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

Abstract

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

Description

Technical Field

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

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

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

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

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

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

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

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

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

[0010] in:

[0011] ABM is an androgen receptor binding group;

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

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

[0014]

[0015] in:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0033] The aforementioned heteroatom is selected from N, O and S.

[0034] In another inventive concept, the present disclosure provides a pharmaceutical composition comprising an effective amount of the aforementioned compound, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof; and a pharmaceutically acceptable carrier.

[0035] In another inventive concept, the present disclosure provides a method for treating an androgen receptor-related disease or abnormality in a subject in need thereof, comprising administering to the subject an effective amount of the aforementioned compound, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, or the aforementioned pharmaceutical composition.

[0036] In some specific embodiments, the CLM is represented by formula (II)-2:

[0037]

[0038] in:

[0039] One end of the –L– is connected to the Q 3 , Q 4 or Q 5 covalent bonding;

[0040] G is selected from the group consisting of -H, -OH, -CH2OH and 2-(trimethylsilyl)ethoxymethyl;

[0041] Q 1 O, S or NR C6 ;

[0042] When one end of -L- is connected to a 3 , Q 4 and Q 5 When any atom of is covalently bonded to, the atom connected to -L- is C; and, selected from Q 3 , Q 4 and Q 5 The other atoms not connected to the -L- are each independently CR C2 ;

[0043] R C2 is selected from the group consisting of -H, -D, halo, unsubstituted alkyl, and alkyl substituted with one or more halo groups; and

[0044] R C6 is selected from -H, -CH2OH, 2-(trimethylsilyl)ethoxymethyl, unsubstituted C 1-6 Alkyl and C substituted by one or more halogen groups 1-6 The group consisting of alkyl groups.

[0045] In some embodiments, the heteroatoms in Formula (II)-1 are independently selected from N, O and S.

[0046] In some embodiments, G is selected from the group consisting of -H, -OH, -CH2OH, -CH2OCOOCH3 and 2-(trimethylsilyl)ethoxymethyl.

[0047] In some specific embodiments, the 2-(trimethylsilyl)ethoxymethyl group is also abbreviated as SEM group.

[0048] In some embodiments, K is bound to the 6-membered ring by a stereospecific bond:

[0049]

[0050]

[0051] In the present disclosure, the carbon connected to K on the 6-membered ring is a chiral carbon center, and the bifunctional compound, or its pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug may have two stereoisomers having CLM represented by formula (II)-1a and formula (II)-1b. The bifunctional compound, or its pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug may have one of the aforementioned stereoisomers, or both stereoisomers.

[0052] In some embodiments, K is selected from -H, unsubstituted C 1-6 Alkyl, R C7 Substituted C 1-6 Alkyl and C 3-8 In some embodiments, K may be an unsubstituted C 1-3 Alkyl or R C7 Substituted C 1-3 alkyl.

[0053] In some embodiments, K is an alkyl group selected from the group consisting of a linear alkyl group and a branched alkyl group, each of which is unsubstituted or substituted with R C7 In some embodiments, K is selected from a linear C 1-6 Alkyl and branched C 1-6 The alkyl group consisting of alkyl groups, each of which is unsubstituted or substituted with R C7 In some embodiments, K is selected from a linear C 1-3 Alkyl and branched C 1-3 The alkyl group consisting of alkyl groups, each of which is unsubstituted or substituted with R C7 replace.

[0054] In some specific embodiments, R C1 Can be unsubstituted C 1-6 Alkyl, R C8 Substituted C 1-6 Alkyl, unsubstituted C 3-8 Aryl, R C8 Substituted C 3-8 Aryl, unsubstituted C 3-8Alkyl-aryl, R C8 Substituted C 3-8 Alkyl-aryl, unsubstituted C 1-6 Alkoxy or R C8 Substituted C 1-6 In some specific embodiments, R C1 Can be unsubstituted C 1-3 Alkyl, R C8 Substituted C 1-3 Alkyl, unsubstituted C 1-3 Alkoxy or R C8 Substituted C 1-3 Alkoxy.

[0055] In some specific embodiments, R C1 is an alkyl group selected from the group consisting of a straight-chain alkyl group and a branched-chain alkyl group, each of which is unsubstituted or substituted with R C8 In some specific embodiments, R C1 For the selection of straight chain C 1-6 Alkyl and branched C 1-6 The alkyl group consisting of alkyl groups, each of which is unsubstituted or substituted with R C8 In some specific embodiments, R C1 Select from straight chain C 1-3 Alkyl and branched C 1-3 The alkyl group consisting of alkyl groups, each of which is unsubstituted or substituted with R C8 replace.

[0056] In the present disclosure, the halide group may be F, Cl, Br or I. In the present disclosure, the halide group may be F or Cl. In the present disclosure, the halide group is F.

[0057] In the present disclosure, R C2 is selected from -H, -D (deuterium), halogen, unsubstituted C 1-6 Alkyl and C substituted by one or more halogen groups 1-6 In the present disclosure, R C2 is selected from -H, -D, -F, -Cl, unsubstituted C 1-3 Alkyl and C substituted by one or more halogen groups 1-3 The group consisting of alkyl groups.

[0058] In the present disclosure, R C4 and R C5 are each independently selected from unsubstituted C 1-6 Alkyl, R C9 Substituted C 1-6 Alkyl, unsubstituted C 3-8 Cycloalkyl, R C9 Substituted C3-8 Cycloalkyl, unsubstituted C 3-8 Heterocyclic group, R C9 Substituted C 3-8 Heterocyclic group, C 3-8 Aryl and C 3-8 In the present disclosure, R C4 and R C5 are each independently selected from unsubstituted C 1-3 Alkyl and R C9 Substituted C 1-3 In the present disclosure, R C4 It can be methyl, ethyl, n-propyl or isopropyl.

[0059] In some specific embodiments, R C4 and R C5 Each is independently an alkyl group selected from the group consisting of a straight chain alkyl group and a branched chain alkyl group, each of which is unsubstituted or substituted with R C9 In some specific embodiments, R C4 and R C5 Each is independently selected from a straight chain C 1-6 Alkyl and branched C 1-6 The alkyl group consisting of alkyl groups, each of which is unsubstituted or substituted with R C9 In some specific embodiments, R C4 and R C5 Each is independently selected from a straight chain C 1-3 Alkyl and branched C 1-3 The alkyl group consisting of alkyl groups, each of which is unsubstituted or substituted with R C9 replace.

[0060] In some specific embodiments, the CLM is represented by Formula (II)-1 or Formula (II)-2, wherein Q 1 NR C6 ; and R C6 is -H, unsubstituted C 1-6 Alkyl or C substituted by one or more halogen groups 1-6 In some specific embodiments, Q 1 NR C6 ; and R C6 H, unsubstituted C 1-3 Alkyl or C substituted by one or more halogen groups 1-3 In some specific embodiments, Q 1 NR C6 ; and R C6 For unsubstituted C 1-3 Alkyl is selected from methyl, ethyl, n-propyl and isopropyl. In some specific embodiments, Q 1NR C6 ; and R C6 is a C selected from methyl, ethyl, n-propyl, isopropyl 1-3 Alkyl groups are independently substituted with one or more halogen groups selected from F, Cl and Br.

[0061] In some embodiments, one end of -L- is connected to Q 4 or Q 5 In some embodiments, one end of -L- is covalently bonded to Q 4 Covalent bonding.

[0062] In some specific embodiments, the -L- is a bonding group represented by formula (III):

[0063]

[0064] in:

[0065] Z is selected from the group consisting of a 3- to 8-membered monocyclic ring, a 5- to 12-membered bicyclic ring, an 8- to 15-membered tricyclic ring, and a 6- to 12-membered spirobicyclic ring, each of which independently has 0 to 4 heteroatoms and 0 or 1 double bonds;

[0066] R L1 is selected from unsubstituted C 1-6 Alkyl, C 1-6 Alkoxy substituted C 1-6 Alkyl, C 1-6 Alkyl, halogen, unsubstituted C 1-6 A group consisting of an alkoxy group, a keto group and an oxide group;

[0067] R L2 A bond or an ethynylene group;

[0068] X 1 is a methylene group or an ethylene group, each of which is unsubstituted or substituted by an alkyl group or a cycloalkyl group;

[0069] X 2 and X 5 are each independently selected from unsubstituted methylene, methylene substituted with alkyl or cycloalkyl, CO, COCO, CONH, NHCO, NHCONR L3 NHCOCONR L3 -、NHSO2NR L3 、SO2NH、CHR L3 NRL4 , O and S;

[0070] X 3 Is to choose free C 1-8 Alkylene group, C 1-8 a group consisting of a heteroalkylene group, a 5- to 8-membered arylene group, a 5- to 8-membered heteroarylene group having 1 to 3 heteroatoms, a 3- to 7-membered cyclic alkylene group, a 3- to 7-membered heterocyclic alkylene group having 1 to 2 heteroatoms, and a 6- to 12-membered spirobicyclic ring having 0 to 4 heteroatoms, each of which is unsubstituted or substituted with an alkyl or cycloalkyl group;

[0071] X 4 For unsubstituted C 1-3 Alkylene or C substituted by alkyl or cycloalkyl 1-6 Alkylene;

[0072] R L3 and R L4 are each independently selected from -H, unsubstituted C 1-6 Alkyl, C 1-6 Alkoxy substituted C 1-6 Alkyl and C substituted by one or more halogen groups 1-6 A group consisting of alkyl groups;

[0073] m is 0, 1, 2, 3, 4, 5 or 6; v1 is 0 or 1; v2 is 0 or 1; v3 is 1; v4 is 0 or 1; and v5 is 1.

[0074] In some embodiments, the heteroatoms in formula (III) are each independently selected from N, O and S. In some embodiments, the Z ring contains one or two heteroatoms selected from N, O and S.

[0075] In some specific embodiments, the -L- is a bonding group represented by formula (III), wherein:

[0076] Z is selected from the group consisting of 3- to 8-membered monocyclic rings, 6- to 10-membered bicyclic rings, and 8- to 11-membered spirobicyclic rings, each of which independently has 1 to 2 heteroatoms and 0 or 1 double bonds;

[0077] R L1 is selected from unsubstituted straight chain C 1-3 The group consisting of alkyl and keto groups;

[0078] R L2It is a bond or ethynylene;

[0079] X 1 is methylene or ethylene, each of which is unsubstituted or substituted by alkyl or cycloalkyl;

[0080] X 2 is selected from unsubstituted methylene, methylene substituted by alkyl or cycloalkyl, CO, NHCO, NR L4 and O;

[0081] X 3 Is to choose free C 1-6 The group consisting of alkylene, 3- to 7-membered cycloalkylene, and 3- to 7-membered heterocycloalkylene having 0 to 2 heteroatoms, each of which is unsubstituted or substituted with alkyl or cycloalkyl;

[0082] X 4 For unsubstituted C 1-3 Alkylene or C substituted by alkyl or cycloalkyl 1-3 Alkylene;

[0083] X 5 is selected from the group consisting of unsubstituted methylene, methylene substituted with alkyl or cycloalkyl, CONH and O;

[0084] R L4 is hydrogen;

[0085] 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; and v5 is 1.

[0086] In some specific embodiments, R L1 is selected from H, unsubstituted C 1-3 Alkyl, C 1-3 Alkoxy substituted C 1-3 Alkyl, C 1-3 Alkyl, halogen, unsubstituted C 1-3 In some specific embodiments, R L1 is an oxygen ion group, which is connected to a heteroatom N of the Z ring to form an N-oxygen ion group (N + –O - ).

