Bifunctional compound for degrading targeted androgen receptor protein and application of bifunctional compound

Abstract

The invention provides a bifunctional compound for targeting androgen receptor protein degradation and application thereof, and belongs to the field of medicines. Specifically, the invention discloses a compound as shown in a formula I, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound in preparation of drugs for preventing or treating androgen-mediated diseases.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and relates to a bifunctional compound targeting androgen receptor, a preparation method thereof, and use thereof in preparing a medicine for treating androgen-mediated related diseases. Background Art

[0002] Androgens play a wide range of roles in development and physiological responses, including participation in male sex differentiation, maintenance of spermatogenesis, and regulation of male gonadotropin. To date, androgens have been shown to be associated with the development of prostate cancer, prostate hypertrophy, androgenic alopecia, and acne. In addition, androgens also play a role in female diseases such as polycystic ovary syndrome, ovarian cancer, and breast cancer.

[0003] Androgens must bind to androgen receptors (AR) to cause physiological and pathological effects. AR belongs to the steroid receptors in the nuclear receptor superfamily. When AR binds to androgens, AR acts as a transcription factor to stimulate the transcription of its target genes to promote the expression of genes responsible for male characteristics. Androgen receptor antagonists bind to AR and can block the binding of androgens to AR, thereby inhibiting the pathological effects of androgen and AR signaling pathways. However, clinically, patients will develop resistance to androgen receptor antagonists, so that the androgen receptor signaling pathway still works. Therefore, targeted androgen receptor protein degradation may be a very promising therapeutic strategy for the treatment of androgen-mediated related diseases, which may be more effective than androgen receptor antagonists.

[0004] Proteolysis targeting chimeras (PROTAC) are a drug development technology that uses the ubiquitin-proteasome system (UPS) to degrade target proteins. Structurally, PROTAC consists of three parts: one end is a target protein binding ligand, and the other end is an E3 ubiquitin ligase ligand. The two active ligands are connected together through a specially designed "Linker" structure, eventually forming a tripartite "PROTAC" active form. In PROTAC compounds, E3 ubiquitin ligase ligands can ubiquitinate target proteins, which are then recognized and degraded by proteasomes. At the same time, PROTAC molecules have catalytic degradation functions and can have good efficacy at lower doses. And as long as there are a small number of PROTAC molecules in the cell, the efficacy can be maintained.

[0005] Although the prior art has disclosed a number of PROTAC compounds that target AR protein degradation, it is still necessary to obtain PROTAC compounds that target AR degradation in order to develop more therapeutic means for treating androgen-mediated related diseases. Summary of the invention

[0006] In a first aspect, the present invention provides a compound as shown in the following formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in:

[0009] Ring A1 or Ring A2 are each independently selected from an aryl group, a heteroaryl group or a heterocyclic group; Ring A1 or Ring A2 may be optionally substituted by 1 to 4 R e replace;

[0010] M1 is selected from CR1 or N;

[0011] M2 is selected from CR2 or N;

[0012] M3 is selected from CR3R4 or NR5;

[0013] R1, R2, R3, R4 or R5 are each independently selected from H, halogen, cyano, hydroxy, amino, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl or heterocyclyl;

[0014] L is -Ak1-Cy1-Ak2-Cy2-Ak3-;

[0015] Ak1, Ak2 and Ak3 are each independently selected from a bond, -(CH2) n1 -, -C(O)-, -O-, -NH-, -C(O)NH-, -(CR6R7) n2 -, -NR8-, -CH2NR9- or alkynylene;

[0016] R6, R7, R8 or R9 are each independently selected from H, halogen, cyano, hydroxy, amino, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl or heterocyclyl;

[0017] n1 or n2 are each independently selected from 0, 1, 2 or 3;

[0018] Cy1 and Cy2 are each independently selected from a bond, a cycloalkylene group, a heterocyclylene group, an arylene group or a heteroarylene group;

[0019] The Cy1 or Cy2 may optionally be substituted with 1 to 4 R f replace;

[0020] X is selected from a bond, -NH-, -S-, -O-, -CH2-, -C(O)NH-, -NHC(O)- or -C(O)-;

[0021] R a , Rb , R c , R d , R e or R f each independently selected from halogen, cyano, oxo, hydroxy, amino, nitro, or alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl which may be optionally substituted by 1 to 4 groups independently selected from halogen, amino, hydroxy, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl;

[0022] or R b and R c Connected to form a cycloalkyl or heterocyclic group; the cycloalkyl or heterocyclic group may be optionally substituted by 1 to 4 groups independently selected from halogen, amino, hydroxy, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy;

[0023] n or m is each independently selected from 0, 1, 2, 3 or 4.

[0024] As a preferred embodiment of the present invention, the ring A1 is selected from a benzene ring,

[0025] Wherein, Z is selected from a bond or is absent, when Z is absent, the ring A1 is selected from

[0026] Ring B1 is selected from a benzene ring or pyridine;

[0027] Ring B2 is selected from a saturated or partially saturated 5-6 membered heterocyclic ring, wherein the 5-6 membered heterocyclic ring optionally contains 1-3 heteroatoms selected from O, N or S;

[0028] Ring B3 is selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclic ring, wherein the 3-6 membered heterocyclic ring optionally contains 1-3 heteroatoms selected from O, N or S;

[0029] The ring A1 may be optionally substituted with 1 to 4 R e Substitution, the R e Selected from halogen, cyano, oxo, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0030] Preferably, the R e Optionally selected from halogen, oxo, C1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy;

[0031] More preferably, the R e Optionally selected from fluorine, chlorine, oxo, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl.

[0032] As a preferred embodiment of the present invention, the ring A2 is selected from a benzene ring or

[0033] wherein Ring B4 is selected from a saturated or partially saturated 5-6 membered heterocyclic ring; the 5-6 membered heterocyclic ring optionally contains 1-3 heteroatoms selected from O, N or S;

[0034] The ring A2 may optionally be substituted with 1 to 4 R e Substitution, the R e Selected from halogen, cyano, oxo, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0035] Preferably, the R e Optionally selected from halogen, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy;

[0036] More preferably, the R e Optionally selected from fluorine, chlorine, oxo, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl.

[0037] As a preferred embodiment of the present invention, the ring A1 is selected from

[0038] The ring A1 may be optionally substituted with 1 to 4 R e Substitution, the R e Optionally selected from fluorine, chlorine, oxo, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl.

[0039] As a preferred embodiment of the present invention, the ring A2 is selected from

[0040] The ring A2 may optionally be substituted with 1 to 4 R e Substitution, the R e Optionally selected from fluorine, chlorine, oxo, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl.

[0041] As a preferred embodiment of the present invention, L is -Ak1-Cy1-Ak2-Cy2-Ak3-;

[0042] Ak1, Ak2 and Ak3 are each independently selected from a bond, -(CH2) n1 -, -C(O)-, -O-, -NH-, -C(O)NH-, -(CR6R7) n2 -, -NR8-, -CH2NR9- or alkynylene;

[0043] R6, R7, R8 or R9 are each independently selected from H, halogen, cyano, hydroxyl, amino, nitro, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0044] Preferably, R6, R7, R8 or R9 are each independently selected from H, halogen, cyano, hydroxyl, amino, nitro, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy;

[0045] Cy1 and Cy2 are each independently selected from a bond, C 5-6 Cycloalkylene, 5-6 membered monocyclic heterocyclylene, 5-8 membered polycyclic heterocyclylene;

[0046] Preferably, Cy1 and Cy2 are each independently selected from a bond, a cyclopentylene, a cyclohexylene, a pyrrolidinylene, a piperidinylene, a piperazinylene or

[0047] The Cy1 or Cy2 may optionally be substituted with 1 to 4 R f replace;

[0048] The R f Selected from halogen, cyano, oxo, hydroxy, amino, nitro, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0049] Preferably, the R f Optionally selected from halogen, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy;

[0050] More preferably, the R f Optionally selected from fluorine, chlorine, oxo, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl.

