a 5-6 membered heteroaromatic ring or a 5-8 membered heterocyclic ring;

[0008] Ring C is selected from a 5-6 membered heteroaromatic ring, a 5-8 membered heterocyclic ring, a benzene ring, a C5-C8 saturated or partially saturated carbocyclic ring;

[0009] Every R 1 、R 2 Independently selected from the following groups:

[0010] (a) Halogen, =O, CN, NO2, -OR b 、-N(R b )2、-S(O)R b 、-SO2R b , 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace;

[0011] or,

[0012] (b)

[0013] M1 is selected from a bond, -NR b -, -C(O)-, -C(O)O-, -SO2-, -S(O)-, -O-, -S-, -C(O)NR b -、-C(=NR b )-, 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene, 5-10 membered heteroarylene, the 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene, 5-10 membered heteroarylene are optionally replaced by R a replace;

[0014] R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 are independently selected from a bond, -NR b -, -C(O)-, -C(O)O-, -SO2-, -S(O)-, -O-, -S-, -NR b C(O)-, -C(=NR b )-、-C(S)-、-P(O)(OR b )O-、-P(O)(OR b )-, 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene, 5-10 membered heteroarylene, the 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene, 5-10 membered heteroarylene are optionally replaced by R a replace;

[0015] R 20 Selected from H, halogen, CN, -OR b 、-N(R b) 2. -S(O)R b 、-SO2R b 、-C(O)R b 、-C(O)OR b 、-OC(O)R b 、-C(O)N(R b) 2. -NR b C(O)R b , 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10Alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace;

[0016] Every R 4 Selected from halogen, CN, OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace;

[0017] Every R a independently selected from halogen, CN, OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R c replace;

[0018] Every R b independently selected from H, halogen, CN, OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R c replace;

[0019] Every R c independently selected from halogen, CN, OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group, said OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R d replace;

[0020] Every R d Independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl;

[0021] n is independently selected from 0, 1, 2, 3 or 4;

[0022] m and p are independently selected from 0, 1, 2, 3, 4, 5 or 6.

[0023] In some embodiments, Ring B is selected from a 5-6 membered heteroaryl ring or a 5-6 membered heterocyclic ring.

[0024] In some embodiments, Ring B is selected from a 5-6 membered heteroaryl ring.

[0025] In some embodiments, Ring C is selected from a 5-6 membered heteroaryl ring, a 5-6 membered heterocyclic ring, a benzene ring, a C5-C6 saturated or partially saturated carbocyclic ring.

[0026] In some embodiments, Ring C is selected from a 5-6 membered heteroaryl ring or a benzene ring.

[0027] In some embodiments, Ring C is selected from a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, or a thiophene ring.

[0028] In some embodiments, Ring C is selected from a benzene ring.

[0029] In some embodiments, R 1 、R 2 Independently selected from halogen, CN, NO2, -OR b 、-N(R b )2、-S(O)R b 、-SO2R b 、C1-C 10 Alkyl or C3-C 10 Cycloalkyl, the C1-C 10 Alkyl or C3-C 10 The cycloalkyl group is optionally replaced by R a replace.

[0030] In some embodiments, R 1 、R2 independently selected from halogen, CN, OH, NH2, C1-C 10 Alkyl or C3-C 10 Cycloalkyl, the C1-C 10 Alkyl or C3-C 10 The cycloalkyl group is optionally replaced by R a replace.

[0031] In some embodiments, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 independently selected from a bond, -C(O)-, -C(O)O-, -O-, -S-, -C(O)NR b -、-NR b -, 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, 4-9 membered heterocyclylene, C6-C 10 Arylene, 5-10 membered heteroarylene, the 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene, 5-10 membered heteroarylene are optionally replaced by R a replace.

[0032] In some embodiments, R 10 、R 12 independently selected from a bond, -C(O)O-, -O-, -S-, -C(O)NR b -、-NR b 、C1-C 10 Alkylene, C2-C 10 Alkenylene or C2-C 10 Alkynylidene, the C1-C 10 Alkylene, C2-C 10 Alkenylene or C2-C 10 The alkynylene group is optionally replaced by R a replace.

[0033] In some embodiments, R 10 、R 12 independently selected from a bond, -C(O)O-, -O-, -S-, -C(O)NR b -、-NRb , C1-C3 alkylene or C2-C3 alkynylene, wherein the C1-C3 alkylene or C2-C3 alkynylene is optionally replaced by R a replace.

[0034] In some embodiments, R 10 、R 12 Independently selected from -O-, -NH, CH2 or C≡C, wherein CH2 is optionally replaced by R a replace.

[0035] In some embodiments, R 10 、R 12 Independently selected from -O-, -NH-, -CF2-, -CH2- or -C≡C-.

[0036] In some embodiments, R 13 Selected from C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene, the C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene is optionally replaced by R a replace.

[0037] In some embodiments, R 13 is selected from C3-C6 cycloalkylene, 5-9 membered heterocyclylene, phenyl or 5-6 membered heteroarylene, wherein the C3-C6 cycloalkylene, 5-9 membered heterocyclylene, phenyl or 5-6 membered heteroarylene is optionally replaced by R a replace.

[0038] In some embodiments, R 13 is selected from phenyl or 5-6 membered heteroarylene, wherein the phenyl or 5-6 membered heteroarylene is optionally replaced by R a replace.

[0039] In some embodiments, R 13 is selected from phenyl, said phenyl being optionally replaced by R a replace.

[0040] In some embodiments, R 11 、R 12 、R 13 independently selected from a bond, -C(O)-, -C(O)O-, -O-, -S-, -C(O)NR b -or-NR b -.

[0041] In some embodiments, R 14 Selected from bond, -O-, -NRb -、-C(O)NR b -, 2-6 membered heteroalkylene, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, 4-6 membered heterocyclylene, C6-C 10 Arylene or 5-6 membered heteroarylene, the 2-6 membered heteroalkylene, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, 4-6 membered heterocyclylene, C6-C 10 Arylene or 5-6 membered heteroarylene is optionally replaced by R a replace.

[0042] In some embodiments, R 14 Selected from bond, -O-, -NR b -、-C(O)NR b -, 2-6 membered heteroalkylene, C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, wherein the C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene is optionally replaced by R a replace.

[0043] In some embodiments, R 14 Selected from bond, -O-, -NR b -、-C(O)NR b -, 2-6 membered heteroalkylene, C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene.

[0044] In some embodiments, R 1 、R 2 Independently selected from Among them, M1, R 10 、R 11 、R 12 、R 13 、R 14 、R 20 As defined above.

[0045] In some embodiments, R 1 、R 2 Independently selected from Among them, R 11 、R 12 、R 13 independently selected from a bond, -C(O)-, -C(O)O-, -O-, -S-, -C(O)NR b -or-NR b -;M1,R 10 、R 14 、R 20 、R b As defined above.

[0046] In some embodiments, R 1 、R 2 Independently selected from Among them, M1, R 10 、R 12 、R 13 、R 14 、R 20 As defined above.

[0047] In some embodiments, R 1 、R 2 Independently selected from Among them, R 10 、R 12 independently selected from a bond, -C(O)-, -C(O)O-, -O-, -S-, -C(O)NR b -or-NR b -;M1,R 13 、R 14 、R 20 、R b As defined above.

[0048] In some embodiments, R 1 、R 2 Independently selected from Among them, R 10 、R 12 independently selected from a bond, -C(O)O-, -O-, -S-, -C(O)NR b -、-NR b -, C1-C3 alkylene or C2-C3 alkynylene, the C1-C3 alkylene or C2-C3 alkynylene is optionally replaced by R a Replacement; R 13 、R 14 、R 20 、R b 、R a As defined above.

[0049] In some embodiments, R 1 、R 2 Independently selected from Among them, R 10 、R 12 are independently selected from -O-, -NH-, -CH2- or -C≡C-, wherein -CH2- is optionally replaced by R a Replacement; R 13 、R 14 、R 20 、R a As defined above.

[0050] In some embodiments, R 1 、R2 Independently selected from Among them, R 10 、R 12 are independently selected from -O-, -NH-, -CH2- or -C≡C-, wherein -CH2- is optionally replaced by R a Replacement; R 13 Selected from C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene, the C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene is optionally replaced by R a Replacement; R 14 、R 20 、R a As defined above.

[0051] In some embodiments, R 1 、R 2 Independently selected from Among them, R 10 、R 12 R is independently selected from -O-, -NH-, -CH2-, -CF2- or -C≡C-; 13 is selected from C3-C6 cycloalkylene, 5-9 membered heterocyclylene, phenyl or 5-6 membered heteroarylene, wherein the C3-C6 cycloalkylene, 5-9 membered heterocyclylene, phenyl or 5-6 membered heteroarylene is optionally replaced by R a Replacement; R 14 、R 20 、R a As defined above.

[0052] In some embodiments, R 1 、R 2 Independently selected from Among them, R 10 、R 12 independently selected from a bond, -C(O)O-, -O-, -S-, -C(O)NR b -、-NR b , C1-C3 alkylene or C2-C3 alkynylene, wherein the C1-C3 alkylene or C2-C3 alkynylene is optionally replaced by R a Replacement; R 13 Selected from C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene, the C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10Arylene or 5-10 membered heteroarylene is optionally replaced by R a Replacement; R 14 、R 20 、R b 、R a As defined above.

[0053] In some embodiments, R 1 、R 2 Independently selected from Among them, R 10 、R 12 are independently selected from -O-, -NH-, -CH2- or -C≡C-, wherein -CH2- is optionally replaced by R a Replacement; R 13 Selected from C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene, the C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene is optionally replaced by R a Replacement; R 14 Selected from bond, -O-, -NR b -、-C(O)NR b -, 2-6 membered heteroalkylene, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, said C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene are optionally replaced by R a Replacement; R 20 、R b 、R a As defined above.

[0054] In some embodiments, R 1 、R 2 Independently selected from Among them, R 10 、R 12 R is independently selected from -O-, -NH, CH2, CF2 or C≡C; 13 is selected from C3-C6 cycloalkylene, 5-9 membered heterocyclylene, phenyl or 5-6 membered heteroarylene, wherein the C3-C6 cycloalkylene, 5-9 membered heterocyclylene, phenyl or 5-6 membered heteroarylene is optionally replaced by R a Replacement; R 14 Selected from bond, -O-, -NR b -、-C(O)NR b -, 2-6 membered heteroalkylene, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, said C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene are optionally replaced by Ra Replacement; R 20 Selected from H, -N(R b) 2. C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a Replacement; R b 、R a As defined above.

[0055] In some embodiments, R 1 、R 2 Independently selected from the following groups:

[0056] In some embodiments, R 1 、R 2 Independently selected from the following groups:

[0057] In some embodiments, R 1 、R 2 Independently selected from Among them, M1, R 10 、R 11 、R 12 、R 13 、R 14 、R 20 As defined above.

[0058] In some embodiments, M1 is selected from a bond, -NH-, -CH2-, -CH2CH2-, -C(O)-, -C(O)O-, -O-, -S-, or -C(O)NH-.

[0059] In some embodiments, M1 is selected from a bond, -CH2-, or -CH2CH2-.

[0060] In some embodiments, M1 is selected from -CH2-.

[0061] In some embodiments, R 20 Selected from H, -N(R b) 2. 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the 2-10 membered heteroalkyl, C1-C 10 Alkyl C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace.

[0062] In some embodiments, R 20 Selected from H, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the 2-10 membered heteroalkyl, C1-C 10 Alkyl C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace.

[0063] In some embodiments, R 20 Selected from H, -N(R b) 2. C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace.

[0064] In some embodiments, R 20 Selected from H, -N(R b) 2. C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-6 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace.

[0065] In some embodiments, R 20 Selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace.

[0066] In some embodiments, R 4 independently selected from halogen, CN, OH, NH2, 2-10 membered heteroalkyl or C1-C 10 Alkyl, the OH, NH2, 2-10 membered heteroalkyl or C1-C 10 The alkyl group is optionally replaced by R a replace.

[0067] In some embodiments, each R a independently selected from halogen, CN, OH, NH2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group, the OH, NH2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R c replace.

[0068] In some embodiments, each R a independently selected from halogen, CN, OH, NH2 or C1-C 10 Alkyl, the OH, NH2, C1-C 10 The alkyl group is optionally replaced by R c replace.

[0069] In some embodiments, each R a are independently selected from halogen or C1-C6 alkyl, the C1-C6 alkyl being optionally replaced by R c replace.

[0070] In some embodiments, each R a Independently selected from F, Cl, CH3 or CF3.

[0071] In some embodiments, each Rb Independently selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R c replace.

[0072] In some embodiments, each R b are independently selected from H or C1-C6 alkyl, the C1-C6 alkyl being optionally replaced by R c replace.

[0073] In some embodiments, each R b Independently selected from H.

[0074] In some embodiments, each R c independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl, the C1-C6 alkyl being optionally replaced by R d replace.

[0075] In some embodiments, each R c Independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl.

[0076] In some embodiments, each R d are independently selected from halogen.

[0077] In some embodiments, m and p are independently selected from 0, 1 or 2.

[0078] In some embodiments, m and p are independently selected from 0 or 1.

[0079] In some embodiments, m is selected from 0 and p is selected from 1.

[0080] In some embodiments, m is selected from 1 and p is selected from 0.

[0081] In some embodiments, n is selected from 0 or 1.

[0082] In some embodiments, n is selected from 0.

[0083] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure is selected from the compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0084] Wherein, X is selected from N or CH, and the CH is optionally replaced by R 2 Substitution; Ring C, R1 、R 2 、R 4 , m, n are as defined above.

