Patent Application
20210246115
The present invention relates to heterocyclic compounds useful as anti-infective agents. The present invention further relates to a method of treating an infection by administering such a compound. The present invention further relates to pharmaceutical compositions comprising such compounds.
Antimicrobial resistance is an increasingly serious threat to global public health. New resistance mechanisms emerge and spread globally, threatening the effective prevention and treatment of a range of infections caused by bacteria, parasites and fungi.
A number of examples can be provided to illustrate the threat posed. In 2013 there was approximately half a million new cases of multi-drug resistant tuberculosis. Resistance to artemisinin-based combination therapies, which are the best available treatment for Plasmodium falciparum malaria, has been detected in the Greater Mekong subregion. Highly resistant bacteria such as MRSA cause a high percentage of hospital-acquired infections and it is also beginning to spread in the community. Patients with such drug-resistant infections have an increased risk of inferior clinical outcomes and death as compared to patients infected with non-resistant bacteria. Ten countries have reported cases where gonorrhoea was untreatable due to resistance to the treatments of last resort antibiotics (3rd generation cephalosporins). Thus, gonorrhoea may soon become untreatable.
This emphasize an increased and urgent need for new anti-infective agents for use in therapy.
The object of the invention is thus to provide compounds useful for the treatment or prevention of infection. A further object is to provide a method of treating an infection, such as a bacterial, fungal or parasitic infection.
These objects are achieved by compounds as disclosed by the appended claims.
The compounds have the formula F-I:
or a pharmaceutically acceptable salt thereof
wherein
X5 is selected from CH, CMe, C═O, and N;
F denotes a double bond when X5 is CH, CMe or N, and a single bond when X5 is C═O;
R1 is selected from the group consisting of
R2 is selected from the group consisting of
R3 is selected from the group consisting of
R4 is selected from the group consisting of
R5 is selected from the group consisting of
or
R4 and R5 together with the atoms to which they are bound form a heteroaliphatic ring;
R6 is selected from the group consisting of
or
R5 and R6 together with the atom to which they are bound form a heteroaliphatic ring optionally substituted with one or more R7 groups;
R7 is selected from the group consisting of -halo, —C1-3 alkyl, —C1-3 alkoxy, phenyl, hydroxy, —CH2OH, -oxo, —C(O)Me, —SO2Me, —SO2Ph optionally substituted with —F, mono- or di-C1-3 alkyl amine, —C(O)—NH2, —NH—C(O)—NH2, —C(═NH)—NH2, —NH—C(═NH)—NH2, —(CH2)s—NH2, piperidine, piperazine, morpholine, —(CH2)t—NH—P(O)(OEt)2, —C(O)—NH—R8, and -phenoxy optionally substituted with —Cl;
R8 is selected from the group consisting of —OH, -(amino)cyclohexyl, -pyrrolidinylethyl, and -methylpiperazinylethyl;
R9 and R10 are each independently selected from the group consisting of —H, -halo, —C1-3 alkyl, —C1-3 perfluoroalkyl, C2-3 alkoxy, —C1-3 perfluoroalkoxy, —NO2, —OH, —CN, —CO2H, —CO2Me, —CO2NH2, —CH2NH2, -Cy, -pyridinyl, -tetrahydropyridinyl, -pyrazinyl optionally substituted with -Me, and -phenyl optionally substituted with -halo, —C1-3 alkyl, —C1-3 perfluoroalkyl, —C1-3 alkoxy, —C1-3 perfluoroalkoxy; and
wherein m, n, p, r, s and t are each independently selected from 0, 1 and 2.
Disclosed herein are also compounds of Formula I:
or a pharmaceutically acceptable salt thereof
wherein
each of X1, X2, X3, and X4 is independently selected from C and N;
X5 is selected from CH CMe C═O, and N;
R1 is selected from the group consisting of
R2 is selected from the group consisting of
R3 is selected from the group consisting of
R4 is selected from the group consisting of
R5 is selected from the group consisting of
or
wherein R4 and R5 together with the atoms to which they are bound form a heteroaliphatic ring;
R6 is selected from the group consisting of
or
wherein R5 and R6 together with the atoms to which they are bound form a heteroaliphatic ring optionally substituted with one or more R7 groups;
R7 is selected from the group consisting of -halo, —C1-3 alkyl, —C1-3 alkoxy, phenyl, hydroxy, —CH2OH, -oxo, —C(O)Me, —SO2Me, —SO2Ph optionally substituted with —F, mono- or di-C1-3 alkyl amine, —C(O)—NH2, —NH—C(O)—NH2, —C(═NH)—NH2, —NH—C(═NH)—NH2, —(CH2)s—NH2, piperidine, piperazine, morpholine, —(CH2)t—NH—P(O)(OEt)2, —C(O)—NH—R, and -phenoxy optionally substituted with —Cl;
R8 is selected from the group consisting of —OH, -(amino)cyclohexyl, -pyrrolidinylethyl, and -methylpiperazinylethyl;
R9 and R10 are each independently selected from the group consisting of —H, -halo, —C1-3 alkyl, —C1-3 perfluoroalkyl, —C1-3 alkoxy, —C1-3 perfluoroalkoxy, —NO2, —OH, —CN, —CO2H, —CO2Me, —CO2NH2, —CH2NH2, -Cy, -pyridinyl, -tetrahydropyridinyl, -pyrazinyl optionally substituted with -Me, and -phenyl optionally substituted with -halo, —C1-3 alkyl, —C1-3 perfluoroalkyl, —C1-3 alkoxy, —C1-3 perfluoroalkoxy; and
wherein m, n, p, r, s and t are each independently selected from 0, 1 or 2.
Compounds, or salts therefore, as defined by Formula I and F-I can be used in the treatment or prevention of infection, especially bacterial infection.
Without wishing to be bound by theory, it is thought that the compounds disclosed above achieve their antimicrobial effect at least in part by inhibition of RNase P. RNase P is a ribonucleoprotein complex present in all living cells and in bacteria RNase P is involved in the processing of RNA transcripts such as removal of 5′ leader sequences from tRNA precursors. In bacteria, RNase P consists of one RNA subunit and a small basic protein, and it has been shown that the catalytic activity is associated with its RNA subunit. RNase P is potentially a good drug target since RNase P is indispensable for bacterial viability and the architecture of RNase P differs between bacteria and eukaryote. For example, the important P-15 loop in bacteria is a good target for antibacterial drug design since it is not present in human (eukaryotic) RNase P RNA.
The compounds of formula F-I may belong to a subset of compounds having Formula F-II:
or a pharmaceutically acceptable salt thereof
wherein
X5 is selected from CH CMe C═O, and N;
denotes a double bond when X5 is CH, CMe or N, and a single bond when X5 is C═O;
R1 is selected from the group consisting of
—R2, —(CH2)m—R2, —C(O)—R2, and —CHMe-R2;
R2 is selected from the group consisting of
R3 is selected from the group consisting of
R4 is selected from the group consisting of
R5 is selected from the group consisting of
or
R4 and R5 together with the atoms to which they are bound form a 6-membered heteroaliphatic ring;
R6 is selected from the group consisting of
or
R5 and R6 together with the atom to which they are bound form a 6-membered heteroaliphatic ring which ring is optionally substituted with one or more R7 groups;
R7 is selected from the group consisting of methyl, fluoro, bromo, phenyl, hydroxy, —CH2OH, -oxo, methoxy, —C(O)Me, , —SO2Me, —SO2Ph optionally substituted with —F, —NH2, —NHMe, —NMe2, —C(O)—NH2, —NH—C(O)—NH2, —C(═NH)—NH2, —NH—C(═NH)—NH2, —(CH2)s—NH2, piperidine, piperazine, morpholine, —(CH2)t—NH—P(O)(OEt)2, —C(O)NH—R8, and phenoxy optionally substituted with —Cl;
R8 is selected from the group consisting of —OH, -(amino)cyclohexyl, -pyrrolidinylethyl, and -methylpiperazinylethyl;
R9 is selected from the group consisting of —H, —F, —Br, —NO2, —OH, —CN, —CO2H, —CO2Me, —CO2NH2, —CH2NH2, -Cy, -pyridinyl, -tetrahydropyridinyl, -pyrazinyl optionally substituted with -Me, and -phenyl optionally substituted with —Cl, -Me, —CF3, —OMe or —OCF3;
R10 is —H or —Br; and
m, n, p, r, s and t are each dependently selected from 0, 1 and 2.
The compounds of formula F-I and F-II may belong to a subset of compounds having Formula F-III:
or a pharmaceutically acceptable salt thereof
wherein R11 is —H, -Me or -oxo;
denotes a double bond when R11 is —H or -Me, and a single bond when R11 is oxo.
The compounds of formula F-I, F-II and F-III may belong to a subset of compounds having Formula F-IV:
or a pharmaceutically acceptable salt thereof.
The compounds of formula F-I, F-II and F-III may belong to a subset of compounds having Formula F-V:
or a pharmaceutically acceptable salt thereof.
The compounds of Formula F-I, F-II and F-III may belong to a subset of compounds having a Formula VI:
or a pharmaceutically acceptable salt thereof,
wherein v is 0 or 1
Z is selected from CH or N
and wherein
whenever Z is CH R12 is —NR5R6 and
whenever Z is N, R12 is selected from an R7 group comprising at least one N atom.
The compounds of any one of Formulas F-I, F-II, F-III, F-IV and F-V may belong to a subset of compounds wherein:
R1 is cyclohexanyl or n-octyl;
n is 2;
R4 is selected from the group consisting of -Cy, -PhOCF3 and pentan-3-yl;
R5 is H;
R6 is —(CH2)3—NH2 or -Cy-NH2;
R9 is —H or —CN; and
R10 is H.
The compound of Formula VI may belong to a subset of compounds wherein:
R1 is cyclohexanyl or n-octyl;
R9 is —H or —CN; and
R10 is H.
The compounds of Formula I may belong to a subset of compounds having a Formula II:
or a pharmaceutically acceptable salt thereof.
Each of X1, X2, X3, and X4 may independently be selected from C and N, with the proviso that when X3 is N then X1 is also N.
X5 may be selected from CH, CMe, C═O, and N.
R1 may be selected from the group consisting of
R2 may be selected from the group consisting of
R3 may selected from the group consisting of
R4 may be selected from the group consisting of
R5 may be selected from the group consisting of
R4 and R5 together with the atoms to which they are bound may form a 6-membered heteroaliphatic ring.
R6 may be selected from the group consisting of
R5 and R6 together with the atoms to which they are bound may form a 6-membered heteroaliphatic ring optionally substituted with one or more R7 groups.
R7 may be selected from the group consisting of methyl, fluoro, bromo, phenyl, hydroxy, —CH2OH, -oxo, methoxy, —C(O)Me, , —SO2Me, —SO2Ph optionally substituted with —F, —NH2, —NHMe, —NMe2, —C(O)—NH2, —NH—C(O)—NH2, —C(═NH)—NH2, —NH—C(═NH)—NH2, —(CH2)s—NH2, piperidine, piperazine, morpholine, —(CH2)t—NH—P(O)(OEt)2, —C(O)NH—R8, and phenoxy optionally substituted with —Cl.
R8 may be selected from the group consisting of —OH, -(amino)cyclohexyl, -pyrrolidinylethyl, and -methylpiperazinylethyl.
R9 may be selected from the group consisting of —H, —F, —Br, —NO2, —OH, —OMe, —CN, —CO2H, —CO2Me, —CO2NH2, —CH2NH2, -Cy, -pyridinyl, -tetrahydropyridinyl, -pyrazinyl optionally substituted with -Me, and -phenyl optionally substituted with —Cl, -Me, —CF3, —OMe or —OCF3.
R10 may be —H or —Br.
m, n, p, r, s and t may each be independently selected from 0, 1 or 2.
The compounds of Formula I or II may belong to a subset of compounds having a Formula III:
or a pharmaceutically acceptable salt thereof
wherein R11 is —H, -Me or -oxo.
The compounds of Formula I-III may belong to a subset of compounds having a Formula IV:
or a pharmaceutically acceptable salt thereof.
The compounds of any one of Formulas I-III may belong to a subset of compounds having a Formula V:
or a pharmaceutically acceptable salt thereof.
The compounds of any one of Formulas I-III may belong to a subset of compounds having a Formula VI:
or a pharmaceutically acceptable salt thereof,
wherein v is 0 or 1
Z is selected from CH or N
and wherein
whenever Z is CH R12 is —NR5R6 and
whenever Z is N, R is selected from an R7 group comprising at least one N atom.
The compounds of any one of Formulas I-VI may belong to a subset of compounds wherein:
R1 is cyclohexanyl or n-octyl;
n is 2;
R4 is selected from the group consisting of -Cy, -PhOCF3 and pentan-3-yl;
R5 is H;
R6 is —(CH2)3—NH2 or -Cy-NH2;
R9 is —H or —CN; and
R10 is H.
The compounds of any one of Formulas I-V may belong to a subset of compounds wherein: each of X1-X4 is C, and X5 is CH.
According to another aspect of the present invention, the objects of the invention are achieved by a compound according to Formula F-I, I or II or any subgroup thereof as disclosed above, for use in a method of treatment of the human or animal body by therapy. The therapy may be treatment or prevention of an infection. The infection may be a bacterial, fungal, or parasite infection. The infection may be a bacterial infection caused or complicated by bacteria of a genus selected from Staphylococcus, Enterococcus, Streptococcus, Pseudomonas, Legionella, Klebsiella, Haemophilus, Neisseria, Listeria, Escherichia, Helicobacter and Mycobacterium. The bacterial infection may be caused or complicated by a bacterial species selected from the group: S. aureus, E. faecalis, E. faecium, S. pneumoniae, E. coli, K. pneumoniae, H. influenza, A. baumannii, P. aeruginosa, P. aeruginosa, N. gonorrhoeae, M. fortuitum, M. phlei, and H. pylori. The bacterial infection may be caused or complicated by a bacterial species selected from the group: Neisseria meningitides, Listeria monocytogenes, Legionella pneumophila, Mycobacterium bovis, and Mycobacteria tuberculosis. The bacterial infection may be caused or complicated by a Methicillin-resistant Staphylococcus aureus (MRSA).
