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) represented by 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 JPEG2025524557000075.jpg48154(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. Further provided is a pharmaceutical composition comprising the bifunctional compound, and a method of treating an androgen receptor-related disease or androgen receptor-related disorder by administering the bifunctional compound.

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 or androgen receptor-related disorders by administering the bifunctional compound.

Background Art

[0002] 2. Description of the Prior Art Since proteins have a large contact surface area, the grooves involved in protein-protein interactions are shallow, or the interfaces are flat, it is difficult to target protein-protein interactions using small molecules. 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, 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. The 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 proliferation 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 the 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. Second-generation anti-androgen drugs such as abiraterone acetate (ABI) and enzalutamide (ENZ) have been approved, and apalutamide (APA) and darolutamide (DARO) have been approved in recent years, resulting in an improvement in 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 is 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 or -dependent diseases or disorders using proteolysis-targeting chimeric (PROTAC) bifunctional compounds. Related patent applications relating to PROTACs are disclosed in WO2018071606, WO2018144649, and WO2021143816. However, there remains a need for compounds with better efficacy in treating androgen receptor-related diseases or disorders. Summary of the Invention [Means for solving the problem]

[0007] The present disclosure provides bifunctional proteolysis-targeting chimeric (PROTAC) compounds that include a cereblon (CRBN) E3 ubiquitin ligase-binding moiety and an androgen receptor-binding moiety. The PROTAC compounds target the ubiquitin-proteasome degradation system to degrade the androgen receptor, and / or inhibit the androgen receptor through other mechanisms. Unexpectedly, the bifunctional compounds have demonstrated high efficacy against androgen receptor degradation.

[0008] In one aspect, the present disclosure provides a bifunctional compound, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite, or prodrug thereof, comprising: 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)-1 below. [ka] (In the formula, [ka] indicates a single or 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 there is a single bond between W 1 and W 2 are each independently CR C2 Or N or W 1 and W 2 If there is a double bond between W 1 and W 2 are C respectively; G is -H, -OH, -CH2OH, -R C3 OC(=O)OR C4 , -R C3 OC(=O)NR C4 R C5 and 2-(trimethylsilyl)ethoxymethyl groups; Q 1 is O, S or NR C6 and; Q 2 and Q 7 If there is a single bond between Q 2 and Q 7 are each independently N or CR C2 or Q 2 and Q 7 If there is a double bond between Q 2 and Q 7 are C respectively; 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 the CR C2 and two atoms adjacent to the C atom on the ring, each of which independently has a single bond, or the 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 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 , and 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 each independently represents -H, an unsubstituted alkyl group, an alkyl group substituted with R C9 a cycloalkyl group substituted with R C9 a heterocyclyl group substituted with R C9 an aryl group substituted with R C9 a heteroaryl group substituted with R, and R C9 is selected from the group consisting of a heteroaryl group substituted with R; R C6 is selected from the group consisting of -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 a heterocyclyl group substituted with one or more halo groups; R C7 is selected from the group consisting of a halo group, -CH2OH, -NR C4 R C5 a 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 a heterocyclyl group substituted with one or more halo groups; R C8 is selected from the group consisting of a halo group, -CH2OH, -NR C4 R C5 a 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 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; wherein the heteroatom is selected from N, O and S), A bifunctional compound, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof is provided.

[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 or disorder 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 of the following formula (II)-2:

Chemical formula

[0012] In some embodiments, the heteroatoms 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 a 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 through a stereospecific bond as shown in the formula below. [ka]

[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, can exist as two stereoisomers having a 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, can have one or both of these stereoisomers.

[0017] In some embodiments, K is —H, unsubstituted C 1-6 Alkyl group, R C7C replaced by 1-6 an alkyl group, and C 3-8 is selected from the group consisting of cycloalkyl groups. 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 an alkyl selected from the group consisting of linear alkyl and branched alkyl, each of which is unsubstituted or substituted with R C7 . In some embodiments, K is an alkyl selected from the group consisting of linear C C7 alkyl and branched C 1-6 alkyl, each of which is unsubstituted or substituted with R 1-6 . In some embodiments, K is an alkyl selected from the group consisting of linear C C7 alkyl and branched C 1-3 alkyl, each of which is unsubstituted or substituted with R 1-3 .

[0019] In some embodiments, R C1 is an unsubstituted C 1-6 alkyl group, a C C8 alkyl group substituted with R 1-6 , an unsubstituted C 3-8 aryl group, a C C8 aryl group substituted with R 3-8 , an unsubstituted C 3-8 alkylaryl group, a C C8 alkylaryl group substituted with R 3-8 , an unsubstituted C 1-6 alkoxyl group, or a C C8 alkoxyl group substituted with R 1-6 may be. In some embodiments, R C1 is an unsubstituted C 1-3 alkyl group, a C C8 alkyl group substituted with R 1-3 , an unsubstituted C 1-3 alkoxyl group, or a C C8 alkoxyl group substituted with R 1-3It may be an alkoxyl group.

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

[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 3-8Cycloalkyl group, unsubstituted C 3-8 Heterocyclyl group, R C9 Substituted C 3-8 Heterocyclyl group, C 3-8 Aryl group, and C 3-8 Selected from the group consisting of heteroaryl groups. In the present disclosure, R C4 And R C5 Are each independently an unsubstituted C 1-3 Alkyl group, and R C9 Substituted C 1-3 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 Substituted with alkyl and branched C 1-6 Selected from the group consisting of alkyl and branched C 1-6 Alkyl. 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 Substituted with alkyl and branched C 1-3 Selected from the group consisting of alkyl and branched C 1-3 Alkyl.

[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, Q1 is NR C6 wherein 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 wherein R C6 is an unsubstituted C 1-3 alkyl group selected from methyl, ethyl, n-propyl, and isopropyl. In some embodiments, Q 1 is NR C6 wherein R C6 is a C 1-3 alkyl group selected from methyl, ethyl, n-propyl, and isopropyl and 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 some embodiments, -L- is of the following formula (III):

Chemical formula

[0028] In some embodiments, the heteroatom in formula (III) is independently selected from N, O, and S respectively. In some embodiments, the Z ring contains one or two heteroatoms selected from N, O, and S.

[0029] In some embodiments, -L- is a linking moiety represented by formula (III), wherein, 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 11-membered spirobicyclic group having 1 to 2 heteroatoms and 0 or 1 double bond respectively; R L1 is selected from the group consisting of an unsubstituted straight-chain C 1-3 alkyl group and a keto group; R L2 is a bond or an ethynylene group; [[ID=2,1]] X 1 is each an unsubstituted, or methylene or ethylene group substituted with alkyl or cycloalkyl; X 2 is selected from the group consisting of an unsubstituted methylene group, a methylene group substituted with alkyl or cycloalkyl, CO, NHCO, NR L4 and O; X 3 is each independently selected from the group consisting of an unsubstituted, or alkyl- or cycloalkyl-substituted, C 1-6 alkylene group, a 3- to 7-membered cyclic alkylene group, and a 3- to 7-membered heteroalicyclic alkylene group having 0 to 2 heteroatoms; X 4 is an unsubstituted C 1-3 alkylene group, or a C 1-3 alkylene group substituted with alkyl or cycloalkyl; X 5 is selected from the group consisting of an unsubstituted methylene group, a methylene group substituted with alkyl or cycloalkyl, CONH, and O; R L4 is hydrogen; m is 0, 1, 2 or 3; v1 is 0 or 1; v2 is 0 or 1; v3 is 1; v4 is 0 or 1; v5 is 1.

[0030] In some embodiments, R L1 is selected from the group consisting of H, unsubstituted C 1-3 alkyl group, C 1-3 alkyl group substituted with a C 1-3 alkoxyl group, C 1-3 alkyl group substituted with one or more halo groups, halo group, unsubstituted C 1-3 alkoxyl group, keto group, and oxide group. In some embodiments, R L1 is an oxide group and is bonded to one heteroatom N on the Z ring to form an N-oxide group (N + -O - ).

[0031] In some embodiments, R L1 are each unsubstituted, substituted with a C 1-6 alkoxyl group, or substituted with one or more halo groups, and are alkyl selected from the group consisting of linear C 1-6 alkyl and branched C 1-6 alkyl. In some embodiments, R L1 are each unsubstituted, substituted with a C 1-6 alkoxyl group, or substituted with one or more halo groups, and are alkyl selected from the group consisting of linear C 1-3 alkyl and branched C 1-3 alkyl. In some embodiments, R L1 is an unsubstituted C 1-3 alkyl group selected from methyl, ethyl, n-propyl, and isopropyl.

[0032] In some embodiments, X 3 are each unsubstituted or are C 1-6 alkyl or C3-6 C substituted with cycloalkyl 1-6 is selected from the group consisting of an alkylene group, a 3- to 7-membered cyclic alkylene group, and a 3- to 7-membered heteroacyclic alkylene group having 0 to 2 heteroatoms. In some embodiments, X 3 is an unsubstituted C selected from the group consisting of a methylene group, an ethylene group, a propylene group, a butylene group, a pentylene group, and a hexylene group 1-6 alkylene group.

[0033] In some embodiments, X 4 is an unsubstituted C selected from the group consisting of a methylene group, an ethylene group, and a propylene group 1-3 alkylene group.

[0034] In some embodiments, X 5 is selected from the group consisting of a methylene group, CONH, and O.

[0035] In some embodiments, R L3 and R L4 are each independently either unsubstituted, substituted with a C 1-6 alkoxyl group, or substituted with one or more halo groups, and are alkyl selected from the group consisting of linear C 1-6 alkyl and branched C 1-6 alkyl. In some embodiments, R L3 and R L4 are each independently either unsubstituted, substituted with a C 1-6 alkoxyl group, or substituted with one or more halo groups, and are alkyl selected from the group consisting of linear C 1-3 alkyl and branched C 1-3 alkyl.

[0036] In some embodiments, -L- is

Chemical formula

[0037] In some embodiments, the ABM is the following formula:

Chemical formula

[0038] In some embodiments, the heteroatom in formula (IV)-a, (IV)-b, (IV)-c or (IV)-d is independently selected from N, O and S.

[0039] In some embodiments, Z 1 is

Chemical formula

[0040] In some embodiments, Z 1 is

Chemical formula

[0041] In some embodiments, Z 2 is

Chemical formula

[0042] In some embodiments, M is

Chemical formula

[0043] 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, a linear C 1-6 alkyl or branched C 1-6 alkyl selected from the group consisting of. 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, a linear C 1-3 alkyl or branched C 1-3In some embodiments, each R M The groups are each independently methyl, ethyl, n-propyl, or isopropyl.

[0044] In some embodiments, R a , R b , R c , R d , R Y1 and R Y2 are each independently unsubstituted or C 1-6 Linear C substituted with alkoxy groups or substituted with one or more halo groups 1-6 Alkyl and Branched C 1-6 In some embodiments, R is an alkyl selected from the group consisting of alkyl. a , R b , R c , R d , R Y1 and R Y2 are each independently unsubstituted or C 1-6 Linear C substituted with alkoxy groups or substituted with one or more halo groups 1-3 Alkyl and Branched C 1-3 In some embodiments, R is an alkyl selected from the group consisting of alkyl. a , R b , R c , R d , R Y1 and R Y2 is independently methyl, ethyl, n-propyl, or isopropyl.

[0045] In some embodiments, the compound represented by formula (IV)-d (Y 3 ) 0-5 teeth, [ka] (R) indicates that the carbon is in the R configuration (right-handed).

[0046] In some embodiments, each R Z2The radicals are each independently an alkyl selected from the group consisting of linear C 1-6 alkyl and branched C 1-6 alkyl, each of which is unsubstituted or substituted with one or more halo groups. In some embodiments, each R Z2 radical is independently an alkyl selected from the group consisting of linear C 1-3 alkyl and branched C 1-3 alkyl, each of which is unsubstituted or substituted with one or more halo groups.

[0047] In some embodiments, R Z2A 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.

[0048] In some embodiments, R Z2A is a heteroalkyl selected from the group consisting of linear C 1-6 heteroalkyl and branched C 1-6 heteroalkyl. In some embodiments, R Z2A is a heteroalkyl selected from the group consisting of linear C 1-3 heteroalkyl and branched C 1-3 heteroalkyl.

[0049] In some embodiments, ABM is

Chemical formula

[0050] In certain embodiments, ABM is an androgen receptor binding moiety represented by formula (IV)-b, wherein M is a 4-membered alicyclic ring having from 0 to 2 heteroatoms, which ring is unsubstituted or substituted with 1 to 6 R M groups. The other groups have the same meanings as described above.

[0051] In certain embodiments, ABM is an androgen receptor binding moiety represented by formula (IV)-b, wherein Z 2 is a bond, C 1-6 alkylene, C 1-6 heteroalkylene, -O-, arylene, heteroarylene, alicyclic divalent, heterocyclic divalent, hetero-bicyclic divalent, bicyclic arylene, or bicyclic heteroarylene, each group being substituted with 1, 2, or 3 R Z2 groups. The other groups have the same meanings as described above. The other groups have the same meanings as described above.

[0052] In certain embodiments, ABM is an androgen receptor binding moiety represented by formula (IV)-b, wherein Z 1 is

Chemical formula

[0053] 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; RY1 and R Y2 is, independently of one another, -H or C 1-6 is an alkyl group; Z 2 is, respectively, one, two or three R w2 which may be substituted with, a bond, aryl, or heteroaryl; Each R w2 is, independently of one another, -H, a halo group, C 1-6 alkyl (which may be substituted with one or more -F), or C 1-3 alkoxyl (which may be substituted with one or more -F); Each R W2 group is, independently of one another, selected from the group consisting of -H, a halo group, a cycloaliphatic group of a 6-membered ring having one or two heteroatoms, and an aromatic group of a 5-membered ring having one, two or three heteroatoms. The other groups have the same meaning as described above.

[0054] In certain embodiments, ABM is an androgen receptor binding moiety represented by formula (IV)-d, wherein in said formula, Z 1 is

Chemical Structure

[0055] In some embodiments, ABM is

Chemical Structure

[0056] In some embodiments, the pharmaceutical composition of the present invention further comprises a second therapeutic agent.

[0057] 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.

[0058] 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.

[0059] In some embodiments, the skin disease related to the androgen receptor is male pattern baldness, acne, hidradenitis suppurativa, hirsutism, or atopic dermatitis.

[0060] 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.

[0061] In some embodiments, the second therapeutic agent may be an androgen receptor inhibitor. Examples of androgen receptor inhibitors include enzalutamide.

[0062] 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.

[0063] In some embodiments, the second therapeutic agent may be a therapeutic agent for treating skin diseases associated with 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

[0064] 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.

[0065] As used herein and in the claims, the term "and / or" means "one or both" of the components combined by this term, that is, it means that there are cases where a plurality of components are combined and cases where a plurality of components are separately present. A plurality of components listed using the term "and / or" should be interpreted in the same way, that is, "one or more" of the plurality of components are described as combined. There may be other components other than the components specifically specified using the term "and / or", and these other components may or may not be related to the specifically specified components. Therefore, for example, when used with an open-ended term such as "comprising", "A and / or B" 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.

[0066] As used in this specification and the claims, the term "or" has the same meaning as "and / or" as defined above. For example, when 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 listed components or at least one of the listed components, but also including two or more of them, and may also include additional items not listed. Terms such as "only one", "exactly only one", or the term "consisting of" recited in the claims, as terms clearly indicating the opposite meaning, mean including only one of the plurality of components or the listed components. Usually, when the term "or" used in this specification is in front of exclusive terms such as "either one", "one of them", "only one of them", or "exactly one of them", it is construed as indicating only exclusive alternatives (i.e., "either one or the other of them, but not both").

[0067] In the foregoing description and claims in this specification, all transitional phrases such as "comprising", "including", "possessing", "having", "containing", "accompanying", "holding", "being composed of", etc. are open-ended expressions, i.e., meaning 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.

[0068] In this specification and the claims, the term "at least one" used in connection with the listing of one or more components means at least one component selected from one or more of the components included in the listed components, but does not necessarily include at least one of all the components specifically recited in the listed components, nor does it exclude any combination of the listed components. This definition also means that there may be components other than those specifically identified in the list of components for 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's, but B need 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's, but A need 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's, and may also refer to at least one B, may include two or more B's (and may include other components); and there may be other aspects, but are not limited thereto.

[0069] 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.

[0070] The term "effective" may mean, but is not limited to, preventing, suppressing the onset, ameliorating, delaying or treating the symptoms of a condition, disorder or disease state, or an amount / dosage of a pharmaceutically active ingredient sufficient (able to alleviate the symptoms to some extent, preferably all symptoms) for such prevention, suppression of onset, amelioration, delay or treatment, when used for its intended use in a subject in need of treatment of a condition, disorder or disease state or a treatment therefor. The term "effective" encompasses any other terms relating to an effective amount or effective concentration, for example, "effective amount / dosage", "pharmaceutically effective amount / dosage", "therapeutically effective amount / dosage", etc., which terms are otherwise defined or used in this application.

[0071] The effective amount is dependent 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 drugs, and other factors recognized by those of ordinary skill in the medical arts. The exact amount can be determined by those of ordinary skill 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).

[0072] The term "pharmaceutically acceptable" or "pharmacologically acceptable" may mean, but is not limited to, substances and compositions that do not produce an adverse, allergic or other untoward reaction when properly administered to an animal or a human.

[0073] 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 incorporated herein 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 incompatible with the active compound. Also, auxiliary active compounds can be included in the pharmaceutical compositions of the present disclosure.

[0074] 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" usually 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 and variables related to the compound are also described.

[0075] One skilled in the art would be able to understand that the molecules described in this specification are stable compounds as outlined below. The following formula: [Chemical formula] When a bond represented by the formula is shown, a double bond or a single bond is shown in accordance with the structure of the compound shown in each formula and the known rules regarding valence interactions, and is thus interpreted as a double bond or a single bond accordingly.

[0076] 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).

[0077] 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.

[0078] 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, cereblon E3 ubiquitin ligase, either alone or in cooperation with E2 (ubiquitin-conjugating enzyme), adds ubiquitin to the lysine of the target protein, thereby guiding the target protein substrate to proteasomal degradation. In this way, E3 ubiquitin ligase, either alone or by forming a complex with 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 only one ubiquitin is added to the substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins are not targeted 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, 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 direct the target protein to proteasomal degradation.

[0079] 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 pathological state 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.

[0080] In all cases disclosed in this specification, 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 "C 1-6 "alkyl" indicates an alkyl having 1 to 6 carbon atoms.

[0081] A detailed description to assist those skilled in the art in practicing the present invention is provided below. Those skilled in the art may make improvements and modifications to the embodiments described herein without departing from the spirit or scope of this disclosure. All published documents, patent applications, patents, drawings, and other references cited herein are hereby expressly incorporated by reference in their entirety.

Brief Description of the Drawings

[0082]

Figure 1

Figure 2

Figure 3

[0083] 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

[0084] Method for Producing the Compounds of the Invention A general method for producing the compounds of the present invention is exemplified below. Extraction and purification may be carried out by procedures carried out in ordinary organic chemistry experiments.

[0085] The synthesis of the compounds of the present invention can be carried out with reference to procedures known in the art.

[0086] As starting compounds, commercially available compounds, the compounds described in this specification, the compounds described in the references cited in this specification, and other known compounds can be used.

[0087] Since the compounds of the present invention include compounds that may have tautomers, the present invention includes all tautomers and mixtures containing these tautomers.

[0088] 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, a salt can be formed by adding an acid or a base.

[0089] In addition, depending on the circumstances, when the compounds of the present invention and their pharmaceutically acceptable salts exist in the form of adducts with water or adducts with various solvents (hydrates or solvates), such adducts are also encompassed by the present invention.

[0090] One or more embodiments of the present invention are described in detail below. Other features, objects, and advantages of the present invention will become apparent from the following description and claims.

[0091] 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.

[0092] Basic Procedures for Preparing the Compounds of the Present Disclosure: Procedure 1

Chemical formula

[0093] 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.

[0094] The following specific examples are illustrative only and do not limit any other matters of the present disclosure. Those skilled in the art are considered to be able to fully utilize the present invention based on the description in this specification without further detailed description. All documents cited in this specification are incorporated herein by reference in their entirety.

Examples

[0095] Synthesis Method A - Synthesis of Compound 1: (1) Preparation of Compound I - A According to the route shown below, first, Compound I-A was prepared from commercially available 2-benzyloxyethanol. [Chemical formula]

[0096] To a solution of 3-nitrophenol (6.67 g, 48.0 mmol), triphenylphosphine (PPh3) (15.11 g, 57.6 mmol), and 2-benzyloxyethanol (6.89 mL, 48.5 mmol) in tetrahydrofuran (THF) (80 mL), diisopropyl azodicarboxylate (DIAD) (11.3 mL, 57.6 mmol) was added dropwise. After adding DIAD, the resulting mixture was stirred for 18 hours (h) under a nitrogen atmosphere to obtain a crude mixture. After distilling off the solvent, ether was added to resuspend the crude mixture, and triphenylphosphine oxide was filtered off. The obtained solid was washed with ether (10 mL), and the filtrate was distilled off to obtain a yellow oil. The yellow oil was purified by silica gel column chromatography (KM3 SCIENTIFIC, particle size 45 - 75 μm) using an eluent (hexane:ethyl acetate = 4:1) to obtain Compound I-a1 (13 g, 47.6 mmol).

[0097] To a solution of Compound I-a1 (21.0 g, 0.077 mol) and NH4Cl (9.96 g, 0.18 mol) in EtOH / H2O (263 mL, v / v = 4:1), iron powder (10.29 g, 0.18 mol) was added at room temperature. The reaction mixture was heated to reflux for 2 hours and then cooled to room temperature. Next, celite (10 g) was added and stirred for 30 minutes (min.). The mixture was filtered, and the obtained solid was washed three times with MeOH (20 mL) and dichloromethane (DCM) (20 mL). The filtrate was washed with 30 mL of saturated aqueous NaHCO3 solution. The aqueous phase was extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (20 mL × 3), dried over Na2SO4, and concentrated under reduced pressure to obtain Compound I-a2 (15.7 g, yield: 84%).

[0098] In a 100 mL two-necked bottle, Pd(OAc)2 (262 mg, 20 mol%) was added to a mixture of compound I-a2 (1.7 g, 6.99 mmol), dimethyl acetylenedicarboxylate (0.71 mL, 5.8 mmol), and dimethylacetamide (DMA) / pivalic acid (PivOH) (4:1 v / v; 28 mL). The inside of the two-necked bottle was purged with air. While purging with air, the reaction mixture was gradually heated from room temperature to 110 °C and stirred for 8 hours while monitoring by LC-MASS. After completion of the reaction, the solution was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with H2O (3 × 10 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 5-(2-benzyloxyethoxy)-1H-indole-2,3-dicarboxylic acid dimethyl ester I-a3 (1.14 g, yield: 50%) as a brown solid.

[0099] A solution of 5-(2-benzyloxyethoxy)-1H-indole-2,3-dicarboxylic acid dimethyl ester I-a3 (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 then warmed to room temperature. After 1 hour, the reaction mixture was separated between DCM and saturated aqueous NH4Cl. The combined organic layers were collected, washed with water (3×) and brine, 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 compound I-a4 (2.7 g, yield: 87%) as a brown solid.

[0100] Compound I-a4 (0.6 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 EtOAc (30 mL), acidified to pH 3 with 1 M HCl, and the layers were separated. Next, the aqueous layer was extracted with EtOAc (30 mL), the organic layers were combined, 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, the monoester was detected by LC-MASS. The reaction mixture was cooled to ambient temperature. Next, the excess Ac2O was removed, dehydrated toluene was added, and the mixture was concentrated. The residue I-a5 thus obtained was used in the next step without further purification.

[0101] The above residue I-a5 was dissolved in THF (20 mL), and 3-aminopiperidine-2,6-dione hydrochloride (0.25 g, 3.0 mmol) and trimethylamine (TEA) (1.52 g, 15.1 mmol) were added. The resulting mixture was stirred at 50 °C for 4 hours. After completion of the reaction, the reaction mixture was cooled to ambient temperature, diluted with EtOAc, and acidified to pH 3 with 1 M HCl. The organic layer was washed with brine, dried (over MgSO4), filtered, and concentrated to obtain a residue. Next, the residue was dissolved in THF (20 mL), N,N'-carbonyldiimidazole (CDI) (0.49 g, 3.0 mmol) and DMAP (18 mg, 0.15 mmol) were added to obtain a mixture. The resulting mixture was stirred at 50 °C for 4 hours. After completion of the reaction, the reaction mixture was cooled to ambient temperature, diluted with EtOAc, and acidified to pH 3 with 1 M HCl. The organic layer was washed with brine, 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 = 1:4) to obtain Compound I-a6 (0.41 g, yield: 60%).

[0102] To a solution of Compound I-a6 (100 mg, 0.22 mmol) in DCM (6 mL) was slowly added a solution of 1 M BBr3 in DCM (0.87 mL) at -78 °C. The resulting mixture was stirred at -60 °C for 3 hours. After completion of the reaction, water was slowly added, and the resulting mixture was warmed to ambient temperature and diluted with THF. The organic layer was washed with brine, dried (over Na2SO4), filtered, and concentrated to obtain Compound I-a7. Next, Compound I-a7 was dissolved in DCM (10 mL), and Dess-Martin periodinane (186 mg, 0.44 mmol) and NaHCO3 (37 mg, 0.44 mmol) were added. The resulting mixture was stirred at room temperature for 17 hours. After completion of the reaction, water was added to obtain a mixture. This mixture was diluted with DCM. The organic layer was washed with brine, dried (over Na2SO4), filtered, and concentrated to obtain Compound I-A. Compound I-A was used in the next synthetic step without further purification.

[0103] (2) Preparation of Secondary Amine Compound I - B The secondary amine Compound I-B was prepared from the commercially available 4-[(trans-3-amino-2,2,4,4-tetramethylcyclobutyl)oxy]-2-chlorobenzonitrile hydrochloride according to the route shown below.

Chemical formula

[0104] A mixture of 4-[(trans-3-amino-2,2,4,4-tetramethylcyclobutyl)oxy]-2-chlorobenzonitrile hydrochloride I-b1 (1 g, 3.59 mmol) and tert-butyl 4-(4-carboxyphenyl)piperazine-1-carboxylate I-b2 (1.2 g, 4.00 mmol) in DMF (8 mL) was added with N,N-diisopropylethylamine (DIPEA) (3.0 mL, 17.20 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (1.6 g, 4.30 mmol) at room temperature, and stirred at room temperature for 24 hours. After concentrating the reaction solution to remove the solvent, water was added to obtain a solution. This solution was extracted with DCM (30 mL × 2). The organic layer was washed with brine, dried (over MgSO4), filtered, and concentrated to obtain compound I-b3 (1.6 g, 76%). Next, compound I-b3 and CF3COOH (2.5 ml) were added to CH2Cl2 (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 (3 mL), dried (over Na2SO4), filtered, and concentrated to obtain compound I-B. This compound I-B was used directly in the next step without purification.

[0105] (3) Preparation of Compound 1 from Compound I - A and Secondary Amine Compound I - B Compound 1 was prepared according to the route shown below. [Chemical formula]

[0106] To a solution of a mixture of Compound I-A (46 mg, 0.125 mmol) and Compound I-B (23 mg, 0.05 mmol) in DCM (1 mL) was added NaBH(OAc)3 (36 mg, 0.17 mmol). The resulting solution was stirred at room temperature for 17 hours. After completion of the reaction, the resulting solution was diluted with water (3 mL). The resulting solution was extracted with DCM (5 mL × 3), and the organic layers were combined. 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 preparative thin-layer chromatography (PLC) (DCM / acetone = 9 / 1) to obtain Compound 1 (7 mg, yield: 17%). MS: m / z 820.3 (M + +1); 1 H NMR (DMSO-d6) δ 11.06 (s, 1H), 7.90 (d, 1H), 7.75 (d, 2H), 7.62 (d, 1H), 7.51 (d, 1H), 7.33(s, 1H), 7.20 (s, 1H), 7.02 - 6.98 (m, 4H), 4.97 (dd, 1H), 4.32 (s, 1H), 4.16 (t, 2H), 4.05 (d, 1H), 3.96 (s, 3H), 3.28 (m, 4H), 2.92 - 2.86 (m, 1H), 2.84 (t, 2H), 2.68 (m, 4H), 2.61 - 2.50 (m, 2H), 2.04 - 2.02 (m, 1H), 1.21 (s, 6H), 1.12 (s, 6H).

[0107] Synthesis Method B - Synthesis of Compound 2: (1) Preparation of Compound I - C According to the following route, first, Compound I-C was prepared from commercially available 4-(2-hydroxyethyl)-piperidine-1-carboxylic acid tert-butyl ester.

Chemical Structure

[0108] To a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (3.5 g, 15.5 mmol) in DCM (50 mL) was added triethylamine (6.3 mL, 46.5 mmol), and then methanesulfonyl chloride (MsCl) (1.8 mL, 23.25 mmol) was added under an ice bath. The mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated NaHCO3 (10 mL) and saturated NH4Cl (aqueous solution) (10 mL), and dried over MgSO4. After removing the solvent to obtain the crude product, the crude product was purified by flash column chromatography using an eluent (hexane / EtOAc = 3 / 1 to 1 / 1) to obtain Compound I-c1 (4.67 g, 98%).

