Bifunctional compounds, pharmaceutical compositions comprising same, and methods for their use in treatment of androgen receptor related diseases

Abstract

The present disclosure provides a bifunctional compound, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, wherein the bifunctional compound is represented by formula (I): ABM-L-CLM (I); wherein: ABM is an androgen receptor binding group; l-L is a bonding group; and CLM is a cerebellar protein E3 ubiquitin ligase binding group represented by formula (II)-1: # imgabs0 # wherein one end of the L-is covalently bonded to Q3, Q4, Q5 or Q6; and the other end of the L-L is covalently bonded with the ABM. The present disclosure also provides a pharmaceutical composition comprising the bifunctional compound, and a method of treating an androgen receptor associated disease by administering the bifunctional compound.

Description

Technical Field

[0001] The present disclosure relates to a bifunctional compound and a pharmaceutical composition comprising the bifunctional compound, as well as a method for treating androgen receptor-related diseases by administering the bifunctional compound. Background Art

[0002] Protein-protein interactions are not easy to target with small molecules, because the contact area of ​​the protein is large, and the shallow groove or flat interface thereon may be related to the interaction. On the other hand, it has been shown that the pathogenic protein is finally degraded by the 26S proteasome system by tagging the pathogenic protein with ubiquitin, and such a therapeutic tool (modality) can widely and comprehensively eliminate the cause of the disease (Sun et al., Signal Transduct. Target Ther. 2019, 4: 64). In addition to E1 enzymes and E2 enzymes, E3 ubiquitin ligases (also referred to as E3 ligases) and their substrate recognition proteins can also make the ubiquitination of the substrate specific, and these components are very important in order to make the target protein substrate specifically and optionally degraded. Recent developments in target protein degradation have shown that E3 ligases such as cereblon (CRBN) E3 ligase, von Hippel-Lindau disease tumor suppressor (VHL) E3 ligase, mouse double minute 2 protein (MDM2) E3 ligase, and cell inhibitor of apoptosis protein (cIAP) E3 ligase have been successfully applied to the design of small molecule protein degradation drugs. These molecules may become candidates for treatment (Wang et al., Acta Pharm Sin B. 2020 Feb; 10(2): 207-238).

[0003] One E3 ligase with therapeutic potential is cerebellin E3 ligase, which is a protein encoded by the CRBN gene in humans. CRBN's orthologs are highly conserved from plants to humans. Cerebellin forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A) and Regulator of Cullins 1 (ROC 1). This complex ubiquitinates many other proteins (Vriend et al., Front Mol Biosci. 2018, 5: 19).

[0004] The androgen receptor (AR) is a member of the nuclear hormone receptor family and is activated by androgens (such as testosterone and dihydrotestosterone). When bound to androgens, AR translocates into the cell nucleus, where it acts as a transcription factor to promote the expression of genes responsible for male sexual characteristics. In addition to being responsible for the development of male sexual characteristics, AR also drives the growth and survival of prostate cancer cells (Salami et al., Commun. Biol. 2018, 1:100).

[0005] Inhibiting AR signaling is a common strategy in the treatment of prostate cancer. Prostate cancer is the second most commonly diagnosed cancer and ranks fifth among the causes of death in men worldwide. Most men with local or regional prostate cancer have a 5-year survival rate of nearly 100%, while men diagnosed with prostate cancer that has spread to other parts of the body have a 5-year survival rate of 31%. According to GLOBOCAN estimates, there were 1.41 million new cases and 375,000 deaths reported worldwide for prostate cancer in 2020. For decades, androgen deprivation therapy (ADT) has been the standard treatment for prostate cancer, which is performed by surgery or chemical castration. However, castration-resistant prostate cancer will eventually develop, and although serum testosterone is only sub-castration concentrations, tumor cell proliferation will be restored. With the approval of second-generation anti-androgen drugs, such as abiraterone acetate (ABI), enzalutamide (ENZ), and the recently approved apalutamide (APA) and darolutamide (DARO), the overall survival rate of patients with castration-resistant prostate cancer (CRPC) has improved. However, as is common in cancer chemotherapy, drug resistant escape mutations will eventually occur during the course of the disease (Zhao et al., Mol Cancer Ther. 2020, 19 (8): 1708-1718). In addition, androgens and AR have also been found to be associated with many skin diseases, such as androgeneticalopecia, acne, hirsutism, atopic dermatitis, etc. A significant amount of sex hormones are synthesized in the skin, and androgens affect hair growth, epidermal barrier homeostasis, wound healing, sebaceous gland growth, differentiation, etc. Antiandrogen drugs such as clascoterone, cyproterone acetate and flutamide are now used to treat these skin diseases.Androgen and AR concentrations may play an important role in the development of these AR signaling-related diseases (Zhou et al., Journal of Biosciences and Medicines 2022, 10: 180-200).

[0006] The present disclosure provides an alternative, which is to treat AR-mediated or AR-related diseases (disease) or abnormalities (disorder) by proteolysis targeting chimeric (PROTAC) bifunctional compounds. Related patent applications for PROTAC have been disclosed in WO2018071606, WO2018144649 and WO2021143816. However, there is still a need for compounds with better efficacy in treating androgen receptor-related diseases or abnormalities. Summary of the invention

[0007] The present disclosure provides proteolysis targeting chimeric (PROTAC) bifunctional compounds comprising a cerebellum protein (CRBN) E3 ubiquitin ligase binding group and an androgen receptor binding group, which can redirect a ubiquitin proteasome degradation system to degrade androgen receptor, thereby degrading and / or inhibiting the androgen receptor. These bifunctional compounds unexpectedly show high potential in androgen receptor degradation.

[0008] In one inventive concept, the present disclosure provides a bifunctional compound, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, wherein the bifunctional compound is represented by formula (I):

[0009] ABM-L-CLM(I);

[0010] in:

[0011] ABM is an androgen receptor binding group;

[0012] -L- is a bonding group; and

[0013] CLM is a cerebellum protein E3 ubiquitin ligase binding group represented by formula (II)-1:

[0014]

[0015] in:

[0016] represents a single bond or a double bond;

[0017] One end of -L- is connected to Q 3 , Q4 , Q 5 or Q 6 covalently bonded; and the other end of the -L- is covalently bonded to the ABM;

[0018] When W 1 and W 2 When there is a single bond between 1 and W 2 Each is independent of CR C2 or N; or, when W 1 and W 2 When there is a double bond between 1 and W 2 Each is C;

[0019] G is selected from -H, -OH, -CH2OH, -R C3 OC(=O)OR C4 , -R C3 OC(=O)NR C4 R C5 and 2-(trimethylsilyl)ethoxymethyl group;

[0020] Q 1 O, S or NR C6 ;

[0021] When Q 2 and Q 7 When there is a single bond between 2 and Q 7 Each is N or CR independently C2 ; or, when Q 2 and Q 7 When there is a double bond between 2 and Q 7 Each is C;

[0022] At one end of the -L- 3 , Q 4 , Q 5 and Q 6 When any atom of -L- is covalently bonded to CR C2 When the CR C2 There are two single bonds between the C atom and its two adjacent atoms on the ring; or when the atom covalently bonded to the -L- is C, there is a double bond between the C atom and one of its two adjacent atoms on the ring; and, selected from Q 3 , Q 4 , Q 5 and Q6 The other atoms not covalently bonded to the -L- are each independently O, S, C(R C2 )2 or NR C2 When the O atom, S atom, C(R C2 )2 C atoms, or NR C2 There are two single bonds between the N atom and its two adjacent atoms on the ring; or selected from Q 3 , Q 4 , Q 5 and Q 6 The other atoms not covalently bonded to the -L- are each independently CR C2 When the CR C2 There is a double bond between the C atom of and one of its two adjacent atoms on the ring;

[0023] K is selected from -H, unsubstituted alkyl, C7 Substituted alkyl, unsubstituted cycloalkyl and R C7 A group consisting of substituted cycloalkyl groups; K is bonded to the 6-membered ring by a stereospecific bond or a non-stereospecific bond;

[0024] R C1 is selected from unsubstituted alkyl, C8 Substituted alkyl, unsubstituted aryl, R C8 Substituted aryl, unsubstituted alkyl-aryl, R C8 Substituted alkyl-aryl, unsubstituted alkoxy and R C8 The group consisting of substituted alkoxy groups;

[0025] R C2 is selected from -H, -D, halogen, -CH2OH, -NR C4 R C5 , alkoxy, unsubstituted alkyl, alkyl substituted by one or more halogen groups, unsubstituted cycloalkyl, cycloalkyl substituted by one or more halogen groups, unsubstituted aryl and aryl substituted by one or more halogen groups;

[0026] R C3 is selected from an unsubstituted alkylene group and an R C7 The group consisting of substituted alkylene;

[0027] R C4 and R C5 are each independently selected from -H, unsubstituted alkyl, C9 Substituted alkyl, unsubstituted cycloalkyl, R C9Substituted cycloalkyl, unsubstituted heterocyclic group, R C9 Substituted heterocyclic group, unsubstituted aryl group, R C9 Substituted aryl, unsubstituted heteroaryl and R C9 The group consisting of substituted heteroaryl groups;

[0028] R C6 is selected from the group consisting of -H, halogen, -CH2OH, 2-(trimethylsilyl)ethoxymethyl, alkoxy, unsubstituted alkyl, alkyl substituted with one or more halogens, unsubstituted cycloalkyl, cycloalkyl substituted with one or more halogens, unsubstituted aryl, aryl substituted with one or more halogens, unsubstituted heteroaryl, heteroaryl substituted with one or more halogens, unsubstituted heterocyclyl, and heterocyclyl substituted with one or more halogens;

[0029] R C7 is selected from halogen, -CH2OH, -NR C4 R C5 , 2-(trimethylsilyl)ethoxymethyl, alkoxy, unsubstituted aryl, aryl substituted with one or more halogen groups, unsubstituted heteroaryl, heteroaryl substituted with one or more halogen groups, unsubstituted heterocyclic group and heterocyclic group substituted with one or more halogen groups;

[0030] R C8 is selected from halogen, -CH2OH, -NR C4 R C5 , 2-(trimethylsilyl)ethoxymethyl, unsubstituted cycloalkyl, cycloalkyl substituted with one or more halogen groups, unsubstituted heteroaryl, heteroaryl substituted with one or more halogen groups, unsubstituted heterocyclyl and heterocyclyl substituted with one or more halogen groups;

[0031] R C9 is selected from the group consisting of halo, -CH2OH, 2-(trimethylsilyl)ethoxymethyl and alkoxy;

[0032] n is 0, 1, 2, 3 or 4; and

[0033] The -L- is represented by formula (III):

[0034]

[0035] in:

[0036] Z is selected from the group consisting of a 3- to 8-membered monocyclic ring, a 5- to 12-membered bicyclic ring, an 8- to 15-membered tricyclic ring, and a 6- to 12-membered spirobicyclic ring, each of which independently has 0 to 4 heteroatoms;

[0037] R L1 is selected from unsubstituted C 1-6 Alkyl, C 1-6 Alkoxy substituted C 1-6 Alkyl, C 1-6 Alkyl, halogen, unsubstituted C 1-6 A group consisting of an alkoxy group, a keto group and an oxide group;

[0038] X 1 is a methylene group or an ethylene group; each of which is unsubstituted or substituted by an alkyl group or a cycloalkyl group;

[0039] X 2 is selected from the group consisting of a 5- to 8-membered arylene group, a 5- to 8-membered heteroarylene group having 1 to 3 heteroatoms, a 3- to 7-membered cyclic alkylene group, a 3- to 7-membered heterocyclic alkylene group having 1 to 2 heteroatoms, a 3- to 8-membered cyclic alkenylene group, a 3- to 8-membered cyclic heteroalkenylene group having 1 to 3 heteroatoms, and a 6- to 12-membered spiro bicyclic bivalent group having 0 to 4 heteroatoms, each of which is unsubstituted or substituted with an alkyl group or a cycloalkyl group;

[0040] m is 0, 1, 2, 3, 4, 5 or 6; v1 is 1 or 2; and v2 is 1 or 2; and

[0041] The aforementioned heteroatom is selected from N, O and S.

[0042] In another inventive concept, the present disclosure provides a pharmaceutical composition comprising an effective amount of the aforementioned compound, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof; and a pharmaceutically acceptable carrier.

[0043] In another inventive concept, the present disclosure provides a method for treating an androgen receptor-related disease in a subject in need thereof, comprising administering to the subject an effective amount of the aforementioned compound, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, or the aforementioned pharmaceutical composition.

[0044] In some specific embodiments, the CLM is represented by formula (II)-2:

[0045]

[0046] in:

[0047] One end of the –L– is connected to the Q 3 , Q 4 or Q 5 covalent bonding;

[0048] G is selected from the group consisting of -H, -OH and -CH2OH;

[0049] Q 1 O, S or NR C6 ;

[0050] When one end of -L- is connected to a 3 , Q 4 and Q 5 When any atom of is covalently bonded to, the atom connected to -L- is C; and, selected from Q 3 , Q 4 and Q 5 The other atoms not connected to the -L- are each independently CR C2 ;as well as

[0051] R C2 is selected from the group consisting of -H, -D, halo, unsubstituted alkyl, and alkyl substituted with one or more halo groups;

[0052] R C6 is selected from -H, -CH2OH, unsubstituted C 1-6 Alkyl, C 1-6 The group consisting of alkyl groups.

[0053] In some embodiments, the heteroatoms in Formula (II)-1 are independently selected from N, O and S.

[0054] In some embodiments, G is selected from the group consisting of -H, -OH, -CH2OH, -CH2OCOOCH3 and 2-(trimethylsilyl)ethoxymethyl.

[0055] In some specific embodiments, the 2-(trimethylsilyl)ethoxymethyl group is also abbreviated as SEM group.

[0056] In some embodiments, K is bound to the 6-membered ring by a stereospecific bond:

[0057]

[0058] In the present disclosure, the carbon connected to K on the 6-membered ring is a chiral carbon center, and the bifunctional compound, or its pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug may have two stereoisomers having CLM represented by formula (II)-1a and formula (II)-1b. The bifunctional compound, or its pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug may have one of the aforementioned stereoisomers, or both stereoisomers.

[0059] In some embodiments, K is selected from -H, unsubstituted C 1-6 Alkyl, R C7 Substituted C 1-6 Alkyl and C 3-8 In some embodiments, K may be an unsubstituted C 1-3 Alkyl or R C7 Substituted C 1-3 alkyl.

[0060] In some embodiments, K is an alkyl group selected from the group consisting of a linear alkyl group and a branched alkyl group, each of which is unsubstituted or substituted with R C7 In some embodiments, K is selected from a linear C 1-6 Alkyl and branched C 1-6 The alkyl group consisting of alkyl groups, each of which is unsubstituted or substituted with R C7 In some embodiments, K is selected from a linear C 1-3 Alkyl and branched C 1-3 The alkyl group consisting of alkyl groups, each of which is unsubstituted or substituted with R C7 replace.

