Bifunctional compound, pharmaceutical composition containing the bifunctional compound, and method for treating androgen receptor-related diseases using these

Abstract

A bifunctional compound, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, wherein the bifunctional compound has the following formula (I): ABM-L-CLM (I) which is represented by In the above formula ABM is an androgen receptor binding moiety -L- is a linking moiety CLM is a cereblon E3 ubiquitin ligase binding moiety represented by the following formula (II)-1 JPEG2025520909000047.jpg48152(wherein one end of -L- is covalently bonded to Q3, Q4, Q5 or Q6, and the other end of -L- is covalently bonded to ABM), a bifunctional compound, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof is provided. Furthermore, a pharmaceutical composition containing the bifunctional compound, and a method for treating androgen receptor-related diseases by administering the bifunctional compound are provided.

Description

Technical Field

[0001] 1. Technical Field of the Invention The present disclosure relates to a bifunctional compound, a pharmaceutical composition containing the bifunctional compound, and a method for treating androgen receptor-related diseases by administering the bifunctional compound.

Background Art

[0002] 2. Description of the Prior Art Proteins have a large contact surface, and it is difficult to target protein-protein interactions using small molecules because the grooves involved in protein-protein interactions are shallow or the interfaces are flat. On the other hand, it has been shown that the modality of tagging pathogenic proteins with ubiquitin and then degrading those pathogenic proteins by the 26S proteasome system can widely and completely remove the cause of the disease (Sun et al., Signal Transduct. Target Ther. 2019, 4:64). Not only E1 enzymes and E2 enzymes, but also E3 ubiquitin ligases (also known as "E3 ligases") and their substrate recognition proteins confer substrate specificity to ubiquitination. These enzymes and substrates are extremely important for the specific and selective degradation of target protein substrates. In recent developments of targeted proteolysis, E3 ligases such as cereblon (CRBN) E3 ligase, von Hippel-Lindau tumor suppressor (VHL) E3 ligase, mouse double minute 2 protein (MDM2) E3 ligase, and cell inhibitor of apoptosis protein (cIAP) E3 ligase have been used in the design of degrader compounds composed of small proteins and have achieved success. These molecules have the potential to become therapeutic candidates (Wang et al., Acta Pharm Sin B. 2020 Feb;10(2):207-238).

[0003] As one of the E3 ligases with therapeutic efficacy, there is cereblon E3 ligase, and cereblon E3 ligase is a protein encoded by the CRBN gene in humans. Orthologs of CRBN are highly conserved from plants to humans. Cereblon forms an E3 ubiquitin ligase complex together with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and Regulator of Cullins 1 (ROC1). The E3 ubiquitin ligase complex ubiquitinates many other proteins (Vriend et al., Front Mol Biosci. 2018, 5:19).

[0004] The androgen receptor (AR) belongs to the nuclear hormone receptor family that is activated by androgens such as testosterone and dihydrotestosterone. When an androgen binds to the androgen receptor, the androgen receptor translocates into the nucleus and acts as a transcription factor to promote the expression of genes responsible for male sexual characteristics. The androgen receptor is responsible for the development of male sexual characteristics, but also promotes the growth and survival of prostate cancer cells (Salami et al., Commun. Biol. 2018, 1:100).

[0005] As a treatment strategy for prostate cancer, suppression of androgen receptor signaling is commonly performed. Prostate cancer is the second most commonly diagnosed cancer worldwide and the fifth leading cause of death in men. In the majority of male patients with localized prostate cancer or prostate cancer with regional lymph node metastasis, the 5-year survival rate approaches 100%. The 5-year survival rate for male patients diagnosed with prostate cancer and found to have metastases to other parts of the body is 31%. Based on GLOBOCAN estimates, the number of newly reported prostate cancer cases worldwide reached 1.41 million in 2020, and 375,000 people have died. Over the decades, androgen deprivation therapy (ADT) by surgical or chemical castration has been performed as a standard treatment for managing prostate cancer. However, ultimately, castration-resistant prostate cancer develops, and tumor cell growth recurs despite serum testosterone levels being below castration levels. The approval of second-generation anti-androgen drugs such as abiraterone acetate (ABI) and enzalutamide (ENZ), and the recent approval of apalutamide (APA) and darolutamide (DARO) have improved the overall survival rate of patients with castration-resistant prostate cancer (CRPC). However, as is often seen in cancer chemotherapy, escape mutations that are resistant to the drug appear as the disease progresses (Zhao et al., Mol Cancer Ther. 2020, 19(8):1708-1718). Also, it has been found that androgens and androgen receptors are involved in many skin diseases such as male pattern baldness, acne, hirsutism, and atopic dermatitis. A large amount of sex hormones are synthesized in the skin, and androgens affect hair growth, epithelial barrier homeostasis, wound healing, and the growth and differentiation of sebaceous glands. In recent years, anti-androgen drugs such as clascoterone, cyproterone acetate, and flutamide have been used in the treatment of these skin diseases. Androgen concentration and androgen receptor concentration may play an important role in the development of diseases involving androgen receptor signaling (Zhou et al., Journal of Biosciences and Medicines 2022, 10:180-200).

[0006] The present disclosure provides an alternative method for treating androgen receptor-mediated diseases or disorders or androgen receptor-dependent diseases or disorders using proteolysis-targeting chimera (PROTAC) bifunctional compounds. Related patent applications regarding PROTACs are disclosed in WO2018071606, WO2018144649, and WO2021143816. However, there is still a need for compounds that have better effects in treating androgen receptor-related diseases or androgen receptor-related disorders. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0007] The present disclosure provides a proteolysis-targeting chimera (PROTAC) bifunctional compound comprising a cereblon (CRBN) E3 ubiquitin ligase binding moiety and an androgen receptor binding moiety. This PROTAC compound directs the ubiquitin-proteasome degradation system to degrade the androgen receptor, degrades the androgen receptor, and / or inhibits the androgen receptor by other actions. Unexpectedly, this bifunctional compound has shown high efficacy against the degradation of the androgen receptor.

[0008] In one aspect, the present disclosure provides a bifunctional compound, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite, or prodrug thereof, wherein the bifunctional compound has the following formula (I): ABM-L-CLM (I) as shown, wherein in the formula, ABM is an androgen receptor binding moiety, -L- is a linking moiety, CLM is a cereblon E3 ubiquitin ligase binding moiety represented by the following formula (II)-1 CHEMICAL FORMULA (wherein, CHEMICAL FORMULA represents a single bond or a double bond; One end of -L- is covalently bonded to Q3, Q4, Q5 or Q6, and the other end of -L- is covalently bonded to ABM; W 1 and W 2 If a single bond exists between them, W 1 and W 2 are each independently CR C2 or N, or if a double bond exists between W 1 and W 2 then W 1 and W 2 are each C; G is selected from the group consisting of -H, -OH, -CH2OH, -R C3 OC(=O)OR C4 , -R C3 OC(=O)NR C4 R C5 , and 2-(trimethylsilyl)ethoxymethyl group; Q 1 is O, S or NR C6 ; Q 2 and Q 7 If a single bond exists between them, Q 2 and Q 7 are each independently N or CR C2 or if a double bond exists between Q 2 and Q 7 then Q 2 and Q 7 are each C; When one end of -L- is covalently bonded to any one atom selected from Q3, Q4, Q5 and Q6, the atom covalently bonded to -L- is CR C2 , and a single bond independently exists between the C atom of the CR C2 and the two atoms adjacent to the C atom on the ring, or the said atom covalently bonded to -L- is C, and a double bond exists between the C atom and one of the two atoms adjacent to the C atom on the ring; Q that is not covalently bonded to -L 3 , Q 4 , Q5 and Q 6 The remaining atoms selected from are each independently O, S, C(R C2 )2 or NR C2 , and a single bond independently exists between the O atom, the S atom, the C atom of the C(R C2 )2 or the N atom of the NR C2 and two atoms adjacent to these atoms on the ring, or it is not covalently bonded to -L-, Q 3 , Q 4 , Q 5 and Q 6 The remaining atoms selected from are each independently CR C2 , and a double bond exists between the C atom of the CR C2 and one of the two atoms adjacent to the C atom on the ring; K is selected from the group consisting of -H, an unsubstituted alkyl group, an alkyl group substituted with R C7 , an unsubstituted cycloalkyl group, and a cycloalkyl group substituted with R C7 , and is bonded to the 6-membered ring shown in the above formula via a stereospecific bond or a non-stereospecific bond; R C1 is selected from the group consisting of an unsubstituted alkyl group, an alkyl group substituted with R C8 , an unsubstituted aryl group, an aryl group substituted with R C8 , an unsubstituted alkylaryl group, an alkylaryl group substituted with R C8 , an unsubstituted alkoxyl group, and an alkoxyl group substituted with R C8 ; R C2 is selected from the group consisting of -H, -D, a halo group, -CH2OH, -NR C4 R C5 , an alkoxyl group, an unsubstituted alkyl group, an alkyl group substituted with one or more halo groups, an unsubstituted cycloalkyl group, a cycloalkyl group substituted with one or more halo groups, an unsubstituted aryl group, and an aryl group substituted with one or more halo groups; R C3 is selected from the group consisting of an unsubstituted alkylene group and an alkylene group substituted with R C7 ; RC4 and R C5 is, independently of one another, -H, an unsubstituted alkyl group, an alkyl group substituted with R C9 a cycloalkyl group substituted with a cycloalkyl group, an unsubstituted heterocyclyl group, R C9 a heterocyclyl group substituted with a heterocyclyl group, an unsubstituted aryl group, R C9 an aryl group substituted with an aryl group, an unsubstituted heteroaryl group, and R C9 a heteroaryl group substituted with a heteroaryl group, and is selected from the group consisting of; C9 R C6 is -H, a halo group, -CH2OH, 2-(trimethylsilyl)ethoxymethyl, an alkoxyl group, an unsubstituted alkyl group, an alkyl group substituted with one or more halo groups, an unsubstituted cycloalkyl group, a cycloalkyl group substituted with one or more halo groups, an unsubstituted aryl group, an aryl group substituted with one or more halo groups, an unsubstituted heteroaryl group, a heteroaryl group substituted with one or more halo groups, an unsubstituted heterocyclyl group, and is selected from the group consisting of a heterocyclyl group substituted with one or more halo groups; R C7 is a halo group, -CH2OH, -NR C4 R C5 a group consisting of, 2-(trimethylsilyl)ethoxymethyl, an alkoxyl group, an unsubstituted aryl group, an aryl group substituted with one or more halo groups, an unsubstituted heteroaryl group, a heteroaryl group substituted with one or more halo groups, an unsubstituted heterocyclyl group, and is selected from the group consisting of a heterocyclyl group substituted with one or more halo groups; R C8 is a halo group, -CH2OH, -NR C4 R C5 a group consisting of, 2-(trimethylsilyl)ethoxymethyl, an unsubstituted cycloalkyl group, a cycloalkyl group substituted with one or more halo groups, an unsubstituted heteroaryl group, a heteroaryl group substituted with one or more halo groups, an unsubstituted heterocyclyl group, and is selected from the group consisting of a heterocyclyl group substituted with one or more halo groups; R C9 is selected from the group consisting of a halo group, -CH2OH, 2-(trimethylsilyl)ethoxymethyl, and an alkoxyl group;​ n is 0, 1, 2, 3 or 4), -L- is the following formula (III):