[0051] As a preferred embodiment of the present invention:

[0052] As a preferred embodiment of the present invention, the R1, R2, R3, R4 or R5 are each independently selected from H, halogen, cyano, hydroxyl, amino, nitro, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy;

[0053] Preferably, R1, R2, R3, R4 or R5 are each independently selected from H;

[0054] and / or, said R6, R7, R8 or R9 are each independently selected from H, halogen, cyano, hydroxyl, amino, nitro, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy;

[0055] Preferably, R6, R7, R8 or R9 are each independently selected from H, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl;

[0056] and / or, X is selected from a bond, -NH- or -C(O)NH-;

[0057] and / or, R a , R b , Rc , R d , R e or R f are independently selected from halogen, cyano, oxo, hydroxyl, amino, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, hydroxyl C 1-3 Alkyl, amino C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0058] or R b and R c The cyclopropyl, cyclobutyl, cyclopentyl or 3-6 membered heterocyclic group is connected to form a cyclopropyl, cyclobutyl, cyclopentyl or 3-6 membered heterocyclic group, wherein the 3-6 membered heterocyclic group optionally contains 1-2 heteroatoms selected from O, N, and S; the cyclopropyl, cyclobutyl, cyclopentyl or 3-6 membered heterocyclic group may be optionally selected from halogen, amino, hydroxyl, cyano, nitro, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 substituted with a haloalkoxy group;

[0059] Preferably, the R a , R b , R c , R d , R e or R f Each is independently selected from fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl;

[0060] or R b and R c Connect to form cyclopropyl, cyclobutyl, and cyclopentyl.

[0061] The compounds of the present invention, their stereoisomers or pharmaceutically acceptable salts thereof are further selected from the following:

[0062]

[0063]

[0064]

[0065]

[0066] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0067] The third aspect of the present invention provides a use of the compound of the present invention, its stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutical composition containing the compound of the present invention, its stereoisomers or pharmaceutically acceptable salts thereof in the preparation of a drug for preventing or treating androgen-mediated diseases.

[0068] The disease is cancer, hair loss, acne or Kennedy's disease;

[0069] The cancer is an androgen receptor positive cancer.

[0070] The cancer is selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer or salivary gland cancer. DETAILED DESCRIPTION

[0071] Explanation of terms

[0072] Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, they should be given the meanings that those skilled in the art would give them based on the disclosure and context.

[0073] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 6 carbon atoms, and more preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, etc., and various branched isomers thereof, etc. Methyl, ethyl, n-propyl, and isopropyl are preferred in the present invention. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0074] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy and butoxy, etc. Alkoxy can be substituted or unsubstituted, and when substituted, it can be substituted at any usable point of attachment, and the substituent is preferably selected from one or more of deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0075] The term "cycloalkyl" refers to a saturated or partially saturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 ring atoms (i.e., 3 to 20-membered cycloalkyl). The cycloalkyl preferably has a cycloalkyl having 3 to 12 ring atoms (i.e., 3 to 12-membered cycloalkyl), more preferably a cycloalkyl having 3 to 8 ring atoms (i.e., 3 to 8-membered cycloalkyl), and most preferably a cycloalkyl having 3 to 6 ring atoms (i.e., 3 to 6-membered cycloalkyl). The monocyclic cycloalkyl, non-limiting examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, etc. The polycyclic cycloalkyl includes: spirocycloalkyl, condensed cycloalkyl, and bridged cycloalkyl.

[0076] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl group.

[0077] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0078] The term "cycloalkylene" refers to a cycloalkyl group in which one hydrogen atom is further substituted. Non-limiting examples include: cyclopentylene, cyclohexylene, The cycloalkylene group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from one or more of halogen, hydroxy, cyano, amino, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0079] The term "heterocyclyl" refers to a saturated or partially saturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl), which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from O, N and S in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but does not include -OO-, -OS- or -SS-), and has 3 to 20 ring atoms (i.e., a 3 to 20-membered heterocyclyl). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclic group); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclic group) or a heterocyclic group having 4 to 6 ring atoms (i.e., a 4- to 6-membered heterocyclic group); most preferably a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclic group). The monocyclic heterocyclic group includes, but is not limited to, oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxane, azepanyl, pyrrolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydropyrrolidinyl, dihydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydrooxazolyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyridinyl, dihydroisoxazol ... oxazolyl, piperidinyl, piperazinyl, tetrahydropyridazinyl, pyrrolidinyl, oxazolidinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably tetrahydropyranyl, 1,4-dioxane, piperidinyl, dihydrofuranyl, dihydrooxazolyl, dihydrothiophenyl, dihydropyranyl, tetrahydrofuranyl, morpholinyl, dihydropyridinyl, pyrrolidinyl, oxazolidinyl, dihydropyrazolyl, tetrahydropyridazinyl and dihydroisoxazolyl, etc.

[0080] The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

[0081] The heterocyclyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0082] The term "heterocyclylene" means that one hydrogen atom of a heterocyclyl is further substituted, including monocyclic heterocyclylene and polycyclic heterocyclylene, wherein the polycyclic heterocyclylene includes spiro heterocyclylene, fused heterocyclylene and bridged heterocyclylene. Non-limiting examples thereof include piperidylene, piperazinylene, pyrrolidinylene, azetidinylene, diazetidinylene, wait.

[0083] The heterocyclylene group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from one or more of halogen, hydroxy, cyano, amino, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0084] The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring that shares adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6 to 10 members, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring. The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from one or more of halogen, hydroxyl, cyano, amino, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0085] The term "arylene" refers to an aryl group in which one hydrogen atom is further substituted, and non-limiting examples thereof include: The arylene group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from one or more of halogen, hydroxy, cyano, amino, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0086] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from O, N and S. The heteroaryl group is preferably a 5-8 membered monoheteroaryl group or an 8-14 membered biheteroaryl group, more preferably a 5-membered monoheteroaryl group, a 6-membered monoheteroaryl group or a 9-membered biheteroaryl group, for example, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyridopyrimidinyl, pyridoimidazolyl, pyrimidoimidazolyl and the like.

[0087] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from one or more of halogen, hydroxy, cyano, amino, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0088] The term "heteroarylene" refers to a heteroaryl group in which one hydrogen atom is further substituted, and non-limiting examples thereof include pyridylene, pyrimidylene, pyrazolylene, pyridazinylene, pyrazinylene and the like.

[0089] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein alkoxy and alkyl are as defined above.

[0090] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0091] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0092] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0093] The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups, wherein alkyl is as defined above.

[0094] The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0095] The term "hydroxy" refers to -OH.

[0096] The term "amino" refers to -NH2.

[0097] The term "cyano" refers to -CN.

[0098] The term "nitro" refers to -NO2.

[0099] The term "oxo" refers to "=0".

[0100] "Optional" or "optionally" means that the event or circumstances described below can but need not occur, and includes both the occurrence and non-occurrence of the event or circumstances. For example, "C optionally substituted with halogen 1-6 The term "alkyl group" includes the case where the alkyl group is substituted by halogen and the case where the alkyl group is not substituted by halogen.

[0101] "Substitution" or "substituted" refers to one or more hydrogen atoms in the group, preferably 1 to 6, more preferably 1 to 4 hydrogen atoms are independently replaced by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without paying too much effort.

[0102] "Pharmaceutical composition" refers to a mixture containing one or more compounds of the present invention, their stereoisomers or pharmaceutically acceptable salts thereof and other pharmaceutically acceptable carriers. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredients and thus exert biological activity.

[0103] When there is a chiral carbon in the structure of the compound of the present invention, the configuration of the chiral atom includes both R configuration and S configuration.

[0104] "Pharmaceutically acceptable salts" refer to salts of the compounds disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and have the desired biological activity. They may be prepared separately during the final separation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0105] The term "pharmaceutically acceptable" as used herein 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 patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0106] The present invention is further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0107] The starting materials and reagents used in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

[0108] The compounds of the present invention can be prepared by referring to the following synthetic routes 1 or 2:

[0109] Synthetic route 1:

[0110]

[0111] Intermediate A and intermediate BL or its salt, such as the hydrochloride of BL, can be reacted in the presence of TEA, NaBH(OAc)3 or NaBH3CN to prepare the compound of formula I. MgSO4 can also be added to the reaction system. The reaction solvent is selected from one or a mixed solvent of DCM, MeOH or DMF.

[0112] Synthetic route 2:

[0113]

[0114] Intermediates AL and BL can be reacted in the presence of K2CO3 to prepare the compound of formula I, and the reaction solvent is DMF.