[0061] In some specific embodiments, R C1 Can be unsubstituted C 1-6 Alkyl, R C8 Substituted C 1-6 Alkyl, unsubstituted C 3-8 Aryl, R C8 Substituted C 3-8 Aryl, unsubstituted C 3-8 Alkyl-aryl, R C8 Substituted C 3-8 Alkyl-aryl, unsubstituted C 1-6 Alkoxy or R C8 Substituted C 1-6 In some specific embodiments, R C1 Can be unsubstituted C 1-3 Alkyl, R C8 Substituted C 1-3 Alkyl, unsubstituted C1-3 Alkoxy or R C8 Substituted C 1-3 Alkoxy.

[0062] In some specific embodiments, R C1 is an alkyl group selected from the group consisting of a straight-chain alkyl group and a branched-chain alkyl group, each of which is unsubstituted or substituted with R C8 In some specific embodiments, R C1 For the selection of straight chain C 1-6 Alkyl and branched C 1-6 The alkyl group consisting of alkyl groups, each of which is unsubstituted or substituted with R C8 In some specific embodiments, R C1 Select from straight chain C 1-3 Alkyl and branched C 1-3 The alkyl group consisting of alkyl groups, each of which is unsubstituted or substituted with R C8 replace.

[0063] In the present disclosure, the halide group may be F, Cl, Br or I. In the present disclosure, the halide group may be F or Cl. In the present disclosure, the halide group is F.

[0064] In the present disclosure, R C2 is selected from -H, -D (deuterium), halogen, unsubstituted C 1-6 Alkyl and C substituted by one or more halogen groups 1-6 In the present disclosure, R C2 is selected from -H, -D, -F, -Cl, unsubstituted C 1-3 Alkyl and C substituted by one or more halogen groups 1-3 The group consisting of alkyl groups.

[0065] In the present disclosure, R C4 and R C5 are each independently selected from unsubstituted C 1-6 Alkyl, R C9 Substituted C 1-6 Alkyl, unsubstituted C 3-8 Cycloalkyl, R C9 Substituted C 3-8 Cycloalkyl, unsubstituted C 3-8 Heterocyclic group, R C9 Substituted C 3-8 Heterocyclic group, C 3-8 Aryl and C 3-8 In the present disclosure, R C4 and R C5 are each independently selected from unsubstituted C 1-3 Alkyl and R C9 Substituted C1-3 In the present disclosure, R C4 It can be methyl, ethyl, n-propyl or isopropyl.

[0066] In some specific embodiments, R C4 and R C5 Each is independently an alkyl group selected from the group consisting of a straight chain alkyl group and a branched chain alkyl group, each of which is unsubstituted or substituted with R C9 In some specific embodiments, R C4 and R C5 Each is independently selected from a straight chain C 1-6 Alkyl and branched C 1-6 The alkyl group consisting of alkyl groups, each of which is unsubstituted or substituted with R C9 In some specific embodiments, R C4 and R C5 Each is independently selected from a straight chain C 1-3 Alkyl and branched C 1-3 The alkyl group consisting of alkyl groups, each of which is unsubstituted or substituted with R C9 replace.

[0067] In some specific embodiments, the CLM is represented by Formula (II)-1 or Formula (II)-2, wherein Q 1 NR C6 ; and R C6 is -H, unsubstituted C 1-6 Alkyl or C substituted by one or more halogen groups 1-6 In some specific embodiments, Q 1 NR C6 ; and R C6 H, unsubstituted C 1-3 Alkyl or C substituted by one or more halogen groups 1-3 In some specific embodiments, Q 1 NR C6 ; and R C6 For unsubstituted C 1-3 Alkyl is selected from methyl, ethyl, n-propyl and isopropyl. In some specific embodiments, Q 1 NR C6 ; and R C6 is a C selected from methyl, ethyl, n-propyl, isopropyl 1-3 Alkyl groups are independently substituted with one or more halogen groups selected from F, Cl and Br.

[0068] In some embodiments, one end of -L- is connected to Q 4 or Q 5 In some embodiments, one end of -L- is covalently bonded to Q4 Covalent bonding.

[0069] In the tricyclic system of formula (II)-1 or formula (II)-2 (composed of one N atom, two C atoms, W 1 , W 2 , Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 and Q 7 ), are represented or understood as double bonds and single bonds within the context of the difunctional compound and according to the well-known rules of valence interactions.

[0070] In some specific embodiments, the -L- is represented by formula (III):

[0071]

[0072] in:

[0073] Z is selected from the group consisting of a 3- to 8-membered monocyclic ring, a 6- to 10-membered bicyclic ring, and an 8- to 10-membered spirobicyclic ring, each of which independently has 1 to 2 heteroatoms;

[0074] X 1 is an unsubstituted methylene group or a methylene group substituted by an alkyl group or a cycloalkyl group;

[0075] X 2 is selected from the group consisting of a 3-7 membered heterocycloalkylene group having 1-2 heteroatoms, a 3-8 membered cycloheteroalkenylene group having 1-2 heteroatoms, and a 6-12 membered spirobicyclic divalent group having 1-2 heteroatoms, each of which is unsubstituted or substituted with an alkyl or cycloalkyl group;

[0076] m is 0, 1 or 2; v1 is 1 or 2; and v2 is 1.

[0077] In some embodiments, the heteroatoms in formula (III) are independently selected from the group consisting of N, O and S. In some embodiments, the Z ring contains one or two heteroatoms selected from N, O and S.

[0078] In some embodiments, Z is an unsubstituted 3, 4, 5, 6, or 7-membered heterocycloalkylene having 1 or 2 heteroatoms. In some embodiments, Z is a 6, 7, 8, 9, 10, 11, or 12-membered spirobicyclic divalent radical having 1 or 2 heteroatoms.

[0079] In some specific embodiments, R L1 is selected from unsubstituted C 1-3Alkyl, C 1-3 Alkoxy substituted C 1-3 Alkyl, C 1-3 Alkyl, halogen, C 1-3 In some specific embodiments, R L1 is an oxygen ion group, which is connected to a heteroatom N of the Z ring to form an N-oxygen ion group (N + –O - ).

[0080] In some specific embodiments, R L1 For the selection of straight chain C 1-6 Alkyl and branched C 1-6 The alkyl groups consisting of alkyl groups are each unsubstituted or C 1-6 In some embodiments, R L1 For the selection of straight chain C 1-3 Alkyl and branched C 1-3 The alkyl groups consisting of alkyl groups are each unsubstituted or C 1-6 The alkoxy group may be substituted or substituted with one or more halogen groups.

[0081] In some specific embodiments, X 1 For 1 or 2 C 1-6 In some specific embodiments, X 1 For 1 or 2 C 1-3 In some specific embodiments, X 1 For 1 or 2 C 3-6 In some specific embodiments, X 1 For 1 or 2 C 3-6 Cycloalkyl substituted methylene.

[0082] In some specific embodiments, X 1 1 to 4 C 1-6 In some specific embodiments, X 1 1 to 4 C 1-3 In some specific embodiments, X 1 1 to 4 C 3-6 In some specific embodiments, X 1 1 to 4 C 3-6 Cycloalkyl-substituted ethylene.

[0083] In some specific embodiments, X 2is a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkylene group having 1 or 2 heteroatoms, each of which is unsubstituted or substituted with an alkyl group or a cycloalkyl group. 2 is a 3-, 4-, 5-, 6-, 7-, or 8-membered cycloheteroalkenylene group having 1 or 2 heteroatoms, each of which is unsubstituted or substituted with an alkyl group or a cycloalkyl group. 2 is a 6-, 7-, 8-, 9-, 10-, 11- or 12-membered spirobicyclic divalent radical having 1 or 2 heteroatoms, each of which is unsubstituted or substituted by an alkyl or cycloalkyl group.

[0084] In some specific embodiments, X 2 is a 3-membered heterocycloalkylene group having 1 heteroatom and substituted by 1 to 3 alkyl or cycloalkyl groups, a 3-membered heterocycloalkylene group having 2 heteroatoms and substituted by 1 to 2 alkyl or cycloalkyl groups, a 4-membered heterocycloalkylene group having 1 heteroatom and substituted by 1 to 5 alkyl or cycloalkyl groups, a 4-membered heterocycloalkylene group having 2 heteroatoms and substituted by 1 to 4 alkyl or cycloalkyl groups, or a 5-7-membered heterocycloalkylene group having 1 to 2 heteroatoms and substituted by 1 to 6 alkyl or cycloalkyl groups.

[0085] In some specific embodiments, X 2 is a 3-membered cycloheteroalkenylene having 1 heteroatom and substituted by 1 to 3 alkyl or cycloalkyl groups, a 4-membered cycloheteroalkenylene having 1 heteroatom and substituted by 1 to 3 alkyl or cycloalkyl groups, a 4-membered cycloheteroalkenylene having 2 heteroatoms and substituted by 1 to 2 alkyl or cycloalkyl groups, a 5-membered cycloheteroalkenylene having 1 heteroatom and substituted by 1 to 5 alkyl or cycloalkyl groups, a 5-membered cycloheteroalkenylene having 2 heteroatoms and substituted by 1 to 4 alkyl or cycloalkyl groups, a 6-, 7- or 8-membered cycloheteroalkenylene having 1 heteroatom and substituted by 1 to 6 alkyl or cycloalkyl groups, and a 6-, 7- or 8-membered cycloheteroalkenylene having 2 heteroatoms and substituted by 1 to 6 alkyl or cycloalkyl groups.

[0086] In some specific embodiments, the -L- is selected from

[0087] The group composed of.

[0088] In some specific embodiments, the ABM is an androgen receptor binding group represented by the following formula:

[0089]

[0090] in:

[0091] Z 1is selected from the group consisting of aryl, heteroaryl, bicyclic group or bi-heterocyclic group, each of which is independently substituted by one or more substituents independently selected from the following groups: halo, hydroxyl, nitro, -CN, -C≡CH, unsubstituted C 1-6 Alkyl, C 1-6 Alkoxy substituted C 1-6 Alkyl, C 1-6 Alkyl, unsubstituted C 1-6 Alkoxy, C 1-6 Alkoxy, unsubstituted C 2-6 Alkenyl, C 2-6 Alkenyl, unsubstituted C 2-6 Alkynyl, C 3-6 Alkynyl and any combination thereof;

[0092] Y 1 and Y 2 Each is independent of NR Y1 , O or S;

[0093] Y 3 , Y 4 and Y 5 are independently selected from a bond, -O-, -NR Y2 -、-C(-R Y1 )(-R Y2 )-, -C(=O)-, -C(=S)-, -S(=O)-, -SO2-, a heteroarylene group and an arylene group;

[0094] Y 6 For -N(-R Y1 )-, -O-, or -S-;

[0095] M is a 3- to 6-membered ring having 0-4 heteroatoms, which is unsubstituted or substituted with 0-6 R M Base substitution;

[0096] Each R M The radicals are independently selected from unsubstituted C 1-6 Alkyl, C 1-6 Alkoxy substituted C 1-6 Alkyl, C 1-6 Alkyl, halide and C 1-6 Alkoxy group; or, two R M The radical and the atoms to which it is attached together form a 3- to 8-membered ring system containing 0 to 2 heteroatoms;

[0097] R a , R b , R c , R d , R Y1 and R Y2 are each independently selected from -H, unsubstituted C 1-6 Alkyl, C 1-6 Alkoxy substituted C 1-6 Alkyl, C 1-6 Alkyl, halogen, C 1-6 The group consisting of alkoxy, cyclic group and heterocyclic group; or, R a , R b Together with the atoms to which they are attached, they form a 3- to 8-membered ring system containing 0 to 2 heteroatoms;

[0098] Z 2 Is to choose from one-key knot, C 1-6 Alkylene, C 1-6 The group consisting of a heteroalkylene group, -O-, an arylene group, a heteroarylene group, an alicyclic bivalent group, a heterocyclic bivalent group, a heterobicyclic bivalent group, a bicyclic arylene group and a bicyclic heteroarylene group, each of which is unsubstituted or substituted with 1 to 10 R Z2 Base substitution;

[0099] Each R Z2 The radicals are independently selected from the group consisting of: -H, halogen, unsubstituted C 1-6 Alkyl, C substituted with one or more -F 1-6 Alkyl, -OR Z2A , C 3-6 Cycloalkyl, C 4-6 Cycloheteroalkyl, unsubstituted C 1-6 Alkyl, C 1-3 Alkyl substituted C 1-6 Alkyl, C 1-6 Alkoxy substituted C 1-6 Alkyl, C 1-6 Alkyl, unsubstituted heterocyclic, C 1-3 Alkyl-substituted heterocyclic group, C 1-6 Alkoxy-substituted heterocyclic group, heterocyclic group substituted by one or more halogen groups, unsubstituted aryl group, C1-3 Alkyl-substituted aryl, C 1-6 Alkoxy-substituted aryl, aryl substituted with one or more halogen groups, unsubstituted heteroaryl, C 1-3 Alkyl-substituted heteroaryl, C 1-6 Alkoxy-substituted heteroaryl, heteroaryl substituted with one or more halogen groups, bicyclic heteroaryl, unsubstituted C 1-3 Alkoxy and one or more selected from -F, -OH, -NH2, -NR Y1 R Y2 and -CN substituted with a substituent 1-3 Alkoxy; and

[0100] R Z2A Is the choice of -H, C 1-6 Alkyl and C 1-6 The group consisting of heteroalkyl, each of which is unsubstituted or substituted by cycloalkyl, cycloheteroalkyl, aryl, heterocyclyl, heteroaryl, halo, or C 1-3 Alkoxy substitution.

[0101] In some embodiments, the heteroatoms in formula (IV)-a, (IV)-b, (IV)-c or (IV)-d are each independently selected from N, O and S.

[0102] In some specific embodiments, Z 1 It is freedom to choose

[0103]

[0104] The group composed of.

[0105] In some specific embodiments, Z 1 It is freedom to choose The group composed of.

[0106] In some specific embodiments, Z 2 It is freedom to choose

[0107] The group composed of.

[0108] In some specific embodiments, M is

[0109] In some specific embodiments, each R M The groups are independently selected from linear C 1-6 Alkyl and branched C 1-6The alkyl groups consisting of alkyl groups are each unsubstituted or C 1-6 In some embodiments, each R M The groups are independently selected from linear C 1-3 Alkyl and branched C 1-3 The alkyl groups consisting of alkyl groups are each unsubstituted or C 1-6 In some embodiments, each R M The groups are independently methyl, ethyl, n-propyl or isopropyl.