Chemical formula

[0009] In another aspect, the present disclosure provides a pharmaceutical composition comprising an effective amount of the compound, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, and a pharmaceutically acceptable carrier.

[0010] In yet another aspect, the present disclosure provides a method for treating an androgen receptor-related disease in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, or the pharmaceutical composition.

[0011] In some embodiments, CLM is represented by the following formula (II)-2:

Chemical formula

[0012] In some embodiments, the heteroatoms included in formula (II)-1 are each independently selected from N, O, and S.

[0013] In some embodiments, G is selected from the group consisting of -H, -OH, -CH2OH, -CH2OCOOCH3, and 2-(trimethylsilyl)ethoxymethyl group.

[0014] In some embodiments, the 2-(trimethylsilyl)ethoxymethyl group is abbreviated as the "SEM group".

[0015] In some embodiments, K is attached to the six-membered ring via a stereospecific bond as shown in the following formula.

Chemical formula

[0016] In the present invention, the carbon on the six-membered ring to which K is attached is a chiral carbon center, and the bifunctional compound of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite, or prodrug thereof, may exist as two stereoisomers having the CLM represented by formula (II)-1a or formula (II)-1b. The bifunctional compound of the present disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite, or prodrug thereof, may have one or both of these stereoisomers.

[0017] In some embodiments, K is -H, unsubstituted C 1-6 alkyl group, C C7 substituted with R 1-6 alkyl group, and C 3-8 cycloalkyl group. In some embodiments, K is an unsubstituted C 1-3 alkyl group, or a C C7 alkyl group substituted with R 1-3 may be.

[0018] In some embodiments, K is each unsubstituted or R C7is an alkyl selected from the group consisting of linear alkyl and branched alkyl, which is replaced by. In some embodiments, K is each unsubstituted or R C7 is an alkyl selected from the group consisting of linear C 1-6 alkyl and branched C 1-6 alkyl. In some embodiments, K is each unsubstituted or R C7 is an alkyl selected from the group consisting of linear C 1-3 alkyl and branched C 1-3 alkyl.

[0019] In some embodiments, R C1 is an unsubstituted C 1-6 alkyl group, a C C8 alkyl group substituted by R 1-6 an unsubstituted C 3-8 aryl group, a C C8 aryl group substituted by R 3-8 an unsubstituted C 3-8 alkylaryl group, a C C8 alkylaryl group substituted by R 3-8 an unsubstituted C 1-6 alkoxyl group, or a C C8 alkoxyl group substituted by R 1-6 C1 In some embodiments, Ris an unsubstituted C 1-3 alkyl group, a C C8 alkyl group substituted by R 1-3 an unsubstituted C 1-3 alkoxyl group, or a C C8 alkoxyl group substituted by R 1-3 C1

[0020] In some embodiments, R C1 is each unsubstituted or is an alkyl selected from the group consisting of linear alkyl and branched alkyl, which is replaced by R C8 In some embodiments, R C1 is each unsubstituted or is an alkyl selected from the group consisting of linear C C8 alkyl and branched C 1-6Alkyl and branched C 1-6 is an alkyl selected from the group consisting of alkyl. In some embodiments, R C1 is each unsubstituted or R C8 substituted, linear C 1-3 alkyl and branched C 1-3 is an alkyl selected from the group consisting of alkyl.

[0021] In the present disclosure, the halo group may be F, Cl, Br, or I. In the present disclosure, the halo group may be F or Cl. In the present disclosure, the halo group is F.

[0022] In the present disclosure, R C2 is selected from the group consisting of -H, -D (deuterium), a halo group, an unsubstituted C 1-6 alkyl group, and a C 1-6 alkyl group substituted with one or more halo groups. In the present disclosure, R C2 is selected from the group consisting of -H, -D, -F, -Cl, an unsubstituted C 1-3 alkyl group, and a C 1-3 alkyl group substituted with one or more halo groups.

[0023] In the present disclosure, R C4 and R C5 are each independently an unsubstituted C 1-6 alkyl group, a C C9 alkyl group substituted with R 1-6 an unsubstituted C 3-8 cycloalkyl group, a C C9 cycloalkyl group substituted with R 3-8 an unsubstituted C 3-8 heterocyclyl group, a C C9 heterocyclyl group substituted with R 3-8 a C 3-8 aryl group, and a C 3-8 heteroaryl group. In the present disclosure, R C4 and R C5 are each independently an unsubstituted C 1-3 alkyl group, and a C C9 alkyl group substituted with R1-3 is selected from the group consisting of alkyl groups. In the present disclosure, R C4 may be methyl, ethyl, n-propyl or isopropyl.

[0024] In some embodiments, R C4 and R C5 are each independently either unsubstituted or an alkyl selected from the group consisting of linear alkyl and branched alkyl substituted with R C9 . In some embodiments, R C4 and R C5 are each independently either unsubstituted or an alkyl selected from the group consisting of linear C C9 alkyl and branched C 1-6 alkyl substituted with R 1-6 . In some embodiments, R C4 and R C5 are each independently either unsubstituted or an alkyl selected from the group consisting of linear C C9 alkyl and branched C 1-3 alkyl substituted with R 1-3 .

[0025] In some embodiments, CLM is represented by formula (II)-1 or formula (II)-2, wherein Q 1 is NR C6 , and R C6 is -H, an unsubstituted C 1-6 alkyl group, or a C 1-6 alkyl group substituted with one or more halo groups. In some embodiments, Q 1 is NR C6 , and R C6 is H, an unsubstituted C 1-3 alkyl group, or a C 1-3 alkyl group substituted with one or more halo groups. In some embodiments, Q 1 is NR C6 , and R C6 is an unsubstituted C 1-3 alkyl selected from methyl, ethyl, n-propyl, and isopropyl.It is an alkyl group. In some embodiments, Q 1 is NR C6 and R C6 is a C 1-3 alkyl group selected from methyl, ethyl, n-propyl, and isopropyl, substituted with one or more halo groups independently selected from F, Cl, and Br.

[0026] In some embodiments, one end of -L- is covalently bonded to Q4 or Q5. In some embodiments, one end of -L- is covalently bonded to Q4.

[0027] In the tricyclic system (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 ) shown in Formula (II)-1 or Formula (II)-2, the double bonds and single bonds are shown and interpreted in accordance with the known rules regarding the constitution of the bifunctional compounds shown in each formula and the valence interactions.

[0028] In some embodiments, -L- is the following formula (III): [Chemical formula] (wherein Z is independently selected from the group consisting of a 3- to 8-membered monocyclic group having 1 to 2 heteroatoms, a 6- to 10-membered bicyclic group, and an 8- to 10-membered spirobicyclic group; X 1 is an unsubstituted methylene group, or a methylene group substituted with alkyl or cycloalkyl; X 2is selected from the group consisting of a 3- to 7-membered heterocyclic alkylene group having 1 to 2 heteroatoms, which are each unsubstituted or substituted with alkyl or cycloalkyl, a 3- to 8-membered heterocyclic alkenylene group having 1 to 2 heteroatoms, and a 6- to 12-membered spiro bicyclic divalent group having 1 to 2 heteroatoms; m is 0, 1 or 2; v1 is 1 or 2; v2 is 1) as shown.