[0115] The intermediate A in the synthetic route 1 can be prepared by referring to the following A1 to A4 or similar methods known in the prior art;

[0116]

[0117] Preparation of intermediate A1

[0118] Synthesis route:

[0119]

[0120] Step 1: 6-Nitrochroman-2-carboxylic acid

[0121]

[0122] Chromanic acid (4.00 g, 22.4 mmol, 1.0 eq.) was added to HNO3 solution (65 mL, 70%) at 0°C. The reaction was stirred at 0°C for 1 hour. TLC (pure EA) showed that the reaction was complete. Ice water (160 mL) was added. The aqueous layer was extracted with EA (2×200 mL). The combined organic layers were concentrated. The crude product was washed with EA / PE (1:2 20 mL) to give 6-nitrochroman-2-carboxylic acid (2.61 g, 52% yield) as a yellow solid.

[0123] Step 2: (6-Nitrochroman-2-yl)methanol

[0124]

[0125] Under N2, at 5 ° C, BH3.THF (30mL, 1mol / L, 30.0mmol, 3.0eq.) was added dropwise to a solution of 6-nitrochroman-2-carboxylic acid (2.33g, 10.0mmol, 1.0eq.) in THF (23mL). After addition, the reactant was stirred at 65 ° C for 2 hours. TLC (pure EA) showed that the reaction was complete. The reactant was cooled to 5 ° C and quenched with water (100mL). The aqueous phase was extracted with EA (100mL). The organic layer was concentrated to give (6-nitrochroman-2-yl) methanol (2.10g, 100% yield) as a yellow solid. The residue was used in the next step without purification.

[0126] Step 3: (6-aminochroman-2-yl)methanol

[0127]

[0128] Pd / C (0.20 g, 0.1 w) was added to a solution of (6-nitrochroman-2-yl)methanol (2.00 g, 9.56 mmol, 1.0 eq.) in MeOH (30 mL). The reaction was stirred under H2 (1 atm) for 16 h. TLC (neat EA) showed that the reaction was complete. The mixture was filtered. The filtrate was concentrated to give (6-aminochroman-2-yl)methanol (1.61 g, 94% yield) as a brown oil.

[0129] Step 4: 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile

[0130]

[0131] TMSOTf (100 mg, 0.45 mmol, 0.05 eq.) and TMSCN (1.25 g, 12.6 mmol, 1.4 eq.) were added to a solution of (6-aminochroman-2-yl)methanol (1.61 g, 8.98 mmol, 1.0 eq.) in DCM (32 mL) and acetone (8 mL). The reaction was stirred at 25 °C for 16 hours. The reaction was concentrated to give 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (2.87 g crude product) as a brown oil. The crude product was used in the next step without purification.

[0132] Step 5: 5-(3-(2-(Hydroxymethyl)chroman-6-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile

[0133]

[0134] 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (2.80 g crude product, 8.98 mmol, 1.0 eq.) and TEA (1.36 g, 13.5 mmol, 1.5 eq.) were added to a solution of 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (2.87 g crude product, 8.98 mmol, 1.0 eq.) in DMF (10 mL). The reaction was stirred at 25 ° C for 1 hour. LCMS showed that the reaction was complete, and MeOH (25 mL) and 3N HCl (25 mL) were added. After stirring the reaction at 25 ° C for 2 hours, EA (200 mL) and water (250 mL) were added. The organic layer was concentrated. The residue was purified by chromatography on silica gel eluting with (PE / EA 2:1 to 1:1) to give 5-(3-(2-(hydroxymethyl)chroman-6-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (2.02 g, 47% yield) as a yellow solid.

[0135] Step 6: 5-(3-(2-Formylchroman-6-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile

[0136]

[0137] IBX (453 mg, 1.62 mmol, 1.1 eq.) was added to a solution of 5-(3-(2-(hydroxymethyl)chroman-6-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (700 mg, 1.47 mmol, 1.0 eq.) in DMSO (15 mL) at room temperature. The reaction was stirred at 85 °C for 2 hours. LCMS showed that the reaction was complete, cooled to room temperature, and water (150 mL) was added. The mixture was filtered to give 5-(3-(2-formylchroman-6-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (640 mg crude product) as a yellow solid.

[0138] Preparation of intermediate A2

[0139] Synthesis route:

[0140]

[0141] Step 1: (1-(4-nitrophenyl)piperidin-4-yl)methanol

[0142]

[0143] K2CO3 (9.8 g, 70.8 mmol, 2.0 eq.) was added to a solution of 1-fluoro-4-nitrobenzene (5.0 g, 35.4 mmol, 1.0 eq.) and piperidin-4-ylmethanol (4.9 g, 42.5 mmol, 1.2 eq.) in DMF (70 mL). The reaction mixture was stirred at 80 ° C for 2 hours. After completion, the reactant was cooled to room temperature, the mixture was poured into ice water (300 mL) and stirred for 20 minutes. The solid was filtered and washed with water (25 mL * 2), dried to give (1- (4-nitrophenyl) piperidin-4-yl) methanol (7.1 g, 85%) as a white solid. MS: m / z = 237 [M + H] +

[0144] Step 2: Referring to the preparation method of intermediate A1, replace A1-3 with A2-2 to prepare A2-3;

[0145] Step 3: 2-((4-(4-(Hydroxymethyl)piperidin-1-yl)phenyl)amino)-2-methylpropionitrile

[0146]

[0147] To a solution of (1-(4-aminophenyl)piperidin-4-yl)methanol (3.0 g, 14.5 mmol, 1.0 eq) in acetone (21 mL) was added TMSCN (4.3 g, 43.5 mmol, 3.0 eq) at room temperature. After stirring for 16 h, the mixture was concentrated under vacuum to give the crude product 2-((4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)amino)-2-methylpropionitrile (5.1 g, crude), which was used in the next step without purification. MS: m / z=274 [M+H] +

[0148] Then, referring to the preparation method of intermediate A1, intermediate A2 was prepared by replacing A1-5 with A2-4.

[0149] Preparation of intermediate A3

[0150] Synthesis route:

[0151]

[0152] Step 1: Ethyl 2-oxo-3-(triphenylphosphinylidene)propionate

[0153]

[0154] At room temperature, 3-bromo-2-oxopropionic acid ethyl ester (20.9g, 107mmol, 1.0eq.) was added to a solution of CCl4 (150mL) with PPh3 (28.1g, 107mmol, 1.0eq.). The reaction was stirred for 1 hour and the mixture was filtered. The filter cake was washed with MTBE (200mL) and then dissolved in MeOH (60mL). The solution was adjusted to pH=10 with Na2CO3 aqueous solution and diluted with water (200mL). The resulting mixture was stirred for 1 hour and filtered at 25°C. Dry the solid to obtain 2-oxo-3-(triphenylphosphinyl)propionic acid ethyl ester (7.9g, 20% yield) as a white solid.

[0155] Step 2: (E)-4-(5-bromo-2-chloropyridin-3-yl)-2-oxobut-3-enoic acid ethyl ester

[0156]

[0157] At room temperature, 5-bromo-2-chloronicotinaldehyde (3.71 g, 16.8 mmol, 1.0 eq.) was added to a solution of 2-oxo-3-(triphenylphosphinyl)propionate (6.33 g, 16.8 mmol, 1.0 eq.) in toluene (60 mL). After stirring the reactants at 85 ° C for 40 hours, they were cooled to room temperature. The reactants were concentrated. The residue was purified with a column (PE / EA 10:1 to 5:1) to give (E)-4-(5-bromo-2-chloropyridin-3-yl)-2-oxobut-3-enoic acid ethyl ester (2.60 g, 48% yield) as a yellow oil.

[0158] Step 3: (E)-4-(5-bromo-2-chloropyridin-3-yl)but-3-ene-1,2-diol

[0159]

[0160] At 5 ° C, NaBH4 (620 mg, 16.3 mmol, 2.0 eq.) was added to a solution of (E)-4-(5-bromo-2-chloropyridin-3-yl)-2-oxobut-3-enoic acid ethyl ester (2.60 g, 8.16 mmol, 1.0 eq.) in MeOH (26 mL). The reactant was stirred at 15 ° C for 2 hours. TLC showed that the reaction was complete. EA (200 mL) and water (200 mL) were added. The aqueous layer was extracted with EA (200 mL). The combined organic layers were concentrated to give (E)-4-(5-bromo-2-chloropyridin-3-yl)but-3-ene-1,2-diol (2.40 g crude product) as a yellow oil.