[0085] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof of the present disclosure is selected from the compound of formula (II-1) or (II-2) or a pharmaceutically acceptable salt thereof,

[0086] in, represents a single bond or a double bond; X is selected from N or CH, and the CH is optionally replaced by R 2 Substituted; Y1, Y2, Y3, Y4 are independently selected from N or CH, the CH is optionally replaced by R 1 Substituted; Q1, Q2, Q3 are independently selected from O, S, NH, CH2, N or CH, wherein NH, CH2, CH are optionally replaced by R 1 Replacement; R 1 、R 2 、R 4 , n are as defined above.

[0087] In some embodiments, is selected from a double bond, Q2 is selected from O, S, NH or CH2, Q1, Q3 are independently selected from N or CH, and the NH, CH2, CH are optionally replaced by R 1 replace.

[0088] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof of the present disclosure is selected from the compound represented by formula (II-1a) or a pharmaceutically acceptable salt thereof,

[0089] Wherein, X is selected from N or CH, and the CH is optionally replaced by R 2 Substituted; Y1, Y3, Y4 are independently selected from N or CH, the CH is optionally replaced by R 1 Substituted; Y2 is selected from CH, said CH is optionally replaced by R 1 Replacement; R 1 、R 2 、R 4 , n are as defined above.

[0090] In some embodiments, Y1, Y2, Y3, and Y4 are independently selected from CH, wherein CH is optionally replaced by R 1 replace.

[0091] In some embodiments, X is selected from CH, which is optionally replaced by R 2 replace.

[0092] In the absence of conflict, it should be understood that the above embodiments can be arbitrarily combined to form a technical solution including the features of the combined embodiments. Such a combined technical solution is within the scope of the present disclosure.

[0093] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0094] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound represented by formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0095] In another aspect, the present disclosure provides a method for treating a disease caused by abnormal cell proliferation in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0096] In another aspect, the present disclosure provides use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating abnormal cell proliferation diseases.

[0097] In another aspect, the present disclosure provides use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating abnormal cell proliferation diseases.

[0098] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating abnormal cell proliferation diseases.

[0099] In some embodiments, the abnormal cell proliferation disorder is selected from cancer.

[0100] In some embodiments, the cancer is selected from a solid tumor, an adenocarcinoma, or a hematological tumor.

[0101] Definitions and Explanations of Terms

[0102] Unless otherwise indicated, the terms used in this disclosure have the following meanings. The definitions of groups and terms described in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions described in tables, and definitions of specific compounds in the examples, may be combined and coupled with each other in any manner. A particular term should not be considered as undefined or unclear unless specifically defined, but should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0103] In this article Indicates the attachment site.

[0104] The diagrammatic representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge and dotted wedge keys are used. To indicate the absolute configuration of a stereocenter, use black real and imaginary bonds. Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

[0105] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom in a molecule between two positions. The compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present disclosure encompasses all tautomeric forms of the compounds.

[0106] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0107] The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so that the compounds of the present invention may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and mixtures thereof. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of which are within the definition of the compounds of the present invention and mixtures thereof. Compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

[0108] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0109] The term "optional" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes that the event or situation occurs and that the event or situation does not occur. For example, an ethyl group is "optionally" substituted with halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, any sterically impossible and / or incomposable replacement or substitution pattern will not be introduced.

[0110] When any variable (such as R a 、R b ) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is represented by two R b is replaced, then each R b There are independent options.

[0111] When one of the variables is selected from a chemical bond or does not exist, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a bond, it means that the structure is actually AZ.

[0112] When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary. L in 1 When selected from "C1-C3 alkylene-O", L 1 You can connect rings Q and R from left to right. 1 Constitute "ring Q-C1-C3 alkylene-OR 1 ", you can also connect rings Q and R from right to left 1 Constitute the "ring QO-C1-C3 alkylene-R 1 ”.

[0113] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. Represents R 5 Substitution can occur at any position on the benzene ring.

[0114] In this article, C m -C n It means having an integer number of carbon atoms in the range mn. For example, "C1-C 10 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

[0115] In this paper, the bonds depicted by solid and dashed lines represents a single bond or a double bond. For example, the structural unit Include

[0116] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "C1-C 10 The term "alkyl" is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl radical include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl , 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C1-C6 alkyl" may be understood to mean an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, specific examples of which include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C3 alkyl" may be understood to mean a straight-chain or branched saturated alkyl group having 1, 2 or 3 carbon atoms. The "C1-C 10 The term "alkyl" may include "C1-C6 alkyl" or "C1-C3 alkyl" and the like, and the "C1-C6 alkyl" may further include "C1-C3 alkyl".

[0117] The term "alkylene" refers to a residue derived from an alkyl group by removing a further hydrogen atom.

[0118] The term "heteroalkyl" refers to an alkyl group containing 1, 2, 3, 4, or 5 heteroatoms or heteroatoms, including but not limited to N, O, S, B, P, -S(=O)2-, -S(=O)-, -NH-, etc. The term "2-10 membered heteroalkyl" is understood to mean a heteroalkyl group having 2, 3, 4, 5, 6, 7, 8, 9, or 10 atoms (carbon and heteroatoms excluding hydrogen). The term "2-6 membered heteroalkyl" is understood to mean a heteroalkyl group having 2, 3, 4, 5, or 6 atoms (carbon and heteroatoms excluding hydrogen). The heteroalkyl group can be attached to other groups via heteroatoms or carbon atoms therein. The heteroatom can be located at any interior position of the heteroalkyl group (including the position at which the heteroalkyl group is attached to other groups), that is, the heteroalkyl group does not include hydroxyalkyl groups (e.g., -CH2OH, -CH(CH3)OH), aminoalkyl groups (e.g., -CH2NH2, -CH(CH3)NH2), etc. Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -CH2-CH2-NH-CH3, -OCH2-CH2-NH-CH3, -OCH2-CH2-NH-CH3, -OCH2-CH2-NH-CH(CH3)2, -SCH3, -SCH2CH3, -S(=O)-CH3, -CH2-S(=O)2-CH3, -CH2-C(=O)NH-CH2-O-CH3.

[0119] The term "heteroalkylene" refers to a residue derived from a heteroalkyl group by further removing a hydrogen atom.

[0120] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. 10 "Alkenyl" is understood to mean a linear or branched unsaturated hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C2-C 10 "Alkenyl" is preferably "C2-C6 alkenyl", further preferably "C2-C4 alkenyl", and further preferably C2 or C3 alkenyl. It will be understood that when the alkenyl contains more than one double bond, the double bonds may be separated from each other or conjugated. Specific examples of the alkenyl include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.

[0121] The term "alkenylene" refers to a residue derived from an alkenyl group by further removing a hydrogen atom.

[0122] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. 10 "Alkynyl" is understood to mean a linear or branched unsaturated hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. "C2-C 10 Examples of "alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH 3、 -CH2C≡CH), but-1-ynyl, but-2-ynyl or but-3-ynyl. "C2-C 10 The term "alkynyl" may include "C2-C3 alkynyl". Examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), and prop-2-ynyl (-CH2C≡CH).

[0123] The term "alkynylene" refers to a residue derived from an alkynyl group by further removing a hydrogen atom.

[0124] The term "cycloalkyl" refers to a fully saturated carbon ring that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered ring. The term "C3-C 10 "Cycloalkyl" is understood to mean a saturated monocyclic, bicyclic, spirocyclic or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, and the like. The term "C3-C 10 "Cycloalkyl" may include "C3-C6 cycloalkyl". The term "C3-C6 cycloalkyl" may be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms, specific examples of which include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The term "C5-C8 cycloalkyl" may be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 5, 6, 7 or 8 carbon atoms, and may also be represented as a C5-C8 saturated carbocyclic ring.

[0125] The term "partially saturated carbocycle" refers to a non-aromatic carbocycle that is not fully saturated and exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocycle is generally a 5- to 8-membered ring. The term "C5-C8 partially saturated carbocycle" is understood to mean a partially saturated monocyclic, fused, spirocyclic, or bridged ring having 5, 6, 7, or 8 carbon atoms. Specific examples of the C5-C8 partially saturated carbocycle include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl.

[0126] The term "cycloalkylene" refers to a residue derived from a cycloalkyl group by further removing a hydrogen atom.

[0127] The term "heterocyclyl" refers to a fully saturated or partially saturated (heteroaromatic as a whole that is not aromatic) monocyclic, fused, spirocyclic or bridged ring group, which contains 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups (i.e., heteroatom-containing atomic groups) in its ring atoms, wherein the "heteroatoms or heteroatomic groups" include, but are not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)-, -P(=O)2-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-. The term "3-10 membered heterocyclyl" refers to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned heteroatoms or heteroatomic groups in its ring atoms. “3-10 membered heterocyclic group” includes “4-7 membered heterocyclic group”, wherein specific examples of 4 membered heterocyclic group include but are not limited to azetidinyl, thietanyl or oxetanyl; specific examples of 5 membered heterocyclic group include but are not limited to tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclic group include but are not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7 membered heterocyclic group include but are not limited to diazepanyl. The heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include but are not limited to hexahydrocyclopenta[c]pyrrol-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include but are not limited to hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group may be a benzo-fused ring group of the above-mentioned 4-7-membered heterocyclic groups, specific examples of which include but are not limited to dihydroisoquinolinyl and the like. "4-10 membered heterocyclyl" may include "5-10 membered heterocyclyl", "4-7 membered heterocyclyl", "5-6 membered heterocyclyl", "6-8 membered heterocyclyl", "4-10 membered heterocycloalkyl", "5-10 membered heterocycloalkyl", "4-7 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", "6-8 membered heterocycloalkyl", "5-8 membered heterocyclyl", etc. "4-7 membered heterocyclyl" may further include "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", "4-7 membered heterocycloalkyl", "4-6 membered heterocycloalkyl", "5-6 membered heterocyclyl", etc. Although some bicyclic heterocyclyl groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclyl group as a whole is still non-aromatic.

[0128] The term "heterocyclylene" refers to a residue derived from a heterocyclyl group by further removing a hydrogen atom.

[0129] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. The aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C6-C 20 "Aryl" is understood to be an aromatic radical having 6 to 20 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 or a ring having 13 carbon atoms ("C 13 aryl) such as fluorenyl; or a ring having 14 carbon atoms ("C 14 The term "C6-C 10 "Aryl" is understood to be an aromatic radical having 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 The term "C6-C 20 "Aryl" may contain "C6-C 10 Aryl".

[0130] The term "arylene" refers to a residue derived from an aryl group by further removing a hydrogen atom.

[0131] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system having aromatic character, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or acinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, and the like. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and containing 1, 2 or 3, preferably 1-2 heteroatoms independently selected from N, O and S, and the remaining ring atoms are C aromatic ring groups.

[0132] The term "heteroarylene" refers to a residue derived from a heteroaryl group by further removing a hydrogen atom.

[0133] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0134] The term "therapeutically effective amount" means:

[0135] An amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein.

[0136] The amount of a compound of the disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0137] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0138] The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable acid addition salts or base addition salts, including salts formed between a compound and an inorganic acid or organic acid, and salts formed between a compound and an inorganic base or an organic base.

[0139] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0140] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0141] The word "comprise" or "comprises" and its English variations such as comprises or comprising are to be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0142] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0143] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0144] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0145] Typical routes of administration of the disclosed compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0146] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.

[0147] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0148] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavoring agents.

[0149] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0150] In all methods of administration of the compounds of formula (I) described herein, the dosage administered per day is 0.01 mg / kg to 200 mg / kg body weight, in the form of single or divided doses. DETAILED DESCRIPTION

[0151] The present disclosure is described in detail below with reference to the embodiments and drawings, but the following embodiments should not be construed as limiting the scope of the present disclosure.

[0152] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The units of NMR shifts are 10 -6 (ppm). The solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 ” refers to the half-maximal inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.

[0153] The eluent mentioned below can be a mixed eluent formed by two or more solvents, and the ratio is the volume ratio of each solvent. For example, "petroleum ether: ethyl acetate = 5:1" means that during the elution process, the volume ratio of petroleum ether to ethyl acetate in the mixed eluent is 5:1.

[0154] Unless otherwise stated, % refers to wt%.

[0155] Abbreviations:

[0156] DCM: dichloromethane; Pyridine: pyridine; CDI: N,N'-carbonyldiimidazole; THF: tetrahydrofuran; LAH: lithium aluminum tetrahydride; EtOH: ethanol; DMF: N,N-dimethylformamide; EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOBt: 1-hydroxybenzotriazole; TEA: triethylamine; NH2OH·HCl: hydroxylamine hydrochloride; Pd(OAc)2: palladium acetate; Cs2CO3: cesium carbonate; Butyldi-1-adamantylphosphine: n-butyldi(1-adamantyl)phosphine; N-boc-Methyltrifluoroborate: potassium N-aminomethyltrifluoroborate; dioxane: 1,4-dioxane; Hydroxymethyl tributylstannane: (tributyltin)methanol; Pd(Ph3)4: tetrakis(triphenylphosphine)palladium; Triphosgene: triphosgene; DMF-DMA: N,N-dimethylformamide dimethyl acetal; BH3Me2S: borane dimethyl sulfide; Propiolic Acid: propiolic acid; DMSO: dimethyl sulfoxide; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; tert-Butyl bromoacetate: tert-butyl bromoacetate; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DIEA: N,N-diisopropylethylamine; DMAP: 4-dimethylaminopyridine; (Boc)2O: di-tert-butyl dicarbonate; TEA: trifluoroacetic acid; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; TBA: tert-butyl acrylate; NN-Dicyclohexylmethylamine: N,N-dicyclohexylmethylamine; Tri-tert-butylphosphinetetrafluoroborate: tri-tert-butylphosphinetetrafluoroborate.