[0029] In some embodiments, the heteroatoms in formula (III) are each independently selected from N, O and S. In some embodiments, the Z ring contains 1 or 2 heteroatoms selected from N, O and S.

[0030] In some embodiments, Z is an unsubstituted heterocyclic alkylene group of 3-, 4-, 5-, 6- or 7-membered ring having 1 or 2 heteroatoms. In some embodiments, Z is a spiro bicyclic divalent group of 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring having 1 or 2 heteroatoms.

[0031] In some embodiments, R L1 is an unsubstituted C 1-3 alkyl group, a C 1-3 alkyl group substituted with a C 1-3 alkoxyl group, a C 1-3 alkyl group substituted with one or more halo groups, a halo group, a C 1-3 alkoxyl group, a keto group, and an oxide group. In some embodiments, R L1 is an oxide group, which is bonded to one heteroatom N on the Z ring to form an N-oxide group (N + -O - ).

[0032] In some embodiments, R L1 are each unsubstituted or C 1-6Linear C substituted with an alkoxyl group or one or more halo groups 1-6 alkyl and branched C 1-6 alkyl selected from the group consisting of alkyl. In some embodiments, R L1 is each unsubstituted or C 1-6 Linear C substituted with an alkoxyl group or one or more halo groups 1-3 alkyl and branched C 1-3 alkyl selected from the group consisting of alkyl.

[0033] In some embodiments, X 1 is a methylene group substituted with one or two C 1-6 alkyl. In some embodiments, X 1 is a methylene group substituted with one or two C 1-3 alkyl. In some embodiments, X 1 is a methylene group substituted with one or two C 3-6 cycloalkyl. In some embodiments, X 1 is a methylene group substituted with one or two C 3-6 cycloalkyl.

[0034] In some embodiments, X 1 is an ethylene group substituted with 1 to 4 C 1-6 alkyl. In some embodiments, X 1 is an ethylene group substituted with 1 to 4 C 1-3 alkyl. In some embodiments, X 1 is an ethylene group substituted with 1 to 4 C 3-6 cycloalkyl. In some embodiments, X 1 is an ethylene group substituted with 1 to 4 C 3-6 cycloalkyl.

[0035] In some embodiments, X 2is a heterocyclic alkylene group of a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered ring having 1 or 2 heteroatoms, each of which is unsubstituted or substituted with alkyl or cycloalkyl. In some embodiments, X 2 is a heteroalkenylene group of a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered ring having 1 or 2 heteroatoms, each of which is unsubstituted or substituted with alkyl or cycloalkyl. In some embodiments, X 2 is a spirobicyclic divalent group of a 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered ring having 1 or 2 heteroatoms, each of which is unsubstituted or substituted with alkyl or cycloalkyl.

[0036] In some embodiments, X 2 is a heterocyclic alkylene group of a 3-membered ring having 1 heteroatom substituted with 1 to 3 alkyl or cycloalkyl, a heterocyclic alkylene group of a 3-membered ring having 2 heteroatoms substituted with 1 to 2 alkyl or cycloalkyl, a heterocyclic alkylene group of a 4-membered ring having 1 heteroatom substituted with 1 to 5 alkyl or cycloalkyl, a heterocyclic alkylene group of a 4-membered ring having 2 heteroatoms substituted with 1 to 4 alkyl or cycloalkyl, or a heterocyclic alkylene group of a 5- to 7-membered ring having 1 to 2 heteroatoms substituted with 1 to 6 alkyl or cycloalkyl.

[0037] In some embodiments, X 2is a 3-membered heterocyclic alkenylene group having one heteroatom substituted with 1 to 3 alkyl or cycloalkyl groups, a 4-membered heterocyclic alkenylene group having one heteroatom substituted with 1 to 3 alkyl or cycloalkyl groups, a 4-membered heterocyclic alkenylene group having two heteroatoms substituted with 1 to 2 alkyl or cycloalkyl groups, a 5-membered heterocyclic alkenylene group having one heteroatom substituted with 1 to 5 alkyl or cycloalkyl groups, a 5-membered heterocyclic alkenylene group having two heteroatoms substituted with 1 to 4 alkyl or cycloalkyl groups, a 6-membered, 7-membered or 8-membered heterocyclic alkenylene group having one heteroatom substituted with 1 to 6 alkyl or cycloalkyl groups, or a 6-membered, 7-membered or 8-membered heterocyclic alkenylene group having two heteroatoms substituted with 1 to 6 alkyl or cycloalkyl groups.

[0038] In some embodiments, -L- is

Chemical formula

[0039] In some embodiments, ABM is of the following formula:

Chemical formula

[0040] 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.

[0041] In some embodiments, Z 1 Is

Chemical formula

[0042] In some embodiments, Z 1 Is

Chemical formula

[0043] In some embodiments, Z 2 Is

Chemical formula

[0044] In some embodiments, M is

Chemical formula

[0045] In some embodiments, each R M group is independently either unsubstituted, substituted with a C 1-6 alkoxyl group, or substituted with one or more halo groups, and is an alkyl selected from the group consisting of linear C 1-6 alkyl and branched C 1-6 alkyl. In some embodiments, each R M group is independently either unsubstituted, substituted with a C 1-6 alkoxyl group, or substituted with one or more halo groups, and is an alkyl selected from the group consisting of linear C 1-3 alkyl and branched C 1-3 alkyl. In some embodiments, each R M group is independently methyl, ethyl, n-propyl or isopropyl.

[0046] In some embodiments, R a , R b , R c , R d , R Y1 and R Y2 are each independently either unsubstituted, substituted with a C 1-6 alkoxyl group, or substituted with one or more halo groups, and are an alkyl selected from the group consisting of linear C 1-6 alkyl and branched C 1-6 alkyl. In some embodiments, R a , R b , R c , R d , R Y1 and R Y2 are each independently either unsubstituted, substituted with a C 1-6 alkoxyl group, or substituted with one or more halo groups, and are an alkyl selected from the group consisting of linear C 1-3Alkyl and branched C 1-3 is alkyl selected from the group consisting of alkyl. In some embodiments, R a , R b , R c , R d , R Y1 and R Y2 are each independently methyl, ethyl, n-propyl or isopropyl.

[0047] In some embodiments, (Y 3 ) 0-5 shown in formula (IV)-d is

Chemical formula

[0048] In some embodiments, each R Z2 group is each independently either unsubstituted or alkyl selected from the group consisting of linear C 1-6 alkyl and branched C 1-6 alkyl substituted with one or more halo groups. In some embodiments, each R Z2 group is each independently either unsubstituted or alkyl selected from the group consisting of linear C 1-3 alkyl and branched C 1-3 alkyl substituted with one or more halo groups.

[0049] In some embodiments, R Z2A is alkyl selected from the group consisting of linear C 1-6 alkyl and branched C 1-6 alkyl. In some embodiments, R Z2A is alkyl selected from the group consisting of linear C 1-3 alkyl and branched C 1-3 alkyl.

[0050] In some embodiments, R Z2A is linear C 1-6 heteroalkyl and branched C1-6 It is a heteroalkyl selected from the group consisting of heteroalkyls. In some embodiments, R Z2A is a straight-chain C 1-3 heteroalkyl and a branched C 1-3 heteroalkyl, which is a heteroalkyl selected from the group consisting of heteroalkyls.

[0051] In some embodiments, ABM is

Chemical formula

[0052] In a specific embodiment, ABM is an androgen receptor binding moiety represented by formula (IV)-b, wherein M in the formula is a 4-membered alicyclic ring having 0 to 2 heteroatoms, and the ring is unsubstituted or may be substituted with 1 to 6 R M . The other groups have the same meanings as described above.

[0053] In a specific embodiment, ABM is an androgen receptor binding moiety represented by formula (IV)-b, wherein Z 2 is a bond, a C 1-6 alkylene group, a C 1-6 heteroalkylene group, -O-, an arylene group, a heteroarylene group, an alicyclic divalent group, a heterocyclic divalent group, a hetero-bicyclic divalent group, a bicyclic arylene group, or a bicyclic heteroarylene group, and each group is substituted with 1, 2 or 3 R Z2 groups. The other groups have the same meanings as described above.

[0054] In a specific embodiment, ABM is an androgen receptor binding moiety represented by formula (IV)-b, wherein in the formula Z 1 is [Chem.] and R ZA1 is -H or -CN; each R Z1B is independently -H, a halo group, or -CF3; t is 0, 1, 2, 3 or 4; Y 3 is -O-; M is a 4- to 6-membered ring unsubstituted or substituted with 1 to 4 R M groups, each R M is independently -H or methyl; Y 4 is -NH-; Y 5 is -C(=O)-; Z 2 is independently an unsubstituted C 5-6 aryl group, a C Z2 aryl group substituted with 1, 2 or 3 R 5-6 groups, a C 5-6 heteroaryl group having 1 to 2 heteroatoms, a C Z2 heteroaryl group having 1 heteroatom substituted with 1, 2 or 3 R 5-6 groups, and a C Z2 heteroaryl group having 2 heteroatoms substituted with 1 or 2 R 5-6 groups, selected from the group consisting of; each R Z2A group is an alkyl selected from the group consisting of linear C 1-6 alkyl and branched C 1-6 alkyl. In some embodiments, R Z2A is an alkyl selected from the group consisting of linear C 1-3 alkyl and branched C 1-3 alkyl. The other groups have the same meaning as described above.