According to a further aspect of the present invention, the objects of the invention are achieved by a method of treating an infection which comprises administering to a patient in need thereof a therapeutically effective amount of a compound as disclosed above. The infection may be a bacterial, fungal, or parasite infection. The infection may be a bacterial infection caused or complicated by bacteria of a genus selected from Staphylococcus, Enterococcus, Streptococcus, Pseudomonas, Legionella, Klebsiella, Haemophilus, Neisseria, Listeria, Escherichia, Helicobacter and Mycobacterium. The bacterial infection may be caused or complicated by a bacterial species selected from the group: S. aureus, E. faecalis, E. faecium, S. pneumoniae, E. coli, K. pneumoniae, H. influenza, A. baumannii, P. aeruginosa, P. aeruginosa, N. gonorrhoeae, M. fortuitum, M. phlei, and H. pylori. The bacterial infection may be caused or complicated by a bacterial species selected from the group: Neisseria meningitides, Listeria monocytogenes, Legionella pneumophila, Mycobacterium bovis, and Mycobacteria tuberculosis. The bacterial infection may be caused or complicated by a Methicillin-resistant Staphylococcus aureus.
According to yet another aspect of the present invention, the object of the invention is achieved by use of a compound as disclosed above, or a salt thereof, in inhibition of bacterial RNase P activity.
According to yet a further aspect of the present invention, the object of the invention is achieved by use of a compound as disclosed above, or a salt thereof, as a bactericide.
According to still a further aspect of the present invention, the object of the invention is achieved by a pharmaceutical composition comprising a compound as disclosed above, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, adjuvant, diluent and/or carrier.
Further aspects, objects and advantages are defined in the detailed description below with reference to the appended drawings.
For the understanding of the present invention and further objects and advantages of it, the detailed description set out below can be read together with the accompanying drawings.
All reactions were carried out under dry nitrogen and or argon atmosphere unless otherwise specified. Unless otherwise stated, all the raw starting materials, solvents, and reagents were purchased from commercial sources (e.g., AVRA Chemicals, Apollo Scientific Limited, Bepharma Ltd., Combi-Blocks Inc., Sigma Aldrich Chemicals Pvt. Ltd., Ultra Labs, Toronto Research Chemicals Inc., Chemical House, RFCL Limited, Spectro Chem Pvt. Ltd., Leonid Chemicals, Loba Chemie, Changzhou Yangyuan, NeoSynth., Rankem, etc.) and used as such without further purification. Alternatively, reagents may be synthesized by procedures known in the literature.
The following abbreviations are used and have the indicated definitions: MHz is megahertz (frequency), m is multiplet, t is triplet, d is doublet, s is singlet, br is broad, CDCl3 is deutero chloroform, calcd is calculated, min is minutes, h is hours, g is grams, mmol is millimoles, mL is milliliters, N is normality (concentration), M is molarity (concentration), M is micromolar, ee is enantiomeric excess, de is diastereomeric excess, ° C. is degree centigrade, HPLC is High Performance Liquid Chromatography, LC-MS is Liquid Chromatography-Mass Spectroscopy, NMR is Nuclear Magnetic Resonance, TLC is Thin Layer Chromatography, THE is tetrahydrofuran, MeOH is methanol, DCM is dichloromethane, DEA is diethylamine, DMA is dimethylacetamide, DMF is N,N-dimethyl formamide, DMSO is dimethyl sulfoxide, EtOH is ethyl alcohol, EtOAc is ethyl acetate, RT is room temperature, HCl is hydrogen chloride or hydrochloric acid, TFA is trifluoroacetic acid, EtMgBr is ethyl magnesium bromide, n-BuLi is n-butyl lithium, NaHCO3 is sodium bicarbonate, Na2CO3 is sodium carbonate, Na2SO4 is sodium sulfate, DCC is N,N-dicyclohexylcarbodiimide, DIPA is diisopropylamine, LDA is lithium diisopropylamine, HOBt is N-hydroxy-benzotriazole, NCS is N-chlorosuccinimide, and TBAB is tetrabutyl ammonium bromide.
Biotage Isolera® One and CombiFlash®(Teledyne Isco) Automated Flash Purification System were used for the purification of crude products using the eluent combination mentioned in the respective procedures. Flash Chromatography was performed using silica gel (60-100, 100-200 and 230-400 mesh) from ChemLabs, with nitrogen and/or compressed air. Preparative thin-layer chromatography was carried out using silica gel (GF 1500 μM 20×20 cm and GF 2000 μM 20×20 cm prep-scored plates from Analtech, Inc. Delaware, USA). Thin-layer chromatography was carried out using pre-coated silica gel sheets (Merck 60 F254). Visual detection was performed with ultraviolet light, p-anisaldehyde stain, ninhydrin stain, dinitrophenyl hydrazine stain, potassium permanganate stain, or iodine. Reactions at lower temperature were performed by using cold baths, e.g., H2O/ice at 0° C., and acetone/dry ice at -78° C. Melting points were determined by using a LabIndia MR-VIS visual melting range apparatus. 1H NMR spectra were recorded at 400 MHz with a Varian V400 spectrometer, Bruker 400 (unless otherwise noted) at ambient temperature, using tetramethylsilane as internal reference. The chemical shift values are quoted in 6 (parts per million). Mass spectra of all the intermediates and final compounds were recorded using Acquity® UPLC-SQD (Waters) & Agilent 1290 Infinity® with 6150 SQD machines. HPLC spectra were recorded using Agilent 1290 Infinity® UHPLC and Alliance (Waters) systems. LCMS spectra were recorded using Agilent 1200® LCMS/Agilent 1290® UHPLC-SQD with diode array detector (DAD) detection LC-MS instruments using Kinetex C18 (50 mm×2.1 mm×2.7mic) and/orX-terra MS C18 (50 mm×2.1 mm×3.0 micron) columns. The purity of each of the final compounds was detected using Waters® PDA with SQD or Aglient® DAD with 6150 SQD instrument. The compounds according to Formulas I & II are prepared using conventional organic synthetic methods. A suitable synthetic route is depicted below in the following general reaction Schemes. The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006). In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
Scheme 1 (
On the other hand compound of formula (Ie) can be obtain from Indole derivatives (If). Compound (Ig) is obtained from (If) by reaction with appropriate R2CHO and Meldrum's acid and subsequent decarboxylation and esterification afford compound of formula (Ih). Key intermediate (Ie) is obtained alkylation of (Ih) with appropriate R1X. Compound (Ie) was reduced using procedure for the reduction ester known in literature to obtain compound (Ii), which on treatment with alkyl or aryl sulfonyl chloride or halogenating agent provide compound of formula (Ij). Finally, compound of formula IA is obtained by the reaction of compound Ij with appropriate amine (R3R4NH). In case, compound of formula Ic, where R5, R6 is halogen can be converted to R5, R6 is CN using cyanation reaction known in literature by CuCN. On the other hand, halogen is converted to aryl, alkyl group under Suzuki coupling known in literature. R1 to R6 containing N/O protecting group usually deprotected as and when required for further steps or to obtain final compound.
Scheme 2 (
Scheme 3 (
General scheme 1 (
To a stirred solution of Indoline (1 g, 8.403 mmol) in DCM (25 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (4.18 g, 21.008 mmol) and reaction mixture was stirred at rt, after 1 h of stirring, was added NaBH(OAC)3 (2.67 g, 12.60 mmol) at 0° C. then stirred the reaction mixture at rt for 24 h. Progress of the reaction was monitored by TLC. The reaction mixture was diluted with aq NaHCO3 solution (30 mL) and compound was extracted with DCM (3×50 mL). The organic layer was dried over anhydrous sodium sulphate, concentrated under reduced pressure. The crude compound was directly used in the next step without further purification (crude wt 1.8 g).
LC-MS m/z (M): calculated 302; found (M+H): 303
To a stirred solution of tert-butyl 4-(indolin-1-yl) piperidine-1-carboxylate (2 g, 6.622 mmol) in THE (20 mL), was added DDQ (2.2 g, 9.933 mmol) at 0° C. and the reaction mixture was stirred at rt for 1 h. Progress of the reaction was monitored by TLC. Reaction mixture was diluted with water (50 mL), extracted with Ethyl acetate (3×60 mL). The organic layer was dried over anhydrous sodium sulphate, concentrated under reduced pressure. The crude compound was purified by column chromatography using 4% EtOAc in Pet-ether as an eluent to afford desired product as gummy mass (yield: 250 mg, 25%).
1H NMR (400 MHz, CDCl3) δ 7.65 (d, J=4.9 Hz, 1H), 7.39 (d, J=9.49 Hz, 2H), 7.23-7.15 (m, 2H), 7.10 (t, J=7.14 Hz, 1H), 6.54 (d, J=10.7 Hz, 1H), 4.40-4.28 (m, 2H), 2.92 (t, J=12.08 Hz, 2H), 2.12-2.05 (m, 2H), 1.94-1.85 (m, 2H), 1.5 (s, 10H)
To a stirred solution of tert-butyl 4-(1H-indol-1-yl) piperidine-1-carboxylate (520 mg, 1.73 mmol) in dry Acetonitrile (6 mL), were added Meldrum's acid (499 mg, 3.46 mmol), m-tolualdehyde (270 mg, 2.25 mmol) and L-proline (20 mg, 0.173 mmol) then reaction mixture was stirred at rt for 16 h. Progress of the reaction was monitored by TLC. The reaction mixture was concentrated under vacuum and the crude product was carried forward to next step without purification (crude wt: 1.3 g).
LC-MS m/z (M): calculated 546.6
To a stirred solution of tert-butyl 4-(3-((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl) (m-tolyl)methyl)-1H-indol-1-yl)piperidine--carboxylate (1.3 g, 2.380 mmol) in a 1:1 mixture of pyridine and Ethanol (20 mL) was added Cu powder (15 mg, 0.238 mmol) and stirred the reaction mixture at 90° C. for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel 60-120 mesh, eluted with 10% EtOAc in Pet-ether) to afford desired product as yellow liquid (yield: 600 mg, 54%).
To a stirred solution of 3-(1-(1-(tert-butoxycarbonyl) piperidin-4-yl)-1H-indol-3-yl)-3-(m-tolyl)propanoic acid (530 mg, 1.08 mmol) in THF/MeOH/H2O (1:1:1) (15 mL) was added LiOH (454 mg, 10.8 mmol) at 0° C. and the reaction mixture was stirred at rt for 6 h. Progress of the reaction was monitored by TLC. The reaction mixture was acidified to pH 6 with citric acid. Off white solid was thrown out during acidification was filtered and air dried (yield: 358 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 7.44 (d, J=7.8 Hz, 1H), 7.31 (d, J=8.38 Hz, 1H), 7.20-7.08 (m, 4H), 7.09-6.98 (m, 3H), 4.74 (t, J=7.87 Hz, 1H), 4.38-4.25 (m, 3H), 3.20-3.12 (m, 1H), 3.09-3.02 (m, 1H), 2.90-2.87 (m, 2H), 2.29 (s, 3H), 2.10-2.0 (m, 2H), 1.92-1.84 (m, 2H), 1.49 (s, 9H) LC-MS m/z (M): calculated 462.59; found (M−H): 461.2
To a stirred solution of 3-(1-(1-(tert-butoxycarbonyl) piperidin-4-yl)-1H-indol-3-yl)-3-(m-tolyl)propanoic acid (350 mg, 0.756 mmol) in DMF (2 mL), were added DIPEA (0.270 mL, 1.512 mmol), HATU (430 mg, 1.134 mmol) followed by tert-butyl (4-aminocyclohexyl)carbamate (210 mg, 0.983 mmol) at 0° C. and the reaction mixture was stirred at rt for 5 h. Progress of the reaction was monitored by TLC. Ice cold water added to reaction mixture at 0° C., extracted with EtOAc. The combined organic layer dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography, eluted with 20% EtOAc in Pet-ether to afford desired product as off white solid (yield: 400 mg, 80%).
1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J=7.92 Hz, 1H), 7.36 (d, J=8.22 Hz, 1H), 7.26-7.20 (m, 1H), 7.18-7.08 (m, 5H), 7.0 (d, J=6.54 Hz, 1H), 5.28-5.25 (m, 1H), 4.63 (t, J=7.53 Hz, 1H), 4.39-4.31 (m, 3H), 3.85-3.62 (m, 3H), 3.35-3.2 (m, 1H), 3.19-3.0 (m, 8H), 2.30 (s, 3H), 2.11-2.0 (m, 2H), 1.91-1.83 (m, 2H), 1.75-1.70 (m, 2H), 1.57-1.51 (m, 20H), 1.40-1.20 (m, 5H)
LC-MS m/z (M): calculated 658.87; found (M+H): 659.4
To a stirred solution of tert-butyl 4-(3-(3-((4-((tert-butoxycarbonyl) amino)cyclohexyl)amino)-1-(m-tolyl)propyl)-1H-indol-1-yl)piperidine-1-carboxylate (200 mg, 0.303 mmol) in dry THF (8 mL), was added BH3 in THF (1M, 4.5 mL, 4.553 mmol) at 0° C. and the reaction mixture was refluxed for 8 h. Progress of the reaction was monitored by TLC. After 8 h of reflux, 5 mL of MeOH was added then refluxed for 5 h. Solvent was removed from reaction mixture under reduced pressure and the crude compound was directly carry forwarded to the next step without further purification (crude yield 220 mg).
To a stirred solution of tert-butyl 4-(3-(3-((4-((tert-butoxycarbonyl) amino)cyclohexyl)amino)-1-(m-tolyl)propyl)-1H-indol-1-yl)piperidine-1-carboxylate (220 mg, 0.34 mmol), in DCM (5 mL) were added TEA (0.25 mL, 1.7 mmol), followed by Boc anhydride (0.37 mL, 1.7 mmol), and the reaction mixture was stirred at rt for 12 h. Progress of the reaction was monitored by TLC. Excess solvent was removed from the reaction mixture and the crude compound was purified by column chromatography using 25% EtOAc in Hexane as an eluent to afford desired compound as colorless liquid (yield: 65 mg, 25%).