[0109] In a vessel purged with air, 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) was added Pd(OAc)2 (1.13 g, 10 mol%). 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 (50 mL × 3) and brine (50 mL), dried over MgSO4, filtered, and the solvent was distilled off under reduced pressure to obtain the 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 a brown solid of Compound I-a2 (8.4 g, 54%).

[0110] Under an N2 atmosphere, Cs2CO3 (9.6 g, 29.47 mmol, 2.0 equivalents) and bromoethane (1.65 mL, 22.10 mmol, 1.5 equivalents) were sequentially added to a solution of Compound I-c2 (5.0 g, 14.73 mmol, 1 equivalent) in CH3CN (50 mL) at 25 °C. The resulting mixture was heated at 80 °C for 4 hours until Compound I-c2 disappeared, and the reaction mixture was cooled to room temperature. The solvent was distilled off until half of its original volume, diluted with ethyl acetate (50 mL), and washed with water (100 mL). After phase separation, the aqueous layer was extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (KM3 SCIENTIFIC, particle size 45 - 75 μm) eluting with 15 - 20% ethyl acetate / hexane to obtain Compound I-c3 (4.8 g, 88%).

[0111] A solution of Compound I-c3 (2.0 g) in MeOH (60 mL) was degassed, Pd / C (0.2 g, 10 wt%) was added, and then the reaction mixture was bubbled with a hydrogen gas balloon and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered through a celite layer, and the filter cake was washed with ethyl acetate (EA). The filtrate was concentrated by solvent evaporation using a rotary evaporator to obtain Compound I-c4 (1.49 g, yield: 99%).

[0112] To a solution of compound I-c4 (1.75 g, 6.31 mmol) in acetonitrile (15 mL) was added K2CO3 (2.65 g, 3.0 equiv.), and the mixture was stirred at 60 °C to obtain a suspension. After 30 minutes, the suspension was cooled, and a solution of compound I-c1 (2.33 g, 1.2 equiv.) in acetonitrile (5 mL) was added to obtain a mixture. The mixture was heated to 80 °C and maintained at this temperature for 16 hours. Then, the reaction mixture was cooled, and EtOAc (20 mL) and water (20 mL) were added for extraction. The resulting mixture was allowed to stand for a while to separate into an aqueous layer and an organic layer, and the aqueous layer was extracted again with EtOAc (20 mL). All the organic layers were combined, washed with brine (20 mL), dried over MgSO4, and purified by flash column chromatography to obtain compound I-c5 (2.26 g, 87%).

[0113] To a solution of compound I-c5 (0.38 g, 1 equiv.) in EtOH (20 mL) was added NaOH (0.56 g, 20 equiv.), and the mixture was stirred at 80 °C for 17 hours. After cooling, EtOH was removed by rotary evaporator, and the residue was diluted with water (10 mL). Next, 1N HCl (aqueous solution) was added under an ice bath until the pH value of the diluted residue was less than 2 (<2). The aqueous layer was extracted with EtOAc (20 mL × 2), the organic layers were combined, washed with brine (10 mL × 1), dried over MgSO4, and concentrated to obtain a crude residue. Next, the crude residue was placed in Ac2O (6 mL), heated to 80 °C, and stirred for 4 hours. After cooling, Ac2O was removed under reduced pressure, and toluene (2 - 3 mL) was added. The solvent was removed under reduced pressure to obtain compound I-c6 (0.30 g, 87%).

[0114] A solution of 3-aminopiperidine-2,6-dione hydrochloride (0.11 g, 2 equiv) and TEA (0.19 mL, 4 equiv) in THF (2 mL) was stirred at room temperature for 30 minutes, and then a solution of compound I-c6 (0.15 g, 1 equiv) in THF (2 mL) was added. After the reaction mixture was stirred at room temperature for 50 minutes, the resulting mixture was diluted with EtOAc (10 mL×1) and water (5 mL×1). 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 EtOAc (10 mL×2), the organic layers were combined, washed with brine (5 mL×1), 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 equiv) and DMAP (4 mg, 0.1 equiv) were added. The reaction mixture was stirred at 50 °C for 2 hours. After cooling, the reaction mixture was diluted with EtOAc (10 mL) and water (5 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 EtOAc (10 mL×2). The organic layer was collected, 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-C (0.16 g, 85%).

[0115] (2) Preparation of Compound I - D Compound I-D was prepared from commercially available 4-(4-aminocyclohexyloxy)-2-chlorobenzonitrile according to the following route. [Chemical formula]

[0116] 4-(4-Aminocyclohexyloxy)-2-chlorobenzonitrile I-d1 (2.06 g, 1 equivalent), compound I-d2 (1.31 g, 1 equivalent), and HATU (4.99 g, 1.6 equivalents) in DCM (30 mL) were added dropwise with DIPEA (4.3 mL, 3 equivalents) under an ice bath and stirred at room temperature for 21 h. Then, water (10 mL) was added and mixed. The organic layer was separated, dried over Na2SO4, concentrated, and purified by flash column chromatography using an eluent (hexane / EtOAc = 1 / 1), and washed with DCM and hexane to obtain compound I-D (1.8 g, 56%). MS: m / z 391.2 (M + +1); 1 H NMR (DMSO-d6) δ 9.14 (d, 1H), 8.22 (d, 1H), 8.10 (d, 1H), 7.85 (d, 1H), 7.39 (d, 1H), 7.14 (dd, 1H), 4.55 - 4.51 (m, 1H), 3.94 - 3.88 (m, 1H), 2.13 - 2.11 (m, 2H), 1.91 - 1.89 (m, 2H), 1.73 - 1.66 (m, 2H), 1.55 - 1.48 (m, 2H).

[0117] (3) Preparation of Compound 2 from Amine Compound I - C Protected with Boc and Compound I - D Compound 2 was prepared according to the following route.

Chemical Structure

[0118] To a solution of compound I-C (100 mg, 1 equivalent) in a mixed solvent of DCM (2 mL) and MeOH (0.4 mL) was added a solution of 2N HCl in ether (1.6 mL, 20 equivalents). The reaction mixture was stirred at room temperature for 40 min, and the solvent was removed to obtain compound I-c1 (80 mg, 98%).

[0119] Next, TEA (0.13 mL, 10 equivalents) was added to a DMSO (0.5 mL) solution of compound I-c1 (51 mg, 1 equivalent) and compound I-D (44 mg, 1.2 equivalents), and the mixture was stirred at 80 °C for 17 hours. After cooling, the reaction mixture was diluted with DCM (10 mL) and water (5 mL). Then, the organic layer was successively washed with water (5 mL) and saturated NH4Cl (3 mL × 3), and dried over Na2SO4. After removing the solvent to obtain the crude material, the crude material was purified by preparative thin-layer chromatography using the mobile phase (DCM / acetone = 9 / 1) to obtain compound 2 (38 mg, 47%). MS: m / z 807.4 (M + +1); 1 H NMR (CDCl3) δ 7.97 (d, 1H), 7.96 - 7.90 (m, 1H), 7.87 (d, 1H), 7.74 (d, 1H), 7.56 (d, 1H), 7.00 - 6.97 (m, 3H), 6.85 (dd, 1H), 6.83 (d, 1H), 4.85 (dd, 1H), 4.55 - 4.52 (m, 2H), 4.38 (q, 2H), 4.35 - 4.29 (m, 1H), 4.21 (t, 2H), 4.08 - 4.02 (m, 1H), 3.10 - 3.06 (m, 2H), 2.91 - 2.88 (m, 1H), 2.84 - 2.70 (m, 2H), 2.22 - 2.15 (m, 5H), 2.00 - 1.94 (m, 3H), 1.85 - 1.82 (m, 2H), 1.71 - 1.65 (m, 2H), 1.53 (t, 3H), 1.50 - 1.42 (m, 2H), 1.38 - 1.33 (m, 2H).

[0120] Synthesis Method C - Synthesis of Compound 3: (1) Preparation of Compound I - E Compound I-E was prepared from commercially available piperazine-1-carboxylic acid tert-butyl ester according to the following route.

Chemical Structure

[0121] A solution of a mixture consisting of Compound I-D (800 mg, 1 equivalent), tert-butyl piperazine-1-carboxylate (399 mg, 1.1 equivalents), and TEA (0.57 mL, 2 equivalents) in DMSO (6 mL) was stirred at 100 °C for 24 hours. After cooling, the resulting mixture was slowly added to water to obtain a suspension. The obtained suspension was filtered to obtain Compound I-e1 (1.03 g, 94%).

[0122] HCl gas was slowly bubbled into a CH2Cl2 (6 mL) mixture of Compound I-e1 (500 mg, 1 equivalent) to obtain a mixture. This mixture was stirred at room temperature for 2 hours, concentrated, and washed with methyl tert-butyl ether (MTBE) to obtain Compound I-E (388 mg, 97%).

[0123] (2) Preparation of Compound I - F Compound I-F was prepared according to the route shown below.

Chemical formula

[0124] To a DCM (2 mL) solution of Compound I-a7 (0.1 g, 0.250 mmol), TEA (0.139 mL, 4.0 equivalents) was added at room temperature. Next, methanesulfonyl chloride (MsCl) (0.0387 mL, 2.0 equivalents) was added dropwise. The mixed reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the resulting mixture was diluted with DCM (10 mL) and washed with saturated NaHCO3 (5 mL) and saturated NH4Cl (5 mL). After extraction, the organic layer was washed with brine (5 mL), dried over Na2SO4 (solid), concentrated, and purified by thin layer chromatography (DCM / acetone = 10 / 1) to obtain Compound I-F (0.1 g, yield approximately 83.85%).

[0125] (3) Preparation of Compound 3 from Compound I - E and Compound I - F Compound 3 was prepared according to the route shown below.

Chemical formula

[0126] A dehydrated CH3CN (1 mL) solution of Compound I-E (100 mg, 0.227 mmol), Compound I-F (102 mg, 0.227 mmol), KI (113 mg, 3.0 equivalents), and DIPEA (0.2 mL, 5.0 equivalents) was heated to 75 °C and reacted for 17 hours. After completion of the reaction, it was diluted with EA (10 mL), alkalized with Na2CO3 (aqueous solution), the organic layer was washed with brine, dried over Na2SO4 (solid), concentrated, and purified by preparative thin-layer chromatography using a mobile phase (DCM / acetone = 9 / 1) to obtain Compound 3 (104 mg, 58%). MS: m / z 794.4 (M + +1); 1 H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.61(d, 1H), 7.86 - 7.82 (m, 2H), 7.62 (d, 1H), 7.39 (d, 1H), 7.37 (d, 1H), 7.33 (d, 1H), 7.13 (dd, 1H), 7.02 (dd, 1H), 6.95 (d, 1H), 4.98 (dd, 1H), 4.57 - 4.49 (m, 1H), 4.44 (q, 2H), 4.26 (t, 2H), 3.96 (s, 3H), 3.90 - 3.82 (m, 1H), 3.74 (bs, 4H), 2.93 - 2.85 (m, 1H), 2.84 (t, 2H), 2.66 (bs, 4H), 2.62 - 2.49 (m, 2H), 2.14 - 2.07 (m, 2H), 2.07 - 2.00 (m, 1H), 1.93 - 1.86 (m, 2H), 1.69 - 1.59 (m, 2H), 1.56 - 1.45 (m, 2H).

[0127] The preparation of Compound 1, Compound 2, and Compound 3 of the present invention was exemplified above. Other compounds of the present invention can be synthesized by methods similar to those shown in Synthetic Method A (Synthetic Schemes 1 - 3), Synthetic Method B (Synthetic Schemes 4 - 6), or Synthetic Method C (Synthetic Schemes 7 - 9), or by known synthetic methods based on general knowledge of organic chemistry.

[0128] Compounds 4 - 223 were prepared in the same manner as Synthesis Method A or Synthesis Method B, except that one or more starting materials were changed so that the desired product could be obtained according to Synthesis Method A (Synthesis Schemes 1 - 3), Synthesis Method B (Synthesis Schemes 4 - 6), or Synthesis Method C (Synthesis Schemes 7 - 9).

[0129] Compound 4: MS: m / z 834.9 (M + +1).

[0130] Compound 5: MS: m / z 835.9 (M + +1).

[0131] Compound 6: MS: m / z 821.6 (M + +1).

[0132] Compound 7: MS: m / z 824.1 (M + +1).

[0133] Compound 8: MS: m / z 835.5 (M + +1); 1 H NMR (CD3CN) δ 8.86 (bs, 1H), 8.58 (d, 1H), 7.90 (dd, 1H), 7.69 (d, 1H), 7.63 (d, 1H), 7.10 (d, 1H), 7.05 (d, 1H), 7.00 (dd, 1H), 6.93 (dd, 1H), 6.73 (d, 1H), 6.49 (d, 1H), 4.86 (q, 1H), 4.22 (s, 1H), 4.17 (t, 2H), 4.08 - 4.04 (m, 1H), 3.93 (s, 3H), 3.63 - 3.62 (m, 4H), 2.79 - 2.63 (m, 3H), 2.57 - 2.55 (m, 2H), 2.54 - 2.53 (m, 4H), 2.02 - 2.00 (m, 2H), 1.97 (m, 1H), 1.23 (s, 6H), 1.15(s, 6H).

[0134] Compound 9: MS: m / z 821.3 (M + +1);1 1H NMR (in CD3CN): δ 8.86 (broad singlet, 1H), 8.24 (doublet, 1H), 8.08 (doublet, 1H), 7.91 (doublet, 1H), 7.69 (doublet, 1H), 7.64 (doublet, 1H), 7.33 (doublet of doublets, 1H), 7.11 (doublet, 1H), 7.09 (doublet, 1H), 7.00 (doublet of doublets, 1H), 6.94 (doublet of doublets, 1H), 4.87 - 4.84 (multiplet, 1H), 4.26 (singlet, 1H), 4.24 (triplet, 2H), 4.01 (doublet, 1H), 3.93 (singlet, 3H), 3.37 - 3.36 (multiplet, 4H), 2.87 (triplet, 2H), 2.79 - 2.63 (multiplet, 7H), 2.14 (multiplet, 1H), 1.22 (singlet, 6H), 1.16 (singlet, 6H).

[0135] Compound 10: MS: m / z 821.5 (M + +1); 1 1H NMR (in DMSO - d6): δ 11.06 (singlet, 1H), 8.35 (doublet, 1H), 8.10 (doublet, 1H), 7.90 (doublet, 1H), 7.84 (doublet, 1H), 7.69 (doublet, 1H), 7.44 (doublet of doublets, 1H), 7.25 (doublet, 1H), 7.21 (singlet, 1H), 7.10 (doublet of doublets, 1H), 7.03 (doublet of doublets, 1H), 5.00 (doublet of doublets, 1H), 4.43 (singlet, 1H), 4.21 (triplet, 2H), 3.97 (singlet, 3H), 3.94 (doublet, 1H), 3.37 (multiplet, 4H), 2.92 - 2.86 (multiplet, 1H), 2.81 (triplet, 2H), 2.68 (multiplet, 4H), 2.60 - 2.55 (multiplet, 2H), 2.05 - 2.03 (multiplet, 1H), 1.19 (singlet, 6H), 1.12 (singlet, 6H).

[0136] Compound 11: MS: m / z 835.4 (M + +1).

[0137] Compound 12: MS: m / z 835.0 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 7.90 (d, 1H), 7.75 (d, 2H), 7.62 (d, 1H), 7.51 (d, 1H), 7.27 (d, 1H), 7.20 (d, 1H), 7.02 - 6.99 (m, 2H), 6.97 (d, 2H), 4.97 (dd, 1H), 4.32 (s, 1H), 4.16 (t, 2H), 4.05 (d, 1H), 3.96 (s, 3H), 3.27 (m, 4H), 2.92 - 2.86 (m, 1H), 2.61 - 2.50 (m, 8H), 2.04 - 1.96 (m, 3H), 1.21 (s, 6H), 1.12 (s, 6H).

[0138] Compound 13: MS: m / z 850.5 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.36 (d, 1H), 8.10 (d, 1H), 7.90 (d, 1H), 7.85 (d, 1H), 7.82 (d, 1H), 7.44 (dd, 1H), 7.25 (d, 1H), 7.20 (d, 1H), 7.09 (dd, 1H), 7.03 (dd, 1H), 5.10 - 5.05 (m, 1H), 5.01 (dd, 1H), 4.43 (s, 1H), 4.21 (t, 2H), 3.94 (d, 1H), 3.37 (m, 4H), 2.92 - 2.86 (m, 1H), 2.81 (t, 2H), 2.68 (m, 4H), 2.61 - 2.50 (m, 2H), 2.07 - 2.05 (m, 1H), 1.59 - 1.57 (m, 6H), 1.19 (s, 6H), 1.12 (s, 6H).

[0139] Compound 14: MS: m / z 839.0 (M + +1).

[0140] Compound 15: MS: m / z 820.3 (M + +1); 11H NMR (DMSO-d6) δ 11.04 (broad singlet, 1H), 7.88 (doublet, 1H), 7.73 (doublet, 2H), 7.67 (doublet, 1H), 7.49 (doublet, 1H), 7.18 (singlet, 2H), 7.09 (doublet of doublets, 1H), 6.99 - 6.95 (multiplet, 3H), 4.98 (doublet of doublets, 1H), 4.30 (singlet, 1H), 4.19 (triplet, 2H), 4.04 (doublet, 1H), 3.96 (singlet, 3H), 3.26 (multiplet, 4H), 2.90 - 2.85 (multiplet, 1H), 2.78 (triplet, 2H), 2.65 (multiplet, 4H), 2.58 - 2.55 (multiplet, 2H), 2.03 - 2.01 (multiplet, 1H), 1.19 (singlet, 6H), 1.11 (singlet, 6H).

[0141] Compound 16: MS: m / z 849.3 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (singlet, 1H), 8.62 (singlet, 1H), 7.96 (doublet, 1H), 7.90 (doublet, 1H), 7.82 (doublet, 1H), 7.61 (doublet, 1H), 7.21 - 7.20 (multiplet, 2H), 7.09 (doublet, 1H), 7.00 (doublet, 1H), 6.88 (doublet, 1H), 5.10 - 5.05 (multiplet, 1H), 5.01 (doublet of doublets, 1H), 4.30 (singlet, 1H), 4.21 (triplet, 2H), 4.05 (doublet, 1H), 3.63 (multiplet, 4H), 2.92 - 2.86 (multiplet, 1H), 2.80 (triplet, 2H), 2.61 (multiplet, 4H), 2.58 - 2.50 (multiplet, 2H), 2.07 - 2.05 (multiplet, 1H), 1.59 - 1.57 (multiplet, 6H), 1.21 (singlet, 6H), 1.12 (singlet, 6H).

[0142] Compound 17: MS: m / z 848.5 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 7.90 (d, 1H), 7.82 (d, 1H), 7.75 (d, 2H), 7.51 (d, 1H), 7.21-7.20 (m, 2H), 7.09 (d, 1H), 7.00-6.97 (m, 3H), 5.10-5.05 (m, 1H), 5.01 (dd, 1H), 4.32 (s, 1H), 4.21 (t, 2H), 4.05 (d, 1H), 3.28 (m, 4H), 2.92-2.86 (m, 1H), 2.80 (t, 2H), 2.66 (m, 4H), 2.58-2.50 (m, 2H), 2.07-2.05 (m, 1H), 1.59-1.57 (m, 6H), 1.21 (s, 6H), 1.12 (s, 6H).

[0143] Compound 18: MS: m / z 848.5 (M + +1)

[0144] Compound 19: MS: m / z 821.6 (M + +1);

[0145] Compound 20: MS: m / z 849.5 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.63 (s, 1H), 7.97 (d, 1H), 7.90 (d, 1H), 7.61 (dd, 2H), 7.34 (d, 1H), 7.20 (d, 1H), 7.02-6.99 (m, 2H), 6.87 (d, 1H), 4.97 (dd, 1H), 4.45-4.41 (m, 2H), 4.29 (s, 1H), 4.17 (t, 2H), 4.06 (d, 1H), 3.62 (m, 4H), 2.91-2.85 (m, 1H), 2.61-2.57 (m, 1H), 2.52-2.49 (m, 7H), 2.06-2.02 (m, 1H), 2.00-1.95 (m, 2H), 1.42 (t, 3H), 1.21 (s, 6H), 1.11 (s, 6H).

[0146] Compound 21: MS: m / z 848.6 (M + +1); 1 H NMR (DMSO-d6) δ 11.03 (s, 1H), 7.90 (d, 1H), 7.76 (dd, 2H), 7.62 (d, 1H), 7.51 (d, 1H), 7.33 (s, 1H), 7.19 (s, 1H), 7.02 - 6.97 (m, 4H), 4.98 (dd, 1H), 4.43(q, 2H), 4.32 (s, 1H), 4.17 (t, 2H), 4.04 (d, 1H), 3.27 (m, 4H), 2.91 - 2.85 (m, 1H), 2.61 - 2.57 (m, 1H), 2.56 - 2.50 (m, 4H), 2.50 - 2.49 (m, 2H), 2.07 - 2.02 (m, 1H), 2.00 - 1.96 (m, 2H), 1.41 (t, 3H), 1.22 (s, 6H), 1.12 (s, 6H).

[0147] Compound 22: MS: m / z 863.5 (M + +1); 1 H NMR (DMSO-d6) δ 11.04 (s, 1H), 8.62 (s, 1H), 7.96 (d, 1H), 7.90 (d, 1H), 7.62 (dd, 2H), 7.34 (d, 1H), 7.21 (d, 1H), 7.04 - 6.97 (m, 2H), 6.85 (d, 1H), 4.97 (dd, 1H), 4.42 - 4.33 (m, 2H), 4.30 (s, 1H), 4.16 (t, 2H), 4.06 (d, 1H), 3.62 (m, 4H), 2.93 - 2.83 (m, 1H), 2.63 - 2.55 (m, 1H), 2.55 - 2.49 (m, 7H), 2.08 - 2.02 (m, 1H), 2.00 - 1.95 (m, 2H), 1.88 - 1.81 (m, 2H), 1.42 (t, 3H), 1.21 (s, 6H), 1.11 (s, 6H), 0.86 (t, 3H).

[0148] Compound 23: MS: m / z 862.5 (M + +1); 1 H NMR (DMSO-d6) δ 11.05 (s, 1H), 7.91 (d, 1H), 7.75 (d, 2H), 7.63 (d, 1H), 7.51 (d, 1H), 7.34 (s, 1H), 7.20(s, 1H), 7.04 - 6.95 (m, 4H), 4.98 (dd, 1H), 4.37 (q, 2H), 4.32 (s, 1H), 4.16 (t, 2H), 4.05 (d, 1H), 3.27 (m, 4H), 2.93 - 2.84 (m, 1H), 2.61 - 2.58 (m, 1H), 2.56 - 2.50 (m, 4H), 2.50 - 2.49 (m, 2H), 2.07 - 2.02 (m, 1H), 2.01 - 1.94 (m, 2H), 1.89 - 1.81 (m, 2H), 1.21 (s, 6H), 1.12 (s, 6H), 0.86 (t, 3H).

[0149] Compound 24: MS: m / z 835.3 (M + +1); 1 H NMR (DMSO-d6) δ 11.08 (s, 1H), 8.62 (s, 1H), 7.96 (d, 1H), 7.89 (d, 1H), 7.61 (d, 1H), 7.30 - 7.22 (m, 2H), 7.20 (s, 1H), 7.02 (dd, 1H), 6.96 (d, 1H), 6.87 (d, 1H), 5.00 (dd, 1H), 4.31 (s, 1H), 4.26 - 4.17 (m, 5H), 4.05 (d, 1H), 3.62 (m, 4H), 2.93 - 2.83 (m, 1H), 2.63 - 2.55 (m, 1H), 2.55 - 2.49 (m, 7H), 2.07 - 2.03 (m, 3H), 1.21 (s, 6H), 1.12 (s, 6H).

[0150] Compound 25: MS: m / z 834.3 (M + +1); 11H NMR (DMSO-d6) δ 11.07 (s, 1H), 7.90 (d, 1H), 7.75 (d, 2H), 7.50 (d, 1H), 7.31 - 7.21 (m, 2H), 7.19 (s, 1H), 7.01 (dd, 1H), 6.99 - 6.94 (m, 3H), 5.00 (dd, 1H), 4.32 (s, 1H), 4.26 - 4.20 (m, 5H), 4.05 (d, 1H), 3.26 (m, 4H), 2.94 - 2.85 (m, 1H), 2.63 - 2.59 (m, 1H), 2.59 - 2.53 (m, 7H), 2.07 - 2.02 (m, 3H), 1.21 (s, 6H), 1.12 (s, 6H).

[0151] Compound 26: MS: m / z 821.4 (M + +1); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.60 (s, 1H), 8.05 (d, 1H), 7.97 (d, 1H), 7.85 (d, 1H), 7.61 (d, 1H), 7.40 (s, 1H), 7.32 (s, 1H), 7.15 (d, 1H), 7.01 (d, 1H), 6.84 (d, 1H), 4.97 (dd, 1H), 4.60 - 4.48 (m, 1H), 4.42 (q, 2H), 4.16 (t, 2H), 3.87 - 3.74 (m, 1H), 3.60 (m, 4H), 2.95 - 2.82 (m, 1H), 2.65 - 2.55 (m, 1H), 2.54 - 2.49 (m, 7H), 2.15 - 2.08 (m, 2H), 2.08 - 2.01 (m, 1H), 2.00 - 1.95 (m, 2H), 1.95 - 1.88 (m, 2H), 1.56 - 1.44 (m, 4H), 1.41 (t, 3H)

[0152] Compound 27: MS: m / z 820.4 (M + +1); 11H NMR (DMSO-d6) δ 11.07 (s, 1H), 8.01 (d, 1H), 7.86 (d, 1H), 7.74 (d, 2H), 7.63 (d, 1H), 7.40 (s, 1H), 7.33 (s, 1H), 7.14 (d, 1H), 7.02 (d, 1H), 6.93 (d, 2H), 4.98 (dd, 1H), 4.58 - 4.49 (m, 1H), 4.43 (q, 2H), 4.14 (t, 2H), 3.86 - 3.74 (m, 1H), 3.24 (m, 4H), 2.95 - 2.80 (m, 1H), 2.63 - 2.57 (m, 1H), 2.57 - 2.49 (m, 7H), 2.13 - 2.07 (m, 2H), 2.07 - 2.01 (m, 1H), 2.00 - 1.94 (m, 2H), 1.93 - 1.84 (m, 2H), 1.58 - 1.44 (m, 4H), 1.41 (t, 3H)

[0153] Compound 28: MS: m / z 863.0 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.75 (s, 2H), 8.12 (d, 1H), 7.87 (d, 1H), 7.62 (bs, 1H), 7.39 (d, 1H), 7.32 (bs, 1H), 7.15 (dd, 1H), 7.03 (bs, 1H), 4.98 (dd, 1H), 4.74 - 4.72 (m, 2H), 4.57 - 4.53 (m, 2H), 3.96 (s, 3H), 3.83 - 3.76 (m, 1H), 3.03 - 2.93 (m, 2H), 2.93 - 2.86 (m, 1H), 2.78 - 2.67 (m, 1H), 2.64 - 2.56 (m, 1H), 2.52 - 2.49 (m, 1H), 2.34 - 2.15 (m, 4H), 2.14 - 2.07 (m, 3H), 2.07 - 1.97 (m, 3H), 1.92 - 1.76 (m, 5H), 1.75 - 1.61 (m, 2H), 1.55 - 1.46 (m, 4H), 1.11 - 0.98 (m, 2H).

[0154] Compound 29: MS: m / z 822.3 (M + +1); 1 H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.61 (d, 1H), 7.85 (d, 1H), 7.84 (d, 1H), 7.62 (d, 1H), 7.39 (d, 1H), 7.36 - 7.32 (m, 2H), 7.13 (dd, 1H), 7.01 (dd, 1H), 4.97 (dd, 1H), 4.58 - 4.49 (m, 1H), 4.42 (q, 2H), 4.16 (t, 2H), 3.91 - 3.79 (m, 1H), 3.71 (bs, 4H), 2.93 - 2.83 (m, 1H), 2.64 - 2.56 (m, 1H), 2.56 - 2.49 (m, 7H), 2.14 - 2.07 (m, 2H), 2.07 - 2.02 (m, 1H), 2.02 - 1.95 (m, 2H), 1.94 - 1.86 (m, 2H), 1.70 - 1.59 (m, 2H), 1.56 - 1.47 (m, 2H), 1.41 (t, 3H).

[0155] Compound 30: MS: m / z 835.5 (M + +1); 1 H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.63 (d, 1H), 7.96 (dd, 1H), 7.90 (d, 1H), 7.61 (dd, 2H), 7.39 (d, 1H), 7.20 (d, 1H), 7.02 - 6.99 (m, 2H), 6.88 (dd, 1H), 4.97 (dd, 1H), 4.48 - 4.40 (m, 2H), 4.30 (s, 1H), 4.25 (t, 2H), 4.06 (d, 1H), 3.63 (m, 4H), 2.92 - 2.85 (m, 1H), 2.82 (t, 2H), 2.62 (m, 4H), 2.60 - 2.54 (m, 1H), 2.50 (m, 1H), 2.08 - 2.03 (m, 1H), 1.43 (t, 3H), 1.21 (s, 6H), 1.11 (s, 6H).