[0161] Step 4: 4-(5-bromo-2-chloropyridin-3-yl)butane-1,2-diol

[0162]

[0163] PtO2 (240 mg, 0.1 w) was added to a solution of (E)-4-(5-bromo-2-chloropyridin-3-yl)but-3-ene-1,2-diol (2.40 g crude product, 8.16 mmol, 1.0 eq.) in THF (24 mL) at room temperature. The reaction was stirred at 15 °C under H2 (1 atm) for 16 hours. The reaction was filtered. The filtrate was concentrated to give 4-(5-bromo-2-chloropyridin-3-yl)butane-1,2-diol (2.30 g crude product) as a yellow oil.

[0164] Step 5: (6-Bromo-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methanol

[0165]

[0166] At room temperature, Cs2CO3 (5.34 g, 16.4 mmol, 2.0 eq.) was added to a solution of 4-(5-bromo-2-chloropyridin-3-yl)butane-1,2-diol (2.30 g crude product, 8.16 mmol, 1.0 eq.) in ACN (115 mL). The reactant was stirred at 90 ° C for 18 hours. LCMS showed that the reaction was complete and cooled to room temperature. The mixture was filtered. The filtrate was concentrated. The residue was purified with a column (pure EA) to obtain (6-bromo-3,4-dihydro-2H-pyrans [2,3-b] pyridine-2-yl) methanol (600 mg, 30% overall yield, over 3 steps) as a white solid.

[0167] Step 6: (6-amino-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methanol

[0168]

[0169] A mixture of (6-bromo-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methanol (660 mg, 2.70 mmol, 1.0 eq.), CuI (103 mg, 0.54 mmol, 0.2 eq.), L-proline (125 mg, 1.08 mmol, 0.4 eq.), K2CO3 (560 mg, 4.06 mmol, 1.5 eq.) and NH4OH (508 mg, 28%, 4.06 mmol, 1.5 eq.) in DMSO (5 mL) was stirred at 90 ° C for 12 hours. LCMS showed that the reaction was complete and cooled to room temperature. MeCN (50 mL) was added. The mixture was filtered. The filtrate was concentrated. The residue was purified by reverse phase chromatography eluting with water (0.05% TFA) and MeCN to give (6-amino-3,4-dihydro-2H-pyrano[2,3-b]pyridin-2-yl)methanol (505 mg, quantitative) as a brown oil.

[0170] Then, referring to the preparation method of intermediate A2, intermediate A3 was prepared by replacing A2-3 with A3-7.

[0171] Preparation of intermediate A4

[0172] Synthesis route:

[0173]

[0174] Step 1: (6-Nitro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanol

[0175]

[0176] At 0 ° C, over 15 minutes, a solution of 4-nitrobenzene-1,2-diol (1.00 g, 64.5 mmol, 1.0 eq.) in DMF (8 mL) was added dropwise to a solution of NaHCO (0.60 g, 7.09 mmol, 1.1 eq.) in DMF (10 mL). The reactant was stirred at 0 ° C for 15 minutes, and a solution of 2-(chloromethyl)oxirane (0.72 g, 7.74 mmol, 1.2 eq.) in DMF (2 mL) was added within 15 minutes. Water (200 mL) and EA (200 mL) were added. The organic layer was washed with NaCO aqueous solution (100 mL) and brine (100 mL) and concentrated to give (6-nitro-2,3-dihydrobenzo [b] [1,4] dioxin-2-yl) methanol (700 mg, 51% yield) as a brown oil.

[0177] Step 2: Referring to the preparation method of intermediate A1, replace A1-3 with A4-2 to obtain A4-3;

[0178] Step 3: 2-((2-(Hydroxymethyl)-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)amino)-2-methylpropionitrile

[0179]

[0180] To a solution of (6-amino-2,3-dihydrobenzo[b][1,4]dioxan-2-yl)methanol (515 mg, 2.84 mmol, 1.0 equiv) in DCM and acetone at room temperature was added trimethylsilyl trifluoromethanesulfonate (32 mg, 0.14 mmol, 0.05 equiv) and TMSCN (395 mg, 3.98 mmol, 1.4 equiv). After the reaction was stirred for 16 hours, the reaction was washed with water and concentrated to give 2-((2-(hydroxymethyl)-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)amino)-2-methylpropionitrile (652 mg crude) as a brown oil. The crude product was used in the next step without purification.

[0181] Then, referring to the preparation method of intermediate A1, intermediate A4 was prepared by replacing A1-5 with A4-4.

[0182] Among them, intermediate AL can be prepared by referring to the following A1-L, A5-L or similar methods known in the prior art;

[0183]

[0184] Preparation of intermediate A1-L

[0185] Synthesis route:

[0186]

[0187] Step 1: tert-Butyl 4-(6-nitrochroman-2-carbonyl)piperazine-1-carboxylate

[0188]

[0189] At room temperature, HATU (1.31 g, 3.45 mmol, 1.1 eq.), tert-butyl piperazine-1-carboxylate (584 mg, 3.14 mmol, 1.0 eq.) and DIEA (1.22 g, 9.41 mmol, 3.0 eq.) were added to a solution of 6-nitrochroman-2-carboxylic acid (700 mg, 3.14 mmol, 1.0 eq.) in DMF (3.5 mL). After stirring the reactants for 16 hours, EA (50 mL) and water (50 mL) were added. The organic layer was concentrated. The residue was purified with a column (PE / EA 1:1) to give tert-butyl 4-(6-nitrochroman-2-carbonyl)piperazine-1-carboxylate (1.08 g, 88% yield) as a white solid.

[0190] Step 2: tert-Butyl 4-(6-aminochroman-2-carbonyl)piperazine-1-carboxylate

[0191]

[0192] Pd / C (100 mg) was added to a solution of tert-butyl 4-(6-nitrochroman-2-carbonyl)piperazine-1-carboxylate (1.08 g, 2.76 mmol, 1.0 eq.) in EA (20 mL) at room temperature. The reaction was stirred under H2 for 16 hours. The mixture was filtered. The filtrate was concentrated to give tert-butyl 4-(6-aminochroman-2-carbonyl)piperazine-1-carboxylate (1.00 g, 100% yield) as a colorless oil.

[0193] Step 3: tert-Butyl 4-(6-((2-cyanopropan-2-yl)amino)chroman-2-carbonyl)piperazine-1-carboxylate

[0194]

[0195] At room temperature, trimethylsilyl trifluoromethanesulfonate (31 mg, 0.14 mmol, 0.05 eq.) and TMSCN (385 mg, 3.87 mmol, 1.4 eq.) were added to a solution of tert-butyl 4-(6-aminochroman-2-carbonyl)piperazine-1-carboxylate (1.00 g, 2.76 mmol, 1.0 eq.) in DCM (20 mL) and acetone (5 mL). After stirring the reaction for 16 hours, the reaction was concentrated to give tert-butyl 4-(6-((2-cyanopropyl-2-yl)amino)chroman-2-carbonyl)piperazine-1-carboxylate (1.27 g crude product) as a brown oil. The crude product was used in the next step without purification.

[0196] Step 4: tert-Butyl 4-(6-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)chroman-2-carbonyl)piperazine-1-carboxylate

[0197]

[0198] 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (0.73 g, 2.76 mmol, 1.0 eq.) and TEA (419 mg, 4.14 mmol, 1.5 eq.) were added to a solution of tert-butyl 4-(6-((2-cyanopropyl-2-yl)amino)chroman-2-carbonyl)piperazine-1-carboxylate (1.27 g, 2.76 mmol, 1.0 eq.) in DMF (10 mL) at room temperature. After stirring the reaction for 3 hours, MeOH (15 mL) and 30% H2SO4 (15 mL) were added. The reaction was stirred at room temperature for another 2 hours, and EA (200 mL) and water (200 mL) were added. The organic layer was concentrated. The residue was purified with column (PE / EA 1:1) to give tert-butyl 4-(6-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)chroman-2-carbonyl)piperazine-1-carboxylate (745 mg, 41% yield) as a yellow solid.