[0055] In certain embodiments, ABM is an androgen receptor binding moiety represented by formula (IV)-d, wherein Z 1 is aryl substituted with one or more halo groups, aryl substituted with -CN, or aryl independently substituted with -CN and one or more halo groups; Y 3 is a bond, -NR Y2 -, -CR Y1 R Y2 -, or -C(=O)-; M is a 5-membered aromatic ring having one or two heteroatoms; R Y1 and R Y2 are each independently H or a C 1-6 alkyl group; Z 2 is each a bond, aryl, or heteroaryl which may be substituted with one, two or three R w2 groups; Each R w2 is each independently -H, a halo group, C 1-6 alkyl (optionally substituted with one or more -F), or C 1-3 alkoxyl (optionally substituted with one or more -F); Each R W2 group is each independently selected from the group consisting of -H, a halo group, a 6-membered alicyclic group having one or two heteroatoms, and a 5-membered aromatic group having one, two or three heteroatoms. The other groups have the same meaning as described above.

[0056] In certain embodiments, ABM is an androgen receptor binding moiety represented by formula (IV)-d, wherein Z 1 is

Chemical formula

[0057] In some embodiments, the ABM is

Chemical formula

[0058] In some embodiments, the pharmaceutical composition of the present invention further comprises a second therapeutic agent.

[0059] In some embodiments, the androgen receptor-related disease is a cancer related to the androgen receptor or a skin disease related to the androgen receptor.

[0060] In some embodiments, the cancer related to the androgen receptor is breast cancer or prostate cancer. In some embodiments, the cancer related to the androgen receptor is breast cancer. In some embodiments, the cancer related to the androgen receptor is prostate cancer. In some embodiments, the prostate cancer is castration-resistant prostate cancer.

[0061] In some embodiments, the skin disease related to the androgen receptor is male pattern baldness, acne, hidradenitis suppurativa, hirsutism, or atopic dermatitis.

[0062] In some embodiments, the method of treating an androgen receptor-related disease further comprises the step of administering a second therapeutic agent in an effective amount.

[0063] In some embodiments, the second therapeutic agent may be an androgen receptor inhibitor. Examples of androgen receptor inhibitors include enzalutamide.

[0064] In some embodiments, the second therapeutic agent may be an anti-cancer agent conventionally used in the art. Examples of conventional anti-cancer agents include docetaxel, flutamide, goserelin acetate, leuprorelin acetate, colchicine, leuprorelin acetate, mitoxantrone hydrochloride, 5-fluorouracil, and olaparib. Further, examples of conventional anti-cancer agents include one or more anti-cancer agents such as cyclophosphamide and mitomycin C.

[0065] In some embodiments, the second therapeutic agent may be a therapeutic agent for treating skin diseases related to androgen receptors conventionally used in the art. Examples of conventional anti-cancer agents include clascoterone, ASC-J9, spironolactone, flutamide, finasteride, dutasteride, cyproterone acetate, Pyrilutamide, minoxidil, ketoconazole, and the like.

Mode for Carrying Out the Invention

[0066] As used herein and in the claims, the articles "a" and "an" are used to refer to one or more (i.e., at least one) of the grammatical objects of these articles, unless otherwise clearly specified. For example, "an element" means one component or a plurality of components.

[0067] As used in this specification and the claims, the term "and / or" means "one or both" of the components so combined, i.e., it means that the multiple components may exist in combination and may also exist separately. Multiple components listed using the term "and / or" should be interpreted in the same way, i.e., "one or more" of the multiple components are described in combination. There may be other components other than those specifically identified using the term "and / or", and these other components may or may not be related to the specifically identified components. Thus, for example, "A and / or B", when used with an open-ended term such as "comprising", may, in one embodiment, refer to only A (and may further include components other than B); in another embodiment, it may refer to only B (and may further include components other than A); in yet another embodiment, it may refer to both A and B (and may further include other components); and there may be other aspects, but are not limited to these.

[0068] As used in this specification and the claims, the term "or" has the same meaning as "and / or" as defined above. For example, when the listed items are separated by the terms "or" or "and / or", these terms are to be construed as inclusive, i.e., including one or more of the recited components or at least one of the recited components, but also including two or more of them, and may also include additional items not recited. Terms such as "only one", "exactly one only", or the term "consisting of" recited in the claims, which clearly indicate the opposite meaning, mean including only one of the multiple components or the recited components. Usually, when the term "or" used in this specification is in front of exclusive terms such as "either", "one of them", "only one of them", or "exactly one of them", it is construed as indicating only exclusive alternatives (i.e., "one or the other of them, but not both").

[0069] In the foregoing description and claims herein, all transitional phrases such as "comprising", "including", "possessing", "having", "containing", "accompanying", "retaining", "constituted by", etc. are open-ended expressions, i.e., they mean including the recited matters but not limited thereto. As described in Section 2111.03 of the Manual of Patent Examining Procedures by the United States Patent and Trademark Office, only the transitional phrase "consisting of" is a closed-ended transitional phrase, and only the transitional phrase "consisting essentially of" is a semi-closed-ended transitional phrase.

[0070] In this specification and the claims, the term "at least one" used in connection with the recitation of one or more components means at least one component selected from one or more of the recited components, but does not necessarily include at least one of all the components specifically recited in the recited components, nor does it exclude any combination of the recited components. This definition also means that there may be components other than those specifically identified in the list of components in which the term "at least one" is used, and the components other than those specifically identified may or may not be related to the specifically recited components. Thus, "at least one of A and B" (or equivalently "at least one of A or B" or "at least one of A and / or B") may, for example, in one embodiment, refer to at least one A, may include two or more A, but B may not be present (and may include components other than B); in another embodiment, it may refer to at least one B, may include two or more B, but A may not be present (and may include components other than A); in yet another embodiment, it may refer to at least one A, may include two or more A, and may also refer to at least one B, may include two or more B (and may include other components); there may be other aspects, but are not limited thereto.

[0071] In a particular method described herein that includes two or more steps or acts, unless otherwise specified, the order of the steps or acts of this method is not necessarily limited to the order in which the steps or acts of this method are described.

[0072] The term "effective" may mean, but is not limited to, preventing, suppressing the onset, improving, delaying or treating the symptoms of a condition, disorder or disease state, or being sufficient for such prevention, suppression of onset, improvement, delay or treatment (able to relieve the symptoms to some extent, preferably all symptoms) in a subject in need of treatment of the condition, disorder or disease state when used for its intended use, an amount / dosage of a pharmaceutical active ingredient. The term "effective" encompasses any other terms related to an effective amount or effective concentration, for example, "effective amount / dosage", "pharmaceutically effective amount / dosage", "therapeutically effective amount / dosage", etc., and these terms are separately explained or used in this application.

[0073] The effective amount depends on the type and severity of the disease, the composition used, the route of administration, the type of mammal being treated, the specific physical characteristics of the particular mammal to be considered, concomitant medications, and other factors recognized by those skilled in the medical arts. The exact amount can be determined by those skilled in the art using known techniques (see, for example, 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).

[0074] The term "pharmaceutically acceptable" or "pharmacologically acceptable" may mean, but is not limited to, substances and compositions that do not cause adverse reactions, allergic reactions, or other undesirable reactions when properly administered to animals or humans.

[0075] The term "pharmaceutically acceptable carrier" or "pharmacologically acceptable carrier" may mean, but is not limited to, any solvent, dispersion medium, coating agent, antibacterial agent, antifungal agent, isotonic agent, absorption delaying agent, etc. Suitable carriers are described in the latest edition of Remington’s Pharmaceutical Sciences, a standard reference book in the art, which is hereby incorporated by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, physiological saline, finger solution, dextrose solution, and 5% human serum albumin. Non-aqueous solvents such as non-volatile oils, or liposomes may also be used. The use of such media and agents with pharmaceutically active substances is well known in the art. Conventional media or agents may be used in the compositions of the present disclosure, except when they are not compatible with the active compound. Also, auxiliary active compounds can be included in the pharmaceutical compositions of the present disclosure.

[0076] As used herein, unless otherwise specified, the term "compound" refers to the specific compounds disclosed herein, which includes tautomers, positional isomers and geometric isomers, and where appropriate, optical isomers (enantiomers) and other stereoisomers (diastereomers), and pharmaceutically acceptable salts and derivatives (including those in the form of prodrugs) thereof, as determined to be appropriate from the description. In the context of the present disclosure, the term "compound" generally refers to a single compound, but may also include other compounds, for example, stereoisomers, positional isomers and / or optical isomers (including racemic mixtures) of the compounds of the present disclosure, as well as specific enantiomers, or mixtures enriched in specific enantiomers. Also, as used herein, the term "compound" also refers to compounds in the form of prodrugs that have been modified to facilitate administration and delivery of the compound to the active site. Note that when describing the compounds of the present disclosure, numerous substituents, variables, etc. related to the compound are also described.