[0156] Compound 31: MS: m / z 807.4 (M + +1); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.60 (d, 1H), 8.05 (d, 1H), 7.96 (d, 1H), 7.86 (d, 1H), 7.61 (d, 1H), 7.39 (m, 2H), 7.14 (dd, 1H), 7.01 (dd, 1H), 6.86 (d, 1H), 4.97 (dd, 1H), 4.59 - 4.49 (m, 1H), 4.44 (q, 2H), 4.25 (t, 2H), 3.84 - 3.74 (m, 1H), 3.61 (m, 4H), 2.94 - 2.85 (m, 1H), 2.82 (t, 2H), 2.62 (m, 4H), 2.59 - 2.53 (m, 1H), 2.49 (m, 1H), 2.10 - 2.08 (m, 2H), 2.08 - 2.02 (m, 1H), 1.94 - 1.86 (m, 2H), 1.57 - 1.45 (m, 4H), 1.42 (t, 3H).

[0157] Compound 32: MS: m / z 828.5 (M + +23); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 7.96 (d, 1H), 7.85 (d, 1H), 7.74 (d, 2H), 7.61 (d, 1H), 7.39 (m, 2H), 7.14 (dd, 1H), 7.01 (dd, 1H), 6.95 (d, 1H), 4.97 (dd, 1H), 4.59 - 4.49 (m, 1H), 4.44 (q, 2H), 4.25 (t, 2H), 3.83 - 3.75 (m, 1H), 3.27 (m, 4H), 2.92 - 2.85 (m, 1H), 2.82 (t, 2H), 2.67 (m, 4H), 2.62 - 2.55 (m, 1H), 2.49 (m, 1H), 2.12 - 2.07 (m, 2H), 2.07 - 2.01 (m, 1H), 1.92 - 1.86 (m, 2H), 1.58 - 1.45 (m, 4H), 1.42 (t, 3H).

[0158] Compound 33: MS: m / z 808.4 (M + +1); 1 H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.61(d, 1H), 7.87-7.81 (m, 2H), 7.62 (d, 1H), 7.39 (m, 2H), 7.37 (d, 1H), 7.13 (d, 1H), 7.01 (d, 1H), 6.95 (d, 1H), 4.98 (dd, 1H), 4.58-4.49 (m, 1H), 4.44 (q, 2H), 4.26 (t, 2H), 3.91-3.81 (m, 1H), 3.73 (m, 4H), 2.93-2.85 (m, 1H), 2.66 (m, 4H), 2.63-2.55 (m, 1H), 2.49 (m, 1H), 2.12-2.07 (m, 2H), 2.07-2.00 (m, 1H), 1.93-1.86 (m, 2H), 1.68-1.59 (m, 2H), 1.56-1.46 (m, 2H), 1.42 (t, 3H).

[0159] Compound 34: MS: m / z 808.3 (M + +1).

[0160] Compound 35: MS: m / z 778.3 (M + +1).

[0161] Compound 36: MS: m / z 873.6 (M + +23); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.59 (d, 1H), 7.86 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.39 (d, 1H), 7.34 - 7.33 (m, 2H), 7.14 (dd, 1H), 7.02 (dd, 1H), 4.98 (dd, 1H), 4.56 - 4.51 (m, 1H), 4.42 (q, 2H), 4.08 - 4.00 (m, 4H), 3.89 - 3.82 (m, 1H), 3.65 - 3.61 (m, 1H), 3.57 - 3.55 (m, 1H), 3.51 - 3.48 (m, 1H), 3.47 - 3.43 (m, 2H), 2.92 - 2.86 (m, 1H), 2.62 - 2.57 (m, 2H), 2.23 - 2.18 (m, 1H), 2.12 - 2.09 (m, 2H), 2.08 - 2.03 (m, 1H), 1.93 - 1.88 (m, 4H), 1.67 - 1.60 (m, 2H), 1.54 - 1.48 (m, 4H), 1.40 (t, 3H), 1.06 (d, 3H).

[0162] Compound 37: MS: m / z 850.3 (M + +1).

[0163] Compound 38: MS: m / z 821.6 (M + +1). 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 9.10 (bs, 2H), 8.60 (d, 1H), 7.87 (d, 1H), 7.63 (d, 1H), 7.40 (d, 1H), 7.35 (bs, 1H), 7.15 (dd, 1H), 7.02 (dd, 1H), 4.98 (dd, 1H), 4.60 - 4.55 (m, 1H), 4.44 (q, 2H), 4.17 (bs, 2H), 3.87 - 3.82 (m, 1H), 3.08 - 2.95 (m, 1H), 2.93 - 2.86 (m, 1H), 2.64 - 2.56 (m, 2H), 2.56 - 2.48 (m, 6H), 2.15 - 2.09 (m, 4H), 2.08 - 2.02 (m, 3H), 2.00 - 1.88 (m, 4H), 1.58 - 1.49 (m, 4H), 1.43 (t, 3H).

[0164] Compound 39: MS: m / z 808.5 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.61 (d, 1H), 7.88 - 7.81 (m, 2H), 7.62 (d, 1H), 7.38 (d, 1H), 7.35 (d, 1H), 7.28 (d, 1H) 7.13 (dd, 1H), 7.01 (dd, 1H), 6.84 (d, 1H), 4.97 (dd, 1H), 4.57 - 4.49 (m, 1H), 4.16 (t, 2H), 3.95 (s, 3H), 3.90 - 3.80 (m, 1H), 3.71 (m, 4H), 2.93 - 2.83 (m, 1H), 2.63 - 2.58 (m, 1H), 2.56 - 2.49 (m, 7H), 2.14 - 2.07 (m, 2H), 2.07 - 1.96 (m, 3H), 1.94 - 1.85 (m, 2H), 1.70 - 1.59 (m, 2H), 1.56 - 1.45 (m, 2H).

[0165] Compound 40: MS: m / z 836.3 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.25 (d, 1H), 7.91 (d, 1H), 7.86 (d, 1H), 7.62 (d, 2H), 7.39 (d, 1H), 7.28 (d, 1H), 7.25 (d, 1H), 7.02 - 6.99 (m, 2H), 4.98 (dd, 1H), 4.46 (s, 1H), 4.17 (t, 2H), 4.00 (d, 1H), 3.96 (s, 3H), 3.74 (m, 4H), 2.92 - 2.85 (m, 1H), 2.62 - 2.58 (m, 1H), 2.56 - 2.49 (m, 7H), 2.06 - 2.02 (m, 1H), 2.02 - 1.96 (m, 2H), 1.22 (s, 6H), 1.14 (s, 6H).

[0166] Compound 41: MS: m / z 807.5 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.62 (d, 1H), 8.23( s, 1H), 7.86 - 7.85 (m, 2H), 7.70 (d, 1H), 7.54 (dd, 1H), 7.41 - 7.37 (m, 2H), 7.37 (d, 1H), 7.14 (dd, 1H), 5.00 (dd, 1H), 4.50 (m, 1H), 3.94 (s, 3H), 3.90 - 3.83 (m, 1H), 3.81 (m, 4H), 3.29 (s, 2H), 2.93 - 2.85 (m, 1H), 2.70 (m, 4H), 2.62 - 2.59 (m, 1H), 2.58 - 2.56 (m, 1H), 2.13 - 2.07 (m, 2H), 2.07 - 2.00 (m, 1H), 1.94 - 1.86 (m, 2H), 1.68 - 1.59 (m, 2H), 1.56 - 1.46 (m, 2H).

[0167] Compound 42: MS: m / z 834.4 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 10.08 1H), 8.63 (s, 1H), 8.22 (s, 1H), 7.96 (d, 1H), 7.89 (d, 1H), 7.69 (d, 1H), 7.64 (d, 1H), 7.53 (d, 1H), 7.20 (d, 1H), 7.00 (dd, 1H), 6.89 (d, 1H), 4.99 (dd, 1H),4.30 (s, 1H), 4.05 (d, 1H), 3.93 (s, 3H), 3.71 (m, 4H), 3.26 (s, 2H), 2.92-2.83 (m, 1H), 2.65 (m, 4H), 2.62-2.59 (m, 1H), 2.59-2.56 (m, 1H), 2.08-2.00 (m, 1H), 1.21 (s, 6H), 1.12 (s, 6H).

[0168] Compound 43: MS: m / z 808.5 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.61 (d, 1H), 7.88-7.80 (m, 2H), 7.39 (d, 1H), 7.36 (d, 1H), 7.30-7.21 (m, 2H) 7.13 (dd, 1H), 6.96 (d, 1H), 5.00 (dd, 1H), 4.58-4.50 (m, 1H), 4.26-4.20 (m, 2H), 4.22 (s, 3H), 3.90-3.81 (m, 1H), 3.71 (m, 4H), 2.94-2.85 (m, 1H), 2.63-2.58 (m, 1H), 2.56-2.49 (m, 7H), 2.15-2.08 (m, 2H), 2.08-2.00 (m, 3H), 1.94-1.86 (m, 2H), 1.70-1.59 (m, 2H), 1.56-1.46 (m, 2H).

[0169] Compound 44: MS: m / z 807.2 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 9.10 (bs, 2H), 8.62 (bs, 1H), 7.87 (d, 1H), 7.63 (d, 1H), 7.41 (d, 1H), 7.29 (bs, 1H), 7.15 (dd, 1H), 7.02 (d, 1H), 4.98 (dd, 1H), 4.60 - 4.56 (m, 1H), 4.17 (bs, 2H), 3.97 (s, 3H), 3.87 - 3.82 (m, 1H), 3.08 - 2.95 (m, 1H), 2.93 - 2.86 (m, 1H), 2.63 - 2.60 (m, 1H), 2.59 - 2.50 (m, 7H), 2.15 - 2.08 (m, 4H), 2.06 - 2.01 (m, 3H), 1.97 - 1.89 (m, 4H), 1.58 - 1.48 (m, 4H).

[0170] Compound 45: MS: m / z 793.4 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 9.09 (s, 2H), 8.62 (d, 1H), 7.87 (d, 1H), 7.62 (d, 1H), 7.40 (d, 1H), 7.35 (bs, 1H), 7.15 (dd, 1H), 7.03 (d, 1H), 4.98 (dd, 1H), 4.60 - 4.55 (m, 1H), 4.24 (bs, 2H), 3.97 (s, 3H), 3.87 - 3.81 (m, 1H), 3.08 (bs, 2H), 2.93 - 2.86 (m, 2H), 2.81 (bs, 2H), 2.62 - 2.56 (m, 1H), 2.52 - 2.49 (m, 3H), 2.27 - 2.19 (m, 1H), 2.12 - 2.08 (m, 2H), 2.06 - 2.02 (m, 1H), 1.98 - 1.90 (m, 3H), 1.89 - 1.81 (m, 1H), 1.58 - 1.48 (m, 4H).

[0171] Compound 46: MS: m / z 836.4 (M + +1); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.53 (d, 1H), 7.85 (d, 1H), 7.80 (d, 1H), 7.60 (d, 1H), 7.38 (d, 1H), 7.26 (s, 1H), 7.17 (d, 1H), 7.13 (dd, 1H), 6.94 (dd, 1H), 4.97 (dd, 1H), 4.56 - 4.49 (m, 1H), 4.41 (q, 2H), 4.06 (t, 2H), 3.90 - 3.80 (m, 3H), 3.76 (bs, 2H), 2.92 - 2.84 (m, 1H), 2.80 (bs, 2H), 2.66 - 2.57 (m, 4H), 2.56 - 2.49 (m, 2H), 2.12 - 2.06 (m, 2H), 2.06 - 2.00 (m, 1H), 1.92 - 1.82 (m, 6H), 1.66 - 1.57 (m, 2H), 1.55 - 1.46 (m, 2H), 1.40 (t, 3H).

[0172] Compound 47: MS: m / z 848.4 (M + +1); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.58 (d, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.62 (d, 1H), 7.38 (d, 1H), 7.33(s, 1H), 7.20 (d, 1H), 7.13 (dd, 1H), 7.02 (d, 1H), 4.97 (dd, 1H), 4.58 - 4.49 (m, 1H), 4.42 (q, 2H), 4.20 (t, 2H), 4.05 - 3.94 (m, 2H), 3.90 - 3.80 (m, 1H), 3.42 (bs, 2H), 3.13 (d, 2H), 2.93 - 2.84 (m, 1H), 2.63 - 2.54 (m, 4H), 2.14 - 2.06 (m, 2H), 2.06 - 2.01 (m, 1H), 2.00 - 1.95 (m, 2H), 1.95 - 1.86 (m, 4H), 1.68 - 1.58 (m, 2H), 1.58 - 1.46 (m, 4H), 1.41 (t, 3H).

[0173] Compound 48: MS: m / z 862.4 (M + +1); 1 H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.54 (d, 1H), 7.85 (d, 1H), 7.82 (d, 1H), 7.62 (d, 1H), 7.38 (d, 1H), 7.33 (d, 1H), 7.13 (dd, 1H), 7.00 (dd, 1H), 6.85 (d, 1H), 4.97 (dd, 1H), 4.58-4.50 (m, 1H), 4.44 (q, 2H), 4.13 (t, 2H), 3.84 (bs, 5H), 2.93-2.84 (m, 1H), 2.64-2.56 (m, 3H), 2.47-2.43 (m, 3H), 2.14-2.07 (m, 2H), 2.07-2.00 (m, 1H), 1.97-1.86 (m, 4H), 1.79 (bs, 4H), 1.70-1.59 (m, 2H), 1.69-1.58 (m 2H), 1.56-1.46 (m, 2H), 1.42 (t, 3H).

[0174] Compound 49: MS: m / z 890.4 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.22 (d, 1H), 7.90 (d, 1H), 7.85 (d, 1H), 7.63 (d, 1H), 7.33 (d, 1H), 7.25 (d, 1H), 7.03 (dd, 1H), 7.00 (dd, 1H), 6.88 (d, 1H), 4.98 (dd, 1H), 4.46 (s, 1H), 4.44 (q, 2H), 4.14 (bs, 2H), 4.00 (d, 1H), 3.88 (bs, 4H), 2.93-2.85 (m, 1H), 2.75 (bs, 2H), 2.62-2.58 (m, 1H), 2.58-2.55 (m, 1H), 2.54-2.49 (m, 4H), 2.08-2.01 (m, 1H), 2.01-1.93 (m, 2H), 1.83 (bs, 4H), 1.42 (t, 3H), 1.21 (s, 6H), 1.14 (s, 6H).

[0175] Compound 50: MS: m / z 835.5 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 10.10 (s, 1H), 8.26 (d, 1H), 8.23 (s, 1H), 7.90 (d, 1H), 7.87 (d, 1H), 7.70 (d, 1H), 7.54 (d, 1H), 7.41 (d, 1H), 7.25 (d, 1H), 7.03 (dd, 1H), 4.99 (dd, 1H), 4.46 (s, 1H), 4.00 (d, 1H), 3.94 (s, 3H), 3.83 (bs, 4H), 3.29 (s, 2H), 2.91-2.86 (m, 1H), 2.70 (bs, 4H), 2.60-2.57 (m, 1H), 2.56-2.49 (m, 1H), 2.07-2.03 (m, 1H), 1.22 (s, 6H), 1.14 (s, 6H).

[0176] Compound 51: MS: m / z 876.5 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.22 (d, 1H), 7.90 (d, 1H), 7.84 (d, 1H), 7.62 (d, 1H), 7.38 (d, 1H), 7.25 (d, 1H), 7.04 (dd, 1H), 7.01 (dd, 1H), 6.88 (d, 1H), 4.98 (dd, 1H), 4.46 (s, 1H), 4.44 (q, 2H), 4.21 (bs, 2H), 4.00 (d, 1H), 3.87 (s, 4H), 2.93 - 2.85 (m, 1H), 2.75 (bs, 2H), 2.62 - 2.58 (m, 1H), 2.58 - 2.54 (m, 1H), 2.54 - 2.49 (m, 4H), 2.08 - 2.01 (m, 1H), 1.81 (bs, 4H), 1.43 (t, 3H), 1.21 (s, 6H), 1.14 (s, 6H).

[0177] Compound 52: MS: m / z 822.3 (M + +1); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.56 (d, 1H), 7.85 (d, 1H), 7.79 (d, 1H), 7.59 (d, 1H), 7.38 (s, 1H), 7.33 (s, 1H), 7.18 (d, 1H), 7.14 (d, 1H), 6.96 (d, 1H), 4.97 (dd, 1H), 4.57 - 4.49 (m, 1H), 4.42 (q, 2H), 4.16 (t, 2H), 3.92 - 3.80 (m, 3H), 3.76 (bs, 2H), 2.96 - 2.89 (m, 4H), 2.89 - 2.84 (m, 1H), 2.75 - 2.69 (m, 2H), 2.62 - 2.55 (m, 1H), 2.55 - 2.49 (m, 1H), 2.14 - 2.07 (m, 2H), 2.07 - 2.00 (m, 1H), 1.93 - 1.84 (m, 4H), 1.67 - 1.57 (m, 2H), 1.55 - 1.46 (m, 2H), 1.40 (t, 3H).

[0178] Compound 53: MS: m / z 850.4 (M + +1); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.22 (d, 1H), 7.90 (d, 1H), 7.82 (d, 1H), 7.60 (d, 1H), 7.34 (d, 1H), 7.25 (d, 1H), 7.20 (d, 1H), 7.03 (dd, 1H), 6.97 (dd, 1H), 4.97 (dd, 1H), 4.45 (s, 1H), 4.42 (q, 2H), 4.17 (t, 2H), 4.00 (d, 1H), 3.88 (bs, 2H), 3.78 (bs, 2H), 2.97-2.91 (m, 4H), 2.91-2.84 (m, 1H), 2.76-2.71 (m, 2H), 2.63-2.55 (m, 1H), 2.55-2.49 (m, 1H), 2.07-2.00 (m, 1H), 1.94-1.87 (m, 2H), 1.41 (t, 3H), 1.22 (s, 6H), 1.14 (s, 6H).

[0179] Compound 54: MS: m / z 864.5 (M + +1); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.21 (d, 1H), 7.90 (d, 1H), 7.82 (d, 1H), 7.60 (d, 1H), 7.28 (s, 1H), 7.25 (d, 1H), 7.20 (d, 1H), 7.03 (dd, 1H), 6.96 (dd, 1H), 4.97 (dd, 1H), 4.45 (s, 1H), 4.42 (q, 2H), 4.08 (bs, 2H), 3.99 (d, 1H), 3.86 (bs, 2H), 3.77 (bs, 2H), 2.93-2.84 (m, 1H), 2.81 (bs, 2H), 2.68-2.55 (m, 5H), 2.55-2.49 (m, 1H), 2.07-2.00 (m, 1H), 1.94-1.82 (m, 4H), 1.40 (t, 3H), 1.22 (s, 6H), 1.13 (s, 6H).

[0180] Compound 55: MS: m / z 836.5 (M + +1); 1 H 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 - 7.37 (m, 2H), 7.30 (d, 1H), 7.14 (dd, 1H), 7.02 (dd, 1H), 4.98 (dd, 1H), 4.62 (bs, 1H), 4.57 - 4.49 (m, 1H), 4.45 (q, 2H), 4.28 - 4.16 (m, 3H), 3.90 - 3.81 (m, 1H), 3.42 - 3.36 (m, 1H), 3.25 - 3.10 (m, 1H), 2.96 - 2.84 (m, 3H), 2.82 - 2.75 (m, 1H), 2.66 - 2.56 (m, 2H), 2.54 - 2.49 (m, 1H), 2.14 - 2.07 (m, 2H), 2.07 - 2.01 (m, 1H), 1.94 - 1.86 (m, 2H), 1.68 - 1.58 (m, 2H), 1.56 - 1.46 (m, 2H), 1.43 (t, 3H), 1.23 (d, 3H), 0.98 (d, 3H).

[0181] Compound 56: MS: m / z 848.5 (M + +1); 11H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.06 (s, 1H), 8.64 (d, 1H), 8.26 (s, 1H), 7.97 (dd, 1H), 7.90 (d, 1H), 7.70 (d, 1H), 7.62 (d, 1H), 7.55 (dd, 1H), 7.21 (d, 1H), 7.00 (dd, 1H), 6.89 (d, 1H), 5.00 (dd, 1H), 4.41 - 4.36 (m, 2H), 4.30 (s, 1H), 4.06 (d, 1H), 3.72 (bs, 4H), 3.26 (s, 2H), 2.92 - 2.86 (m, 1H), 2.67 - 2.65 (m, 4H), 2.61 - 2.57 (m, 2H), 2.07 - 2.03 (m, 1H), 1.44 (t, 3H), 1.22 (s, 6H), 1.12 (s, 6H).

[0182] Compound 57: MS: m / z 822.4 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.61(d, 1H), 7.87 - 7.81 (m, 2H), 7.62 (d, 1H), 7.40 - 7.37 (m, 2H), 7.31 (d, 1H), 7.13 (dd, 1H), 7.03 (dd, 1H), 4.98 (dd, 1H), 4.67 (bs, 1H), 4.57 - 4.49 (m, 1H), 4.44 (q, 2H), 4.28 (t, 2H), 4.28 - 4.20 (m, 1H), 3.91 - 3.81 (m, 1H), 3.22 - 3.09 (m, 2H), 2.96 (d, 1H), 2.93 - 2.85 (m, 1H), 2.82 (t, 2H), 2.63 - 2.49 (m, 2H), 2.43 - 2.37 (m, 1H), 2.26 - 2.18 (m, 1H), 2.14 - 2.07 (m, 2H), 2.07 - 2.00 (m, 1H), 1.93 - 1.86 (m, 2H), 1.68 - 1.59 (m, 2H), 1.56 - 1.46 (m, 2H), 1.43 (t, 3H), 1.21 (d, 3H).

[0183] Compound 58: MS: m / z 836.4 (M + +1); 1 H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.61(d, 1H), 7.85 (d, 1H), 7.81 (d, 1H), 7.62 (d, 1H), 7.40-7.37 (m, 2H), 7.31 (d, 1H), 7.13 (dd, 1H), 7.02 (dd, 1H), 4.98 (dd, 1H), 4.57-4.49 (m, 1H), 4.50-4.40 (m, 3H), 4.34-4.22 (m, 3H), 3.90-3.82 (m, 1H), 3.20-3.13 (m, 1H), 3.09 (t, 2H), 2.93-2.84 (m, 1H), 2.84-2.78 (m, 2H), 2.63-2.49 (m, 2H), 2.32-2.25 (m, 1H), 2.25-2.18 (m, 1H), 2.14-2.08 (m, 2H), 2.08-2.01 (m, 1H), 1.93-1.86 (m, 3H), 1.69-1.57 (m, 3H), 1.56-1.46 (m, 2H), 1.43 (t, 3H), 0.81 (d, 3H).

[0184] Compound 59: MS: m / z 850.4 (M + +1); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.57 (d, 1H), 7.85 (d, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.39 (d, 1H), 7.33 (d, 1H), 7.29 (d, 1H), 7.13 (dd, 1H), 7.02 (dd, 1H), 4.97 (dd, 1H), 4.62 (bs, 1H), 4.57 - 4.50 (m, 1H), 4.43 (q, 2H), 4.22 - 4.13 (m, 3H), 3.90 - 3.80 (m, 1H), 3.40 - 3.34 (m, 1H), 3.15 - 3.10 (m, 1H), 2.93 - 2.85 (m, 1H), 2.82 - 2.76 (m, 1H), 2.66 - 2.58 (m, 2H), 2.58 - 2.49 (m, 3H), 2.13 - 2.07 (m, 2H), 2.07 - 2.01 (m, 1H), 1.98 - 1.85 (m, 4H), 1.68 - 1.58 (m, 2H), 1.56 - 1.46 (m, 2H), 1.41 (t, 3H), 1.22 (d, 3H), 0.92 (d, 3H).

[0185] Compound 60: MS: m / z 850.5 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.61(d, 1H), 7.85 (d, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.38 (d, 1H), 7.33 (s, 1H), 7.30 (d, 1H), 7.14 (dd, 1H), 7.02 (d, 1H), 4.97 (dd, 1H), 4.57-4.49 (m, 1H), 4.49-4.40 (m, 3H), 4.33-4.24 (m, 1H), 4.21-4.14 (m, 2H), 3.90-3.81 (m, 1H), 3.19-3.11 (m, 1H), 2.99 (t, 2H), 2.94-2.84 (m, 1H), 2.63-2.55 (m, 2H), 2.54-2.49 ( m, 1H), 2.14-2.02 (m, 6H), 2.00-1.93 (m, 2H), 1.93-1.86 (m, 2H), 1.87-1.80 (m, 1H), 1.69-1.56 (m, 3H), 1.56-1.46 (m, 2H), 1.42 (t, 3H), 0.80 (d, 3H).

[0186] Compound 61: MS: m / z 822.3 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (broad singlet, 1H), 8.61 (singlet, 1H), 8.26 (singlet, 1H), 8.12 (doublet, 1H), 7.86 (doublet, 1H), 7.62 (doublet, 1H), 7.37 (doublet, 1H), 7.34 (singlet, 1H), 7.12 (doublet of doublets, 1H), 7.01 (doublet of doublets, 1H), 4.97 (doublet of doublets, 1H), 4.53 - 4.50 (multiplet, 1H), 4.43 (quartet, 2H), 4.16 (triplet, 2H), 3.86 - 3.80 (multiplet, 1H), 3.70 (broad singlet, 4H), 2.92 - 2.85 (multiplet, 1H), 2.64 - 2.56 (multiplet, 1H), 2.56 - 2.49 (multiplet, 6H), 2.11 - 2.07 (multiplet, 2H), 2.06 - 2.02 (multiplet, 1H), 2.00 - 1.96 (multiplet, 2H), 1.90 - 1.87 (multiplet, 2H), 1.64 - 1.58 (multiplet, 2H), 1.53 - 1.47 (multiplet, 2H), 1.42 (triplet, 3H).

[0187] Compound 62: MS: m / z 808.3 (M + + 1); 1 1H NMR (DMSO-d6) δ 11.06 (singlet, 1H), 8.61 (singlet, 1H), 8.27 (singlet, 1H), 8.11 (doublet, 1H), 7.85 (doublet, 1H), 7.62 (doublet, 1H), 7.38 (doublet, 1H), 7.37 (doublet, 1H), 7.12 (doublet of doublets, 1H), 7.01 (doublet of doublets, 1H), 4.97 (doublet of doublets, 1H), 4.54 - 4.49 (multiplet, 1H), 4.43 (quartet, 2H), 4.25 (triplet, 2H), 3.86 - 3.81 (multiplet, 1H), 3.72 (broad singlet, 4H), 2.93 - 2.82 (multiplet, 3H), 2.65 (broad singlet, 4H), 2.62 - 2.57 (multiplet, 1H), 2.49 (multiplet, 1H), 2.12 - 2.02 (multiplet, 3H), 1.88 - 1.86 (multiplet, 2H), 1.63 - 1.57 (multiplet, 2H), 1.53 - 1.47 (multiplet, 2H), 1.42 (triplet, 3H).

[0188] Compound 63: MS: m / z 822.6 (M + +1); 1 H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.62 (d, 1H), 7.87-7.83 (m, 2H), 7.62 (d, 1H), 7.39-7.34 (m, 3H), 7.14 (dd, 1H), 7.02 (dd, 1H), 4.98 (dd, 1H), 4.56-4.51 (m, 1H), 4.44 (q, 2H), 4.18 (t, 2H), 3.89-3.83 (m, 1H), 3.72 (bs, 4H), 2.93-2.86 (m, 1H), 2.63-2.58 (m, 1H), 2.58-2.53 (m, 7H), 2.14-2.08 (m, 2H), 2.07-2.03 (m, 1H), 2.02-1.97 (m, 2H), 1.93-1.88 (m, 2H), 1.68-1.62 (m, 2H), 1.55-1.49 (m, 2H), 671.42 (t, 3H).

[0189] Compound 64: MS: m / z 834.4 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.59 (d, 1H), 7.85 (d, 1H), 7.82 (d, 1H), 7.62 (d, 1H), 7.39 (m, 2H), 7.22 (d, 1H), 7.13 (d, 1H), 7.02 (d, 1H), 4.98 (dd, 1H), 4.57 - 4.50 (m, 1H), 4.44 (q, 2H), 4.25 (t, 2H), 4.07 - 3.97 (m, 2H), 3.91 - 3.81 (m, 1H), 3.54 (m, 2H), 3.15 (d, 2H), 2.92 - 2.86 (m, 1H), 2.86 - 2.82 (m, 2H), 2.62 - 2.49 (m, 2H), 2.12 - 2.07 (m, 2H), 2.07 - 2.01 (m, 1H), 1.99 - 1.93 (m, 2H), 1.93 - 1.86 (m, 2H), 1.67 - 1.60 (m, 2H), 1.60 - 1.55 (m, 2H), 1.55 - 1.47 (m, 2H), 1.42 (t, 3H).