To a stirred solution of tert-butyl 4-(3-(3-((tert-butoxycarbonyl) (4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-1-(m-tolyl)propyl)-1H-indol-1-yl)piperidine-1-carboxylate (65 mg, 0.087) in DCM (2 mL), was added HCl in dioxane (4M, 1.2 mL) at 0° C. and reaction mixture was stirred at rt for 2 h. Progress of the reaction was monitored by TLC. Excess solvent was removed under reduced pressure and washed with diethyl ether to get an off white solid (yield: 10 mg, 26%).
1H NMR (400 MHz, DMSO-d6) δ 8.90-8.85 (m, 3H), 8.7 (brs, 1H), 7.96 (brs, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.45 (d, J=8.04 Hz, 1H), 7.33 (s, 1H), 7.10-7.19 (m, 4H), 6.99-6.94 (m, 2H), 4.70-4.65 (m, 1H), 4.28-4.25 (m, 1H), 3.43 (d, J=11 Hz, 2H), 3.30-3.12 (m, 5H), 2.95-2.90 (m, 1H), 2.80-2.72 (m, 1H), 2.40-2.35 (m, 1H), 2.25-2.18 (m, 5H), 2.17-2.12 (m, 2H), 1.95-1.90 (m, 1H), 1.80-1.62 (m, 8H),
LC-MS m/z (M): calculated 445.6; found (M+H): 446.4
See
To a stirred solution of 5-bromo-1-cyclohexyl-1H-indole (3 g, 11.07 mmol) in DMF, was added CuCN (2.95 g, 33.21 mmol) and the reaction mixture was stirred at 140° C. for 20 h. Progress of the reaction was monitored by TLC. Reaction mixture was diluted with ice cold water (50 mL), extracted with Ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate, concentrated under reduced pressure. The crude compound was purified by column chromatography using 5% EtOAc in Pet-ether as an eluent to afford desired product as colourless viscous liquid (yield: 850 mg, 35%).
1H NMR (400 MHz, CDCl3) δ 7.9 (s, 1H), 7.41 (s, 2H), 7.34 (d, J=3.29 Hz, 1H), 6.58 (d, J=3.25 Hz, 1H), 4.28-4.19 (m, 1H), 2.12 (d, J=11.58 Hz, 2H), 1.96 (d, J=13.47 Hz, 2H), 1.80-1.85 (m, 1H), 1.78-1.62 (m, 2H), 1.53-1.48 (m, 2H), 1.45-1.23 (m, 1H)
LC-MS m/z (M): calculated 224.3; found (M+H): 225.2
To a stirred solution of 1-cyclohexyl-1H-indole-5-carbonitrile (830 mg, 3.700 mmol) in dry Acetonitrile, were added Meldrum's acid (959 mg, 6.66 mmol), 3-(trifluoromethoxy) benzaldehyde (0.68 mL, 4.81 mmol) and DL-proline (43 mg, 0.37 mmol) then reaction mixture was stirred at rt for 16 h. Progress of the reaction was monitored by TLC. The reaction mixture was concentrated under vacuum and the crude product was carried forward to next step without purification (crude wt 3.26 g).
LC-MS m/z (M): calculated 540.5; found (M+H): 541.18
To a stirred solution of 1-cyclohexyl-3-((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl) (3-(trifluoromethoxy)phenyl)methyl)-1H-indole-5-carbonitrile (3.26 g, 6.03 mmol) in a 1:1 mixture of pyridine and Ethanol (40 mL) was added Cu powder (77 mg, 1.206 mmol) and stirred the reaction mixture at 90° C. for 16 h. Progress of the reaction was monitored by TLC. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel 60-120 mesh, eluted with 10% EtOAc in Pet-ether) to afford desired product as yellow solid (yield: 1.57 g, 87%).
1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.37 (s, 2H), 7.36-7.30 (m, 1H), 7.25-7.20 (m, 2H), 7.10-7.08 (m, 2H), 4.78 (t, J=7.91 Hz, 1H), 4.22-4.16 (m, 1H), 4.08-4.0 (m, 2H), 3.12-3.05 (m, 1H), 3.04-2.95 (m, 1H), 2.15-2.02 (m, 3H), 2.0-1.92 (m, 2H), 1.85-1.79 (m, 1H), 1.76-1.62 (m, 2H), 1.52-1.46 (m, 2H), 1.35-1.24 (m, 2H), 1.19-1.10 (m, 3H)
LC-MS m/z (M): calculated 484.5; found (M+H): 485.2
To a stirred solution of ethyl 3-(5-cyano-1-cyclohexyl-1H-indol-3-yl)-3-(3-(trifluoromethoxy) phenyl)propanoate (1.55 g, 3.199) in dry THF, was added LiBH4 (211 mg, 9.597 mmol) at 0° C. and reaction mixture was stirred at 60° C. for 10 h. Progress of the reaction was monitored by TLC. Reaction mixture was quenched with ice cold water, extracted with DCM. Combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was carried forward to next step without purification (crude wt: 1.5 g).
1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.75 (s, 1H), 7.67 (d, J=8.65 Hz, 1H), 7.42-7.38 (m, 4H), 7.15-7.10 (m, 1H), 4.50-4.20 (m, 4H), 3.38-3.36 (m, 2H), 2.32-2.26 (m, 1H), 2.20-2.10 (m, 1H), 1.98-1.88 (m, 2H), 1.87-1.60 (m, 6H), 1.58-1.40 (m, 3H), 1.30-1.20 (m, 2H), 1.18-1.12 (m, 1H)
LC-MS m/z (M): calculated 442.4; found (M+H): 443.2
To a stirred solution of 1-cyclohexyl-3-(3-hydroxy-1-(3-(trifluoromethoxy) phenyl)propyl)-1H-indole-5-carbonitrile (520 mg, 1.176 mmol) in CH2Cl2 (6 mL), were added TEA (0.33 mL, 2.352 mmol) followed by methane sulphonylchloride (0.11 mL, 1.411 mmol) dropwise at 0° C. and stirred the reaction mixture at room temperature for 2 h. Progress of the reaction was monitored by TLC. The reaction mixture was diluted with H2O (20 mL) and compound was extracted with CH2Cl2 (3×20 mL), combined organic layer was washed with saturated NaHCO3 (20 mL), which was dried over anhydrous sodium sulphate, concentrated under reduced pressure. The crude compound was carried forward to next step without purification (crude wt: 630 mg).
LC-MS m/z (M): calculated 520.5; found (M+H): 521.2
To a stirred solution of 3-(5-cyano-1-cyclohexyl-1H-indol-3-yl)-3-(3-(trifluoromethoxy) phenyl)propyl methanesulfonate (630 mg, 1.210 mmol) in dry DMF (5 mL), were added K2CO3 (500 mg, 3.63 mmol) and tert-butyl (3-aminopropyl)carbamate (253 mg, 1.452 mmol) then the reaction mixture was stirred at 80° C. for 10 h. Progress of the reaction was monitored by TLC. The reaction mixture was poured in to ice-cold water (20 mL), solid was precipitated out, which was filtered and soluble in CH2Cl2 (20 mL), concentrated under reduced pressure. The crude compound was purified by preparative TLC (eluted with 5% MeOH in CH2Cl2) to afford desired product as light brown liquid (yield: 166 mg, 22.9%).
1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.75 (s, 1H), 7.68 (d, J=8.65 Hz, 1H), 7.42-7.35 (m, 4H), 7.15-7.10 (m, 1H), 6.82-6.79 (m, 1H), 4.42-4.35 (m, 2H), 4.10-4.05 (m, 2H), 3.18-3.13 (m, 5H), 2.96-2.90 (m, 2H), 2.46-2.40 (m, 3H), 2.30-2.22 (m, 1H), 2.20-2.12 (m, 1H), 1.96-1.88 (m, 2H), 1.86-1.78 (m, 4H), 1.76-1.68 (m, 1H), 1.56-1.48 (m, 4H), 1.34 (s, 9H), 1.25-1.20 (m, 3H)
LC-MS m/z (M): calculated 598.2; found (M+H): 599.45
To a stirred solution of tert-butyl (3-((3-(5-cyano-1-cyclohexyl-1H-indol-3-yl)-3-(3-(trifluoromethoxy)phenyl)propyl)amino)propyl)carbamate (160 mg, 0.267 mmol) in DCM (2 mL), was added HCl in dioxane(4M, 2 mL) at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the crude compound was washed with diethyl ether to afford desired compound as off white solid (yield: 118 mg, 77%). MP: 190-194° C.
1H NMR (400 MHz, DMSO-d6) δ 9.38-9.30 (m, 2H), 8.00-7.70 (m, 5H), 7.71 (d, J=8.61 Hz, 1H), 7.44-7.42 (m, 4H), 7.18 (brs, 1H), 4.55 (t, J=7.40 Hz, 1H), 4.42-4.39 (m, 1H), 3.10-2.77 (m, 6H), 2.60-2.55 (m, 1H), 2.43-2.38 (m, 1H), 1.95-1.93 (m, 4H), 1.86-1.81 (m, 4H), 1.77-1.73 (m, 1H), 1.59-1.42 (m, 2H), 1.35-1.20 (m, 2H)
LC-MS m/z (M): calculated 498.5; found (M+H): 499.3
To a stirred solution of tert-butyl (3-((3-(5-cyano-1-cyclohexyl-1H-indol-3-yl)-3-(3-(trifluoromethoxy) phenyl)propyl)amino)propyl)carbamate (30 mg, 0.058 mmol) in EtOH:H2O (9:1) (2 mL), was added KOH and the reaction mixture was stirred at 90° C. for 50 h. Progress of the reaction was monitored by TLC. Reaction mixture was cooled to rt, acidified with 6N HCl until pH of the reaction mixture became 1 and compound extracted with 10% MeOH in DCM. Organic layer was dried over sodium sulphate and concentrated afford desired compound as off white solid (yield: 6 mg, 25%).
1H NMR (400 MHz, DMSO-d6) δ 8.10 (brs, 1H), 7.80 (brs, 1H), 7.68-7.61 (m, 2H), 7.51 (d, J=8.69 Hz, 1H), 7.40-7.34 (m, 3H), 7.13-7.07 (m, 2H), 4.34 (t, J=11.72 Hz, 1H), 2.85-2.81 (m, 2H), 2.74-2.70 (m, 2H), 2.29-2.25 (m, 2H), 2.00-1.93 (m, 2H), 1.89 (s, 1H), 1.87-1.72 (m, 7H), 1.54-1.45 (m, 2H), 1.32-1.22 (m, 4H)
LC-MS m/z (M): calculated 516.6; found (M+H): 517.2
Following the procedure described in scheme 1/Example A, compounds of Table 1 are prepared by using suitable starting materials and proper conditions.
The general scheme 2 (
To a stirred solution of 1H-indole-5-carbonitrile (1.5 g, 10.56 mmol) in DMF (8 mL) were added KI (1.75 g, 10.56 mmol) followed by NaH (1.26 g, 31.68 mmol) in portion wise at 0° C. and reaction mixture was stirred at the same temperature for 5 min. After 5 min, 4-(bromomethyl) tetrahydro-2H-pyran (2.1 mL, 15.84 mmol) was added to reaction mixture at 0° C. then stirred at rt for 4 h. Progress of the reaction was monitored by TLC. Reaction mixture was quenched with crushed ice stirred for 15 min solid obtained in the reaction mixture was filtered off, dried under vacuum to get the pale cream solid (yield: 2.25 g, 88.9%).
1H NMR (400 MHz, CDCl3) δ 8.0 (s, 1H), 7.47-7.36 (m, 2H), 7.18 (d, J=3.14 Hz, 1H), 6.58 (d, J=3.0 Hz, 1H), 4.02 (d, J=7.29 Hz, 2H), 3.98 (d, J=3.38 Hz, 2H), 3.38-3.28 (m, 2H), 2.10-2.05 (m, 1H), 1.51-1.40 (m, 4H),
LC-MS m/z (M): calculated 240; found (M+H): 241
To a stirred solution of 1-((tetrahydro-2H-pyran-4-yl) methyl)-1H-indole-5-carbonitrile (2.2 g, 9.166 mmol) in dry Acetonitrile (20 mL), were added Meldrum's acid (2.63 g, 18.33 mmol), m-tolualdehyde (1.4 mL, 11.91 mmol) and DL-proline (105.3 mg, 0.916 mmol) then reaction mixture was stirred at rt for 16 h. Progress of the reaction was monitored by TLC. The reaction mixture was concentrated under vacuum and the crude product was carried forward to next step without purification (crude wt: 5.6 g)
LC-MS m/z (M): calculated 486.5; found (M+H): 487.3
To a stirred solution of 3-((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl) (m-tolyl)methyl)-1-(tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-5-carbonitrile (5.6 g, 11.5 mmol) in a 1:1 mixture of pyridine and Ethanol (60 mL) was added Cu powder (147 mg, 2.30 mmol) and stirred the reaction mixture at 90° C. for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel 60-120 mesh, eluted with 10% EtOAc in Pet-ether) to afford desired product as yellow solid (yield: 950 mg, 25%).
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=7.92 Hz, 1H), 7.31 (d, J=8.25 Hz, 1H), 7.17-7.05 (m, 5H), 7.01-6.9 (m, 2H), 4.74 (t, J=7.91 Hz, 1H), 4.20-4.12 (m, 1H), 4.04-3.95 (m, 2H), 3.10-3.05 (m, 1H), 2.28 (s, 3H), 2.15-2.10 (m, 2H), 1.94-1.90 (m, 2H), 1.80-1.62 (m, 3H), 1.50-1.41 (m, 2H), 1.32-1.24 (m, 5H), 1.26 (t, J=3.5 Hz, 3H),
LC-MS m/z (M): calculated 430.54; found (M+H): 430.9
To a stirred solution of ethyl 3-(5-cyano-1-((tetrahydro-2H-pyran-4-yl) methyl)-1H-indol-3-yl)-3-(m-tolyl)propanoate (400 mg, 0.930 mmol) in THF/MeOH/H2O (1:1:1) (12 mL) was added LiOH.H2O (390 mg, 9.30 mmol) at 0° C. and the reaction mixture was stirred at rt for 7 h. Progress of the reaction was monitored by TLC. The reaction mixture was acidified to pH 6 with citric acid, extracted with EtOAc, separated organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography, eluted with 80 % EtOAc in hexane to afford pale cream solid (yield: 300 mg, 80%).