[0157] Intermediate 1: (4-nitrophenyl)-N-(3-chloro-4-methyl-phenyl)carbamate

[0158] Intermediate 1-1 (500 mg, 2.48 mmol) and 3-chloro-p-toluidine (386 mg, 2.73 mmol) were placed in a reaction tube. The air in the reaction tube was replaced with argon and the reaction tube was cooled in a water bath. Dichloromethane (2 mL) and pyridine (392 mg, 4.96 mmol) were added to the reaction tube. The reaction solution was naturally warmed to room temperature and stirred for one hour. After the reaction, the reaction solution was concentrated to obtain a crude product. The crude product was then separated by normal phase chromatography (petroleum ether:ethyl acetate = 5:1) to obtain Intermediate 1 (532 mg, 70% yield). m / z (ESI): 307 [M+H]+ .

[0159] Intermediate 2: tert-Butyl (4-amino-2-chlorophenyl)(methyl)carbamate

[0160] Step 1: 2-Chloro-N-methyl-4-nitroaniline (Intermediate 2-2)

[0161] Intermediate 2-1 (500 mg, 2.85 mmol), methylamine hydrochloride (384 mg, 5.70 mmol), and cesium carbonate (1.86 g, 5.70 mmol) were placed in a reaction flask. Dimethyl sulfoxide (5 mL) was added, and the reaction solution was stirred in an oil bath at 100°C for 1 hour. After completion of the reaction, intermediate 2-2 (500 mg, 94% yield) was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1, 0.1% formic acid). m / z (ESI): 187 [M+H] + .

[0162] Step 2: tert-Butyl (2-chloro-4-nitrophenyl)(methyl)carbamate (Intermediate 2-3)

[0163] Intermediate 2-2 (500 mg, 2.68 mmol) and sodium hydride (128 mg, 3.22 mmol, 60% purity) were placed in a reaction tube. The atmosphere in the reaction tube was replaced with argon. Tetrahydrofuran (5 mL) was added at 0°C and stirred for 0.5 hours. Di-tert-butyl dicarbonate (877 mg, 4.02 mmol) was then added. The mixture was stirred in a 50°C oil bath for 5 hours. After completion of the reaction, the mixture was concentrated and purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain Intermediate 2-3 (500 mg, 65% yield). m / z (ESI): 287 [M+H] + .

[0164] Step 3: tert-Butyl (4-amino-2-chlorophenyl)(methyl)carbamate (Intermediate 2)

[0165] Intermediate 2-3 (500 mg, 1.74 mmol) was dissolved in acetic acid (5 mL), and iron powder (292 mg, 5.23 mmol) was added. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain Intermediate 2 (250 mg, 55% yield). m / z (ESI): 257 [M+H] + .

[0166] Example 1: 3-(3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)piperidine-2,6-dione

[0167] Step 1: 1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (Compound 1-2)

[0168] Compound 1-1 (400 mg, 2.73 mmol) and N,N'-carbonyldiimidazole (488 mg, 3.01 mmol) were placed in a dry, sealed tube. Tetrahydrofuran (3 mL) was added and the tube was sealed. The reaction mixture was stirred in a 90°C oil bath for 12 h. After the reaction, the reaction mixture was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1, 0.1% formic acid) to obtain compound 1-2 (170 mg, 36% yield). m / z (ESI): 173 [M+H] + .

[0169] Step 2: 3-(3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)piperidine-2,6-dione (Compound 1)

[0170] Under a nitrogen atmosphere, compound 1-2 (80 mg, 0.46 mmol) was dissolved in tetrahydrofuran (2 mL) and cooled to 0°C. Sodium hydride (55.7 mg, 2.32 mmol) was added and stirred at this temperature for 0.5 h. A solution of 3-bromopiperidine-2,6-dione (107.0 mg, 0.55 mmol) in tetrahydrofuran (2 mL) was then added dropwise to the reaction mixture. After the addition was complete, the reaction was continued at this temperature for 10 min. The reaction mixture was then stirred in an oil bath at 60°C for 4 h. After the reaction, the reaction mixture was cooled to 0°C and quenched by the addition of acetic acid (105.0 mg, 1.75 mmol) and saturated ammonium chloride solution (5 mL). The reaction mixture was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1, containing 0.1% formic acid) to obtain compound 1 (17.5 mg, 13% yield).

[0171] m / z(ESI):284[M+H] + .

[0172] 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),7.84(d,J=7.8Hz,1H),7.64(d,J=7.6Hz,1H),7.25(dt,J=15.6,7.4Hz,2H),6.52(s,1H),4.96(dd,J=1 3.5,5.1Hz,1H),4.59(d,J=16.5Hz,1H),4.42(d,J=16.4Hz,1H),2.97–2.86(m,1H),2.61(d,J=17.4Hz,1H),2.43–2.30(m,1H),2.10(s,1H).

[0173] Example 2: 1-(3-chloro-4-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)methyl)urea

[0174] Step 1: 5-Bromo-1H-indole-2-carbaldehyde oxime (Compound 2-2)

[0175] 5-Bromo-1H-indole-2-carbaldehyde (1000 mg, 4.46 mmol), hydroxylamine hydrochloride (465 mg, 6.69 mmol), and sodium bicarbonate (749 mg, 8.92 mmol) were placed in a flask. Ethanol (15 mL) and water (10 mL) were added, and the reaction solution was stirred in a 70°C oil bath for 3 hours. After the reaction, the reaction solution was concentrated and extracted with ethyl acetate and water. The organic phase was dried and concentrated to give compound 2-2 (1010 mg, 95% yield). m / z (ESI): 239 [M+H] + .

[0176] Step 2: (5-Bromo-1H-indol-2-yl)methanamine (Compound 2-3)

[0177] Compound 2-2 (1010 mg, 4.22 mmol) was placed in a flask, and anhydrous tetrahydrofuran (25 mL) was added. The reaction solution was stirred in an ice bath at 0°C and cooled. After cooling to 0°C, lithium aluminum tetrahydride (240 mg, 6.33 mmol) was slowly added. After complete addition, the reaction solution was stirred in an oil bath at 70°C for 2 h. After completion of the reaction, the reaction solution was stirred in an ice bath at 0°C and quenched by slowly adding sodium sulfate decahydrate. After quenching, the reaction solution was filtered, and the filtrate was extracted with ethyl acetate and water. The organic phase was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 2-3 (694 mg, 73% yield). m / z (ESI): 225 [M+H] + .

[0178] Step 3: 7-bromo-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (Compound 2-4)

[0179] Compound 2-3 (694 mg, 3.08 mmol) was placed in a dry, sealed tube. The air in the reaction tube was replaced with argon. Tetrahydrofuran (3 mL) was added and the tube was sealed. The reaction solution was stirred in an ethanol-dry ice bath to cool. N,N'-carbonyldiimidazole (550 mg, 3.39 mmol) was dissolved in tetrahydrofuran (3 mL) and slowly added dropwise to the reaction solution. After the addition was complete, the temperature was naturally raised to room temperature and stirred for 1 hour. The reaction solution was then placed in a 95°C oil bath and stirred for 16 hours. After the reaction, the reaction solution was concentrated to obtain the crude product, which was purified by normal phase column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain compound 2-4 (526 mg, 68% yield). m / z (ESI): 251 [M+H] + .

[0180] Step 4: Dimethyl 2-(7-bromo-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)glutarate (Compound 2-5)

[0181] Compound 2-4 (526 mg, 2.10 mmol) and sodium hydride (75.2 mg, 3.14 mmol) were placed in a dry reaction tube. The air in the reaction tube was replaced with argon and the reaction tube was cooled in an ethanol-dry ice bath. N,N-dimethylformamide (2 mL) was added to the reaction tube. The reaction solution was naturally warmed to room temperature and stirred for half an hour. The mixture was then placed in an ice-water bath and stirred. Dimethyl 2-bromoglutarate (749 mg, 3.14 mmol) was added dropwise to the reaction solution. Stirring was continued in the ice-water bath for half an hour and then at room temperature for one hour. After completion of the reaction, acetic acid (250 mg, 4.2 mmol) was added to quench the reaction. The reaction solution was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 2-5 (686 mg, 80% yield). m / z (ESI): 409 [M+H] + .

[0182] Step 5: 2-(7-bromo-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)pentanedioic acid (Compound 2-6)

[0183] Compound 2-5 (686 mg, 1.68 mmol) and lithium hydroxide (161 mg, 6.72 mmol) were placed in a flask, tetrahydrofuran (4 mL) and water (2 mL) were added, and the mixture was stirred at room temperature for 3 to 5 hours. After the reaction, hydrochloric acid (3N) was added to adjust the pH of the reaction solution to 3 to 5. The reaction solution was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 2-6 (170 mg, yield 90%). m / z (ESI): 381 [M+H] + .

[0184] Step 6: 3-(7-bromo-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)piperidine-2,6-dione (Compound 2-7)

[0185] Compound 2-6 (575 mg, 1.51 mmol), trifluoroacetamide (255 mg, 2.26 mmol), 1-hydroxybenzotriazole (448 mg, 3.32 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1012 mg, 5.28 mmol) were placed in a dry reaction tube. The air in the reaction tube was replaced with argon and the reaction tube was cooled in an ethanol-dry ice bath. Dichloromethane (10 mL) and triethylamine (687 mg, 6.80 mmol) were added to the reaction tube. The reaction solution was naturally warmed to room temperature and stirred for half an hour. The reaction solution was then stirred in a 35°C oil bath for 5 hours. After completion of the reaction, the reaction solution was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 2-7 (448 mg, yield 82%). m / z (ESI): 362 [M+H] + .

[0186] Step 7: Tert-butyl ((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)methyl)carbamate (Compound 2-8)

[0187] Compound 2-7 (448 mg, 1.24 mmol), palladium acetate (20.6 mg, 0.09 mmol), n-butyldi(1-adamantyl)phosphine (88.9 mg), potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate) (382 mg, 1.61 mmol), and cesium carbonate (808 mg, 2.48 mmol) were placed in a reaction tube. The atmosphere in the reaction tube was replaced with argon. 1,4-Dioxane (3 mL) and water (0.3 mL) were added to the reaction tube. The reaction tube was stirred in a 100°C oil bath for 5-8 hours. After completion of the reaction, the reaction solution was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 2-8 (296 mg, 58% yield). m / z (ESI): 413 [M+H] + .

[0188] Step 8: 3-(7-(Aminomethyl)-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)piperidine-2,6-dione (Compound 2-9)

[0189] Compound 2-8 (296 mg, 0.72 mmol) was placed in a reaction tube. The air in the reaction tube was replaced with argon. 1,4-dioxane (2 mL) and 1,4-dioxane-hydrochloride (4 M) (2 mL) were added to the reaction tube. The reaction tube was placed in a 25°C oil bath and stirred for 5 hours. After the reaction, the solvent in the reaction solution was dried to obtain crude compound 2-9 (245 mg, yield 98%). m / z (ESI): 313 [M+H] + .

[0190] Step 9: 1-(3-chloro-4-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)methyl)urea (Compound 2)

[0191] Compound 2-9 (245 mg, 0.78 mmol) and (4-nitrophenyl)-N-(3-chloro-4-methyl-phenyl)carbamate (260 mg, 0.85 mmol) were placed in a dry reaction tube. The air in the reaction tube was replaced with argon. Dichloromethane (3 mL) and triethylamine (179 mg, 1.77 mmol) were added to the reaction tube. The reaction tube was stirred in a 25°C oil bath for 4 hours. After the reaction, the reaction solution was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 2 (179 mg, 53% yield). m / z (ESI): 480 [M+H] + .

[0192] 1 H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.76(d,J=3.8Hz,1H),7.87–7.76(m,1H),7.68 (s,1H),7.56(s,1H),7.24(d,J=8.3Hz,1H),7.15(q,J=8.6Hz,2H),6.80(s,1H),6.52 (s,1H),4.96(d,J=13.0Hz,1H),4.59(d,J=16.6Hz,1H),4.49–4.37(m,4H),2.92(t,J =14.0Hz,1H),2.63(t,J=16.9Hz,1H),2.37(d,J=16.5Hz,1H),2.23(d,J=2.2Hz,3H).

[0193] Example 3: (2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)methyl-(3-chloro-4-methylphenyl)carbamate (Compound 3)

[0194] Step 1: 3-(7-(Hydroxymethyl)-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)piperidine-2,6-dione (Compound 3-1)

[0195] Under nitrogen, compound 2-7 (27 mg, 0.074 mmol), (tributyltin)methanol (36 mg, 0.112 mmol), and tetrakis(triphenylphosphine)palladium (8 mg, 0.007 mmol) were added to 1,4-dioxane (1 mL) and reacted at 80°C for 16 hours. After completion of the reaction, the reaction solution was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 3-1 (6 mg, yield 28%). m / z (ESI): 314 [M+H] + .

[0196] Step 2: (2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)methyl-(3-chloro-4-methylphenyl)carbamate (Compound 3)

[0197] Under nitrogen, 3-chloro-p-toluidine (10 mg, 0.07 mmol) and triethylamine (15 mg, 0.14 mmol) were dissolved in dichloromethane (1 mL). Triphosgene (8 mg, 0.027 mmol) dissolved in dichloromethane (1 mL) was added to the reaction mixture at 0°C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. After concentration, it was dissolved in N,N-dimethylformamide (1 mL). After nitrogen was replaced three times, compound 3-1 (18 mg, 0.057 mmol) was added to the solution. The mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 3 (11 mg, 30% yield). m / z (ESI): 481 [M+H] + .

[0198] 1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.88(s,1H),7.91–7.85(m,1H),7.73(s,1H),7.61 (s,1H),7.37(d,J=8.4Hz,1H),7.33–7.22(m,2H),6.57(s,1H),5.25(s,2H),4.97(d,J=1 3.3Hz,1H),4.61(d,J=16.7Hz,1H),4.44(d,J=16.5Hz,1H),2.92(t,J=15.4Hz,1H),2.62 (d,J=17.4Hz,1H),2.38(q,J=12.9Hz,1H),2.25(d,J=2.3Hz,3H),2.10(d,J=11.9Hz,1H).