[0199] Step 5: 5-(4,4-dimethyl-5-oxo-3-(2-(piperazine-1-carbonyl)chroman-6-yl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile

[0200]

[0201] At 15 ° C, HCl / EA (4N, 2.5 mL) was added to a solution of tert-butyl 4-(6-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)chroman-2-carbonyl)piperazine-1-carboxylate (150 mg, 0.228 mmol, 1.0 eq.) in EA (5 mL). After stirring the reaction at 15 ° C for 16 hours, the mixture was filtered. The solid was dried to give 5-(4,4-dimethyl-5-oxo-3-(2-(piperazine-1-carbonyl)chroman-6-yl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (53 mg, 41% yield) as a yellow solid.

[0202] Preparation of intermediate A5-L

[0203] Synthesis route:

[0204]

[0205] Referring to the preparation method of intermediate A1-L, intermediate A5-L is prepared by replacing A1-L-2 with A5-L-1. Among them, BL can be prepared by referring to the following B1-L to B10-L or similar methods known in the prior art;

[0206]

[0207] Preparation of intermediate B1-L

[0208] Synthesis route:

[0209]

[0210] Step 1: tert-Butyl 4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-2-oxoethyl)piperazine-1-carboxylate

[0211]

[0212] At room temperature, HATU (306 mg, 0.81 mmol, 1.1 eq.) and DIEA (283 mg, 2.2 mmol, 3 eq.) were added to a solution of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)acetic acid (196 mg, 0.81 mmol, 1.1 eq.) in DMF (1 mL), and after stirring for 0.5 hours, 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (200 mg, 0.73 mmol, 1 eq.) was added, and stirring was continued for 6 hours. The mixture was diluted with H2O (50 mL) and extracted with EA (50 mL*2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give tert-butyl 4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-2-oxoethyl)piperazine-1-carboxylate (91 mg, 24.1% yield) as a white solid.

[0213] MS: m / z = 500 [M + H] +

[0214] Step 2: N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-(piperazin-1-yl)acetamide

[0215]

[0216] To a solution of tert-butyl 4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-2-oxoethyl)piperazine-1-carboxylate (91 mg) in DCM (2 mL) was added dropwise 4M HCl in dioxane (3 mL) at room temperature. After stirring for 6 hours, it was filtered and the filter cake was washed with 6 mL of DCM and dried in vacuo to give N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-(piperazin-1-yl)acetamide (65 mg, 90.1% yield) as a white solid.

[0217] MS: m / z = 400 [M + H] +

[0218] Preparation of intermediate B2-L:

[0219] Synthesis route:

[0220]

[0221] Step 1: 2-Bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide

[0222]

[0223] At room temperature, 2-bromoacetyl chloride (691 mg, 4.39 mmol, 1.2 eq.) was added to a solution of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1 g, 3.66 mmol, 1.0 eq.) in THF (10 mL). After stirring at 70° C. for 16 hours, the mixture was cooled to room temperature and concentrated to give 2-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)acetamide (1.2 g, crude product) as a yellow solid. MS: m / z=394 [M+H] +

[0224] Step 2: tert-Butyl 4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxoethyl)piperazine-1-carboxylate

[0225]

[0226] At room temperature, tert-butyl piperazine-1-carboxylate (566 mg, 3.04 mmol, 1.0 eq.) was added to a solution of 2-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (1.2 g, 3.04 mmol, 1.0 eq.) and K2CO3 (1.26 g, 9.13 mmol, 3.0 eq.) in DMF (12 mL). After stirring for 3 hours, EA (50 mL) and H2O (50 mL) were added. The organic layer was concentrated. The residue was purified by reverse phase chromatography eluting with water (0.05% TFA) and MeCN to give tert-butyl 4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxoethyl)piperazine-1-carboxylate (900 mg, 59% yield) as a yellow solid. MS: m / z=500[M+H] +

[0227] Then, referring to the preparation method of intermediate B2-L, intermediate B2-L is prepared by replacing B1-L-1 with B2-L-2. Preparation of intermediate B4-L:

[0228] Synthesis route:

[0229]

[0230] Step 1: 5-Chlorobenzene-1,3-diamine

[0231]

[0232] PtO2 (100 mg, 0.05 wt.) was added to a solution of 3-chloro-5-nitroaniline (2.0 g, 11.62 mmol, 1.0 eq.) in MeOH (20 mL) at room temperature. After the resulting mixture was stirred under H2 atmosphere for 4 hours, the mixture was filtered and washed with MeOH (5 mL). The filtrate was concentrated and the residue was purified by flash chromatography on silica gel eluted with hexane / ethyl acetate (8:1) to give 5-chlorobenzene-1,3-diamine (420 mg, 25.4% yield) as a white solid. MS: m / z=143 [M+H] +

[0233] Step 2: tert-Butyl (3-amino-5-chlorophenyl)carbamate

[0234]

[0235] At room temperature, Boc2O (644.7 mg, 2.95 mmol, 1.0 eq.) was added to a solution of tert-butyl (3-amino-5-chlorophenyl)carbamate (420 mg, 2.95 mmol, 1.0 eq.) in THF (10 mL). After stirring for 2 hours, the resulting mixture was concentrated. The residue was purified by flash chromatography on silica gel eluted with hexane / ethyl acetate (4:1) to give tert-butyl (3-amino-5-chlorophenyl)carbamate (410 mg, 57.5% yield) as a white solid. MS: m / z=243 [M+H] +

[0236] Step 3: tert-Butyl (3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)carbamate

[0237]

[0238] At room temperature, 3-bromopiperidine-2,6-dione (482 mg, 2.54 mmol, 1.5 eq.) and NaHCO3 (284.6 mg, 3.38 mmol, 2.0 eq.) were added to a solution of tert-butyl (3-amino-5-chlorophenyl)carbamate (410 mg, 1.69 mmol, 1.0 eq.) in DMF (2 mL). After stirring at 80 ° C for 12 hours, it was cooled to room temperature. The reaction mixture was purified by reverse phase chromatography (TFA buffer) to give tert-butyl (3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)carbamate (70 mg, 11.7% yield) as a white solid. MS: m / z=354[M+H] +

[0239] Step 4: 3-((3-amino-5-chlorophenyl)amino)piperidine-2,6-dione

[0240]

[0241] At room temperature, EA (3 mL) containing 4M HCl was added to a solution of tert-butyl (3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)carbamate (70.0 mg, 0.19 mmol, 1.0 eq.) in DCM (3 mL). After stirring for 2 hours, the mixture was concentrated to give a quantitative yield of 3-((3-amino-5-chlorophenyl)amino)piperidine-2,6-dione (50.6 mg, crude product) as a white solid. MS: m / z=278 [M+H] +

[0242] Then, referring to the preparation method of intermediate B1-L, B4-L was prepared by replacing B1 with B4.

[0243] Synthesis of intermediate B6-L

[0244] Synthesis route:

[0245]

[0246] Step 1: tert-Butyl 4-(2-((4-fluoro-3-(methoxycarbonyl)phenyl)amino)-2-oxoethyl)piperazine-1-carboxylate

[0247]

[0248] 1-Methylimidazole (1.6 g, 19.6 mmol, 3.5 eq.) and 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)acetic acid (1.3 g, 5.6 mmol, 1.0 eq.) were added to a solution of TCFH (1.8 g, 6.7 mmol, 1.2 eq.) in DMF (5 mL) at room temperature. After stirring for 20 minutes, methyl 5-amino-2-fluorobenzoate (0.95 g, 5.6 mmol, 1.0 eq.) was added. After the reaction was complete, the mixture was partitioned between H2O (50 mL) and EA (50 mL) and the aqueous layer was extracted with EA (3×50 mL). The organic layer was dried and evaporated. The residue was purified by chromatography on silica gel eluting with EA / ACN (1:1) to give tert-butyl 4-(2-((4-fluoro-3-(methoxycarbonyl)phenyl)amino)-2-oxoethyl)piperazine-1-carboxylate (1.9 g, 86.3% yield) as a yellow solid. MS: m / z=396 [M+H] +

[0249] Step 2: 5-(2-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)acetamido)-2-fluorobenzoic acid

[0250]