[0190] Compound 65: MS: m / z 836.4 (M + +1); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.61(d, 1H), 7.86 (d, 1H), 7.83 (d, 1H), 7.62 (d, 1H), 7.39 (d, 1H), 7.34 (d, 1H), 7.30 (d, 1H), 7.13 (dd, 1H), 7.02 (dd, 1H), 4.98 (dd, 1H), 4.66 (bs, 1H), 4.57-4.49 (m, 1H), 4.43 (q, 2H), 4.26-4.14 (m, 3H), 3.91-3.81 (m, 1H), 3.20-3.12 (m, 1H), 3.02 (d, 1H), 2.93-2.83 (m, 2H), 2.63-2.53 (m, 2H), 2.53-2.49 (m, 2H), 2.25-2.18 (m, 1H), 2.14-2.08 (m, 2H), 2.07-2.02 (m, 2H), 2.02-1.94 (m, 2H), 1.93-1.86 (m, 2H), 1.69-1.59 (m, 2H), 1.56-1.46 (m, 2H), 1.41 (t, 3H), 1.20 (d, 3H).

[0191] Compound 66: MS: m / z 806.4 (M + +1)

[0192] Compound 67: MS: m / z 794.4 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.61(d, 1H), 7.86-7.82 (m, 2H), 7.62 (d, 1H), 7.39 (d, 1H), 7.37 (d, 1H), 7.33 (d, 1H), 7.13 (dd, 1H), 7.02 (dd, 1H), 6.95 (d, 1H), 4.98 (dd, 1H), 4.57-4.49 (m, 1H), 4.44 (q, 2H), 4.26 (t, 2H), 3.96 (s, 3H), 3.90-3.82 (m, 1H), 3.74 (bs, 4H), 2.93-2.85 (m, 1H), 2.84 (t, 2H), 2.66 (bs, 4H), 2.62-2.49 (m, 2H), 2.14-2.07 (m, 2H), 2.07-2.00 (m, 1H), 1.93-1.86 (m, 2H), 1.69-1.59 (m, 2H), 1.56-1.45 (m, 2H).

[0193] Compound 68: MS: m / z 821.4 (M + +1); 11H NMR (DMSO-d6) δ 11.07 (s, 1H), 9.86 (s, 1H), 8.57 (d, 1H), 8.17 (s, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.65 (d, 1H), 7.38 (d, 1H), 7.30 (d, 1H), 7.23 (d, 1H), 7.14 (dd, 1H), 4.99 (dd, 1H), 4.56 - 4.49 (m, 1H), 4.00 - 3.88 (m, 2H), 3.92 (s, 3H), 3.88 - 3.78 (m, 3H), 3.36 (s, 2H), 2.99 - 2.93 (m, 2H), 2.92 - 2.84 (m, 1H), 2.81 - 2.75 (m, 2H), 2.62 - 2.54 (m, 1H), 2.55 - 2.49 (m, 1H), 2.14 - 2.06 (m, 2H), 2.06 - 1.98 (m, 1H), 1.98 - 1.92 (m, 2H), 1.92 - 1.84 (m, 2H), 1.67 - 1.57 (m, 2H), 1.55 - 1.46 (m, 2H).

[0194] Compound 69: MS: m / z 875.3 (M + +1); 1 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.00 (s, 1H), 8.23 (d, 1H), 8.22 (s, 1H), 7.90 (d, 1H), 7.84 (d, 1H), 7.69 (d, 1H), 7.54 (d, 1H), 7.25 (d, 1H), 7.03 (dd, 1H), 6.90 (d, 1H), 5.00 (dd, 1H), 4.46 (s, 1H), 4.00 (d, 1H), 3.95 (s, 3H), 3.89 (s, 4H), 3.19 (s, 2H), 2.94 - 2.84 (m, 1H), 2.63 - 2.56 (m, 2H), 2.56 - 2.54 (m, 2H), 2.54 - 2.49 (m, 2H), 2.07 - 2.00 (m, 1H), 1.89 (bs, 4H), 1.21 (s, 6H), 1.14 (s, 6H).

[0195] Compound 70: MS: m / z 834.3 (M + +1); 1 H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.58 (d, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.59 (d, 1H), 7.39 (d, 1H), 7.34 (s, 1H), 7.26 (d, 1H), 7.14 (dd, 1H), 6.96 (d, 1H), 4.97 (dd, 1H), 4.73 (bs, 2H) 4.57-4.50 (m, 1H), 4.42 (q, 2H), 4.19 (t, 2H), 3.90-3.81 (m, 1H), 2.93-2.84 (m, 1H), 2.81-2.75 (m, 2H), 2.75-2.70 (m, 2H), 2.63-2.55 (m, 1H), 2.50-2.49 (m, 1H), 2.47-2.43 (m, 2H), 2.14-2.06 (m, 2H), 2.06-2.00 (m, 1H), 1.99-1.96 (m, 2H), 1.94-1.85 (m, 4H), 1.68-1.58 (m, 2H), 1.56-1.47 (m, 2H), 1.42 (t, 3H).

[0196] Compound 71: MS: m / z 848.4 (M + +1); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.58 (d, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.61 (d, 1H), 7.39 (d, 1H), 7.32 (s, 1H), 7.25 (d, 1H), 7.14 (dd, 1H), 7.00 (d, 1H), 4.97 (dd, 1H), 4.72 (bs, 2H), 4.57 - 4.50 (m, 1H), 4.43 (q, 2H), 4.14 (t, 2H), 3.90 - 3.82 (m, 1H), 2.93 - 2.84 (m, 1H), 2.75 - 2.69 (m, 2H), 2.62 - 2.55 (m, 1H), 2.50 - 2.49 (m, 1H), 2.44 - 2.39 (m, 2H), 2.29 - 2.24 (m, 2H), 2.14 - 2.07 (m, 2H), 2.07 - 2.01 (m, 1H), 1.98 - 1.93 (m, 2H), 1.93 - 1.85 (m, 6H), 1.68 - 1.59 (m, 2H), 1.56 - 1.47 (m, 2H), 1.41 (t, 3H).

[0197] Compound 72: MS: m / z 862.4 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.58 (d, 1H), 7.86 (d, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.38 - 7.33 (m, 3H), 7.13 (d, 1H), 7.00 (dd, 1H), 4.97 (dd, 1H), 4.56 - 4.51 (m, 1H), 4.44 (q, 2H), 4.12 (t, 2H), 3.86 - 3.85 (m, 1H), 3.68 (s, 4H), 3.03 (bs, 4H), 2.92 - 2.85 (m, 1H), 2.61 - 2.57 (m, 2H), 2.11 - 2.09 (m, 2H), 2.05 - 2.03 (m, 1H), 1.90 - 1.88 (m, 2H), 1.80 (bs, 2H), 1.75 (bs, 4H), 1.66 - 1.60 (m 2H), 1.54 - 1.48 (m, 2H), 1.42 (t, 3H).

[0198] Compound 73: MS: m / z 822.3 (M + +1); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.57 (d, 1H), 7.85 (d, 1H), 7.82 (d, 1H), 7.61 (d, 1H), 7.40 - 7.35 (m, 3H), 7.13 (d, 1H), 7.00 (d, 1H), 4.97 (dd, 1H), 4.57 - 4.49 (m, 1H), 4.43 (q, 2H), 4.22 (t, 2H), 4.19 - 4.08 (m, 2H), 3.90 - 3.81 (m, 1H), 3.17 - 3.09 (m, 1H), 3.07 - 3.00 (m, 2H), 2.93 - 2.83 (m, 1H), 2.83 - 2.75 (m, 1H), 2.68 - 2.58 (m, 2H), 2.58 - 2.49(m, 3H), 2.14 - 2.07 (m, 2H), 2.07 - 2.00 (m, 1H), 1.94 - 1.86 (m, 2H), 1.69 - 1.58 (m, 2H), 1.56 - 1.46 (m, 2H), 1.42 (t, 3H), 1.12 (d, 3H).

[0199] Compound 74: MS: m / z 836.4 (M + +1); 1 H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.59 (d, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.62 (d, 1H), 7.39 (s, 1H), 7.36 (d, 1H), 7.34 (s, 1H), 7.13 (d, 1H), 7.01 (d, 1H), 4.98 (dd, 1H), 4.57 - 4.49 (m, 1H), 4.43 (q, 2H), 4.18 - 4.10 (m, 3H), 4.10 - 4.03 (m, 1H), 3.90 - 3.81 (m, 1H), 3.07 - 2.99 (m, 1H), 2.97 - 2.83 (m, 3H), 2.63 - 2.55 (m, 1H), 2.55 - 2.49 (m, 3H), 2.46 - 2.40 (m,1H), 2.37 - 2.31 (m, 1H), 2.14 - 2.07 (m, 2H), 2.07 - 2.00 (m, 1H), 1.98 - 1.87 (m, 4H), 1.69 - 1.59 (m, 2H), 1.56 - 1.46 (m, 2H), 1.41 (t, 3H), 1.05 (d, 3H).

[0200] Compound 75: MS: m / z 808.5 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.56 (d, 1H), 7.86 (d, 1H), 7.79 (d, 1H), 7.59 (d, 1H), 7.39 (s, 1H), 7.27 (s, 1H), 7.18 (d, 1H), 7.13 (d, 1H), 6.97 (d, 1H), 4.97 (dd, 1H), 4.57-4.50 (m, 1H), 4.20-4.12 (m, 2H), 3.94 (s, 3H), 3.91-3.81 (m, 3H), 3.76 (bs, 2H), 2.99-2.90 (m, 4H), 2.90-2.84 (m, 1H), 2.77-2.69 (m, 2H), 2.62-2.55 (m, 1H), 2.55-2.49 (m, 1H), 2.14-2.06 (m, 2H), 2.06-2.00 (m, 1H), 1.94-1.85 (m, 4H), 1.67-1.58 (m, 2H), 1.56-1.46 (m, 2H).

[0201] Compound 76: MS: m / z 850.4 (M + +1); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.56 (d, 1H), 7.85 (d, 1H), 7.81 (d, 1H), 7.62 (d, 1H), 7.41 - 7.35 (m, 2H), 7.32 (s, 1H), 7.14 (dd, 1H), 6.98 (d, 1H), 4.97 (dd, 1H), 4.57 - 4.50 (m, 1H), 4.42 (q, 2H), 4.33 (d, 2H), 4.11 (t, 2H), 3.91 - 3.81 (m, 1H), 3.71 (m, 4H), 2.94 - 2.84 (m, 3H), 2.78 - 2.70 (m, 2H), 2.66 - 2.55 (m, 3H), 2.54 - 2.49 (m, 1H), 2.13 - 2.07 (m, 2H), 2.07 - 2.00 (m, 1H), 1.93 - 1.87 (m, 2H), 1.87 - 1.80 (m, 2H), 1.67 - 1.59 (m, 2H), 1.56 - 1.46 (m, 2H), 1.41 (t, 3H), 1.12 (d, 6H).

[0202] Compound 77: MS: m / z 836.4 (M + +1); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.56 (d, 1H), 7.85 (d, 1H), 7.82 (d, 1H), 7.60 (d, 1H), 7.41 - 7.37 (m, 2H), 7.35 (s, 1H), 7.13 (d, 1H), 6.96 (d, 1H), 4.97 (dd, 1H), 4.57 - 4.50 (m, 1H), 4.43 (q, 2H), 4.40 - 4.33 (m, 2H), 4.13 (t, 2H), 3.90 - 3.81 (m, 1H), 3.12 (t, 2H), 2.94 - 2.84 (m, 1H), 2.82 - 2.70 (m, 4H), 2.64 - 2.54 (m, 1H), 2.54 - 2.49 (m, 1H), 2.15 - 2.07 (m, 2H), 2.07 - 2.01 (m, 1H), 1.94 - 1.87 (m, 2H), 1.68 - 1.57 (m, 2H), 1.56 - 1.46 (m, 2H), 1.41 (t, 3H), 1.18 (d, 6H).

[0203] Compound 78: MS: m / z 835.7 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.51 (d, 1H), 7.84 (d, 1H), 7.62 (d, 1H), 7.61 (d, 1H), 7.37 - 7.34 (m, 2H), 7.02 (d, 1H), 6.94 (s, 1H), 6.82 (d, 1H), 4.97 (dd, 1H), 4.44 (q, 2H), 4.26 (t, 2H), 3.86 - 3.84 (m, 1H), 3.80 - 3.76 (m, 1H), 3.74 (bs, 4H), 2.91 - 2.85 (m, 1H), 2.85 (s, 3H), 2.60 - 2.54 (m, 8H), 2.05 - 2.03 (m, 1H), 2.00 - 1.98 (m, 2H), 1.93 - 1.91 (m, 2H), 1.78 - 1.72 (m, 2H), 1.68 - 1.63 (m, 4H), 1.42 (t, 3H).

[0204] Compound 79: MS: m / z 821.6 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.51 (d, 1H), 7.84 (d, 1H), 7.62 (d, 1H), 7.61 (d, 1H), 7.39 (s, 1H), 7.37 (d, 1H), 7.01 (d, 1H), 6.94 (s, 1H), 6.82 (d, 1H), 4.97 (dd, 1H), 4.43 (q, 2H), 4.16 (t, 2H), 3.85-3.84 (m, 1H), 3.80-3.76 (m, 1H), 3.72 (bs, 4H), 2.89-2.85 (m, 3H), 2.85 (s, 3H), 2.67 (bs, 4H), 2.60-2.54 (m, 1H), 2.54-2.49 (m, 1H), 2.06-2.04 (m, 1H), 1.92-1.91 (m, 2H), 1.78-1.72 (m, 2H), 1.68-1.63 (m, 4H), 1.43 (t, 3H).

[0205] Compound 80: MS: m / z 848.2 (M + +1)

[0206] Compound 81: MS: m / z 848.4 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.55 (d, 1H), 7.86 (d, 1H), 7.83 (d, 1H), 7.61 (d, 1H), 7.40 - 7.33 (m, 2H), 7.13 (dd, 1H), 7.00 (dd, 1H), 6.85 (d, 1H), 4.97 (dd, 1H), 4.58 - 4.50 (m, 1H), 4.44 (q, 2H), 4.21 (t, 2H), 3.85 (bs, 5H), 2.93 - 2.84 (m, 1H), 2.74 (t, 2H), 2.64 - 2.56 (m, 1H), 2.56 - 2.49 (m, 5H), 2.14 - 2.07 (m, 2H), 2.07 - 2.01 (m, 1H), 1.94 - 1.86 (m, 2H), 1.81 (bs, 4H), 1.68 - 1.58 (m, 2H), 1.56 - 1.46 (m 2H), 1.42 (t, 3H).

[0207] Compound 82: MS: m / z 858.4 (M + +1); 1 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 8.61 (d, 1H), 7.85 (d, 1H), 7.84 (d, 1H), 7.64 (d, 1H), 7.43 (s, 1H), 7.39 (s, 1H), 7.36 (d. 1H), 7.13 (d, 1H), 7.04 (d, 1H), 6.52 (t, 1H), 4.98 (dd, 1H), 4.91 (t, 2H), 4.58 - 4.49 (m, 1H), 4.15 (t, 2H), 3.91 - 3.81 (m, 1H), 3.71 (bs, 4H), 2.93 - 2.84 (m, 1H), 2.63 - 2.56 (m, 1H), 2.56 - 2.49 (m, 7H), 2.14 - 2.07 (m, 2H), 2.07 - 2.02 (m, 1H), 2.02 - 1.95 (m, 2H), 1.94 - 1.86 (m, 2H), 1.70 - 1.59 (m, 2H), 1.57 - 1.46 (m, 2H).

[0208] Compound 83: MS: m / z 871.4 (M + +1); 1 H NMR (DMSO-d6) δ 11.07 (s, 1H), 8.51 (d, 1H), 7.84 (d, 1H), 7.64 (d, 1H), 7.61 (d, 1H), 7.44 (s, 1H), 7.36 (d, 1H), 7.04 (d, 1H), 6.94 (s, 1H), 6.83 (d, 1H), 6.52 (t, 1H), 4.99 (dd, 1H), 4.92 (t, 2H), 4.15 (t, 2H), 3.86-3.84 (m, 1H), 3.80-3.76 (m, 1H), 3.71 (bs, 4H), 2.92-2.85 (m, 1H), 2.85 (s, 3H), 2.60-2.57 (m, 1H), 2.57-2.50 (m, 3H), 2.54 (bs, 4H), 2.06-2.04 (m, 1H), 2.00-1.98 (m, 2H), 1.93-1.91 (m, 2H), 1.78-1.72 (m, 2H), 1.68-1.63 (m, 4H).

[0209] Compound 84: MS: m / z 924.5 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.61 (d, 1H), 7.85 (d, 1H), 7.83 (d, 1H), 7.65 (d, 1H), 7.39 (d, 1H), 7.38 - 7.33 (m, 2H), 7.14 (dd, 1H), 7.05 (dd, 1H), 5.75 (dd, 2H), 5.00 (dd, 1H), 4.57 - 4.50 (m, 1H), 4.15 (t, 2H), 3.90 - 3.80 (m, 1H), 3.71 (bs, 4H), 3.57 (t, 2H), 2.94 - 2.85 (m, 1H), 2.63 - 2.56 (m, 1H), 2.56 - 2.49 (m, 7H), 2.14 - 2.07 (m, 2H), 2.07 - 2.01 (m, 1H), 2.01 - 1.95 (m, 2H), 1.94 - 1.85 (m, 2H), 1.69 - 1.59 (m, 2H), 1.56 - 1.46 (m, 2H), 0.89 - 0.80 (m, 2H), -0.11(s, 9H).

[0210] Compound 85: MS: m / z 824.4 (M + +1); 11H NMR (DMSO-d6) δ 11.07 (s, 1H), 9.81(bs, 1H), 8.69 (d, 1H), 7.96 (d, 1H), 7.86 (d, 1H), 7.67 (d, 1H), 7.51 (d, 1H), 7.39 (s, 1H), 7.36 (s, 1H), 7.14 (d, 1H), 7.04 (d, 1H), 5.71 (s, 2H), 5.00 (dd, 1H), 4.70-4.58 (m, 2H), 4.57-4.49 (m, 1H), 4.19 (t, 2H), 3.90-3.80 (m, 1H), 3.43-3.32 (m, 4H), 3.25-3.14 (m, 2H), 2.94-2.84 (m, 1H), 2.64-2.56 (m, 1H), 2.56-2.49 (m, 3H), 2.29-2.20 (m, 2H), 2.15-2.07 (m, 2H), 2.07-2.00 (m, 1H), 1.94-1.86 (m, 2H), 1.71-1.60 (m, 2H), 1.56-1.46 (m, 2H).

[0211] Compound 86: MS: m / z 794.4 (M + +1)

[0212] Compound 87: MS: m / z 822.4 (M + +1); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.53 (d, 1H), 7.86 (d, 1H), 7.79 (d, 1H), 7.60 (d, 1H), 7.38 (d, 1H), 7.18 (s, 1H), 7.17 (d, 1H), 7.13 (dd, 1H), 6.94 (dd, 1H), 4.97 (dd, 1H), 4.56 - 4.49 (m, 1H), 4.09 - 4.01 (m, 2H), 3.94 (s, 3H), 3.90 - 3.79 (m, 3H), 3.76 (bs, 2H), 2.92 - 2.84 (m, 1H), 2.80 (bs, 2H), 2.66 - 2.57 (m, 4H), 2.57 - 2.49 (m, 2H), 2.14 - 2.06 (m, 2H), 2.05 - 1.99 (m, 1H), 1.94 - 1.79 (m, 6H), 1.66 - 1.56 (m, 2H), 1.55 - 1.45 (m, 2H).

[0213] Compound 88: MS: m / z 834.4 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.55 (d, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.61 (d, 1H), 7.38 (d, 1H), 7.32 (d, 1H), 7.14 (dd, 1H), 7.01 (dd, 1H), 6.85 (d, 1H), 4.98 (dd, 1H), 4.57 - 4.50 (m, 1H), 4.21 (t, 2H), 3.96 (s, 3H), 3.85 (bs, 5H), 2.94 - 2.84 (m, 1H), 2.75 (t, 2H), 2.64 - 2.56 (m, 2H), 2.56 - 2.49 (m, 4H), 2.14 - 2.07 (m, 2H), 2.07 - 2.00 (m, 1H), 1.94 - 1.86 (m, 2H), 1.81 (bs, 4H), 1.69 - 1.58 (m, 2H), 1.56 - 1.46 (m 2H).

[0214] Compound 89: MS: m / z 836.4 (M+ +1); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.61 (d, 1H), 7.86 (d, 1H), 7.83 (d, 1H), 7.62 (d, 1H), 7.39 (dd, 1H), 7.36 - 7.32 (m, 2H), 7.13 (dd, 1H), 7.00 (dd, 1H), 4.97 (dd, 1H), 4.57 - 4.50 (m, 1H), 4.43 (q, 2H), 4.13 (t, 2H), 3.90 - 3.81 (m, 1H), 3.69 (m, 4H), 2.93 - 2.83 (m, 1H), 2.62 - 2.55 (m, 1H), 2.55 - 2.49 (m, 5H), 2.42 (t, 2H), 2.13 - 2.07 (m, 2H), 2.07 - 2.00 (m, 1H), 1.93 - 1.86 (m, 2H), 1.86 - 1.78 (m, 2H), 1.70 - 1.59 (m, 4H), 1.55 - 1.47 (m, 2H), 1.41 (t, 3H).

[0215] Compound 90: MS: m / z 850.4 (M + +1); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.55 (d, 1H), 7.85 (d, 1H), 7.79 (d, 1H), 7.60 (d, 1H), 7.38 (d, 1H), 7.30 (d, 1H), 7.16 (d, 1H), 7.13 (dd, 1H), 6.98 (dd, 1H), 4.98 (dd, 1H), 4.57 - 4.49 (m, 1H), 4.43 (q, 2H), 4.06 (t, 2H), 3.90 - 3.79 (m, 3H), 3.76 (bs, 2H), 2.93 - 2.84 (m, 1H), 2.79 - 2.73 (m, 2H), 2.63 - 2.58 (m, 1H), 2.58 - 2.54 (m, 2H), 2.54 - 2.49 (m, 3H), 2.13 - 2.07 (m, 2H), 2.07 - 2.00 (m, 1H), 1.92 - 1.81 (m, 4H), 1.76 - 1.69 (m, 2H), 1.67 - 1.54 (m, 4H), 1.54 - 1.46 (m, 2H), 1.41 (t, 3H).

[0216] Compound 91: MS: m / z 849.4 (M + +1); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.50 (d, 1H), 7.84 (d, 1H), 7.62 (d, 1H), 7.60 (d, 1H), 7.36 - 7.33 (m, 2H), 7.02 (d, 1H), 6.94(d, 1H), 6.82 (dd, 1H), 4.97 (dd, 1H), 4.43 (q, 2H), 4.13 (t, 2H), 3.86 - 3.84 (m, 1H), 3.80 - 3.76 (m, 1H), 3.70 (bs, 4H), 2.91 - 2.85 (m, 1H), 2.85 (s, 3H), 2.62 - 2.56 (m, 2H), 2.54 - 2.49 (m, 4H), 2.42 (t, 2H), 2.06 - 2.03 (m, 1H), 1.92 - 1.91 (m, 2H), 1.85 - 1.80 (m, 2H), 1.78 - 1.72 (m, 2H), 1.68 - 1.62 (m, 6H), 1.41 (t, 3H).

[0217] Compound 92: MS: m / z 848.3 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.54 (d, 1H), 7.85 (d, 1H), 7.82 (d, 1H), 7.62 (d, 1H), 7.38 (d, 1H), 7.26 (d, 1H), 7.13 (dd, 1H), 7.00 (dd, 1H), 6.85 (d, 1H), 4.98 (dd, 1H), 4.57 - 4.49 (m, 1H), 4.13 (t, 2H), 3.96 (s, 3H), 3.84 (bs, 5H), 2.93 - 2.84 (m, 1H), 2.63 - 2.54 (m, 2H), 2.54 - 2.43 (m, 6H), 2.14 - 2.07 (m, 2H), 2.07 - 2.00 (m, 1H), 1.99 - 1.92 (m, 2H), 1.92 - 1.85 (m 2H), 1.80 (bs, 4H), 1.68 - 1.58 (m, 2H), 1.56 - 1.46 (m 2H).

[0218] Compound 93: MS: m / z 898.8 (M + +1); 1 H NMR (DMSO-d6) δ 11.07 (s, 1H), 8.55 (d, 1H), 7.86 (d, 1H), 7.83 (d, 1H), 7.65 (d, 1H), 7.43 (s, 1H), 7.39 (d, 1H), 7.13 (dd, 1H), 7.03 (dd, 1H), 6.85 (d, 1H), 6.52 (t, 1H), 4.99 (dd, 1H), 4.91 (t, 2H), 4.58-4.49 (m, 1H), 4.12 (bs, 2H), 3.84 (bs, 5H), 2.94-2.84 (m, 1H), 2.63-2.54 (m, 2H), 2.54-2.31 (m, 6H), 2.14-2.08 (m, 2H), 2.08-2.01 (m, 1H), 2.01-1.86 (m, 4H), 1.80 (bs, 4H), 1.69-1.58 (m, 2H), 1.56-1.46 (m 2H).

[0219] Compound 94: MS: m / z 992.4 (M + +1); 11H NMR (DMSO-d6) δ 8.58 (d, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.62 (d, 1H), 7.38 - 7.34 (m, 3H), 7.13 (dd, 1H), 7.01 (dd, 1H), 5.10 (dd, 1H), 5.08 (s, 2H), 4.56 - 4.51 (m, 1H), 4.44 (q, 2H), 4.14 (bs, 2H), 3.88 - 3.83 (m, 1H), 3.69 (bs, 4H), 3.58 - 3.54 (m, 1H), 3.50 - 3.46 (m, 1H), 3.32 - 3.31 (m, 4H), 3.05 - 2.99 (m, 1H), 2.80 - 2.77 (m, 1H), 2.58 - 2.49 (m, 3H), 2.11 - 2.08 (m, 3H), 1.91 - 1.79 (m, 8H), 1.66 - 1.60 (m 2H), 1.53 - 1.48 (m, 2H), 1.42 (t, 3H), 0.89 - 0.81 (m, 2H), -0.01 (s, 9H).

[0220] Compound 95: MS: m / z 892.4 (M + +1); 11H NMR (DMSO-d6) δ 9.88 (broad singlet, 1H), 8.58 (doublet, 1H), 7.86 (doublet, 1H), 7.84 (doublet, 1H), 7.67 (doublet, 1H), 7.41 (doublet, 1H), 7.39 (doublet, 1H), 7.35 (doublet, 1H), 7.13 (doublet of doublets, 1H), 7.03 (doublet of doublets, 1H), 5.08 - 5.03 (multiplet, 3H), 4.56 - 4.51 (multiplet, 1H), 4.44 (quartet, 2H), 4.18 (triplet, 2H), 4.10 - 4.07 (multiplet, 2H), 3.97 - 3.94 (multiplet, 2H), 3.88 - 3.83 (multiplet, 1H), 3.46 - 3.41 (multiplet, 4H), 3.05 - 2.99 (multiplet, 1H), 2.78 - 2.75 (multiplet, 1H), 2.61 - 2.49 (multiplet, 3H), 2.11 - 2.06 (multiplet, 3H), 2.04 - 2.00 (multiplet, 2H), 1.91 - 1.87 (multiplet, 6H), 1.66 - 1.60 (multiplet, 2H), 1.55 - 1.49 (multiplet, 2H), 1.43 (triplet, 3H).

[0221] Compound 96: MS: m / z 862.4 (M + +1)

[0222] Compound 97: MS: m / z 876.4 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.55 (d, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.62 (d, 1H), 7.39 (d, 1H), 7.32 (d, 1H), 7.13 (dd, 1H), 7.00 (dd, 1H), 6.85 (d, 1H), 4.97 (dd, 1H), 4.57 - 4.50 (m, 1H), 4.43 (q, 2H), 4.11 (t, 2H), 3.83 (bs, 5H), 2.93 - 2.84 (m, 1H), 2.74 (t, 2H), 2.64 - 2.54 (m, 2H), 2.33 (bs, 4H), 2.13 - 2.07 (m, 2H), 2.07 - 2.00 (m, 1H), 1.94 - 1.85 (m, 2H), 1.85 - 1.71 (m, 6H), 1.69 - 1.57 (m, 4H), 1.56 - 1.46 (m 2H), 1.42 (t, 3H).

[0223] Compound 98: MS: m / z 836.3 (M + +1); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.61(d, 1H), 7.85 (d, 1H), 7.83 (d, 1H), 7.62 (d, 1H), 7.39 (d, 1H), 7.34 (d, 1H), 7.30 (d, 1H), 7.13 (dd, 1H), 7.02 (dd, 1H), 4.97 (dd, 1H), 4.65 (bs, 1H), 4.57-4.49 (m, 1H), 4.43 (q, 2H), 4.25-4.15 (m, 3H), 3.90-3.81 (m, 1H), 3.20-3.12 (m, 1H), 3.02 (d, 1H), 2.93-2.84 (m, 2H), 2.63-2.53 (m, 2H), 2.53-2.49 (m, 2H), 2.25-2.19 (m, 1H), 2.14-2.08 (m, 2H), 2.07-2.02 (m, 2H), 2.02-1.95 (m, 2H), 1.93-1.86 (m, 2H), 1.69-1.59 (m, 2H), 1.56-1.46 (m, 2H), 1.41 (t, 3H), 1.20 (d, 3H).