[0199] Example 4: N-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)methyl)-3-(4-methyl-3-(methylamino)phenyl)propynamide

[0200] Step 1: (E)-N'-(5-iodo-2-methylphenyl)-N,N-dimethylacetamidine (Compound 4-2)

[0201] Compound 4-1 (233 mg, 1 mmol) and N,N-dimethylformamide dimethyl acetal (600 mg, 5 mmol) were added to a flask. N,N-dimethylformamide (2 mL) was added and the reaction mixture was stirred in an oil bath at 100°C for 3 hours. After the reaction, the reaction mixture was concentrated and extracted with ethyl acetate and water. The organic phase was dried and concentrated to give crude compound 4-2 (296 mg, 97% yield). m / z (ESI): 303 [M+H] + .

[0202] Step 2: N,2-dimethyl-5-iodoaniline (Compound 4-3)

[0203] Compound 4-2 (296 mg, 0.97 mmol) was placed in a flask, anhydrous tetrahydrofuran (1 mL) was added, and the argon atmosphere was replaced by vacuum three times. Borane dimethyl sulfide solution (1.5 mL, 2 M) was added via syringe. After complete addition, the reaction solution was stirred at room temperature for 2 h. After completion of the reaction, methanol was slowly added to quench the reaction. 1 M hydrochloric acid was added and stirred for 30 min. The organic phase reaction solution was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 4-3 (152 mg, yield 61%). m / z (ESI): 248 [M+H] + .

[0204] Step 3: 3-(4-methyl-3-(methylamino)phenyl)propiolic acid (Compound 4-4)

[0205] Compound 4-3 (152 mg, 0.60 mmol), cuprous iodide (17 mg, 0.9 mmol), and tetrakis(triphenylphosphine)palladium (17 mg, 0.015 mmol) were placed in a dry, sealed tube. The air in the reaction tube was replaced with argon, and dimethyl sulfoxide (2 mL) was added and sealed. 1,8-diazabicyclo[5.4.0]undec-7-ene (273 mg, 1.8 mmol) and propiolic acid (63 mg, 0.9 mmol) were added to the reaction solution via syringe, respectively. The temperature was raised to 70°C and stirred for 1 h. After completion of the reaction, compound 4-4 (75 mg, 60% yield) was purified by normal phase column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to obtain compound 4-4. m / z (ESI): 190 [M+H] + .

[0206] Step 4: N-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)methyl)-3-(4-methyl-3-(methylamino)phenyl)propanamide (Compound 4)

[0207] Compound 4-4 (10 mg, 0.05 mmol), compound 2-9 (18 mg, 0.06 mmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (22 mg, 0.06 mmol) were placed in a dry reaction tube. Tetrahydrofuran (0.5 mL) and N,N-diisopropylethylamine (15 mg, 0.11 mmol) were added to the reaction tube and stirred at room temperature for one hour. After completion of the reaction, compound 4 (5.58 mg, 24% yield) was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 4.

[0208] m / z(ESI):484[M+H] +

[0209] 1H NMR (400MHz, DMSO-d6) δ11.06(s,1H),9.27(t,J=6.1Hz,1H),8.38(s,1H),7.81(d,J=8.3Hz,1H),7.55 (s,1H),7.22(dd,J=8.4,1.6Hz,1H),7.02(d,J=7.6Hz,1H),6.72(dd,J=7.5,1.5Hz,1H),6.61–6.51(m ,2H),5.32(q,J=5.0Hz,1H),4.97(dd,J=13.4,5.1Hz,1H),4.60(dd,J=16.5,1.7Hz,1H),4.44(d,J=5. 6Hz,2H),3.02–2.85(m,2H),2.72(d,J=4.8Hz,3H),2.66–2.57(m,1H),2.40–2.30(m,1H),2.09(s,3H).

[0210] Example 5: 2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)methyl(2-fluoro-5-trifluoromethoxy)phenyl)carbamate

[0211] 2-Fluoro-3-(trifluoromethoxy)aniline (12.5 mg, 0.064 mmol) was placed in a dry reaction tube. The air in the reaction tube was replaced with argon. Dichloromethane (2 mL) and triethylamine (13 mg, 0.128 mmol) were added to the reaction tube. The reaction tube was placed in an ice-water bath at 0°C and stirred. After cooling, triphosgene (7.6 mg, 0.025 mmol) was dissolved in dichloromethane (1 mL) and the triphosgene solution was slowly added dropwise to the reaction solution. The temperature was naturally raised to room temperature and the reaction was continued for 0.5 hours. The solvent was then dried by rotary evaporation. Compound 3-1 (10.0 mg, 0.032 mmol) was dissolved in N,N-dimethylformamide (1 mL) and added to the reaction tube. The reaction was continued at room temperature for 2-3 hours. Compound 5 (6.0 mg, 35% yield) was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 5. m / z (ESI): 535 [M+H] + .

[0212] 1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.84(s,1H),7.88–7.83(m,2H),7.74(s ,1H),7.42–7.32(m,2H),7.17–7.09(m,1H),6.57(s,1H),5.28(s,2H),4.97(dd ,J=13.4,5.1Hz,1H),4.61(dd,J=16.5,1.7Hz,1H),4.44(dd,J=16.5,1.8Hz,1H ),2.99–2.85(m,1H),2.70–2.57(m,1H),2.44–2.31(m,1H),2.14–2.07(m,1H).

[0213] Example 6: (2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-8-yl)-methyl-(3-chloro-4-(2-(2-(methylamino)ethoxy)ethyl)phenyl)carbamate

[0214] Step 1: (E)-4-Bromo-1H-indole-2-carbaldehyde oxime (Compound 6-2)

[0215] Compound 6-1 (1000 mg, 4.46 mmol), hydroxylamine hydrochloride (465 mg, 6.69 mmol), and sodium bicarbonate (749 mg, 8.92 mmol) were placed in a flask. Ethanol (15 mL) and water (10 mL) were added, and the reaction solution was stirred in a 70°C oil bath for 3 h. After the reaction, the reaction solution was concentrated and extracted with ethyl acetate and water. The organic phase was dried and concentrated to give crude compound 6-2 (1010 mg, 95% yield). m / z (ESI): 239 [M+H] + .

[0216] Step 2: (4-Bromo-1H-indol-2-yl)methanamine (Compound 6-3)

[0217] Compound 6-2 (1010 mg, 4.22 mmol) was placed in a flask, and anhydrous tetrahydrofuran (25 mL) was added. The reaction solution was stirred in an ice bath at 0°C and cooled. After cooling, lithium aluminum tetrahydride (240 mg, 6.33 mmol) was slowly added. After complete addition, the reaction solution was stirred in an oil bath at 70°C for 2 h. After the reaction was completed, the reaction solution was stirred in an ice bath at 0°C and cooled. Sodium sulfate decahydrate was slowly added to quench the reaction. After quenching, the reaction solution was filtered, and the filtrate was extracted with ethyl acetate and water. The organic phase was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 6-3 (694 mg, 73% yield). m / z (ESI): 225 [M+H]+ .

[0218] Step 3: 8-bromo-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (Compound 6-4)

[0219] Compound 6-3 (694 mg, 3.08 mmol) was placed in a dry, sealed tube. The air in the reaction tube was replaced with argon. Tetrahydrofuran (3 mL) was added and the tube was sealed. The reaction solution was stirred in an ethanol-dry ice bath to cool. N,N'-carbonyldiimidazole (550 mg, 3.39 mmol) was placed in a dry flask and dissolved in tetrahydrofuran (3 mL). The N,N'-carbonyldiimidazole solution was slowly added dropwise to the reaction solution. After the addition was complete, the temperature was naturally raised to room temperature and stirred for 1 hour. The reaction solution was then placed in a 95°C oil bath and stirred for 16 hours. After the reaction, the reaction solution was concentrated to obtain the crude product, which was purified by normal phase column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to obtain compound 6-4 (526 mg, 68% yield). m / z (ESI): 251 [M+H] + .

[0220] Step 4: Dimethyl 2-(8-bromo-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)glutarate (Compound 6-5)

[0221] Compound 6-4 (526 mg, 2.10 mmol) and sodium hydride (75.2 mg, 3.14 mmol) were placed in a dry reaction tube. The air in the reaction tube was replaced with argon and the reaction tube was cooled in an ethanol-dry ice bath. N,N-dimethylformamide (2 mL) was added to the reaction tube. The reaction solution was naturally warmed to room temperature and stirred for half an hour. The mixture was then stirred in an ice-water bath. Dimethyl 2-bromoglutarate (749 mg, 3.14 mmol) was added dropwise to the reaction solution. Stirring was continued in the ice-water bath for half an hour and then at room temperature for one hour. After completion of the reaction, acetic acid (250 mg, 4.2 mmol) was added to quench the reaction. The reaction solution was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 6-5 (686 mg, 80% yield). m / z (ESI): 409 [M+H] + .

[0222] Step 5: 2-(8-bromo-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)pentanedioic acid (Compound 6-6)

[0223] Compound 6-5 (686 mg, 1.68 mmol) and lithium hydroxide (161 mg, 6.72 mmol) were placed in a flask, tetrahydrofuran (4 mL) and water (2 mL) were added, and the mixture was stirred at room temperature for 3 to 5 hours. After the reaction, hydrochloric acid (3N) was added to adjust the pH of the reaction solution to 3 to 5. The reaction solution was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 6-6 (170 mg, yield 90%). m / z (ESI): 381 [M+H] + .

[0224] Step 6: 3-(8-Bromo-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)-piperidine-2,6-dione (Compound 6-7)

[0225] Compound 6-6 (575 mg, 1.51 mmol), trifluoroacetamide (255 mg, 2.26 mmol), 1-hydroxybenzotriazole (448 mg, 3.32 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1012 mg, 5.28 mmol) were placed in a dry reaction tube. The air in the reaction tube was replaced with argon and the reaction tube was cooled in an ethanol-dry ice bath. Dichloromethane (10 mL) and triethylamine (687 mg, 6.80 mmol) were added to the reaction tube. The reaction solution was naturally warmed to room temperature and stirred for half an hour. The reaction solution was then stirred in a 35°C oil bath for 5 hours. After completion of the reaction, the reaction solution was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 6-7 (448 mg, 82% yield). m / z (ESI): 362 [M+H] + .

[0226] Step 7: 3-(8-(Hydroxymethyl)-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)piperidine-2,6-dione (Compound 6-8)

[0227] Compound 6-7 (270 mg, 0.74 mmol) and tetrakis(triphenylphosphine)palladium (86 mg, 0.07 mmol) were placed in a reaction tube. The air in the reaction tube was replaced with argon. 1,4-Dioxane (6 mL) and tributyltin carbinol (360 mg, 1.1 mmol) were added to the reaction tube. The reaction tube was stirred in an 80°C oil bath for 15-20 hours. After completion of the reaction, the reaction solution was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 6-8 (150 mg, yield 64%). m / z (ESI): 314 [M+H] + .

[0228] Step 8: (2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-8-yl)-methyl-(3-chloro-4-(2-(2-(methylamino)ethoxy)ethyl)phenyl)carbamate (Compound 6)

[0229] Tert-butyl N-[2-[2-(4-amino-2-chloro-phenyl)ethoxy]ethyl]-N-methylcarbamate (21.0 mg, 0.064 mmol) was placed in a dry reaction tube, and the air in the reaction tube was replaced with argon. Dichloromethane (2 mL) and triethylamine (13.0 mg, 0.127 mmol) were added to the reaction tube, and the reaction tube was placed in an ice-water bath at 0°C with stirring. After cooling, triphosgene (7.6 mg, 0.025 mmol) was dissolved in dichloromethane (1 mL), and the triphosgene solution was slowly added dropwise to the reaction solution. The temperature was naturally raised to room temperature and the reaction was carried out for 0.5 hours. The solvent was then dried by rotary evaporation, and compound 6-8 (10 mg, 0.032 mmol) was dissolved in N,N-dimethylformamide (1 mL) and injected into the reaction tube. The reaction was carried out at room temperature for 2-3 hours, and then the intermediate was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain the intermediate. The intermediate was placed in a dry reaction tube, and the air in the reaction tube was replaced with argon. Tetrahydrofuran (0.5 mL) was added to the reaction tube, and the reaction tube was cooled to 0°C in an ice bath with stirring. Then, a dioxane hydrochloride solution (4M, 1.5 mL) was slowly added dropwise. After stirring in an ice bath for 1-2 hours, the reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 6 (6.0 mg, yield 31%). m / z (ESI): 568 [M+H] + .

[0230] 1 H NMR (400MHz, DMSO-d6) δ9.90 (s, 1H), 8.33 (s, 1H), 7.86 (dd, J = 7.0, 2.1Hz, 1H), 7.60 (s, 1H), 7.3 6–7.24(m,4H),6.68(s,1H),5.44(s,2H),4.98(dd,J=13.3,5.1Hz,1H),4.62(d,J=17.5Hz,1H),4 .45(d,J=18.3Hz,1H),3.57(t,J=7.0Hz,2H),3.50(t,J=5.5Hz,2H),2.99–2.83(m,4H),2.73(t, J=5.5Hz,2H),2.63(dd,J=17.2,13.3Hz,1H),2.41–2.34(m,1H),2.33(s,3H),2.15–2.06(m,1H).

[0231] Example 7: (2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)methyl-(3-chloro-4-((2-(methylamino)ethoxy)methyl)phenyl)carbamate

[0232] Step 1: 2-chloro-4-nitrobenzyl alcohol (Compound 7-2)

[0233] Compound 7-1 (1000 mg, 4.96 mmol) was placed in a reaction tube. The air in the reaction tube was replaced with argon. Tetrahydrofuran (3 mL) was added with stirring. Borane tetrahydrofuran (1 M) (7.5 mL) was slowly added to the reaction tube. The reaction tube was placed in a 60°C oil bath with stirring for 2 hours. After the reaction was completed, methanol (2 mL) was slowly added to quench the reaction. The reaction solution was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 7-2 (675 mg, yield 73%). m / z (ESI): 188 [M+H] + .