[0077] One skilled in the art would understand that the molecules described herein are stable compounds, as outlined below. The following formula:

Chem.

[0078] As used herein, an "alkoxyl group" refers to an alkyl group bonded to oxygen via a single bond, such as methoxy (-O-CH3) or ethoxy (-O-CH2CH3).

[0079] As used herein, "derivative" may mean a composition formed directly from a natural compound, or a composition formed by modifying or partially substituting a natural compound. As used herein, "analogue" may mean a composition having a structure similar to, but not identical to, a natural compound.

[0080] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transport of ubiquitin to a specific substrate protein and target the degradation of that substrate protein. For example, the cereblon E3 ubiquitin ligase, either alone or in cooperation with an E2 (ubiquitin-conjugating enzyme), adds ubiquitin to the lysine of a target protein, thereby leading the target protein substrate to proteasomal degradation. In this way, the E3 ubiquitin ligase, either alone or by forming a complex with an E2 (ubiquitin-conjugating enzyme), is responsible for the transport of the target protein to ubiquitin. Usually, ubiquitin ligase is involved in polyubiquitination, in which the second ubiquitin is added to the first ubiquitin, and the third ubiquitin is added to the second ubiquitin, and so on. Polyubiquitination marks the proteins that need to be degraded by the proteasome. On the other hand, there are also ubiquitination events limited to monoubiquitination, in which case only one ubiquitin is added to the substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins are not targets for proteasomal degradation, but can change their intracellular localization and function, for example, by binding to other proteins that have a domain capable of binding to ubiquitin. Furthermore, the E3 ubiquitin ligase promotes the formation of polyubiquitin chains via the lysine residues of ubiquitin. The most predominant polyubiquitination is the Lys48-linked ubiquitin chain, which can lead the target protein to proteasomal degradation.

[0081] Throughout this specification, the terms "patient" or "subject" are used to describe a cell, tissue or animal, preferably a mammal such as a human or livestock, in which treatment (including prophylactic treatment) using the compositions of the present disclosure is performed. For example, with respect to the treatment of a specific infectious disease, condition or disorder specific to a particular animal such as a human patient, the term "patient" refers to a particular animal including livestock such as dogs and cats, farm animals such as horses, cows and sheep. In the present disclosure, the term "patient" usually refers to a human patient unless otherwise specified or unless it is clear from the context in which the term is used.

[0082] In all cases disclosed herein, the integer range of a variable is to be interpreted as indicating the recited range, the individual numerical values included within that range, and every sub-range that the variable can take. For example, the description that n is an integer from 0 to 4 describes a range that includes the integers 0, 1, 2, 3, and 4 as individually selectable numerical values. Also, the description that n is an integer from 0 to 4 describes every sub-range, and these sub-ranges include ranges where n is from 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, or 3 to 4. Also, the term " 1-6 "C

[0083] A detailed description to assist those skilled in the art in practicing the present invention is set forth below. Those skilled in the art may make improvements and modifications to the embodiments described herein without departing from the spirit or scope of the present disclosure. All published documents, patent applications, patents, drawings, and other references cited herein are hereby expressly incorporated by reference in their entirety.

[0084] Detailed Description of the Preferred Embodiment Exemplary bifunctional compounds having the structure represented by ABM-L-CLM according to the present invention are shown in Table 1 below.

Table 1

[0085] Method for Producing the Compounds of the Invention A general method for producing the compounds of the present invention is illustrated below. Extraction and purification may be carried out by procedures performed in ordinary organic chemistry experiments.

[0086] The synthesis of the compounds of the present invention can be carried out with reference to procedures known in the art.

[0087] As starting compounds, commercially available compounds, compounds described in this specification, compounds described in the references cited herein, and other known compounds can be used.

[0088] Since the compounds of the present invention may include compounds that can exist as tautomers, the present invention encompasses all tautomers and mixtures containing these tautomers.

[0089] When attempting to obtain a salt of the compound of the present invention, if the compound of the present invention is obtained in the form of a salt, this salt can be purified as it is. If the compound of the present invention is obtained in the free form, according to the usual method, after dissolving or suspending the compound in the free form in an appropriate organic solvent, an acid or a base can be added to form a salt.

[0090] Also, depending on the situation, when the compounds of the present invention and their pharmaceutically acceptable salts exist in the form of an adduct of water or an adduct of various solvents (hydrate or solvate), such adducts are also encompassed by the present invention.

[0091] One or more embodiments of the present invention will be described in detail below. Other features, objects, and advantages of the present invention will become apparent from the following description and claims.

[0092] The compounds of the present invention can be synthesized from commercially available starting materials by methods known in the art. For example, the compounds of the present invention can be prepared by the routes shown below.

[0093] Basic Procedure for Preparing the Compounds of the Present Disclosure: Procedure 1

Chemical formula

[0094] Procedure 1 shows the basic method for preparing the bifunctional compounds of the present disclosure. In the first step, the diester compound (i) was condensed with 3-aminopiperidine-2,6-dione to obtain the intermediate (ii). In the second step, the intermediate (ii) was further condensed with a specific ABM compound to obtain the desired compound (iii). In the above Procedure 1, "P" represents a protecting group.

[0095] The following specific examples are merely illustrative and do not limit any other matters of the present disclosure. A person skilled in the art would be able to fully utilize the present invention based on the description in this specification without further detailed explanation. All documents cited in this specification are incorporated herein by reference in their entirety.

Example

[0096] Synthesis Method A - Synthesis of Compound 1: (1) Preparation of Intermediate I-A According to the route shown below, first, the intermediate I-A was prepared from commercially available 3-benzyloxyphenylamine.

Chemical formula

[0097] In a vessel purged with air, Pd(OAc)2 (1.13 g, 10 mol%) was added to a solution consisting of 3-benzyloxyphenylamine (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 and reacted for 8 hours. After completion of the reaction, 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 MgSO4, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (KM3 SCIENTIFIC, particle size 45 - 75 μm) using an eluent (hexane:ethyl acetate = 5:1) to obtain dimethyl 6-benzyloxy-1H-indole-2,3-dicarboxylate I-a1 (8.4 g, 54%) as a brown solid.

[0098] A solution of dimethyl 6-benzyloxy-1H-indole-2,3-dicarboxylate I-a1 (3.0 g, 8.84 mmol) in ice-cooled Ν,Ν-dimethylformamide (DMF) (15 ml) was treated with 60% NaH (0.53 g, 13.3 mmol) and methyl iodide (0.82 ml, 13.3 mmol), and warmed to room temperature. After 1 hour, the reaction mixture was separated between dichloromethane (DCM) (60 mL) and saturated aqueous NH4Cl solution (20 mL). The combined organic layers were collected, washed with water (3 × 20 mL) and brine (20 mL), dried over MgSO4, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (KM3 SCIENTIFIC, particle size 45 - 75 μm) using an eluent (hexane:ethyl acetate = 3:1) to obtain brown solid I-a2 (2.7 g, 87%).

[0099] To a solution of dimethyl 6-benzyloxy-1-methyl-1H-indole-2,3-dicarboxylate I-a2 (5.0 g) in MeOH (150 mL) was added Pd / C (0.5 g), and the mixture was stirred under a hydrogen atmosphere for 2 hours. After completion of the reaction, the mixture was filtered through a Celite pad, rinsed with ethyl acetate (10 mL), and the organic solvent was recovered and removed using a rotary evaporator to obtain intermediate I-a3 (3.72 g, 100%).

[0100] While stirring a solution of dimethyl 6-hydroxy-1-methyl-1H-indole-2,3-dicarboxylate I-a3 (2.85 g, 10.83 mmol, 1.0 equiv) in DCM (60 mL), N,N-diisopropylethylamine (DIPEA) (5.6 mL, 32.49 mmol, 3 equiv) was added at 0 °C, and the resulting mixture was stirred at the same temperature for 10 minutes. Trifluoromethanesulfonic anhydride (Tf2O) (2.9 mL, 16.25 mmol, 1.5 equiv) was added dropwise to the reaction solution, and the resulting mixture was stirred at 0 °C for 1 hour. The reaction solution was diluted with DCM (40 mL) and washed successively with saturated NaHCO3 (10 mL), saturated NH4Cl (10 mL), water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated to obtain a dark brown oily substance. The dark brown oily substance was purified by eluting with a 10% ethyl acetate in hexane solution using silica gel column chromatography (KM3 SCIENTIFIC, particle size 45 - 75 μm) to obtain the title compound as the pure product I-a4 (3.68 g, 86%).

[0101] A solution of dimethyl 1-methyl-6-trifluoromethanesulfonyloxy-1H-indole-2,3-dicarboxylate I-a4 (0.77 g, 1.94 mmol, 1.0 eq) in toluene (20 mL) was stirred while adding tert-butyl piperazine-1-carboxylate (1.08 g, 5.82 mmol, 3.0 eq), XPhos (0.18 g, 20 mol%) and Cs2CO3 (1.9 g, 5.82 mmol, 3 eq). The resulting mixture was degassed with N2 for 10 minutes and Pd(OAc)2 (0.087 g, 20 mol%) was added. The resulting mixture was stirred at 80 °C for 17 hours until the starting material disappeared. The reaction solution 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), the combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to obtain a crude material. The crude material was purified by eluting with a 25% ethyl acetate in hexane solution on a silica gel column chromatography (KM3 SCIENTIFIC, particle size 45 - 75 μm) to obtain the title compound as the pure product I-a5 (0.72 g, 86%).