[0087] In some specific embodiments, R L1 For the selection of straight chain C 1-6 Alkyl and branched C 1-6 The alkyl groups consisting of alkyl groups are each unsubstituted or C 1-6 In some embodiments, RL1 For the selection of straight chain C 1-3 Alkyl and branched C 1-3 The alkyl groups consisting of alkyl groups are each unsubstituted or C 1-6 Alkoxy is substituted or substituted by one or more halo groups. In some specific embodiments, R L1 For unsubstituted C 1-3 An alkyl group selected from the group consisting of methyl, ethyl, n-propyl and isopropyl.

[0088] In some specific embodiments, X 3 Is to choose free C 1-6 The group consisting of alkylene, 3- to 7-membered cycloalkylene and 3- to 7-membered heterocycloalkylene having 0 to 2 heteroatoms, each of which is unsubstituted or C 1-6 Alkyl or C 3-6 In some specific embodiments, X 3 is an unsubstituted C 1-6 An alkylene group selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene and hexylene.

[0089] In some specific embodiments, X 4 is an unsubstituted C 1-3 An alkylene group selected from the group consisting of a methylene group, an ethylene group, and a propylene group.

[0090] In some specific embodiments, X 5 is selected from the group consisting of methylene, CONH and O.

[0091] In some specific embodiments, R L3 and R L4 Each is independently selected from a straight chain C 1-6 Alkyl and branched C 1-6 The alkyl groups consisting of alkyl groups are each unsubstituted or C 1-6 In some embodiments, R L3 and R L4 Each is independently selected from a straight chain C 1-3 Alkyl and branched C 1-3 The alkyl groups consisting of alkyl groups are each unsubstituted or C 1-6 The alkoxy group is substituted or substituted by one or more halogen groups.

[0092] In some specific embodiments, the -L- is selected from

[0093]

[0094]

[0095] the groups formed;

[0096] wherein f is an integer of 0, 1, 2, 3 or 4; and

[0097] g is an integer of 0, 1, 2 or 3.

[0098] In some specific embodiments, the ABM is an androgen receptor binding group represented by the following formula:

[0099]

[0100] in:

[0101] Z 1 is selected from the group consisting of aryl, heteroaryl, bicyclic group or bi-heterocyclic group, each of which is independently substituted by one or more substituents independently selected from the group consisting of halo, hydroxyl, nitro, -CN, -C≡CH, unsubstituted C 1-6 Alkyl, C 1-6 Alkoxy substituted C 1-6 Alkyl, C 1-6 Alkyl, unsubstituted C 1-6 Alkoxy, C 1-6 Alkoxy, unsubstituted C 2-6 Alkenyl, C 2-6 Alkenyl, unsubstituted C 2-6 Alkynyl, C 3-6 Alkynyl and any combination thereof;

[0102] Y 1 and Y 2 Each is independent of NR Y1 , O or S;

[0103] Y 3 , Y 4 and Y 5 are independently selected from a bond, -O-, -NR Y2 -、-C(-R Y1 )(-R Y2 )-, -C(=O)-, -C(=S)-, -S(=O)-, -SO2-, a heteroarylene group and an arylene group;

[0104] Y 6 For -N(-R Y1)-, -O-, or -S-;

[0105] M is a 3- to 6-membered ring having 0-4 heteroatoms, which is unsubstituted or substituted with 0-6 R M Base substitution;

[0106] Each R M The radicals are independently selected from unsubstituted C 1-6 Alkyl, C 1-6 Alkoxy substituted C 1-6 Alkyl, C 1-6 Alkyl, halide and C 1-6 Alkoxy group; or, two R M The radical and the atoms to which it is attached together form a 3- to 8-membered ring system containing 0 to 2 heteroatoms;

[0107] R a , R b , R c , R d , R Y1 and R Y2 are each independently selected from -H, unsubstituted C 1-6 Alkyl, C 1-6 Alkoxy substituted C 1-6 Alkyl, C 1-6 Alkyl, halogen, C 1-6 The group consisting of alkoxy, cyclic group and heterocyclic group; or, R a , R b Together with the atoms to which they are attached, they form a 3- to 8-membered ring system containing 0 to 2 heteroatoms;

[0108] Z 2 Is to choose from one-key knot, C 1-6 Alkylene, C 1-6 The group consisting of a heteroalkylene group, -O-, an arylene group, a heteroarylene group, an alicyclic bivalent group, a heterocyclic bivalent group, a heterobicyclic bivalent group, a bicyclic arylene group and a bicyclic heteroarylene group, each of which is unsubstituted or substituted with 1 to 10 R Z2 Base substitution;

[0109] Each R Z2The radicals are independently selected from the group consisting of: -H, halogen, unsubstituted C 1-6 Alkyl, C substituted with one or more -F 1-6 Alkyl, -OR Z2A , C 3-6 Cycloalkyl, C 4-6 Cycloheteroalkyl, unsubstituted C 1-6 Alkyl, C 1-3 Alkyl substituted C 1-6 Alkyl, C 1-6 Alkoxy substituted C 1-6 Alkyl, C 1-6 Alkyl, unsubstituted heterocyclic, C 1-3 Alkyl-substituted heterocyclic group, C 1-6 Alkoxy-substituted heterocyclic group, heterocyclic group substituted by one or more halogen groups, unsubstituted aryl group, C 1-3 Alkyl-substituted aryl, C 1-6 Alkoxy-substituted aryl, aryl substituted with one or more halogen groups, unsubstituted heteroaryl, C 1-3 Alkyl-substituted heteroaryl, C 1-6 Alkoxy-substituted heteroaryl, heteroaryl substituted with one or more halogen groups, bicyclic heteroaryl, unsubstituted C 1-3 Alkoxy and one or more selected from -F, -OH, -NH2, -NR Y1 R Y2 and -CN substituted with a substituent 1-3 Alkoxy; and

[0110] R Z2A Is the choice of -H, C 1-6 Alkyl and C 1-6 The group consisting of heteroalkyl, each of which is unsubstituted or substituted with cycloalkyl, cycloheteroalkyl, aryl, heterocyclyl, heteroaryl, halo, or C 1-3 Alkoxy substitution.

[0111] In some embodiments, the heteroatoms in formula (IV)-a, (IV)-b, (IV)-c or (IV)-d are each independently selected from N, O and S.

[0112] In some specific embodiments, Z 1 It is freedom to choose

[0113] The group composed of.

[0114] In some specific embodiments, Z 1 It is freedom to choose The group composed of.

[0115] In some specific embodiments, Z 2 It is freedom to choose

[0116] The group composed of.

[0117] In some specific embodiments, M is

[0118] In some specific embodiments, each R M The groups are independently selected from linear C 1-6 Alkyl and branched C 1-6 The alkyl groups consisting of alkyl groups are each unsubstituted or C 1-6 In some embodiments, each R M The groups are independently selected from linear C 1-3 Alkyl and branched C 1-3 The alkyl groups consisting of alkyl groups are each unsubstituted or C 1-6 In some embodiments, each R M The groups are independently methyl, ethyl, n-propyl or isopropyl.

[0119] In some specific embodiments, R a , R b , R c , R d , R Y1 and R Y2 are independently selected from the linear C 1-6 Alkyl and branched C 1-6 The alkyl groups consisting of alkyl groups are each unsubstituted or C 1-6 In some embodiments, R a , R b , R c , R d , R Y1 and R Y2 are independently selected from the linear C 1-3 Alkyl and branched C 1-3 The alkyl groups consisting of alkyl groups are each unsubstituted or C 1-6 In some embodiments, R a , R b , R c , R d , RY1 and R Y2 Each is independently methyl, ethyl, n-propyl or isopropyl.

[0120] In some specific embodiments, (Y 3 ) 0-5 for The designation (R) means that the carbon has the R (rectus) configuration.

[0121] In some specific embodiments, each R Z2 The groups are independently selected from linear C 1-6 Alkyl and branched C 1-6 The alkyl groups of the group consisting of alkyl groups are each unsubstituted or substituted with one or more halogen groups. Z2 The groups are independently selected from linear C 1-3 Alkyl and branched C 1-3 The alkyl groups of the group consisting of alkyl are individually unsubstituted or substituted by one or more halogen groups.

[0122] In some specific embodiments, R Z2A For the selection of straight chain C 1-6 Alkyl and branched C 1-6 In some specific embodiments, R Z2A For the selection of straight chain C 1-3 Alkyl and branched C 1-3 The alkyl group of the group consisting of alkyl.

[0123] In some specific embodiments, R Z2A For a free straight chain C 1-6 Heteroalkyl and branched C 1-6 In some specific embodiments, R Z2A For a free straight chain C 1-3 Heteroalkyl and branched C 1-3 The heteroalkyl group is composed of heteroalkyl groups.

[0124] In some specific embodiments, the ABM is selected from

[0125]

[0126] the groups formed;

[0127] in:

[0128] A1 is selected from -Cl, -F, -Br or -CF3;

[0129] A2 is selected from -O-, -NH-, -NCH3- or -NCH2CH3-; and

[0130] A3, A4, A5 and A6 are each independently CH or N.

[0131] In some specific embodiments, the ABM is an androgen receptor binding group represented by formula (IV)-b, wherein M is a 4-membered alicyclic ring having 0 to 2 heteroatoms, which is unsubstituted or optionally substituted with 1 to 6 R M The other groups are as defined above.

[0132] In some specific embodiments, the ABM is an androgen receptor binding group represented by formula (IV)-b, wherein Z 2 For a key, C 1-6 Alkylene, C 1-6 heteroalkylene, -O-, arylene, heteroarylene, alicyclic divalent group, heterocyclic divalent group, heterobicyclic divalent group, bicyclic arylene and bicyclic heteroarylene, each of which is substituted by 1, 2 or 3 R Z2 The other groups are as defined above.

[0133] In some specific embodiments, the ABM is an androgen receptor binding group represented by formula (IV)-b, wherein

[0134] Z 1 for

[0135] R ZA1 is -H or -CN;

[0136] Each R Z1B is independently -H, halo or -CF3; t is 0, 1, 2, 3 or 4;

[0137] Y 3 -O- or -NRY 2 -;

[0138] M is a 4- to 6-membered ring which is unsubstituted or substituted with 1 to 4 R M and each R M is independently -H or methyl;

[0139] Y 4 is -NH-;

[0140] Y 5 is -C(=O)-;

[0141] Z 2 is independently selected from an unsubstituted C 5-6 Aryl, one, two or three R Z2 C 5-6 Aryl, a C 5-6Heteroaryl, a group having 1 heteroatom and 1, 2 or 3 R Z2 C 5-6 heteroaryl and a radical having 2 heteroatoms and 1 or 2 R Z2 C 5-6 The group consisting of heteroaryl groups;

[0142] R Y2 is -H or unsubstituted C 1-3 an alkyl group selected from methyl, ethyl, n-propyl or isopropyl;

[0143] Each R Z2A The group is selected from a straight chain C 1-6 Alkyl and branched C 1-6 In some specific embodiments, R Z2A For the selection of straight chain C 1-3 Alkyl and branched C 1-3 The other groups are as defined above.