[0234] Step 2: tert-Butyl 2-((2-chloro-4-nitrobenzyl)oxy)acetate (Compound 7-3)

[0235] Compound 7-2 (675 mg, 3.6 mmol) and sodium hydroxide (288 mg, 7.2 mmol) were placed in a reaction tube. The air in the reaction tube was replaced with argon. 1,4-dioxane (4 mL) was added to the reaction tube and stirred. Tert-butyl bromoacetate (2106 mg, 10.8 mmol) was slowly added to the reaction tube. The reaction tube was stirred at room temperature for 8 hours. After the reaction was completed, the reaction solution was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 7-3 (130 mg, yield 12%). m / z (ESI): 302 [M+H] + .

[0236] Step 3: 2-(2-chloro-4-nitrobenzoyloxy)acetic acid (Compound 7-4)

[0237] Compound 7-3 (130 mg, 0.43 mmol) was placed in a reaction tube. The air in the reaction tube was replaced with argon. Dichloromethane (1 mL) and trifluoroacetic acid (1 mL) were added to the reaction tube. The reaction tube was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 7-4 (80 mg, yield 76%). m / z (ESI): 246 [M+H] + .

[0238] Step 4: 2-((2-chloro-4-nitrobenzyl)oxy)-N-methylacetamide (Compound 7-5)

[0239] Compound 7-4 (80 mg, 0.33 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (190 mg, 0.50 mmol), and methylamine hydrochloride (45 mg, 0.66 mmol) were placed in a reaction tube. The air in the reaction tube was replaced with argon and stirred in an ice bath. N,N-dimethylformamide (1 mL) and triethylamine (101 mg, 1.0 mmol) were added to the reaction tube, and the reaction tube was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 7-5 (75 mg, yield 89%). m / z (ESI): 259 [M+H] + .

[0240] Step 5: 2-((2-chloro-4-nitrobenzyl)oxy)-N-methylethan-1-amine (Compound 7-6)

[0241] Compound 7-5 (75 mg, 0.29 mmol) was placed in a reaction tube. The air in the reaction tube was replaced with argon. Tetrahydrofuran (2 mL) was stirred, and borane tetrahydrofuran (1 M) (0.66 mL) was slowly added to the reaction tube. The reaction tube was placed in a 60°C oil bath and stirred for 2 hours. After the reaction, methanol (1 mL) was slowly added to quench the reaction. The reaction tube was concentrated, and methanol (1 mL) and hydrochloric acid (10%) (3 mL) were added to the reaction tube. The reaction tube was stirred in an 80°C oil bath for 3 hours. After the reaction was completed, the reaction solution was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 7-6 (65 mg, yield 92%). m / z (ESI): 245 [M+H] + .

[0242] Step 6: tert-Butyl (2-((2-chloro-4-nitrobenzyl)oxy)ethyl)(methyl)carbamate (Compound 7-7)

[0243] Compound 7-6 (65 mg, 0.265 mmol), 4-dimethylaminopyridine (2.0 mg, 0.016 mmol), and di-tert-butyl dicarbonate (116.0 mg, 0.53 mmol) were placed in a reaction tube. The air in the reaction tube was replaced with argon. Tetrahydrofuran (3 mL) and triethylamine (101 mg, 1.0 mmol) were added to the reaction tube. The reaction tube was placed in a 50°C oil bath and stirred for 5 hours. After completion of the reaction, the reaction mixture was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 7-7 (80 mg, yield 88%). m / z (ESI): 345 [M+H]+ .

[0244] Step 7: tert-Butyl (2-((4-amino-2-chlorobenzyl)oxy)ethyl)(methyl)carbamate (Compound 7-8)

[0245] Compound 7-7 (80 mg, 0.23 mmol), iron powder (64 mg, 1.15 mmol), and ammonium chloride (37.0 mg, 0.69 mmol) were placed in a reaction tube. The air in the reaction tube was replaced with argon. Ethanol (2 mL) and water (2 mL) were added to the reaction tube. The reaction tube was placed in an 80°C oil bath and stirred for 2 hours. After the reaction, the mixture was extracted with ethyl acetate and water. The organic phase was concentrated and the reaction solution was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 7-8 (55 mg, yield 75%). m / z (ESI): 315 [M+H] + .

[0246] Step 8: (2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)methyl-(3-chloro-4-((2-(methylamino)ethoxy)methyl)phenyl)carbamate (Compound 7)

[0247] Compound 7-8 (20 mg, 0.064 mmol) was placed in a dry reaction tube, the air in the reaction tube was replaced with argon, dichloromethane (2 mL) and triethylamine (13 mg, 0.128 mmol) were added to the reaction tube, and the reaction tube was placed in an ice-water bath at 0°C and stirred. After cooling, triphosgene (7.6 mg, 0.025 mmol) was dissolved in dichloromethane (1 mL), and the triphosgene solution was slowly dripped into the reaction solution. After naturally warming to room temperature and reacting for 0.5 hours, the solvent was dried, and compound 3-1 (10.0 mg, 0.032 mmol) was dissolved in N,N-dimethylformamide (1 mL) and then injected into the reaction tube for reaction at room temperature for 2 to 3 hours. The intermediate was purified by reverse phase column chromatography (acetonitrile: water = 1:1) to obtain the intermediate. The intermediate was placed in a dry reaction tube, and the air in the reaction tube was replaced with argon. Tetrahydrofuran (0.5 mL) was added to the reaction tube and stirred in an ice bath. 1,4-dioxane hydrochloride (4 M) (1.5 mL) was then added to the reaction tube and stirred in an ice bath for 2 hours. The reaction solution was concentrated at low temperature and then purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to obtain compound 7 (3.6 mg, yield 20%). m / z (ESI): 554 [M+H] + .

[0248] 1H NMR (400MHz, DMSO-d6) δ10.00(s,1H),8.32(s,1H),7.87(d,J=8.3Hz,1H),7.73(d,J=1.5Hz,1H),7.64( d,J=1.9Hz,1H),7.47–7.33(m,3H),6.57(s,1H),5.26(s,2H),4.97(dd,J=13.4,5.1Hz,1H),4.61(dd,J =16.6,1.7Hz,1H),4.49(s,2H),4.44(dd,J=16.6,1.8Hz,1H),3.57(t,J=5.4Hz,3H),2.99–2.85(m,1H) ,2.81(t,J=5.5Hz,2H),2.71–2.56(m,1H),2.4–32.32(m,1H),2.37(s,3H),2.10(dd,J=9.6,4.2Hz,1H).

[0249] Example 8: (2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)methyl-(3-chloro-4-(methylamino)phenyl)carbamate

[0250] Intermediate 2 (16.5 mg, 0.064 mmol) was placed in a dry reaction tube, the air in the reaction tube was replaced with argon, dichloromethane (2 mL) and triethylamine (13 mg, 0.128 mmol) were added to the reaction tube, and the reaction tube was placed in an ice-water bath at 0°C with stirring. After cooling, triphosgene (7.6 mg, 0.025 mmol) was dissolved in dichloromethane (1 mL), and the triphosgene solution was slowly dripped into the reaction solution. After naturally warming to room temperature and reacting for 0.5 hours, the solvent was dried, and compound 3-1 (10.0 mg, 0.032 mmol) was dissolved in N,N-dimethylformamide (1 mL) and then injected into the reaction tube for reaction at room temperature for 2 to 3 hours. The intermediate was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to obtain the intermediate. The intermediate was placed in a dry reaction tube, and the air in the reaction tube was replaced with argon. Tetrahydrofuran (0.5 mL) was added to the reaction tube and stirred in an ice bath. 1,4-dioxane hydrochloride (4 M) (1.5 mL) was then added to the reaction tube and stirred in an ice bath for 2 hours. The reaction solution was concentrated at low temperature and then purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to obtain compound 8 (4.5 mg, yield 28%). m / z (ESI): 496 [M+H] + .

[0251] 1H NMR (400MHz, DMSO-d6) δ11.06(s,1H),9.48(s,1H),7.86(d,J=8.3Hz,1H),7.70(s,1H),7.43(s ,1H),7.35(dd,J=8.4,1.6Hz,1H),7.21(d,J=8.7Hz,1H),6.62–6.54(m,2H),5.24–5.17(m,3H) ,4.97(dd,J=13.3,5.2Hz,1H),4.61(dd,J=16.5,1.7Hz,1H),4.44(dd,J=16.5,1.7Hz,1H),2.9 8–2.85(m,1H),2.71(d,J=5.0Hz,3H),2.70–2.56(m,1H),2.42–2.30(m,1H),2.14–2.06(m,1H).

[0252] Example 9: (2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)methyl-(4-chloro-3-(2-(2-(methylamino)ethoxy)ethyl)phenyl)carbamate

[0253] Step 1: 2-(2-chloro-5-nitrophenylethane) alcohol (Compound 9-2)

[0254] Compound 9-1 (1200 mg, 5.55 mmol) was placed in a reaction tube. The air in the reaction tube was replaced with argon. Tetrahydrofuran (5 mL) was added with stirring. Borane tetrahydrofuran (1 M) (8 mL) was slowly added to the reaction tube. The reaction tube was placed in a 60°C oil bath with stirring for 2 hours. After the reaction was completed, methanol (2 mL) was slowly added to quench the reaction. The reaction solution was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 9-2 (900 mg, yield 80%). m / z (ESI): 202 [M+H] + .

[0255] Step 2: tert-Butyl 2-(2-chloro-5-nitrophenylethoxy)acetate (Compound 9-3)

[0256] Compound 9-2 (900 mg, 4.45 mmol) and sodium hydroxide (356 mg, 8.9 mmol) were placed in a reaction tube. The air in the reaction tube was replaced with argon. 1,4-dioxane (5 mL) was added to the reaction tube and stirred. Tert-butyl bromoacetate (2670 mg, 13.6 mmol) was slowly added to the reaction tube. The reaction tube was stirred at room temperature for 8 hours. After the reaction was completed, the reaction solution was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 9-3 (870 mg, yield 62%). m / z (ESI): 316 [M+H] + .

[0257] Step 3: 2-(2-chloro-5-nitrophenylethoxy)acetic acid (Compound 9-4)

[0258] Compound 9-3 (870 mg, 2.75 mmol) was placed in a reaction tube. The air in the reaction tube was replaced with argon. Dichloromethane (1 mL) and trifluoroacetic acid (1 mL) were added to the reaction tube. The reaction tube was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 9-4 (640 mg, yield 89%). m / z (ESI): 260 [M+H] + .

[0259] Step 4: 2-(2-chloro-5-nitrophenylethoxy)-N-methylacetamide (Compound 9-5)

[0260] Compound 9-4 (640 mg, 2.46 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1403 mg, 3.69 mmol), and methylamine hydrochloride (332 mg, 4.92 mmol) were placed in a reaction tube. The air in the reaction tube was replaced with argon and stirred in an ice bath. N,N-dimethylformamide (2 mL) and triethylamine (497 mg, 4.92 mmol) were added to the reaction tube, and the reaction tube was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 9-5 (550 mg, yield 82%). m / z (ESI): 273 [M+H] + .

[0261] Step 5: 2-(2-chloro-5-nitrophenylethoxy)-N-methylethane-1-amine (Compound 9-6)

[0262] Compound 9-5 (550 mg, 2.0 mmol) was placed in a reaction tube, the air in the reaction tube was replaced with argon, tetrahydrofuran (4 mL) was added and stirred, borane tetrahydrofuran (1 M) (4 mL) was slowly added to the reaction tube, and the reaction tube was placed in a 60°C oil bath and stirred for 2 hours. After the reaction was completed, methanol (1 mL) was slowly added to quench the reaction, and the reaction was concentrated. Methanol (2 mL) and hydrochloric acid (10%) (8 mL) were then added to the reaction tube, and the reaction was stirred in an 80°C oil bath for 3 hours. After the reaction was completed, saturated sodium bicarbonate solution and ethyl acetate were used for extraction, and the organic phase was concentrated to obtain crude compound 9-6 (508 mg, yield 98%). m / z (ESI): 259 [M+H] + .

[0263] Step 6: tert-Butyl (2-(2-chloro-5-nitrophenethoxy)ethyl)(methyl)carbamate (Compound 9-7)

[0264] Compound 9-6 (508 mg, 1.96 mmol), 4-dimethylaminopyridine (12 mg, 0.098 mmol), and di-tert-butyl dicarbonate (854 mg, 3.92 mmol) were placed in a reaction tube. The air in the reaction tube was replaced with argon. Tetrahydrofuran (10 mL) and triethylamine (594 mg, 5.88 mmol) were added to the reaction tube. The reaction tube was placed in a 50°C oil bath and stirred for 5 hours. After completion of the reaction, the reaction mixture was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 9-7 (660 mg, yield 94%). m / z (ESI): 359 [M+H] + .

[0265] Step 7: tert-Butyl (2-(5-amino-2-chlorophenethoxy)ethyl)(methyl)carbamate (Compound 9-8)

[0266] Compound 9-7 (660 mg, 1.84 mmol), iron powder (515 mg, 9.2 mmol), and ammonium chloride (298 mg, 5.5 mmol) were placed in a reaction tube. The air in the reaction tube was replaced with argon. Ethanol (4 mL) and water (4 mL) were added to the reaction tube. The reaction tube was placed in an 80°C oil bath and stirred for 2 hours. After the reaction, the mixture was extracted with ethyl acetate and water. The organic phase was concentrated and the reaction solution was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 9-8 (530 mg, yield 88%). m / z (ESI): 329 [M+H] + .