[0102] The pure product I-a5 (0.65 g, 1.51 mmol) was treated with a solution of NaOH (0.6 g, 15.1 mmol) in EtOH (30 mL) and heated to reflux (bath temperature: 85 °C). After 4 hours, the reaction mixture was cooled to ambient temperature, the excess EtOH was removed, diluted with ethyl acetate (30 mL), acidified to pH 3 with 1 M HCl, and the layers were separated. Next, the aqueous layer was extracted with ethyl acetate (30 mL), the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to obtain a white solid. Next, the obtained white solid was mixed with Ac2O (5 mL) and heated to 140 °C. After 2 hours, a monoester was detected by liquid chromatography mass spectrometry (LC-MASS). The reaction mixture was cooled to ambient temperature. Next, the excess Ac2O was removed, dehydrated toluene (5 mL) was added, mixed, and concentrated. The residue I-a6 thus obtained was used in the next step without further purification.

[0103] A solution of 3-aminopiperidine-2,6-dione hydrochloride (0.11 g, 2 equivalents) and N,N-diisopropylethylamine (DIPEA) (0.23 mL, 4 equivalents) in tetrahydrofuran (THF) (2 mL) was stirred at room temperature for 30 minutes, and then a solution of compound I-a6 (0.13 g, 1 equivalent) in THF (2 mL) was added. The reaction mixture was stirred at room temperature for 50 minutes, and the resulting mixture was diluted with ethyl acetate (10 mL) and water (10 mL). Next, 1N HCl (aqueous solution) was added until the pH value of the aqueous layer was less than 2 (<2). The aqueous layer was extracted with ethyl acetate (2 × 10 mL), the organic layers were combined, washed with brine (10 mL), and dried over MgSO4. The crude material obtained by removing the solvent was used in the next step without purification. This crude material was dissolved in THF (4 mL), and carbonyldiimidazole (CDI) (0.11 g, 2 equivalents) and 4-dimethylaminopyridine (DMAP) (4 mg, 0.1 equivalent) 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). Next, 1N HCl (aqueous solution) was added until the pH value of the aqueous layer was less than 2 (<2), and then the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The recovered organic layers were combined, washed with brine (10 mL), and dried over Na2SO4. After removing the solvent to obtain the crude product, the crude product was purified by flash column chromatography using an eluent (hexane / EtOAc = 1 / 1 to 1 / 2) to obtain compound I-a7 (0.28 g, 85%). Next, CF3COOH (TFA solution) (1 ml) was mixed with this solid compound I-a7, charged into CH2Cl2 (4 mL), and stirred at room temperature for 4 hours. After completion of the reaction, the excess CF3COOH was removed under reduced pressure to obtain a residue. The residue was diluted with DCM (10 mL), basified to pH 10 with Na2CO3, the organic layer was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated to obtain intermediate I-A. This intermediate I-A was used directly in the next step without purification.

[0104] (2) Preparation of Intermediate I-B Intermediate I-B was prepared from commercially available 4-[(trans-3-amino-2,2,4,4-tetramethylcyclobutyl)oxy]-2-chlorobenzonitrile hydrochloride according to the route shown below. [Chemical formula]

[0105] A solution of a mixture consisting of 6-chloro-N-(trans-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide I-b1 (800 mg, 1 equivalent), compound I-b2 (200 mg, 1.1 equivalents), and (triethyl)amine (TEA) (0.57 mL, 2 equivalents) in dimethyl sulfoxide (DMSO) (6 mL) was stirred at 100 °C for 24 hours. After cooling, this mixture was slowly added to water (30 mL). The resulting suspension was filtered to obtain compound I-b3 (0.85 g, 94%).

[0106] To a solution of compound I-b3 (0.60 g, 1.36 mmol) in DCM (25 mL), Dess-Martin periodinane (0.75 g, 1.78 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was washed successively with saturated Na2S2O3 (10 mL × 2), saturated NaHCO3 (10 mL), and brine (10 mL), dried over Na2SO4, and concentrated to obtain intermediate I-B (0.54 g, 90%).

[0107] (3) Preparation of Compound 1 from Intermediate I-A and Intermediate I-B Compound 1 was prepared according to the route shown below. [Chemical formula]

[0108] To a solution of a mixture of Intermediate I-A (100 mg, 0.25 mmol) and Intermediate I-B (111 mg, 0.25 mmol) in DCM (1 mL), NaBH(OAc)3 (107 mg, 0.50 mmol) was added. The resulting solution was stirred at room temperature for 17 h. After completion of the reaction, water was added to obtain a solution. This solution was 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 silica gel column chromatography (KM3 SCIENTIFIC, particle size 45 - 75 μm) to obtain Compound 1 (160 mg, 78%). MS: m / z 819.5 (M + +1); 1 H NMR (DMSO-d6) δ 11.05 (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, 2H), 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 - 3.82 (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 - 2.49 (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).

[0109] Compound 1 can also be prepared by the route shown below.

Chemical Structure

[0110] To a solution of Compound I-b3 (0.1 g, 0.25 mmol) in DCM (2 mL), DIPEA (0.16 mL, 4.0 equivalents) was added at room temperature. Next, methanesulfonyl chloride (MsCl) (0.038 mL, 2.0 equivalents) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 1 - 2 hours. After completion of the reaction, it was diluted with DCM (10 mL) and washed successively with saturated NaHCO3 (5 mL), saturated NH4Cl (5 mL), and brine (5 mL), dried over Na2SO4 (solid), concentrated, and purified by silica gel column chromatography (KM3 SCIENTIFIC, particle size 45 - 75 μm) (DCM / acetone = 10 / 1) to obtain Intermediate I-b3-1 (0.11 g, 84%).

[0111] A dehydrated CH3CN (ACN) (2 mL) solution consisting of Intermediate I-b3-1 (0.104 g, 0.20 mmol), Intermediate I-A (0.079 g, 0.20 mmol), KI (0.1 g, 3.0 equivalents), and DIPEA (0.17 mL, 5.0 equivalents) was heated to 75 °C and reacted 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 (solid), concentrated, and purified by silica gel column chromatography (KM3 SCIENTIFIC, particle size 45 - 75 μm) to obtain Compound 1 (0.095 g, 58%).

[0112] Synthesis Method B - Synthesis of Compound 2: (1) Preparation of Intermediate I-C According to the following route, first, Residue I-C was prepared from the 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.

Chemical Structure

[0113] A solution of 1-methyl-6-trifluoromethanesulfonyloxy-1H-indole-2,3-dicarboxylic acid dimethyl ester I-a4 (683 mg, 1.72 mmol, 1.0 equiv) in 1,4-dioxane (17 mL) was stirred, and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (797 mg, 2.58 mmol, 1.5 equiv) and Cs2CO3 (1.06 g, 3.26 mmol, 1.9 equiv) were added at 25 °C. The resulting mixture was degassed with N2 for 15 minutes, and Pd(dppf)Cl2 (63 mg, 0.09 mmol, 5 mol%) was added at 25 °C. The reaction solution was stirred at 25 °C for 5 hours until the starting material disappeared. 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 obtain a crude material. The crude material was purified by eluting with a hexane solution of 10% - 15% ethyl acetate on silica gel column chromatography (KM3 SCIENTIFIC, particle size 45 - 75 μm) to obtain intermediate I-c1 (470 mg, 64%, R f = 0.21 in EA / Hex = 1 / 5).

[0114] Pd / C (0.2 g) was added to a solution of intermediate I-c1 (2.0 g) in MeOH (20 mL), and the mixture was stirred under a hydrogen atmosphere for 2 hours. After completion of the reaction, the mixture was filtered through a Celite pad, rinsed with EtOAc (10 mL), and the organic solvent was recovered and removed by a rotary evaporator to obtain intermediate I-c2 (2.0 g, 100%).

[0115] Intermediate I-c2 (0.65 g, 1.51 mmol) was treated with a solution of NaOH (0.6 g, 15.1 mmol) in EtOH (30 mL) and heated to reflux. After 4 h, the reaction mixture was cooled to ambient temperature, excess EtOH was removed, diluted with ethyl acetate (30 mL), and acidified to pH 3 with 1 M HCl. Next, the aqueous layer was extracted with ethyl acetate (30 mL), the organic layers were combined, washed with brine, dried (over MgSO4), filtered, and concentrated to give a white solid. Next, the white solid obtained was mixed with Ac2O (5 mL) and heated to 140 °C. After 2 h, monoesters were detected by LC-MASS. The reaction mixture was cooled to ambient temperature. Next, excess Ac2O was removed, dehydrated toluene (5 mL) was added, and the mixture was concentrated. The Intermediate I-c3 thus obtained was used in the next step without further purification.