1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.40-7.28 (m, 2H), 7.17 (t, J=7.47 Hz, 1H), 7.09-7.04 (m, 4H), 4.70 (t, J=7.81 Hz, 1H), 4.01-3.92 (m, 4H), 3.35-3.28 (m, 2H), 3.12-3.0 (m, 2H), 2.30 (s, 3H), 2.09-2.0 (m, 1H), 1.5-1.25 (m, 5H),
LC-MS m/z (M): calculated 402.49; found (M−H): 401.1
To a stirred solution of 3-(5-cyano-1-((tetrahydro-2H-pyran-4-yl) methyl)-1H-indol-3-yl)-3-(m-tolyl)propanoic acid (350 mg, 0.870 mmol) in DMF (3 mL), were added DIPEA (0.32 mL, 1.305 mmol), HATU (495 mg, 1.305 mmol) followed by tert-butyl ((1s,4s)-4-aminocyclohexyl)carbamate (242.5 mg, 1.131 mmol) at 0° C. and the reaction mixture was stirred at rt for 2 h. Progress of the reaction was monitored by TLC. Ice cold water added to reaction mixture at 0° C., extracted with EtOAc. The combined organic layer dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography, eluted with 70% EtOAc in Pet-ether to afford desired product as off white solid (yield: 500 mg, 96%).
1H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.39 (d, J=8.59 Hz, 1H), 7.31 (d, J=8.59 Hz, 1H), 7.18 (t, J=7.42 Hz, 1H), 7.10 (d, J=5.87 Hz, 2H), 7.04 (d, J=7.53 Hz, 2H), 4.66 (t, J=7.7 Hz, 1H), 4.28 (d, J=7.04 Hz, 1H), 4.0-3.95 (m, 4H), 3.80-3.71 (m, 2H), 3.45 (brs, 1H), 3.35-3.30 (m, 2H), 2.90-2.80 (m, 2H), 2.30 (s, 3H), 2.05-2.0 (m, 2H), 1.52-1.40 (m, 21H),
LC-MS m/z (M): calculated 598.7; found (M-Boc): 499.2
To a stirred solution of tert-butyl ((1S,4S)-4-(3-(5-cyano-1-((tetrahydro-2H-pyran-4-yl) methyl)-1H-indol-3-yl)-3-(m-tolyl)propanamido)cyclohexyl)carbamate (300 mg, 0.501) in dry THE (6 mL), was added BH3 in THF (1 M, 10 mL, 10.00 mmol)) at 0° C. and the reaction mixture was refluxed for 8 h. Progress of the reaction was monitored by TLC. After 8 h of reflux, 5 mL of MeOH was added then refluxed for 5 h. Solvent was removed from reaction mixture under reduced pressure and the crude compound was directly carry forward to the next step without further purification (crude wt: 450 mg).
To a stirred solution of tert-butyl ((1S,4S)-4-((3-(5-(aminomethyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indol-3-yl)-3-(m-tolyl)propyl)amino)cyclohexyl)carbamate (450 mg, 0.765 mmol), were added TEA (0.55 mL, 3.825 mmol), followed by Boc anhydride (0.66 mL, 3.061 mmol), and the reaction mixture was stirred at rt for 12 h. Progress of the reaction was monitored by TLC. Excess solvent was removed from the reaction mixture and the crude compound was purified by column chromatography using 20% EtOAc in Hexane as an eluent to afford desired compound as brown liquid (yield: 120 mg, 30%).
1H NMR (400 MHz, DMSO-d6) δ 7.35 (d, J=8.7 Hz, 1H), 7.30-7.25 (m, 2H), 7.24-7.20 (m, 3H), 7.0-6.0 (m, 2H), 4.10-4.05 (m, 2H), 4.04-3.99 (m, 3H), 3.80-3.65 (m, 4H), 3.21-3.05 (m, 3H), 3.0-2.91 (m, 1H), 2.21 (s, 3H), 2.02-1.95 (m, 1H), 1.69-1.60 (m, 2H), 1.51-1.42 (m, 5H), 1.42-1.30 (m, 22H), 1.30-1.20 (m, 8H),
LC-MS m/z (M): calculated 789; found (M-Boc): 689
To a stirred solution of tert-butyl ((s,4s)-4-((tert-butoxycarbonyl) amino)cyclohexyl)(3-(5-(((tert-butoxycarbonyl)amino)methyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indol-3-yl)-3-(m-tolyl)propyl)carbamate (120 mg, 0.152) in DCM (1.2 mL), was added 4 M HCl in 1,4-dioxane (1.2 mL) at 0° C. and reaction mixture was stirred at rt for 10 h. Progress of the reaction was monitored by TLC. Excess solvent was removed under reduced pressure and washed with diethyl ether to get off white solid (yield: 80 mg, 94%). MP: 130-134° C.
1H NMR (400 MHz, DMSO-d6) δ 9.28 (brs, 1H), 9.17 (brs, 1H), 8.96 (brs, 2H), 8.30 (brs, 3H), 8.12 (brs, 1H), 7.66 (s, 1H), 7.51 (d, J=8.47 Hz, 1H), 7.46 (s, 1H), 7.21 (d, J=8.47 Hz, 1H), 7.18-7.14 (m, 3H), 6.97 (d, J=5.88 Hz, 1H), 4.23-4.19 (m, 1H), 4.10-4.01 (m, 4H), 3.79 (d, J=10.73 Hz, 2H), 3.21-3.10 (m, 4H), 2.95-2.84 (m, 2H), 2.72-2.65 (m, 1H), 2.40-2.38 (m, 1H), 2.24 (s, 3H), 2.10-1.98 (m, 3H), 1.90-1.60 (m, 6H), 1.85-1.20 (m, 4H)
LC-MS m/z (M): calculated 488.3; found (M+H): 489.3
Following the procedure described in scheme 2/Example II, compounds of Table 2 are prepared by using suitable starting materials and proper conditions.
General Scheme 3 (
To a stirred solution of 5-bromoindoline (10 g, 50.48 mmol, compound-1) in EDC (200 mL) was added cyclohexanone (15.8 ml-cyclohexyl-1H-indole-5-carbonitrile L, 151.46 mmol) at rt. After stirring the reaction mixture for 1 h was added NaBH(OAc)3 (53.5 g, 252.41 mmol) and stirred the reaction mixture at rt for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with NaHCO3 solution (100 mL), extracted with ethyl acetate (2×200 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude compound was purified column chromatography (silica gel 60-120 mesh, eluted with 2% EtOAc in pet ether) to afford 5-bromo-1-cyclohexylindoline (13.2 g, yield: 92%) as pale yellow liquid.
1H NMR (400 MHz, CDCl3) δ 1.10-1.17 (m, 1H), 1.30-1.39 (m, 4H), 1.68 (d, J=12.7 Hz, 1H), 1.76-1.84 (m, 4H), 2.90 (t, J=8.4 Hz, 2H), 3.23-3.39 (m, 1H), 3.36 (t, J=8.4 Hz, 2H), 6.22-6.24 (m, 1H), 7.08-7.09 (m, 2H)
To a stirred solution of 5-bromo-1-cyclohexylindoline (13 g, 46.55 mmol) in dry THF(130 mL) was added DDQ (11.6 g, 51.21 mmol) at 0° C. and stirred the reaction mixture at same temperature for 5 min. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (2×20 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude compound was purified column chromatography (silica gel 60-120 mesh, eluted with 2% EtOAc in pet-ether) to afford 5-bromo-1-cyclohexyl-1H-indole (10 g, yield: 77%) as light greenish liquid.
To a stirred solution of 5-bromo-1-cyclohexyl-1H-indole (5 g, 17.985 mmol) in CH3CN (50 mL) was added m-Toulaldehyde (3.1 mL, 26.97 mmol), DL-proline (207 mg, 1.798 mmol) followed by Meldrum's acid (5.1 g, 35.971 mmol) and stirred the reaction mixture at rt for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to afford 5-((5-bromo-1-cyclohexyl-1H-indol-3-yl) (m-tolyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (13 g, crude) as brown semi-solid. The crude compound was used in the next step.
LC-MS m/z (M−H): 429.4
To a stirred solution of 5-((5-bromo-1-cyclohexyl-1H-indol-3-yl) (m-tolyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (13 g, 24.787 mmol) in EtOH/pyridine (195 mL, 1:1 v/v) was added Cu powder (143 mg, 2.478 mmol) and stirred the reaction mixture at 90° C. for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to rt, filtered through, the filtrate was concentrated under reduced pressure. The crude compound was purified by combi-flash column chromatography (eluted with 10% EtOAc in pet ether) to afford ethyl 3-(5-bromo-1-cyclohexyl-1H-indol-3-yl)-3-(m-tolyl) propanoate (7 g, yield: 60%) as pale yellow semi-solid. 1H NMR (400 MHz, CDCl3) δ 1.10 (t, J=2.1 Hz, 3H), 1.22-1.33 (m, 1H), 1.42-1.53 (m, 2H), 1.61-1.71 (m, 2H), 1.78 (d, J=13.1 Hz, 1H), 1.92 (d, J=13.3 Hz, 2H), 2.08 (s, 2H), 2.30 (s, 3H), 2.93-2.99 (m, 1H), 3.03-3.09 (m, 1H), 4.00-4.09 (m, 2H), 4.10-4.15 (m, 1H), 4.67 (t, J=7.9 Hz, 1H), 6.99 (d, J=7.3 Hz, 1H), 7.06-7.08 (m, 3H), 7.13-7.20 (m, 3H), 7.53 (d, J=1.5 Hz, 1H)
LC-MS m/z (M+H): 468.4
To a stirred solution of ethyl 3-(5-bromo-1-cyclohexyl-1H-indol-3-yl)-3-(m-tolyl) propanoate (500 mg, 1.068 mmol) in Dioxane/H2O (10 mL, 4:1 v/v) was added (1-methyl-1H-pyrazol-5-yl)boronic acid (161 mg, 1.282 mmol, Na2CO3 (339 mg, 3.205 mmol) at rt. After degassed for 10 min was added Pd(PPh3)4 (123 mg, 0.106 mmol) again degassed for 5 min and stirred the reaction mixture in microwave at 120° C. for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was filtered through a pad of celite, the filtrate was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude compound was purified by combi-flash column chromatography (eluted with 13% EtOAc in pet ether) to afford ethyl 3-(5-bromo-1-cyclohexyl-1H-indol-3-yl)-3-(m-tolyl) propanoate (300 mg, yield: 33%) as pale yellow semi-solid.
LC-MS m/z (M+H): 470.3
To a stirred solution of ethyl 3-(5-bromo-1-cyclohexyl-1H-indol-3-yl)-3-(m-tolyl) propanoate (300 mg, 0.639 mmol) in THF (6 mL) was added LAH (48 mg, 1.279 mmol) at 0° C. and stirred the reaction mixture at rt for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was slowly poured into Na2SO4 paste, filtered and the filtrate was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 3-(1-cyclohexyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-indol-3-yl)-3-(m-tolyl) propan-1-ol (250 mg, yield: 91%) as pale yellow semi-solid.
LC-MS m/z (M+H): 428.3
To a stirred solution of 3-(1-cyclohexyl-5-(1-methyl-H-pyrazol-5-yl)-1H-indol-3-yl)-3-(m-tolyl) propan-1-ol (250 mg, 0.585 mmol) in CH2Cl2 (5 mL) was added TEA (0.2 mL, 1.463 mmol) followed by MsCl (0.07 mL, 0.877 mmol) at 0° C. and stirred the reaction mixture at rt for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL), extracted with DCM (2×10 mL). The combined organic layer was washed with NaHCO3 solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 3-(1-cyclohexyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-indol-3-yl)-3-(m-tolyl) propyl methanesulfonate (340 mg, crude) as yellow semi-solid. The crude compound was used in the next step.
To a stirred solution of 3-(1-cyclohexyl-5-(1-methyl-H-pyrazol-5-yl)-1H-indol-3-yl)-3-(m-tolyl) propyl methane sulfonate (340 mg, 0.672 mmol) in DMF (5 mL) was added tert-butyl ((1R,4R)-4-aminocyclohexyl)carbamate (216 mg, 1.008 mmol) followed by K2CO3 (278 mg, 2.017 mmol) and stirred the reaction mixture at 80° C. for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL), filtered, the residue was dissolved in ethyl acetate (20 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude compound was purified by preparative TLC (5% MeOH/CH2Cl2) to afford tert-butyl ((1R,4R)-4-((3-(1-cyclohexyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-indol-3-yl)-3-(m-tolyl) propyl)amino) cyclohexyl) carbamate (100 mg, yield: 23%) as yellow liquid.
LC-MS m/z (M+H): 624.3
To a stirred solution of tert-butyl ((1r,4r)-4-((3-(1-cyclohexyl-5-(1-methyl-H-pyrazol-5-yl)-1H-indol-3-yl)-3-(m-tolyl) propyl)amino)cyclohexyl)carbamate (70 mg, 0.113 mmol) in CH2C12 (2 mL) was added HCl in Dioxane (2 mL) and stirred the reaction mixture at rt for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The crude compound was washed with pentane (5 mL) to afford (1R,4R)-N1-(3-(1-cyclohexyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-indol-3-yl)-3-(m-tolyl) propyl) cyclohexane-1,4-diamine dihydrochloride (16 mg, yield: 23%) as off white solid.