[0267] Step 8: (2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)methyl-(4-chloro-3-(2-(2-(methylamino)ethoxy)ethyl)phenyl)carbamate (Compound 9)

[0268] Compound 9-8 (21 mg, 0.064 mmol) was placed in a dry reaction tube, the air in the reaction tube was replaced with argon, dichloromethane (2 mL) and triethylamine (13 mg, 0.128 mmol) were added to the reaction tube, and the reaction tube was placed in an ice-water bath at 0°C and stirred. After cooling, triphosgene (7.6 mg, 0.025 mmol) was dissolved in dichloromethane (1 mL), and the triphosgene solution was slowly dripped into the reaction solution. After naturally warming to room temperature and reacting for 0.5 hours, the solvent was dried, and compound 3-1 (10.0 mg, 0.032 mmol) was dissolved in N,N-dimethylformamide (1 mL) and then injected into the reaction tube for reaction at room temperature for 2 to 3 hours. The intermediate was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to obtain the intermediate. The intermediate was placed in a dry reaction tube, and the air in the reaction tube was replaced with argon. Tetrahydrofuran (0.5 mL) was added to the reaction tube and stirred in an ice bath. 1,4-dioxane hydrochloride (4 M) (1.5 mL) was then added to the reaction tube and stirred in an ice bath for 2 hours. The reaction solution was concentrated at low temperature and then purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to obtain compound 9 (7.6 mg, yield 42%). m / z (ESI): 568 [M+H] + .

[0269] 1 H NMR (400MHz, DMSO-d6) δ9.89(s,1H),8.33(s,1H),7.87(d,J=8.3Hz,1H),7.72(d,J=1.5Hz,1H),7.5 2(d,J=2.3Hz,1H),7.40–7.28(m,3H),6.57(d,J=1.8Hz,1H),5.25(s,2H),4.97(dd,J=13.4,5.1Hz, 1H),4.61(dd,J=16.6,1.7Hz,1H),4.52–4.39(m,1H),3.60(t,J=6.9Hz,2H),3.53(t,J=5.5Hz,2H), 2.97–2.87(m,4H),2.77(t,J=5.4Hz,2H),2.68–2.58(m,1H),2.42–2.32(m,4H),2.14–2.05(m,1H).

[0270] Example 10: 1-(3-chloro-4-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-6-yl)methyl)urea

[0271] Step 1: 5-Bromo-1H-indole-2-carbaldehyde oxime (Compound 10-2)

[0272] Compound 10-1 (1000 mg, 4.46 mmol), hydroxylamine hydrochloride (465 mg, 6.69 mmol), and sodium bicarbonate (749 mg, 8.92 mmol) were placed in a flask. Ethanol (15 mL) and water (10 mL) were added, and the reaction mixture was stirred in a 70°C oil bath for 3 h. After the reaction, the reaction mixture was concentrated and extracted with ethyl acetate and water. The organic phase was dried and concentrated to give the crude product, compound 10-2 (1010 mg, 95% yield). m / z (ESI): 239 [M+H] + .

[0273] Step 2: (6-Bromo-1H-indol-2-yl)methanamine (Compound 10-3)

[0274] Compound 10-2 (1010 mg, 4.22 mmol) was placed in a flask, and anhydrous tetrahydrofuran (25 mL) was added. The reaction solution was stirred in an ice bath at 0°C and cooled. After cooling, lithium aluminum tetrahydride (240 mg, 6.33 mmol) was slowly added. After complete addition, the reaction solution was stirred in an oil bath at 70°C for 2 h. After completion of the reaction, the reaction solution was stirred in an ice bath at 0°C and cooled. Sodium sulfate decahydrate was slowly added to quench the reaction. After quenching, the reaction solution was filtered, and the filtrate was extracted with ethyl acetate and water. The organic phase was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 10-3 (694 mg, 73% yield). m / z (ESI): 225 [M+H] + .

[0275] Step 3: 6-bromo-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (Compound 10-4)

[0276] Compound 10-3 (694 mg, 3.08 mmol) was placed in a dry, sealed tube. The air in the reaction tube was replaced with argon. Tetrahydrofuran (3 mL) was added and the tube was sealed. The reaction solution was stirred in an ethanol-dry ice bath to cool. N,N'-Carbonyldiimidazole (550 mg, 3.39 mmol) was placed in a dry flask and dissolved in tetrahydrofuran (3 mL). The N,N'-Carbonyldiimidazole solution was slowly added dropwise to the reaction solution. After the addition was complete, the temperature was naturally raised to room temperature and stirred for 1 hour. The reaction solution was then placed in a 95°C oil bath and stirred for 16 hours. After the reaction, the reaction solution was concentrated to obtain the crude product, which was purified by normal phase column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to obtain compound 10-4 (526 mg, 68% yield). m / z (ESI): 251 [M+H] + .

[0277] Step 4: Dimethyl 2-(6-bromo-3-carbonyl-1H-imidazo[1,5-a]indol-2(3H)-yl)glutarate (Compound 10-5)

[0278] Compound 10-4 (526 mg, 2.10 mmol) and sodium hydride (75.2 mg, 3.14 mmol) were placed in a dry reaction tube. The air in the reaction tube was replaced with argon and the reaction tube was cooled in an ethanol-dry ice bath. N,N-dimethylformamide (2 mL) was added to the reaction tube. The reaction solution was naturally warmed to room temperature and stirred for half an hour. The mixture was then stirred in an ice-water bath. Dimethyl 2-bromoglutarate (749 mg, 3.14 mmol) was added dropwise to the reaction solution. Stirring was continued in the ice-water bath for half an hour and then at room temperature for one hour. After completion of the reaction, acetic acid (250 mg, 4.2 mmol) was added to quench the reaction. The reaction solution was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 10-5 (686 mg, 80% yield). m / z (ESI): 409 [M+H] + .

[0279] Step 5: 2-(6-bromo-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)glutaric acid (Compound 10-6)

[0280] Compound 10-5 (686 mg, 1.68 mmol) and lithium hydroxide (161 mg, 6.72 mmol) were placed in a flask, tetrahydrofuran (4 mL) and water (2 mL) were added, and the mixture was stirred at room temperature for 3 to 5 hours. After the reaction, hydrochloric acid (3N) was added to adjust the pH of the reaction solution to 3 to 5. The reaction solution was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 10-6 (170 mg, yield 90%). m / z (ESI): 381 [M+H] + .

[0281] Step 6: 3-(6-bromo-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)piperidine-2,6-dione (Compound 10-7)

[0282] Compound 10-6 (575 mg, 1.51 mmol), trifluoroacetamide (255 mg, 2.26 mmol), 1-hydroxybenzotriazole (448 mg, 3.32 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1012 mg, 5.28 mmol) were placed in a dry reaction tube. The air in the reaction tube was replaced with argon and the reaction tube was cooled in an ethanol-dry ice bath. Dichloromethane (10 mL) and triethylamine (687 mg, 6.80 mmol) were added to the reaction tube. The reaction solution was naturally warmed to room temperature and stirred for half an hour. The reaction solution was then stirred in a 35°C oil bath for 5 hours. After completion of the reaction, the reaction solution was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 10-7 (448 mg, yield 82%). m / z (ESI): 362 [M+H] + .

[0283] Step 7: tert-Butyl [(2-(2,6-dioxo-3-oxo-1H-imidazo[1,5-a]indol-6-yl)methyl)carbamate (Compound 10-8)

[0284] Compound 10-7 (80 mg, 0.22 mmol), palladium acetate (5.0 mg, 0.022 mmol), n-butyldi(1-adamantyl)phosphine (15.8 mg, 0.044 mmol), potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (68.0 mg, 0.028 mmol), and cesium carbonate (215.0 mg, 0.66 mmol) were placed in a reaction tube. The atmosphere in the reaction tube was replaced with argon. 1,4-Dioxane (3 mL) and water (0.3 mL) were added to the reaction tube. The reaction tube was stirred in an oil bath at 100°C for 5-8 hours. After completion of the reaction, the reaction solution was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 10-8 (296 mg, 58% yield). m / z (ESI): 413 [M+H] + .

[0285] Step 8: 3-(6-aminomethyl)-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)piperidine-2,6-dione (Compound 10-9)

[0286] Compound 10-8 (11.0 mg, 0.027 mmol) was placed in a reaction tube. The air in the reaction tube was replaced with argon. 1,4-dioxane (2 mL) and 1,4-dioxane-hydrochloride (4 M) (2 mL) were added to the reaction tube. The reaction tube was placed in a 25°C oil bath and stirred for 5 hours. After the reaction, the solvent in the reaction solution was dried to obtain crude compound 10-9 (9.2 mg, yield 99%). m / z (ESI): 313 [M+H] + .

[0287] Step 9: 1-(3-chloro-4-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-6-yl)methyl)urea (Compound 10)

[0288] Compound 10-9 (9.2 mg, 0.027 mmol) and (4-nitrophenyl)-N-(3-chloro-4-methylphenyl)carbamate (Intermediate 1, 9.8 mg, 0.032 mmol) were placed in a dry reaction tube. The air in the reaction tube was replaced with argon. Dichloromethane (2 mL) and triethylamine (5.94 mg, 0.057 mmol) were added to the reaction tube. The reaction tube was stirred in a 25°C oil bath for 4 hours. After the reaction, the reaction solution was concentrated to obtain the crude product, which was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 10 (5.1 mg, yield 39%). m / z (ESI): 480 [M+H] + .

[0289] 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),8.75(s,1H),7.81(s,1H),7.66(d,J=2.1Hz ,1H),7.59(d,J=8.2Hz,1H),7.22–7.11(m,3H),6.81(t,J=5.9Hz,1H),6.50(s,1H) ,4.96(dd,J=13.4,5.1Hz,1H),4.59(d,J=16.5Hz,1H),4.44–4.39(m,2H),2.97–2 .88(m,1H),2.67–2.59(m,2H),2.42–2.31(m,1H),2.23(s,3H),2.13–2.07(m,1H).

[0290] Example 11: 1-(3-chloro-4-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-9-yl)methyl)urea

[0291] Step 1: 3-Bromo-1H-indole-2-carbaldehyde oxime (Compound 11-2)

[0292] Compound 11-1 (1000 mg, 4.46 mmol), hydroxylamine hydrochloride (465 mg, 6.69 mmol), and sodium bicarbonate (749 mg, 8.92 mmol) were placed in a flask. Ethanol (15 mL) and water (10 mL) were added, and the reaction mixture was stirred in a 70°C oil bath for 3 h. After the reaction, the reaction mixture was concentrated and extracted with ethyl acetate and water. The organic phase was dried and concentrated to give crude compound 11-2 (1010 mg, 95% yield). m / z (ESI): 239 [M+H] + .

[0293] Step 2: (3-Bromo-1H-indol-2-yl)methanamine (Compound 11-3)

[0294] Compound 11-2 (1010 mg, 4.22 mmol) was placed in a flask, and anhydrous tetrahydrofuran (25 mL) was added. The reaction solution was stirred in an ice bath at 0°C and cooled. After cooling, lithium aluminum tetrahydride (240 mg, 6.33 mmol) was slowly added. After complete addition, the reaction solution was stirred in an oil bath at 70°C for 2 h. After completion of the reaction, the reaction solution was stirred in an ice bath at 0°C and cooled. Sodium sulfate decahydrate was slowly added to quench the reaction. After quenching, the reaction solution was filtered, and the filtrate was extracted with ethyl acetate and water. The organic phase was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 11-3 (694 mg, 73% yield). m / z (ESI): 225 [M+H] + .

[0295] Step 3: 9-bromo-1,2-dihydro-3H-imidazo[1,5-a]indol-3-one (Compound 11-4)

[0296] Compound 11-3 (694 mg, 3.08 mmol) was placed in a dry, sealed tube. The air in the reaction tube was replaced with argon. Tetrahydrofuran (3 mL) was added and the tube was sealed. The reaction solution was stirred in an ethanol-dry ice bath to cool. N,N'-carbonyldiimidazole (550 mg, 3.39 mmol) was placed in a dry flask and dissolved in tetrahydrofuran (3 mL). The N,N'-carbonyldiimidazole solution was slowly added dropwise to the reaction solution. After the addition was complete, the temperature was naturally raised to room temperature and stirred for 1 hour. The reaction solution was then placed in a 95°C oil bath and stirred for 16 hours. After the reaction, the reaction solution was concentrated to obtain the crude product, which was purified by normal phase column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to obtain compound 11-4 (526 mg, 68% yield). m / z (ESI): 251 [M+H] + .

[0297] Step 4: Dimethyl 2-(9-bromo-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)glutarate (Compound 11-5)

[0298] Compound 11-4 (526 mg, 2.10 mmol) and sodium hydride (75.2 mg, 3.14 mmol) were placed in a dry reaction tube. The air in the reaction tube was replaced with argon and the reaction tube was cooled in an ethanol-dry ice bath. N,N-dimethylformamide (2 mL) was added to the reaction tube. The reaction solution was naturally warmed to room temperature and stirred for half an hour. The mixture was then stirred in an ice-water bath. Dimethyl 2-bromoglutarate (749 mg, 3.14 mmol) was added dropwise to the reaction solution. Stirring was continued in the ice-water bath for half an hour and then at room temperature for one hour. After completion of the reaction, acetic acid (250 mg, 4.2 mmol) was added to quench the reaction. The reaction solution was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 11-5 (686 mg, 80% yield). m / z (ESI): 409 [M+H] + .

[0299] Step 5: 2-(9-bromo-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)glutaric acid (Compound 11-6)

[0300] Compound 11-5 (686 mg, 1.68 mmol) and lithium hydroxide (161 mg, 6.72 mmol) were placed in a flask, tetrahydrofuran (4 mL) and water (2 mL) were added, and the mixture was stirred at room temperature for 5 hours. After the reaction, hydrochloric acid (3N) was added to adjust the pH of the reaction solution to 3-5. The reaction solution was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 11-6 (170 mg, yield 90%). m / z (ESI): 381 [M+H] + .