[0251] At room temperature, LiOH.H2O (212 mg, 5.06 mmol, 2 eq.) was added to a solution of tert-butyl 4-(2-((4-fluoro-3-(methoxycarbonyl)phenyl)amino)-2-oxoethyl)piperazine-1-carboxylate (1.00 g, 2.53 mmol, 1 eq.) in THF / H2O=1:1 (10 mL). After stirring for 6 hours, the reaction mixture was poured into 50 mL of ice water and the aqueous phase was washed with EtOAc (10 mL×3) and acidified to pH=6 with 2N HCl. The resulting precipitate was collected by filtration to give the product, which was then dissolved in EtOAc (50 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give 5-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)acetamido)-2-fluorobenzoic acid (902 mg, 93.3% yield) as a white solid. MS: m / z = 382 [M + H] +

[0252] Step 3: tert-Butyl 4-(2-((3-((2,6-dioxopiperidin-3-yl)carbamoyl)-4-fluorophenyl)amino)-2-oxoethyl)piperazine-1-carboxylate

[0253]

[0254] TCFH (1.32 g, 4.72 mmol, 2 eq.) and NMI (968 mg, 11.8 mmol, 5 eq.) were added to a solution of 3-aminopiperidine-2,6-dione (453 mg, 3.54 mmol, 1.5 eq.) in ACN (10 mL) at room temperature. After stirring for 0.5 h, 4-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)acetamido)-2-fluorobenzoic acid (900 mg, 2.36 mmol, 1 eq.) was added and stirring was continued at room temperature for 6 h. The reaction mixture was washed with saturated NaHCO3 (10 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give tert-butyl 4-(2-((3-((2,6-dioxopiperidin-3-yl)carbamoyl)-4-fluorophenyl)amino)-2-oxoethyl)piperazine-1-carboxylate (507 mg, 43.1% yield) as a white solid. MS: m / z = 492 [M+H] +

[0255] Step 4: N-(2,6-dioxopiperidin-3-yl)-2-fluoro-5-(2-(piperazin-1-yl)acetamido)benzamide

[0256]

[0257] To a solution of tert-butyl 4-(2-((3-((2,6-dioxopiperidin-3-yl)carbamoyl)-4-fluorophenyl)amino)-2-oxoethyl)piperazine-1-carboxylate (270 mg, 549 μmol, 1 eq.) in DCM (2 mL) was added dropwise 4M HCl in dioxane (3 mL) at room temperature and stirring was continued for 6 hours. The reaction mixture was filtered and the filter cake was washed with 6 mL of DCM and dried in vacuo to give N-(2,6-dioxopiperidin-3-yl)-2-fluoro-5-(2-(piperazin-1-yl)acetamido)benzamide (210 mg, 93.1% yield) as a white solid. MS: m / z=392 [M+H] +

[0258] Preparation of intermediate B7-L:

[0259] Synthesis route:

[0260]

[0261] Step 1: tert-Butyl 4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)piperazine-1-carboxylate

[0262]

[0263] At room temperature, Pd2(dba)3 (0.18 g, 0.19 mmol, 0.04 eq.) and RuPhos (0.18 g, 0.37 mmol, 0.08 eq.) were added to 6-bromobenzo[d]oxazol-2(3H)-one (1.0 g, 4.67 mmol, 1.0 eq.), tert-butyl piperazine-1-carboxylate (1.75 g, 9.34 mmol, 2.0 eq.), NaO tBu (0.9 g, 9.34 mmol, 2.0 eq.) in a solution of toluene (25 mL). Under N2 atmosphere, stir at 120 ° C for 3 hours and cool to room temperature. The mixture is quenched with saturated NH4Cl aqueous solution (30 mL), and then extracted with EA (30 mL * 3). The combined organic layer is washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is eluted with PE / EA (100 / 1 to 1 / 2) and purified by silica gel column chromatography to give tert-butyl 4- (2-oxo-2,3-dihydrobenzo [d] oxazol-6-yl) piperazine-1-carboxylate (0.99 g, 66% yield) as a yellow solid. MS: m / z = 320 [M + H] +

[0264] Step 2: tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)piperazine-1-carboxylate

[0265]

[0266] At room temperature, Cs2CO3 (1.83 g, 5.6 mmol, 2.0 eq.) was added to a solution of tert-butyl 4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)piperazine-1-carboxylate (0.9 g, 2.8 mmol, 1.0 eq.) and 3-bromopiperidine-2,6-dione (1.08 g, 5.6 mmol, 2.0 eq.) in DMF (13 mL). After stirring at 70 ° C for 8 hours, it was cooled to room temperature, and the mixture was diluted with saturated NH4Cl aqueous solution (60 mL) and extracted with DCM (60 mL * 2). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (100 / 1 to 1 / 2) to give tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)piperazine-1-carboxylate (0.53 g, 44% yield) as a purple solid. MS: m / z=431 [M+H] +

[0267] Step 3: 3-(2-Oxo-6-(piperazin-1-yl)benzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione

[0268]

[0269] At room temperature, HCl (15 mL, 4 M in dioxane) was added to a solution of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)piperazine-1-carboxylate (250 mg, 0.58 mmol, 1.0 eq.) in dioxane (5 mL). After stirring at 70°C for 16 hours, it was cooled to room temperature. The solution was concentrated to give 3-(2-oxo-6-(piperazin-1-yl)benzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione hydrochloride (220 mg, quantitative) as an amber solid. MS: m / z=331 [M+H] +

[0270] Preparation of intermediate B9-L

[0271] Synthesis route:

[0272]

[0273] Step 1: 7-Bromo-3-iodo-1H-indazole

[0274]

[0275] At 0 ° C, KOH (86 mg, 1.5 mmol, 1.5 eq.) was added to a solution of 7-bromo-1H-indazole (200 mg, 1.01 mmol, 1.0 eq.) and I2 (387 mg, 1.5 mmol, 1.5 eq.) in DMF (4 mL). After stirring at 15 ° C for 16 hours, the reaction mixture was poured into H2O (200 mL) and stirred for 10 minutes. The reaction mixture was filtered and the filter cake was washed 3 times with H2O (50 mL) and dried under vacuum to give 7-bromo-3-iodo-1H-indazole (200 mg, 61% yield) as a yellow solid. MS: m / z=322 [M+H] +

[0276] Step 2: 7-Bromo-3-iodo-1-methyl-1H-indazole

[0277]

[0278] At 0°C, CH3I (2.1 mL, 1.67 mmol, 1.8 eq.) was added to 7-bromo-3-iodo-1H-indazole (6 g, 0.93 mmol, 1.0 eq.), KO tA solution of Bu (4.2 g, 1.86 mmol, 2 eq.) in THF (100 mL) was stirred at 15 ° C for 2 hours, and the mixture was diluted with H2O (400 mL) and extracted with EA (100 mL*2). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (PE: EA = 20: 1) to give 7-bromo-3-iodo-1-methyl-1H-indazole (6 g, 71% yield) as a yellow solid. MS: m / z = 336 [M+H] +

[0279] Step 3: 3-(2,6-Bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole

[0280]

[0281] At room temperature, 7-bromo-3-iodo-1-methyl-1H-indazole (400 mg, 1.19 mmol, 1.0 eq.), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (593 mg, 1.42 mmol, 1.2 eq.), K3PO4 (2.2 g, 9.87 mmol, 8.3 eq.) and Pd(PPh3)4 (100 mg, 0.06 mmol, 0.05 eq.) in 1,4-dioxane (20 mL) and H2O (5 mL) were added. After stirring at 85° C. under N2 atmosphere for 16 hours, the mixture was cooled to room temperature. The mixture was diluted with H2O (100 mL) and extracted with EA (40 mL*3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (PE:EA=20:1) to give 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole (400 mg, 67% yield) as a white solid. MS: m / z=500 [M+H] +

[0282] Step 4: N-Benzyl-3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-7-amine

[0283]