[0116] A solution of 3-aminopiperidine-2,6-dione hydrochloride (0.22 g, 2 equivalents) and N,N-diisopropylethylamine (DIPEA) (0.46 mL, 4 equivalents) in THF (2 mL) was stirred at room temperature for 30 minutes, and then a solution of intermediate I-c3 (0.26 g, 1 equivalent) in THF (2 mL) was added. The reaction mixture was stirred at room temperature for 50 minutes, and the resulting mixture was diluted with ethyl acetate (20 mL) and water (20 mL). Next, 1N HCl (aqueous solution) was added until the pH value of the aqueous layer was less than 2 (<2). The aqueous layer was extracted with ethyl acetate (2 × 20 mL), the organic layers were combined, washed with brine (20 mL), and dried over MgSO4. The crude material obtained by removing the solvent was used in the next step without purification. This crude material was dissolved in THF (8 mL), and CDI (0.22 g, 2 equivalents) and DMAP (8 mg, 0.1 equivalent) 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). Next, 1N HCl (aqueous solution) was added until the pH value of the aqueous layer was less than 2, and then the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The recovered organic layers were combined, washed with brine (20 mL), and dried over Na2SO4. After removing the solvent to obtain a crude product, the crude product was purified by flash column chromatography using an eluent (hexane / EtOAc = 1 / 1 to 1 / 2) to obtain intermediate I-c4 (0.26 g, 80%). Next, CF3COOH (2.5 ml) was mixed with this intermediate I-c4, charged into DCM (10 mL), and stirred at room temperature for 4 hours. After completion of the reaction, the excess CF3COOH was removed under reduced pressure to obtain a residue. Next, the residue was diluted with DCM (10 mL), basified to pH 10 with Na2CO3, the organic layer was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated to obtain intermediate I-C. This intermediate I-C was used directly in the next step without purification.

[0117] (2) Preparation of Compound 2 from Intermediate I-B and Intermediate I-C Compound 2 was prepared according to the route shown below.

Chemical formula

[0118] To a solution of a mixture of Intermediate I-B (112 mg, 0.254 mmol) and Intermediate I-C (100 mg, 0.254 mmol) in DCM (1 mL) was added NaBH(OAc)3 (107 mg, 0.508 mmol). The resulting solution was stirred at room temperature for 17 hours. After completion of the reaction, water was added to obtain a solution. This solution was 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 silica gel column chromatography (KM3 SCIENTIFIC, particle size 45 - 75 μm) to obtain Compound 2 (156 mg, 75%). MS: 841.5 (M + +23); 1 H NMR (DMSO-d6) δ 11.07 (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).

[0119] Synthesis Method C - Synthesis of Chiral Intermediate I-D: Intermediate I-D was prepared from Compound I-a6 according to the following route.

Chemical Structure

[0120] (S)-3-Aminopiperidine-2,6-dione hydrochloride (0.11 g, 2 equivalents) and N,N-diisopropylethylamine (DIPEA) (0.23 mL, 4 equivalents) in THF (2 mL) were stirred at room temperature for 30 minutes, and then a solution of compound I-a6 (0.13 g, 1 equivalent) in THF (2 mL) was added. The reaction mixture was stirred at room temperature for 50 minutes, and the resulting mixture was diluted with ethyl acetate (10 mL) and water (10 mL). Next, 1N HCl (aqueous solution) was added until the pH value of the aqueous layer was less than 2 (<2). The aqueous layer was extracted with ethyl acetate (2 × 10 mL), the organic layers were combined, washed with brine (10 mL), and dried over MgSO4. The crude material obtained by removing the solvent was used in the next step without purification. This crude material was dissolved in THF (4 mL), and CDI (0.11 g, 2 equivalents) and DMAP (4 mg, 0.1 equivalent) 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). Next, 1N HCl (aqueous solution) was added until the pH value of the aqueous layer was less than 2 (<2), and then the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The organic layer was recovered, washed with brine (10 mL), and dried over Na2SO4. After removing the solvent to obtain the crude product, the crude product was purified by flash column chromatography using an eluent (hexane / EtOAc = 1 / 1 to 1 / 2) to obtain the chiral intermediate I-D (0.15 g, 90%). The chiral compound of the present invention can be obtained using this chiral intermediate I-D instead of intermediate I-A or intermediate I-C.

[0121] The preparation of Compound 1 and Compound 2 of the present invention is exemplified above. Compounds 3 to 51 of the present invention can be synthesized by the same method as shown in Synthesis Method A (Synthesis Schemes 1 to 4), Synthesis Method B (Synthesis Schemes 5 to 6), or Synthesis Method C, or by changing one or more starting materials so that the desired product can be obtained by a known synthetic method based on general knowledge of organic chemistry.

[0122] Compound 3: MS: m / z 855.6 (M + +23); 11H NMR (DMSO-d6) δ 11.05 (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, 3H), 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), 3.29 (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), 2.12 - 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).

[0123] Compound 4: MS: m / z 882.6 (M + +23); 1 1H 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).

[0124] Compound 5: MS: m / z 882.9 (M + +23); 1 H 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).

[0125] 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).

[0126] Compound 7: MS: m / z 910.7 (M + +23); 11H 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).

[0127] 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).

[0128] Compound 9: MS: m / z 889.9 (M + +1); 11H 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).

[0129] 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).

[0130] 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).

[0131] Compound 12: MS: m / z 861.0 (M + +1); 1 H NMR (DMSO-d6) δ 11.07 (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).

[0132] Compound 13: MS: m / z 886.8 (M + +1).

[0133] Compound 14: MS: m / z 900.8 (M + +1).

[0134] 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).

[0135] Compound 16: MS: m / z 888.0 (M + +1).

[0136] Compound 17: MS: m / z 847.9 (M + +1); 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), 6.96 (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).

[0137] Compound 18: MS: m / z 846.6 (M + +1); 11H NMR (DMSO-d6) δ 11.07 (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), 3.06 - 3.00 (m, 1H), 2.93 - 2.87 (m, 1H), 2.72 - 2.63 (m, 2H), 2.63 - 2.59 (m, 1H), 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).

[0138] Compound 19: MS: m / z 887.4 (M + +1).

[0139] Compound 20: MS: m / z 901.5 (M + +1).

[0140] Compound 21: MS: m / z 869.7 (M + +23).

[0141] 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).

[0142] Compound 23: MS: m / z 883.8 (M + +23); 11H 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).

[0143] 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).

[0144] Compound 25: MS: m / z 883.5 (M + +23); 11H 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).

[0145] Compound 26: MS: m / z 883.5 (M + +23); 1 1H 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).

[0146] Compound 27: MS: m / z 874.8 (M + +1); 1 H 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).

[0147] 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).

[0148] 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).

[0149] Compound 30: MS: m / z 846.6 (M + +1); 1 H NMR (DMSO-d6) δ 11.07 (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, 1H), 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).

[0150] Compound 31: MS: m / z 886.8 (M + +1).

[0151] Compound 32: MS: m / z 900.8 (M + +1).

[0152] 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).

[0153] Compound 34: MS: m / z 832.4 (M + +1); 11H 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).

[0154] Compound 35: MS: m / z 847.4 (M + + 1); 11H NMR (DMSO-d6) δ 11.05 (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).

[0155] Compound 36: MS: m / z 861.7 (M + +1); 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), 7.40 (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).

[0156] Compound 37: MS: m / z 886.8 (M + +1).

[0157] Compound 38: MS: m / z 900.8 (M + +1).

[0158] Compound 39: MS: m / z 862.0 (M + +1); 1 H 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).

[0159] Compound 40: MS: m / z 860.9 (M + +1); 11H 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).

[0160] Compound 41: MS: m / z 869.9 (M + +23); 11H NMR (DMSO-d6) δ 11.06 (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).

[0161] Compound 42: MS: m / z 869.7 (M + +23); 1 1H NMR (DMSO-d6) δ 11.06 (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).

[0162] Compound 43: MS: m / z 886.8 (M + +1).

[0163] Compound 44: MS: m / z 900.6 (M + +1).

[0164] Compound 45: MS: m / z 861.4 (M + +1).

[0165] Compound 46: MS: m / z 846.8 (M + +1).

[0166] Compound 47: MS: m / z 841.6 (M + +23); 1 H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.56 (d, 1H), 7.87 - 7.82 (m, 2H), 7.63 (d, 1H), 7.39 (d, 1H), 7.29 (dd, 1H), 7.14 (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).

[0167] Compound 48: MS: m / z 858.5 (M + +1).

[0168] Compound 49: MS: m / z 858.5 (M + +1); 11H NMR (DMSO-d6) δ 11.08 (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).

[0169] Compound 50: MS: m / z 886.8 (M + +1).

[0170] Compound 51: MS: m / z 902.7 (M + +1); 11H NMR (DMSO-d6) δ 11.05 (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), 1.54 - 1.48 (m, 2H), 1.39 (t, 3H), 1.16 - 1.09 (m, 2H).

[0171] Furthermore, to perform the assays described below, compound ARV - 110 was purchased from BLD Pharmatech (Catalog No.: BD01398519; Lot No.: CKA112, purity: 97%). ARV - 110 is a well - known bifunctional compound with androgen receptor degrading activity.