[0301] Step 6: 3-(9-bromo-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)piperidine-2,6-dione (Compound 11-7)

[0302] Compound 11-6 (90 mg, 0.236 mmol), trifluoroacetamide (40 mg, 0.354 mmol), 1-hydroxybenzotriazole (70 mg, 0.519 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (158.0 mg, 0.826 mmol) were placed in a dry reaction tube. The air in the reaction tube was replaced with argon and the reaction tube was cooled in an ethanol-dry ice bath. Dichloromethane (10 mL) and triethylamine (107.0 mg, 1.0 mmol) were added to the reaction tube. The reaction solution was naturally warmed to room temperature and stirred for half an hour. The reaction solution was then stirred in a 35°C oil bath for 5 hours. After completion of the reaction, the reaction solution was concentrated and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 11-7 (20.0 mg, yield 23%). m / z (ESI): 362 [M+H] + .

[0303] Step 7: Tert-butyl [(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-9-yl)methyl)carbamate (Compound 11-8)

[0304] Compound 11-7 (20 mg, 0.055 mmol), palladium acetate (2.0 mg, 0.008 mmol), n-butyldi(1-adamantyl)phosphine (6.0 mg, 0.016 mmol), potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate) (13.0 mg, 0.055 mmol), and cesium carbonate (54.0 mg, 0.166 mmol) were placed in a reaction tube. The atmosphere in the reaction tube was replaced with argon. 1,4-Dioxane (3 mL) and water (0.3 mL) were added to the reaction tube. The reaction tube was stirred in an oil bath at 100°C for 8 hours. After completion of the reaction, the reaction solution was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 11-8 (16.0 mg, 70% yield). m / z (ESI): 413 [M+H] + .

[0305] Step 8: 3-(9-aminomethyl)-3-oxo-1H-imidazo[1,5-a]indol-2(3H)-yl)piperidine-2,6-dione (Compound 11-9)

[0306] Compound 11-8 (16.0 mg, 0.038 mmol) was placed in a reaction tube. The air in the reaction tube was replaced with argon. 1,4-dioxane (2 mL) and 1,4-dioxane-hydrochloride (4 M) (2 mL) were added to the reaction tube. The reaction tube was placed in a 25°C oil bath and stirred for 5 hours. After the reaction, the solvent in the reaction solution was dried to obtain crude compound 11-9 (11.0 mg, 90% yield). m / z (ESI): 313 [M+H] + .

[0307] Step 9: 1-(3-chloro-4-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-9-yl)methyl)urea (Compound 11)

[0308] Compound 11-9 (11 mg, 0.035 mmol) and (4-nitrophenyl) N-(3-chloro-4-methyl-phenyl)carbamate (Intermediate 1, 13.0 mg, 0.042 mmol) were placed in a dry reaction tube. The air in the reaction tube was replaced with argon. Dichloromethane (2 mL) and triethylamine (7.8 mg, 0.077 mmol) were added to the reaction tube. The reaction tube was stirred in a 25°C oil bath for 4 hours. After the reaction, the reaction solution was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 11 (7.5 mg, 44% yield). m / z (ESI): 480 [M+H] + .

[0309] 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),8.85(s,1H),7.86–7.79(m,1H),7.73(d,J=6.7Hz,1H ),7.63(d,J=2.0Hz,1H),7.34–7.22(m,2H),7.20–7.08(m,2H),6.83(t,J=5.8Hz,1H),4.95( dd,J=13.3,5.1Hz,1H),4.63(d,J=16.2Hz,1H),4.48(d,J=16.3Hz,1H),4.42(d,J=5.8Hz,2H ),2.98–2.84(m,1H),2.67–2.59(m,1H),2.41–2.34(m,1H),2.22(s,3H),2.14–2.05(m,1H).

[0310] Example 12: N-(3-chloro-4-methylphenyl)-3-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)propanamide

[0311] Step 1: (E)-tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)acrylate (Compound 12-1)

[0312] Compound 2-7 (35 mg, 96.64 μmol), tris(dibenzylideneacetone)dipalladium (17.68 mg, 19.33 μmol), tri-tert-butylphosphine tetrafluoroborate (15.37 mg, 53.15 μmol), and N,N-dicyclohexylmethylamine (33.38 mg, 0.17 mmol) were placed in a dry reaction tube, and the atmosphere was replaced with nitrogen. 1,4-Dioxane (1 mL) and tert-butyl acrylate (32.82 mg, 256.09 μmol) were added via syringe. The solution was heated to 60°C and stirred for 16 hours. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was concentrated and purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 12-1 (26 mg, 66% yield). m / z (ESI): 410 [M+H] + .

[0313] Step 2: 3-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)propanoic acid (Compound 12-2)

[0314] Compound 12-1 (26 mg, 0.063 mmol), palladium on carbon (7.0 mg, 55% water content), and THF (2 mL) were placed in a dry reaction tube. The air in the reaction tube was replaced with hydrogen. The mixture was stirred at 25°C for 6 hours. The reaction was then monitored by LC-MS. After the reaction was complete, the reaction solution was filtered to obtain a clear solution, and the solvent was removed by rotary evaporation to obtain the intermediate product. Dichloromethane (1.0 mL) and trifluoroacetic acid (0.5 mL) were then added to the reaction tube. The solution was stirred at room temperature for 6 hours. The reaction was then monitored by LC-MS. After the reaction was complete, the solvent was removed by rotary evaporation to obtain the crude product, which was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 12-2 (14 mg, yield 62%). m / z (ESI): 356 [M+H] + .

[0315] Step 3: N-(3-chloro-4-methylphenyl)-3-(2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-7-yl)propanamide (Compound 12)

[0316] Compound 12-2 (14 mg, 0.039 mmol), 3-chloro-p-toluidine (8.4 mg, 0.059 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (22.30 mg, 0.059 mmol) were placed in a dry reaction tube. The air in the reaction tube was replaced with argon. N,N-dimethylformamide (2 mL) and triethylamine (7.97 mg, 0.079 mmol) were added to the reaction tube. After reacting at room temperature for 2-3 hours, the mixture was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 12 (11.2 mg, yield 59%). m / z (ESI): 479 [M+H] + .

[0317] 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),10.00(s,1H),7.79(d,J=2.1Hz,1H),7.75(d,J=8.3Hz,1H), 7.49(s,1H),7.32(dd,J=8.3,2.2Hz,1H),7.24(d,J=8.4Hz,1H),7.18(dd,J=8.3,1.6Hz,1H),6.47( s,1H),4.95(dd,J=13.4,5.1Hz,1H),4.57(d,J=17.1Hz,1H),4.40(d,J=16.5Hz,1H),3.00(t,J=7. 7Hz,2H),2.97–2.86(m,1H),2.70–2.57(m,3H),2.43–2.30(m,1H),2.25(s,3H),2.14–2.04(m,1H).

[0318] Example 13: 2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-a]indol-8-yl)methyl(3-chloro-4-methylphenyl)carbamate

[0319] 3-Chloro-p-toluidine (10.8 mg, 0.076 mmol) was placed in a dry reaction tube. The air in the reaction tube was replaced with argon. Dichloromethane (2 mL) and triethylamine (15 mg, 0.153 mmol) were added to the reaction tube. The reaction tube was placed in an ice-water bath at 0°C and stirred. After cooling, triphosgene (9 mg, 0.03 mmol) was dissolved in dichloromethane (1 mL). The triphosgene solution was slowly added dropwise to the reaction solution. The temperature was naturally raised to room temperature and the reaction was continued for 0.5 hours. The solvent was then dried by rotary evaporation. Compound 6-8 (18.0 mg, 0.057 mmol) was dissolved in N,N-dimethylformamide (1 mL) and added to the reaction tube. The reaction was continued at room temperature for 2-3 hours. Compound 13 (11.2 mg, 30% yield) was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 13 (m / z (ESI): 481 [M+H] + .

[0320] 1 H NMR (400MHz, DMSO-d6) δ11.06 (s, 1H), 9.86 (s, 1H), 7.86 (dd, J = 7.2, 2.0Hz, 1H), 7.60 (d, J=2.1Hz,1H),7.36–7.20(m,4H),6.69(s,1H),5.43(s,2H),4.98(dd,J=13.4,5.1Hz,1H), 4.63(dd,J=16.7,1.7Hz,1H),4.45(dd,J=16.6,1.8Hz,1H),2.92(ddd,J=18.0,13.6,5.4 Hz,1H),2.65–2.58(m,1H),2.38(qd,J=13.0,4.3Hz,1H),2.25(s,3H),2.14–2.06(m,1H).

[0321] Example 14: 3-(1-oxo-1H-benzo[d]imidazo[1,5-a]imidazol-2(3H)-yl)piperidine-2,6-dione

[0322] Referring to the synthesis method of Example 1, the starting material compound 1-1 was replaced with (1H-benzimidazole-2-methylene)amine to prepare compound 14 (9 mg, yield 6%). m / z (ESI): 285 [M+H] + .

[0323] 1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),8.43(s,1H),7.86–7.73(m,2H),7.40–7.37(m,1H) ,5.04(dd,J=13.2,5.0Hz,1H),4.74–4.53(m,2H),2.95–2.88(m,2H),2.40–2.32(m,2H).

[0324] Compounds other than the compounds synthesized in Examples 1-14 can be synthesized by referring to the synthesis routes and source materials in Examples 1-14.

[0325] Biological activity and related properties test examples

[0326] Test Example 1: Cereblon binding experiment

[0327] 1. Experimental instruments and materials

[0328] The detection kit used in the experiment (HTRF Human Cereblon Binding Kits) is a This assay quantitatively measures Cereblon WT ligand. The assay is based on HTRF technology. A specifically labeled GST antibody (Euroum Cryptate, donor) simultaneously binds to GST-tagged human Cereblon WT ligand and the XL665-labeled lenalidomide tracer (acceptor). Excitation of the donor by a light source triggers fluorescence resonance energy transfer (FRET) to the acceptor, which emits fluorescence at a specific wavelength of 665 nm. Addition of the compound competes with the XL665-labeled lenalidomide, preventing FRET. The FRET signal ratio is inversely proportional to compound concentration.

[0329] Other reagents and consumables required for the experiment are as follows:

[0330] 2. Experimental steps

[0331] The disclosed compounds were dissolved in DMSO with a stock concentration of 10 mM. The compound stock solution was gradiently diluted using the dose-response program of the compound dilution and sample injector. The total experimental system of the dilution program was 20 μL, the starting concentration of the test compound was 100 μM, the starting concentration of the standard was 200 μM, 4-fold dilution, 8 concentration points, and the DMSO content was 1%. After the program was completed, 5 μL of 1×9# diluent in the kit was added to each well, followed by 5 μL of GST-labeled human Cereblon WT ligand, mixed thoroughly, and then 10 μL of HTRF detection reagent was added and incubated at room temperature for 3 hours. The HTRF signal in each well was measured using an Envision plate reader. 100% binding inhibition was defined as the signal ratio under treatment with 200 μM standard lenalidomide.

[0332] 3. Data Analysis

[0333] Calculate the ratio of the acceptor and donor emission signals for each well:

[0334] Ratio = 665nm signal / 620nm signal

[0335] Coefficient of variation (%) = standard deviation / mean ratio

[0336] Cereblon binding inhibition rate (%) = 100% - 100% × (Sample-L) / (HL)

[0337] in:

[0338] Sample=Ave (test sample group);

[0339] H = Ave (DMSO-treated group);

[0340] L=Ave (200 μM lenalidomide standard treatment group).

[0341] Data analysis was performed using GraphPad Prism 9. Concentration-effect curves were fitted using a nonlinear four-parameter curve, and the IC of the compounds was calculated. 50 :

[0342] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0343] in:

[0344] X: Log compound concentration;

[0345] Y: inhibition rate (%);

[0346] Bottom is the minimum inhibition percentage;

[0347] Top is the maximum inhibition percentage;

[0348] HillSlope is the slope coefficient of the curve.

[0349] The binding ability of the disclosed compounds to Cereblon was determined by the above test, and the measured IC 50 See Table 1 for values.

[0350] Table 1

[0351] A:IC 50 <1μM; B:1μM≤IC 50 <10μM; C:10μM≤IC 50 <100 μM; D:IC 50 ≥100μM.

[0352] Test Example 2: Anti-proliferative activity test on CAL51 cells

[0353] 1. Experimental instruments and materials

[0354] Instruments and Equipment

[0355] Experimental reagents and consumables

[0356] 2. Experimental steps

[0357] (1) Cell plating

[0358] Remove the culture medium of the target cells CAL51 (CBP60360, Kebai), rinse once with PBS, and then digest with trypsin (Trypsin-EDTA (0.25%)) for 5 minutes. After digestion, add 10 mL of complete culture medium (DMEM containing 10% FBS) to neutralize the trypsin, pipette the cells, collect the cells, centrifuge at 300g for 5 minutes, count, and adjust the cell density to 40,000 cells / mL. Take 90 μL of the cell suspension and add it to a 96-well low-adsorption plate. Add 200 μL of PBS to the edge wells. Centrifuge at 300g for 5 minutes to aggregate the cells into spheres, and place them in a cell culture incubator overnight.

[0359] (2) Cell dosing

[0360] The compounds disclosed herein were dissolved in DMSO, and the stock concentration of the stock solution was 10 mM. Before administration, the DMSO gradient was diluted 10-fold, with a total of 6 gradient working solutions. Take 2 μL of each working solution of different concentrations, add it to a dilution plate with 198 μL of culture medium, and mix it by pipetting. Take 10 μL of culture medium containing the compound from the dilution plate and add it to the cell plate containing 90 μL of cell suspension laid the day before. The final concentrations of each gradient compound are 10,000, 1000, 100, 10, 1, and 0.1 nM. The positive control is CC-885. Add the diluted compound, 10 μL per well, centrifuge and place in a carbon dioxide incubator for 3 days.