[0224] Compound 99: MS: m / z 822.5 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.61(d, 1H), 7.85 (d, 1H), 7.83 (d, 1H), 7.63 (d, 1H), 7.39-7.38 (m, 2H), 7.31 (d, 1H), 7.13 (dd, 1H), 7.03 (dd, 1H), 4.97 (dd, 1H), 4.67 (bs, 1H), 4.55-4.51 (m, 1H), 4.44 (q, 2H), 4.28-4.22 (m, 3H), 3.90-3.81 (m, 1H), 3.20-3.10 (m, 2H), 2.97 (d, 1H), 2.93-2.84 (m, 1H), 2.81 (t, 2H), 2.63-2.55 (m, 1H), 2.53-2.49 (m, 1H), 2.42-2.38 (m, 1H), 2.25-2.19 (m, 1H), 2.14-2.08 (m, 2H), 2.07-2.02 (m, 1H), 1.93-1.86 (m, 2H), 1.69-1.59 (m, 2H), 1.56-1.46 (m, 2H), 1.43 (t, 3H), 1.21 (d, 3H).

[0225] Compound 100: MS: m / z 862.6 (M + +1); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.58 (d, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.61 (d, 1H), 7.39 (d, 1H), 7.32 (s, 1H), 7.18 (d, 1H), 7.13 (dd, 1H), 7.01 (dd, 1H), 4.97 (dd, 1H), 4.55 - 4.52 (m, 1H), 4.42 (q, 2H), 4.15 (t, 2H), 3.98 - 3.97 (m, 2H), 3.87 - 3.85 (m, 1H), 3.39 (bs, 2H), 3.10 (d, 2H), 2.91 - 2.85 (m, 1H), 2.59 - 2.57 (m, 2H), 2.45 (bs, 2H), 2.11 - 2.09 (m, 2H), 2.05 - 2.04 (m 1H), 1.91 - 1.84 (m, 6H), 1.66 - 1.60 (m, 4H), 1.53 - 1.48 (m, 4H), 1.40 (t, 3H).

[0226] Compound 101: MS: m / z 850.5 (M + +1); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.61(d, 1H), 7.86 (d, 1H), 7.83 (d, 1H), 7.62 (d, 1H), 7.39 (d, 1H), 7.33 (d, 1H), 7.29 (d, 1H), 7.13 (dd, 1H), 7.01 (dd, 1H), 4.97 (dd, 1H), 4.65 (bs, 1H), 4.55-4.50 (m, 1H), 4.43 (q, 2H), 4.21 (d, 1H), 4.14 (t, 2H), 3.88-3.81 (m, 1H), 3.18-3.10 (m, 1H), 3.00 (d, 1H), 2.93-2.84 (m, 2H), 2.63-2.55 (m, 1H), 2.53-2.49 (m, 1H), 2.46-2.40 (m, 1H), 2.40-2.33 (m, 1H), 2.20-2.14 (m, 1H), 2.13-2.08 (m, 2H), 2.07-2.00 (m, 2H), 1.93-1.86 (m, 2H), 1.86-1.82 (m, 2H), 1.69-1.59 (m, 4H), 1.56-1.46 (m, 2H), 1.41 (t, 3H), 1.19 (d, 3H).

[0227] Compound 102: MS: m / z 884.3 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.59 (d, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.64 (d, 1H), 7.43 (d, 1H), 7.39 (d, 1H), 7.20 (d, 1H), 7.14 (dd, 1H), 7.05 (d, 1H), 6.51 (t, 1H), 4.98 (dd, 1H), 4.94 - 4.88 (m, 2H), 4.19 (t, 2H), 4.00 - 3.98 (m, 2H), 3.88 - 3.84 (m, 1H), 3.42 (bs, 2H), 3.12 (d, 2H), 2.92 - 2.85 (m, 1H), 2.60 - 2.57 (m, 4H), 2.11 - 2.09 (m, 2H), 2.08 - 2.02 (m, 1H), 2.00 - 1.94 (m, 2H), 1.93 - 1.89 (m, 4H), 1.67 - 1.60 (m, 2H), 1.56 - 1.48 (m, 4H).

[0228] Compound 103: MS: m / z 884.5 (M + +1); 1 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 8.55 (d, 1H), 7.86 (d, 1H), 7.83 (d, 1H), 7.64 (d, 1H), 7.47 (d, 1H), 7.39 (d, 1H), 7.13 (dd, 1H), 7.04 (dd, 1H), 6.85 (d, 1H), 6.52 (t, 1H), 4.99 (dd, 1H), 4.91 (t, 2H), 4.57 - 4.50 (m, 1H), 4.19 (t, 2H), 3.84 (bs, 5H), 2.94 - 2.84 (m, 1H), 2.75 (t, 2H), 2.63 - 2.54 (m, 2H), 2.54 - 2.49 (m, 4H), 2.13 - 2.07 (m, 2H), 2.07 - 2.01 (m, 1H), 1.94 - 1.85 (m, 2H), 1.81 (bs, 4H), 1.69 - 1.58 (m, 2H), 1.56 - 1.46 (m 2H).

[0229] Compound 104: MS: m / z 857.3 (M + +1); 1 H NMR (DMSO-d6) δ 11.07 (s, 1H), 8.51 (d, 1H), 7.84 (d, 1H), 7.65 (d, 1H), 7.61 (d, 1H), 7.49 (dd, 1H), 7.37 (d, 1H), 7.06 (dd, 1H), 6.94 (d, 1H), 6.83 (dd, 1H), 6.53 (t, 1H), 4.99 (dd, 1H), 4.92 (t, 2H), 4.24 (t, 2H), 3.87-3.82 (m, 1H), 3.80-3.76 (m, 1H), 3.73 (bs, 4H), 2.92-2.87 (m, 1H), 2.85-2.83 (m, 2H), 2.85 (s, 3H), 2.66 (bs, 4H), 2.60-2.57 (m, 2H), 2.07-2.03 (m, 1H), 1.92-1.91 (m, 2H), 1.78-1.72 (m, 2H), 1.68-1.63 (m, 4H).

[0230] Compound 105: MS: m / z 844.3 (M + +1); 11H NMR (DMSO-d6) δ 11.07 (s, 1H), 8.61 (d, 1H), 7.86 (d, 1H), 7.84 (d, 1H), 7.65 (d, 1H), 7.49 (s, 1H), 7.39 (d, 1H), 7.37 (d. 1H), 7.14 (dd, 1H), 7.05 (dd, 1H), 6.53 (t, 1H), 4.99 (dd, 1H), 4.92 (t, 2H), 4.56 - 4.52 (m, 1H), 4.25 (t, 2H), 3.91 - 3.81 (m, 1H), 3.73 (bs, 4H), 2.92 - 2.87 (m, 1H), 2.84 (t, 2H), 2.67 - 2.66 (m, 4H), 2.63 - 2.56 (m, 1H), 2.56 - 2.49 (m, 1H), 2.14 - 2.07 (m, 2H), 2.07 - 2.02 (m, 1H), 1.93 - 1.87 (m, 2H), 1.67 - 1.61 (m, 2H), 1.54 - 1.49 (m, 2H).

[0231] Compound 106: MS: m / z 861.4 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.44 (d, 1H), 7.83 (d, 1H), 7.64 - 7.58 (m, 2H), 7.38 (s, 1H), 7.00 (d, 1H), 6.95 (d, 1H), 6.85 (d,1H), 6.82 (dd, 1H), 4.98 (dd, 1H), 4.44 (q, 2H), 4.21 (bs, 2H), 3.85 (bs, 5H), 3.81 - 3.74 (m, 1H), 2.93 - 2.84 (m, 1H), 2.85 (s, 3H), 2.75 (bs, 2H), 2.63 - 2.54 (m, 2H), 2.54 - 2.49 (m, 4H), 2.08 - 2.01 (m, 1H), 1.96 - 1.87 (m, 2H), 1.81 (bs, 4H), 1.78 - 1.70 (m, 2H), 1.70 - 1.61 (m 4H), 1.43 (t, 3H).

[0232] Compound 107: MS: m / z 875.5 (M + +1); 1 H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.44 (d, 1H), 7.83 (d, 1H), 7.64-7.58 (m, 2H), 7.33 (s, 1H), 7.00 (dd, 1H), 6.94 (d, 1H), 6.85 (d, 1H), 6.83 (dd, 1H), 4.98 (dd, 1H), 4.44 (q, 2H), 4.13 (bs, 2H), 3.84 (bs, 5H), 3.81-3.74 (m, 1H), 2.93-2.82 (m, 1H), 2.85 (s, 3H), 2.63-2.54 (m, 2H), 2.54-2.42 (m, 4H), 2.42-2.31 (m, 2H), 2.08-2.01 (m, 1H), 1.98-1.88 (m, 4H), 1.80 (bs, 4H), 1.78-1.70 (m, 2H), 1.70-1.60 (m 4H), 1.42 (t, 3H).

[0233] Compound 108: MS: m / z 897.4 (M + +1); 11H NMR (DMSO-d6) δ 11.07 (s, 1H), 8.45 (d, 1H), 7.83 (d, 1H), 7.64 (d, 1H), 7.61 (d, 1H), 7.48 (s, 1H), 7.04 (d, 1H), 6.94 (d, 1H), 6.86 (d,1H), 6.82 (dd, 1H), 6.52 (t, 1H), 4.99 (dd, 1H), 4.92 (t, 2H), 4.19 (bs, 2H), 3.85 (bs, 5H), 3.82 - 3.75 (m, 1H), 2.94 - 2.83 (m, 1H), 2.85 (s, 3H), 2.75 (bs, 2H), 2.63 - 2.54 (m, 2H), 2.54 - 2.49 (m, 4H), 2.09 - 2.01 (m, 1H), 1.95 - 1.87 (m, 2H), 1.81 (bs, 4H), 1.78 - 1.71 (m, 2H), 1.70 - 1.61 (m 4H).

[0234] Compound 109: MS: m / z 849.5 (M + +1); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.43 (d, 1H), 7.80 (d, 1H), 7.63 - 7.57 (m, 2H), 7.26 (s, 1H), 7.17 (d, 1H), 6.97 - 6.91 (m, 2H), 6.82 (dd, 1H), 4.97 (dd, 1H), 4.41 (q, 2H), 4.13 - 4.00 (m, 2H), 3.95 - 3.67 (m, 6H), 2.92 - 2.84 (m, 1H), 2.84 (s, 3H), 2.80 (bs, 2H), 2.66 - 2.58 (m, 4H), 2.58 - 2.49 (m, 2H), 2.07 - 2.00 (m, 1H), 1.94 - 1.82 (m, 6H), 1.78 - 1.69 (m, 2H), 1.69 - 1.58 (m, 4H), 1.40 (t, 3H).

[0235] Compound 110: MS: m / z 837.4 (M + +1); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.45 (d, 1H), 7.80 (d, 1H), 7.62 - 7.58 (m, 2H), 7.33 (d, 1H), 7.18 (d, 1H), 6.96 (dd, 1H), 6.94 (d, 1H), 6.83 (dd, 1H), 4.97 (dd, 1H), 4.42 (q, 2H), 4.16 (t, 2H), 3.95 - 3.69 (m, 6H), 2.97 - 2.91 (m, 4H), 2.91 - 2.84 (m, 1H), 2.85 (s, 3H), 2.69 - 2.70 (m, 2H), 2.63 - 2.54 (m, 1H), 2.58 - 2.49 (m, 1H), 2.07 - 2.00 (m, 1H), 1.94 - 1.85 (m, 4H), 1.80 - 1.70 (m, 2H), 1.70 - 1.60 (m, 4H), 1.40 (t, 3H).

[0236] Compound 111: MS: m / z 889.2 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.44 (d, 1H), 7.84 (d, 1H), 7.64 - 7.58 (m, 2H), 7.33 (d, 1H), 7.00 (dd, 1H), 6.94 (d, 1H), 6.85 (d, 1H), 6.83 (dd, 1H), 4.97 (dd, 1H), 4.43 (q, 2H), 4.12 (bs, 2H), 3.84 (bs, 5H), 3.81 - 3.74 (m, 1H), 2.93 - 2.82 (m, 1H), 2.85 (s, 3H), 2.63 - 2.53 (m, 2H), 2.53 - 2.49 (m, 4H), 2.34 (bs, 4H), 2.08 - 2.00 (m, 1H), 1.96 - 1.87 (m, 2H), 1.80 (bs, 4H), 1.80 - 1.70 (m, 4H), 1.70 - 1.59 (m, 6H), 1.42 (t, 3H).

[0237] Compound 112: MS: m / z 863.5 (M ++1); 1 1H NMR (DMSO-d6) δ 11.05 (singlet, 1H), 8.45 (broad singlet, 1H), 7.80 (broad singlet, 1H), 7.60 (doublet, 2H), 7.30 (broad singlet, 1H), 7.16 (broad singlet, 1H), 6.98 (doublet, 1H), 6.94 (broad singlet, 1H), 6.82 (doublet, 1H), 4.97 (doublet of doublets, 1H), 4.42 (quartet, 2H), 4.07 (broad singlet, 2H), 3.91 - 3.68 (multiplet, 6H), 2.93 - 2.82 (multiplet, 1H), 2.85 (singlet, 3H), 2.76 (broad singlet, 2H), 2.63 - 2.53 (multiplet, 3H), 2.58 - 2.49 (multiplet, 3H), 2.07 - 2.00 (multiplet, 1H), 1.94 - 1.80 (multiplet, 4H), 1.80 - 1.70 (multiplet, 4H), 1.70 - 1.60 (multiplet, 4H), 1.60 - 1.52 (multiplet, 2H), 1.41 (triplet, 3H).

[0238] Compound 113: MS: m / z 852.5 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (singlet, 1H), 8.60 (doublet, 1H), 7.85 (doublet, 1H), 7.82 (doublet, 1H), 7.62 (doublet, 1H), 7.39 - 7.36 (multiplet, 2H), 7.33 (doublet, 1H), 7.13 (doublet of doublets, 1H), 7.01 (doublet of doublets, 1H), 4.97 (doublet of doublets, 1H), 4.55 - 4.51 (multiplet, 1H), 4.42 (quartet, 2H), 4.24 (triplet, 2H), 3.88 - 3.82 (multiplet, 1H), 3.80 (triplet, 2H), 3.69 - 3.65 (multiplet, 6H), 2.91 - 2.85 (multiplet, 1H), 2.62 - 2.53 (multiplet, 7H), 2.53 - 2.49 (multiplet, 1H), 2.11 - 2.09 (multiplet, 2H), 2.06 - 2.02 (multiplet, 1H), 1.91 - 1.89 (multiplet, 2H), 1.67 - 1.61 (multiplet, 2H), 1.54 - 1.48 (multiplet, 2H), 1.41 (triplet, 3H).

[0239] Compound 114: MS: m / z 865.4 (M + +1); 1 H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.50 (d, 1H), 7.83 (d, 1H), 7.62 (d, 1H), 7.60 (d, 1H), 7.38 (d, 1H), 7.33 (d, 1H), 7.01 (d, 1H), 6.94 (d, 1H), 6.83 (dd, 1H), 4.98 (dd, 1H), 4.43 (q, 2H), 4.24 (t, 2H), 3.85-3.76 (m, 2H), 3.80 (t, 2H), 3.67-3.66 (m, 6H), 2.91-2.85 (m, 1H), 2.85 (s, 3H), 2.59-2.50 (m, 7H), 2.50-2.49 (m, 1H), 2.06-2.03 (m, 1H), 1.92-1.91 (m, 2H), 1.78-1.72 (m, 2H), 1.68-1.62 (m, 4H), 1.42 (t, 3H).

[0240] Compound 115: MS: m / z 850.5 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.61 (d, 1H), 7.86 (d, 1H), 7.83 (d, 1H), 7.61 (d, 1H), 7.39 (d, 1H), 7.36 - 7.33 (m, 2H), 7.14 (dd, 1H), 6.99 (dd, 1H), 4.97 (dd, 1H), 4.56 - 4.50 (m, 1H), 4.43 (q, 2H), 4.10 (t, 2H), 3.90 - 3.81 (m, 1H), 3.69 (m, 4H), 2.92 - 2.85 (m, 1H), 2.62 - 2.55 (m, 1H), 2.55 - 2.49 (m, 5H), 2.36 (m, 2H), 2.11 - 2.07 (m, 2H), 2.07 - 2.02 (m, 1H), 1.91 - 1.89 (m, 2H), 1.83 - 1.78 (m, 2H), 1.67 - 1.61 (m, 2H), 1.60 - 1.53 (m, 2H), 1.53 - 1.47 (m, 4H), 1.41 (t, 3H).

[0241] Compound 116: MS: m / z 863.4 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.51 (d, 1H), 7.83 (d, 1H), 7.62 - 7.60 (m, 2H), 7.35 - 7.33 (m, 2H), 7.00 (dd, 1H), 6.94 (d, 1H), 6.82 (dd, 1H), 4.97 (dd, 1H), 4.43 (q, 2H), 4.10 (t, 2H), 3.87 - 3.82 (m, 1H), 3.80 - 3.76 (m, 1H), 3.69 (bs, 4H), 2.92 - 2.88 (m, 1H), 2.85 (s, 3H), 2.60 - 2.54 (m, 1H), 2.54 - 2.49 (m, 5H), 2.36 (t, 2H), 2.06 - 2.03 (m, 1H), 1.93 - 1.91 (m, 2H), 1.83 - 1.78 (m, 2H), 1.76 - 1.72 (m, 2H), 1.68 - 1.62 (m, 4H), 1.58 - 1.54 (m, 2H), 1.52 - 1.48 (m, 2H), 1.41 (t, 3H).

[0242] Compound 117: MS: m / z 855.6 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.38 (d, 1H), 8.29 (d, 1H), 8.01 (dd, 1H), 7.62 (d, 1H), 7.35 (d, 1H), 7.18 (d, 2H), 7.06 (d, 2H), 7.02 (dd, 1H), 4.98 (dd, 1H), 4.44 (q, 2H), 4.16 (t, 2H), 3.25 (bs, 4H), 2.92 - 2.86 (m, 1H), 2.60 - 2.49 (m, 8H), 2.07 - 2.02 (m, 1H), 2.00 - 1.99 (m, 2H), 1.48 (s, 6H), 1.42 (t, 3H).

[0243] Compound 118: MS: m / z 841.1 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.38 (d, 1H), 8.29 (d, 1H), 8.07 (dd, 1H), 7.62 (d, 1H), 7.40 (d, 1H), 7.18 (d, 2H), 7.07 (d, 2H), 7.02 (dd, 1H), 4.98 (dd, 1H), 4.44 (q, 2H), 4.27 (t, 2H), 3.26 (bs, 4H), 2.92-2.84 (m, 3H), 2.69 (bs, 4H), 2.62-2.57 (m, 1H), 2.50-2.49 (m, 1H), 2.07-2.02 (m, 1H), 1.48 (s, 6H), 1.42 (t, 3H).

[0244] Compound 119: MS: m / z 869.2 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.38 (d, 1H), 8.29 (d, 1H), 8.07 (dd, 1H), 7.62 (d, 1H), 7.33 (d, 1H), 7.18 (d, 2H), 7.05 (d, 2H), 7.01 (dd, 1H), 4.98 (dd, 1H), 4.43 (q, 2H), 4.14 (t, 2H), 3.22 (bs, 4H), 2.91-2.85 (m, 1H), 2.60-2.57 (m, 1H), 2.53-2.52 (m, 5H), 2.43 (t, 2H), 2.08-2.03 (m, 1H), 1.85-1.80 (m, 2H), 1.68-1.66 (m, 2H), 1.48 (s, 6H), 1.41 (t, 3H).

[0245] Compound 120: MS: m / z 852.4 (M + +1); 11H NMR (DMSO-d6) δ 8.65 (d, 1H), 7.88 (d, 1H), 7.86 (d, 1H), 7.65 (d, 1H), 7.41 (d, 1H), 7.39 (d, 1H), 7.37 (d, 1H), 7.14 (d, 1H), 7.07 (d, 1H), 5.09 - 5.02 (m, 5H), 4.57 - 4.51 (m, 1H), 4.42 (q, 2H), 3.86 (bs, 4H), 3.75 (bs, 4H), 3.05 - 2.99 (m, 1H), 2.77 - 2.75 (m, 1H), 2.61 - 2.55 (m, 1H), 2.55 - 2.49 (m, 1H), 2.12 - 2.07 (m, 3H), 1.91 - 1.89 (m, 2H), 1.69 - 1.62 (m, 2H), 1.54 - 1.49 (m, 2H), 1.43 (t, 3H).

[0246] Compound 121: MS: m / z 822.3 (M + +1).

[0247] Compound 122: MS: m / z 914.1 (M + +23); 1 1H NMR (DMSO-d6) δ 8.56 (d, 1H), 7.88 (d, 1H), 7.86 (d, 1H), 7.64 (d, 1H), 7.39 (d, 1H), 7.34 (d, 1H), 7.14 (dd, 1H), 7.04 (dd, 1H), 6.93 (d, 1H), 5.10 - 5.02 (m, 3H), 4.95 (s, 2H), 4.57 - 4.50 (m, 1H), 4.42 (q, 2H), 3.98 - 3.91 (m, 5H), 3.50 (bs, 4H), 3.06 - 2.98 (m, 1H), 2.80 - 2.74 (m, 1H), 2.63 - 2.54 (m, 1H), 2.14 - 2.04 (m, 3H), 1.89 (bs, 4H), 1.77 (bs, 2H), 1.68 - 1.59 (m, 2H), 1.56 - 1.46 (m 2H), 1.43 (t, 3H).

[0248] Compound 123: MS: m / z 862.4 (M + +1).

[0249] Compound 124: MS: m / z 865.3 (M + +1).

[0250] Compound 125: MS: m / z 835.3 (M + +1).

[0251] Compound 126: MS: m / z 892.3 (M + +1); 1 H NMR (DMSO-d6) δ 8.60 (d, 1H), 7.85 (d, 1H), 7.82 (d, 1H), 7.64 (d, 1H), 7.41 - 7.38 (m, 2H), 7.35 (d, 1H), 7.14 (dd, 1H), 7.06 (dd, 1H), 5.10 - 5.03 (m, 3H), 4.76 (s, 2H), 4.55 - 4.52 (m, 1H), 4.43 (q, 2H), 4.09 (s, 2H), 3.89 - 3.82 (m, 1H), 3.73 (bs, 6H), 3.06 - 2.99 (m, 1H), 2.78 - 2.75 (m, 1H), 2.63 - 2.55 (m, 1H), 2.11 - 2.06 (m, 3H), 1.91 - 1.88 (m, 2H), 1.79 (bs, 4H), 1.67 - 1.61 (m, 2H), 1.54 - 1.48 (m 2H), 1.43 (t, 3H).

[0252] Compound 127: MS: m / z 862.3 (M + +1).

[0253] Compound 128: MS: m / z 905.4 (M + +1); 11H NMR (DMSO-d6) δ 8.45 (d, 1H), 7.88 (d, 1H), 7.64 (d, 1H), 7.61 (d, 1H), 7.34 (d, 1H), 7.04 (dd, 1H), 6.94 (d, 1H), 6.92 (d, 1H), 6.82 (dd, 1H), 5.10 - 5.02 (m, 3H), 4.95 (s, 2H), 4.42 (q, 2H), 3.98 - 3.90 (m, 4H), 3.88 - 3.82 (m, 1H), 3.82 - 3.74 (m, 1H), 3.06 - 2.98 (m, 1H), 2.85 (s, 3H), 2.80 - 2.72 (m, 1H), 2.63 - 2.53 (m, 1H), 2.10 - 2.04 (m, 3H), 1.95 - 1.84 (m, 4H), 1.80 - 1.71 (m, 4H), 1.70 - 1.60 (m, 4H), 1.43 (t, 3H).

[0254] Compound 129: MS: m / z 875.3 (M + +1).

[0255] Compound 130: MS: m / z 879.5 (M + +1).

[0256] Compound 131: MS: m / z 849.3 (M + +1).

[0257] Compound 132: MS: m / z 862.3 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.53 (d, 1H), 7.86 - 7.82 (m, 2H), 7.62 (d, 1H), 7.39 (d, 1H), 7.34 (s, 1H), 7.13 (dd, 1H), 7.00 (d, 1H), 6.94 (d, 1H), 4.98 (dd, 1H), 4.55 - 4.52 (m, 1H), 4.43 (q, 2H), 4.16 (bs, 2H), 3.88 - 3.84 (m, 1H), 3.58 (bs, 4H), 2.92 - 2.85 (m, 1H), 2.60 - 2.57 (m, 2H), 2.50 - 2.49 (m, 6H), 2.11 - 2.02 (m, 7H), 1.91 - 1.81 (m, 4H), 1.66 - 1.60 (m, 2H), 1.54 - 1.48 (m, 2H), 1.41 (t, 3H).

[0258] Compound 133: MS: m / z 848.3 (M + +1); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.53 (d, 1H), 7.85 (d, 1H), 7.81 (d, 1H), 7.60 (d, 1H), 7.39 (d, 1H), 7.36 (d, 1H), 7.13 (dd, 1H), 7.00 (dd, 1H), 6.94 (d, 1H), 4.97 (dd, 1H), 4.55 - 4.52 (m, 1H), 4.42 (q, 2H), 4.20 (t, 2H), 3.88 - 3.82 (m, 1H), 3.57 - 3.42 (m, 4H), 2.92 - 2.86 (m, 3H), 2.79 - 2.69 (m, 1H), 2.70 - 2.68 (m, 2H), 2.60 - 2.57 (m, 2H), 2.11 - 2.09 (m, 2H), 2.07 - 2.01 (m, 2H), 2.00 - 1.97 (m,1H), 1.90 - 1.89 (m, 2H), 1.83 - 1.81 (m, 2H),1.67 - 1.60 (m, 2H), 1.54 - 1.48 (m, 2H), 1.42 (t, 3H).

[0259] Compound 134: MS: m / z 876.4 (M + +1); 1 H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.53 (d, 1H), 7.86 - 7.82 (m, 2H), 7.61 (d, 1H), 7.38 (d, 1H), 7.33 (s, 1H), 7.13 (dd, 1H), 6.99 (d, 1H), 6.93 (d, 1H), 4.97 (dd, 1H), 4.55 - 4.52 (m, 1H), 4.43 (q, 2H), 4.12 (bs, 2H), 3.88 - 3.83 (m, 1H), 3.58 (bs, 4H), 2.92 - 2.85 (m, 1H), 2.60 - 2.57 (m, 2H), 2.50 - 2.49 (m, 6H), 2.11 - 2.02 (m, 7H), 1.91 - 1.81 (m, 6H), 1.66 - 1.60 (m, 2H), 1.54 - 1.48 (m, 2H), 1.41 (t, 3H).

[0260] Compound 135: MS: m / z 892.3 (M + +1); 1 H NMR (DMSO-d6) δ 8.54 - 8.51 (m, 1H), 7.88 - 7.85 (m, 2H), 7.65 - 7.62 (m, 1H), 7.39 - 7.38 (m, 1H), 7.33 - 7.31 (m, 1H), 7.14 - 7.12 (m, 1H), 7.07 - 7.00 (m, 2H), 5.09 - 5.03 (m, 3H), 4.90 (s, 1H), 4.84 (s, 1H), 4.55 - 4.52 (m, 1H), 4.44 - 4.39 (m, 2H), 3.88 - 3.82 (m, 5H), 3.53 - 3.38 (m, 4H), 3.00 - 2.99 (m, 1H), 2.78 - 2.74 (m, 1H), 2.60 - 2.57 (m, 1H), 2.11 - 2.04 (m, 6H), 1.97 - 1.90 (m, 3H),1.67 - 1.61 (m, 2H), 1.54 - 1.49 (m, 2H), 1.44 - 1.40 (m, 3H).

[0261] Compound 136: MS: m / z 862.3 (M + +1).

[0262] Compound 137: MS: m / z 850.5 (M + +1); 1 H NMR (CDCl3) δ 7.98 (s, 1H), 7.96 (d, 1H), 7.84 (d, 1H), 7.73 (d, 1H), 7.43 (d, 1H), 7.01 (dd, 1H), 6.96 (d, 1H), 6.87 (d, 1H), 6.73 (d, 1H), 6.61 (dd, 1H), 4.85 (dd, 1H), 4.53-4.51 (m, 2H), 4.37 (q, 2H), 4.21 (t, 2H), 4.00-3.92 (m, 1H), 3.85 (t, 2H), 3.69-3.64 (m, 1H), 3.45 (d, 2H), 3.07-3.02 (m, 2H), 2.91-2.88 (m, 1H), 2.85 (s, 3H), 2.82-2.70 (m, 2H), 2.22-2.21 (m, 2H), 2.18-2.15 (m, 1H), 2.04-1.98 (m, 1H), 1.93-1.91 (m, 2H), 1.86-1.84 (m, 2H), 1.78-1.71 (m, 2H), 1.52 (t, 3H), 1.48-1.43 (m, 2H), 1.38-1.31 (m, 2H).