Chemical Structure

[0172] Androgen Receptor Degradation Assay Using Western Blot Analysis LNCaP.FGC cells (Catalog No. 60088, Bioresource Collection and Research Center, Hsinchu City, Taiwan) grown in RPMI 1640 medium (Catalog No. 31800022, Thermo Fisher Scientific, Waltham, MA, USA) supplemented with 10% FBS (Catalog No. 10437028, Thermo Fisher Scientific, Waltham, MA, USA), 10 mM HEPES (Catalog No. 15630080, Thermo Fisher Scientific, Waltham, MA, USA) and 1 mM sodium pyruvate (Catalog No. 11360070, Thermo Fisher Scientific, Waltham, MA, USA) were seeded at a density of 2 × 10 5 cells per well in a 24-well tissue culture plate. The cells were incubated at 37 °C and 5% CO2 for 24 hours (hr), and then treated with any one of compounds 1 - 51 at a concentration of 100 nanomolar (nM) or ARV-110 for 24 hours. After treatment, the cells were harvested, washed with PBS, and lysed with RIPA lysis and extraction buffer (Catalog No. 89900, Thermo Fisher Scientific, Waltham, MA, USA) supplemented with Halt protease inhibitor cocktail (Catalog No. 78430, Thermo Fisher Scientific, Waltham, MA, USA) to recover protein samples.

[0173] Each protein sample was separated by polyacrylamide gel electrophoresis and transferred to a PVDF membrane for immunoblotting (Catalog No. 1620177, Bio-Rad Laboratories, Hercules, CA, USA). The androgen receptor was detected in each protein sample by standard Western blotting using an anti-androgen receptor antibody (1:2000 dilution) (Catalog No. 5153, Cell Signaling Technology, Danvers, MA, USA) and a goat anti-rabbit HRP-labeled secondary antibody (1:5000 dilution) (C04003, Croyez Bioscience, Taipei City, Taiwan). The internal loading control GAPDH was detected using a mouse monoclonal antibody (1:5000) (GTX627408, GeneTex International, Hsinchu City, Taiwan) and a goat anti-mouse HRP-labeled secondary antibody (1:5000 dilution) (C04001, Croyez Bioscience, Taipei City, Taiwan). A chemiluminescent signal was generated using Clarity Western ECL Substrate (Catalog No. 1705061, Bio-Rad Laboratories, Hercules, CA, USA) and detected with a digital image processing device, iBright FL1500 (Invitrogen, Carlsbad, CA, USA).

[0174] Several compounds were selected and serially diluted (10-fold) in RPMI medium, and LNCaP.FGC cells were treated with each diluted compound. A calibration curve was created using the serially diluted samples of each compound, and the concentration required to degrade 50% of the androgen receptor (AR DC 50 ) was calculated for each compound. The results are shown in Table 2.

[0175] In Table 2, the results of compounds with AR DC 50 less than 10 nM are indicated as "A", the results of compounds with AR DC 50 between 10 nM and less than 25 nM are indicated as "B", the results of compounds with AR DC 50 between 25 nM and less than 100 nM are indicated as "C", and the results of compounds with AR DC 50The results of the compounds with a concentration of 100 nM or more are indicated by "D". It has been clearly shown that most of the compounds of the present invention have good androgen receptor degradation activity. Under the same operating conditions, many of the compounds of the present invention degrade more androgen receptors than ARV-100 at the same concentration (100 nM), and overall have a lower AR DC than ARV-100. 50 (nM) is shown.

[0176]

Table 2

[0177] Other Embodiments All features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by another feature that serves the same purpose, an equivalent purpose, or a similar purpose. Therefore, unless otherwise clearly stated, each feature of this disclosure is only an example of equivalent or similar general features.

[0178] A person skilled in the art can understand the essential characteristics of the present invention from the foregoing description, and without departing from the gist and scope of the present invention, various changes and improvements can be made to the present invention to adapt the present invention to various uses and conditions. Therefore, other embodiments are also included within the scope of the claims.

Claims

1. A bifunctional compound, or a pharmaceutically acceptable salt or hydrate thereof, The bifunctional compound has the following formula (I): ABM-L-CLM (I) is shown by In the above formula, ABM is an androgen receptor binding moiety, -L- is a linking moiety, CLM is the cereblon E3 ubiquitin ligase binding moiety shown in formula (II)-2 below. 【Chemistry 1】 (In the formula, One end of -L- is Q 3 , Q 4 or Q5, and the other end of -L- is covalently bonded to ABM; G is -H, -OH, and -CH 2 is selected from the group consisting of OH; Q 1 is NR C6 and When one end of -L- is covalently bonded to any one atom selected from Q 3 , Q 4 and Q 5 , the atom bonded to -L- is C; and the remaining atoms not bonded to -L- and selected from Q 3 , Q 4 and Q 5 are each independently CR C2 ; R C2 is selected from the group consisting of -H, -D, a halo group, an unsubstituted C 1-6 alkyl group, and a C 1-6 alkyl group substituted with one or more halo groups; R C6 is the unsubstituted C 1-6 C substituted with alkyl groups and one or more halo groups 1-6 alkyl groups), -L- is represented by the following formula (III): 【Chemistry 2】 (In the formula, Z is independently selected from the group consisting of a 3- to 8-membered monocyclic group, a 6- to 10-membered bicyclic group, and an 8- to 10-membered tricyclic group, each of which has 1 to 2 heteroatoms; R L1 is the unsubstituted C 1-6 Alkyl group, C 1-6 Alkoxy-substituted C 1-6 Alkyl groups, C substituted with one or more halo groups 1-6 Alkyl groups, halo groups, unsubstituted C 1-6 selected from the group consisting of alkoxyl groups, keto groups, and oxide groups; X 1 is an unsubstituted methylene group or a methylene group substituted with a C 1-6 alkyl group or a C 3-6 cycloalkyl group; X 2 is selected from the group consisting of a 3- to 7-membered heterocyclic alkylene group having 1 to 2 heteroatoms, a 3- to 8-membered heterocyclic alkenylene group having 1 to 2 heteroatoms, and a 6- to 12-membered spiro bicyclic divalent group having 1 to 2 heteroatoms, each of which is unsubstituted or substituted with a C 1-6 alkyl group or a C 3-6 cycloalkyl group; m is 0, 1 or 2; v1 is 1 or 2; v2 is 1; The heteroatoms and the heteroatoms in the heterocyclic alkylene or heterocyclic alkenylene groups are selected from N, O and S. is shown by ABM has the following formula (IV)-b: 【Transformation 3】 (In the formula, Z 1 is 【Chemistry 4】 selected from the group consisting of: Y3, Y4, and Y5 are each independently selected from the group consisting of a bond, -O-, -NR Y2 -, -C(-R Y1 )(-R Y2 )-, -C(=O)-, -C(=S)-, -S(=O)-, -SO 2 -, a heteroarylene group, and an arylene group; M is a 6-membered ring with no heteroatoms that is unsubstituted or substituted with 0-6 RM groups; each RM group is independently selected from the group consisting of an unsubstituted C 1-6 alkyl group, a C 1-6 alkyl group substituted with a C 1-6 alkoxyl group, a C 1-6 alkyl group substituted with one or more halo groups, a halo group, and a C 1-6 alkoxyl group, or two RM groups together with the atoms to which they are attached form a 3- to 8-membered ring system; R Y1 and R Y2 are each independently selected from the group consisting of -H, an unsubstituted C 1-6 alkyl group, a C 1-6 alkyl group substituted with a C 1-6 alkoxyl group, a C 1-6 alkyl group substituted with one or more halo groups, a halo group, a C 1-6 alkoxyl group, a cyclic group, and a heterocyclic group; Z2 is 【Transformation 5】 selected from the group consisting of: The heteroatoms, and the heteroatoms in the heterocyclic or heteroarylene groups, are selected from N, O and S. or a pharmaceutically acceptable salt or hydrate thereof.

2. -L-, 【Transformation 6】 2. The bifunctional compound of claim 1, wherein:

3. ABM, 【Transformation 7】 (In the formula, A 1 -Cl, -F, -Br and -CF 3 Selected from: A 2 is selected from -O-, -NH-, -N(-methyl)- and -N(-ethyl)-; A 3 , A 4 , A 5 and A 6 are each independently -CH- or -N-.

2. The bifunctional compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, selected from the group consisting of:

4. The bifunctional compound is 【Transformation 8】 【change】 【change】 2. The bifunctional compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, selected from the group consisting of:

5. A pharmaceutical composition comprising an effective amount of the bifunctional compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

6. 6. The pharmaceutical composition of claim 5, further comprising a second therapeutic agent.

7. 10. The bifunctional compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, or the pharmaceutical composition of claim 5 or 6, for use in treating an androgen receptor-associated disease in a subject in need thereof, the bifunctional compound comprising administering to the subject an effective amount of the bifunctional compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, or the pharmaceutical composition of claim 5 or 6.

8. 8. The bifunctional compound, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition according to claim 7, wherein the androgen receptor-associated disease is an androgen receptor-associated cancer or an androgen receptor-associated skin disease.

9. 9. The bifunctional compound, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition according to claim 8, wherein the androgen receptor-associated cancer is breast cancer or prostate cancer, and the androgen receptor-associated skin disease is male pattern baldness, acne, hidradenitis suppurativa, hirsutism, or atopic dermatitis.

10. 10. The bifunctional compound, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition according to claim 9, wherein the prostate cancer is castration-resistant prostate cancer and the breast cancer is triple-negative breast cancer.

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