[0144] In some specific embodiments, the ABM is an androgen receptor binding group represented by formula (IV)-d, wherein

[0145] Z 1 is an aryl group substituted by one or more halogen groups, or an aryl group substituted by -CN, or an aryl group independently substituted by -CN and one or more halogen groups;

[0146] Y 3 For a bond, -NR Y2 -、-CR Y1 R Y2 - or -C(=O)-;

[0147] M is a 5-membered aromatic ring having 1 or 2 heteroatoms;

[0148] R Y1 and R Y2 Each is independently H or C 1-6 alkyl;

[0149] Z 2 is a bond, aryl or heteroaryl, each of which is optionally substituted by 1, 2 or 3 R w2 Replace; and each R w2 is independently -H, halogen, C 1-6 Alkyl (optionally substituted with one or more -F), C 1-3 Alkoxy (optionally substituted with one or more -F);

[0150] R W2The radical is independently selected from the group consisting of -H, a halogen radical, a 6-membered alicyclic radical having 1 or 2 heteroatoms, or a 5-membered aromatic radical having 1, 2 or 3 heteroatoms. The definitions of the other radicals are as described above.

[0151] In some specific embodiments, the ABM is an androgen receptor binding group represented by formula (IV)-d, wherein

[0152] Z 1 for

[0153] Among them, each R Z1A is halogen or CN; and each R Z1B are independently H or halogen. The other groups are as defined above.

[0154] In some embodiments, the ABM is selected from

[0155]

[0156]

[0157] The group composed of.

[0158] In some embodiments, the pharmaceutical compositions of the present disclosure further comprise a second therapeutic agent.

[0159] In some embodiments, the androgen receptor-related disease is an androgen receptor-related cancer or an androgen receptor-related skin disease.

[0160] In some embodiments, the androgen receptor-related cancer is breast cancer or prostate cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the prostate cancer is castration-resistant prostate cancer.

[0161] In some specific embodiments, the androgen receptor-associated skin disease is androgenic alopecia, acne, hidradenitis suppurativa, hirsutism or atopic dermatitis.

[0162] In some embodiments, the method of treating an androgen receptor-related disease further comprises administering an effective amount of a second therapeutic agent.

[0163] In some embodiments, the second therapeutic agent may be an androgen receptor inhibitor. An example of the androgen receptor inhibitor may be enzalutamide.

[0164] In some specific embodiments, the second therapeutic agent may be an antitumor agent known in the art. Examples of known antitumor agents include docetaxel, flutamide, goserelin acetate, leuprolide acetate, colchicine, leuprolide acetate, mitoxantrone hydrochloride, 5-fluorouracil and olaparib. Examples include one or more cyclophosphamide, mitomycin C, etc.

[0165] In some specific embodiments, the second therapeutic agent may be a therapeutic agent known in the art for treating AR-related skin diseases. Examples of known anti-tumor agents include Clascoterone, ASC-J9, Spironolactone, Flutamide, Finasteride, Dutasteride, Cyproterone acetate, Pyrilutamide, Minoxidil, Ketoconazole, etc.

[0166] When used in this specification and claims, the articles "a" and "an" refer to one or more than one (ie, at least one) of the grammatical objects of the article unless the context clearly indicates otherwise. For example, "a component" means one component or more than one component.

[0167] When used in this specification and claims, the word "and / or" should be understood to mean "either or both" of the components so connected, that is, in some cases, the components are present together; and in some cases, the components are present separately. Multiple components listed with "and / or" should be interpreted in the same way, that is, "one or more" of the multiple components so connected. Other components other than the components specifically defined by the "and / or" clause may optionally exist, whether related or unrelated to those specifically defined components. Therefore, as a non-limiting example, when "A and / or B" is used with an open term such as "comprising", it may refer to only A (optionally including components other than B) in one specific embodiment; it may refer to only B (optionally including components other than A) in another specific embodiment; it may refer to both A and B (optionally including other components) in yet another specific embodiment, etc.

[0168] When used in this specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as inclusive, i.e., including at least one of the multiple components or components in the list, but also including more than one component, and optionally including additional items not listed. Only when the words clearly indicate the opposite meaning, such as "only one of" or "exactly one of", or when "consisting of" is used in the claims, it will refer to including exactly one of the multiple components or components in the list. Generally speaking, when there is an exclusive term such as "either", "one of", "only one of" or "exactly one of", the word "or" used in this article should only be interpreted as referring to exclusive alternative items (i.e., "one or the other, but not both".

[0169] In the claims and the foregoing specification, all conjunctions such as "comprise," "include," "carry," "have," "contain," "involve," "hold," "composed of," and the like are to be understood as open-ended, that is, meaning including but not limited to. Only the conjunctions "consisting of" and "consisting essentially of" shall be closed or semi-closed conjunctions, respectively, as provided in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0170] When used in this specification and claims, the term "at least one" referring to a list of one or more components should be understood to mean at least one component selected from any one or more components in the list of components, but does not necessarily include at least one component of each and every component specifically listed in the list of components, and does not exclude any combination of components in the list of components. This definition also allows components other than the components specifically defined in the list of components referred to by the term "at least one" to optionally exist, whether related or unrelated to those specifically defined components. Therefore, as a non-limiting example, "at least one of A and B" (or equivalently "at least one of A or B", or equivalently "at least one of A and / or B") may refer to at least one, and optionally more than one A, without B (and optionally including components other than B) in one specific embodiment; and may refer to at least one, and optionally more than one B, without A (and optionally including components other than A) in another specific embodiment; and may refer to at least one, and optionally more than one A, and at least one, and optionally more than one B (and optionally including other components), etc. in another specific embodiment.

[0171] It should also be understood that in some of the methods described herein that include more than one step or action, unless otherwise specified, the order of those steps or actions in the method are not necessarily limited to the order of those steps or actions in the method described.

[0172] The term "effective" may mean, but is in no way limited to, an amount / dose that can achieve or is sufficient to prevent, inhibit the occurrence, alleviate, delay or treat (relieve symptoms to a certain extent, preferably all) the symptoms of a condition, disorder or disease state in a subject who needs such treatment or is receiving such treatment when the active pharmaceutical ingredient is used for the intended use in the context. The term "effective" encompasses all other effective amount or effective concentration terms, such as "effective amount / dose", "pharmaceutically effective amount / dose" or "therapeutically effective amount / dose" otherwise described or used in this application.

[0173] The effective amount depends on the type and severity of the disease, the composition used, the route of administration, the species of mammal to be treated, the physical characteristics of the particular mammal under consideration, and the concomitant drugs and other factors that can be recognized by those skilled in the art of medicine. The exact amount can be determined by those skilled in the art by conventional techniques (e.g., see Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0174] The terms "pharmaceutically acceptable" or "pharmaceutically acceptable" may mean, but are in no way limited to, entities and compositions that do not produce adverse, allergic or other untoward reactions when administered to an animal or a human as desired.

[0175] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable carrier" may mean, but is in no way limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are compatible with the administration of the pharmaceutical. Suitable carriers are described in the latest edition of Remington's Pharmaceutical Sciences, a standard reference text in this field, incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutical active ingredients is well known in the art. Unless any conventional media or agent is incompatible with the active compound, its use in the composition should be considered. Supplementary active compounds may also be incorporated into the composition.

[0176] Unless otherwise indicated, the term "compound" as used herein refers to any specific chemical compound disclosed herein, and includes tautomers, regioisomers, geometric isomers thereof; where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers); where applicable, pharmaceutically acceptable salts and derivatives thereof (including prodrug forms). In its use in the context, the term compound generally refers to a single compound, but may also include other compounds, such as stereoisomers, regioisomers and / or optical isomers (including racemic mixtures), as well as specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds. In this context, the term also refers to prodrug forms of compounds that are modified to facilitate administration and delivery of the compound to an active site. It should be noted that in describing the compounds herein, a number of substituents and associated variations are specifically described with respect thereto.

[0177] It will be understood by those skilled in the art that the molecules described herein are stable compounds as described below. When double bonds and single bonds are used, they are represented or understood within the context of the compound being described and according to the well-known rules of valence interactions.

[0178] As used herein, "alkoxy" refers to an alkyl group having a single bond to oxygen; for example, methoxy (-O-CH3) and ethoxy (-O-CH2CH3).

[0179] As used herein, "derivatives" may refer to compositions directly formed from natural compounds by modification or by partial substitution. As used herein, "analogs" may refer to compositions having structures similar to, but not identical to, natural compounds.

[0180] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting them for degradation. For example, the cerebellum protein E3 ubiquitin ligase, when present alone or in combination with an E2 ubiquitin-conjugating enzyme, attaches ubiquitin to a lysine on a target protein, which is then targeted to a specific substrate protein for degradation by the proteasome. Thus, E3 ubiquitin ligases, when present alone or in a complex with an E2 ubiquitin conjugating enzyme, are responsible for the transfer of ubiquitin to a target protein. In general, ubiquitin ligases involve polyubiquitination, whereby a second ubiquitin is attached to the first; a third to the second, and so on. Polyubiquitination marks a protein for degradation by the proteasome. However, some ubiquitination events are defined as mono-ubiquitination, where only a single ubiquitin is added to a substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins are not targeted for degradation by the proteasome, but may change their cellular location or function; for example, by binding to other proteins with domains that can bind ubiquitin. Further, E3 ubiquitin ligases promote the formation of polyubiquitin chains through lysine residues on ubiquitin. Lys48-linked chains are the main type of polyubiquitination, which can target proteins to the proteasome for degradation.

[0181] The term "patient" or "subject" is used throughout the specification to describe a cell, tissue or animal, preferably a mammal, such as a human or a domesticated animal, to which the compositions of the present disclosure are provided for treatment (including prophylactic treatment). For a specific treatment for an infection, disorder or disease state in a specific animal, such as a human patient, the term "patient" refers to a specific animal, including a domestic animal such as a dog or cat, or a farm animal such as a horse, a cow, a sheep, etc. Unless otherwise indicated or implied in the context of the term, in the present disclosure, the term "patient" generally refers to a human patient.

[0182] It should be understood that in all examples disclosed herein, the description of an integer range for any variable describes the range of the variable, all individual numbers within the range, and all possible subranges. For example, the description that n is an integer from 0 to 4 describes 0, 1, 2, 3, and 4 as independently selectable values ​​within the range. In addition, the description that n is an integer from 0 to 4 also describes its individual and all subranges, where n is individually 0 to 4, 0 to 3, 0 to 2, 0 to 1, 1 to 4, 1 to 3, 1 to 2, 2 to 4, 2 to 3, and 3 to 4. In addition, the term "C 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbons.

[0183] The following is a detailed description to assist those skilled in the art in implementing the present disclosure. Those skilled in the art may modify or vary the specific embodiments described herein without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, drawings, and other references mentioned herein are expressly incorporated herein by reference in their entirety. BRIEF DESCRIPTION OF THE DRAWINGS

[0184] Figure 1 This is a color chart with skin color scores from 1 to 8 used in the hair regrowth experiment in C57BL / 6 mice.

[0185] Figure 2 The photographs are of the corn oil + vehicle group and the DHT + vehicle group.

[0186] Figure 3 is a line graph showing the hair regrowth efficacy of the disclosed compounds. DETAILED DESCRIPTION

[0187] Table 1 below shows examples of bifunctional compounds having an ABM-L-CLM structure according to the present disclosure:

[0188] Table 1

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206] Methods of producing compounds of the present disclosure

[0207] The following is an example of a general method for producing the compounds of the present disclosure. In addition, extraction and purification can be carried out using conventional organic chemical experimental treatments.

[0208] The synthesis of the compounds disclosed herein can be carried out by referring to procedures known in the art.

[0209] The starting material compounds described in this specification, commercially available compounds, compounds disclosed in the present invention, compounds described in references cited in this specification, and other known compounds can be used.

[0210] Among the compounds disclosed herein, some compounds may exist as tautomers, and the present disclosure includes all possible isomers and mixtures thereof, including the above-mentioned tautomers.