[0284] At room temperature, Cs2CO3 (260 mg, 0.8 mmol, 2.0 eq.) and Pd2(dba)3 (40 mg, 0.04 mmol, 0.1 eq.) were added to a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole (200 mg, 0.4 mmol, 1.0 eq.), NH2Bn (85 μL, 0.8 eq, 2.0 eq.), BINAP (40 mg, 0.06 mmol, 0.15 eq.) in anhydrous 1,4-dioxane (8 mL). After stirring at 110° C. under N2 atmosphere for 16 hours, the mixture was cooled to room temperature, diluted with H2O (50 mL), and extracted with EA (20 mL*3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (PE:EA=20:1) to give N-benzyl-3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-7-amine (170 mg, 73% yield) as a yellow solid. MS: m / z=527 [M+H] +

[0285] Step 5: 3-(7-amino-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0286]

[0287] AcOH (20 mg, 0.28 mmol, 1 eq.) was added to a solution of N-benzyl-3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-7-amine (150 mg, 0.28 mmol, 1.0 eq.), wet Pd / C (40 mg, 53 w.t%) in EtOH (10 mL) and THF (10 mL) at room temperature. After the reaction mixture was stirred at 45° C. for 16 hours under 50 psi (0.3 MPa) H2 atmosphere, it was cooled to room temperature, the mixture was filtered and concentrated under vacuum, and the residue was purified by column chromatography (DCM:MeOH=20:1) to give 3-(7-amino-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (70 mg, 72% yield) as a yellow solid. MS: m / z=259 [M+H] +

[0288] Then, referring to the preparation method of intermediate B1-L, B9-L was prepared by replacing B1 with B9.

[0289] Preparation of intermediate B10-L:

[0290] Synthesis route:

[0291]

[0292] Step 1: 1-Methyl-7-nitro-1H-indazol-3-amine

[0293]

[0294] At room temperature, methylhydrazine (22.4 g, 155 mmol, 3.0 eq.) and DIEA (50.2 g, 388 mmol, 7.5 eq.) were added to a solution of 2-fluoro-3-nitrobenzonitrile (8.60 g, 51.8 mmol, 1.0 eq.) in DMF (86 mL). After stirring the reactant for 1 hour, EA (800 mL) and water (850 mL) were added. The organic layer was concentrated to 100 mL. The mixture was cooled to room temperature and filtered. The residue was dried to give 1-methyl-7-nitro-1H-indazole-3-amine (7.71 g, 77% yield) as a red solid.

[0295] Step 2: Methyl 3-((1-methyl-7-nitro-1H-indazol-3-yl)amino)propanoate

[0296]

[0297] A mixture of lactic acid (2.15 g, 85%, 20.3 mmol, 1.3 eq.) and DBU (3.09 g, 20.3 mmol, 1.3 eq.) was stirred at 25 ° C for 16 hours. 1-methyl-7-nitro-1H-indazole-3-amine (3.00 g, 15.6 mmol, 1.0 eq.) and methyl acrylate (9.40 g, 109 mmol, 7.0 eq.) were added. After stirring at 85 ° C for 40 hours, it was cooled to room temperature. EA (100 mL) and water (100 mL) were added. The organic layer was concentrated. The residue was purified by column (PE / EA 3:1) to obtain methyl 3-((1-methyl-7-nitro-1H-indazole-3-yl) amino) propanoate (2.08 g, 54% yield) as a red solid.

[0298] Step 3: Methyl 3-(1-(1-methyl-7-nitro-1H-indazol-3-yl)ureido)propanoate

[0299]

[0300] At room temperature, KCNO (1.73 g, 21.4 mmol, 3.0 eq.) was added to a solution of methyl 3-((1-methyl-7-nitro-1H-indazole-3-yl)amino)propanoate (1.98 g, 7.13 mmol, 1.0 eq.) in AcOH (20 mL). After stirring for 16 hours, water (100 mL) and EA (100 mL) were added. The organic layer was concentrated. The residue was purified with a column (PE / EA 1:1 to pure EA) to give methyl 3-(1-(1-methyl-7-nitro-1H-indazole-3-yl)ureido)propanoate (1.26 g, 61% yield) as a yellow solid.

[0301] Step 4: 1-(1-methyl-7-nitro-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0302]

[0303] Triton-B (492 mg, 40% in water, 1.18 mmol, 0.3 eq.) was added to a solution of methyl 3-(1-(1-methyl-7-nitro-1H-indazol-3-yl)ureido)propanoate (1.26 g, 3.92 mmol, 1.0 eq.) in MeCN (13 mL) at 15 °C. After stirring for 72 hours, water (100 mL) and EA (100 mL) were added. The organic layer was concentrated to give 1-(1-methyl-7-nitro-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.04 g, 92% yield) as a yellow solid.

[0304] Step 5: 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0305]

[0306] Fe (520 mg, 9.34 mmol, 1.0 eq.) and NH4Cl aqueous solution (10%, 10 mL) were added to a solution of 1-(1-methyl-7-nitro-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.00 g, 3.11 mmol, 1.0 eq.) in MeOH (10 mL) and THF (10 mL) at room temperature. After stirring at 70°C for 4 hours, the mixture was cooled to room temperature. The mixture was filtered. The filter cake was washed with THF (50 mL). The filtrate was concentrated. Water (100 mL) and EA (100 mL) were added. The aqueous layer was extracted with EA (5×100 mL). The combined organic layers were concentrated to give 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (820 mg, 92% yield) as a red solid.

[0307] Then, referring to the preparation method of intermediate B1-L, B10-L was prepared by replacing B1 with B10.

[0308] Among them, the intermediate BL can be prepared by referring to similar methods known in the prior art;

[0309]

[0310] Example 1 Preparation of Compound 1

[0311] Synthesis route:

[0312]

[0313] 5-(3-(2-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)chroman-6-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile

[0314]

[0315] TEA (107 mg, 1.05 mmol, 5.0 eq.) and MgSO4 (254 mg, 2.11 mmol, 10.0 eq.) were added to a solution of 5-(3-(2-formylchroman-6-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (100 mg, 0.21 mmol, 1.0 eq.) and 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride (80 mg, 0.21 mmol, 1.0 eq.) in DCM (2 mL) at room temperature. After stirring for 1 hour, NaBH(OAc)3 (112 mg, 0.53 mmol, 2.5 eq.) was added. Stirring was continued for 16 hours, and DCM (20 mL) and water (20 mL) were added. The organic layer was concentrated. The residue was purified by preparative HPLC (TFA buffer) and lyophilized to give 38 mg of a yellow solid. Purity 73.5% MS: m / z = 801 [M+H] +1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),9.23(d,J=2.0Hz,1H),8.81(d,J=2.0Hz,1H),7.7 7(d,J=8.8Hz,1H),7.50(d,J=2.0Hz,1H),7.37(dd,J=8.8,2.0Hz,1H),7.13-7.11(m,2H) ,7.01(d,J=8.4Hz,1H),5.12-5.07(m,1H),4.72-4.66(m,1H),4.30-4.14(m,2H),3.44-3 .18(m,6H),2.92-2.86(m,4H),2.61-2.52(m,4H),2.07-2.01(m,2H),1.51-1.46(m,6H).

[0316] Example 2 Preparation of Compound 25

[0317] Synthesis route:

[0318]

[0319] 2-(4-((5-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)benzofuran-2-yl)methyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0320]

[0321] K2CO3 (10 mg, 0.18 mmol, 2.0 eq.) was added to a solution of 5-(4,4-dimethyl-5-oxo-3-(2-(piperazin-1-ylmethyl)benzofuran-5-yl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (20 mg, 0.09 mmol, 1.0 eq.), 2-bromo-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide (17 mg, 0.1 mmol, 1.2 eq.) in DMF (1 mL) at room temperature. After stirring for 2 hours, the mixture was purified by reverse phase chromatography eluting with MeCN:H2O=55% to give 2-(4-((5-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)benzofuran-2-yl)methyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide (10 mg, 32%) as a white solid. MS: m / z=827[M+H] +

[0322] The corresponding intermediates were synthesized by referring to the preparation method of the above intermediates or methods known in the prior art, and the following compounds were prepared by referring to the preparation method of Example 1 or Example 2. The compounds and their MS: m / z data are shown in the following table.

[0323]

[0324]

[0325]

[0326]

[0327] Biological activity test

[0328] The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

[0329] Test Example 1 The compound of the present invention was co-cultured with human prostate cancer cells LNcap and then the degradation level of androgen receptor AR protein was detected.