1HNMR (400 MHz, DMSO-d6) δ 1.22-1.44 (m, 5H), 1.46-1.56 (m, 2H), 1.70-1.85 (m, 5H), 1.95-2.06 (m, 6H), 2.24 (s, 3H), 2.31 (s, 1H), 2.79 (s, 1H), 2.92 (s, 3H), 3.79 (s, 4H), 4.31-4.37 (m, 2H), 6.96 (s, 1H), 7.13-7.18 (m, 4H), 7.41 (d, J=1.5 Hz, 1H), 7.49 (s, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.61 (s, 1H), 7.99 (s, 3H), 9.03 (s, 1H), 9.14 (s, 1H)
LC-MS m/z (M+H): 524.3
Following the procedure described in scheme 3/Example III, compounds of Table 3 are prepared by using suitable starting materials and proper conditions.
General scheme 4 (
To a stirred solution of 5-bromo-1-cyclohexyl-1H-indole (3 g, 10.791 mmol) in DME (39 mL), was added Pd(PPh3)4 (623 mg, 0.539 mmol) under nitrogen atmosphere and the reaction mixture was stirred at rt for 15 mins. After 15 mins, (3-(trifluoromethoxy) phenyl)boronic acid (2.22 g, 10.791 mmol) in EtOH (10 mL) was added to the reaction mixture and was stirred at rt again for 15 min. Finally, aq Na2CO3 (2 M) solution (39 mL) was added and the reaction mixture was stirred at 90° C. for 16 h. Progress of the reaction was monitored by TLC. Reaction mixture was cooled to rt, filtered through celite bed then filtrate was extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulphate, concentrated under reduced pressure. The crude compound was purified by column chromatography using 2% EtOAc in Pet-ether as an eluent to afford desired product as colourless liquid (yield: 1.19 g, 30.7%).
1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.63-7.55 (m, 1H), 7.50-7.38 (m, 3H), 7.29-7.26 (m, 1H), 7.25-7.18 (m, 1H), 7.16-7.08 (m, 1H), 4.28-4.20 (m, 1H), 2.20-2.10 (m, 2H), 2.00-1.90 (m, 2H), 1.85-1.68 (m, 3H), 1.52-1.46 (m, 2H), 1.38-1.22 (m, 1H)
LC-MS m/z (M): calculated 359.3; found (M+H): 360.17
To a stirred solution of 1-cyclohexyl-5-(3-(trifluoromethoxy) phenyl)-1H-indole (1.19 g, 3.311 mmol) in dry ACN (12 mL), were added cyclohex-2-enone (0.32 mL, 3.311 mmol) followed by ZrCl4 at 0° C. and the reaction mixture was stirred at rt for 1.5 h. Reaction mixture was turned into blue colour and progress of the reaction was monitored by TLC. The reaction mixture was diluted with water, extracted with EtOAc, dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by column chromatography using 6% EtOAc in Pet-ether as an eluent to afford desired product as brown colour liquid (yield: 238 mg, 15.8%).
1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.58-7.55 (m, 1H), 7.48-7.42 (m, 3H), 7.20-7.15 (m, 1H), 7.04 (s, 1H), 7.02-6.98 (m, 1H), 4.24-4.18 (m, 1H), 3.52-3.48 (m, 1H), 2.82-2.78 (m, 1H), 2.68-2.60 (m, 1H), 2.49-2.40 (m, 2H), 2.39-2.32 (m, 1H), 2.30-2.22 (m, 1H), 2.15-2.10 (m, 2H), 2.05-1.90 (m, 4H), 1.88-1.78 (m, 2H), 1.75-1.68 (m, 2H), 1.55-1.45 (m, 2H), 1.35-1.20 (m, 5H), 0.90-0.80 (m, 2H)
LC-MS m/z (M): calculated 455.51; found (M+H): 456.2
To a stirred solution of 3-(1-cyclohexyl-5-(3-(trifluoromethoxy)phenyl)-1H-indol-3-yl) cyclohexanone (120 mg, 0.263 mmol) in MeOH (3 mL), were added tert-butyl (3-aminopropyl) carbamate (59.6 mg, 0.342 mmol), AcOH (36.2 mg, 0.604 mmol) and reaction mixture was stirred at rt, after 1 h of stirring, was added NaCNBH4 (33 mg, 0.526) at 0° C. then stirred the reaction mixture at rt for 16 h. Progress of the reaction was monitored by TLC. The reaction mixture was diluted with aq NaHCO3 solution (10 mL) and compound was extracted with 10% MeOH in DCM (3×10 mL). The organic layer was dried over anhydrous sodium sulphate, concentrated under reduced pressure. The crude compound was purified by preparative HPLC method to afford desired product as colourless gummy mass (yield: 30 mg, 18.6%).
1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.72-7.68 (m, 1H), 7.60-7.52 (m, 3H), 7.40 (d, J=8.71 Hz, 1H), 7.30-7.22 (m, 2H), 6.82-6.78 (m, 1H), 4.32-4.28 (m, 1H), 3.02-2.88 (m, 3H), 2.60-2.55 (m, 2H), 2.20-2.18 (m, 1H), 2.0-1.90 (m, 4H), 1.88-1.78 (m, 3H), 1.75-1.68 (m, 3H), 1.15-1.45 (m, 5H), 1.38-1.36 (m, 1H), 1.32 (s, 9H), 1.25-1.20 (m, 6H)
LC-MS m/z (M): calculated 613.7; found (M+H): 614.23
To a stirred solution of tert-butyl (3-((3-(1-cyclohexyl-5-(3-(trifluoromethoxy) phenyl)-1H-indol-3-yl)cyclohexyl)amino)propyl)carbamate (30 mg, 0.048 mmol) in CH2C12 (1 mL), was added HCl in dioxane (4M, 1 mL) at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the crude compound was washed with n-pentane to afford desired compound as off white solid (yield: 25 mg, 87%).
MP: 202-206° C.
1H NMR (400 MHz, DMSO-d6) δ 9.05-9.02 (m, 2H), 8.80-8.74 (m, 2H), 7.89-7.88 (m, 1H), 7.74 (d, J=7.88 Hz, 1H), 7.61-7.45 (m, 3H), 7.44 (d, J=8.36 Hz, 1H), 7.30-7.28 (m, 2H), 4.33 (t, J=11.56 Hz, 1H), 3.59-3.52 (m, 2H), 2.42-2.38 (m, 1H), 2.25-2.10 (m, 3H), 2.0-1.90 (m, 4H), 1.89-1.80 (m, 5H), 1.75-1.62 (m, 3H), 1.60-1.40 (m, 6H), 1.32-1.30 (m, 1H),
LC-MS m/z (M): calculated 513.6; found (M+H): 514.33
Following the procedure described in scheme 4/Example IV, compounds of Table 4 are prepared by using suitable starting materials and proper conditions.
Synthetic route for the synthesis of compound V is described in general scheme 5A (
A mixture of indole (2.0 g, 17.1 mmol), Meldrum's acid (3.03 g, 21.0 mmol), m-tolualdehyde (4.1 g 34.2 mmol and DL-proline (100 mg) in CH3CN (25 mL) were stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum, and the crude product was carried forward to next step without purification.
To the crude product (4.6 g, 12.6 mmol) in a 1:1 mixture of pyridine and EtOH (60 mL) from previous step Cu powder (80 mg, 1.26 mmol) was added. The reaction mixture was heated to reflux for 16 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (silica gel, ethyl acetate/hexanes) to afford as red color oil (2.15 g, 54%). ESI MS m/z 308 [M+H]+.
To a mixture of (1.0 g, 3.45 mmol) and CS2CO3 (1.70 g, 5.18 mmol) in DMF (10 mL), benzyl bromide (0.5 mL, 3.80 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched by the addition of ice water (10 mL) followed by extraction with EtOAc (2×25 mL). The organic layers are recombined, dried over anhydrous MgSO4 and concentrated under reduced pressure and the crude material was purified by column chromatography (silica gel, EtOAc/Hexanes) to provide intermediate (320 mg, 32%) as a yellow oil. ESI MS m/z 398 [M+H]+.
To a solution of (320 mg 0.8 mmol) in mixture of THF/MeOH/H2O (6 mL), LiGH (192 mg, 8 mmol) was added. The reaction mixture was stirred at room temperature for 8 h and concentrated under vacuum. The residue was dissolved in H2O (5 mL) and the pH was adjusted to 6.0 using 1N HCl and the aqueous layer was extracted with EtOAc (2×20 mL). The organic layers are recombined, dried over anhydrous MgSO4 and concentrated under reduced pressure to provide intermediate (254 mg, 85%) as an off white solid. ESI MS m/z 370 [M+H]+.
To a mixture of (48 mg, 0.13 mmol) in DMF (1.5 mL, HATU (69 mg, 0.18 mmol), DIPEA (45 uL, 0.26 mmol) and) tert-butyl 4-(2-aminoethyl) piperidine-1-carboxylate (35 mg. 0.15 mmol) were added. The reaction mixture was stirred at room temperature for 16 h and was purified by reverse phase column chromatography to afford intermediate (33 mg, 44%) as a white solid. ESI MS m/z 580 [M+H]+.
To a solution of (30 mg, 0.052 mmol) in MeOH (2 mL), HCl in dioxane (4 M, 1 mL) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum and the residue was lyophilized to afford product (25 mg, 70%) as a brown-red semisolid. 1H NMR (400 MHz, DMSO-d6) 8.49 (bs, 1H), 8.21 (bs, 1H), 7.81 (t, J=5.74 Hz, 1H), 7.43 (bs, 1H), 7.36 (d, J=8.61 Hz, 2H), 7.32-7.23 (m, 3H), 7.19-7.15 (m, 2H), 7.13-7.08 (m, 3H), 7.03 (t, J=7.76 Hz, 1H), 6.95-6.88 (m, 2H), 5.37 (bs, 2H), 4.64 (t, J=7.98 Hz, 1H), 3.19-2.98 (m, 4H), 2.95-2.83 (m, 2H), 2.74 (dd, J=14.0, 8.10 Hz, 1H), 2.61-2.55 (m, 1H), 2.23 (bs, 3H), 1.67-1.55 (m, 2H), 1.20-1.08 (m, 5H); HPLC (Method 6) 96.4% (AUC), tR=19.83 min, ESI MS m/z 480 [M+H]+.
Synthetic route for the synthesis of compound VB is described in general scheme 5B (
To a slurry of NaH (2.0 g, 0.51 mmol) in DMF (25 mL), indole (4.0 g, 34.0 mmol) was added at 0° C. (bromomethyl)cyclohexane (9.8 g, 0.51 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction was quenched by the addition of water (15 mL) and then extracted with EtOAc (2×30 mL). The EtOAc layer dried (Na2SO4), concentrated and the residue was purified by column chromatography (silica gel, EtOAc/Hexanes) to provide 1-(cyclohexylmethyl)-1H-indole as a white sticky solid (6.3 g, 86% yield). ESI MS m/z 214 [M+H]+.
5-((1-(cyclohexylmethyl)-1H-indol-3-yl)(m-tolyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was prepared by the procedure described for the synthesis of intermediate by stirring a solution of (1.0 equiv), m-tolualdehyde (1.3 equiv), Meldrum's acid (2.0 equiv) and DL-proline (0.1 equiv) in CH3CN at room temperature for 16 h. The crude 5-((1-(cyclohexylmethyl)-1H-indol-3-yl)(m-tolyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was carried forward to next step. ESI MS m/z 460 [M+H]+.
Ethyl 3-(1-(cyclohexylmethyl)-1H-indol-3-yl)-3-(m-tolyl) propanoate was prepared by the procedure described for the synthesis of intermediate 1-5 by heating a solution of 5-((1-(cyclohexylmethyl)-1H-indol-3-yl)(m-tolyl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.0 equiv) and Cu powder (0.1 equiv) in a mixture of pyridine/EtOH at 90° C. for 16 h. It was obtained as brown oil (58% yield).
3-(1-(cyclohexylmethyl)-1H-indol-3-yl)-3-(m-tolyl)propanoic acid was prepared by the ester hydrolysis of ethyl 3-(1-(cyclohexylmethyl)-1H-indol-3-yl)-3-(m-tolyl)propanoate (1.0 equiv) and LiGH (10.0 equiv) in a mixture of THF/MeOH/H20 (1:1:1) at room temperature for 4-6 h. It was obtained as an off-white solid (90% yield).
General Procedure for the Synthesis of Amide Intermediates:
To a mixture of 8 (1.0 equiv) HATU (1.5 equiv) and DIPEA (2.0 equiv) in DMF (1 mL) the corresponding amines (1.3 equiv) were added. The reaction mixture was stirred at room temperature for 16 h and was purified by either reverse phase C18 column chromatography or by precipitation by addition of water to afford the amide intermediates.
General Procedure for the Deprotection of BOC Group:
The amide intermediates with a Boc group were subjected Boc deprotection by adding HCl in dioxane to a solution of amide intermediates in MeOH. The reaction mixture was then concentrated in vacuo, the residue was washed with solvents such as EtOAc or CH3CN, followed by lyophilisation. Those intermediates that have basic nitrogen are converted to the corresponding hydrochloride salts by the addition of 1 M HCl to a suspension of the intermediate in H2O followed by lyophilisation.
1H NMR (400 MHz, Methanol-d4) δ 7.30 (t, J=8.8 Hz, 2H), 7.14-7.04 (m, 5H), 6.96 (t, J=7.5 Hz, 1H), 6.91-6.86 (m, 1H), 4.69 (t, J=8.1 Hz, 1H), 3.96 (d, J=7.2 Hz, 2H), 3.04-2.92 (m, 2H), 2.84-2.75 (m, 1H), 2.25 (s, 3H), 2.00-1.91 (m, 2H), 1.90-1.81 (m, 1H), 1.80-1.65 (m, 5H), 1.64-1.54 (m, 2H), 1.45-1.32 (m, 2H), 1.27-1.17 (m, 4H), 1.16-0.95 (m, 4H; HPLC (Method 5) 93.6% (AUC), tR=12.28 min; ESI-MS m/z 472 [M+H]+.
Following the procedure described in scheme 5A & 5B/Example VA & VB, compounds of Table 5 are prepared by varying suitable starting materials and proper conditions.