[0110] In some specific embodiments, R a , R b , R c , R d , R Y1 and R Y2 are independently selected from the linear C 1-6 Alkyl and branched C 1-6 The alkyl groups consisting of alkyl groups are each unsubstituted or C 1-6 In some embodiments, R a , R b , R c , R d , R Y1 and R Y2 are independently selected from the linear C 1-3 Alkyl and branched C 1-3 The alkyl groups consisting of alkyl groups are each unsubstituted or C 1-6 In some embodiments, R a , R b , R c , R d , R Y1 and R Y2 Each is independently methyl, ethyl, n-propyl or isopropyl.

[0111] In some specific embodiments, (Y 3 ) 0-5 for The designation (R) means that the carbon has the R (rectus) configuration.

[0112] In some specific embodiments, each R Z2 The groups are independently selected from linear C 1-6 Alkyl and branched C 1-6 The alkyl groups of the group consisting of alkyl groups are each unsubstituted or substituted with one or more halogen groups.Z2 The groups are independently selected from linear C 1-3 Alkyl and branched C 1-3 The alkyl groups of the group consisting of alkyl are individually unsubstituted or substituted by one or more halogen groups.

[0113] In some specific embodiments, R Z2A For the selection of straight chain C 1-6 Alkyl and branched C 1-6 In some specific embodiments, R Z2A For the selection of straight chain C 1-3 Alkyl and branched C 1-3 The alkyl group of the group consisting of alkyl.

[0114] In some specific embodiments, R Z2A For a free straight chain C 1-6 Heteroalkyl and branched C 1-6 In some specific embodiments, R Z2A For a free straight chain C 1-3 Heteroalkyl and branched C 1-3 The heteroalkyl group is composed of heteroalkyl groups.

[0115] In some specific embodiments, the ABM is selected from

[0116]

[0117] the groups formed;

[0118] in:

[0119] A1 is selected from -Cl, -F, -Br or -CF3;

[0120] A2 is selected from -O-, -NH-, -NCH3- or -NCH2CH3-; and

[0121] A3, A4, A5 and A6 are each independently CH or N.

[0122] In some specific embodiments, the ABM is an androgen receptor binding group represented by formula (IV)-b, wherein M is a 4-membered alicyclic ring having 0 to 2 heteroatoms, which is unsubstituted or optionally substituted with 1 to 6 R M The other groups are as defined above.

[0123] In some specific embodiments, the ABM is an androgen receptor binding group represented by formula (IV)-b, wherein Z 2 For a key, C 1-6Alkylene, C 1-6 heteroalkylene, -O-, arylene, heteroarylene, alicyclic divalent group, heterocyclic divalent group, heterobicyclic divalent group, bicyclic arylene and bicyclic heteroarylene, each of which is substituted by 1, 2 or 3 R Z2 The other groups are as defined above.

[0124] In some specific embodiments, the ABM is an androgen receptor binding group represented by formula (IV)-b, wherein

[0125] Z 1 for

[0126] R ZA1 is -H or -CN;

[0127] Each R Z1B is independently -H, halo or -CF3; t is 0, 1, 2, 3 or 4;

[0128] Y 3 for -O-;

[0129] M is a 4- to 6-membered ring which is unsubstituted or substituted with 1 to 4 R M and each R M is independently -H or methyl;

[0130] Y 4 is -NH-;

[0131] Y 5 is -C(=O)-;

[0132] Z 2 is independently selected from an unsubstituted C 5-6 Aryl, one, two or three R Z2 C 5-6 Aryl, a C 5-6 Heteroaryl, a group having 1 heteroatom and 1, 2 or 3 R Z2 C 5-6 heteroaryl and a radical having 2 heteroatoms and 1 or 2 R Z2 C 5-6 The group consisting of heteroaryl groups;

[0133] Each R Z2A The group is selected from a straight chain C 1-6 Alkyl and branched C 1-6 In some specific embodiments, R Z2A For the selection of straight chain C 1-3 Alkyl and branched C 1-3 The other groups are as defined above.

[0134] In some specific embodiments, the ABM is an androgen receptor binding group represented by formula (IV)-d, wherein

[0135] Z 1 is an aryl group substituted by one or more halogen groups, or an aryl group substituted by -CN, or an aryl group independently substituted by -CN and one or more halogen groups;

[0136] Y 3 For a bond, -NR Y2 -、-CR Y1 R Y2 - or -C(=O)-;

[0137] M is a 5-membered aromatic ring having 1 or 2 heteroatoms;

[0138] R Y1 and R Y2 Each is independently H or C 1-6 alkyl;

[0139] Z 2 is a bond, aryl or heteroaryl, each of which is optionally substituted by 1, 2 or 3 R w2 Replace; and each R w2 is independently -H, halogen, C 1-6 alkyl (optionally substituted with one or more -F), C 1-3 Alkoxy (optionally substituted with one or more -F);

[0140] R W2 The radical is independently selected from the group consisting of -H, a halogen radical, a 6-membered alicyclic radical having 1 or 2 heteroatoms, or a 5-membered aromatic radical having 1, 2 or 3 heteroatoms. The definitions of the other radicals are as described above.

[0141] In some specific embodiments, the ABM is an androgen receptor binding group represented by formula (IV)-d, wherein

[0142] Z 1 for

[0143] Among them, each R Z1A is halogen or CN; and each R Z1B are independently H or halogen. The other groups are as defined above.

[0144] In some embodiments, the ABM is selected from

[0145]

[0146]

[0147] The group composed of.

[0148] In some embodiments, the pharmaceutical compositions of the present disclosure further comprise a second therapeutic agent.

[0149] In some embodiments, the androgen receptor-related disease is an androgen receptor-related cancer or an androgen receptor-related skin disease.

[0150] In some embodiments, the androgen receptor-related cancer is breast cancer or prostate cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the prostate cancer is castration-resistant prostate cancer.

[0151] In some embodiments, the androgen receptor-associated skin disease is androgenic alopecia, acne, hidradenitis suppurativa, hirsutism, or atopic dermatitis.

[0152] In some embodiments, the method of treating an androgen receptor-related disease further comprises administering an effective amount of a second therapeutic agent.

[0153] In some embodiments, the second therapeutic agent may be an androgen receptor inhibitor. An example of the androgen receptor inhibitor may be enzalutamide.

[0154] In some specific embodiments, the second therapeutic agent may be an antitumor agent known in the art. Examples of known antitumor agents include docetaxel, flutamide, goserelin acetate, leuprolide acetate, colchicine, leuprolide acetate, mitoxantrone hydrochloride, 5-fluorouracil and olaparib. Examples include one or more cyclophosphamide, mitomycin C, etc.

[0155] In some specific embodiments, the second therapeutic agent may be a therapeutic agent known in the art for treating AR-related skin diseases. Examples of known anti-tumor agents include Clascoterone, ASC-J9, Spironolactone, Flutamide, Finasteride, Dutasteride, Cyproterone acetate, Pyrilutamide, Minoxidil, Ketoconazole, etc.

[0156] When used in this specification and claims, the articles "a" and "an" refer to one or more than one (ie, at least one) of the grammatical objects of the article unless the context clearly indicates otherwise. For example, "a component" means one component or more than one component.

[0157] When used in this specification and claims, the word "and / or" should be understood to mean "either or both" of the components so connected, that is, in some cases, the components are present together; and in some cases, the components are present separately. Multiple components listed with "and / or" should be interpreted in the same way, that is, "one or more" of the multiple components so connected. Other components other than the components specifically defined by the "and / or" clause may optionally exist, whether related or unrelated to those specifically defined components. Therefore, as a non-limiting example, when "A and / or B" is used with an open term such as "comprising", it may refer to only A (optionally including components other than B) in one specific embodiment; it may refer to only B (optionally including components other than A) in another specific embodiment; it may refer to both A and B (optionally including other components) in yet another specific embodiment, etc.

[0158] When used in this specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as inclusive, i.e., including at least one of the multiple components or components in the list, but also including more than one component, and optionally including additional items not listed. Only when the words clearly indicate the opposite meaning, such as "only one of" or "exactly one of", or when "consisting of" is used in the claims, it will refer to including exactly one of the multiple components or components in the list. Generally speaking, when there is an exclusive term such as "either", "one of", "only one of" or "exactly one of", the word "or" used in this article should only be interpreted as referring to exclusive alternative items (i.e., "one or the other, but not both".

[0159] In the claims and the foregoing specification, all conjunctions such as "comprise," "include," "carry," "have," "contain," "involve," "hold," "composed of," and the like are to be understood as open-ended, that is, meaning including but not limited to. Only the conjunctions "consisting of" and "consisting essentially of" shall be closed or semi-closed conjunctions, respectively, as provided in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0160] When used in this specification and claims, the term "at least one" referring to a list of one or more components should be understood to mean at least one component selected from any one or more components in the list of components, but does not necessarily include at least one component of each and every component specifically listed in the list of components, and does not exclude any combination of components in the list of components. This definition also allows components other than the components specifically defined in the list of components referred to by the term "at least one" to optionally exist, whether related or unrelated to those specifically defined components. Therefore, as a non-limiting example, "at least one of A and B" (or equivalently "at least one of A or B", or equivalently "at least one of A and / or B") may refer to at least one, and optionally more than one A, without B (and optionally including components other than B) in one specific embodiment; and may refer to at least one, and optionally more than one B, without A (and optionally including components other than A) in another specific embodiment; and may refer to at least one, and optionally more than one A, and at least one, and optionally more than one B (and optionally including other components), etc. in another specific embodiment.

[0161] It should also be understood that in some of the methods described herein that include more than one step or action, unless otherwise specified, the order of those steps or actions in the method are not necessarily limited to the order of those steps or actions in the method described.

[0162] The term "effective" may mean, but is in no way limited to, an amount / dose that can achieve or is sufficient to prevent, inhibit the occurrence, alleviate, delay or treat (relieve symptoms to a certain extent, preferably all) the symptoms of a condition, disorder or disease state in a subject who needs such treatment or is receiving such treatment when the active pharmaceutical ingredient is used for the intended use in the context. The term "effective" encompasses all other effective amount or effective concentration terms, such as "effective amount / dose", "pharmaceutically effective amount / dose" or "therapeutically effective amount / dose" otherwise described or used in this application.

[0163] The effective amount depends on the type and severity of the disease, the composition used, the route of administration, the species of mammal to be treated, the physical characteristics of the particular mammal under consideration, and the concomitant drugs and other factors that can be recognized by those skilled in the art of medicine. The exact amount can be determined by those skilled in the art by conventional techniques (e.g., see Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0164] The terms "pharmaceutically acceptable" or "pharmaceutically acceptable" may mean, but are in no way limited to, entities and compositions that do not produce adverse, allergic or other untoward reactions when administered to an animal or a human as desired.

[0165] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable carrier" may mean, but is in no way limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are compatible with the administration of the pharmaceutical. Suitable carriers are described in the latest edition of Remington's Pharmaceutical Sciences, a standard reference text in this field, incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutical active ingredients is well known in the art. Unless any conventional media or agent is incompatible with the active compound, its use in the composition should be considered. Supplementary active compounds may also be incorporated into the composition.

[0166] Unless otherwise indicated, the term "compound" as used herein refers to any specific chemical compound disclosed herein, and includes tautomers, regioisomers, geometric isomers thereof; where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers); where applicable, pharmaceutically acceptable salts and derivatives thereof (including prodrug forms). In its use in the context, the term compound generally refers to a single compound, but may also include other compounds, such as stereoisomers, regioisomers and / or optical isomers (including racemic mixtures), as well as specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds. In this context, the term also refers to prodrug forms of compounds that are modified to facilitate administration and delivery of the compound to an active site. It should be noted that in describing the compounds herein, a number of substituents and associated variations are specifically described with respect thereto.

[0167] It will be understood by those skilled in the art that the molecules described herein are stable compounds as described below. When double bonds and single bonds are used, they are represented or understood within the context of the compound being described and according to the well-known rules of valence interactions.

[0168] As used herein, "alkoxy" refers to an alkyl group having a single bond to oxygen; for example, methoxy (-O-CH3) and ethoxy (-O-CH2CH3).

[0169] As used herein, "derivatives" may refer to compositions directly formed from natural compounds by modification or by partial substitution. As used herein, "analogs" may refer to compositions having structures similar to, but not identical to, natural compounds.

[0170] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting them for degradation. For example, the cerebellum protein E3 ubiquitin ligase, when present alone or in combination with an E2 ubiquitin-conjugating enzyme, attaches ubiquitin to a lysine on a target protein, which is then targeted to a specific substrate protein for degradation by the proteasome. Thus, E3 ubiquitin ligases, when present alone or in a complex with an E2 ubiquitin conjugating enzyme, are responsible for the transfer of ubiquitin to a target protein. In general, ubiquitin ligases involve polyubiquitination, whereby a second ubiquitin is attached to the first; a third to the second, and so on. Polyubiquitination marks a protein for degradation by the proteasome. However, some ubiquitination events are defined as mono-ubiquitination, where only a single ubiquitin is added to a substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins are not targeted for degradation by the proteasome, but may change their cellular location or function; for example, by binding to other proteins with domains that can bind ubiquitin. Further, E3 ubiquitin ligases promote the formation of polyubiquitin chains through lysine residues on ubiquitin. Lys48-linked chains are the main type of polyubiquitination, which can target proteins to the proteasome for degradation.

[0171] The term "patient" or "subject" is used throughout the specification to describe a cell, tissue or animal, preferably a mammal, such as a human or a domesticated animal, to which the compositions of the present disclosure are provided for treatment (including prophylactic treatment). For a specific treatment for an infection, disorder or disease state in a specific animal, such as a human patient, the term "patient" refers to a specific animal, including a domestic animal such as a dog or cat, or a farm animal such as a horse, a cow, a sheep, etc. Unless otherwise indicated or implied in the context of the term, in the present disclosure, the term "patient" generally refers to a human patient.

[0172] It should be understood that in all examples disclosed herein, the description of an integer range for any variable describes the range of the variable, all individual numbers within the range, and all possible subranges. For example, the description that n is an integer from 0 to 4 describes 0, 1, 2, 3, and 4 as independently selectable values ​​within the range. In addition, the description that n is an integer from 0 to 4 also describes its individual and all subranges, where n is individually 0 to 4, 0 to 3, 0 to 2, 0 to 1, 1 to 4, 1 to 3, 1 to 2, 2 to 4, 2 to 3, and 3 to 4. In addition, the term "C 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbons.