[0211] When it is desired to obtain a salt of the compound of the present disclosure, when the compound of the present disclosure is obtained in the form of a salt, it can be purified as such, and when the compound of the present disclosure is obtained in the free form, a conventional method can be used to form a salt by dissolving or suspending the compound in a suitable organic solvent and adding an acid or a base.

[0212] Furthermore, in some cases, the compounds of the present disclosure and their pharmaceutically acceptable salts exist in the form of an addition product with water or various solvents (hydrates or solvates), and these addition products are included in the present disclosure.

[0213] The details of one or more specific embodiments of the present disclosure are as described below in the specification. Other features, objectives and advantages of the present disclosure will be apparent from the description and claims.

[0214] The compounds of the present disclosure can be synthesized from commercially available starting materials by methods known in the art. For example, the compounds of the present disclosure can be prepared by the following pathways:

[0215] General steps for compound preparation:

[0216] Step 1

[0217]

[0218] Step 1 depicts a general method for preparing the bifunctional compound of the present disclosure. In the first stage, the diester compound (i) is condensed with 3-aminopiperidine-2,6-dione to form an intermediate (ii). In the second stage, the intermediate (ii) is further condensed with a specific ABM compound to obtain the desired compound (iii). The letter "P" shown in the aforementioned step 1 represents a protecting group.

[0219] The following specific examples should be interpreted as merely illustrative and will not limit the remainder of the disclosure in any way. Without further elaboration, it is believed that those skilled in the art will be able to maximize the disclosure based on the description herein. All publications cited herein are incorporated herein by reference in their entirety.

[0220] Synthesis method A-Synthesis of compound 1:

[0221] (1) Preparation of Compound IA

[0222] Compound IA was first prepared from commercially available 2-benzyloxyethanol by the following route:

[0223] Synthesis process Figure 1

[0224]

[0225] In a tetrahydrofuran (THF) solution (80 mL) containing 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), diisopropyl azodicarboxylate (DIAD) (11.3 mL, 57.6 mmol) was added dropwise. After the addition of DIAD, the mixture was stirred under nitrogen for 18 hours (h) to obtain a crude mixture. After the solvent was evaporated, ether was added to resuspend the crude mixture, and triphenylphosphine oxide was filtered off. The solid was washed with ether (10 mL), and the filtrate was evaporated to obtain a yellow oil. The yellow oil was purified by column chromatography using silica gel (KM3 SCIENTIFIC CORP., particle size 45-75 μm) with an eluent (n-hexane:ethyl acetate=4:1) to obtain compound I-a1 (13 g, 47.6 mmol).

[0226] Iron powder (10.29 g, 0.18 mol) was added to an ethanol / water (EtOH / H2O) solution (263 mL, v / v=4:1) containing compound I-a1 (21.0 g, 0.077 mol) and ammonium chloride (NH4Cl) (9.96 g, 0.18 mol) at room temperature. The reaction mixture was heated to reflux for 2 hours and then cooled to room temperature. Celite (10 g) was then added and stirred for 30 minutes (min.). The mixture was filtered and the solid was washed three times with methanol (MeOH) (20 mL) and dichloromethane (DCM) (20 mL). The filtrate was washed with 30 mL of saturated sodium bicarbonate (NaHCO3) aqueous solution. The aqueous phase was extracted with DCM (20 mL×3). The combined organic phase was washed with brine (20 mL x 3), dried over sodium sulfate (Na2SO4), and concentrated in vacuo to give compound I-a2 (15.7 g, yield: 84%).

[0227] Palladium acetate (Pd(OAc)2) (262 mg, 20 mol%) was added to compound I-a2 (1.7 g, 6.99 mmol), dimethyl acetylenedicarboxylate (0.71 mL, 5.8 mmol) and a mixture of dimethylacetamide (DMA) / pivalic acid (PivOH) (4:1 v / v; 28 mL) in a 100 mL two-necked bottle, and then the bottle was purged with air. The reaction mixture was gradually heated from room temperature to 110°C under air purging and stirred for 8 hours, during which it was monitored by liquid chromatography mass spectrometry (LC-MASS). After the reaction was completed, the solution was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with H2O (3×10 mL), dried over magnesium sulfate (MgSO4), filtered, and evaporated in vacuo to obtain a crude product. The crude product was purified by column chromatography using silica gel (KM3 SCIENTIFIC CORP., particle size 45-75 μm) with an eluent (n-hexane: ethyl acetate = 5: 1) to obtain 5-(2-benzyloxy-ethoxy)-1H-indole-2,3-dicarboxylic acid dimethyl ester (5-(2-benzyloxy-ethoxy)-1H-indole-2,3-dicarboxylic acid dimethyl ester) I-a3 (1.14 g, yield: 50%) as a brown solid.

[0228] An ice-cold solution of 5-(2-benzyloxy-ethoxy)-1H-indole-2,3-dicarboxylic acid dimethyl ester I-a3 (3.0 g, 8.84 mmol) in N,N-dimethylformamide (DMF) (15 mL) was treated with 60% sodium hydride (NaH) (0.53 g, 13.3 mmol) and iodomethane (0.82 ml, 13.3 mmol) and then warmed to room temperature. After 1 hour, the reaction mixture was partitioned between DCM and saturated aqueous NH4Cl. The combined organic layers were collected, washed with water (3×) and brine, then dried over MgSO4, filtered and concentrated to give a crude product. The crude product was purified by column chromatography using silica gel (KM3 SCIENTIFIC CORP., particle size 45-75 μm) and an eluent (n-hexane: ethyl acetate = 3:1) to obtain a brown solid compound I-a4 (2.7 g, yield: 87%).

[0229] Compound I-a4 (0.6 g, 1.51 mmol) was treated with a solution of sodium hydroxide (NaOH) (0.6 g, 15.1 mmol) in EtOH (30 mL) and heated to reflux (85°C bath temperature). After 4 hours, the reaction mixture was cooled to ambient temperature, excess EtOH was removed, diluted with ethyl acetate (EtOAc) (30 mL), acidified to pH=3 with 1M hydrochloric acid (HCl), and the layers were separated. The aqueous layer was then extracted with EtOAc (30 mL), and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give a white solid. The white solid was then combined with acetic anhydride (Ac2O) (5 mL) and heated to 140°C. After 2 hours, a monoester was found by LC-MASS, and the reaction mixture was cooled to ambient temperature. Excess Ac2O was then removed, anhydrous toluene was added and concentrated. Thus, the residue I-a5 was produced, which was used without any further purification.

[0230] The above residue I-a5 was dissolved in THF (20 mL), and then 3-aminopiperidine-2,6-dione hydrochloride (0.25 g, 3.0 mmol) and triethylamine (TEA) (1.52 g, 15.1 mmol) were added. The mixture was stirred at 50°C for 4 hours. After the reaction was completed, the reaction mixture was cooled to ambient temperature, diluted with EtOAc, and acidified to pH = 3 with 1M HCl. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to obtain a residue. The residue was then dissolved in THF (20 mL), and N,N'-carbonyldiimidazole (CDI) (0.49 g, 3.0 mmol) and 4-dimethylaminopyridine (DMAP) (18 mg, 0.15 mmol) were added to obtain a mixture. The mixture was stirred at 50°C for 4 hours. After the reaction was completed, the reaction mixture was cooled to ambient temperature, diluted with EtOAc, and acidified to pH = 3 with 1M 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 column chromatography using silica gel (KM3 SCIENTIFIC CORP., particle size 45-75 μm) with an eluent (n-hexane: ethyl acetate = 1: 4) to obtain compound I-a6 (0.41 g, yield: 60%).

[0231] To a solution of compound I-a6 (100 mg, 0.22 mmol) in DCM (6 mL), 1 M boron tribromide (BBr3) (0.87 mL) in DCM was slowly added at -78 °C. The mixture was stirred at -60 °C for 3 hours. After the reaction was complete, water was slowly added, the resulting mixture was warmed to ambient temperature, and diluted with THF. The organic matter was washed with brine, dried with Na2SO4, filtered and concentrated to obtain compound I-a7. Compound I-a7 was then dissolved in DCM (10 mL), and Dess-Martin periodinane (186 mg, 0.44 mmol) and NaHCO3 (37 mg, 0.44 mmol) were added. The mixture was stirred at room temperature for 17 hours. After the reaction was complete, water was added to obtain a mixture, and the mixture was diluted with DCM. The organic matter was washed with brine, dried with Na2SO4, filtered and concentrated to obtain compound IA. Compound IA was used in the next synthetic step without further purification.

[0232] (2) Preparation of Compound IB

[0233] Secondary amine compound IB was prepared from commercially available 4-[(trans-3-amino-2,2,4,4-tetramethylcyclobutyl)oxy]-2-chloro-, hydrochloride by the following route:

[0234] Synthesis process Figure 2

[0235]

[0236] To a mixture of 4-[(trans-3-amino-2,2,4,4-tetramethylcyclobutyl)oxy]-2-chloro-benzonitrile hydrochloride (1 g, 3.59 mmol) I-b1 and 4-(4-carboxyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.2 g, 4.00 mmol) I-b2 in DMF (8 mL) was added 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 at room temperature. hexafluorophosphate, HATU) (1.6 g, 4.30 mmol) and then stirred at room temperature for 24 hours. The reaction was concentrated to remove the solvent, and then water was added to obtain a solution, and the solution was extracted with DCM (30 mL×2). The organic matter was washed with brine, dried over MgSO4, filtered and concentrated to obtain compound I-b3 (1.6 g, 76%). Compound I-b3 and trifluoroacetic acid (CF3COOH) (2.5 mL) were then combined and stirred in dichloromethane (CH2Cl2) (10 mL) at room temperature for 4 hours. After the reaction was completed, the excess CF3COOH was removed under vacuum to obtain a residue. The residue was then diluted with DCM (10 mL) and alkalized to pH=10 with sodium carbonate (Na2CO3). The organic layer was washed with brine (3 mL), dried over Na2SO4, filtered and concentrated to obtain a compound IB, which was used directly without purification.

[0237] (3) Preparation of Compound 1 from Compound IA and Secondary Amine Compound IB

[0238] Compound 1 is prepared by the following route:

[0239] Synthesis process Figure 3

[0240]

[0241] To a mixture of compound IA (46 mg, 0.125 mmol) and compound IB (23 mg, 0.05 mmol) in DCM (1 mL) was added sodium triacetoxyborohydride (NaBH(OAc)3) (36 mg, 0.17 mmol). The resulting solution was stirred at room temperature for 17 hours. After the reaction was completed, the 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 HNMR(DMSO-d6)δ11.06(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).

[0242] Synthesis method B-Synthesis of compound 2:

[0243] (1) Preparation of Compound IC

[0244] Compound IC was first prepared from commercially available 4-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester by the following route:

[0245] Synthesis Flow Chart 4

[0246]

[0247] In a DCM solution (50 mL) containing tert-butyl 4-(2-hydroxy-ethyl)-piperidine-1-carboxylate (3.5 g, 15.5 mmol), triethylamine (6.3 mL, 46.5 mmol) was added, followed by methanesulfonyl chloride (MsCl) (1.8 mL, 23.25 mmol) in an ice bath and stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated NaHCO3 (10 mL) and saturated NH4Cl (aq) (10 mL), and dried over MgSO4. The solvent was removed to obtain a crude product, which was purified by flash column with eluent (n-hexane / EtOAc=3 / 1 to 1 / 1) to obtain compound I-c1 (4.67 g, 98%).