[0263] Compound 138: MS: m / z 837.5 (M + +1); 11H NMR (CDCl3) δ 7.97 - 7.95 (m, 2H), 7.86 (d, 1H), 7.73 (d, 1H), 7.56 (d, 1H), 7.02 - 7.00 (m, 2H), 6.97 (d, 1H), 6.87 - 6.84 (m, 2H), 4.85 (dd, 1H), 4.53 - 4.51 (m, 2H), 4.37 (q, 2H), 4.35 - 4.29 (m, 1H), 4.21 (t, 2H), 4.08 - 4.02 (m, 1H), 3.85 (t, 2H), 3.45 (d, 2H), 3.07 - 3.02 (m, 2H), 2.91 - 2.88 (m, 1H), 2.84 - 2.70 (m, 2H), 2.22 - 2.13 (m, 5H), 2.04 - 1.97 (m, 1H), 1.93 - 1.91 (m, 2H), 1.71 - 1.65 (m, 2H), 1.52 (t, 3H), 1.50 - 1.42 (m, 2H), 1.38 - 1.31 (m, 2H).

[0264] Compound 139: MS: m / z 857.8 (M + +1).

[0265] Compound 140: MS: m / z 820.1 (M + +1); 11H NMR (CDCl3) δ 7.98 - 7.96 (m, 2H), 7.85 (d, 1H), 7.74 (d, 1H), 7.43 (d, 1H), 7.00 - 6.97 (m, 2H), 6.83 (d, 1H), 6.73 (d, 1H), 6.61 (dd, 1H), 4.85 (dd, 1H), 4.55 - 4.52 (m, 2H), 4.38 (q, 2H), 4.12 (t, 2H), 4.00 - 3.93 (m, 1H), 3.69 - 3.64 (m, 1H), 3.10 - 3.05 (m, 2H), 2.91 - 2.88 (m, 1H), 2.85 (s, 3H), 2.82 - 2.70 (m, 2H), 2.24 - 2.22 (m, 2H), 2.19 - 2.15 (m, 1H), 2.00 - 1.95 (m, 3H), 1.86 - 1.83 (m, 4H), 1.78 - 1.72 (m, 2H), 1.53 (t, 3H), 1.48 - 1.42 (m, 2H), 1.40 - 1.34 (m, 2H).

[0266] Compound 141: MS: m / z 893.3 (M + + 1); 1 1H NMR (DMSO - d6) δ 8.48 (d, 1H), 8.23 (t, 1H), 7.82 (d, 1H), 7.67 (d, 1H), 7.61 (d, 1H), 7.37 - 7.36 (m, 2H), 7.10 (dd, 1H), 6.94 (d, 1H), 6.83 (dd, 1H), 5.09 - 5.03 (m, 3H), 4.64 (s, 2H), 4.45 - 4.40 (m, 4H), 3.85 - 3.75 (m, 2H), 3.10 - 3.08 (m, 2H), 3.06 - 2.95 (m, 3H), 2.85 (s, 3H), 2.78 - 2.73 (m, 1H), 2.61 - 2.53 (m, 1H), 2.08 - 2.06 (m, 1H), 1.92 - 1.91 (m, 2H), 1.85 - 1.82 (m, 1H), 1.78 - 1.62 (m, 10H), 1.42 (t, 3H).

[0267] Compound 142: MS: m / z 863.4 (M + +1).

[0268] Compound 143: MS: m / z 879.4 (M + +1); 1 H NMR (DMSO-d6) δ 8.52 (d, 1H), 8.09 (d, 1H), 7.84 (d, 1H), 7.65 (d, 1H), 7.61 (d, 1H), 7.40 (d, 1H), 7.34 (d, 1H), 7.10 (dd, 1H), 6.95 (d, 1H), 6.83 (dd, 1H), 5.08-5.03 (m, 3H), 4.62 (s, 2H), 4.45-4.40 (m, 4H), 4.10-4.04 (m, 1H), 3.85-3.75 (m, 2H), 3.19-3.13 (m, 2H), 3.05-2.99 (m, 1H), 2.85 (s, 3H), 2.78-2.73 (m, 1H), 2.61-2.53 (m, 1H), 2.08-2.06 (m, 1H), 1.92-1.91 (m, 2H), 1.84-1.83 (m, 2H), 1.78-1.72 (m, 2H), 1.68-1.62 (m, 4H), 1.56-1.50 (m, 2H), 1.41 (t, 3H).

[0269] Compound 144: MS: m / z 849.3 (M + +1).

[0270] Compound 145: MS: m / z 891.4 (M + +1); 11H NMR (DMSO-d6) δ 8.45 (d, 1H), 7.88 (d, 1H), 7.88 (d, 1H), 7.66 (d, 1H), 7.61 (d, 1H), 7.36 (d, 1H), 7.06 (dd, 1H), 7.02 (d, 1H), 6.94 (d, 1H), 6.83 (dd, 1H), 5.08 - 5.02 (m, 3H), 4.76 (s, 2H), 4.43 (q, 2H), 4.37 (d, 1H), 4.32 (d, 1H), 4.00 - 4.94 (m, 2H), 3.86 - 3.75 (m, 6H), 3.05 - 2.99 (m, 1H), 2.85 (s, 3H), 2.77 - 2.75 (m, 1H), 2.61 - 2.55 (m, 1H), 2.29 - 2.25 (m, 2H), 2.08 - 2.06 (m, 1H), 1.93 - 1.91 (m, 2H), 1.78 - 1.72 (m, 2H), 1.68 - 1.62 (m, 4H), 1.43 (t, 3H).

[0271] Compound 146: MS: m / z 861.3 (M + +1).

[0272] Compound 147: MS: m / z 863.6 (M + +1); 11H NMR (CDCl3) δ 7.97 (s, 1H), 7.96 (d, 1H), 7.86 (d, 1H), 7.74 (d, 1H), 7.56 (d, 1H), 7.02 (dd, 1H), 7.00 (d, 1H), 6.97 (d, 1H), 6.88 (d, 1H), 6.85 (dd, 1H), 4.85 (dd, 1H), 4.38 (q, 2H), 4.35 - 4.29 (m, 1H), 4.21 (t, 2H), 4.18 - 4.14 (m, 1H), 4.08 - 4.02 (m, 1H), 3.77 (t, 2H), 3.75 - 3.73 (m, 2H), 3.67 - 3.65 (m, 2H), 2.91 - 2.88 (m, 1H), 2.84 - 2.70 (m, 2H), 2.33 - 2.29 (m, 2H), 2.20 - 2.15 (m, 5H), 1.89 - 1.86 (m, 2H), 1.72 - 1.67 (m, 6H), 1.52 (t, 3H), 1.49 - 1.42 (m, 2H).

[0273] Compound 148: MS: m / z 876.4 (M + + 1); 11H NMR (CDCl3) δ 7.97 (s, 1H), 7.96 (d, 1H), 7.84 (d, 1H), 7.74 (d, 1H), 7.43 (d, 1H), 7.02 (dd, 1H), 6.96 (d, 1H), 6.88 (d, 1H), 6.73 (d, 1H), 6.61 (dd, 1H), 4.85 (dd, 1H), 4.38 (q, 2H), 4.21 (t, 2H), 4.18 - 4.14 (m, 1H), 4.00 - 3.92 (m, 1H), 3.77 (t, 2H), 3.75 - 3.74 (m, 2H), 3.66 - 3.64 (m, 3H), 2.91 - 2.88 (m, 1H), 2.85 (s, 3H), 2.83 - 2.70 (m, 2H), 2.33 - 2.30 (m, 2H), 2.23 - 2.21 (m, 2H), 2.19 - 2.15 (m, 1H), 1.89 - 1.84 (m, 4H), 1.78 - 1.69 (m, 6H), 1.52 (t, 3H), 1.48 - 1.42 (m, 2H).

[0274] Compound 149: MS: m / z 872.4(M + +23); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.66 (d, 1H), 7.87 (d, 1H), 7.85 (d, 1H), 7.60 (d, 1H), 7.39 (d, 1H), 7.34 (d, 1H), 7.32 (d, 1H), 7.14 (dd, 1H), 6.99 (dd, 1H), 4.97 (dd, 1H), 4.55 - 4.51 (m, 1H), 4.42 (q, 2H), 4.27 (s, 2H), 4.11 (t, 2H), 3.94 (t, 2H), 3.89 - 3.83 (m, 1H), 3.54 - 3.52 (m, 2H), 3.49 - 3.45 (m, 2H), 2.91 - 2.86 (m, 1H), 2.62 - 2.53 (m, 2H), 2.11 - 2.09 (m, 2H), 2.07 - 2.03 (m, 1H), 1.90 - 1.88 (m, 2H), 1.78 - 1.72 (m, 4H), 1.68 - 1.62 (m, 2H), 1.53 - 1.48 (m, 2H), 1.40 (t, 3H).

[0275] Compound 150: MS: m / z 863.3 (M + +1).

[0276] Compound 151: MS: m / z 836.5 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.67 (d, 1H), 7.88 (d, 1H), 7.86 (d, 1H), 7.60 (d, 1H), 7.39 (d, 1H), 7.36 (d, 1H), 7.32 (d, 1H), 7.14 (dd, 1H), 6.97 (dd, 1H), 4.98 (dd, 1H), 4.56 - 4.51 (m, 1H), 4.41 (q, 2H), 4.27 (s, 2H), 4.14 (t, 2H), 3.96 (t, 2H), 3.89 - 3.84 (m, 1H), 3.59 - 3.55 (m, 4H), 2.91 - 2.86 (m, 1H), 2.62 - 2.51 (m, 2H), 2.11 - 2.09 (m, 2H), 2.06 - 2.02 (m, 3H), 1.90 - 1.88 (m, 2H), 1.68 - 1.62 (m, 2H), 1.54 - 1.48 (m, 2H), 1.40 (t, 3H).

[0277] Compound 152: MS: m / z 863.8 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.53 (d, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.62 (d, 1H), 7.39 (d, 1H), 7.37 (d, 1 H), 7.13 (dd, 1H), 7.01 (dd, 1H), 6.84 (d, 1H), 4.98 (dd, 1H), 4.58 - 4.50 (m, 1H), 4.43 (q, 2H), 4.21 (t, 2H), 3.88 - 3.84 (m, 1H), 3.82 - 3.80 (m, 6H), 3.44 - 3.42 (m, 1H), 2.92 - 2.85 (m, 1H), 2.61 - 2.56 (m, 1H), 2.55 - 2.49 (m, 1H), 2.10 - 2.07 (m, 2H), 2.06 - 2.03 (m, 1H), 1.92 - 1.86 (m, 4H), 1.81 (bs, 2H), 1.66 - 1.57 (m, 4H), 1.53 - 1.48 (m 2H), 1.42 (t, 3H), 1.43 - 1.36 (m, 2H).

[0278] Compound 153: MS: m / z 823.6 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.60 (d, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.62 (d, 1H), 7.39 - 7.36 (m, 3H), 7.13 (dd, 1H), 7.02 (dd, 1H), 4.97 (dd, 1H), 4.56 - 4.51 (m, 1H), 4.42 (q, 2H), 4.25 (t, 2H), 4.11 - 4.09 (m, 2H), 3.88 - 3.82 (m, 3H), 3.76 - 3.72 (m, 1H), 3.44 - 3.41 (m, 2H), 2.92 - 2.85 (m, 1H), 2.61 - 2.56 (m, 1H), 2.54 - 2.49 (m, 1H), 2.12 - 2.09 (m, 2H), 2.06 - 2.02 (m, 1H), 1.97 - 1.94 (m, 2H), 1.90 - 1.88 (m, 2H), 1.66 - 1.60 (m, 2H), 1.55 - 1.48 (m 4H), 1.41 (t, 3H).

[0279] Compound 154: MS: m / z 836.9 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.49 (d, 1H), 7.82 (d, 1H), 7.62 (d, 1H), 7.60 (d, 1H), 7.39 - 7.36 (m, 2H), 7.02 (dd, 1H), 6.94 (d, 1H), 6.82 (dd, 1H), 4.97 (dd, 1H), 4.42 (q, 2H), 4.25 (t, 2H), 4.12 - 4.08 (m, 2H), 3.88 - 3.82 (m, 3H), 3.82 - 3.72 (m, 2H), 3.44 - 3.41 (m, 2H), 2.92 - 2.85 (m, 1H), 2.84 s, 3H), 2.61 - 2.56 (m, 1H), 2.54 - 2.49 (m, 1H), 2.07 - 2.02 (m, 1H), 1.98 - 1.95 (m, 2H), 1.92 - 1.90 (m, 2H), 1.78 - 1.72 (m, 2H), 1.67 - 1.62 (m, 4H), 1.55 - 1.49 (m 2H), 1.41 (t, 3H).

[0280] Compound 155: MS: m / z 850.7 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.48 (d, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.61 (d, 1H), 7.35 - 7.33 (m, 2H), 7.00 (dd, 1H), 6.94 (d, 1H), 6.82 (dd, 1H), 4.97 (dd, 1H), 4.42 (q, 2H), 4.18 (t, 2H), 4.07 - 4.04 (m, 2H), 3.85 - 3.82 (m, 1H), 3.80 - 3.75 (m, 1H), 3.67 - 3.62 (m, 3H), 3.43 - 3.39 (m, 2H), 2.92 - 2.84 (m, 1H), 2.84 (s, 3H), 2.61 - 2.56 (m, 1H), 2.54 - 2.49 (m, 1H), 2.07 - 1.99 (m, 3H), 1.92 - 1.90 (m, 4H), 1.78 - 1.72 (m, 2H), 1.68 - 1.62 (m, 4H), 1.52 - 1.47 (m, 2H), 1.40 (t, 3H).

[0281] Compound 156: MS: m / z 877.0 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.42 (d, 1H), 7.82 (d, 1H), 7.63 - 7.60 (m, 2H), 7.37 (d, 1H), 7.01 (dd, 1H), 6.94 (d, 1H), 6.84 - 6.81 (m, 2H), 4.98 (dd, 1H), 4.43 (q, 2H), 4.22 (t, 2H), 3.86 - 3.78 (m, 8H), 3.44 - 3.42 (m, 1H), 2.92 - 2.85 (m, 1H), 2.84 (s, 3H), 2.61 - 2.57 (m, 1H), 2.55 - 2.49 (m, 1H), 2.06 - 2.03 (m, 1H), 1.92 - 1.91 (m, 4H), 1.81 (bs, 2H), 1.78 - 1.71 (m, 2H), 1.68 - 1.64 (m, 4H), 1.60 - 1.56 (m 2H), 1.42 (t, 3H), 1.41 - 1.36 (m, 2H).

[0282] Compound 157: MS: m / z 904.8 (M + +1); 1 H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.57 (d, 1H), 7.86 (d, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.39 (d, 1H), 7.34 - 7.32 (m, 2H), 7.13 (dd, 1H), 6.99 (dd, 1H), 4.97 (dd, 1H), 4.56 - 4.49 (m, 3H), 4.43 (q, 2H), 4.12 (bs, 2H), 3.89 - 3.82 (m, 1H), 2.95 - 2.85 (m, 3H), 2.61 - 2.56 (m, 1H), 2.55 - 2.48 (m, 7H), 2.14 - 2.08 (m, 2H), 2.07 - 2.02 (m, 1H), 1.97 - 1.86 (m, 4H), 1.85 - 1.76 (m, 3H), 1.72 - 1.60 (m, 3H), 1.54 - 1.48 (m, 2H), 1.41 (t, 3H), 1.29 - 1.00 (6H).

[0283] Compound 158: MS: m / z 912.7 (M + +23); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.58 (d, 1H), 7.86 (d, 1H), 7.80 (d, 1H), 7.62 (bs, 1H), 7.39 - 7.36 (m, 2H), 7.33 (d, 1H), 7.13 (dd, 1H), 7.00 (bs, 1H), 4.98 (dd, 1H), 4.56 - 4.49 (m, 3H), 4.43 (q, 2H), 4.21 (bs, 2H), 3.89 - 3.82 (M, 1H), 3.00 (bs, 1H), 2.95 - 2.86 (m, 3H), 2.71 (bs, 1H), 2.61 - 2.56 (m, 1H), 2.55 - 2.48 (m, 5H), 2.14 - 2.08 (m, 2H), 2.07 - 2.02 (m, 1H), 2.00 - 1.93 (m, 1H), 1.92 - 1.86 (m, 2H), 1.82 - 1.76 (m, 2H), 1.69 - 1.60 (m, 3H), 1.54 - 1.48 (m, 2H), 1.42 (t, 3H), 1.29 - 1.13 (m, 6H).

[0284] Compound 159: MS: m / z 837.5 (M + +1); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.59 (d, 1H), 7.85 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.39 (d, 1H), 7.34 - 7.33 (m, 2H), 7.13 (dd, 1H), 7.00 (dd, 1H), 4.97 (dd, 1H), 4.55 - 4.51 (m, 1H), 4.42 (q, 2H), 4.18 (t, 2H), 4.07 - 4.04 (m, 2H), 3.88 - 3.82 (m, 1H), 3.67 - 3.62 (m, 3H), 3.43 - 3.39 (m, 2H), 2.91 - 2.85 (m, 1H), 2.62 - 2.57 (m, 1H), 2.54 - 2.49 (m, 1H), 2.11 - 2.08 (m, 2H), 2.06 - 1.99 (m, 3H), 1.94 - 1.88 (m, 4H), 1.67 - 1.60 (m, 2H), 1.53 - 1.46 (m, 4H), 1.40 (t, 3H).

[0285] Compound 160: MS: m / z 848.6 (M + + 1); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.55 (d, 1H), 7.85 (d, 1H), 7.84 (d, 1H), 7.62 (d, 1H), 7.38 (d, 1H), 7.34 (d, 1H), 7.13 (dd, 1H), 7.00 (dd, 1H), 6.86 (d, 1H), 4.97 (dd, 1H), 4.56 - 4.51 (m, 1H), 4.43 (q, 2H), 4.15 (bs, 2H), 4.08 - 4.06 (m, 4H), 3.88 - 3.82 (m, 1H), 2.91 - 2.86 (m, 1H), 2.80 (bs, 2H), 2.61 - 2.57 (m, 3H), 2.54 - 2.49 (m, 3H), 2.11 - 2.09 (m, 4H), 2.07 - 2.02 (m, 1H), 1.96 (bs, 2H), 1.91 - 1.88 (m, 2H), 1.66 - 1.60 (m, 2H), 1.54 - 1.48 (m, 2H), 1.42 (t, 3H).

[0286] Compound 161: MS: m / z 834.1 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.54 (d, 1H), 7.85 (d, 1H), 7.83 (d, 1H), 7.61 (d, 1H), 7.38 (d, 1H), 7.37 (d, 1H), 7.13 (dd, 1H), 7.01 (dd, 1H), 6.86 (d, 1H), 4.97 (dd, 1H), 4.56 - 4.51 (m, 1H), 4.43 (q, 2H), 4.21 (t, 2H), 4.09 - 4.04 (m, 4H), 3.88 - 3.82 (m, 1H), 2.90 - 2.87 (m, 5H), 2.70 - 2.67 (m, 2H), 2.61 - 2.57 (m, 1H), 2.54 - 2.49 (m, 1H), 2.12 - 2.09 (m, 4H), 2.07 - 2.02 (m, 1H), 1.91 - 1.89 (m, 2H), 1.65 - 1.60 (m, 2H), 1.54 - 1.48 (m, 2H), 1.42 (t, 3H).

[0287] Compound 162: MS: m / z 849.6 (M + +1); 1 H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.52 (d, 1H), 7.86 (dd, 1H), 7.83 - 7.80 (m, 1H), 7.62 (dd, 1H), 7.39 - 7.36 (m, 2H), 7.14 (dd, 1H), 7.02 (dd, 1H), 6.94 - 6.90 (m, 1H), 4.97 (dd, 1H), 4.56 - 4.51 (m, 1H), 4.43 (q, 2H), 4.21 (t, 2H), 4.18 - 4.13 (m, 1H), 3.88 - 3.82 (m, 1H), 3.73 - 3.68 (m, 2H), 3.62 - 3.43 (m, 4H), 2.92 - 2.85 (m, 1H), 2.62 - 2.55 (m, 1H), 2.54 - 2.49 (m, 1H), 2.36 - 2.31 (m, 2H), 2.12 - 2.09 (m, 2H), 2.07 - 1.96 (m, 5H), 1.91 - 1.89 (m, 2H), 1.66 - 1.60 (m, 2H), 1.54 - 1.48 (m, 2H), 1.42 (t, 3H).

[0288] Compound 163: MS: m / z 843.5 (M + +23); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.58 (d, 1H), 7.85 (d, 1H), 7.80 (d, 1H), 7.61 (d, 1H), 7.39 (d, 1H), 7.35 - 7.32 (m, 2H), 7.13 (dd, 1H), 7.00 (dd, 1H), 4.97 (dd, 1H), 4.56 - 4.47 (m, 3H), 4.42 (q, 2H), 4.10 (t, 2H), 3.89 - 3.82 (m, 1H), 3.00 (t, 2H), 2.91 - 2.85 (m, 1H), 2.61 - 2.56 (m, 1H), 2.52 - 2.49 (m, 1H), 2.12 - 2.09 (m, 2H), 2.07 - 2.02 (m, 1H), 1.91 - 1.88 (m, 2H), 1.83 - 1.81 (m, 4H), 1.69 - 1.60 (m, 3H), 1.54 - 1.48 (m, 4H), 1.41 (t, 3H), 1.19 - 1.12 (m, 2H).

[0289] Compound 164: MS: m / z 884.9 (M + +23); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.42 (dd, 1H), 7.83 - 7.80 (m, 1H), 7.63 - 7.60 (m, 2H), 7.36 (d, 1H), 7.02 (dd, 1H), 6.94 - 6.89 (m, 3H), 6.82 (dd, 1H), 4.97 (dd, 1H), 4.43 (q, 2H), 4.23 - 4.22 (m, 2H), 4.18 - 4.13 (m, 1H), 3.88 - 3.75 (m, 2H), 3.72 - 3.70 (m, 2H), 3.60 - 3.43 (m, 4H), 2.91 - 2.85 (m, 1H), 2.85 (s, 3H), 2.62 - 2.55 (m, 1H), 2.54 - 2.49 (m, 1H), 2.36 - 2.31 (m, 2H), 2.06 - 1.95 (m, 5H), 1.95 - 1.89 (m, 2H), 1.78 - 1.71 (m, 2H), 1.69 - 1.62 (m, 4H), 1.41 (t, 3H).

[0290] Compound 165: MS: m / z 856.8 (M + +23); 1 H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.48 (d, 1H), 7.81 (d, 1H), 7.60 (dd, 1H), 7.35-7.32 (m, 2H), 6.99 (dd, 1H), 6.94 (d, 1H), 6.82 (dd, 1H), 4.97 (dd, 1H), 4.51-4.48 (m, 2H), 4.43 (q, 2H), 4.10 (t, 2H), 3.88-3.75 (m, 2H), 3.02-2.98 (m, 2H), 2.91-2.85 (m, 1H), 2.85 (s, 3H), 2.61-2.56 (m, 1H), 2.52-2.49 (m, 1H), 2.07-2.02 (m, 1H), 1.93-1.90 (m, 2H), 1.83-1.81 (m, 4H), 1.78-1.72 (m, 2H), 1.69-1.62 (m, 5H), 1.44-1.40 (m, 2H), 1.41 (t, 3H), 1.19-1.12 (m, 2H).

[0291] Compound 166: MS: m / z 925.7 (M + +23); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.47 (d, 1H), 7.81 (d, 1H), 7.64 - 7.59 (m, 2H), 7.38 (bs, 1H), 7.33 (d, 1H), 7.00 (bs, 1H), 6.94 (d, 1H), 6.82 (dd, 1H), 4.98 (dd, 1H), 4.54 - 4.52 (m, 2H), 4.43 (q, 2H), 4.19 (bs, 1H), 3.89 - 3.75 (m, 2H), 3.52 - 3.33 (m, 1H), 3.00 (bs, 1H), 2.95 - 2.86 (m, 3H), 2.85 (s, 3H), 2.71 (bs, 1H), 2.61 - 2.56 (m, 2H), 2.55 - 2.48 (m, 4H), 2.07 - 2.02 (m, 1H), 2.01 - 1.94 (m, 1H), 1.94 - 1.89 (m, 2H), 1.82 - 1.71 (m, 4H), 1.70 - 1.62 (m, 5H), 1.42 (t, 3H), 1.29 - 1.14 (6H).

[0292] Compound 167: MS: m / z 939.8 (M + +23); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.47 (d, 1H), 7.80 (d, 1H), 7.62 - 7.60 (m, 2H), 7.34 - 7.32 (m, 2H), 6.99 (dd, 1H), 6.94 (d, 1H), 6.82 (dd, 1H), 4.97 (dd, 1H), 4.53 - 4.52 (m, 2H), 4.43 (q, 2H), 4.13 (bs, 2H), 3.88 - 3.76 (m, 2H), 2.96 - 2.87 (m, 3H), 2.85 (s, 3H), 2.61 - 2.56 (m, 1H), 2.55 - 2.48 (m, 5H), 2.07 - 2.02 (m, 1H), 1.95 - 1.89 (m, 3H), 1.82 - 1.70 (m, 4H), 1.70 - 1.62 (m, 5H), 1.42 (t, 3H), 1.29 - 1.04 (m, 6H).

[0293] Compound 168: MS: m / z 831.6 (M + +23); 1 H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.59 (d, 1H), 7.85 (d, 1H), 7.82 (d, 1H), 7.61 (d, 1H), 7.39 - 7.36 (m, 2H), 7.31 (d, 1H), 7.13 (dd, 1H), 7.02 (dd, 1H), 4.97 (dd, 1H), 4.56 - 4.51 (m, 1H), 4.25 - 4.24 (m, 2H), 4.12 - 4.07 (m, 2H), 3.95 (s, 3H), 3.88 - 3.82 (m, 3H), 3.76 - 3.72 (m, 1H), 3.45 - 3.41 (m, 2H), 2.92 - 2.85 (m, 1H), 2.62 - 2.52 (m, 2H), 2.12 - 2.08 (m, 2H), 2.06 - 2.00 (m, 1H), 1.98 - 1.93 (m, 2H), 1.93 - 1.87 (m, 2H), 1.67 - 1.61 (m, 2H), 1.56 - 1.48 (m 4H).

[0294] Compound 169: MS: m / z 844.6 (M + +23); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.49 (d, 1H), 7.82 (d, 1H), 7.62 - 7.59 (m, 2H), 7.37 (d, 1H), 7.31 (d, 1H), 7.02 (dd, 1H), 6.94 (d, 1H), 6.82 (dd, 1H), 4.97 (dd, 1H), 4.24 (t, 2H), 4.12 - 4.08 (m, 2H), 3.95 (s, 3H), 3.88 - 3.82 (m, 3H), 3.81 - 3.72 (m, 2H), 3.45 - 3.41 (m, 2H), 2.92 - 2.85 (m, 1H), 2.85 (s, 3H), 2.62 - 2.55 (m, 1H), 2.54 - 2.49 (m, 1H), 2.05 - 2.00 (m, 1H), 1.98 - 1.93 (m, 2H), 1.93 - 1.89 (m, 2H), 1.78 - 1.72 (m, 2H), 1.70 - 1.62 (m, 4H), 1.55 - 1.50 (m 2H).

[0295] Compound 170: MS: m / z 871.7 (M + +23); 11H NMR (DMSO-d6) δ 11.04 (s, 1H), 8.56 (d, 1H), 7.84 (d, 1H), 7.78 (d, 1H), 7.60 (d, 1H), 7.37 (d, 1H), 7.32 (d, 1H), 7.28 (d, 1H), 7.11 (dd, 1H), 7.00 (dd, 1H), 4.96 (dd, 1H), 4.54 - 4.49 (m, 1H), 4.21 - 4.19 (m, 2H), 4.13 - 4.08 (m, 1H), 3.94 (s, 3H), 3.87 - 3.80 (m, 1H), 3.68 - 3.65 (m, 4H), 3.63 - 3.60 (m, 2H), 2.94 - 2.84 (m, 1H), 2.60 - 2.53 (m, 1H), 2.53 - 2.47 (m, 1H), 2.24 - 2.21 (m, 2H), 2.11 - 2.06 (m, 2H), 2.04 - 1.99 (m, 1H), 1.90 - 1.86 (m, 2H), 1.72 - 1.68 (m, 2H), 1.65 - 1.55 (m, 6H), 1.52 - 1.46 (m, 2H).

[0296] Compound 171: MS: m / z 884.7 (M + +23); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.48 (d, 1H), 7.81 (d, 1H), 7.64-7.60 (m, 2H), 7.35 (d, 1H), 7.31 (d, 1H), 7.03 (dd, 1H), 6.95 (d, 1H), 6.83 (dd, 1H), 4.98 (dd, 1H), 4.23-4.22 (m, 2H), 4.15-4.11 (m, 1H), 3.96 (s, 3H), 3.88-3.76 (m, 2H), 3.70-3.68 (m, 4H), 3.65-3.63 (m, 2H), 2.92-2.85 (m, 1H), 2.85 (s, 3H), 2.62-2.56 (m, 1H), 2.55-2.48 (m, 1H), 2.26-2.23 (m, 2H), 2.06-2.02 (m, 1H), 1.94-1.90 (m, 2H), 1.78-1.65 (m, 8H), 1.63-1.58 (m, 4H).