[0173] The following is a detailed description to assist those skilled in the art in implementing the present disclosure. Those skilled in the art may modify or vary the specific embodiments described herein without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, drawings, and other references mentioned herein are expressly incorporated herein by reference in their entirety. DETAILED DESCRIPTION

[0174] Table 1 below shows examples of bifunctional compounds having an ABM-L-CLM structure according to the present disclosure:

[0175] Table 1

[0176]

[0177]

[0178]

[0179]

[0180]

[0181] Methods of producing compounds of the present disclosure

[0182] The following is an example of a general method for producing the compounds of the present disclosure. In addition, extraction and purification can be carried out using conventional organic chemical experimental procedures.

[0183] The synthesis of the compounds disclosed herein can be carried out by referring to procedures known in the art.

[0184] The starting material compounds described in this specification, commercially available compounds, compounds disclosed in the present invention, compounds described in references cited in this specification, and other known compounds can be used.

[0185] Among the compounds disclosed herein, some compounds may exist as tautomers, and the present disclosure includes all possible isomers and mixtures thereof, including the above-mentioned tautomers.

[0186] When it is desired to obtain a salt of the compound of the present disclosure, when the compound of the present disclosure is obtained in the form of a salt, it can be purified as such, and when the compound of the present disclosure is obtained in the free form, a conventional method can be used to form a salt by dissolving or suspending the compound in a suitable organic solvent and adding an acid or a base.

[0187] Furthermore, in some cases, the compounds of the present disclosure and their pharmaceutically acceptable salts exist in the form of an addition product with water or various solvents (hydrates or solvates), and these addition products are included in the present disclosure.

[0188] The details of one or more specific embodiments of the present disclosure are as described below in the specification. Other features, objectives and advantages of the present disclosure will be apparent from the description and claims.

[0189] The compounds of the present disclosure can be synthesized from commercially available starting materials by methods known in the art. For example, the compounds of the present disclosure can be prepared by the following pathways:

[0190] General steps for compound preparation:

[0191] Step 1

[0192]

[0193] Step 1 depicts a general method for preparing the bifunctional compound of the present disclosure. In the first stage, the diester compound (i) is condensed with 3-aminopiperidine-2,6-dione to form an intermediate (ii). In the second stage, the intermediate (ii) is further condensed with a specific ABM compound to obtain the desired compound (iii). The letter "P" shown in the aforementioned step 1 represents a protecting group.

[0194] The following specific examples should be interpreted as merely illustrative and will not limit the remainder of the disclosure in any way. Without further elaboration, it is believed that those skilled in the art will be able to maximize the disclosure based on the description herein. All publications cited herein are incorporated herein by reference in their entirety.

[0195] Synthesis method A-Synthesis of compound 1:

[0196] (1) Preparation of intermediate IA

[0197] Intermediate IA was first prepared from commercially available 3-benzyloxy-aniline by the following route:

[0198] Synthesis Flowchart 1

[0199]

[0200] Palladium acetate (Pd(OAc)2) (1.13 g, 10 mol%) was added to a vessel purged with air, which contained a solution of 3-benzyloxy-aniline (10 g, 50.1 mmol), dimethyl acetylenedicarboxylate (5.86 mL, 47.6 mmol) and dimethylacetamide (DMA) / pivalic acid (PivOH) (4:1 v / v; 100 mL). The reaction mixture was gradually heated to 120°C for 8 hours. After the reaction was completed, the solution was cooled to room temperature, diluted with ethyl acetate (200 mL), washed with water (3×50 mL) and brine (50 mL), dried over magnesium sulfate (MgSO4), filtered, and evaporated in vacuo to obtain a crude product. The crude product was purified by column chromatography using silica gel (KM3 SCIENTIFIC CORP., particle size 45-75 μm) with an eluent (n-hexane: ethyl acetate = 5: 1) to obtain 6-benzyloxy-1H-indole-2,3-dicarboxylic acid dimethyl ester I-a1 (8.4 g, 54%) as a brown solid.

[0201] An ice-cold solution of 6-benzyloxy-1H-indole-2,3-dicarboxylic acid dimethyl ester I-a1 (3.0 g, 8.84 mmol) in N,N-dimethylformamide (DMF) (15 mL) was treated with 60% sodium hydride (NaH) (0.53 g, 13.3 mmol) and iodomethane (0.82 mL, 13.3 mmol) and then warmed to room temperature. After 1 hour, the reaction mixture was partitioned between dichloromethane (DCM) (60 mL) and saturated aqueous ammonium chloride (NH4Cl) (20 mL). The combined organic layers were collected, washed with water (3×20 mL) and brine (20 mL), then dried over MgSO4, filtered and concentrated to give a crude product. The crude product was purified by column chromatography using silica gel (KM3 SCIENTIFIC CORP., particle size 45-75 μm) and an eluent (n-hexane: ethyl acetate = 3:1) to obtain a brown solid I-a2 (2.7 g, 87%).

[0202] Palladium on carbon (Pd / C) (0.5 g) was added to a methanol (MeOH) solution (150 mL) containing 6-benzyloxy-1-methyl-1H-indole-2,3-dicarboxylic acid dimethyl ester) I-a2 (5.0 g) and stirred for 2 hours under a hydrogen atmosphere. After the reaction was completed, the mixture was passed through a Celite pad and rinsed with ethyl acetate (10 mL), and the organic solvent was collected and removed using a rotor to obtain an intermediate I-a3 (3.72 g, 100%).

[0203] To a stirred solution of 6-hydroxy-1-methyl-1H-indole-2,3-dicarboxylic acid dimethyl ester I-a3 (2.85 g, 10.83 mmol, 1.0 eq) in DCM (60 mL) was added N,N-diisopropylethylamine (DIPEA) (5.6 mL, 32.49 mmol, 3 eq) at 0°C and the mixture was stirred at the same temperature for 10 minutes. Trifluoromethanesulfonic anhydride (Tf2O) (2.9 mL, 16.25 mmol, 1.5 eq) was added dropwise to the reaction and the resulting mixture was stirred at 0°C for 1 hour. The reaction was diluted with DCM (40 mL) and washed with saturated sodium bicarbonate (NaHCO3) (10 mL), saturated NH4Cl (10 mL), water and brine. The organic layer was dried over MgSO4, filtered and concentrated to give a dark brown oil. The dark brown oil was purified by column chromatography using silica gel (KM3 SCIENTIFIC CORP., particle size 45-75 μm) eluted with 10% ethyl acetate in n-hexane to give the title compound as pure product I-a4 (3.68 g, 86%).

[0204] To a stirred toluene solution (20 mL) containing 1-methyl-6-trifluoromethanesulfonyloxy-1H-indole-2,3-dicarboxylic acid dimethyl ester I-a4 (0.77 g, 1.94 mmol, 1.0 eq), tert-butyl piperazine-1-carboxylate (1.08 g, 5.82 mmol, 3.0 eq), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) (0.18 g, 20 mol%) and cesium carbonate (Cs2CO3) (1.9 g, 5.82 mmol, 3 eq) were added. The mixture was degassed with nitrogen (N2) for 10 minutes, and Pd(OAc)2 (0.087 g, 20 mol%) was added to the mixture. The resulting mixture was stirred at 80°C for 17 hours until no starting material remained. The reaction was cooled to room temperature, diluted with ethyl acetate (30 mL) and water (10 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (30 mL), and the combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered and concentrated to give a crude material. The crude material was purified by column chromatography using silica gel (KM3 SCIENTIFIC CORP., particle size 45-75 μm) eluted with 25% ethyl acetate in n-hexane to give the title compound, which was pure product I-a5 (0.72 g, 86%).

[0205] I-a5 (0.65 g, 1.51 mmol) was treated with NaOH (0.6 g, 15.1 mmol) in ethanol (EtOH) (30 mL) and heated to reflux (85°C bath temperature). After 4 hours, the reaction mixture was cooled to ambient temperature, the excess EtOH was removed, diluted with ethyl acetate (30 mL) and acidified to pH 3 with 1 M hydrochloric acid (HCl), and the layers were separated. The aqueous layer was then extracted with ethyl acetate (30 mL), and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give a white solid. The white solid was then mixed with acetic anhydride (Ac2O) (5 mL) and heated to 140°C. After 2 hours, a mono-ester was found by liquid chromatography mass spectrometry (LC-MASS), and the reaction mixture was cooled to ambient temperature. The excess Ac2O was then removed, and anhydrous toluene (5 mL) was added, mixed and concentrated. This yielded the residue I-a6 which was used without further purification.

[0206] A tetrahydrofuran (THF) solution (2 mL) of 3-aminopiperidine-2,6-dione hydrochloride (0.11 g, 2 eq) and N,N-diisopropylethylamine (DIPEA) (0.23 mL, 4 eq) was stirred at room temperature for 30 minutes, and then a THF solution (2 mL) of compound I-a6 (0.13 g, 1 eq) was added. The reaction was stirred at room temperature for 50 minutes, and then the mixture was diluted with ethyl acetate (10 mL) and water (10 mL). Then 1N HCl was added. (aq) , until the pH value of the aqueous layer is less than 2 (<2). The aqueous layer was extracted with ethyl acetate (2×10 mL), and the organic layers were combined, washed with brine (10 mL), and dried over MgSO4. The solvent was removed to obtain a crude material, which was used in the next step without purification. The above crude material was dissolved in THF (4 mL), and carbonyldiimidazole (CDI) (0.11 g, 2 eq) and 4-dimethylaminopyridine (DMAP) (4 mg, 0.1 eq) were added. The reaction mixture was stirred at 50°C for 2 hours. After cooling, the reaction mixture was diluted with ethyl acetate (10 mL) and water (10 mL). Then 1N HCl was added (aq), until the pH value of the aqueous layer is less than 2 (<2), and then the aqueous layer is extracted with ethyl acetate (2×10 mL). The organic layers are collected and combined, washed with brine (10 mL), and dried over sodium sulfate (Na2SO4). The solvent is removed to obtain a crude product, and then the crude product is purified by flash column chromatography with an eluent (n-hexane / ethyl acetate (EtOAc) = 1 / 1 to 1 / 2) to obtain a compound I-a7 (0.28 g, 85%). Then, solid I-a7 and trifluoroacetic acid (CF3COOH) (trifluoroacetic acid, TFA) (1 mL) are combined and stirred in dichloromethane (CH2Cl2) (4 mL) at room temperature for 4 hours. After the reaction is completed, the excess CF3COOH is removed under vacuum to obtain a residue. The residue was then diluted with DCM (10 mL) and basified to pH 10 with sodium carbonate (Na2CO3). The organic layer was washed with brine (5 mL), dried over Na2SO4, filtered and concentrated to afford an intermediate IA, which was used directly without purification.

[0207] (2) Preparation of intermediate IB

[0208] Intermediate IB was prepared from commercially available 4-[(trans-3-amino-2,2,4,4-tetramethylcyclobutyl)oxy]-2-chloro-, hydrochloride by the following route:

[0209] Synthesis Flowchart 2

[0210]

[0211] A mixture of 6-Chloro-N-(trans-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide I-b1 (800 mg, 1 eq), compound I-b2 (200 mg, 1.1 eq) and triethylamine (TEA) (0.57 mL, 2 eq) in dimethyl sulfoxide (DMSO) (6 mL) was stirred at 100° C. for 24 hours. After cooling, the mixture was slowly added to water (30 mL). The suspension was filtered to obtain compound I-b3 (0.85 g, 94%).

[0212] Dess-Martin periodinane (0.75 g, 1.78 mmol) was added to a DCM solution (25 mL) containing I-b3 (0.60 g, 1.36 mmol) at room temperature, followed by stirring at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was washed with saturated sodium thiosulfate (Na2S2O3) (10 mL×2), saturated NaHCO3 (10 mL), and brine (10 mL), dried over Na2SO4, and concentrated to provide intermediate IB (0.54 g, 90%).

[0213] (3) Preparation of Compound 1 from Intermediate IA and Intermediate IB

[0214] Compound 1 is prepared by the following route:

[0215] Synthesis Flowchart 3

[0216]

[0217] To a mixture of intermediate IA (100 mg, 0.25 mmol) and IB (111 mg, 0.25 mmol) in DCM (1 mL), sodium triacetoxyborohydride (NaBH(OAc)3) (107 mg, 0.50 mmol) was added. The resulting solution was stirred at room temperature for 17 hours. After the reaction was completed, water was added to obtain a solution, which was then diluted with DCM (10 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography using silica gel (KM3 SCIENTIFIC CORP., particle size 45-75 μm) to obtain compound 1 (160 mg, 78%). MS: m / z 819.5 (M + +1); 1H NMR(DMSO-d6)δ11.05(s,1H),8.55(d,1H),7.87-7.82(m,2H),7.56(d,1H),7.39(d,1H),7.17-7.12(m,2 H),7.07(s,1H),6.87(d,1H),4.96(dd,1H),4.56-4.51(m,1H),4.26-4.24(m,2H),3.93(s,3H),3.88-3.8 2(m,3H),3.29(bs,4H),3.13-3.08(m,1H),2.92-2.86(m,1H),2.72-2.70(m,2H),2.59(bs,4H),2.60-2.4 9(m,2H),2.12-2.09(m,2H),2.05-2.01(m,1H),1.92-1.89(m,2H),1.67-1.61(m,2H),1.54-1.49(m,2H).

[0218] Compound 1 can also be prepared by the following route:

[0219] Synthesis Flow Chart 4

[0220]

[0221] In a DCM solution (2 mL) containing I-b3 (0.1 g, 0.25 mmol), DIPEA (0.16 mL, 4.0 eq) was added at room temperature. Methanesulfonyl chloride (MsCl) (0.038 mL, 2.0 eq) was then added dropwise. The reaction mixture was stirred at room temperature for 1 to 2 hours. After the reaction was completed, it was diluted with DCM (10 mL), washed with saturated NaHCO3 (5 mL), saturated NH4Cl (5 mL) and brine (5 mL), dried with Na2SO4 (s), concentrated, and purified by column chromatography using silica gel (KM3 SCIENTIFIC CORP., particle size 45-75 μm) (DCM / acetone=10 / 1) to obtain intermediate I-b3-1 (0.11 g, 84%).

[0222] A solution of I-b3-1 (0.104 g, 0.20 mmol), IA (0.079 g, 0.20 mmol), potassium iodide (KI) (0.1 g, 3.0 eq) and DIPEA (0.17 mL, 5.0 eq) in anhydrous acetonitrile (CH3CN) (ACN) (2 mL) was heated to 75°C for 17 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (10 mL) and basified to pH 10 with saturated Na2CO3. The organic layer was washed with brine (5 mL), dried over Na2SO4(s), concentrated and purified by column chromatography using silica gel (KM3SCIENTIFIC CORP., particle size 45-75 μm) to give compound 1 (0.095 g, 58%).