[0248] Pd(OAc)2 (1.13 g, 10 mol%) was added to a solution of 3-benzyloxy-aniline (10 g, 50.1 mmol), dimethyl butynedioate (5.86 mL, 47.6 mmol) and dimethylacetamide (DMA) / pivalic acid (PivOH) (4:1 v / v; 100 mL) in a container flushed with air. The reaction mixture was gradually heated to 120°C for 8 hours. After the reaction was completed, the solution was cooled to room temperature, diluted with ethyl acetate (200 mL), washed with water (50 mL×3) and brine (50 mL), dried with MgSO4, filtered, and evaporated in vacuo to obtain a crude product. The crude product was purified by column chromatography using silica gel (KM3 SCIENTIFIC CORP., particle size 45-75 μm) with an eluent (n-hexane: ethyl acetate = 5:1) to obtain compound I-c2 (8.4 g, 54%) as a brown solid.

[0249] To a solution of compound I-c2 (5.0 g, 14.73 mmol, 1 eq.) in acetonitrile (CH3CN) (50 mL), cesium carbonate (Cs2CO3) (9.6 g, 29.47 mmol, 2.0 eq.) and ethyl bromide (1.65 mL, 22.10 mmol, 1.5 eq.) were added in sequence in a nitrogen (N2) atmosphere at 25°C. The mixture was heated at 80°C for 4 hours until no compound I-c2 remained, and the reaction mixture was cooled to room temperature. The solvent was reduced to half of the original volume, diluted with ethyl acetate (50 mL), and washed with water (100 mL). The layers were separated, and 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 in vacuo. The crude material was purified by flash column chromatography using silica gel (KM3 SCIENTIFIC CORP., particle size 45-75 μm) eluted with 15-20% ethyl acetate / n-hexane to give compound I-c3 (4.8 g, 88%).

[0250] Compound I-c3 (2.0 g) was degassed in MeOH solution (60 mL), and palladium on carbon (Pd / C) (0.2 g, 10 wt%) was added, after which the reaction mixture was bubbled with a hydrogen balloon and stirred at room temperature for 2 hours. When the reaction was complete, the reaction mixture was filtered through a Celite plug, and the filter cake was washed with ethyl acetate (EA). The filtrate was concentrated by rotary evaporation to give compound I-c4 (1.49 g, 99% yield).

[0251] Potassium carbonate (K2CO3) (2.65 g, 3.0 eq) was added to a solution of compound I-c4 (1.75 g, 6.31 mmol) in acetonitrile (15 mL), and stirred at 60°C to obtain a suspension. After 30 minutes, the suspension was cooled, and an acetonitrile solution (5 mL) of compound I-c1 (2.33 g, 1.2 eq) was added to obtain a mixture. The mixture was heated to 80°C and maintained at the temperature for 16 hours. Thereafter, the reaction mixture was cooled, and EtOAc (20 mL) and water (20 mL) were added for extraction. The mixture was allowed to stand for a period of time, and the water and organic layers were separated, and the water layer was extracted again with EtOAc (20 mL). All organic layers were combined, washed with brine (20 mL), dried with MgSO4, and purified by flash column to obtain a compound I-c5 (2.26 g, 87%).

[0252] NaOH (0.56 g, 20 eq) was added to an EtOH solution (20 mL) containing compound I-c5 (0.38 g, 1 eq) and stirred at 80 °C for 17 hours. After cooling, the EtOH was removed using a rotor and the residue was diluted with water (10 mL). 1N HCl was then added in an ice bath. (aq) , until the pH of the diluted residue is less than 2 (<2). The aqueous layer was extracted with EtOAc (20 mL×2), and the organic layers were combined, washed with brine (10 mL×1), dried over MgSO4, and concentrated to give a crude residue. The crude residue was heated to 80° C. in Ac2O (6 mL) and stirred for 4 hours. After cooling, Ac2O was evaporated in vacuo, and toluene (2-3 mL) was added. The solvent was evaporated in vacuo to give compound I-c6 (0.30 g, 87%).

[0253] A solution of 3-aminopiperidine-2,6-dione hydrochloride (0.11 g, 2 eq) and TEA (0.19 mL, 4 eq) in THF (2 mL) was stirred at room temperature for 30 minutes, and then a solution of compound I-c6 (0.15 g, 1 eq) in THF (2 mL) was added. The reaction was stirred at room temperature for 50 minutes, and then the mixture was diluted with EtOAc (10 mL×1) and water (5 mL×1). 1N HCl was then added (aq) , until the pH value of the aqueous layer is less than 2 (<2). The aqueous layer was extracted with EtOAc (10 mL×2), and the organic layers were combined, washed with brine (5 mL×1), and dried over MgSO4. The solvent was removed to obtain a crude material, which was used in the next step without any further purification. The aforementioned crude material was dissolved in THF (4 mL), and CDI (0.11 g, 2 eq) and DMAP (4 mg, 0.1 eq) were added. The reaction mixture was stirred at 50°C for 2 hours. After cooling, the reaction mixture was diluted with EtOAc (10 mL) and water (5 mL). 1N HCl was then added (aq) , 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 layers were collected, washed with brine (10 mL), and dried over Na2SO4. The solvent was removed to obtain a crude product, which was purified by flash column chromatography with an eluent (n-hexane / EtOAc=1 / 1 to 1 / 2) to obtain Compound IC (0.16 g, 85%).

[0254] (2) Preparation of compound ID

[0255] Compound ID was prepared from commercially available 4-(4-Amino-cyclohexyloxy)-2-chloro-benzonitrile by the following route:

[0256] Synthesis Flowchart 5

[0257]

[0258] In a DCM (30 mL) solution containing 4-(4-amino-cyclohexyloxy)-2-chloro-benzonitrile I-d1 (2.06 g, 1 eq), compound I-d2 (1.31 g, 1 eq) and HATU (4.99 g, 1.6 eq), DIPEA (4.3 mL, 3 eq) was added in an ice bath, and stirred at room temperature for 21 hours. Then, water (10 mL) was added and mixed, and the organic layer was separated, dried over Na2SO4, concentrated, and purified by flash column with eluent (n-hexane / EtOAc=1 / 1), and then washed with DCM and n-hexane to obtain compound ID (1.8 g, 56%). MS: m / z 391.2 (M + +1); 1 H NMR(DMSO-d6)δ9.14(d,1H),8.22(d,1H),8.10(d,1H),7.85(d,1H),7.39(d,1H),7.14(dd,1H),4.55-4.5 1(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).

[0259] (3) Preparation of Compound 2 from Boc-protected Amine Compound IC and Compound ID

[0260] Compound 2 was prepared by the following route:

[0261] Synthesis Flowchart 6

[0262]

[0263] To a solution of compound IC (100 mg, 1 eq) in DCM (2 mL) and MeOH (0.4 mL) was added 2N HCl in ether (1.6 mL, 20 eq). The reaction was stirred at room temperature for 40 min, and the solvent was removed to give compound I-c1 (80 mg, 98%).

[0264] Then, TEA (0.13 mL, 10 eq) was added to a dimethyl sulfoxide (DMSO) solution (0.5 mL) containing compound I-c1 (51 mg, 1 eq) and compound ID (44 mg, 1.2 eq), and 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 washed with water (5 mL), saturated NH4Cl (3 mL×3), and dried over Na2SO4. The solvent was removed to obtain a crude material, which was purified by preparative TLC with a mobile phase (DCM / acetone=9 / 1) to obtain compound 2 (38 mg, 47%). MS: m / z 807.4 (M + +1); 1 HNMR(CDCl3)δ7.97(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,2 H),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).

[0265] Synthesis method C-Synthesis of compound 3:

[0266] (1) Preparation of Compound IE

[0267] Compound IE was prepared from commercially available piperazine-1-carboxylic acid tert-butyl ester by the following route:

[0268] Synthesis Flowchart 7

[0269]

[0270] A mixture of compound ID (800 mg, 1 eq), tert-butyl piperazine-1-carboxylate (399 mg, 1.1 eq) and TEA (0.57 mL, 2 eq) in DMSO (6 mL) was stirred at 100° C. for 24 hours. After cooling, the mixture was slowly added to water to obtain a suspension. The suspension was filtered to obtain compound I-e1 (1.03 g, 94%).

[0271] HCl gas was slowly bubbled into a mixture of compound I-e1 (500 mg, 1 eq) in CH2Cl2 (6 mL) to give a mixture which was stirred at room temperature for 2 h, then concentrated and washed with methyl tert-butylether (MTBE) to give compound IE (388 mg, 97%).

[0272] (2) Preparation of Compound IF

[0273] Compound IF was prepared by the following route:

[0274] Synthesis Flowchart 8

[0275]

[0276] TEA (0.139 mL, 4.0 eq) was added to a DCM solution (2 mL) of compound I-a7 (0.1 g, 0.250 mmol) at room temperature. Methanesulfonyl chloride (MsCl) (0.0387 mL, 2.0 eq) was then added dropwise. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the 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 with Na2SO4 (s), concentrated, and purified by TLC (DCM / acetone=10 / 1) to obtain compound IF (0.1 g, yield of about 83.85%).

[0277] (3) Preparation of Compound 3 from Compound IE and Compound IF

[0278] Compound 3 was prepared by the following route:

[0279] Synthesis Flowchart 9

[0280]

[0281] A solution of compound IE (100 mg, 0.227 mmol), compound IF (102 mg, 0.227 mmol), potassium iodide (KI) (113 mg, 3.0 eq) and DIPEA (0.2 mL, 5.0 eq) in anhydrous CH3CN (1 mL) was heated to 75°C for 17 hours. After the reaction was completed, it was diluted with ethyl acetate (EA) (10 mL) and Na2CO 3(aq) After alkalization, the organic layer was washed with brine, dried over Na2SO4(s), concentrated, and purified by preparative TLC with a mobile phase (DCM / acetone=9 / 1) to obtain compound 3 (104 mg, 58%). MS: m / z 794.4 (M + +1); 1 HNMR(DMSO-d6)δ11.06(s,1H),8.61(d,1H),7.86-7.82(m,2H),7.62(d,1H),7.39(d,1H),7.37(d,1H),7.3 3(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).

[0282] The preparation of compounds 1, 2 and 3 of the present disclosure is exemplified above. Other compounds of the present disclosure can be prepared by the same method as in Synthesis Method A (Synthesis Scheme Figures 1 to 3 ), Synthesis Method B (Synthesis Schemes 4 to 6) or Synthesis Method C (Synthesis Schemes 7 to 9), or any method analogous to a known synthesis method based on general knowledge of organic chemistry.

[0283] According to the synthesis method A (synthesis process Figures 1 to 3 ), Synthesis Method B (Synthesis Schemes 4 to 6) or Synthesis Method C (Synthesis Schemes 7 to 9), using a method similar to Synthesis Method A or Synthesis Method B to prepare Compound 4-223 is by changing one or more starting materials to obtain the target product.

[0284] Compound 4: MS: m / z 834.9 (M + +1).

[0285] Compound 5: MS: m / z 835.9 (M + +1).

[0286] Compound 6: MS: m / z 821.6 (M + +1).

[0287] Compound 7: MS: m / z 824.1 (M + +1).

[0288] Compound 8: MS: m / z 835.5 (M + +1); 1 H NMR(CD3CN)δ8.86(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),2.5 7-2.55(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).