[0361] (3) 3D Cell Viability Assay

[0362] Remove the cells from the incubator and allow them to return to room temperature for 30 minutes. Add 50 μL of 3D Cell Viability Assay reagent was shaken and mixed for 10 minutes before reading the plate on an Envision microplate reader.

[0363] 3. Data Analysis

[0364] The anti-proliferative activity of the compounds disclosed herein on CAL51 cells was determined by the above test, and the cell growth inhibition rate of each sample well was calculated based on the raw data.

[0365] Inhibition rate (%) = 100% * (1-sample reading / DMSO reference average reading)

[0366] Sample reading: refers to the signal value of the experimental group;

[0367] DMSO reference average reading: refers to the average signal value of the DMSO control group. The DMSO control group does not receive the test compound, and all other procedures are the same as the experimental group.

[0368] Data analysis was performed using GraphPad Prism 9. Concentration-effect curves were fitted using a nonlinear four-parameter curve, and the IC of the compounds was calculated. 50 :

[0369] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0370] in:

[0371] X: Log compound concentration;

[0372] Y: inhibition rate (%);

[0373] Bottom is the minimum inhibition percentage;

[0374] Top is the maximum inhibition percentage;

[0375] HillSlope is the slope coefficient of the curve.

[0376] The anti-proliferative activities of the compounds disclosed herein on CAL51 cells are shown in Table 2.

[0377] Table 2 Antiproliferative activity of CAL51 cells

[0378] Test Example 3: Intracellular GSPT1 protein degradation activity experiment

[0379] 1. Experimental instruments and materials

[0380] Instruments and Equipment

[0381] Experimental reagents and consumables

[0382] 2. Experimental steps

[0383] (1) Cell plating

[0384] Remove the culture medium from CAL51 (CBP60360, Kebai) cells, rinse once with PBS, and then digest with trypsin (0.25%) for 5 minutes. After digestion, add 10 mL of complete culture medium (DMEM + 10% FBS containing 10% FBS) to neutralize the trypsin. Pipette cells, collect them, centrifuge at 300 g for 5 minutes, count them, and adjust the cell density to 266,667 cells / mL. Take 30 μL of the cell suspension and add it to a 384-well plate. Centrifuge at 300 g for 1 minute and place in a cell culture incubator overnight.

[0385] (2) Cell dosing

[0386] The compounds of the present disclosure were dissolved in DMSO to a stock concentration of 10 mM. A serial dilution of the compound stock solution was performed using the dose-response program on the compound dilution and pipetting instrument. The dilution program consisted of 30 μL of total volume, a 30 μM starting concentration of the test compound, four-fold dilutions, and 10 concentration points. The positive control was CC-885 from Test Example 2, and the negative control was DMSO. The DMSO content in all wells was 0.3%. After the program, the cells were centrifuged and incubated in a CO2 incubator for 6 hours.

[0387] (3) Incubation with antibodies

[0388] Six hours after administration, the supernatant was discarded, and the cells were washed with 50 μL of cold PBS. The cells were then fixed with 50 μL / well of 4% paraformaldehyde / general tissue fixative and incubated for 1 hour at room temperature. The paraformaldehyde was discarded, and 50 μL / well of PBS-0.1% Triton X-100 was added to permeabilize the cells for 30 minutes. The PBS-Triton was discarded, and 50 μL / well of blocking buffer (927-70001, Li-COR) was added and incubated for 1 hour at room temperature. The blocking buffer was removed, and a cocktail of rabbit anti-GSPT1 (1:300) (HPA052488, Sigma) and mouse anti-α-Tubulin (1:2000) (T6074, Sigma) primary antibodies (30 μL / well) were added and incubated overnight at 4°C. The cells were then washed four times with 50 μL / well of PBST (0.1% Tween-20), soaking for 10 minutes each time. Add 30 μL / well of a secondary antibody mixture (1:5000) of goat anti-mouse 680RD (P / N 925-68070, Li-COR) and goat anti-rabbit 800CW (P / N 925-32211, Li-COR) and incubate at room temperature for 1-1.5 hours in the dark. Wash with 50 μL / well of PBST, soaking for 10 minutes each time, four times. Invert the centrifuge plate, cover with toilet paper, and centrifuge at 1000 rpm for 1 minute to dry the bottom of the plate. Scan the 384-well plate with the Azure WB Imaging System (Sapphire) for data.

[0389] 3. Data Analysis

[0390] The degradation activity of the compounds of the present disclosure on GSPT1 protein in CAL51 cells was determined by the above test, and the protein degradation rate of each sample well was calculated based on the raw data.

[0391] Degradation rate (%) = 100% × (1-sample reading / DMSO reference average reading)

[0392] Sample reading: refers to the signal value of the experimental group;

[0393] DSMO reference average reading: refers to the average signal value of the DSMO control group. The positive control group does not contain test compound, and all other operations are the same as the experimental group.

[0394] Data analysis was performed using GraphPad Prism 9. Concentration-effect curves were fitted using a nonlinear four-parameter curve, and the DC of the compound was calculated. 50 :

[0395] Y=Bottom+(Top-Bottom) / (1+10^((LogDC 50 -X)*HillSlope))

[0396] in:

[0397] X: Log compound concentration;

[0398] Y: degradation rate (%);

[0399] Bottom is the minimum degradation percentage;

[0400] Top is the maximum degradation percentage;

[0401] HillSlope is the slope coefficient of the curve.

[0402] DC measured by the disclosed compounds 50 The values ​​are shown in Table 3.

[0403] Table 3 GSPT1 protein degradation activity

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, Ring B is selected from a 5-6 membered heteroaromatic ring or a 5-8 membered heterocyclic ring; Ring C is selected from a 5-6 membered heteroaromatic ring, a 5-8 membered heterocyclic ring, a benzene ring, a C5-C8 saturated or partially saturated carbocyclic ring; Every R 1 、R 2 Independently selected from the following groups: (a) Halogen, =O, CN, NO2, -OR b 、-N(R b )2、-S(O)R b 、-SO2R b , 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace; or, (b) M1 is selected from a bond, -NR b -、-C(O)-、-C(O)O-、-SO2-、-S(O)-、-O-、-S-、-C(O)NR b -、-C(=NR b )-, 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene, 5-10 membered heteroarylene, the 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene, 5-10 membered heteroarylene are optionally replaced by R a replace; R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 are independently selected from a bond, -NR b -, -C(O)-, -C(O)O-, -SO2-, -S(O)-, -O-, -S-, -NR b C(O)-, -C(=NR b )-、-C(S)-、-P(O)(OR b )O-、-P(O)(OR b )-, 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene, 5-10 membered heteroarylene, the 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene, 5-10 membered heteroarylene are optionally replaced by R a replace; R 20 Selected from H, halogen, CN, -OR b 、-N(R b) 2. -S(O)R b 、-SO2R b 、-C(O)R b 、-C(O)OR b 、-OC(O)R b 、-C(O)N(R b) 2. -NR b C(O)R b , 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace; Every R 4 Selected from halogen, CN, OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace; Every R a independently selected from halogen, CN, OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R c replace; Every R b independently selected from H, halogen, CN, OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-8 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R c replace; Every R c independently selected from halogen, CN, OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group, said OH, NH2, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R d replace; Every R d Independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl; n is independently selected from 0, 1, 2, 3 or 4; m and p are independently selected from 0, 1, 2, 3, 4, 5 or 6.

2. The compound of formula (I) or a pharmaceutically acceptable salt according to claim 1, wherein Ring B is selected from a 5-6 membered heteroaromatic ring or a 5-6 membered heterocyclic ring; or, Ring B is selected from a 5-6 membered heteroaromatic ring.

3. The compound of formula (I) or a pharmaceutically acceptable salt according to claim 1 or 2, wherein: Ring C is selected from a 5-6 membered heteroaromatic ring, a 5-6 membered heterocyclic ring, a benzene ring, a C5-C6 saturated or partially saturated carbon ring; or, Ring C is selected from a 5-6 membered heteroaromatic ring or a benzene ring.

4. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein: R 1 、R 2 Independently selected from halogen, CN, NO2, -OR b 、-N(R b )2、-S(O)R b 、-SO2R b 、C1-C 10 Alkyl or C3-C 10 Cycloalkyl, the C1-C 10 Alkyl or C3-C 10 The cycloalkyl group is optionally replaced by R a replace.

5. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein: R 1 、R 2 Independently selected from Among them, M1, R 10 、R 11 、R 12 、R 13 、R 14 、R 20 As defined in any one of claims 1 to 3.

6. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 3 or 5, wherein: R 1 、R 2 Independently selected from Among them, R 11 、R 12 、R 13 independently selected from a bond, -C(O)-, -C(O)O-, -O-, -S-, -C(O)NR b -or-NR b -;M1,R 10 、R 14 、R 20 、R b As defined in any one of claims 1 to 3 or 5.

7. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 3 or 5 to 6, wherein: R 1 、R 2 Independently selected from Among them, M1, R 10 、R 12 、R 13 、R 14 、R 20 As defined in any one of claims 1 to 3 or 5 to 6.

8. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 3 or 5 to 7, wherein: M1 is selected from a bond, -NH-, -CH2-, -CH2CH2-, -C(O)-, -C(O)O-, -O-, -S- or -C(O)NH-.

9. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 3 or 5 to 8, wherein: R 1 、R 2 Independently selected from Among them, R 10 、R 12 independently selected from a bond, -C(O)O-, -O-, -S-, -C(O)NR b -、-NR b -, C1-C3 alkylene or C2-C3 alkynylene, the C1-C3 alkylene or C2-C3 alkynylene is optionally replaced by R a Replacement; R 13 、R 14 、R 20 、R a 、R b As defined in any one of claims 1 to 3 or 5 to 8.

10. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 3 or 5 to 9, wherein: R 13 Selected from C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene, the C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene or 5-10 membered heteroarylene is optionally replaced by R a replace; Or, R 13 is selected from C3-C6 cycloalkylene, 5-9 membered heterocyclylene, phenyl or 5-6 membered heteroarylene, wherein the C3-C6 cycloalkylene, 5-9 membered heterocyclylene, phenyl or 5-6 membered heteroarylene is optionally replaced by R a replace.

11. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 3 or 5 to 10, wherein: R 14 Selected from bond, -O-, -NR b -、-C(O)NR b -, 2-6 membered heteroalkylene, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, 4-6 membered heterocyclylene, C6-C 10 Arylene or 5-6 membered heteroarylene, the 2-6 membered heteroalkylene, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, 4-6 membered heterocyclylene, C6-C 10 Arylene or 5-6 membered heteroarylene is optionally replaced by R a replace; Or, R 14 Selected from bond, -O-, -NR b -、-C(O)NR b -, 2-6 membered heteroalkylene, C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, wherein the C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene is optionally replaced by R a replace.

12. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein: R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 independently selected from a bond, -C(O)-, -C(O)O-, -O-, -S-, -C(O)NR b -、-NR b -, 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, 4-9 membered heterocyclylene, C6-C 10 Arylene, 5-10 membered heteroarylene, the 2-10 membered heteroalkylene, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 Alkynylidene, C3-C 10 Cycloalkylene, 4-9 membered heterocyclylene, C6-C 10 Arylene, 5-10 membered heteroarylene are optionally replaced by R a replace.

13. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 12, wherein: R 20 Selected from H, 2-10 membered heteroalkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the 2-10 membered heteroalkyl, C1-C 10 Alkyl C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace; or R 20 Selected from H, -N(R b) 2. C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace.

14. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 13, wherein: R 4 independently selected from halogen, CN, OH, NH2, 2-10 membered heteroalkyl or C1-C 10 Alkyl, the OH, NH2, 2-10 membered heteroalkyl or C1-C 10 The alkyl group is optionally replaced by R a replace.

15. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 14, wherein: Every R a independently selected from halogen, CN, OH, NH2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group, the OH, NH2, C1-C 10 Alkyl, C3-C 10 Cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R c replace; Or each R a independently selected from halogen, CN, OH, NH2 or C1-C 10 Alkyl, the OH, NH2, C1-C 10 The alkyl group is optionally replaced by R c replace.

16. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 15, wherein: Every R c independently selected from halogen, CN, OH, NH2 or C1-C6 alkyl, the C1-C6 alkyl being optionally replaced by R d replace.

17. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 16, wherein: m and p are independently selected from 0, 1 or 2; Or m is selected from 1, p is selected from 0; Alternatively, m is selected from 0 and p is selected from 1.

18. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 17, wherein: n is selected from 0 or 1; Alternatively, n is selected from 0.

19. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 18, wherein: The compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (II) or a pharmaceutically acceptable salt thereof, Wherein, X is selected from N or CH, and the CH is optionally replaced by R 2 Replacement; R 1 、R 2 、R 4 , m, n are as defined in any one of claims 1-18.

20. The compound of formula (I) or a pharmaceutically acceptable salt according to any one of claims 1 to 19, wherein: The compound of formula (II) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (II-1) or (II-2) or a pharmaceutically acceptable salt thereof, in, represents a single bond or a double bond; X is selected from N or CH, and the CH is optionally replaced by R 2 Substituted; Y1, Y2, Y3, Y4 are independently selected from N or CH, the CH is optionally replaced by R 1 Substituted; Q1, Q2, Q3 are independently selected from O, S, NH, CH2, N or CH, wherein NH, CH2, CH are optionally replaced by R 1 Replacement; R 1 、R 2 、R 4 , n as defined in any one of claims 1-19.

21. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein The compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof, 22. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

23. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, or the pharmaceutical composition according to claim 22, in the preparation of a medicament for preventing or treating abnormal cell proliferation diseases.

24. A method for treating abnormal cell proliferation diseases in mammals, comprising administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, or the pharmaceutical composition according to claim 22.

25. The use according to claim 23 or the method according to claim 24, wherein the abnormal cell proliferation disease is selected from cancer; preferably, the cancer is selected from solid tumors, adenocarcinomas or hematological tumors.

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