[0297] Compound 172: MS: m / z 899.7 (M + +23); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.56 (d, 1H), 7.86 (d, 1H), 7.78 (d, 1H), 7.62 (d, 1H), 7.39 (d, 1H), 7.35 (d, 1H), 7.31 (d, 1H), 7.13 (dd, 1H), 7.00 (dd, 1H), 4.97 (dd, 1H), 4.55 - 4.51 (m, 1H), 4.44 (q, 2H), 4.16 (t, 2H), 4.05 - 4.00 (m, 1H), 3.88 - 3.82 (m, 1H), 3.67 - 3.65 (m, 2H), 3.59 - 3.57 (m, 2H), 3.47 (t, 2H), 2.92 - 2.85 (m, 1H), 2.62 - 2.56 (m, 1H), 2.55 - 2.48 (m, 1H), 2.22 - 2.19 (m, 2H), 2.11 - 2.08 (m, 2H), 2.07 - 2.02 (m, 1H), 2.02 - 1.98 (m, 2H), 1.92 - 1.86 (m, 2H), 1.68 - 1.60 (m, 4H), 1.59 - 1.48 (m, 6H), 1.42 (t, 3H).

[0298] Compound 173: MS: m / z 913.0 (M + +23); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.47 (d, 1H), 7.79 (d, 1H), 7.62 - 7.59 (m, 2H), 7.35 (d, 1H), 7.31 (d, 1H), 7.00 (dd, 1H), 6.94 (d, 1H), 6.82 (dd, 1H), 4.98 (dd, 1H), 4.44 (q, 2H), 4.16 (t, 2H), 4.05 - 4.00 (m, 1H), 3.87 - 3.74 (m, 2H), 3.67 - 3.65 (m, 2H), 3.59 - 3.57 (m, 2H), 3.47 (t, 2H), 2.92 - 2.85 (m, 1H), 2.84 (s, 3H), 2.61 - 2.55 (m, 1H), 2.54 - 2.48 (m, 1H), 2.22 - 2.18 (m, 2H), 2.07 - 2.02 (m, 1H), 2.02 - 1.98 (m, 2H), 1.92 - 1.89 (m, 2H), 1.78 - 1.71 (m, 2H), 1.70 - 1.62 (m, 6H), 1.59 - 1.51 (m, 4H), 1.42 (t, 3H).

[0299] Compound 174: MS: m / z 857.6 (M + +23); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.52 (d, 1H), 7.85 (d, 1H), 7.83 - 7.80 (m, 1H), 7.62 (dd, 1H), 7.39 (d, 1H), 7.30 (d, 1H), 7.13 (dd, 1H), 7.02 (d, 1H), 6.93 - 6.89 (m, 1H), 4.97 (dd, 1H), 4.56 - 4.51 (m, 1H), 4.23 - 4.21 (m, 2H), 4.18 - 4.13 (m, 1H), 3.95 (s, 3H), 3.89 - 3.82 (m, 1H), 3.73 - 3.69 (m, 2H), 3.62 - 3.42 (m, 4H), 2.92 - 2.86 (m, 1H), 2.62 - 2.55 (m, 1H), 2.54 - 2.49 (m, 1H), 2.36 - 2.31 (m, 2H), 2.12 - 2.09 (m, 2H), 2.06 - 1.96 (m, 5H), 1.92 - 1.89 (m, 2H), 1.66 - 1.60 (m, 2H), 1.54 - 1.48 (m, 2H).

[0300] Compound 175: MS: m / z 870.2 (M + +23); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.42 (d, 1H), 7.83 - 7.80 (m, 1H), 7.63 - 7.60 (m, 2H), 7.30 (bs, 1H), 7.03 (d, 1H), 6.94 - 6.90 (m, 2H), 6.82 (d, 1H), 4.98 (dd, 1H), 4.23 - 4.21 (m, 2H), 4.18 - 4.13 (m, 1H), 3.95 (s, 3H), 3.87 - 3.77 (m, 2H), 3.71 (bs, 2H), 3.60 - 3.44 (m, 4H), 2.92 - 2.85 (m, 1H), 2.85 (s, 3H), 2.62 - 2.55 (m, 1H), 2.54 - 2.49 (m, 1H), 2.36 - 2.31 (m, 2H), 2.06 - 1.96 (m, 5H), 1.92 - 1.90 (m, 2H), 1.78 - 1.72 (m, 2H), 1.70 - 1.62 (m, 4H).

[0301] Compound 176: MS: m / z 863.8 (M + +1); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.51 (d, 1H), 7.85 (d, 1H), 7.82 - 7.78 (m, 1H), 7.61 (dd, 1H), 7.39 (d, 1H), 7.35 (bs, 1H), 7.13 (dd, 1H), 7.00 (d, 1H), 6.91 - 6.86 (m, 1H), 4.97 (dd, 1H), 4.56 - 4.51 (m, 1H), 4.43 (q, 2H), 4.16 (t, 2H), 3.88 - 3.81 (m, 1H), 3.58 - 3.40 (m, 6H), 2.92 - 2.85 (m, 1H), 2.61 - 2.56 (m, 1H), 2.55 - 2.49 (m, 1H), 2.32 - 2.28 (m, 2H), 2.12 - 2.07 (m, 2H), 2.06 - 1.97 (m, 5H), 1.97 - 1.87 (m, 4H), 1.66 - 1.60 (m, 2H), 1.54 - 1.48 (m, 2H), 4.41 (t, 3H).

[0302] Compound 177: MS: m / z 899.0 (M + +23); 1 H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.41 (d, 1H), 7.82 - 7.78 (m, 1H), 7.62 - 7.60 (m, 2H), 7.35 (bs, 1H), 7.00 (d, 1H), 6.94 (d, 1H), 6.91 - 6.87 (m, 1H), 6.82 (dd, 1H), 4.97 (dd, 1H), 4.43 (q, 2H), 4.17 - 4.15 (m, 2H), 4.08 - 4.04 (m, 1H), 3.87 - 3.76 (m, 2H), 3.57 - 3.43 (m, 6H), 2.92 - 2.85 (m, 1H), 2.85 (s, 3H), 2.62 - 2.55 (m, 1H), 2.54 - 2.49 (m, 1H), 2.32 - 2.28 (m, 2H), 2.06 - 1.89 (m, 9H), 1.78 - 1.72 (m, 2H), 1.70 - 1.61 (m, 4H), 1.41 (t, 3H).

[0303] Compound 178: MS: m / z 884.6 (M + +23); 1 H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.41 (d, 1H), 7.82 - 7.81 (m, 1H), 7.62 - 7.60 (m, 2H), 7.29 (bs, 1H), 7.00 (d, 1H), 6.94 (d, 1H), 6.91 - 6.87 (m, 1H), 6.83 (dd, 1H), 4.97 (dd, 1H), 4.17 - 4.15 (m, 2H), 4.06 (s, 3H), 3.87 - 3.76 (m, 2H), 3.57 - 3.43 (m, 6H), 2.92 - 2.85 (m, 1H), 2.85 (s, 3H), 2.62 - 2.55 (m, 1H), 2.54 - 2.49 (m, 1H), 2.32 - 2.28 (m, 2H), 2.00 - 1.89 (m, 9H), 1.78 - 1.72 (m, 2H), 1.70 - 1.60 (m, 4H).

[0304] Compound 179: MS: m / z 872.0 (M + +23); 1 H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.51 (dd, 1H), 7.85 (d, 1H), 7.82 - 7.77 (m, 1H), 7.61 (dd, 1H), 7.39 (d, 1H), 7.29 (bs, 1H), 7.13 (dd, 1H), 7.02 - 7.00 (m, 1H), 6.92 - 6.87 (m, 1H), 4.97 (dd, 1H), 4.56 - 4.51 (m, 1H), 4.16 (t, 2H), 4.08 - 4.03 (m, 1H), 3.96 (s, 3H), 3.88 - 3.81 (m, 1H), 3.56 - 3.42 (m, 6H), 2.92 - 2.85 (m, 1H), 2.62 - 2.56 (m, 1H), 2.55 - 2.49 (m, 1H), 2.32 - 2.27 (m, 2H), 2.12 - 2.08 (m, 2H), 2.06 - 1.97 (m, 5H), 1.97 - 1.87 (m, 4H), 1.66 - 1.60 (m, 2H), 1.54 - 1.48 (m, 2H).

[0305] Compound 180: MS: m / z 889.8 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.48 (d, 1H), 7.81 (d, 1H), 7.65 - 7.60 (m, 2H), 7.41 - 7.31 (m, 2H), 7.01 (bs, 1H), 6.94 (d, 1H), 6.83 (dd, 1H), 4.98 (dd, 1H), 4.44 (q, 2H), 4.20 (bs, 2H), 3.87 - 3.75 (m, 2H), 3.71 (bs, 4H), 2.92 - 2.85 (m, 1H), 2.85 (s, 3H), 2.77 (bs, 2H), 2.63 - 2.56 (m, 2H), 2.56 - 2.50 (m, 4H), 2.07 - 2.02 (m, 1H), 1.93 - 1.89 (m, 2H), 1.78 - 1.72 (m, 2H), 1.71 - 1.62 (m, 4H), 1.62 - 1.46 (m, 8H), 1.42 (t, 3H).

[0306] Compound 181: MS: m / z 925.8 (M + +23); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.48 (d, 1H), 7.81 (d, 1H), 7.68 - 7.60 (m, 2H), 7.35 (bs, 2H), 7.00 (d, 1H), 6.94 (bs, 1H), 6.82 (d, 1H), 4.98 (dd, 1H), 4.48 - 4.42 (m, 2H), 4.16 (bs, 2H), 3.89 - 3.74 (m, 2H), 3.72 (bs, 4H), 2.92 - 2.85 (m, 1H), 2.85 (s, 3H), 2.63 - 2.55 (m, 2H), 2.56 - 2.50 (m, 4H), 2.45 - 2.33 (m, 2H), 2.09 - 2.02 (m, 1H), 1.97 - 1.89 (m, 4H), 1.78 - 1.62 (m, 8H), 1.62 - 1.46 (m, 6H), 1.42 (t, 3H).

[0307] Compound 182: MS: m / z 890.0 (M + +23); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.58 (d, 1H), 7.86 (d, 1H), 7.80 (d, 1H), 7.62 (bs, 1H), 7.42 - 7.36 (m, 2H), 7.33 (d, 1H), 7.13 (dd, 1H), 7.01 (bs, 1H), 4.98 (dd, 1H), 4.56 - 4.51 (m, 1H), 4.44 (q, 2H), 4.21 (bs, 2H), 3.89 - 3.82 (m, 1H), 3.71 (bs, 4H), 2.92 - 2.85 (m, 1H), 2.77 (bs, 2H), 2.63 - 2.56 (m, 2H), 2.55 - 2.48 (m, 4H), 2.14 - 2.08 (m, 2H), 2.07 - 2.02 (m, 1H), 1.93 - 1.86 (m, 2H), 1.67 - 1.47 (m, 12H), 1.42 (t, 3H).

[0308] Compound 183: MS: m / z 891.0 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.58 (d, 1H), 7.85 (d, 1H), 7.81 (d, 1H), 7.63 (d, 1H), 7.39 (d, 1H), 7.37 - 7.31 (m, 2H), 7.14 (dd, 1H), 7.00 (dd, 1H), 4.98 (dd, 1H), 4.56 - 4.51 (m, 1H), 4.44 (q, 2H), 4.15 (bs, 2H), 3.89 - 3.82 (m, 1H), 3.71 (bs, 4H), 2.92 - 2.85 (m, 1H), 2.63 - 2.55 (m, 2H), 2.55 - 2.46 (m, 4H), 2.46 - 2.31 (m, 2H), 2.14 - 2.07 (m, 2H), 2.06 - 2.01 (m, 1H), 1.98 - 1.87 (m, 4H), 1.67 - 1.45 (m, 12H), 1.42 (t, 3H).

[0309] Compound 184: MS: m / z 886.9 (M + +23);1 1H NMR (DMSO-d6) δ 11.05 (singlet, 1H), 8.49 (doublet, 1H), 7.81 (doublet, 1H), 7.61 - 7.60 (multiplet, 2H), 7.36 (doublet, 1H), 7.32 (doublet, 1H), 7.00 (doublet of doublets, 1H), 6.94 (doublet, 1H), 6.82 (doublet of doublets, 1H), 4.97 (doublet of doublets, 1H), 4.20 (quartet, 2H), 4.12 (triplet, 2H), 4.09 - 4.04 (multiplet, 2H), 3.88 - 3.82 (multiplet, 1H), 3.80 - 3.76 (multiplet, 1H), 3.63 - 3.59 (multiplet, 1H), 3.54 (triplet, 2H), 3.45 - 3.40 (multiplet, 2H), 2.92 - 2.85 (multiplet, 1H), 2.85 (singlet, 3H), 2.61 - 2.55 (multiplet, 1H), 2.54 - 2.50 (multiplet, 1H), 2.07 - 2.02 (multiplet, 1H), 1.94 - 1.89 (multiplet, 4H), 1.86 - 1.82 (multiplet, 2H), 1.78 - 1.62 (multiplet, 6H), 1.52 - 1.46 (multiplet, 2H), 1.41 (triplet, 3H).

[0310] Compound 185: MS: m / z 873.9 (M + +23); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.59 (d, 1H), 7.85 (d, 1H), 7.81(d, 1H), 7.61 (d, 1H), 7.39 (d, 1H), 7.36 (d, 1H), 7.32 (d, 1H), 7.13 (dd, 1H), 6.99 (dd, 1H), 4.97 (dd, 1H), 4.56-4.51 (m, 1H), 4.42 (q, 2H), 4.12 (t, 2H), 4.08-4.04 (m, 2H), 3.89-3.82 (m, 1H), 3.63-3.59 (m, 1H), 3.54 (t, 2H), 3.45-3.40 (m, 2H), 2.91-2.85 (m, 1H), 2.62-2.52 (m, 2H), 2.11-2.08 (m, 2H), 2.07-2.07 (m, 1H), 1.93-1.87 (m, 4H), 1.86-1.81 (m, 2H), 1.73-1.67 (m, 2H), 1.67-1.61 (m, 2H), 1.54-1.48 (m, 4H), 1.41 (t, 3H).

[0311] Compound 186: MS: m / z 851.0 (M + +1); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.49 (d, 1H), 7.81 (d, 1H), 7.61 - 7.59 (m, 2H), 7.36 (d, 1H), 7.26 (d, 1H), 7.00 (dd, 1H), 6.94 (d, 1H), 6.82 (dd, 1H), 4.97 (dd, 1H), 4.12 (t, 2H), 4.09 - 4.04 (m, 2H), 3.94 (s, 3H), 3.87 - 3.82 (m, 1H), 3.80 - 3.76 (m, 1H), 3.63 - 3.60 (m, 1H), 3.55 (t, 2H), 3.45 - 3.41 (m, 2H), 2.92 - 2.84 (m, 1H), 2.85 (s, 3H), 2.61 - 2.55 (m, 1H), 2.54 - 2.50 (m, 1H), 2.06 - 2.00 (m, 1H), 1.95 - 1.89 (m, 4H), 1.87 - 1.82 (m, 2H), 1.78 - 1.62 (m, 6H), 1.52 - 1.46 (m, 2H).

[0312] Compound 187: MS: m / z 837.6 (M + +1); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.59 (d, 1H), 7.85 (d, 1H), 7.80(d, 1H), 7.61 (d, 1H), 7.39 (d, 1H), 7.36 (d, 1H), 7.26 (d, 1H), 7.13 (dd, 1H), 7.00 (dd, 1H), 4.97 (dd, 1H), 4.56-4.51 (m, 1H), 4.12 (t, 2H), 4.08-4.04 (m, 2H), 3.94 (s, 3H), 3.89-3.82 (m, 1H), 3.63-3.59 (m, 1H), 3.54 (t, 2H), 3.45-3.40 (m, 2H), 2.92-2.85 (m, 1H), 2.61-2.53 (m, 2H), 2.11-2.08 (m, 2H), 2.05-2.00 (m, 1H), 1.95-1.87 (m, 4H), 1.87-1.82 (m, 2H), 1.73-1.67 (m, 2H), 1.66-1.61 (m, 2H), 1.54-1.46 (m, 4H).

[0313] Compound 188: MS: m / z 844.9 (M + +23); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.61 (d, 1H), 7.86 - 7.83 (m, 2H), 7.62 (d, 1H), 7.39 (d, 1H), 7.35 (d, 1H), 7.27 (d, 1H), 7.13 (dd, 1H), 7.02 (d, 1H), 4.97 (dd, 1H), 4.55 - 4.51 (m, 1H), 4.11 - 4.08 (m, 1H), 4.00 - 3.96 (m, 1H), 3.96 (s, 3H), 3.89 - 3.83 (m, 1H), 3.72 (bs, 4H), 2.92 - 2.86 (m, 1H), 2.62 - 2.56 (m, 1H), 2.54 - 2.46 (m, 6H), 2.30 - 2.24 (m, 2H), 2.12 - 2.08 (m, 2H), 2.05 - 2.01 (m, 1H), 1.91 - 1.87 (m, 2H), 1.67 - 1.61 (m, 2H), 1.54 - 1.48 (m, 2H), 1.07 (d, 3H).

[0314] Compound 189: MS: m / z 857.6 (M + +23); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.50 (d, 1H), 7.84 (d, 1H), 7.63 - 7.60 (m, 2H), 7.35 (d, 1H), 7.27 (d, 1H), 7.03 (dd, 1H), 6.94 (d, 1H), 6.82 (dd, 1H), 4.97 (dd, 1H), 4.11 - 4.08 (m, 1H), 3.99 - 3.96 (m, 1H), 3.96 (s, 3H), 3.88 - 3.81 (m, 1H), 3.80 - 3.75 (m, 1H), 3.71 (bs, 4H), 2.92 - 2.86 (m, 1H), 2.85 (s, 3H), 2.62 - 2.58 (m, 1H), 2.58 - 2.46 (m, 6H), 2.29 - 2.24 (m, 2H), 2.05 - 2.01 (m, 1H), 1.94 - 1.89 (m, 2H), 1.78 - 1.71 (m, 2H), 1.70 - 1.62 (m, 4H), 1.07 (d, 3H).

[0315] Compound 190: MS: m / z 819.5 (M + +1); 1 H NMR (DMSO-d6) δ 11.05 (s, 1H), 9.03 (d, 1H), 8.11 - 8.07 (m, 2H), 7.86 (d, 1H), 7.62 (d, 1H), 7.40 (d, 1H), 7.34 (d, 1H), 7.14 (dd, 1H), 7.01 (dd, 1H), 6.95 - 6.93 (m, 1H), 4.97 (dd, 1H), 4.57 - 4.52 (m, 1H), 4.43 (q, 2H), 4.17 (t, 2H), 3.95 - 3.88 (m, 1H), 3.26 (bs, 2H), 2.92 - 2.85 (m, 1H), 2.74 (bs, 4H), 2.66 - 2.63 (m, 2H), 2.62 - 2.55 (m, 1H), 2.54 - 2.48 (m, 1H), 2.15 - 2.10 (m, 2H), 2.06 - 2.00 (m, 3H), 1.94 - 1.89 (m, 2H), 1.72 - 1.66 (m, 2H), 1.56 - 1.50 (m, 2H), 1.41 (t, 3H).

[0316] Compound 191: MS: m / z 827.6 (M + +23); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 9.04 (d, 1H), 8.12 - 8.09 (m, 2H), 7.86 (d, 1H), 7.63 (d, 1H), 7.41 - 7.40 (m, 2H), 7.15 (dd, 1H), 7.03 (dd, 1H), 6.96 - 6.94 (m, 1H), 4.98 (dd, 1H), 4.58 - 4.53 (m, 1H), 4.44 (q, 2H), 4.30 (t, 2H), 3.95 - 3.89 (m, 1H), 3.38 (bs, 2H), 2.95 - 2.93 (m, 2H), 2.92 - 2.85 (m, 3H), 2.76 (bs, 2H), 2.63 - 2.56 (m, 2H), 2.15 - 2.10 (m, 2H), 2.08 - 2.03 (m, 1H), 1.94 - 1.91 (m, 2H), 1.73 - 1.66 (m, 2H), 1.57 - 1.50 (m, 2H), 1.43 (t, 3H).

[0317] Compound 192: MS: m / z 858.3 (M + +23); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.61 (d, 1H), 7.87 - 7.83 (m, 2H), 7.63 (d, 1H), 7.39 (d, 1H), 7.36 - 7.33 (m, 2H), 7.14 (dd, 1H), 7.02 (d, 1H), 4.98 (dd, 1H), 4.56 - 4.51 (m, 1H), 4.44 (q, 2H), 4.10 - 4.08 (m, 1H), 4.00 - 3.97 (m, 1H), 3.89 - 3.82 (m, 1H), 3.71 (bs, 4H), 2.92 - 2.86 (m, 1H), 2.64 - 2.56 (m, 2H), 2.54 - 2.48 (m, 4H), 2.30 - 2.24 (m, 2H), 2.12 - 2.08 (m, 3H), 2.07 - 2.02 (m, 1H), 1.91 - 1.87 (m, 2H), 1.67 - 1.61 (m, 2H), 1.54 - 1.49 (m, 2H), 1.42 (t, 3H), 1.07 (d, 3H).

[0318] Compound 193: MS: m / z 871.9 (M + +23); 1 H NMR (DMSO-d6) δ 11.07 (s, 1H), 8.52 (d, 1H), 7.85 (d, 1H), 7.64-7.61 (m, 2H), 7.36 (d, 1H), 7.34 (d, 1H), 7.03 (dd, 1H), 6.95 (d, 1H), 6.84 (dd, 1H), 4.99 (dd, 1H), 4.44 (q, 2H), 4.11-4.09 (m, 1H), 4.00-3.98 (m, 1H), 3.89-3.82 (m, 1H), 3.81-3.71 (m, 1H), 3.72 (bs, 4H), 2.93-2.86 (m, 1H), 2.86 (s, 3H), 2.63-2.58 (m, 1H), 2.58-2.46 (m, 6H), 2.30-2.24 (m, 2H), 2.08-2.03 (m, 1H), 1.96-1.90 (m, 2H), 1.79-1.72 (m, 2H), 1.71-1.64 (m, 4H), 1.43 (t, 3H), 1.08 (d, 3H).

[0319] Compound 194: MS: m / z 899.0 (M + +23); 11H NMR (DMSO-d6) δ 11.07 (s, 1H), 8.58 (d, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.64 (d, 1H), 7.39 (d, 1H), 7.37 - 7.31 (m, 1H), 7.29 (bs, 1H), 7.14 (dd, 1H), 7.01 (dd, 1H), 4.98 (dd, 1H), 4.56 - 4.52 (m, 1H), 4.16 (bs, 2H), 3.97 (s, 3H), 3.89 - 3.83 (m, 1H), 3.72 (bs, 4H), 2.93 - 2.86 (m, 1H), 2.63 - 2.56 (m, 1H), 2.55 - 2.46 (m, 5H), 2.46 - 2.31 (m, 2H), 2.14 - 2.10 (m, 2H), 2.06 - 2.00 (m, 1H), 1.99 - 1.88 (m, 4H), 1.67 - 1.42 (m, 12H).

[0320] Compound 195: MS: m / z 885.4 (M + +23); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.59 (d, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.63 (bs, 1H), 7.39 (d, 1H), 7.37 - 7.31 (m, 2H), 7.14 (dd, 1H), 7.03 (bs, 1H), 4.98 (dd, 1H), 4.56 - 4.52 (m, 1H), 4.21 (bs, 2H), 3.97 (s, 3H), 3.89 - 3.83 (m, 1H), 3.72 (bs, 4H), 2.93 - 2.86 (m, 1H), 2.78 (bs, 2H), 2.63 - 2.56 (m, 2H), 2.55 - 2.48 (m, 4H), 2.14 - 2.10 (m, 2H), 2.06 - 2.01 (m, 1H), 1.93 - 1.88 (m, 2H), 1.73 - 1.45 (m, 12H).

[0321] Compound 196: MS: m / z 805.6 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 9.04 (d, 1H), 8.12 - 8.07 (m, 2H), 7.86 (d, 1H), 7.62 (d, 1H), 7.40 (d, 1H), 7.29 (d, 1H), 7.15 (dd, 1H), 7.02 (dd, 1H), 6.95 - 6.93 (m, 1H), 4.98 (dd, 1H), 4.58 - 4.52 (m, 1H), 4.18 (t, 2H), 3.95 (s, 3H), 3.94 - 3.89 (m, 1H), 3.26 (bs, 2H), 2.92 - 2.86 (m, 1H), 2.74 (bs, 4H), 2.66 - 2.64 (m, 2H), 2.62 - 2.56 (m, 2H), 2.15 - 2.10 (m, 2H), 2.06 - 2.01 (m, 3H), 1.96 - 1.91 (m, 2H), 1.73 - 1.66 (m, 2H), 1.57 - 1.50 (m, 2H).

[0322] Compound 197: MS: m / z 791.3 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 9.04 (d, 1H), 8.12 - 8.09 (m, 2H), 7.86 (d, 1H), 7.63 (d, 1H), 7.40 (d, 1H), 7.35 (d, 1H), 7.15 (dd, 1H), 7.04 (dd, 1H), 6.96 - 6.94 (m, 1H), 4.98 (dd, 1H), 4.58 - 4.52 (m, 1H), 4.30 (t, 2H), 3.97 (s, 3H), 3.94 - 3.89 (m, 1H), 3.38 (bs, 2H), 2.95 - 2.94 (m, 2H), 2.92 - 2.83 (m, 3H), 2.76 (bs, 2H), 2.63 - 2.56 (m, 1H), 2.55 - 2.50 (m, 1H), 2.14 - 2.10 (m, 2H), 2.06 - 2.02 (m, 1H), 1.95 - 1.90 (m, 2H), 1.73 - 1.66 (m, 2H), 1.56 - 1.50 (m, 2H).

[0323] Compound 198: MS: m / z 890.0 (M + +1); 1 H NMR (DMSO-d6) δ 11.07 (s, 1H), 8.48 (d, 1H), 7.82 (d, 1H), 7.68 - 7.59 (m, 2H), 7.40 - 7.26 (m, 2H), 7.02 (d, 1H), 6.95 (d, 1H), 6.83 (dd, 1H), 4.99 (dd, 1H), 4.18 (bs, 2H), 3.97 (s, 3H), 3.88 - 3.75 (m, 2H), 3.73 (bs, 4H), 2.93 - 2.85 (m, 1H), 2.86 (s, 3H), 2.63 - 2.55 (m, 2H), 2.56 - 2.50 (m, 4H), 2.45 - 2.32 (m, 2H), 2.07 - 2.01 (m, 1H), 1.99 - 1.89 (m, 4H), 1.79 - 1.73 (m, 2H), 1.73 - 1.63 (m, 6H), 1.63 - 1.44 (m, 6H).

[0324] Compound 199: MS: m / z 875.6 (M + +1); 1 H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.48 (d, 1H), 7.81 (d, 1H), 7.65 - 7.60 (m, 2H), 7.35 - 7.31 (m, 2H), 7.01 (d, 1H), 6.95 (d, 1H), 6.83 (dd, 1H), 4.98 (dd, 1H), 4.21 (bs, 2H), 3.97 (s, 3H), 3.88 - 3.75 (m, 2H), 3.71 (bs, 4H), 2.93 - 2.85 (m, 1H), 2.85 (s, 3H), 2.78 (bs, 2H), 2.63 - 2.56 (m, 2H), 2.56 - 2.50 (m, 4H), 2.06 - 2.01 (m, 1H), 1.94 - 1.89 (m, 2H), 1.79 - 1.72 (m, 2H), 1.71 - 1.62 (m, 4H), 1.61 - 1.45 (m, 8H).

[0325] Compound 200: MS: m / z 819.8 (M + +1); 1 H NMR (DMSO-d6) δ 11.06 (s, 1H), 9.04 (d, 1H), 8.12 - 8.08 (m, 2H), 7.86 (d, 1H), 7.62 (d, 1H), 7.40 (d, 1H), 7.27 (d, 1H), 7.15 (dd, 1H), 7.03 (dd, 1H), 6.95 - 6.93 (m, 1H), 4.98 (dd, 1H), 4.58 - 4.52 (m, 1H), 4.12 - 4.09 (m, 1H), 4.00 - 3.96 (m, 1H), 3.95 (s, 3H), 3.94 - 3.89 (m, 1H), 3.26 (bs, 2H), 2.92 - 2.86 (m, 1H), 2.78 - 2.66 (m, 4H), 2.62 - 2.55 (m, 3H), 2.40 - 2.35 (m, 1H), 2.34 - 2.28 (m, 1H), 2.15 - 2.10 (m, 2H), 2.06 - 2.01 (m, 1H), 1.95 - 1.89 (m, 2H), 1.73 - 1.67 (m, 2H), 1.56 - 1.50 (m, 2H), 1.08 (d, 3H).