[0289] Compound 9: MS: m / z 821.3 (M + +1); 1 H NMR(CD3CN)δ8.86(bs,1H),8.24(d,1H),8.08(d,1H),7.91(d,1H),7.69(d,1H),7 .64(d,1H),7.33(dd,1H),7.11(d,1H),7.09(d,1H),7.00(dd,1H),6.94(dd,1H), 4.87-4.84(m,1H),4.26(s,1H),4.24(t,2H),4.01(d,1H),3.93(s,3H),3.37-3.3 6(m,4H),2.87(t,2H),2.79-2.63(m,7H),2.14(m,1H),1.22(s,6H),1.16(s,6H).

[0290] Compound 10: MS: m / z 821.5 (M + +1); 1H NMR(DMSO-d6)δ11.06(s,1H),8.35(d,1H),8.10(d,1H),7.90(d,1H),7.84(d,1H),7.69( d,1H),7.44(dd,1H),7.25(d,1H),7.21(s,1H),7.10(dd,1H),7.03(dd,1H),5.00(dd,1H ),4.43(s,1H),4.21(t,2H),3.97(s,3H),3.94(d,1H),3.37(m,4H),2.92-2.86(m,1H),2 .81(t,2H),2.68(m,4H),2.60-2.55(m,2H),2.05-2.03(m,1H),1.19(s,6H),1.12(s,6H).

[0291] Compound 11: MS: m / z 835.4 (M + +1).

[0292] Compound 12: MS: m / z 835.0 (M + +1); 1 H NMR(DMSO-d6)δ11.06(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,1 H),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).

[0293] Compound 13: MS: m / z 850.5 (M + +1); 11H 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).

[0294] Compound 14: MS: m / z 839.0 (M + +1).

[0295] Compound 15: MS: m / z 820.3 (M + +1); 1 1H NMR (DMSO-d6) δ 11.04 (bs, 1H), 7.88 (d, 1H), 7.73 (d, 2H), 7.67 (d, 1H), 7.49 (d, 1H), 7.18 (s, 2H), 7.09 (dd, 1H), 6.99 - 6.95 (m, 3H), 4.98 (dd, 1H), 4.30 (s, 1H), 4.19 (t, 2H), 4.04 (d, 1H), 3.96 (s, 3H), 3.26 (m, 4H), 2.90 - 2.85 (m, 1H), 2.78 (t, 2H), 2.65 (m, 4H), 2.58 - 2.55 (m, 2H), 2.03 - 2.01 (m, 1H), 1.19 (s, 6H), 1.11 (s, 6H).

[0296] Compound 16: MS: m / z 849.3 (M + +1); 1H NMR(DMSO-d6)δ11.06(s,1H),8.62(s,1H),7.96(d,1H),7.90(d,1H),7.82(d,1H),7.61(d,1 H),7.21-7.20(m,2H),7.09(d,1H),7.00(d,1H),6.88(d,1H),5.10-5.05(m,1H),5.01(dd,1 H),4.30(s,1H),4.21(t,2H),4.05(d,1H),3.63(m,4H),2.92-2.86(m,1H),2.80(t,2H),2.6 1(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).

[0297] Compound 17: MS: m / z 848.5 (M + +1); 1 H NMR(DMSO-d6)δ11.06(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,4 H),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).

[0298] Compound 18: MS: m / z 848.5 (M + +1).

[0299] Compound 19: MS: m / z 821.6 (M + +1).

[0300] Compound 20: MS: m / z 849.5 (M + +1); 11H 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).

[0301] Compound 21: MS: m / z 848.6 (M + + 1); 1 1H 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).

[0302] Compound 22: MS: m / z 863.5 (M + + 1); 11H 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).

[0303] Compound 23: MS: m / z 862.5 (M + +1); 1 1H 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).

[0304] Compound 24: MS: m / z 835.3 (M + +1); 11H 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).

[0305] Compound 25: MS: m / z 834.3 (M + + 1); 1 1H 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).

[0306] Compound 26: MS: m / z 821.4 (M + + 1); 11H 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).

[0307] Compound 27: MS: m / z 820.4 (M + +1); 1 1H 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).

[0308] Compound 28: MS: m / z 863.0 (M + +1); 11H 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).

[0309] Compound 29: MS: m / z 822.3 (M + +1); 1 1H 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).

[0310] Compound 30: MS: m / z 835.5 (M + +1); 11H 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).

[0311] 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).

[0312] Compound 32: MS: m / z 828.5 (M + +23); 1H NMR(DMSO-d6)δ11.06(s,1H),7.96(d,1H),7.85(d,1H),7.74(d,2H),7.61(d,1H),7.39(m,2H),7.1 4(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),2.4 9(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).

[0313] Compound 33: MS: m / z 808.4 (M + +1); 1 H NMR(DMSO-d6)δ11.06(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).

[0314] Compound 34: MS: m / z 808.3 (M + +1).

[0315] Compound 35: MS: m / z 778.3 (M + +1).

[0316] 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).

[0317] Compound 37: MS: m / z 850.3 (M + +1).

[0318] Compound 38: MS: m / z 821.6 (M + +1); 1 1H 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).

[0319] Compound 39: MS: m / z 808.5 (M + +1); 11H 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).

[0320] Compound 40: MS: m / z 836.3 (M + +1); 1 1H 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).

[0321] Compound 41: MS: m / z 807.5 (M + +1); 11H 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).

[0322] Compound 42: MS: m / z 834.4 (M + +1); 1 1H 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).

[0323] Compound 43: MS: m / z 808.5 (M + +1); 11H 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).

[0324] Compound 44: MS: m / z 807.2 (M + +1); 1 1H 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).

[0325] Compound 45: MS: m / z 793.4 (M + +1); 11H 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).

[0326] Compound 46: MS: m / z 836.4 (M + +1); 1 1H 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).

[0327] Compound 47: 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), 7.62 (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).

[0328] Compound 48: MS: m / z 862.4 (M + +1); 1 1H 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).

[0329] 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).

[0330] 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).

[0331] 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).

[0332] 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).

[0333] Compound 53: MS: m / z 850.4 (M + +1); 11H 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).

[0334] 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).

[0335] Compound 55: MS: m / z 836.5 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.59 (d, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.63 (d, 1H), 7.40 - 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).

[0336] Compound 56: MS: m / z 848.5 (M + +1); 1 1H 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).

[0337] Compound 57: MS: m / z 822.4 (M + +1); 11H 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).

[0338] Compound 58: MS: m / z 836.4 (M + +1); 1 1H 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).

[0339] 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).

[0340] Compound 60: MS: m / z 850.5 (M + +1); 1 1H 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).

[0341] 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).

[0342] 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).

[0343] Compound 63: MS: m / z 822.6 (M + + 1); 11H 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), 1.42 (t, 3H).

[0344] Compound 64: MS: m / z 834.4 (M + +1); 1 1H 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).

[0345] 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).

[0346] Compound 66: MS: m / z 806.4 (M + +1).

[0347] Compound 67: MS: m / z 794.4 (M + +1); 1 1H 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).

[0348] 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).

[0349] 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).

[0350] Compound 70: MS: m / z 834.3 (M + + 1); 11H 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).

[0351] Compound 71: 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), 7.61 (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).

[0352] 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).

[0353] 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).

[0354] Compound 74: MS: m / z 836.4 (M + +1); 11H 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).

[0355] Compound 75: MS: m / z 808.5 (M + +1); 1 1H 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).

[0356] 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 - 80 (m, 2H), 1.67 - 1.59 (m, 2H), 1.56 - 1.46 (m, 2H), 1.41 (t, 3H), 1.12 (d, 6H).

[0357] Compound 77: MS: m / z 836.4 (M + +1); 1 1H 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).

[0358] Compound 78: MS: m / z 835.7 (M + +1); 1H NMR(DMSO-d6)δ11.06(s,1H),8.51(d,1H),7.84(d,1H),7.62(d,1H),7.61(d,1H),7.37-7.34(m,2 H),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,1 H),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),2.05-2.0 3(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).

[0359] Compound 79: MS: m / z 821.6 (M + +1); 1 H NMR(DMSO-d6)δ11.06(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).

[0360] Compound 80: MS: m / z 848.2 (M + +1).

[0361] 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).

[0362] 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).

[0363] Compound 83: MS: m / z 871.4 (M + +1); 11H 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).

[0364] Compound 84: MS: m / z 924.5 (M + +1); 1 1H 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).

[0365] Compound 85: MS: m / z 824.4 (M + +1); 1H NMR(DMSO-d6)δ11.07(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,3 H),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).

[0366] Compound 86: MS: m / z 794.4 (M + +1).

[0367] Compound 87: MS: m / z 822.4 (M + +1); 1 H NMR(DMSO-d6)δ11.05(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),2.57-2.4 9(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).

[0368] Compound 88: MS: m / z 834.4 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.55 (d, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.61 (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).

[0369] 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).

[0370] 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).

[0371] Compound 91: MS: m / z 849.4 (M + +1); 1 1H 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).

[0372] Compound 92: MS: m / z 848.3 (M + +1); 11H 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).

[0373] Compound 93: MS: m / z 898.8 (M + +1); 1 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 8.55 (d, 1H), 7.86 (d, 1H), 7.83 (d, 1H), 7.65 (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).

[0374] Compound 94: MS: m / z 992.4 (M + +1); 1H NMR(DMSO-d6)δ8.58(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).

[0375] Compound 95: MS: m / z 892.4 (M + +1); 1 H NMR(DMSO-d6)δ9.88(bs,1H),8.58(d,1H),7.86(d,1H),7.84(d,1H),7.67(d,1H),7.41(d,1H),7.39(d,1H),7.35 (d,1H),7.13(dd,1H),7.03(dd,1H),5.08-5.03(m,3H),4.56-4.51(m,1H),4.44(q,2H),4.18(t,2H),4.10-4.07(m ,2H),3.97-3.94(m,2H),3.88-3.83(m,1H),3.46-3.41(m,4H),3.05-2.99(m,1H),2.78-2.75(m,1H),2.61-2.49(m ,3H),2.11-2.06(m,3H),2.04-2.00(m,2H),1.91-1.87(m,6H),1.66-1.60(m,2H),1.55-1.49(m,2H),1.43(t,3H).

[0376] Compound 96: MS: m / z 862.4 (M + +1).

[0377] 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).

[0378] Compound 98: MS: m / z 836.3 (M + +1); 1 1H 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).

[0379] 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).

[0380] Compound 100: MS: m / z 862.6 (M + +1); 1 1H 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).

[0381] 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).

[0382] Compound 102: MS: m / z 884.3 (M + +1); 1 1H 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).

[0383] Compound 103: MS: m / z 884.5 (M + +1); 11H 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).

[0384] Compound 104: MS: m / z 857.3 (M + +1); 1 1H 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).

[0385] 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).

[0386] 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).

[0387] Compound 107: MS: m / z 875.5 (M + +1); 11H 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).

[0388] Compound 108: MS: m / z 897.4 (M + +1); 1 1H 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).

[0389] Compound 109: MS: m / z 849.5 (M + +1); 11H 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).

[0390] Compound 110: MS: m / z 837.4 (M + +1); 1 1H 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).

[0391] Compound 111: MS: m / z 889.2 (M + +1); 11H 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).

[0392] Compound 112: MS: m / z 863.5 (M + +1); 1 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.45 (bs, 1H), 7.80 (bs, 1H), 7.60 (d, 2H), 7.30 (bs, 1H), 7.16 (bs, 1H), 6.98 (d, 1H), 6.94 (bs, 1H), 6.82 (d, 1H), 4.97 (dd, 1H), 4.42 (q, 2H), 4.07 (bs, 2H), 3.91 - 3.68 (m, 6H), 2.93 - 2.82 (m, 1H), 2.85 (s, 3H), 2.76 (bs, 2H), 2.63 - 2.53 (m, 3H), 2.58 - 2.49 (m, 3H), 2.07 - 2.00 (m, 1H), 1.94 - 1.80 (m, 4H), 1.80 - 1.70 (m, 4H), 1.70 - 1.60 (m, 4H), 1.60 - 1.52 (m, 2H), 1.41 (t, 3H).