[0330] Test steps:

[0331] Step 1: Cell seeding and compound treatment

[0332] 1. Ensure that the cell viability is >90% during cell culture. Digest the cultured cells, resuspend and dilute to 100,000 cells per ml in culture medium, seed 100 μl of cells into 10,000 cells per well of a cell culture plate, and incubate in a cell culture incubator at 37°C, 5% CO2 for 4-8 hours.

[0333] 2. Dilute the test compound 4-fold with DMSO (300 μM to 18 nM). Add 1 μl of the test compound to the cell culture plate (final compound concentration 3000 nM to 0.18 nM), the positive reference well is 3000 nM ARV110, and the negative reference well is DMSO without compound.

[0334] 3. Incubate in an incubator at 37°C, 5% CO2 for 8 hours.

[0335] Step 2: Elisa test

[0336] 1. Discard the culture medium, add 1X cell lysis buffer to treat the cells, and transfer 100uL of the supernatant to a microplate coated with AR antibody (the reagents for Elisa detection were purchased from Cell Signaling Technology, Cat. No. 12850).

[0337] Place at 2.4°C overnight, discard the liquid in the wells, wash 4 times with 1X washing buffer, 200 μl each time. Add 100 μl of recombinant detection antibody to each well and incubate the plate at 37°C for 1 hour.

[0338] 3. Repeat the washing procedure. Add 100 μl of recombinant HRP-linked secondary antibody to each well and incubate the plate at 37°C for 30 minutes.

[0339] 4. Repeat the washing procedure. Add 100 μl of TMB substrate to each well.

[0340] 5. After incubation for 5-15 minutes, read the absorbance OD450 value on the Envision instrument.

[0341] 6. Calculate the degradation rate using the OD450 value.

[0342] %Degradation=100-(OD value of compound well-OD value of positive reference well) / (OD value of negative reference well-OD value of positive reference well)×100.

[0343] 7. The DC50 value was calculated using the 4-parameter model using Graphpad 8.0 software.

[0344] The test results are shown in the following table:

[0345]

[0346]

Claims

1. A compound represented by the following formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof: in: Ring A1 or Ring A2 are each independently selected from an aryl group, a heteroaryl group or a heterocyclic group; Ring A1 or Ring A2 may be optionally substituted by 1 to 4 R e replace; M1 is selected from CR1 or N; M2 is selected from CR2 or N; M3 is selected from CR3R4 or NR5; R1, R2, R3, R4 or R5 are each independently selected from H, halogen, cyano, hydroxy, amino, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl or heterocyclyl; L is -Ak1-Cy1-Ak2-Cy2-Ak3-; Ak1, Ak2 and Ak3 are each independently selected from a bond, -(CH2) n1 -, -C(O)-, -O-, -NH-, -C(O)NH-, -(CR6R7) n2 -, -NR8-, -CH2NR9- or alkynylene; R6, R7, R8 or R9 are each independently selected from H, halogen, cyano, hydroxy, amino, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl or heterocyclyl; n1 or n2 are each independently selected from 0, 1, 2 or 3; Cy1 and Cy2 are each independently selected from a bond, a cycloalkylene group, a heterocyclylene group, an arylene group or a heteroarylene group; The Cy1 or Cy2 may optionally be replaced by 1 to 4 R f replace; X is selected from a bond, -NH-, -S-, -O-, -CH2-, -C(O)NH-, -NHC(O)- or -C(O)-; R a , R b , R c , R d , R e or R f each independently selected from halogen, cyano, oxo, hydroxy, amino, nitro, or alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl which may be optionally substituted by 1 to 4 groups independently selected from halogen, amino, hydroxy, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl; or R b and R c Connected to form a cycloalkyl or heterocyclic group; the cycloalkyl or heterocyclic group may be optionally substituted by 1 to 4 groups independently selected from halogen, amino, hydroxy, cyano, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy; n or m is each independently selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The ring A1 is selected from a benzene ring, Wherein, Z is selected from a bond or is absent, when Z is absent, the ring A1 is selected from Ring B1 is selected from a benzene ring or pyridine; Ring B2 is selected from a saturated or partially saturated 5-6 membered heterocyclic ring, wherein the 5-6 membered heterocyclic ring optionally contains 1-3 heteroatoms selected from O, N or S; Ring B3 is selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclic ring, wherein the 3-6 membered heterocyclic ring optionally contains 1-3 heteroatoms selected from O, N or S; The ring A1 may be optionally substituted with 1 to 4 R e Substitute, the R e Selected from halogen, cyano, oxo, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Preferably, the R e Optionally selected from halogen, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy.

3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The ring A2 is selected from a benzene ring or wherein Ring B4 is selected from a saturated or partially saturated 5-6 membered heterocyclic ring; the 5-6 membered heterocyclic ring optionally contains 1-3 heteroatoms selected from O, N or S; The ring A2 may optionally be substituted with 1 to 4 R e Substitute, the R e Selected from halogen, cyano, oxo, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Preferably, the R e Optionally selected from halogen, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy.

4. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The ring A1 is selected from The ring A1 may be optionally substituted with 1 to 4 R e Substitute, the R e Optionally selected from fluorine, chlorine, oxo, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl.

5. The compound according to claim 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Said Ring A2 is selected from The ring A2 may optionally be substituted with 1 to 4 R e Substitute, the R e Optionally selected from fluorine, chlorine, oxo, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl.

6. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: L is -Ak1-Cy1-Ak2-Cy2-Ak3-; Ak1, Ak2 and Ak3 are each independently selected from a bond, -(CH2) n1 -, -C(O)-, -O-, -NH-, -C(O)NH-, -(CR6R7) n2 -, -NR8-, -CH2NR9- or alkynylene; R6, R7, R8 or R9 are each independently selected from H, halogen, cyano, hydroxyl, amino, nitro, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Preferably, R6, R7, R8 or R9 are each independently selected from H, halogen, cyano, hydroxyl, amino, nitro, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy; Cy1 and Cy2 are each independently selected from a bond, C 5-6 Cycloalkylene, 5-6 membered monocyclic heterocyclylene, 5-8 membered polycyclic heterocyclylene; Preferably, Cy1 and Cy2 are each independently selected from a bond, a cyclopentylene, a cyclohexylene, a pyrrolidinylene, a piperidinylene, a piperazinylene or The Cy1 or Cy2 may optionally be replaced by 1 to 4 R f replace; The R f Selected from halogen, cyano, oxo, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Preferably, the R f Optionally selected from halogen, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy.

7. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The L is selected from 8. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R1, R2, R3, R4 or R5 are each independently selected from H, halogen, cyano, hydroxyl, amino, nitro, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy; Preferably, R1, R2, R3, R4 or R5 are each independently selected from H; and / or, said R6, R7, R8 or R9 are each independently selected from H, halogen, cyano, hydroxyl, amino, nitro, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy; Preferably, R6, R7, R8 or R9 are each independently selected from H, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl; and / or, X is selected from a bond, -NH- or -C(O)NH-; and / or, R a , R b , R c , R d , R e or R f are independently selected from halogen, cyano, oxo, hydroxyl, amino, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, hydroxyl C 1-3 Alkyl, amino C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; or R b and R c The cyclopropyl, cyclobutyl, cyclopentyl or 3-6 membered heterocyclic group is connected to form a cyclopropyl, cyclobutyl, cyclopentyl or 3-6 membered heterocyclic group, wherein the 3-6 membered heterocyclic group optionally contains 1-2 heteroatoms selected from O, N, and S; the cyclopropyl, cyclobutyl, cyclopentyl or 3-6 membered heterocyclic group may be optionally selected from halogen, amino, hydroxyl, cyano, nitro, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 substituted with a haloalkoxy group; Preferably, the R a , R b , R c , R d , R e or R f Each is independently selected from fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl; or R b and R c Connect to form cyclopropyl, cyclobutyl, and cyclopentyl.

9. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is further selected from the group consisting of:

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

11. Use of the compound according to any one of claims 1 to 9, its stereoisomer or pharmaceutically acceptable salt thereof, and the pharmaceutical composition according to claim 10 in the preparation of a medicament for preventing or treating androgen-mediated diseases.

12. The use according to claim 11, wherein the disease is cancer, alopecia, acne or Kennedy's disease; preferably, the cancer is selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer or salivary gland cancer.

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