[0223] Synthesis method B-Synthesis of compound 2:

[0224] (1) Preparation of intermediate IC

[0225] Residue IC was first prepared from commercially available 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester by the following route:

[0226] Synthesis Flowchart 5

[0227]

[0228] To a stirred solution (17 mL) of 1,4-dioxane containing dimethyl 1-methyl-6-trifluoromethanesulfonyloxy-1H-indole-2,3-dicarboxylate I-a4 (683 mg, 1.72 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (797 mg, 2.58 mmol, 1.5 eq) and Cs2CO3 (1.06 g, 3.26 mmol, 1.9 eq) were added at 25°C. The mixture was degassed with N2 for 15 minutes, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dp pf)Cl2) (63 mg, 0.09 mmol, 5 mol%) was added at 25°C. The reaction was stirred at 25°C for 5 hours until no starting material remained. The reaction solution was diluted with ethyl acetate (30 mL) and water (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (15 mL×2). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give a crude material. The crude material was purified by column chromatography using silica gel (KM3 SCIENTIFIC CORP., particle size 45-75 μm) eluted with 10% to 15% ethyl acetate in n-hexane to give intermediate I-c1 (470 mg, 64%, R f =0.21 in EA / Hex=1 / 5).

[0229] Pd / C (0.2 g) was added to a solution of intermediate I-c1 (2.0 g) in MeOH (20 mL) and stirred for 2 hours under hydrogen atmosphere. After the reaction was completed, the mixture was passed through a Celite pad and rinsed with EtOAc (10 mL), the organic solvent was collected and removed on a rotor to give an intermediate I-c2 (2.0 g, 100%).

[0230] Intermediate I-c2 (0.65 g, 1.51 mmol) was treated with NaOH (0.6 g, 15.1 mmol) in EtOH (30 mL) and heated to reflux. After 4 hours, the reaction mixture was cooled to ambient temperature, excess EtOH was removed, diluted with ethyl acetate (30 mL) and acidified to pH 3 with 1M HCl. The aqueous layer was then extracted with ethyl acetate (30 mL), the organic layers were combined, washed with brine, dried (using MgSO4), filtered and concentrated to give a white solid. The white solid was then combined with Ac2O (5 mL) and heated to 140°C. After 2 hours, a monoester was found by LC-MASS and the reaction mixture was cooled to ambient temperature. Excess Ac2O was then removed, followed by addition of anhydrous toluene (5 mL) and concentrated. This produced intermediate I-c3, which was then used without further purification.

[0231] A THF solution (2 mL) of 3-aminopiperidine-2,6-dione hydrochloride (0.22 g, 2 eq) and N,N-diisopropylethylamine (DIPEA) (0.46 mL, 4 eq) was stirred at room temperature for 30 minutes, and then a THF solution (2 mL) of intermediate I-c3 (0.26 g, 1 eq) was added. The reaction was stirred at room temperature for 50 minutes, and then the mixture was diluted with ethyl acetate (20 mL) and water (20 mL). 1N HCl was then added. (aq) , until the pH value of the aqueous layer is less than 2 (<2). The aqueous layer was extracted with ethyl acetate (2×20 mL), and the organic layers were combined, washed with brine (20 mL), and dried over MgSO4. The solvent was removed to obtain a crude material, and the crude material was used in the next step without purification. The above crude material was dissolved in THF (8 mL), and CDI (0.22 g, 2 eq) and DMAP (8 mg, 0.1 eq) were added. The reaction mixture was stirred at 50°C for 2 hours. After cooling, the reaction mixture was diluted with ethyl acetate (20 mL) and water (20 mL). Then 1N HCl was added (aq), until the pH value of the aqueous layer is less than 2, then the aqueous layer is extracted with ethyl acetate (2×20 mL). The organic layers are collected and combined, washed with brine (20 mL), and dried over Na2SO4. The solvent is removed to obtain a crude product, which is then purified by flash column chromatography with an eluent (n-hexane / EtOAc=1 / 1 to 1 / 2) to obtain intermediate I-c4 (0.26 g, 80%). Intermediate I-c4 and CF3COOH (2.5 mL) are then combined and stirred in DCM (10 mL) at room temperature for 4 hours. After the reaction is completed, the excess CF3COOH is removed under vacuum to obtain a residue. The residue is then diluted with DCM (10 mL) and basified to pH 10 with Na2CO3, and the organic layer is washed with brine (5 mL), dried over Na2SO4, filtered and concentrated to obtain intermediate IC, which is used directly without purification.

[0232] (2) Preparation of Compound 2 from Intermediate IB and Intermediate IC

[0233] Compound 2 was prepared by the following route:

[0234] Synthesis Flowchart 6

[0235]

[0236] To a mixture of intermediate IB (112 mg, 0.254 mmol) and IC (100 mg, 0.254 mmol) in DCM (1 mL), NaBH(OAc)3 (107 mg, 0.508 mmol) was added. The resulting solution was stirred at room temperature for 17 hours. After the reaction was completed, water was added to obtain a solution, which was then diluted with DCM (10 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4, filtered and concentrated to obtain a crude product. The crude product was then purified by column chromatography using silica gel (KM3SCIENTIFIC CORP., particle size 45-75 μm) to obtain compound 2 (156 mg, 75%). MS: 841.5 (M + +23); 1H NMR(DMSO-d6)δ11.07(s,1H),8.56(d,1H),7.87-7.83(m,2H),7.69-7.65(m,2H),7.39(d,1H),7.31(d,1H) ,7.14(dd,1H),6.87(d,1H),5.00(dd,1H),4.57-4.52(m,1H),4.24(bs,2H),4.00(s,3H),3.89-3.81(m,3H ),3.12-3.05(m,1H),3.04-2.98(m,1H),2.93-2.87(m,1H),2.73-2.64(m,2H),2.63-2.50(m,6H),2.13-2. 07(m,2H),2.07-2.01(m,1H),1.94-1.88(m,2H),1.87-1.74(m,4H),1.68-1.62(m,2H),1.55-1.49(m,2H).

[0237] Synthesis Method C-Synthesis of Chiral Intermediate ID:

[0238] Intermediate ID is prepared from I-a6 by the following route:

[0239] Synthesis Flowchart 7

[0240]

[0241] A THF solution (2 mL) of (S)3-aminopiperidine-2,6-dione hydrochloride (0.11 g, 2 eq) and N,N-diisopropylethylamine (DIPEA) (0.23 mL, 4 eq) was stirred at room temperature for 30 minutes, and then a THF solution (2 mL) of compound I-a6 (0.13 g, 1 eq) was added. The reaction was stirred at room temperature for 50 minutes, and then the mixture was diluted with ethyl acetate (10 mL) and water (10 mL). Then 1N HCl was added (aq) , until the pH value of the aqueous layer is less than 2 (<2). The aqueous layer was extracted with ethyl acetate (2×10 mL), and the organic layers were combined, washed with brine (10 mL), and dried over MgSO4. The solvent was removed to obtain a crude material, and the crude material was used in the next step without purification. The aforementioned crude material was dissolved in THF (4 mL), and CDI (0.11 g, 2 eq) and DMAP (4 mg, 0.1 eq) were added. The reaction mixture was stirred at 50°C for 2 hours. After cooling, the reaction mixture was diluted with ethyl acetate (10 mL) and water (10 mL). Then 1N HCl was added (aq), until the pH value of the aqueous layer is less than 2 (<2), and then the aqueous layer is extracted with ethyl acetate (2×10 mL). The organic layer is collected, washed with brine (10 mL), and dried over Na2SO4. The solvent is removed to obtain a crude product, and then the crude product is purified by flash column chromatography with an eluent (n-hexane / EtOAc=1 / 1 to 1 / 2) to obtain a chiral intermediate ID (0.15 g, 90%). The chiral intermediate ID can be used to replace IA or IC to obtain the chiral compound of the present disclosure.

[0242] The preparation of compounds 1 and 2 of the present disclosure is exemplified above. Compounds 3 to 51 of the present disclosure can be synthesized by a method similar to Synthesis Method A (Synthesis Schemes 1 to 4), Synthesis Method B (Synthesis Schemes 5 to 6) or Synthesis Method C, or any known method based on the general knowledge of organic chemistry, which is obtained by changing one or more starting materials to obtain the target product.

[0243] Compound 3: MS: m / z 855.6 (M + +23); 1 H NMR(DMSO-d6)δ11.05(s,1H),8.55(d,1H),7.87-7.82(m,2H),7.56(d,1H),7.39(d,1H),7.17-7.12(m,3 H),6.87(d,1H),4.96(dd,1H),4.56-4.51(m,1H),4.41(q,2H),4.26-4.24(m,2H),3.89-3.82(m,3H),3.2 9(bs,4H),3.13-3.08(m,1H),2.92-2.86(m,1H),2.72-2.70(m,2H),2.60(bs,4H),2.60-2.49(m,2H),2.1 2-2.09(m,2H),2.06-2.03(m,1H),1.92-1.89(m,2H),1.67-1.61(m,2H),1.55-1.49(m,2H),1.41(t,3H).

[0244] Compound 4: MS: m / z 882.6 (M + +23); 11H NMR (DMSO-d6) δ 11.04 (s, 1H), 8.57 (m, 1H), 7.98 - 7.93 (m, 2H), 7.85 (m, 1H), 7.56 (m, 1H), 7.39 (m, 1H), 7.16 - 7.10 (m, 3H), 6.44 (m, 1H), 4.98 - 4.95 (m, 1H), 4.54 (m, 1H), 4.40 (m, 2H), 3.79 (m, 1H), 3.71 (m, 1H), 3.58 (m, 1H), 3.33 - 3.26 (m, 5H), 3.03 (m, 1H), 2.91 - 2.86 (m, 1H), 2.64 - 2.50 (m, 5H), 2.45 - 2.39 (m, 1H), 2.30 (m, 1H), 2.16 - 2.04 (m, 4H), 1.90 (m, 2H), 1.66 (m, 3H), 1.54 - 1.46 (m, 4H), 1.40 (m, 3H), 1.24 (m, 2H).

[0245] Compound 5: MS: m / z 882.9 (M + +23); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.59 (d, 1H), 8.02 (d, 1H), 7.94 (dd, 1H), 7.86 (d, 1H), 7.56 (d, 1H), 7.39 (m, 1H), 7.16 - 7.14 (m, 2H), 7.12 (s, 1H), 6.83 (d, 1H), 4.96 (dd, 1H), 4.57 - 4.53 (m, 1H), 4.43 - 4.38 (m, 4H), 3.84 - 3.78 (m, 1H), 3.28 (bs, 4H), 2.92 - 2.86 (m, 3H), 2.62 - 2.58 (m, 1H), 2.55 (bs, 4H), 2.52 - 2.49 (m, 1H), 2.23 - 2.22 (m, 2H), 2.12 - 2.10 (m, 2H), 2.07 - 2.02 (m, 1H), 1.94 - 1.85 (m, 3H), 1.85 - 1.80 (m, 2H), 1.56 - 1.46 (m, 4H), 1.41 (t, 3H), 1.12 - 1.07 (m, 2H).

[0246] Compound 6: MS: m / z 910.7 (M + +23); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.62 (d, 1H), 7.94 (dd, 1H), 7.91 (d, 1H), 7.57 - 7.54 (m, 2H), 7.21 (d, 1H), 7.16 (d, 1H), 7.12 (s, 1H), 7.00 (dd, 1H), 6.47 (d, 1H), 4.96 (dd, 1H), 4.41 (q, 2H), 4.31 (s, 1H), 4.06 (d, 1H), 3.73 (m, 1H), 3.63 - 3.57 (m, 1H), 3.33 - 3.29 (m, 1H), 3.29 (bs, 4H), 3.07 - 3.04 (m, 2H), 2.92 - 2.85 (m, 1H), 2.62 - 2.54 (m, 5H), 2.47 - 2.41 (m, 1H), 2.34 - 2.28 (m, 1H), 2.19 - 2.14 (m, 1H), 2.07 - 2.02 (m, 1H), 1.71 - 1.64 (m, 3H), 1.41 (t, 3H), 1.28 - 1.21 (m, 2H), 1.22 (s, 6H), 1.12 (s, 6H).

[0247] Compound 7: MS: m / z 910.7 (M + +23); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.63 (d, 1H), 7.94 (d, 1H), 7.91 (d, 1H), 7.60 - 7.56 (m, 2H), 7.22 (d, 1H), 7.16 (d, 1H), 7.12 (s, 1H), 7.01 (dd, 1H), 6.86 (d, 1H), 4.96 (dd, 1H), 4.44 - 4.40 (m, 4H), 4.31 (s, 1H), 4.06 (d, 1H), 3.28 (bs, 4H), 3.08 - 3.04 (m, 2H), 2.92 - 2.86 (m, 3H), 2.62 - 2.60 (m, 1H), 2.55 (bs, 4H), 2.53 - 2.49 (m, 1H), 2.26 - 2.21 (m, 2H), 2.07 - 2.01 (m, 1H), 1.94 - 1.87 (m, 1H), 1.84 - 1.82 (m, 2H), 1.41 (t, 3H), 1.28 - 1.21 (m, 2H), 1.22 (s, 6H), 1.12 (s, 6H).

[0248] Compound 8: MS: m / z 912.0 (M + +23); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.22 (d, 1H), 7.91 (d, 1H), 7.84 (d, 1H), 7.56 (d, 1H), 7.26 (d, 1H), 7.17 (d, 1H), 7.12 (s, 1H), 7.04 (dd, 1H), 6.98 (d, 1H), 4.96 (dd, 1H), 4.46 (s, 1H), 4.41 (q, 2H), 4.01 (d, 1H), 3.89 - 3.64 (m, 2H), 3.32 - 3.24 (m, 6H), 2.93 - 2.86 (m, 1H), 2.65 - 2.55 (m, 5H), 2.47 - 2.42 (m, 1H), 2.40 - 2.33 (m, 1H), 2.24 - 2.18 (m, 1H), 2.07 - 2.02 (m, 1H), 1.74 - 1.67 (m, 3H), 1.41 (t, 3H), 1.29 - 1.21 (m, 2H), 1.22 (s, 6H), 1.15 (s, 6H).

[0249] Compound 9: MS: m / z 889.9 (M + +1); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.24 (d, 1H), 7.91 (d, 1H), 7.83 (d, 1H), 7.56 (d, 1H), 7.38 (d, 1H), 7.26 (d, 1H), 7.16 (d, 1H), 7.12 (s, 1H), 7.04 (dd, 1H), 4.96 (dd, 1H), 4.53 - 4.50 (m, 2H), 4.47 (s, 1H), 4.42 - 4.39 (m, 2H), 4.01 (d, 1H), 3.28 (bs, 4H), 3.08 - 3.04 (m, 2H), 2.92 - 2.86 (m, 1H), 2.62 - 2.60 (m, 1H), 2.56 (bs, 4H), 2.53 - 2.48 (m, 1H), 2.26 - 2.24 (m, 2H), 2.08 - 2.02 (m, 1H), 2.00 - 1.93 (m, 1H), 1.88 - 1.86 (m, 2H), 1.41 (t, 3H), 1.22 (s, 6H), 1.14 (s, 6H), 1.20 - 1.12 (m, 2H).