Compound VI-a (General Scheme 6,
See
Pd(PPh3)4 (5.3 mg, 0.0046 mmol), sodium carbonate (14.49 mg, 0.138 mmol), phenylboronic acid (6.67, 0.552 mmol) and tert-butyl ((1R,4R)-4-(3-(5-bromo-1-(cyclohexylmethyl)-1H-indol-3-yl)-3-(m-tolyl)propanamido)cyclohexyl)carbamate (30 mg, 0.046 mmol) were added to the 2 mL of degassed mixture of 1,4-dioxane and water (8:2). Reaction was heated in a microwave oven for 1 h at 120° C. The reaction mixture was diluted with EtOAc (25 mL) and washed with H2O (30 ml×2). The EtOAc layer was dried (Na2SO4), concentrated in vacuo and the residue was purified by combi-flash chromatography (silica gel, Ethyl acetate/hexanes) to afford tert-butyl ((1R,4R)-4-(3-(1-(cyclohexylmethyl)-5-phenyl-1H-indol-3-yl)-3-(m-tolyl)propanamido)cyclohexyl)carbamate (17 mg, 33%) as a white solid. APCI MS m/z 648 [M+H]+. Which was deprotected under acidic condition to obtain title compound.
1H NMR (400 MHz, DMSO-d6) δ 7.80 (bs, 4H), 7.55-7.50 (m, 3H), 7.47 (d, J=7.4 Hz, 1H), 7.41 (t, J=7.4 Hz, 2H), 7.37-7.32 (m, 1H), 7.30-7.23 (m, 2H), 7.14-7.03 (m, 3H), 6.94-6.87 (m, 1H), 4.68 (t, J=7.9 Hz, 1H), 3.98 (d, J=7.2 Hz, 2H), 3.70-3.53 (m, 1H), 3.40-3.32 (m, 1H), 3.16-3.06 (m, 1H), 2.99-2.79 (m, 2H), 2.76-2.61 (m, 1H), 2.21 (s, 3H), 1.89-1.81 (m, 2H), 1.69-1.60 (m, 4H), 1.56-1.50 (m, 1H), 1.30-1.23 (m, 7H), 1.17-1.07 (m, 3H). HPLC (Method 5) 98.1% (AUC), tR=13.31 min; ESI-MS m/z 548.6 [M+H]+.
Following the procedure described in scheme 6/Example VI, compounds of Table 6 are prepared by using suitable starting materials and proper conditions.
The general scheme 8 (
General Procedure for Reductive Amination:
A mixture of tryptamine (1.0 equiv) and the corresponding aldehyde (1.05 equiv) was stirred at room temperature for 1 h. The reaction mixture was then cooled to 0° C. and NaBH4 (1.2 equiv) was added. The reaction mixture was stirred at room temperature for 2-16 h. Upon completion, the reaction mixture was cooled to 0° C., quenched by dropwise addition of H2O and extracted with CH2Cl2. The CH2C12 layer was dried (Na2SO4), concentrated and the residue was purified by column chromatography (silica gel, EtOAc/Hexanes) to afford intermediates VIII-b.
General Procedure for Boc Deprotection/HCl Salt Formation:
The intermediates with a Boc group were subjected Boc deprotection by adding HCl in dioxane to a solution of intermediates in MeOH. The reaction mixture was then concentrated in vacuo, the residue was washed with solvents such as EtOAc or CH3CN, followed by lyophilisation. Those intermediates that have a basic nitrogen are converted to the corresponding hydrochloride salts.
Following the procedure described in scheme 8/Example VIII, compounds of Table 8 are prepared by using suitable starting materials and proper conditions.
The general scheme 9 (
A solution of 2-(5-bromo-1H-indol-3-yl) acetic acid (500 mg, 1.97 mmol) anhydrous MeOH (100 mL) was treated with PTSA (34 mg, 0.197 mmol) and heated at 75° C. for 16 h. The mixture was concentrated, the residue was dissolved in CH2C12 (50 mL), washed with water (3×20 mL) and brine (20 mL). The CH2C12 layer was separated, dried (Na2SO4), filtered and concentrated to give methyl 2-(5-bromo-1H-indol-3-yl) acetate as a dark red solid (465 mg, 88%). ESI-MS m/z 268 [M]+.
To a slurry of caesium carbonate (486 mg, 1.49 mmol) in DMF (3 mL) at 0° C., a solution of methyl 2-(5-bromo-1H-indol-3-yl) acetate (200 mg, 0.746 mmol) in DMF (10 mL) was added followed by the addition of bromomethyl cyclohexane (0.156 mL, 1.12 mmol). The reaction mixture was gradually warmed to room temperature over 16 h. The reaction mixture was quenched with water, dissolved in EtOAc (50 mL), washed with water (3×20 mL) and brine (20 mL). The EtOAc layer was separated, dried (Na2SO4), filtered and concentrated. The residue was purified by combi-flash chromatography (silica gel, EtOAc/Hexanes) to give methyl 2-(5-bromo-1-(cyclohexylmethyl)-1H-indol-3-yl) acetate as a yellow oil (64 mg, 24%). ESI-MS m/z 364 [M]+.
2-(5-bromo-1-(cyclohexylmethyl)-1H-indol-3-yl) acetic acid was prepared by the ester hydrolysis of 180-3 (155 mg, 0.425 mmol) with lithium hydroxide (102 mg, 4.25 mmol) in MeOH/THF/H2O (1:1:1) using the procedure described for intermediate 1-7 (Scheme 4). It was obtained as a yellow solid (126 mg, 85%). ESI-MS m/z 350 [M]+.
tert-butyl((1r,4r)-4-(2-(5-bromo-1-(cyclohexylmethyl)-1H-indol-3-yl) acetamido) cyclo hexyl) carbamate was prepared by coupling 2-(5-bromo-1-(cyclohexylmethyl)-1H-indol-3-yl)acetic acid (86 mg, 0.245 mmol) with tert-butyl ((r,4r)-4-aminocyclohexyl) carbamate (63 mg, 0.295 mmol) with HATU (130 mg, 0.343 mmol) as the coupling reagent and DIPEA (0.08 mL, 0.49 mmol), as the base in DMF as described for the synthesis of intermediate 1-9. It was obtained as a yellow solid (74 mg, 56%). ESI-MS m/z 546 [M]+.
A solution of tert-butyl ((1R,4R)-4-(2-(5-bromo-1-(cyclohexylmethyl)-1H-indol-3-yl) acetamido)cyclohexyl) carbamate (80 mg, 0.146 mmol), m-tolylboronic acid (30 mg, 0.220 mmol), caesium carbonate (142 mg, 0.438 mmol) dissolved in 1,4 dioxane (1.6 mL) and water (0.4 mL) was bubbled with Ar gas for 10 min. Pd(dppf) (5 mg, 0.007 mmol) was then added into the vial and sealed. The reaction mixture was heated at 100° C. for 16 h. It was filtered dissolved in EtOAc (20 mL), washed with water (3×10 mL) and brine (10 mL). The EtOAc layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in MeOH and purified by C18 reverse phase combi-flash chromatography (Acetonitrile/Water) to give tert-butyl ((1R,4R)-4-(2-(1-(cyclohexylmethyl)-5-(m-tolyl)-1H-indol-3-yl) acetamido)cyclohexyl)carbamate as a light yellow solid (16 mg, 20%). ESI-MS m/z 558 [M+H]+.
Title compound was prepared by deprotection of the Boc group of 5 (30 mg, 0.05 mmol) with HCl in dioxane using the procedure described earlier. It was obtained as an amorphous off-white solid (6 mg, 43%). 1H NMR (400 MHz, Methanol-d4) δ 7.90 (d, J=7.3 Hz, 1H), 7.77 (s, 1H), 7.46-7.39 (m, 4H), 7.28 (t, J=7.6 Hz, 1H), 7.13-7.08 (m, 2H), 3.98 (d, J=7.3 Hz, 2H), 3.65 (s, 3H), 3.07-3.01 (m, 1H), 2.40 (s, 3H), 2.06-1.97 (m, 4H), 1.99-1.83 (m, 1H), 1.79-1.71 (m, 2H), 1.69-1.59 (m, 3H), 1.53-1.41 (m, 2H), 1.39-1.28 (m, 2H), 1.27-1.17 (m, 3H), 1.11-0.99 (m, 2H); HPLC (Method 5) 97.1% (AUC), tR=12.62 min; ESI-MS m/z 458 [M+H]+.
Following the procedure described in scheme 9/Example IX, compounds of Table 9 are prepared by using suitable starting materials and proper conditions.
The general scheme 10 (
Compound of formula X, mentioned in Table 10, were prepared following the process of preparation of compound VA described in general scheme VA starting from appropriate azaindole/instead of indole derivatives.
See General scheme 11 (
A mixture of 5-bromo-1H-indole (1.0 g, 5.10 mmol), 1,4-dioxaspiro[4.5]decan-8-one (795 mg, 5.10 mmol) and potassium hydroxide (16 g, 25.50 mmol) in MeOH (10 mL) was heated to reflux for 2-3 h. Reaction mixture was cooled to room temperature and water (20 mL) was added to quench the reaction. The reaction mixture was extracted with EtOAc (50 mL), washed with water (30 mL×2) and brine (15 mL). The EtOAc layer was dried (Na2SO4), concentrated in vacuo and the residue was purified by combi-flash chromatography (silica gel, EtOAc/Hexanes) to afford 5-bromo-3-(1,4-dioxaspiro [4.5]dec-7-en-8-yl)-1H-indole (1.50 g, 87%) as white solid. ESI MS m/z 334 [M+H]+.
5-bromo-1-(cyclohexylmethyl)-3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-indole was prepared by N-alkylation of 5-bromo-3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-indole with (bromomethyl) cyclohexane and NaH as the base using the procedure described for the synthesis of intermediate (XI-c). It was obtained as colorless oil (70% yield). ESI MS m/z 430 [M+H]+.
5-bromo-1-(cyclohexylmethyl)-3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-indole (450 mg) (5) was dissolved in 10 ml of EtOAc and to that 5 mg of platinum oxide was added. Reaction mixture was shaken at 35 PSI hydrogen gas pressure in the Parr shaker for 8 h. The reaction mixture was filtered through a celite bed and concentrated in vacuo to afford 5-bromo-1-(cyclohexylmethyl)-3-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-indole (450 mg) as a semisolid, which was used as such in the next step without purification. ESI MS m/z 432 [M+H]+.
5-bromo-1-(cyclohexylmethyl)-3-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-indole (450 mg) was taken in the mixture of 6 ml of THE and 6 ml of N HCl. The reaction mixture was stirred at room temperature for 14 h and neutralized with a saturated solution of sodium bicarbonate. The reaction mixture was extracted with EtOAc (50 mL), washed with water (30 mL×2) and brine (15 mL). The EtOAc layer was dried (Na2SO4) and concentrated in vacuo to afford 4-(5-bromo-1-(cyclohexylmethyl)-1H-indol-3-yl)cyclohexanone (350 mg, 86%) semisolid mass. ESI MS m/z 388 [M+H]+.
tert-butyl ((1R,4R)-4-aminocyclohexyl)carbamate (145 mg, 0.68 mmol), 4-(5-bromo-1-(cyclohexylmethyl)-1H-indol-3-yl)cyclohexanone (220 mg, 0.56 mmol) and NaBH(OAc)3 were taken in 5 mL of 1,2-dichloroethane and acetic acid (0.1 mL) was added. The reaction mixture was stirred at room temperature for 16 h and was neutralized with saturated solution of sodium bicarbonate. The reaction mixture was extracted with CH2Cl2 (50 ml) and washed with brine (15 mL). The CH2Cl2 layer was separated, dried (Na2SO4), concentrated in vacuo and the residue was purified by combi-flash chromatography (silica gel, EtOAc/Hexanes) to afford of tert-butyl ((1R,4R)-4-((4-(5-bromo-1-(cyclohexylmethyl)-1H-indol-3-yl)cyclohexyl) amino)cyclohexyl) carbamate (30 mg, 9%) as Diastereomer A (XI-ga), 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=1.7 Hz, 1H), 7.23 (dd, J=8.6, 1.8, Hz, 1H), 7.21 (d, J=1.9 Hz, 1H), 7.13 (d, J=8.7 Hz, 1H), 4.36 (bs, 1H), 3.87 (d, J=7.8 Hz, 2H), 3.39 (bs, 1H), 3.01-2.84 (m, 2H), 2.58-2.42 (m, 1H), 2.06-1.89 (m, 4H), 1.86-1.75 (m, 5H), 1.73-1.62 (m, 8H), 1.61-1.55 (m, 2H), 1.43 (s, 9H), 1.29-1.06 (m, 7H), 1.04-0.90 (m, 2H); ESI MS m/z 586 [M+H]+ and tert-butyl ((1R,4R)-4-((4-(5-bromo-1-(cyclohexylmethyl)-1H-indol-3-yl)cyclo hexyl) amino)cyclohexyl) carbamate (20 mg, 6%) as Diasteromer B (XI-gb) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=1.8 Hz, 1H), 7.23 (dd, J=8.6, 1.8 Hz, 1H), 7.13 (d, J=8.7 Hz, 1H), 6.77 (s, 1H), 4.36 (bs, 1H), 3.82 (d, J=7.2 Hz, 2H), 3.42 (bs, 1H), 2.78-2.59 (m, 3H), 2.14-2.05 (m, 3H), 2.04-1.96 (m, 5H), 1.94-1.87 (m, 3H), 1.81-1.74 (m, 1H), 1.72-1.64 (m, 3H), 1.61-1.55 (m, 2H), 1.53-1.48 (m, 1H), 1.43 (s, 9H), 1.34-1.30 (m, 1H), 1.26-1.18 (m, 3H), 1.17-1.09 (m, 4H), 1.01-0.89 (m, 2H); ESI MS m/z 586 [M+H]+.
(1R,4R)—N1-(4-(5-bromo-1-(cyclohexylmethyl)-1H-indol-3-yl)cyclohexyl)cyclo hexane-1,4-diamine dihydrochloride was prepared by deprotection of the Boc group of tert-butyl ((1R,4R)-4-((4-(5-bromo-1-(cyclohexylmethyl)-1H-indol-3-yl)cyclohexyl) amino)cyclohexyl) carbamate (XI-ga), with HCl in dioxane using the procedure described elsewhere. It was obtained as an amorphous white solid (70% yield).