[0326] Compound 201: MS: m / z 832.7 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.95 (d, 1H), 8.13 - 8.09 (m, 2H), 7.63 - 7.61 (m, 2H), 7.35 (d, 1H), 7.02 (dd, 1H), 6.97 - 6.94 (m, 2H), 6.84 (dd, 1H), 4.98 (dd, 1H), 4.43 (q, 2H), 4.18 (t, 2H), 3.95 - 3.88 (m, 1H), 3.82 - 3.78 (m, 1H), 3.27 (bs, 2H), 2.92 - 2.86 (m, 1H), 2.86 (s, 3H), 2.74 (bs, 4H), 2.68 - 2.63 (m, 2H), 2.63 - 2.54 (m, 2H), 2.07 - 2.02 (m, 3H), 1.97 - 1.92 (m, 2H), 1.81 - 1.68 (m, 6H), 1.42 (t, 3H).

[0327] Compound 202: MS: m / z 818.6 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.94 (d, 1H), 8.13 - 8.09 (m, 2H), 7.64 - 7.60 (m, 2H), 7.41 (d, 1H), 7.04 (dd, 1H), 6.97 - 6.94 (m, 2H), 6.84 (dd, 1H), 4.98 (dd, 1H), 4.44 (q, 2H), 4.30 (t, 2H), 3.95 - 3.88 (m, 1H), 3.82 - 3.78 (m, 1H), 3.39 - 3.37 (m, 2H), 2.95 - 2.93 (m, 2H), 2.92 - 2.84 (m, 1H), 2.86 (s, 3H), 2.76 (bs, 2H), 2.63 - 2.56 (m, 1H), 2.55 - 2.50 (m, 3H), 2.08 - 2.03 (m, 1H), 1.97 - 1.92 (m, 2H), 1.81 - 1.68 (m, 6H), 1.43 (t, 3H).

[0328] Compound 203: MS: m / z 876.3 (M + +1);1 1H NMR (DMSO-d6) δ 11.06 (singlet, 1H), 8.58 (doublet, 1H), 7.86 (doublet, 1H), 7.81 (doublet, 1H), 7.62 (doublet, 1H), 7.40 - 7.36 (multiplet, 2H), 7.33 (doublet, 1H), 7.14 (doublet of doublets, 1H), 7.02 (doublet, 1H), 4.98 (doublet of doublets, 1H), 4.60 - 4.51 (multiplet, 2H), 4.51 - 4.46 (multiplet, 2H), 4.43 (quartet, 2H), 3.89 - 3.83 (multiplet, 1H), 3.03 - 3.00 (multiplet, 2H), 2.92 - 2.86 (multiplet, 1H), 2.72 (broad singlet, 2H), 2.63 - 2.56 (multiplet, 2H), 2.32 - 2.22 (multiplet, 2H), 2.21 - 2.16 (multiplet, 2H), 2.14 - 2.08 (multiplet, 2H), 2.07 - 1.96 (multiplet, 3H), 1.93 - 1.87 (multiplet, 2H), 1.87 - 1.80 (multiplet, 2H), 1.73 - 1.59 (multiplet, 5H), 1.55 - 1.49 (multiplet, 2H), 1.41 (triplet, 3H), 1.16 - 1.07 (multiplet, 2H).

[0329] Compound 204: MS: m / z 876.8 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.52 (d, 1H), 7.86 (d, 1H), 7.83 (d, 1H), 7.62 (d, 1H), 7.43 - 7.32 (m, 2H), 7.14 (d, 1H), 7.02 (bs, 1H), 6.94 (d, 1H), 4.98 (dd, 1H), 4.69 - 4.50 (m, 3H), 4.50 - 4.38 (m, 6H), 3.89 - 3.83 (m, 1H), 3.60 - 3.58 (m, 1H), 3.18 - 3.06 (m, 1H), 2.92 - 2.86 (m, 1H), 2.83 - 2.72 (m, 2H), 2.63 - 2.56 (m, 2H), 2.37 - 2.25 (m, 2H), 2.23 - 2.15 (m, 2H), 2.15 - 2.08 (m, 2H), 2.08 - 1.97 (m, 3H), 1.95 - 1.87 (m, 2H), 1.73 - 1.59 (m, 7H), 1.57 - 1.49 (m, 2H), 1.58 - 1.38 (m, 3H).

[0330] Compound 205: MS: m / z 821.5 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 9.02 (d, 1H), 8.13 (bs, 1H), 7.86 (d, 1H), 7.84 (d, 1H), 7.64 (d, 1H), 7.40 (d, 1H), 7.36 (bs, 1H), 7.14 (dd, 1H), 7.02 (dd, 1H), 4.98 (dd, 1H), 4.57 - 4.52 (m, 1H), 4.44 (q, 2H), 4.18 (bs, 2H), 3.95 - 3.89 (m, 1H), 3.13 - 2.96 (m, 1H), 2.92 - 2.86 (m, 1H), 2.63 - 2.56 (m, 2H), 2.56 - 2.50 (m, 6H), 2.18 - 2.08 (m, 4H), 2.08 - 2.03 (m, 2H), 1.98 - 1.84 (m, 5H), 1.73 - 1.66 (m, 2H), 1.56 - 1.50 (m, 2H), 1.43 (t, 3H).

[0331] Compound 206: MS: m / z 807.2 (M + +1); 1 H NMR (DMSO-d6) δ 11.06 (s, 1H), 9.03 (d, 1H), 8.11 (d, 1H), 7.87-7.83 (m, 2H), 7.63 (d, 1H), 7.43-7.36 (m, 2H), 7.14 (dd, 1H), 7.03 (d, 1H), 4.98 (dd, 1H), 4.57-4.52 (m, 1H), 4.45 (q, 2H), 4.25 (bs, 2H), 3.95-3.89 (m, 1H), 3.13 (bs, 2H), 3.06-2.95 (m, 1H), 2.93-2.77 (m, 3H), 2.63-2.52 (m, 2H), 2.31-2.18 (m, 2H), 2.14-2.08 (m, 2H), 2.08-2.00 (m, 1H), 1.98-1.79 (m, 6H), 1.72-1.66 (m, 2H), 1.56-1.50 (m, 2H), 1.43 (t, 3H).

[0332] Compound 207: MS: m / z 807.6 (M + +1); 11H NMR (DMSO-d6) δ 11.07 (s, 1H), 9.03 (d, 1H), 8.13 (bs, 1H), 7.87 - 7.83 (m, 2H), 7.64 (d, 1H), 7.40 (d, 1H), 7.30 (bs, 1H), 7.15 (dd, 1H), 7.03 (d, 1H), 4.98 (dd, 1H), 4.57 - 4.52 (m, 1H), 4.19 (bs, 2H), 3.97 (s, 3H), 3.95 - 3.89 (m, 1H), 3.13 - 2.97 (m, 1H), 2.93 - 2.87 (m, 1H), 2.63 - 2.59 (m, 1H), 2.58 - 2.50 (m, 7H), 2.15 - 2.07 (m, 5H), 2.06 - 2.01 (m, 2H), 1.97 - 1.85 (m, 4H), 1.73 - 1.66 (m, 2H), 1.56 - 1.50 (m, 2H).

[0333] Compound 208: MS: m / z 793.1 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 9.03 (d, 1H), 8.11 (d, 1H), 7.87 - 7.83 (m, 2H), 7.63 (d, 1H), 7.40 (d, 1H), 7.35 (bs, 1H), 7.15 (dd, 1H), 7.03 (d, 1H), 4.98 (dd, 1H), 4.57 - 4.52 (m, 1H), 4.25 (bs, 2H), 3.97 (s, 3H), 3.95 - 3.89 (m, 1H), 3.13 (bs, 2H), 3.04 - 2.97 (m, 1H), 2.92 - 2.79 (m, 3H), 2.63 - 2.59 (m, 1H), 2.58 - 2.52 (m, 1H), 2.31 - 2.22 (m, 2H), 2.15 - 2.10 (m, 2H), 2.06 - 2.01 (m, 1H), 1.97 - 1.83 (m, 6H), 1.72 - 1.66 (m, 2H), 1.56 - 1.50 (m, 2H).

[0334] Compound 209: MS: m / z 858.6 (M+ +23); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.61 (d, 1H), 7.87 - 7.82 (m, 2H), 7.62 (d, 1H), 7.39 (d, 1H), 7.36 - 7.34 (m, 2H), 7.14 (dd, 1H), 7.02 (dd, 1H), 4.98 (dd, 1H), 4.76 - 4.72 (m, 1H), 4.56 - 4.51 (m, 1H), 4.43 (q, 2H), 3.89 - 3.83 (m, 1H), 3.70 (bs, 4H), 2.92 - 2.86 (m, 1H), 2.64 - 2.55 (m, 2H), 2.54 - 2.48 (m, 6H), 2.12 - 2.08 (m, 2H), 2.07 - 2.02 (m, 1H), 1.91 - 1.81 (m, 4H), 1.67 - 1.61 (m, 2H), 1.54 - 1.49 (m, 2H), 1.41 (t, 3H), 1.33 (d, 3H).

[0335] Compound 210: MS: m / z 870.9 (M + +23); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.55 (d, 1H), 7.87 - 7.82 (m, 2H), 7.62 (d, 1H), 7.39 - 7.37 (m, 2H), 7.14 (dd, 1H), 7.02 (dd 1H), 6.86 (d, 1H), 4.98 (dd, 1H), 4.64 - 4.51 (m, 2H), 4.44 (q, 2H), 4.27 - 4.20 (m, 2H), 3.89 - 3.78 (m, 3H), 3.10 - 3.00 (m, 1H), 2.92 - 2.86 (m, 1H), 2.80 - 2.63 (m, 4H), 2.63 - 2.56 (m, 1H), 2.52 - 2.49 (m, 1H), 2.38 - 2.75 (m, 2H), 2.12 - 2.07 (m, 2H), 2.08 - 1.96 (m, 3H), 1.95 - 1.87 (m, 2H), 1.75 - 1.61 (m, 4H), 1.55 - 1.49 (m, 2H), 1.41 (t, 3H).

[0336] Compound 211: MS: m / z 835.2 (M + +1); 1 H NMR (DMSO-d6) δ 11.06 (s, 1H), 9.02 (d, 1H), 8.14 (bs, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.64 (d, 1H), 7.40 (d, 1H), 7.38 (bs, 1H), 7.14 (dd, 1H), 7.03 (dd, 1H), 4.98 (dd, 1H), 4.82 - 4.72 (m, 1H), 4.57 - 4.52 (m, 1H), 4.44 (q, 2H), 3.95 - 3.88 (m, 1H), 3.08 - 2.94 (m, 1H), 2.92 - 2.86 (m, 1H), 2.63 - 2.56 (m, 2H), 2.56 - 2.50 (m, 6H), 2.24 - 2.08 (m, 5H), 2.08 - 2.02 (m, 2H), 2.00 - 1.82 (m, 4H), 1.72 - 1.66 (m, 2H), 1.57 - 1.50 (m, 2H), 1.42 (t, 3H), 1.34 (d, 3H).

[0337] Compound 212: MS: m / z 926.8 (M + +23).

[0338] Compound 213: MS: m / z 926.6 (M + +23); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.24 (d, 1H), 7.91 (d, 1H), 7.82 (d, 1H), 7.62 (d, 1H), 7.41 - 7.36 (m, 2H), 7.25 (d, 1H), 7.05 - 7.01 (m, 2H), 4.98 (dd, 1H), 4.64 - 4.55 (m, 1H), 4.54 - 4.41 (m, 4H), 4.47 (s, 1H), 4.01 (d, 1H), 3.05 - 3.01 (m, 2H), 2.92 - 2.86 (m, 1H), 2.72 (bs, 2H), 2.63 - 2.56 (m, 2H), 2.34 - 2.15 (m, 4H), 2.09 - 1.96 (m, 3H), 1.94 - 1.81 (m, 3H), 1.73 - 1.63 (m, 2H), 1.41 (t, 3H), 1.29 - 1.22 (m, 2H), 1.23 (s, 6H), 1.15 (s, 6H).

[0339] Compound 214: MS: m / z 924.9 (M + +23); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 7.91 (d, 1H), 7.75 (d, 2H), 7.62 (d, 1H), 7.39-7.37 (m, 2H), 7.21 (d, 1H), 7.03-7.00 (m, 2H), 6.54 (d, 2H), 4.98 (dd, 1H), 4.63-4.54 (m, 1H), 4.44 (q, 2H), 4.32 (s, 1H), 4.06 (d, 1H), 3.52-3.49 (m, 1H), 3.40-3.37 (m, 1H), 3.30-3.25 (m, 1H), 2.95-2.85 (m, 2H), 2.76 (bs, 1H), 2.62-2.59 (m, 1H), 2.59-2.54 (m, 1H),2.44-2.37 (m, 1H), 2.34-2.24 (m, 3H), 2.19-2.13 (m, 1H), 2.07-1.97 (m, 3H), 1.74-1.57 (m, 5H), 1.41 (t, 3H), 1.29-1.22 (m, 2H), 1.22 (s, 6H), 1.13 (s, 6H).

[0340] Compound 215: MS: m / z 884.3 (M + +23); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.59 (d, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.61 (d, 1H), 7.39 (d, 1H), 7.34 - 7.31 (m, 2H), 7.14 (dd, 1H), 7.02 (d, 1H), 4.98 (dd, 1H), 4.59 - 4.51 (m, 2H), 4.50 - 4.48 (m, 2H), 3.96 (s, 3H), 3.90 - 3.83 (m,1H), 3.04 - 2.99 (m, 2H), 2.93 - 2.86 (m, 1H), 2.72 (bs, 2H), 2.63 - 2.55 (m, 2H), 2.30 - 2.22 (m, 2H), 2.21 - 2.16 (m, 2H), 2.13 - 2.08 (m, 2H), 2.07 - 1.98 (m, 3H), 1.94 - 1.86 (m, 2H), 1.86 - 1.80 (m, 2H), 1.73 - 1.62 (m, 5H), 1.54 - 1.49 (m, 2H), 1.15 - 1.09 (m, 2H).

[0341] Compound 216: MS: m / z 884.5 (M + +23); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.53 (d, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.62 (d, 1H), 7.39 (d, 1H), 7.31 (s, 1H), 7.14 (dd, 1H), 7.02 (d, 1H), 6.94 (d, 1H), 4.98 (dd, 1H), 4.60 - 4.51 (m, 2H), 3.96 (s, 3H), 3.90 - 3.83 (m,1H), 3.83 - 3.57 (m, 2H), 3.49 - 3.40 (m, 1H), 3.17 - 3.07 (m, 1H), 2.92 - 2.86 (m, 1H), 2.76 (bs, 2H), 2.63 - 2.55 (m, 2H), 2.43 - 2.38 (m, 1H), 2.37 - 2.22 (m, 2H), 2.21 - 2.16 (m, 1H), 2.15 - 2.08 (m, 2H), 2.06 - 1.98 (m, 3H), 1.94 - 1.88 (m, 2H), 1.72 - 1.61 (m, 7H), 1.55 - 1.49 (m, 2H).

[0342] Compound 217: MS: m / z 834.4 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.55 (d, 1H), 7.87 - 7.82 (m, 2H), 7.61 (d, 1H), 7.39 (d, 1H), 7.31 (bs, 1H), 7.14 (dd, 1H), 7.02 (dd 1H), 6.86 (d, 1H), 4.98 (dd, 1H), 4.59 - 4.51 (m, 2H), 4.24 - 4.21 (m, 2H), 3.96 (s, 3H), 3.89 - 3.83 (m, 1H), 3.82 - 3.79 (m, 2H), 3.07 - 3.02 (m, 1H), 2.92 - 2.86 (m, 1H), 2.75 (bs, 2H), 2.70 - 2.64 (m, 2H), 2.63 - 2.56 (m, 1H), 2.52 - 2.49 (m, 1H), 2.35 - 2.29 (m, 2H), 2.12 - 2.09 (m, 2H), 2.06 - 2.00 (m, 3H), 1.92 - 1.89 (m, 2H), 1.71 - 1.61 (m, 4H), 1.55 - 1.49 (m, 2H).

[0343] Compound 218: MS: m / z 848.6 (M + + 1); 11H NMR (DMSO-d6) δ 11.07 (s, 1H), 8.52 (d, 1H), 7.87 (d, 1H), 7.82 (d, 1H), 7.62 (d, 1H), 7.40 (d, 1H), 7.32 (d, 1H), 7.14 (dd, 1H), 7.03 (dd, 1H), 6.96 (d, 1H), 4.98 (dd, 1H), 4.62 - 4.51 (m, 2H), 3.96 (s, 3H), 3.90 - 3.83 (m, 1H), 3.79 - 3.58 (m, 2H), 3.56 - 3.46 (m, 1H), 3.30 - 3.20 (m, 1H), 2.93 - 2.86 (m, 1H), 2.85 - 2.72 (m, 2H), 2.66 - 2.57 (m, 2H), 2.44 - 2.39 (m, 2H), 2.38 - 2.26 (m, 2H), 2.20 - 2.10 (m, 4H), 2.07 - 1.98 (m, 3H), 1.96 - 1.90 (m, 2H), 1.80 - 1.74 (m, 1H), 1.74 - 1.62 (m, 4H), 1.55 - 1.50 (m, 2H), 1.15 - 1.09 (m, 2H).

[0344] Compound 219: MS: m / z 910.8 (M + +23); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 7.91 (d, 1H), 7.75 (d, 2H), 7.62 (d, 1H), 7.38 (d, 1H), 7.31 (bs, 1H), 7.21 (d, 1H), 7.03 - 7.00 (m, 2H), 6.54 (d, 2H), 4.98 (dd, 1H), 4.61 - 4.54 (m, 1H), 4.33 (s, 1H), 4.06 (d, 1H), 3.96 (s, 3H), 3.52 - 3.49 (m, 1H), 3.40 - 3.36 (m, 1H), 3.30 - 3.26 (m, 1H), 2.95 - 2.86 (m, 2H), 2.76 (bs, 1H), 2.62 - 2.59 (m, 1H), 2.59 - 2.54 (m, 1H), 2.44 - 2.37 (m, 1H), 2.34 - 2.23 (m, 3H), 2.19 - 2.14 (m, 1H), 2.07 - 1.97 (m, 3H), 1.75 - 1.59 (m, 5H), 1.29 - 1.22 (m, 2H), 1.22 (s, 6H), 1.13 (s, 6H).

[0345] Compound 220: MS: m / z 822.6 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.77 (s, 2H), 8.14 (d, 1H), 7.86 (d, 1H), 7.62 (d, 1H), 7.39 (d, 1H), 7.34 (d, 1H), 7.15 (dd, 1H), 7.01 (dd, 1H), 4.98 (dd, 1H), 4.58 - 4.53 (m, 1H), 4.44 (q, 2H), 4.18 - 4.15 (m, 2H), 3.87 - 3.77 (m, 5H), 2.92 - 2.86 (m, 1H), 2.61 - 2.50 (m, 6H), 2.49 - 2.45 (m, 2H), 2.12 - 2.08 (m, 2H), 2.07 - 2.03 (m, 1H), 2.00 - 1.95 (m, 2H), 1.95 - 1.90 (m, 2H), 1.54 - 1.46 (m, 4H), 1.42 (t, 3H).

[0346] Compound 221: MS: m / z 889.7 (M + +1); 1 H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.62 (s, 1H), 7.94-7.90 (m, 2H), 7.62-7.57 (m, 2H), 7.31 (s, 1H), 7.21 (s, 1H), 7.03-7.00 (m, 2H), 6.85 (d, 1H), 4.98 (dd, 1H), 4.60-4.52 (m, 1H), 4.42-4.40 (m, 2H), 4.30 (s, 1H), 4.05 (d, 1H), 3.95 (s, 3H), 2.92-2.86 (m, 3H), 2.72 (bs, 2H), 2.63-2.55 (m, 2H), 2.30-2.21 (m, 2H), 2.21-2.14 (m, 2H), 2.07-1.97 (m, 3H), 1.86-1.78 (m, 3H), 1.73-1.63 (m, 2H), 1.28-1.22 (m, 2H), 1.22 (s, 6H), 1.12 (s, 6H).

[0347] Compound 222: MS: m / z 889.5 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.62 (d, 1H), 7.94 (d, 1H), 7.91 (d, 1H), 7.62 (d, 1H), 7.55 (d, 1H), 7.32 (bs, 1H), 7.21 (d, 1H), 7.03 - 7.00 (m, 2H), 6.47 (d, 2H), 4.98 (dd, 1H), 4.61 - 4.52 (m, 1H), 4.31 (s, 1H), 4.06 (d, 1H), 3.96 (s, 3H), 3.75 - 3.66 (m, 1H), 3.41 - 3.33 (m, 1H), 3.08 - 3.01 (m, 1H), 2.93 - 2.86 (m, 1H), 2.81 - 2.67 (m, 2H), 2.64 - 2.56 (m, 2H), 2.43 - 2.36 (m, 1H), 2.34 - 2.22 (m, 2H), 2.19 - 2.13 (m, 1H), 2.08 - 1.98 (m, 3H), 1.75 - 1.58 (m, 5H), 1.28 - 1.22 (m, 2H), 1.22 (s, 6H), 1.12 (s, 6H).

[0348] Compound 223: MS: m / z 794.4 (M + +1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.77 (s, 2H), 8.14 (d, 1H), 7.87 (d, 1H), 7.62 (d, 1H), 7.39 (d, 1H), 7.34 (d, 1H), 7.15 (dd, 1H), 7.03 (dd, 1H), 4.98 (dd, 1H), 4.56 - 4.53 (m, 1H), 4.26 - 4.24 (m, 2H), 3.97 (s, 3H), 3.86 - 3.84 (m, 4H), 3.83 - 3.77 (m, 1H), 2.93 - 2.86 (m, 1H), 2.84 - 2.82 (m, 2H), 2.61 - 2.56 (m, 5H), 2.52 - 2.49 (m, 1H), 2.13 - 2.07 (m, 2H), 2.06 - 2.01 (m, 1H), 1.94 - 1.90 (m, 2H), 1.54 - 1.48 (m, 4H).

[0349] 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 formula

[0350] 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, Massachusetts, USA) supplemented with 10% FBS (Catalog No. 10437028, Thermo Fisher Scientific, Waltham, Massachusetts, USA), 10 mM HEPES (Catalog No. 15630080, Thermo Fisher Scientific, Waltham, Massachusetts, USA) and 1 mM sodium pyruvate (Catalog No. 11360070, Thermo Fisher Scientific, Waltham, Massachusetts, USA) were seeded at 2×10 per well in a 24-well tissue culture plate. 5They were seeded at a density of [quantity not specified]. The cells were incubated at 37 °C with 5% CO₂ for 24 hours (hr), and then treated with any one of Compounds 1 to 223 at a concentration of 100 nanomolar (nM) or ARV-110 for 24 hours. After treatment, the cells were harvested, washed with PBS, and lysed and extracted with RIPA buffer (Catalog No. 89900, Thermo Fisher Scientific, Waltham, Massachusetts, USA) supplemented with Halt protease inhibitor cocktail (Catalog No. 78430, Thermo Fisher Scientific, Waltham, Massachusetts, USA) to recover protein samples. Cells not treated with the above compounds were used as negative controls.

[0351] Each protein sample was separated by polyacrylamide gel electrophoresis and transferred to a PVDF membrane for immunoblotting (Catalog No. 1620177, Bio-Rad Laboratories, Hercules, California, USA). 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, Massachusetts, USA) and a goat anti-rabbit HRP-labeled secondary antibody (1:5000 dilution) (C04003, Croyez Bioscience, Taipei City, Taiwan). GAPDH, an internal loading control, 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). Chemiluminescent signals were generated using Clarity Western ECL substrate (Catalog No. 1705061, Bio-Rad Laboratories, Hercules, California, USA) and detected with a digital image processing device, iBright FL1500 (Invitrogen, Carlsbad, California, USA).

[0352] The residual rate of the androgen receptor was determined from the androgen receptor signal (100%) in the protein sample obtained from untreated cells and the intensity difference of the androgen receptor signal in the protein sample obtained from cells treated with each compound (each androgen receptor signal was normalized with GAPDH, which is its respective internal loading control). The results of Compounds 1 to 169 are shown in Table 2. "Cpd. No." indicates the number of each compound.

[0353] Furthermore, several compounds were selected and stock solutions for treatment at a concentration of 100 nM were prepared in RPMI medium. These stock solutions for treatment were individually serially diluted (10-fold) with RPMI medium, and LNCaP.FGC cells seeded at a density of 2 × 10 5 cells / well were treated with the serially diluted samples of each 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 3. In Table 3, the results of the compounds with AR DC 50 less than 10 nM are indicated by "A", the results of the compounds with AR DC 50 of 10 nM or more and less than 25 nM are indicated by "B", the results of the compounds with AR DC 50 of 25 nM or more and less than 100 nM are indicated by "C", and the results of the compounds with AR DC 50 of 100 nM or more are indicated by "D".

[0354] It is clearly shown from Tables 2 and 3 that the compounds of the present invention have a good androgen receptor degradation effect. 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 show an overall lower AR DC 50 (nM) than ARV-100.

[0355]

Table 2

[0356]

Table 3

[0357] In Vivo Efficacy of the Compounds of the Invention in Hair Regeneration in a Male Pattern Alopecia (AGA) Mouse Model Seven-week-old male C57BL / 6 mice (black body hair) purchased from BioLASCO Taiwan were divided into groups of 6 - 8 mice per cage and administered dihydrotestosterone (DHT) (1 mg / day, dissolved in corn oil) or corn oil alone intraperitoneally once a day for 4 days. DHT is an agonist of the androgen receptor and can be used to induce symptoms of male pattern alopecia.

[0358] Four days later, depilatory cream (Nair Sensitive Hair Removal Cream, 100 mg - 200 mg per mouse) was applied to the backs of the mice to depilate them. After depilation, photographs were taken at a resolution of 4032×3024 pixels to record the skin color (Day 1, D1). The next day (D2), Compound 29 and Compound 33 were each dissolved in a solvent to prepare test solutions (3.5 μg / cm 2(Japan) Each test solution or solvent alone was topically administered to the depilated site once a day for 20 days. The depilatory cream, test solutions, and solvents were applied to separate sites on the back of the mice. The photos were analyzed using in-house developed software that utilized automatic image segmentation mainly focused on the boundaries of the depilated areas. This segmentation process included the classification of different regions within the image. This software enabled the identification of the boundaries of the depilated areas in the photos and the conversion of the colors of the depilated areas in each photo into a single color block. Next, each photo was converted into a skin color score. As shown in the color chart of Figure 1, the score was on a scale of 1 to 8, where score 1 corresponded to the depilated skin (the color of the skin itself), score 8 corresponded to the fully regrown body hair (black), and scores 2 to 7 corresponded to various stages between score 1 and score 8. Figure 2 shows photos of the depilated areas of the corn oil + solvent group and the DHT + solvent group at D1, D10, D14, D16, D17, D18, D19, and D20, and the color change indicates the effectiveness of hair regrowth. The effectiveness of hair regrowth could be evaluated by each photo and / or the skin color score.

[0359] As shown in Figure 3, in the corn oil + solvent group, the average skin color score on the 15th day reached nearly 8. Pretreatment with DHT clearly impaired the hair regrowth ability, and the impaired hair regrowth ability could be restored by the compound of the present invention. In the DHT + compound 29 group, the average skin color score reached 8 on the 20th day, and in the DHT + compound 33 group, the average skin color score reached 6.5 on the 20th day. The scores of both groups were much higher than the average skin color score of the DHT + solvent group, which reached 3.5 on the 20th day.

[0360] 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.

[0361] 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, -CH 2 OH, and 2-(trimethylsilyl)ethoxymethyl groups; 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-, 【Chemistry 2】 【change】 (In the formula, f is an integer of 0, 1, 2, 3, or 4; g is an integer of 0, 1, 2, or 3. is a linking portion represented by The 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; 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; 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; Z2 is 【Transformation 5】 selected from the group consisting of: The heteroatoms and heteroatoms in heteroarylene groups are selected from N, O and S. or a pharmaceutically acceptable salt or hydrate thereof.

2. ABM, 【Transformation 6】 (In the formula, A 1 -Cl, -F, -Br and -CF 3 Selected from: A 2 -O-, -NH-, -NCH 3 - and -NCH 2 CH 3 - selected from; 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:

3. The bifunctional compound is 【Transformation 7】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 2. The bifunctional compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, selected from the group consisting of:

4. A pharmaceutical composition comprising an effective amount of the bifunctional compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

5. 5. The pharmaceutical composition of claim 4, further comprising a second therapeutic agent.

6. 10. The bifunctional compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, or the pharmaceutical composition of claim 4 or 5, for use in treating an androgen receptor-related disease or disorder 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 4 or 5.

7. 7. The bifunctional compound, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition according to claim 6, wherein the androgen receptor-associated disease is an androgen receptor-associated cancer or an androgen receptor-associated skin disease.

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 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.

9. 9. The bifunctional compound, or a pharmaceutically acceptable salt or hydrate thereof, or a pharmaceutical composition according to claim 8, wherein the prostate cancer is castration-resistant prostate cancer and the breast cancer is triple-negative breast cancer.

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