[0250] Compound 10: MS: m / z 854.8 (M + +23); 11H NMR (DMSO-d6) δ 11.07 (s, 1H), 8.55 (d, 1H), 7.87 - 7.83 (m, 2H), 7.72 (s, 1H), 7.67 (d, 1H), 7.39 (d, 1H), 7.30 (d, 1H), 7.14 (dd, 1H), 6.87 (d, 1H), 5.00 (dd, 1H), 4.57 - 4.52 (m, 1H), 4.48 (q, 2H), 4.26 - 4.23 (m, 2H), 3.89 - 3.82 (m, 3H), 3.12 - 3.05 (m, 1H), 3.04 - 2.98 (m, 1H), 2.93 - 2.87 (m, 1H), 2.73 - 2.64 (m, 3H), 2.63 - 2.50 (m, 4H), 2.15 - 2.04 (m, 3H), 1.94 - 1.88 (m, 2H), 1.87 - 1.74 (m, 4H), 1.67 - 1.62 (m, 2H), 1.55 - 1.49 (m, 2H), 1.44 (t, 3H).

[0251] Compound 11: MS: m / z 860.9 (M + +1); 1 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 8.59 (d, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.71 - 7.66 (m, 2H), 7.39 (d, 1H), 7.34 (d, 1H), 7.30 (d, 1H), 7.14 (dd, 1H), 5.00 (dd, 1H), 4.56 - 4.46 (m, 5H), 3.89 - 3.83 (m, 1H), 3.06 - 2.95 (m, 3H), 2.93 - 2.86 (m, 1H), 2.72 - 2.64 (m, 1H), 2.63 - 2.56 (m, 1H), 2.55 - 2.50 (m, 4H), 2.23 - 2.17 (m, 2H), 2.12 - 2.09 (m, 2H), 2.08 - 1.98 (m, 3H), 1.92 - 1.76 (m, 7H), 1.67 - 1.62 (m, 2H), 1.55 - 1.49 (m, 2H), 1.44 (t, 3H), 1.19 - 1.10 (m, 2H).

[0252] Compound 12: MS: m / z 861.0 (M + +1); 1H NMR(DMSO-d6)δ11.07(s,1H),8.52(d,1H),7.87-7.83(m,3H),7.74-7.65(m,2H),7.39(d,1H),7.30(d,1H),7.14(dd,1H),6. 95(d,1H),5.00(dd,1H),4.60-4.52(m,1H),4.48(q,2H),3.89-3.83(m,1H),3.82-3.62(m,2H),3.22-3.10(m,1H),3.10-2.96 (m,2H),2.93-2.86(m,1H),2.64-2.59(m,1H),2.58-2.50(m,5H),2.42-2.33(m,1H),2.26-2.16(m,1H),2.14-2.09(m,2H),2. 08-1.98(m,3H),1.92-1.88(m,2H),1.88-1.75(m,4H),1.75-1.61(m,5H),1.56-1.49(m,2H),1.44(t,3H),1.29-1.24(m,2H).

[0253] Compound 13: MS: m / z 886.8 (M + +1).

[0254] Compound 14: MS: m / z 900.8 (M + +1).

[0255] Compound 15: MS: m / z 909.5 (M + +23); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 7.91 (d, 1H), 7.75 (d, 1H), 7.56 (d, 1H), 7.38 (d, 1H), 7.21 (d, 1H), 7.17 (d, 1H), 7.12 (s, 1H), 7.01 (dd, 1H), 6.54 (d, 1H), 4.96 (dd, 1H), 4.46 (s, 1H), 4.41 (q, 2H), 4.32 (s, 2H), 4.06 (d, 1H), 3.54 - 3.51 (m, 1H), 3.41 - 3.37 (m, 2H), 3.29 (bs, 4H), 2.97 - 2.94 (m, 1H), 2.92 - 2.85 (m, 1H), 2.61 - 2.54 (m, 5H), 2.47 - 2.42 (m, 1H), 2.35 - 2.31 (m, 1H), 2.24 - 2.18 (m, 1H), 2.19 - 2.17 (m, 1H), 2.06 - 2.03 (m, 1H), 1.70 - 1.65 (m, 3H), 1.41 (t, 3H), 1.28 - 1.23 (m, 2H), 1.22 (s, 6H), 1.13 (s, 6H).

[0256] Compound 16: MS: m / z 888.0 (M + +1).

[0257] Compound 17: MS: m / z 847.9 (M + +1); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.52 (d, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.56 (d, 1H), 7.39 (d, 1H), 7.17 - 7.12 (m, 3H), 6.96 (d, 1H), 4.96 (dd, 1H), 4.57 - 4.52 (m, 1H), 4.41 (q, 2H), 3.89 - 3.83 (m, 1H), 3.80 - 3.60 (m, 2H), 3.57 - 3.45 (m, 1H), 3.32 - 3.26 (m, 5H), 2.92 - 2.86 (m, 1H), 2.71 - 2.55 (m, 5H), 2.47 - 2.45 (m, 2H), 2.19 - 2.14 (m, 1H), 2.12 - 2.09 (m, 2H), 2.06 - 2.02 (m, 1H), 1.92 - 1.91 (m, 2H), 1.82 - 1.76 (m, 1H), 1.67 - 1.61 (m, 2H), 1.55 - 1.49 (m, 2H), 1.41 (t, 3H), 1.29 - 1.24 (m, 2H).

[0258] Compound 18: MS: m / z 846.6 (M + +1); 1 H NMR(DMSO-d6)δ11.07(s,1H),8.51(d,1H),7.86(d,1H),7.83(d,1H),7.72(s,1H),7.67(d,1H),7.40(d,1H),7.31(d,1H),7.14(dd,1H),6 .96(d,1H),5.00(dd,1H),4.57-4.53(m,1H),4.49(q,2H),3.89-3.83(m,1H),3.79-3.57(m,2H),3.56-3.46(m,1H),3.14-3.07(m,1H),3.0 6-3.00(m,1H),2.93-2.87(m,1H),2.72-2.63(m,2H),2.63-2.59(m,1 H),2.58-2.53(m,3H),2.44-2.40(m,2H),2.19-2.14(m,1H),2.13-2. 10(m,2H),2.08-2.04(m,2H),1.93-1.90(m,2H),1.87-1.76(m,5H),1 .67-1.62(m,2H),1.55-1.49(m,2H),1.44(t,3H),1.29-1.24(m,2H).

[0259] Compound 19: MS: m / z 887.4 (M + +1).

[0260] Compound 20: MS: m / z 901.5 (M + +1).

[0261] Compound 21: MS: m / z 869.7 (M + +23).

[0262] Compound 22: MS: m / z 869.3 (M + +23); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.52 (d, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.56 (d, 1H), 7.39 (d, 1H), 7.17 (d, 1H), 7.14 (dd, 1H), 7.07 (bs, 1H), 6.94 (d, 1H), 4.96 (dd, 1H), 4.56 - 4.51 (m, 1H), 3.93 (s, 3H), 3.88 - 3.83 (m, 1H), 3.50 - 3.42 (m, 2H), 3.42 - 3.30 (m, 1H), 3.29 (bs, 4H), 3.18 - 3.11 (m, 1H), 2.92 - 2.86 (m, 1H), 2.62 - 2.55 (m, 5H), 2.48 - 2.41 (m, 1H), 2.40 - 2.33 (m, 1H), 2.24 - 2.18 (m, 1H), 2.12 - 2.09 (m, 2H), 2.06 - 2.01 (m, 1H), 1.94 - 1.89 (m, 2H), 1.75 - 1.61 (m, 5H), 1.55 - 1.49 (m, 2H), 1.29 - 1.21 (m, 2H).

[0263] Compound 23: MS: m / z 883.8 (M + + 23); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.59 (d, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.56 (d, 1H), 7.39 (d, 1H), 7.34 (d, 1H), 7.17 - 7.12 (m, 3H), 4.96 (dd, 1H), 4.56 - 4.48 (m, 3H), 4.41 (q, 2H), 3.87 - 3.86 (m, 1H), 3.28 (bs, 4H), 3.06 - 3.02 (m, 2H), 2.92 - 2.86 (m, 1H), 2.62 - 2.60 (m, 1H), 2.55 (bs, 4H), 2.53 - 2.48 (m, 1H), 2.26 - 2.21 (m, 2H), 2.12 - 2.09 (m, 2H), 2.06 - 2.02 (m, 1H), 1.97 - 1.85 (m, 5H), 1.67 - 1.61 (m, 2H), 1.55 - 1.49 (m, 2H), 1.41 (t, 3H), 1.18 - 1.12 (m, 2H).

[0264] Compound 24: MS: m / z 908.6 (M + + 23); 11H NMR (DMSO-d6) δ 11.07 (s, 1H), 7.92 (d, 1H), 7.75 (d, 2H), 7.72 - 7.66 (m, 2H), 7.39 (d, 1H), 7.30 (d, 1H), 7.21 (d, 1H), 7.01 (dd, 1H), 6.55 (d, 1H), 5.00 (dd, 1H), 4.47 (q, 2H), 4.33 (s, 1H), 4.07 (d, 1H), 3.54 - 3.51 (m, 1H), 3.43 - 3.34 (m, 2H), 3.12 - 3.00 (m, 1H), 2.99 - 2.94 (m, 1H), 2.93 - 2.87 (m, 1H), 2.65 - 2.59 (m, 1H), 2.59 - 2.49 (m, 5H), 2.36 - 2.31 (m, 1H), 2.21 - 2.15 (m, 1H), 2.09 - 2.02 (m, 2H), 1.94 - 1.77 (m, 4H), 1.72 - 1.63 (m, 2H), 1.44 (t, 3H), 1.28 - 1.22 (m, 2H), 1.22 (s, 6H), 1.13 (s, 6H).

[0265] Compound 25: MS: m / z 883.5 (M + + 23); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.75 (bs, 2H), 8.11 (d, 1H), 7.87 (d, 1H), 7.56 (d, 1H), 7.40 (d, 1H), 7.17 - 7.14 (m, 2H), 7.12 (bs, 1H), 4.96 (dd, 1H), 4.75 - 4.73 (m, 2H), 4.58 - 4.53 (m, 1H), 4.42 - 4.39 (m, 2H), 3.83 - 3.77 (m, 1H), 3.28 (bs, 4H), 3.00 - 2.96 (m, 2H), 2.92 - 2.86 (m, 1H), 2.62 - 2.59 (m, 2H), 2.55 (bs, 4H), 2.24 - 2.22 (m, 2H), 2.12 - 2.09 (m, 2H), 2.07 - 2.01 (m, 1H), 1.94 - 1.89 (m, 3H), 1.84 - 1.83 (m, 2H), 1.55 - 1.47 (m, 4H), 1.41 (t, 3H), 1.10 - 1.03 (m, 2H).

[0266] Compound 26: MS: m / z 883.5 (M + + 23); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.75 (bs, 2H), 8.12 (d, 1H), 7.86 (d, 1H), 7.56 (d, 1H), 7.39 (s, 1H), 7.17 - 7.12 (m, 3H), 4.96 (dd, 1H), 4.59 - 4.52 (m, 1H), 4.42 - 4.39 (m, 2H), 3.86 - 3.75 (m, 2H), 3.30 - 3.25 (m, 1H), 3.13 - 3.10 (m, 1H), 2.92 - 2.86 (m, 1H), 2.62 - 2.52 (m, 6H), 2.33 - 2.67 (m, 1H), 2.19 - 2.07 (m, 3H), 2.07 - 2.01 (m, 1H), 1.94 - 1.87 (m, 2H), 1.72 - 1.62 (m, 3H), 1.55 - 1.47 (m, 4H), 1.40 (t, 3H), 1.28 - 1.23 (m, 2H).

[0267] Compound 27: MS: m / z 874.8 (M + +1); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.62 (bs, 1H), 7.94 (dd, 1H), 7.90 (d, 1H), 7.57 - 7.54 (m, 2H), 7.21 (d, 1H), 7.17 (d, 1H), 7.06 (s, 1H), 7.01 (dd, 1H), 6.47 (d, 1H), 4.96 (dd, 1H), 4.31 (s, 1H), 4.06 (d, 1H), 3.93 (s, 3H), 3.75 - 3.68 (m, 1H), 3.63 - 3.56 (m, 1H), 3.31 - 3.24 (m, 5H), 3.07 - 3.04 (m, 1H), 2.92 - 2.86 (m, 1H), 2.61 - 2.54 (m, 5H), 2.46 - 2.42 (m, 1H), 2.34 - 2.28 (m, 1H), 2.20 - 2.14 (m, 1H), 2.04 - 2.00 (m, 1H), 1.69 - 1.64 (m, 3H), 1.28 - 1.21 (m, 2H), 1.22 (s, 6H), 1.12 (s, 6H).

[0268] Compound 28: MS: m / z 896.7 (M + +23); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.62 (bs, 1H), 7.94 (d, 1H), 7.91 (d, 1H), 7.60 - 7.55 (m, 2H), 7.22 (s, 1H), 7.17 (d, 1H), 7.06 (s, 1H), 7.01 (d, 1H), 6.86 (d, 1H), 4.96 (dd, 1H), 4.44 - 4.40 (m, 2H), 4.31 (s, 1H), 4.06 (d, 1H), 3.93 (s, 3H), 3.35 - 3.33 (m, 2H), 3.29 (bs, 4H), 2.97 - 2.86 (m, 3H), 2.61 - 2.54 (m, 6H), 2.24 - 2.22 (m, 2H), 2.06 - 2.00 (m, 1H), 1.94 - 1.87 (m, 1H), 1.86 - 1.81 (m, 2H), 1.26 - 1.22 (m, 2H), 1.22 (s, 6H), 1.13 (s, 6H).

[0269] Compound 29: MS: m / z 846.3 (M + +1); 1 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 8.59 (d, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.67 - 7.64 (m, 2H), 7.39 (d, 1H), 7.34 (d, 1H), 7.31 (d, 1H), 7.14 (dd, 1H), 5.00 (dd, 1H), 4.57 - 4.48 (m, 3H), 4.00 (s, 3H), 3.90 - 3.83 (m, 1H), 3.05 - 2.98 (m, 3H), 2.93 - 2.87 (m, 1H), 2.72 - 2.64 (m, 1H), 2.63 - 2.56 (m, 1H), 2.55 - 2.50 (m, 4H), 2.24 - 2.17 (m, 2H), 2.12 - 2.09 (m, 2H), 2.07 - 1.99 (m, 3H), 1.92 - 1.76 (m, 7H), 1.68 - 1.62 (m, 2H), 1.55 - 1.49 (m, 2H), 1.19 - 1.10 (m, 2H).