(1R,4R)—N1-(4-(5-bromo-1-(cyclohexylmethyl)-1H-indol-3-yl)cyclohexyl)cyclo hexane-1,4-diamine dihydrochloride was prepared by deprotection of the Boc group of tert-butyl ((1R,4R)-4-((4-(5-bromo-1-(cyclohexylmethyl)-1H-indol-3-yl)cyclohexyl) amino)cyclohexyl) carbamate (XI-gb)), with HCl in dioxane using the procedure described earlier. It was obtained as an amorphous white solid (52% yield).
Salts of the compounds of formula F-I, I or any subgroup thereof can be prepared by subjecting the compound to the desired acid. The method is depicted for Compound 372 in Scheme 12.
To a stirred solution of tert-butyl (3-((3-(5-cyano-1-cyclohexyl-1H-indol-3-yl)-3-(3-(trifluoromethoxy) phenyl) propyl) amino) propyl) carbamate (500 mg, 0.836 mmol, 1 eq) in DCM (5 mL) was added 4M HCl in 1,4 Dioxane (5 mL) at 0° C. and stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC analysis. After completion of reaction, the reaction mixture was concentrated under reducer pressure to obtain crude compound. The crude compound was basified with saturated aqueous NaHCO3 solution (20 mL), extracted with DCM (2×30 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude compound was washed with diethyl ether to afford product (yield: 350 mg, 84%) as pale yellow Solid.
1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.77 (s, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.40 (d, J=9.3 Hz, 4H), 7.12 (d, J=6.7 Hz, 2H), 4.40 (s, 2H), 3.55 (s, 2H), 3.15 (s, 1H), 2.64 (s, 1H), 2.43-2.37 (m, 2H), 2.24 (s, 1H), 2.15 (s, 1H), 1.91 (s, 2H), 1.82 (s, 3H), 1.78-1.66 (m, 4H), 1.49 (d, J=12.4 Hz, 5H), 1.30 (d, J=17.8 Hz, 2H), 1.23 (d, J=10.8 Hz, 3H)
To a stirred solution of 3-(3-((3-aminopropyl) amino)-1-(3-(trifluoromethoxy) phenyl) propyl)-1-cyclohexyl-1H-indole-5-carbonitrile (50 mg, 0.100 mmol, 1 eq) in Ethanol (2 mL) was added Benzene Sulfonic acid (19 mg, 0.12 mmol, 1.2 eq) at 0° C. and stirred the reaction mixture at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure at low temperature. The crude compound was washed with diethyl ether to afford product (yield: 38.6 mg, 58%) as white solid.
The salts of compound 372 listed in Table 11 were prepared using the appropriate acid according to method described in Scheme 12.
Characterisation of the Synthesised Compounds
Table XI below provides LC-MS data on the compounds synthesised and indicates which general synthetic method (Scheme number) was used to obtain the compound.
1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1H), 9.27 (bs, 2H), 7.99 (s, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.69 (t, J = 7.7 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.38-7.35 (m, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.13-7.07 (m, 1H), 7.04-6.98 (m, 1H), 4.32 (s, 2H), 3.24-3.16 (m, 2H), 3.15-3.08 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 10.96 (bs, 1H), 9.42 (bs, 2H), 8.25 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.11-7.08 (m, 1H), 7.03-6.99 (m, 1H), 4.33 (s, 2H), 3.26 (t, J = 9.6 Hz, 2H), 3.11(t, J = 8.0 Hz, 2H);
1H NMR (400 MHz, DMSO-d6): δ 10.97 (bs, 1H), 9.91 (bs, 2H), 9.02 (s, 1H), 7.85-7.77 (m, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.37-7.24 (m, 2H), 7.15-6.62 (m, 3H), 4.32 (s, 2H), 3.21 (bs, 2H), 3.13 (bs, 2H);
1H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H), 7.70-7.57 (m, 4H), 7.32 (d, J = 8.7 Hz, 2H), 7.25-7.18 (m, 2H), 7.16- 7.12 (m, 1H), 7.08-7.02 (m, 1H), 6.95-6.89 (m, 1H), 4.66- 3.94 (m, 8H), 3.05 (s, 2H);
1H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 9.02 (bs, 2H), 7.55 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.12-7.06 (m, 1H), 7.03-6.96 (m, 3H), 4.11 (s, 2H), 3.77 (s, 3H), 3.15-3.04 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1H), 9.23 (bs, 2H), 7.86 (t, J = 7.7 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.64- 7.54 (m, 2H), 7.36 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 7.10-6.97 (m, 2H), 4.38 (s, 2H), 3.29-3.21 (m, 2H), 3.18-3.08 (m, 2H);
1H NMR (400 MHz, Methanol-d4): δ 7.70 (s, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.40-7.36 (m, 2H), 7.17 (s, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 4.21 (s, 2H), 3.35 (t, J = 7.6 Hz, 2H), 3.18 (t, J = 7.6 Hz, 2H);
1H NMR (400 MHz, DMSO-d6): δ 11.01-10.93 (m, 2H), 9.05 (bs, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.12-7.06 (m, 1H), 7.03-6.98 (m, 1H), 6.85-6.82 (m, 1H), 6.23-6.20 (m, 1H), 6.07-6.03 (m, 1H), 4.14 (s, 2H), 3.13-3.01 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 9.35-9.16 (m, 2H), 7.56- 7.45 (m, 3H), 7.38-7.30 (m, 1H), 7.29-7.23 (m, 2H), 7.20- 7.08 (m, 6H), 7.07-6.93 (m, 2H), 4.61 (s, 1H), 4.47 (s, 1H), 4.17-4.12 (m, 1H), 4.04-4.00 (m, 1H), 3.90 (s, 2H), 3.57- 3.50 (m, 1H), 3.43-3.40 (m, 1H), 2.97-2.84 (m, 2H), 2.29 (d, J = 7.3 Hz, 3H);
1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1H), 9.36 (bs, 2H), 9.23 (d, J = 1.9 Hz, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 7.12-7.07 (m, 1H), 7.03-6.98 (m, 1H), 4.38 (t, J = 5.6 Hz, 2H), 3.23-3.17 (m, 2H), 3.13-3.07 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1H), 9.06 (br s, 2H), 7.61-7.48 (m, 2H), 7.36 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 1.7 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 7.04-6.95 (m, 1H), 6.81 (d, J = 8.7 Hz, 1H), 6.66 (d, J = 7.2 Hz, 1H), 4.22-4.16 (m, 4H), 3.54 (t, J = 4.9 Hz, 4H), 3.33-3.19 (m, 2H), 3.18- 3.05 (m, 2H), 1.67-1.47 (m, 6H);
1H NMR (400 MHz, DMSO-d6): δ 10.98 (bs, 1H), 9.22 (s, 2H), 9.12-9.01 (m, 1H), 8.97-8.82 (m, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 2.3 Hz, 1H), 7.13-7.06 (m, 1H), 7.04-6.97 (m, 1H), 3.26 (d, J = 12.7 Hz, 2H), 3.14 (s, 4H), 2.94-2.80 (m, 4H), 2.11-1.93 (m, 3H), 1.51-1.39 (m, 2H);
1H NMR (400 MHz, Methanol-d4): δ 7.57-7.51 (m, 2H), 7.37 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.16-7.09 (m, 2H), 7.08-7.03 (m, 2H), 4.29 (s, 2H), 3.37 (t, J = 8.0 Hz, 2H), 3.19 (t, J = 8.0 Hz, 2H);
1H NMR (400 MHz, Methanol-d4): δ 7.58 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.18 (s, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 3.21-3.14 (m, 2H), 3.01 (t, J = 7.6 Hz, 1H), 2.18 (m, 1H), 1.94-1.83 (m, 2H), 1.75-1.56 (m, 4H), 1.32-1.22 (m, 2H);
1H NMR (400 MHz, Methanol-d4): δ 7.55 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.13 (t, J = 7.4 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 6.72 (d, J = 9.6 Hz, 2H), 4.28 (s, 2H), 3.84 (s, 3H), 3.35 (t, J = 8.0 Hz, 2H), 3.19 (t, J = 8.0 Hz, 2H);
1H NMR (400 MHz, Methanol-d4): δ 7.68 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.40 (m, 1H), 7.36 (s, 1H), 7.16 (s, 1H), 7.11 (m, 1H), 7.09 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 4.13 (s, 2H), 3.90 (s, 3H), 3.36-3.32 (m, 2H), 3.17-3.10 (m, 2H);
1H NMR (400 MHz, Methanol-d4): δ 7.52 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.25 (dd, J = 8.4, 2.0 Hz, 1H), 7.21 (s, 1H), 7.16 (s, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.10 (s, 2H), 3.58 (s, 3H), 3.30-3.28 (m, 2H), 3.16 (t, J = 7.6 Hz, 2H), 2.82 (s, 3H);
1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1H), 9.29 (s, 2H), 7.77-7.72 (m, 2H), 7.71-7.68 (m, 2H), 7.67-7.63 (m, 2H), 7.57 (d, J = 7.9 Hz, 1H), 7.51-7.46 (m, 2H), 7.42-7.34 (m, 2H), 7.23 (d, J = 2.4 Hz, 1H), 7.12-7.07 (m, 1H), 7.03- 6.98 (m, 1H), 4.24 (s, 2H), 3.23-3.10 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1H), 9.18 (s, 2H), 7.60-7.53 (m, 3H), 7.45-7.34 (m, 3H), 7.22 (d, J = 2.4 Hz, 1H), 7.21-7.15 (m, 1H), 7.13-6.98 (m, 6H), 4.17 (s, 2H), 3.20-3.07 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 9.25 (s, 2H), 7.59-7.53 (m, 3H), 7.48-7.41 (m, 3H), 7.38-7.34 (m, 1H), 7.22 (d, J = 2.4 Hz, 1H), 7.12-7.06 (m, 1H), 7.03-6.98 (m, 1H), 4.19 (s, 2H), 3.18-3.08 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1H), 9.46 (s, 2H), 8.00 (d, J = 8.2 Hz, 2H), 7.87-7.82 (m, 2H), 7.57 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 7.13-7.06 (m, 1H), 7.04-6.98 (m, 1H), 4.32 (s, 2H), 3.24 (s, 3H), 3.22-3.10 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 10.93 (s, 1H), 8.69 (br s, 2H), 7.53 (d, J = 7.8 Hz, 1H), 7.48-7.39 (m, 3H), 7.35 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.22 (s, 1H), 7.19 (d, J = 2.3 Hz, 1H), 7.12-7.01 (m, 4H), 7.01-6.95 (m, 1H), 4.12 (s, 2H), 3.15-3.00 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 9.56 (s, 2H), 7.78 (t, J = 8.3 Hz, 1H), 7.61-7.52 (m, 2H), 7.43-7.34 (m, 2H), 7.23 (d, J = 2.4 Hz, 1H), 7.12-7.06 (m, 1H), 7.04- 6.98 (m, 1H), 4.23 (s, 2H), 3.24-3.11 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 9.43 (s, 2H), 7.79-7.76 (m, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.12-7.07 (m, 1H), 7.03-6.97 (m, 1H), 6.66 (d, J = 3.1 Hz, 1H), 6.53 (dd, J = 3.2, 1.9 Hz, 1H), 4.27 (s, 2H), 3.18-3.05 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 9.21 (s, 2H), 7.56 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 1.6 Hz, 1H), 7.12-7.07 (m, 1H), 7.04-6.98 (m, 2H), 6.96 (d, J = 8.0 Hz, 1H), 6.05 (s, 2H), 4.09 (s, 2H), 3.10 (s, 4H);