[0393] Compound 113: MS: m / z 852.5 (M + +1); 11H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.60 (d, 1H), 7.85 (d, 1H), 7.82 (d, 1H), 7.62 (d, 1H), 7.39 - 7.36 (m, 2H), 7.33 (d, 1H), 7.13 (dd, 1H), 7.01 (dd, 1H), 4.97 (dd, 1H), 4.55 - 4.51 (m, 1H), 4.42 (q, 2H), 4.24 (t, 2H), 3.88 - 3.82 (m, 1H), 3.80 (t, 2H), 3.69 - 3.65 (m, 6H), 2.91 - 2.85 (m, 1H), 2.62 - 2.53 (m, 7H), 2.53 - 2.49 (m, 1H), 2.11 - 2.09 (m, 2H), 2.06 - 2.02 (m, 1H), 1.91 - 1.89 (m, 2H), 1.67 - 1.61 (m, 2H), 1.54 - 1.48 (m, 2H), 1.41 (t, 3H).

[0394] Compound 114: MS: m / z 865.4 (M + +1); 1 1H 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).

[0395] 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).

[0396] Compound 116: MS: m / z 863.4 (M + +1); 1 1H 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).

[0397] Compound 117: MS: m / z 855.6 (M + +1); 11H 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).

[0398] Compound 118: MS: m / z 841.1 (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), 7.40 (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).

[0399] 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).

[0400] Compound 120: MS: m / z 852.4 (M + +1); 1 H NMR(DMSO-d6)δ8.65(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).

[0401] Compound 121: MS: m / z 822.3 (M + +1).

[0402] Compound 122: MS: m / z 914.1 (M + +23); 1 H NMR(DMSO-d6)δ8.56(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).

[0403] Compound 123: MS: m / z 862.4 (M + +1).

[0404] Compound 124: MS: m / z 865.3 (M + +1).

[0405] Compound 125: MS: m / z 835.3 (M + +1).

[0406] Compound 126: MS: m / z 892.3 (M + +1); 1 H NMR(DMSO-d6)δ8.60(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(m2H),1.43(t,3H).

[0407] Compound 127: MS: m / z 862.3 (M + +1).

[0408] Compound 128: MS: m / z 905.4 (M + +1); 1 H NMR(DMSO-d6)δ8.45(d,1H),7.88(d,1H),7.64(d,1H),7.61(d,1H),7.34(d,1H),7.04(dd,1H),6.9 4(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).

[0409] Compound 129: MS: m / z 875.3 (M + +1).

[0410] Compound 130: MS: m / z 879.5 (M + +1).

[0411] Compound 131: MS: m / z 849.3 (M + +1).

[0412] Compound 132: MS: m / z 862.3 (M + +1); 1 H NMR(DMSO-d6)δ11.06(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).

[0413] Compound 133: MS: m / z 848.3 (M + +1); 1 H NMR(DMSO-d6)δ11.05(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),2.07-2.0 1(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).

[0414] Compound 134: MS: m / z 876.4 (M + +1); 1 H NMR(DMSO-d6)δ11.05(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).

[0415] Compound 135: MS: m / z 892.3 (M + +1); 1 H NMR(DMSO-d6)δ8.54-8.51(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).

[0416] Compound 136: MS: m / z 862.3 (M + +1).

[0417] Compound 137: MS: m / z 850.5 (M + +1); 11H 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).

[0418] Compound 138: MS: m / z 837.5 (M + + 1); 1 1H 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).

[0419] Compound 139: MS: m / z 857.8 (M + + 1).

[0420] Compound 140: MS: m / z 820.1 (M + + 1);1 H NMR(CDCl3)δ7.98-7.96(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,1 H),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).

[0421] Compound 141: MS: m / z 893.3 (M + +1); 1 H NMR(DMSO-d6)δ8.48(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).

[0422] Compound 142: MS: m / z 863.4 (M + +1).

[0423] Compound 143: MS: m / z 879.4 (M + +1); 11H 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).

[0424] Compound 144: MS: m / z 849.3 (M + + 1).

[0425] Compound 145: MS: m / z 891.4 (M + + 1); 1 1H 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).

[0426] Compound 146: MS: m / z 861.3 (M + + 1).

[0427] Compound 147: MS: m / z 863.6 (M + +1); 1 1H 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).

[0428] Compound 148: MS: m / z 876.4 (M + +1); 1 1H 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).

[0429] 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).

[0430] Compound 150: MS: m / z 863.3 (M + + 1).

[0431] Compound 151: MS: m / z 836.5 (M + + 1); 1 1H 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).

[0432] 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, 1H), 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).

[0433] Compound 153: MS: m / z 823.6 (M + +1); 1 1H 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).

[0434] 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).

[0435] Compound 155: MS: m / z 850.7 (M + +1); 1 1H 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).

[0436] Compound 156: MS: m / z 877.0 (M + +1); 11H 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).

[0437] Compound 157: MS: m / z 904.8 (M + +1); 1 1H 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).

[0438] 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).

[0439] Compound 159: MS: m / z 837.5 (M + +1); 1 1H 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).

[0440] 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).

[0441] 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).

[0442] Compound 162: MS: m / z 849.6 (M + + 1); 11H 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).

[0443] Compound 163: MS: m / z 843.5 (M + +23); 1 1H 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).

[0444] Compound 164: MS: m / z 884.9 (M + +23); 11H 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).

[0445] Compound 165: MS: m / z 856.8 (M + +23); 1 1H 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).

[0446] 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).

[0447] 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).

[0448] Compound 168: MS: m / z 831.6 (M + +23); 11H 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).

[0449] Compound 169: MS: m / z 844.6 (M + +23); 1 1H 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).

[0450] 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).

[0451] Compound 171: MS: m / z 884.7 (M + + 23); 1 1H 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).

[0452] 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).

[0453] Compound 173: MS: m / z 913.0 (M + +23); 1 1H 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).

[0454] 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).

[0455] Compound 175: MS: m / z 870.2 (M + + 23); 1 1H 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).

[0456] Compound 176: MS: m / z 863.8 (M + + 1); 11H 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).

[0457] Compound 177: MS: m / z 899.0 (M + +23); 1 1H 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).

[0458] Compound 178: MS: m / z 884.6 (M + +23); 11H 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).

[0459] Compound 179: MS: m / z 872.0 (M + +23); 1 1H 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).

[0460] 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).

[0461] 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).

[0462] 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).

[0463] 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).

[0464] Compound 184: MS: m / z 886.9 (M + +23); 11H NMR (DMSO-d6) δ 11.05 (s, 1H), 8.49 (d, 1H), 7.81 (d, 1H), 7.61 - 7.60 (m, 2H), 7.36 (d, 1H), 7.32 (d, 1H), 7.00 (dd, 1H), 6.94 (d, 1H), 6.82 (dd, 1H), 4.97 (dd, 1H), 4.20 (q, 2H), 4.12 (t, 2H), 4.09 - 4.04 (m, 2H), 3.88 - 3.82 (m, 1H), 3.80 - 3.76 (m, 1H), 3.63 - 3.59 (m, 1H), 3.54 (t, 2H), 3.45 - 3.40 (m, 2H), 2.92 - 2.85 (m, 1H), 2.85 (s, 3H), 2.61 - 2.55 (m, 1H), 2.54 - 2.50 (m, 1H), 2.07 - 2.02 (m, 1H), 1.94 - 1.89 (m, 4H), 1.86 - 1.82 (m, 2H), 1.78 - 1.62 (m, 6H), 1.52 - 1.46 (m, 2H), 1.41 (t, 3H).

[0465] Compound 185: MS: m / z 873.9 (M + + 23); 1 1H 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).

[0466] 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).

[0467] Compound 187: MS: m / z 837.6 (M + +1); 1 1H 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).

[0468] 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).

[0469] 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).

[0470] Compound 190: MS: m / z 819.5 (M + +1); 11H 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).

[0471] Compound 191: MS: m / z 827.6 (M + +23); 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), 7.41 - 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).

[0472] Compound 192: MS: m / z 858.3 (M + +23); 11H 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).

[0473] Compound 193: MS: m / z 871.9 (M + +23); 1 1H 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).

[0474] 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).

[0475] 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).

[0476] 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).

[0477] 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).

[0478] Compound 198: MS: m / z 890.0 (M + + 1); 11H 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).

[0479] Compound 199: MS: m / z 875.6 (M + +1); 1 1H 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).

[0480] Compound 200: MS: m / z 819.8 (M + +1); 11H 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).

[0481] Compound 201: MS: m / z 832.7 (M + +1); 1 1H 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).

[0482] Compound 202: MS: m / z 818.6 (M + +1); 11H 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).

[0483] Compound 203: MS: m / z 876.3 (M + + 1); 1 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.58 (d, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.62 (d, 1H), 7.40 - 7.36 (m, 2H), 7.33 (d, 1H), 7.14 (dd, 1H), 7.02 (d, 1H), 4.98 (dd, 1H), 4.60 - 4.51 (m, 2H), 4.51 - 4.46 (m, 2H), 4.43 (q, 2H), 3.89 - 3.83 (m, 1H), 3.03 - 3.00 (m, 2H), 2.92 - 2.86 (m, 1H), 2.72 (bs, 2H), 2.63 - 2.56 (m, 2H), 2.32 - 2.22 (m, 2H), 2.21 - 2.16 (m, 2H), 2.14 - 2.08 (m, 2H), 2.07 - 1.96 (m, 3H), 1.93 - 1.87 (m, 2H), 1.87 - 1.80 (m, 2H), 1.73 - 1.59 (m, 5H), 1.55 - 1.49 (m, 2H), 1.41 (t, 3H), 1.16 - 1.07 (m, 2H).

[0484] 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).

[0485] 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).

[0486] Compound 206: MS: m / z 807.2 (M + +1); 11H 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).

[0487] Compound 207: MS: m / z 807.6 (M + +1); 1 1H 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).

[0488] Compound 208: MS: m / z 793.1 (M + +1); 11H 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).

[0489] 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).

[0490] Compound 210: MS: m / z 870.9 (M + +23); 1H NMR(DMSO-d6)δ11.06(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).

[0491] Compound 211: MS: m / z 835.2 (M + +1); 1 H NMR(DMSO-d6)δ11.06(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).

[0492] Compound 212: MS: m / z 926.8 (M + +23).

[0493] 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).

[0494] Compound 214: MS: m / z 924.9 (M + +23); 1 1H 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).

[0495] 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).

[0496] Compound 216: MS: m / z 884.5 (M + +23); 1 1H 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).

[0497] 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).

[0498] Compound 218: MS: m / z 848.6 (M + +1); 1 1H 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).

[0499] 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).

[0500] 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).

[0501] Compound 221: MS: m / z 889.7 (M + +1); 11H 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).

[0502] Compound 222: MS: m / z 889.5 (M + +1); 1 1H 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).

[0503] Compound 223: MS: m / z 794.4 (M + +1); 1H NMR(DMSO-d6)δ11.06(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,5 H),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).

[0504] In addition, the compound ARV-110 (Cat. No.: BD01398519; Lot No.: CKA112; purity: 97%) purchased from BLD Pharmatech Ltd. was used for subsequent tests. ARV-110 is a well-known bifunctional compound that can be used for AR degradation.