[0270] Compound 30: MS: m / z 846.6 (M + +1); 1H NMR(DMSO-d6)δ11.07(s,1H),8.52(d,1H),7.86(d,1H),7.83(d,1H),7.71-7.65(m,1H),7.63(bs,1H),7.39(d,1H),7 .30(d,1H),7.14(dd,1H),6.95(d,1H),5.00(dd,1H),4.57-4.52(m,1H),4.00(s,3H),3.89-3.83(m,1H),3.55-3.40(m ,2H),3.20-2.98(m,3H),2.93-2.87(m,1H),2.75-2.64(m,1H),2.63-2.50(m,4H),2.45-2.32(m,2H),2.25-2.17(m,1 H),2.12-2.10(m,2H),2.07-1.98(m,3H),1.92-1.88(m,3H),1.88-1.74(m,4H),1.74-1.62(m,4H),1.55-1.49(m,2H).

[0271] Compound 31: MS: m / z 886.8 (M + +1).

[0272] Compound 32: MS: m / z 900.8 (M + +1).

[0273] Compound 33: MS: m / z 884.0 (M + +23); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.52 (d, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.56 (d, 1H), 7.39 (d, 1H), 7.17 - 7.12 (m, 3H), 6.94 (d, 1H), 4.96 (dd, 1H), 4.56 - 4.51 (m, 1H), 4.42 - 4.39 (m, 2H), 3.88 - 3.83 (m, 1H), 3.31 - 3.27 (m, 8H), 3.06 - 3.02 (m, 2H), 2.92 - 2.86 (m, 1H), 2.62 - 2.60 (m, 1H), 2.65 - 2.55 (m, 5H), 2.48 - 2.43 (m, 1H), 2.37 - 2.34 (m, 1H), 2.21 - 2.17 (m, 1H), 2.12 - 2.09 (m, 2H), 2.06 - 2.02 (m, 1H), 1.97 - 1.89 (m, 2H), 1.74 - 1.61 (m, 5H), 1.55 - 1.49 (m, 2H), 1.41 (t, 3H), 1.26 - 1.23 (m, 2H).

[0274] Compound 34: MS: m / z 832.4 (M + + 1); 1 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 8.51 (d, 1H), 7.86 (d, 1H), 7.83 (d, 1H), 7.68 - 7.65 (m, 2H), 7.40 (d, 1H), 7.32 (d, 1H), 7.14 (dd, 1H), 6.96 (d, 1H), 5.00 (dd, 1H), 4.57 - 4.53 (m, 1H), 4.00 (s, 3H), 3.89 - 3.83 (m, 1H), 3.78 - 3.59 (m, 2H), 3.55 - 3.45 (m, 1H), 3.14 - 3.07 (m, 1H), 3.06 - 2.99 (m, 1H), 2.93 - 2.87 (m, 1H), 2.74 - 2.63 (m, 2H), 2.63 - 2.59 (m, 1H), 2.58 - 2.53 (m, 3H), 2.46 - 2.39 (m, 2H), 2.19 - 2.04 (m, 5H), 1.95 - 1.88 (m, 2H), 1.87 - 1.76 (m, 5H), 1.67 - 1.61 (m, 2H), 1.55 - 1.49 (m, 2H).

[0275] Compound 35: MS: m / z 847.4 (M + + 1); 1H NMR(DMSO-d6)δ11.05(s,1H),8.75(s,2H),8.11(d,1H),7.87(d,1H),7.56(d,1H),7.40(d,1H),7.17-7.14(m,2H ),7.06(bs,1H),4.96(dd,1H),4.75-4.73(m,2H),4.58-4.53(m,1H),3.93(s,3H),3.83-3.77(m,1H),3.28(bs,4H ),3.00-2.96(m,2H),2.92-2.86(m,1H),2.62-2.59(m,1H),2.55(bs,4H),2.55-2.49(m,1H),2.24-2.22(m,2H),2 .12-2.08(m,2H),2.06-2.00(m,1H),1.95-1.88(m,3H),1.84-1.83(m,2H),1.55-1.46(m,4H),1.10-1.03(m,2H).

[0276] Compound 36: MS: m / z 861.7 (M + +1); 1 H NMR(DMSO-d6)δ11.05(s,1H),8.59(d,1H),7.86(d,1H),7.81(d,1H),7.56(d,1H),7.40(d,1H),7.34(d,1H) ,7.17-7.12(m,3H),4.96(dd,1H),4.57-4.48(m,3H),4.41(q,2H),3.89-3.83(m,1H),3.28(bs,4H),3.06-3 .02(m,2H),2.92-2.86(m,1H),2.62-2.60(m,1H),2.58-2.52(m,5H),2.26-2.22(m,2H),2.13-2.09(m,2H), 2.06-2.02(m,1H),1.97-1.85(m,5H),1.67-1.62(m,2H),1.55-1.48(m,2H),1.41(t,3H),1.18-1.12(m,2H).

[0277] Compound 37: MS: m / z 886.8 (M + +1).

[0278] Compound 38: MS: m / z 900.8 (M + +1).

[0279] Compound 39: MS: m / z 862.0 (M+ +1); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.52 (d, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.56 (d, 1H), 7.39 (d, 1H), 7.17 - 7.12 (m, 3H), 6.94 (d, 1H), 4.96 (dd, 1H), 4.57 - 4.52 (m, 1H), 4.41 (q, 2H), 3.88 - 3.83 (m, 1H), 3.82 - 3.60 (m, 2H), 3.50 - 3.41 (m, 1H), 3.31 - 3.27 (m, 4H), 3.18 - 3.09 (m, 1H), 2.92 - 2.86 (m, 1H), 2.62 - 2.54 (m, 5H), 2.48 - 2.43 (m, 1H), 2.39 - 2.32 (m, 1H), 2.23 - 2.17 (m, 1H), 2.12 - 2.09 (m, 2H), 2.06 - 2.02 (m, 1H), 1.93 - 1.89 (m, 2H), 1.74 - 1.61 (m, 5H), 1.55 - 1.49 (m, 2H), 1.41 (t, 3H), 1.29 - 1.24 (m, 2H).

[0280] Compound 40: MS: m / z 860.9 (M + +1); 1 1H NMR (DMSO-d6) δ 11.04 (s, 1H), 9.02 (d, 1H), 8.11 (d, 1H), 7.86 (d, 1H), 7.84 (d, 1H), 7.53 (d, 1H), 7.40 (d, 1H), 7.15 (dd, 1H), 6.78 (d, 1H), 6.61 (s, 1H), 4.94 (dd, 1H), 4.57 - 4.52 (m, 1H), 4.36 (q, 2H), 3.95 - 3.89 (m, 1H), 3.56 - 3.55 (m, 1H), 3.46 - 3.43 (m, 1H), 3.10 - 2.95 (m, 3H), 2.92 - 2.85 (m, 1H), 2.62 - 2.54 (m, 2H), 2.54 - 2.49 (m, 4H), 2.46 - 2.40 (m, 1H), 2.38 - 2.32 (m, 1H), 2.23 - 2.17 (m, 1H), 2.15 - 2.00 (m, 5H), 1.97 - 1.82 (m, 6H), 1.74 - 1.64 (m, 5H), 1.56 - 1.50 (m, 2H), 1.40 (t, 3H).

[0281] Compound 41: MS: m / z 869.9 (M + +23); 1H NMR(DMSO-d6)δ11.06(s,1H),8.59(d,1H),7.86(d,1H),7.81(d,1H),7.63(d,1H),7.40(d,1H),7.34(d,1H),7.28( dd,1H),7.14(dd,1H),7.03(bs,1H),4.98(dd,1H),4.57-4.52(m,1H),4.52-4.46(m,2H),3.96(s,3H),3.90-3.83(m ,1H),3.18(bs,4H),3.05-3.01(m,2H),2.93-2.87(m,1H),2.62-2.52(m,6H),2.24-2.22(m,2H),2.12-2.08(m,2H) ,2.06-2.01(m,1H),1.97-1.88(m,3H),1.87-1.83(m,2H),1.68-1.62(m,2H),1.55-1.49(m,2H),1.18-1.12(m,2H).

[0282] Compound 42: MS: m / z 869.7 (M + +23); 1 H NMR(DMSO-d6)δ11.06(s,1H),8.52(d,1H),7.86(d,1H),7.82(d,1H),7.63(d,1H),7.39(d,1H), 7.28(dd,1H),7.14(dd,1H),7.03(bs,1H),6.94(d,1H),4.98(dd,1H),4.57-4.52(m,1H),3.96(s ,3H),3.89-3.82(m,1H),3.74-3.63(m,1H),3.51-3.60(m,2H),3.19(bs,4H),3.16-3.09(m,1H) ,2.92-2.86(m,1H),2.62-2.54(m,5H),2.47-2.41(m,1H),2.39-2.32(m,1H),2.22-2.17(m,1H).

[0283] Compound 43: MS: m / z 886.8 (M + +1).

[0284] Compound 44: MS: m / z 900.6 (M + +1).

[0285] Compound 45: MS: m / z 861.4 (M + +1).

[0286] Compound 46: MS: m / z 846.8 (M + +1).

[0287] Compound 47: MS: m / z 841.6 (M + +23); 1 H NMR(DMSO-d6)δ11.06(s,1H),8.56(d,1H),7.87-7.82(m,2H),7.63(d,1H),7.39(d,1H),7.29(dd,1H),7.1 4(dd,1H),7.04(s,1H),6.87(d,1H),4.99(dd,1H),4.56-4.51(m,1H),4.26-4.23(m,2H),3.96(s,3H),3.89 -3.82(m,3H),3.19(bs,4H),3.12-3.07(m,1H),2.93-2.87(m,1H),2.72-2.70(m,2H),2.60(bs,4H),2.60-2 .49(m,1H),2.11-2.09(m,2H),2.06-2.01(m,1H),1.92-1.89(m,2H),1.67-1.61(m,2H),1.55-1.49(m,2H).

[0288] Compound 48: MS: m / z 858.5 (M + +1).

[0289] Compound 49: MS: m / z 858.5 (M + +1); 1 H NMR(DMSO-d6)δ11.08(s,1H),8.56(d,1H),7.87-7.83(m,3H),7.70(d,1H),7.52(dd,1H),7.39(d,1H),7.14(dd ,1H),6.87(d,1H),6.35-6.32(m,1H),5.01(dd,1H),4.56-4.49(m,3H),4.26-4.24(m,2H),3.89-3.83(m,3H),3 .20-3.16(m,1H),3.16-3.09(m,1H),2.93-2.87(m,1H),2.79-2.75(m,1H),2.74-2.72(m,1H),2.64-2.60(m,2H ),2.59-2.50(m,5H),2.14-2.04(m,3H),1.93-1.88(m,2H),1.67-1.61(m,2H),1.55-1.49(m,2H),1.44(t,3H).

[0290] Compound 50: MS: m / z 886.8 (M + +1).

[0291] Compound 51: MS: m / z 902.7 (M + +1); 1 H NMR(DMSO-d6)δ11.05(s,1H),8.55(d,1H),7.85(d,1H),7.80(d,1H),7.54(d,1H),7.37(d,1H),7.32(d,1H),7.15-7.11( m,2H),7.09(bs,1H),4.94(dd,1H),4.55-4.50(m,1H),4.48-4.43(m,2H),4.38(q,2H),3.89-3.82(m,1H),3.22(bs,4H),3 .00-2.96(m,2H),2.90-2.84(m,1H),2.62-2.57(m,2H),2.56-2.49(m,4H),2.18-2.16(bs,2H),2.11-2.07(m,2H),2.06- 2.00(m,1H),1.92-1.87(m,2H),1.86-1.75(m,3H),1.66-1.60(m,2H),4.54-1.48(m,2H),1.39(t,3H),1.16-1.09(m,2H).

[0292] In addition, the compound ARV-110 (Cat. No.: BD01398519; Lot No.: CKA112; purity: 97%) purchased from BLD Pharmatech Ltd. was used for subsequent tests. ARV-110 is a well-known bifunctional compound that can be used for AR degradation.

[0293]

[0294] Androgen receptor degradation assay by Western blot analysis

[0295] LNCaP.FGC cells (Cat. 60088, Bioresource Conservation and Research Center, Hsinchu City, Taiwan, China) were grown in RPMI 1640 (Cat. 31800022, Thermo Fisher Scientific, Waltham, Massachusetts, United States) medium supplemented with 10% FBS (Cat. 10437028, Thermo Fisher Scientific, Waltham, Massachusetts, United States), 10 mM HEPES (Cat. 15630080, Thermo Fisher Scientific, Waltham, Massachusetts, United States), and 1 mM sodium pyruvate (Cat. 11360070, Thermo Fisher Scientific, Waltham, Massachusetts, United States) at a plate density of 2 × 10 cells / well. 5 Cells were seeded into 24-well cell culture plates. The cells were cultured at 37°C, 5% CO2 for 24 hours (hr), and then treated with 100 nanomolar concentrations (nM) of one of the compounds 1 to 51 or ARV-110 for 24 hours. After treatment, the cells were harvested, washed with phosphate buffered saline (PBS), and hydrolyzed with RIPA Lysis and Extraction Buffer (Cat. 89900, Thermo Fisher Scientific, Waltham, Massachusetts, United States) supplemented with Halt Protease Inhibitor Cocktail (Cat. 78430, Thermo Fisher Scientific, Waltham, Massachusetts, United States) to collect protein samples.

[0296] Protein samples were separated by polyacrylamide gel electrophoresis and then transferred to an Immuno-Blot polyvinylidene difluoride (PVDF) membrane (Cat. 1620177, Bio-Rad Laboratories, Hercules, California, United States). Protein samples with the presence of androgen receptor were detected by standard Western blotting using anti-AR antibody (1:2000 dilution) (Cat. 5153, Cell Signaling Technology Inc., Danvers, Massachusetts, United States) and a goat anti-rabbit horseradish peroxidase (HRP)-conjugated secondary antibody (1:5000 dilution) (C04003, Anxin Biotechnology, Taipei, Taiwan, China). The internal loading control, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), was detected using a mouse monoclonal antibody (1:5000) (GTX627408, Yikang Biotechnology, Hsinchu City, Taiwan, China) and a goat anti-mouse HRP-conjugated secondary antibody (1:5000 dilution) (C04001, Anxin Biotechnology, Taipei City, Taiwan, China). The chemiluminescent information was developed using Clarity Western ECL Substrate (Cat. 1705061, Bio-Rad Laboratories, Hercules, California, United States) and detected using a digital imager iBright FL1500 (Invitrogen Corp., Carlsbad, California, United States).