[0505]

[0506] Androgen receptor degradation assay by Western blot analysis

[0507] LNCaP.FGC cells (Cat. 60088, Bioresource Conservation and Research Center, Hsinchu City, Taiwan, China) were grown in RPMI 1640 (Cat. 31800022, Thermo Fisher Scientific, Waltham, Massachusetts, United States) medium supplemented with 10% FBS (Cat. 10437028, Thermo Fisher Scientific, Waltham, Massachusetts, United States), 10 mM HEPES (Cat. 15630080, Thermo Fisher Scientific, Waltham, Massachusetts, United States), and 1 mM sodium pyruvate (Cat. 11360070, Thermo Fisher Scientific, Waltham, Massachusetts, United States) at a plate density of 2 × 10 cells / well. 5Cells were seeded into 24-well cell culture plates. The cells were cultured at 37°C, 5% CO2 for 24 hours (hr), and then treated with 100 nanomolar concentrations (nM) of one of the compounds 1 to 223 or ARV-110 for 24 hours. After treatment, the cells were harvested, washed with phosphate buffered saline (PBS), and hydrolyzed with RIPA hydrolysis extraction buffer (Cat. 89900, Thermo Fisher Scientific, Waltham, Massachusetts, United States) supplemented with Halt Protease Inhibitor Cocktail (Cat. 78430, Thermo Fisher Scientific, Waltham, Massachusetts, United States) to collect protein samples. Cells not treated with any of the above compounds were used as negative controls.

[0508] Protein samples were separated by polyacrylamide gel electrophoresis and then transferred to an Immuno-Blot polyvinylidene difluoride (PVDF) membrane (Cat. 1620177, Bio-Rad Laboratories, Hercules, California, United States). Protein samples with androgen receptor were detected by standard Western blotting, which used anti-AR antibody (1:2000 dilution) (Cat. 5153, Cell Signaling Technology Inc., Danvers, Massachusetts, United States) and a goat anti-rabbit horseradish peroxidase (HRP)-conjugated secondary antibody (1:5000 dilution) (C04003, Anxin Biotechnology, Taipei, Taiwan, China). The internal loading control glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was detected using a mouse monoclonal antibody (1:5000) (GTX627408, Yikang Biotechnology, Hsinchu City, Taiwan, China) and a goat anti-mouse HRP-conjugated secondary antibody (1:5000 dilution) (C04001, Anxin Biotechnology, Taipei City, Taiwan, China). The chemiluminescent information was developed using Clarity Western ECL substrate (Cat. 1705061, Bio-Rad Laboratories, Hercules, California, United States) and detected using a digital imager iBrightFL1500 (Invitrogen Corp., Carlsbad, California, United States).

[0509] The percentage of AR remaining was determined as the difference in the intensity of AR information (normalized to the corresponding internal loading control GAPDH) between the protein samples of untreated cells (100%) and the protein samples of treated cells. The results of compounds 1 to 169 are shown in Table 2. "Compound #" indicates the compound number above.

[0510] In addition, several compounds were selected to prepare a 100 nM treatment stock solution in RPMI medium. The treatment stock solution was serially diluted in RPMI medium and used to treat 2×10 5The LNCaP.FGC cells were seeded in 24-well tissue culture plates. A calibration curve was prepared with serial dilutions of each compound, and the concentration of each compound required to achieve 50% AR degradation (AR DC 50 The results are shown in Table 3. In Table 3, when the AR DC 50 When the AR DC of the compound is less than 10 nM, the result is marked as "A". 50 When the AR DC of the compound is equal to or greater than 10 nM and less than 25 nM, the result is marked as "B". 50 When the AR DC of the compound is equal to or greater than 25 nM and less than 100 nM, the result is marked as "C"; and when the AR DC 50 When it is equal to or greater than 100 nM, the result is marked as "D".

[0511] It is clear from Tables 2 and 3 that the compounds of the present disclosure have good AR degradation efficacy. Under the same operating conditions, many compounds of the present disclosure have higher AR degradation ability than ARV-100 at the same concentration (100 nM), and they generally have lower AR DC 50 (nM).

[0512] Table 2: Androgen receptor residual amount (%) of the compounds disclosed in the present invention at 100 nM

[0513]

[0514]

[0515]

[0516] Table 3: AR DC of compounds of the present disclosure 50 (nM)

[0517]

[0518]

[0519] In vivo hair regrowth efficacy of the disclosed compounds in the androgenetic alopecia (AGA) mouse model

[0520] Seven-week-old male C57BL / 6 mice (with black fur) were purchased from BioLASCO Taiwan Co., Ltd., grouped into 6 to 8 mice per cage, and intraperitoneally administered with dihydrotestosterone (DHT) (1 mg / day, dissolved in corn oil) or corn oil alone, once a day for four days. DHT is an androgen receptor agonist that can be used to induce symptoms of male pattern baldness.

[0521] Four days later, the dorsal area of ​​the mice was depilated with a depilatory cream (Nair Sensitive Hair Removal Cream, 100 mg to 200 mg per mouse). After depilation, the skin color was recorded with a resolution of 4032×3024 pixels (Day 1, D1). The next day (D2), test solutions of compound 29 and compound 33 in a vehicle (3.5 μg / cm 2 / day), and each test solution or the vehicle alone was topically administered to the depilatory area once a day for a total of 20 days. The depilatory cream, the test solution and the vehicle were rubbed into the back area of ​​the mice respectively. The photos were analyzed using self-developed software, which uses auto-image segmentation and focuses mainly on the boundaries of the depilatory areas. This segmentation method involves grading different areas in the image. The software can determine the boundaries of the depilatory areas in the photos, and mix the colors in the depilatory areas in each photo and convert them into a single color block. Afterwards, the photos will be converted into a skin color score. Figure 1 As shown in the color chart, the score ranges from 1 to 8, with score 1 corresponding to the skin after hair removal (skin color), score 8 corresponding to completely regrown hair (black), and scores 2 to 7 corresponding to different stages between scores 1 and 8. Figure 2 The photos of the depilated areas of the corn oil + vehicle group and the DHT + vehicle group at D1, D10, D14, D16, D17, D18, D19 and D20 are shown, and the color change corresponds to the efficacy of hair regrowth. The efficacy of hair regrowth can be evaluated by the photos and / or the skin color score.

[0522] like Figure 3As shown, it can be found that the average skin color score of the corn oil + vehicle group on day 15 is close to 8. DHT pretreatment obviously impairs the ability of hair regrowth, and the compounds disclosed in the present invention can restore the damaged hair regrowth ability. The average skin color score of the DHT + compound 29 group on day 20 reached 8, and the average skin color score of the DHT + compound 33 group on day 20 reached 6.5, both of which were significantly higher than the average skin color score of 3.5 achieved by the DHT + vehicle group on day 20.

[0523] Other specific embodiments

[0524] All features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature for the same, equal or similar purpose. Therefore, unless otherwise clearly indicated, each feature disclosed is only an example of an equivalent or similar superordinate series of features.

[0525] From the foregoing description, those skilled in the art can easily identify the essential features of the present disclosure, and make various changes or modifications to the present disclosure without departing from its spirit and scope, so as to make it suitable for various uses and conditions. Therefore, other specific embodiments also fall within the scope of the claims.

Claims

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

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

3. The bifunctional compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, characterized in that: The -L- is a bonding group represented by formula (III): in: Z is selected from the group consisting of a 3- to 8-membered monocyclic ring, a 5- to 12-membered bicyclic ring, an 8- to 15-membered tricyclic ring, and a 6- to 12-membered spirobicyclic ring, each of which independently has 0 to 4 heteroatoms and 0 or 1 double bond; R L1 is selected from unsubstituted C 1-6 Alkyl, C 1-6 Alkoxy substituted C 1-6 Alkyl, C 1-6 Alkyl, halogen, unsubstituted C 1-6 The group consisting of alkoxy, keto and oxygen ion groups; R L2 It is a bond or ethynylene; X 1 is methylene or ethylene, each of which is unsubstituted or substituted by alkyl or cycloalkyl; X 2 and X 5 are each independently selected from unsubstituted methylene, methylene substituted with alkyl or cycloalkyl, CO, COCO, CONH, NHCO, NHCONR L3 NHCOCONR L3 -、NHSO2NR L3 、SO2NH、CHR L3 NR L4 , O and S; X 3 Is to choose free C 1-8 Alkylene, C 1-8 the group consisting of heteroalkylene, 5- to 8-membered arylene, 5- to 8-membered heteroarylene having 1 to 3 heteroatoms, 3- to 7-membered cycloalkylene, 3- to 7-membered heterocycloalkylene having 1 to 2 heteroatoms, and 6- to 12-membered spirobicyclic ring having 0 to 4 heteroatoms, each of which is unsubstituted or substituted with alkyl or cycloalkyl; X 4 is an unsubstituted C 1-6 Alkylene or a C 1-6 Alkylene; R L3 and R L4 are each independently selected from -H, unsubstituted C 1-6 Alkyl, C 1-6 Alkoxy substituted C 1-6 Alkyl and C substituted by one or more halogen groups 1-6 A group consisting of alkyl groups; m is 0, 1, 2, 3, 4, 5 or 6; v1 is 0 or 1; v2 is 0 or 1; v3 is 1; v4 is 0 or 1; and v5 is 1.

4. The bifunctional compound according to claim 3, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, characterized in that: The -L- is a bonding group represented by formula (III): in: Z is selected from the group consisting of 3- to 8-membered monocyclic rings, 6- to 10-membered bicyclic rings, and 8- to 11-membered spirobicyclic rings, each of which independently has 1 to 2 heteroatoms and 0 or 1 double bonds; R L1 is selected from unsubstituted straight chain C 1-3 The group consisting of alkyl and keto groups; R L2 It is a bond or ethynylene; X 1 is methylene or ethylene, each of which is unsubstituted or substituted by alkyl or cycloalkyl; X 2 is selected from unsubstituted methylene, methylene substituted by alkyl or cycloalkyl, CO, NHCO, NR L4 and O; X 3 Is to choose free C 1-6 The group consisting of alkylene, 3- to 7-membered cycloalkylene, and 3- to 7-membered heterocycloalkylene having 0 to 2 heteroatoms, each of which is unsubstituted or substituted with alkyl or cycloalkyl; X 4 is an unsubstituted C 1-3 Alkylene or a C 1-3 Alkylene; X 5 is selected from the group consisting of an unsubstituted methylene group, a methylene group substituted with an alkyl group or a cycloalkyl group, 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; and v5 is 1.

5. The bifunctional compound according to claim 3, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, characterized in that: The –L– is in: f is an integer of 0, 1, 2, 3 or 4; and g is an integer of 0, 1, 2 or 3.

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

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

8. The bifunctional compound according to claim 6, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, characterized in that: Z 2 It is freedom to choose The group composed of.

9. The bifunctional compound according to claim 6, or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug thereof, characterized in that: The ABM is selected from the groups formed; in: A1 is selected from -Cl, -F, -Br or -CF3; A2 is selected from -O-, -NH-, -NCH3- or -NCH2CH3-; and A3, A4, A5 and A6 are each independently -CH- or -N-.

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

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

12. The pharmaceutical composition of claim 11, further comprising a second therapeutic agent.

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

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

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

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

17. The method according to claim 15, characterized in that The breast cancer is triple-negative breast cancer.

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

19. The method of claim 13, further comprising administering an effective amount of a second therapeutic agent.

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