[0297] Several compounds were selected and serially diluted (10×) in RPMI medium for treating LNCaP.FGC cells. A calibration curve was prepared using serial dilution samples of each compound, and the concentration required for 50% AR degradation (ARDC) was calculated. 50 ). The results are shown in Table 2.

[0298] In Table 2, when the AR DC of the compound 50 When the AR DC of the compound is less than 10 nM, the result is marked as "A". 50 When the AR DC of the compound is equal to or greater than 10 nM and less than 25 nM, the result is marked as "B". 50When the AR DC of the compound is equal to or greater than 25 nM and less than 100 nM, the result is marked as "C"; and when the AR DC 50 When the concentration of the compound is equal to or greater than 100 nM, the result is marked as "D". Most of the compounds disclosed in the present invention obviously have good AR degradation efficacy. Under the same operating conditions, many compounds disclosed in the present invention have higher AR degradation ability than ARV-100 at the same concentration (100 nM), and they generally have lower AR DC 50 (nM).

[0299] Table 2: AR DC of compounds of the present disclosure 50 (nM)

[0300]

[0301]

[0302] Other specific embodiments

[0303] All features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature for the same, equal or similar purpose. Therefore, unless otherwise clearly indicated, each feature disclosed is only an example of an equivalent or similar superordinate series of features.

[0304] From the foregoing description, those skilled in the art can easily identify the essential features of the present disclosure, and make various changes or modifications to the present disclosure without departing from its spirit and scope, so as to make it suitable for various uses and conditions. Therefore, other specific embodiments also fall within the scope of the claims.

Claims

1. A bifunctional compound, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, characterized in that: The bifunctional compound is represented by formula (I): ABM-L-CLM(I); in: ABM is an androgen receptor binding group; -L- is a bonding group; and CLM is a cerebellum protein E3 ubiquitin ligase binding group represented by formula (II)-1: in: represents a single bond or a double bond; One end of -L- is connected to Q 3 , Q 4 , Q 5 or Q 6 covalently bonded; and the other end of the -L- is covalently bonded to the ABM; When W 1 and W 2 When there is a single bond between 1 and W 2 Each is independent of CR C2 or N; or, when W 1 and W 2 When there is a double bond between 1 and W 2 Each is C; G is selected from -H, -OH, -CH2OH, -R C3 OC(=O)OR C4 , -R C3 OC(=O)NR C4 R C5 and 2-(trimethylsilyl)ethoxymethyl; Q 1 O, S or NR C6 ; When Q 2 and Q 7 When there is a single bond between 2 and Q 7 Each is N or CR independently C2 ; or, when Q 2 and Q 7 When there is a double bond between 2 and Q 7 Each is C; At one end of the -L- 3 , Q 4 , Q 5 and Q 6 When any atom of -L- is covalently bonded to CR C2 When the CR C2 There are two single bonds between the C atom and its two adjacent atoms on the ring; or when the atom covalently bonded to the -L- is C, there is a double bond between the C atom and one of its two adjacent atoms on the ring; and, selected from Q 3 , Q 4 , Q 5 and Q 6 The other atoms not covalently bonded to the -L- are each independently O, S, C(R C2 )2 or NR C2 When the O atom, S atom, C(R C2 )2 C atoms, or NR C2 There are two single bonds between the N atom and its two adjacent atoms on the ring; or selected from Q 3 , Q 4 , Q 5 and Q 6 The other atoms not covalently bonded to the -L- are each independently CR C2 When the CR C2 There is a double bond between the C atom of and one of its two adjacent atoms on the ring; K is selected from -H, unsubstituted alkyl, C7 Substituted alkyl, unsubstituted cycloalkyl and R C7 A group consisting of substituted cycloalkyl groups; K is bonded to the 6-membered ring by a stereospecific bond or a non-stereospecific bond; R C1 is selected from unsubstituted alkyl, C8 Substituted alkyl, unsubstituted aryl, R C8 Substituted aryl, unsubstituted alkyl-aryl, R C8 Substituted alkyl-aryl, unsubstituted alkoxy and R C8 The group consisting of substituted alkoxy groups; R C2 is selected from -H, -D, halogen, -CH2OH, -NR C4 R C5 , alkoxy, unsubstituted alkyl, alkyl substituted by one or more halogen groups, unsubstituted cycloalkyl, cycloalkyl substituted by one or more halogen groups, unsubstituted aryl and aryl substituted by one or more halogen groups; R C3 is selected from unsubstituted alkylene and R C7 The group consisting of substituted alkylene; R C4 and R C5 are each independently selected from -H, unsubstituted alkyl, C9 Substituted alkyl, unsubstituted cycloalkyl, R C9 Substituted cycloalkyl, unsubstituted heterocyclic group, R C9 Substituted heterocyclic group, unsubstituted aryl group, R C9 Substituted aryl, unsubstituted heteroaryl and R C9 The group consisting of substituted heteroaryl groups; R C6 is selected from the group consisting of -H, halogen, -CH2OH, 2-(trimethylsilyl)ethoxymethyl, alkoxy, unsubstituted alkyl, alkyl substituted with one or more halogens, unsubstituted cycloalkyl, cycloalkyl substituted with one or more halogens, unsubstituted aryl, aryl substituted with one or more halogens, unsubstituted heteroaryl, heteroaryl substituted with one or more halogens, unsubstituted heterocyclyl, and heterocyclyl substituted with one or more halogens; R C7 is selected from halogen, -CH2OH, -NR C4 R C5 , 2-(trimethylsilyl)ethoxymethyl, alkoxy, unsubstituted aryl, aryl substituted with one or more halogen groups, unsubstituted heteroaryl, heteroaryl substituted with one or more halogen groups, unsubstituted heterocyclic group and heterocyclic group substituted with one or more halogen groups; R C8 is selected from halogen, -CH2OH, -NR C4 R C5 , 2-(trimethylsilyl)ethoxymethyl, unsubstituted cycloalkyl, cycloalkyl substituted with one or more halogen groups, unsubstituted heteroaryl, heteroaryl substituted with one or more halogen groups, unsubstituted heterocyclyl and heterocyclyl substituted with one or more halogen groups; R C9 is selected from the group consisting of halo, -CH2OH, 2-(trimethylsilyl)ethoxymethyl and alkoxy; n is 0, 1, 2, 3 or 4; and The -L- is represented by formula (III): in: Z is selected from the group consisting of a 3- to 8-membered monocyclic ring, a 5- to 12-membered bicyclic ring, an 8- to 15-membered tricyclic ring, and a 6- to 12-membered spirobicyclic ring, each of which independently has 0 to 4 heteroatoms; R L1 is selected from unsubstituted C 1-6 Alkyl, C 1-6 Alkoxy substituted C 1-6 Alkyl, C 1-6 Alkyl, halogen, unsubstituted C 1-6 The group consisting of alkoxy, keto and oxygen ion groups; X 1 is methylene or ethylene; each of which is unsubstituted or substituted by alkyl or cycloalkyl; X 2 is selected from the group consisting of 5- to 8-membered arylene, 5- to 8-membered heteroarylene having 1 to 3 heteroatoms, 3- to 7-membered cycloalkylene, 3- to 7-membered heterocycloalkylene having 1 to 2 heteroatoms, 3- to 8-membered cycloalkenylene, 3- to 8-membered cycloheteroalkenylene having 1 to 3 heteroatoms, and 6- to 12-membered spirobicyclic divalent radical having 0 to 4 heteroatoms, each of which is unsubstituted or substituted with an alkyl or cycloalkyl group; m is 0, 1, 2, 3, 4, 5 or 6; v1 is 1 or 2; and v2 is 1 or 2; and The aforementioned heteroatom is selected from N, O and S.

2. The bifunctional compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, characterized in that: The CLM is represented by formula (II)-2: in: One end of the –L– is connected to the Q 3 , Q 4 or Q 5 covalent bonding; G is selected from the group consisting of -H, -OH and -CH2OH; Q 1 O, S or NR C6 ; When one end of -L- is connected to a 3 , Q 4 and Q 5 When any atom of is covalently bonded to, the atom connected to -L- is C; and, selected from Q 3 , Q 4 and Q 5 The other atoms not connected to the -L- are each independently CR C2 ;as well as R C2 is selected from the group consisting of -H, -D, halo, unsubstituted alkyl, and alkyl substituted with one or more halo groups; R C6 is selected from -H, -CH2OH, unsubstituted C 1-6 Alkyl and C substituted by one or more halogen groups 1-6 The group consisting of alkyl groups.

3. The bifunctional compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, characterized in that: The -L- is a bonding group represented by formula (III): in: Z is selected from the group consisting of a 3- to 8-membered monocyclic ring, a 6- to 10-membered bicyclic ring, and an 8- to 10-membered spirobicyclic ring, each of which independently has 1 to 2 heteroatoms; X 1 is an unsubstituted methylene group or a methylene group substituted by an alkyl group or a cycloalkyl group; X 2 is selected from the group consisting of 3-7 membered heterocycloalkylene having 1-2 heteroatoms, 3-8 membered cycloheteroalkenylene having 1-2 heteroatoms, and 6-12 membered spirobicyclic divalent radical having 1-2 heteroatoms, each of which is unsubstituted or substituted with alkyl or cycloalkyl; m is 0, 1 or 2; v1 is 1 or 2; and v2 is 1.

4. The bifunctional compound according to claim 3, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, characterized in that: The –L– is 5. The bifunctional compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, characterized in that: The ABM is an androgen receptor binding group represented by the following formula: in: Z 1 is selected from the group consisting of aryl, heteroaryl, bicyclic, or biheterocyclic, each of which is independently substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, nitro, -CN, -C≡CH, unsubstituted C 1-6 Alkyl, C 1-6 Alkoxy substituted C 1-6 Alkyl, C 1-6 Alkyl, unsubstituted C 1-6 Alkoxy, C 1-6 Alkoxy, unsubstituted C 2-6 Alkenyl, C 2-6 Alkenyl, unsubstituted C 2-6 Alkynyl, C 3-6 Alkynyl and any combination thereof; Y 1 and Y 2 Each is independent of NR Y1 , O or S; Y 3 , Y 4 and Y 5 are independently selected from a one-bond, -O-, -NR Y2 -、-C(-R Y1 )(-R Y2 )-, -C(=O)-, -C(=S)-, -S(=O)-, -SO2-, heteroarylene and arylene groups; Y 6 For -N(-R Y1 )-, -O-, or -S-; M is a 3- to 6-membered ring having 0-4 heteroatoms, which is unsubstituted or substituted with 0-6 R M Base substitution; Each R M The radicals are independently selected from unsubstituted C 1-6 Alkyl, C 1-6 Alkoxy substituted C 1-6 Alkyl, C 1-6 Alkyl, halide and C 1-6 Alkoxy group; or, two R M The radical and the atoms to which it is attached together form a 3- to 8-membered ring system containing 0 to 2 heteroatoms; R a , R b , R c , R d , R Y1 and R Y2 are each independently selected from -H, unsubstituted C 1-6 Alkyl, C 1-6 Alkoxy substituted C 1-6 Alkyl, C 1-6 Alkyl, halogen, C 1-6 The group consisting of alkoxy, cyclic group and heterocyclic group; or, R a , R b Together with the atoms to which they are attached, they form a 3- to 8-membered ring system containing 0 to 2 heteroatoms; Z 2 Is to choose from one-key knot, C 1-6 Alkylene, C 1-6 The group consisting of heteroalkylene, -O-, arylene, heteroarylene, alicyclic divalent group, heterocyclic divalent group, heterobicyclic divalent group, bicyclic arylene and bicyclic heteroarylene, each of which is unsubstituted or substituted with 1 to 10 R Z2 Base substitution; Each R Z2 The radicals are independently selected from the group consisting of: -H, halogen, unsubstituted C 1-6 Alkyl, C substituted with one or more -F 1-6 Alkyl, -OR Z2A , C 3-6 Cycloalkyl, C 4-6 Cycloheteroalkyl, unsubstituted C 1-6 Alkyl, C 1-3 Alkyl substituted C 1-6 Alkyl, C 1-6 Alkoxy substituted C 1-6 Alkyl, C 1-6 Alkyl, unsubstituted heterocyclic, C 1-3 Alkyl-substituted heterocyclic group, C 1-6 Alkoxy-substituted heterocyclic group, heterocyclic group substituted by one or more halogen groups, unsubstituted aryl group, C 1-3 Alkyl-substituted aryl, C 1-6 Alkoxy-substituted aryl, aryl substituted with one or more halogen groups, unsubstituted heteroaryl, C 1-3 Alkyl-substituted heteroaryl, C 1-6 Alkoxy-substituted heteroaryl, heteroaryl substituted with one or more halogen groups, bicyclic heteroaryl, unsubstituted C 1-3 Alkoxy and one or more selected from -F, -OH, -NH2, -NR Y1 R Y2 and -CN substituted with a substituent 1-3 Alkoxy; and R Z2A Is selected from H, C 1-6 Alkyl and C 1-6 The group consisting of heteroalkyl, each of which is unsubstituted or substituted with cycloalkyl, cycloheteroalkyl, aryl, heterocyclyl, heteroaryl, halo, or C 1-3 Alkoxy substitution.

6. The bifunctional compound according to claim 5, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, characterized in that: Z 1 It is freedom to choose The group composed of.

7. The bifunctional compound according to claim 5, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, characterized in that: Z 2 It is freedom to choose The group composed of.

8. The bifunctional compound according to claim 5, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, characterized in that: The ABM is selected from the groups formed; in: A1 is selected from -Cl, -F, -Br or -CF3; A2 is selected from -O-, -NH-, -N(-methyl)- or -N(-ethyl)-; and A3, A4, A5 and A6 are each independently -CH- or -N-.

9. The bifunctional compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, characterized in that: The bifunctional compound is selected from the group consisting of:

10. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof; and a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 10 , further comprising a second therapeutic agent.

12. A method for treating an androgen receptor-related disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 10 or 11.

13. The method according to claim 12, characterized in that The androgen receptor-related disease is an androgen receptor-related cancer or an androgen receptor-related skin disease.

14. The method according to claim 13, characterized in that The androgen receptor-related cancer is breast cancer or prostate cancer.

15. The method according to claim 14, characterized in that The prostate cancer is castration-resistant prostate cancer.

16. The method according to claim 14, characterized in that The breast cancer is triple-negative breast cancer.

17. The method according to claim 13, characterized in that The androgen receptor-related skin disease is androgenic alopecia, acne, hidradenitis suppurativa, hirsutism, or atopic dermatitis.

18. The method of claim 12, further comprising administering an effective amount of a second therapeutic agent.

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