1H NMR (400 MHz, Methanol-d4): δ 7.53 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 7.00 (s, 1H), 6.89 (dd, J = 8.4, 2.0 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 4.11 (s, 2H), 3.58 (s, 3H), 3.36-3.33 (m, 2H), 3.20-3.13 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 10.97 (s, 1H), 9.12 (s, 1H), 7.64-7.52 (m, 2H), 7.36 (d, J = 8.1 Hz, 1H), 7.25-7.21 (m, 1H), 7.12-7.06 (m, 1H), 7.02-6.97 (m, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.76 (d, J = 7.1 Hz, 1H), 4.21 (t, J = 5.7 Hz, 2H), 3.69 (t, J = 4.8 Hz, 4H), 3.47 (t, J = 4.8 Hz, 4H), 3.29- 3.18 (m, 2H), 3.17-3.09 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 10.97 (s, 1H), 9.46 (bs, 2H), 8.14 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.27-7.16 (m, 2H), 7.13-7.04 (m, 1H), 7.04-6.95 (m, 1H), 4.17 (t, J = 5.8 Hz, 2H), 3.31-3.18 (m, 2H), 3.18-3.08 (m, 2H), 3.04-2.88 (m, 4H), 1.66-1.55 (m, 4H), 1.55-1.46 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1H), 9.13 (bs, 2H), 7.79 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 7.12-7.06 (m, 1H), 7.04-6.97 (m, 1H), 6.86 (d, J = 8.7 Hz, 1H), 4.14 (t, J = 5.6 Hz, 2H), 3.59-3.47 (m, 4H), 3.27-3.15 (m, 2H), 3.15- 3.05 (m, 2H), 1.68-1.56 (m, 2H), 1.56-1.44 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 14.27 (s, 1H), 14.05 (s, 1H), 8.96 (s, 1H), 8.49 (dd, J = 1.4 Hz, 1H), 8.05 (t, J = 5.8 Hz, 1H), 7.72 (dd, J = 1.52 Hz, 1H), 7.54 (s, 1H), 7.30- 7.18 (m, 6H), 7.13-6.93 (m, 5H), 5.44 (s, 2H), 4.61 (t, J = 8.0 Hz, 1H), 3.26-3.17 (m, 2H), 2.85 (dd, J = 7.8 Hz, 1H), 2.71 (dd, J = 7.8 Hz, 1H), 2.57 (t, J = 6.8 Hz, 2H), 2.21 (s, 3H);
1H NMR (400 MHz, DMSO-d6): δ 8.80 (bs, 1H), 8.53 (bs, 1H), 8.21 (d, J = 4.2 Hz, 1H), 7.89-7.82 (m, 2H), 7.6 (s, 1H), 7.32-7.31 (m, 5H), 7.11-7.03 (m, 4H), 6.94 (d, J = 6.9 Hz, 1H), 5.47 (s, 2H), 4.63 (t, J = 7.8 Hz, 1H), 3.51- 3.48 (m, 1H), 3.14 (d, J = 8.0 Hz, 2H), 3.02-2.72 (m, 5H), 2.23 (s, 3H), 1.59 (t, J = 8.0 Hz, 2H), 1.23-1.12 (m, 5H);
1H NMR (400 MHz, DMSO-d6): δ 10.08 (bs, 1H), 8.26 (t, J = 5.64 Hz, 1H), 8.19 (dd, J = 4.8, 1.2 Hz, 1H), 7.76 (dd, J = 8.0, 2.4 Hz, 1H), 7.61 (s, 1H), 7.32-7.29 (m, 2H), 7.29- 7.20 (m, 3H), 7.14-7.03 (m, 3H), 7.02-6.95 (m, 2H), 5.46 (s, 2H), 4.65 (d, J = 8.0 Hz, 1H), 3.32-3.23 (m, 2H), 2.98- 2.90 (m, 3H), 2.83-2.78 (m, 1H), 2.63 (s, 6H), 2.23 (s, 3H);
1H NMR (400 MHz, DMSO-d6): δ 8.19 (d, J = 3.2 Hz, 1H), 7.90 (bs, 3H), 7.72 (t, J = 7.2 Hz, 2H), 7.57 (s, 1H), 7.31- 7.24 (m, 3H), 7.19-7.06 (m, 5H), 7.101-6.93 (m, 2H), 5.51 (q, J = 15.2 Hz, 2H), 4.63 (t, J = 8.0 Hz, 1H), 3.51- 3.39 (m, 3H), 2.97-2.92 (m, 1H), 2.80-2.75 (m, 1H), 2.22 (s. 3H), 1.61-1.48 (m, 5H), 1.39-1.37 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 8.64 (d, J = 6.8 Hz, 2H), 8.20 (dd, J = 4.8, 1.6 Hz, 1H), 8.06 (t, J = 5.8 Hz, 1H), 7.73 (dd, J = 8.0, 1.6 Hz, 1H), 7.67 (d, J = 6.4 Hz, 2H), 7.54 (s, 1H), 7.30-7.19 (m, 5H), 6.93-7.11 (m, 5H), 5.44 (s, 2H), 4.58 (t, J = 8.0 Hz, 1H), 3.39-3.24 (m, 2H), 2.89-2.78 (m, 3H), 2.69-2.66 (m, 1H), 2.21 (s, 3H) );
1H NMR (400 MHz, DMSO-d6): δ 14.2 (bs, 1H), 8.98 (s, 1H), 8.19 (dd, J = 8.0, 1.6 Hz, 1H), 8.09 (t, J = 6.0 Hz, 1H), 7.77 (dd, J = 8.0, 1.6 Hz, 1H), 7.66 (s, 1H), 7.61-7.59 (m, 2H), 7.29-7.24 (m, 5H), 7.23-7.11 (m, 3H), 7.02-6.99 (m, 1H), 6.94-6.92 (m, 1H), 5.4 (q, J = 15.2 Hz, 2H), 4.64 (t, J = 8.0 Hz, 1H), 3.82 (t, J = 6.8 Hz, 2H), 2.97-2.76 (m, 4H), 2.21(s, 3H), 1.70 (t, J = 6.8 Hz, 2H);
1H NMR (400 MHz, DMSO-d6): δ 8.51-8.48 (m, 2H), 7.98 (t, J = 5.74 Hz, 1H), 7.44-7.42 (m, 2H), 7.41 (bs, 1H), 7.36 (d, J = 8.16 Hz, 1H), 7.33-7.25 (m, 3H), 7.24-7.08 (m, 5H), 7.06-7.02 (m, 3H), 6.95-6.88 (m, 2H), 5.36 (bs, 2H), 4.61 (t, J = 8.0 Hz, 1H), 3.23-3.18 (m, 2H), 2.89-2.82 (m, 1H), 2.77- 2.67 (m, 3H), 2.21 (s, 3H);
1H NMR (400 MHz, DMSO-d6): δ □ 9.46 (bs, 1H), 8.17 (t, J = 5.75 Hz, 1H), 7.44 (bs, 1H), 7.36-7.28 (m, 4H), 7.26-7.23 (m, 1H), 7.18-7.15 (m, 2H), 7.11-7.07 (m, 3H), 7.04-7.01 (m, 1H), 6.96-6.90 (m, 2H), 5.38 (bs, 2H), 4.65 (t, J = 8.0 Hz, 1H), 2.97-2.90 (m, 4H), 2.80-2.78 (m, 2H), 2.66 (bs, 6H), 2.23 (bs, 3H);
1H NMR (400 MHz, DMSO-d6): δ 14.26-13.89 (bs, 2H), 8.94 (d, J = 1.28 Hz, 1H), 8.03 (t, J = 5.83 Hz, 1H), 7.41 (bs, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.33-7.26 (m, 3H), 7.24- 7.19 (m, 2H), 7.16-7.13 (m, 2H), 7.13-7.08 (m, 1H), 7.08- 7.00 (m, 3H), 6.94-6.87 (m, 2H), 5.37 (bs, 2H), 4.62 (t, J = 8.0 Hz, 1H), 3.27-3.16 (m, 2H), 2.87 (dd, J = 14.2, 8.0 Hz, 1H), 2.74-2.72 (m, 1H), 2.61 (t, J = 7.00 Hz, 2H), 2.22-2.20 (s, 3H);
1H NMR (400 MHz, DMSO-d6): δ 14.43 (bs, 1H), 8.95 (bs, 1H), 8.13 (t, J = 5.74 Hz, 1H), 7.65 (t, J = 1.68, 1H), 7.59 (t, J = 1.68, 1H), 7.48 (bs, 1H), 7.39-7.33 (m, 2H), 7.29-7.20 (m, 3H), 7.18-7.14 (m, 2H), 7.13-7.10 (m, 3H), 7.05-7.00 (m, 1H), 6.93-6.87 (m, 2H), 5.37 (bs, 2H), 4.66 (t, J = 7.75 Hz, 1H), 3.83 (t, J = 6.75 Hz, 2H), 2.99-2.85 (m, 3H), 2.78 (dd, J = , 13.97, 7.86, Hz, 1H), 2.21 (s, 3H), 1.78-1.70 (s, 2H);
1H NMR (400 MHz, DMSO-d6): δ 7.80 (bs, 2H), 7.75-7.73 (m, 2H), 7.42 (bs, 1H), 7.36-7.23 (m, 5H), 7.18-7.14 (m, 2H), 7.11-7.01 (m, 4H), 6.93 (d, J = 7.28 Hz, 1H), 6.88 (t, J = 7.28 Hz, 1H), 5.37 (bs, 2H), 4.63 (t, J = 8.0 Hz, 1H), 2.94- 2.82 (m, 2H), 2.67 (dd, J = 14.04, 7.62 Hz, 1H), 2.22 (bs, 3H), 1.88-1.80 (m, 2H), 1.65-1.53 (m, 3H), 1.36-1.18 (m, 2H), 1.08-1.03 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 8.49 (bs, 1H), 8.21 (bs, 1H), 7.81 (t, J = 5.74 Hz, 1H), 7.43 (bs, 1H), 7.36 (d, J = 8.61 Hz, 2H), 7.32-7.23 (m, 3H), 7.19-7.15 (m, 2H), 7.13- 7.08 (m, 3H), 7.03 (t, J = 7.76 Hz, 1H), 6.95-6.88 (m, 2H), 5.37 (bs, 2H), 4.64 (t, J = 7.98 Hz, 1H), 3.19-2.98 (m, 4H), 2.95-2.83 (m, 2H), 2.74 (dd, J = 14.0, 8.10 Hz, 1H), 2.61- 2.55 (m, 1H), 2.23 (bs, 3H), 1.67-1.55 (m, 2H), 1.20-1.08 (m, 5H);
1H NMR (400 MHz, DMSO-d6): δ 11.1 (s, 1H), 10.70 (bs, 1H), 9.28 (s, 1H), 7.99 (s, 1H), 8.40 (t, J = 5.6 Hz, 1H), 7.43- 7.32 (m, 10H), 7.53-7.47 (m, 1H), 7.08-7.05 (m, 1H), 6.85 (t, J = 8.0 Hz, 1H), 5.41-5.26 (m, 4H), 4.80 (t, J = 7.2 Hz, 1H), 3.45-3.31 (m, 2H), 3.08-3.01 (m, 2H), 2.93- 3.0 (m, 4H), 2.92-2.90 (m, 3H), 1.95-1.90 (m, 1H), 1.89- 1.86 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 14.48 (bs, 1H), 11.05 (s, 1H), 10.47 (bs, 1H), 9.07 (bs, 1H), 8.36 (s, 1H), 7.63 (bs, 1H), 7.41-7.34 (m, 7H), 7.27 (s, 1H), 7.09-6.93 (m, 2H), 5.34 (s, 2H), 4.80 (t, J = 7.6 Hz, 1H), 3.36-3.31 (m, 2H), 3.04-3.02 (m, 2H), 2.98-2.80 (m, 6H), 1.85 (bs, 4H);
1H NMR (400 MHz, DMSO-d6): δ 10.24 (bs, 1H), 9.0 (s, 1H), 8.27 (t, J = 5.6 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.41 (s, 1H), 7.38-7.28 (m, 4H), 7.25-7.23 (m, 1H), 7.19-7.16 (m, 2H), 7.0 (dt, J = 8.0, 1.0 Hz, 1H), 6.93 (dt, J = 7.2, 1.0 Hz, 1H), 5.36 (s, 2H), 4.93 (t, J = 7.6 Hz, 1H), 3.42-3.38 (m, 2H), 3.28 (q, J = 5.6 Hz, 2H), 3.07-2.93 (m, 4H), 2.75- 2.71 (m, 2H), 1.84-1.79 (m, 2H), 1.76-1.74 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 7.78 (bs, 3H), 7.71 (d, J = 6.06 Hz, 1H), 7.43 (bs, 1H), 7.36-7.23 (m, 5H), 7.16-7.07 (m, 5H), 7.04-7.00 (m, 1H), 6.94-6.86 (m, 2H), 5.38 (bs, 2H), 4.64 (t, J = 8.0 Hz, 1H), 3.63-3.57 (m, 1H), 3.08-2.87 (m, 3H), 2.80-2.74 (m, 1H), 2.22 (bs, 3H), 1.64-1.57 (m, 3H), 1.55-1.49 (m, 2H), 1.47-1.40 (m, 2H);
1H NMR (400 MHz, DMSO-d6): 7.83 (bs, 3H), 7.72 (d, J = 6.24 Hz, 1H), 7.45 (s, 1H), 7.36-7.23 (m, 5H), 7.16-7.12 (m, 3H), 7.0 (d, J = 10.4 Hz, 1H), 6.86, (dd, J = 7.2 Hz, 1H), 6.78-6.65 (m, 2H), 6.61-6.56 (m, 1H), 5.39 (s, 2H), 4.64 (t, J = 7.6 Hz, 1H), 3.68 (s, 3H), 3.58 (bs, 1H), 3.02 (bs, 1H), 2.91 (d, J = 8.0 Hz, 1H), 2.76 (d, J = 8.0 Hz, 1H), 1.62-1.43 (m, 8H);
1H NMR (400 MHz, DMSO-d6): 10.19 (bs, 1H), 8.27 (t, J = 5.6 Hz, 1H), 7.5 (s, 1H), 7.38-7.14 (m, 8H), 7.05-7.01 (m, 1H), 6.95-6.84 (m, 3H), 6.72-6.70 (m, 1H), 5.38 (s, 2H), 4.67 (t, J = 7.6 Hz, 1H), 3.68 (s, 3H), 3.32-3.24 (m, 3H), 3.05-2.92 (m, 3H), 2.85-2.66 (m, 4H), 1.87-1.72 (m, 4H)
1H NMR (400 MHz, DMSO-d6): δ 8.57 (bs, 1H), 8.30 (bs, 1H), 7.82 (t, J = 5.6 Hz, 1H), 7.49-7.30 (m, 3H), 7.29- 7.18 (m, 6H), 7.13 (t, J = 6.4 Hz, 1H), 7.05-6.88 (m, 3H), 6.68 (dd, J = 5.6, 1.6 Hz, 1H), 5.37 (s, 2H), 4.64 (t, J = 8.0 Hz, 1H), 3.68 (s, 3H), 3.57-3.46 (m, 2H), 3.16-3.01 (m, 4H), 2.90-2.56 (m, 3H), 1.65-1.57 (m, 2H), 1.16-1.10 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 8.68 (bs, 1H), 8.39 (bs, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.92 (t, J = 5.6 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.32-7.20 (m, 5H), 7.15- 7.08 (m, 3H), 7.03-6.94 (m, 2H), 5.45 (s, 2H), 4.61 (t, J = 7.6 Hz, 1H), 3.77-3.66 (m, 1H), 3.50-3.46 (m, 1H), 3.06 (bs, 2H), 2.91-2.80 (m, 2H), 2.78-2.68 (m, 2H), 2.23 (s, 3H), 1.37-1.34 (m, 3H), 1.07-1.04 (m, 2H);
1H NMR (400 MHz, DMSO-d6): bs, 2H), 8.19 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 6.8 Hz, 1H), 7.55 (s, 1H), 7.32-7.12 (m, 5H), 6.94-7.10 (m, 5H), 5.41 (q, J = 15.6 Hz, 2H), 4.62 (t, J = 8.0 Hz, 1H), 3.72-3.65 (m, 3H), 3.51-3.45 (m, 2H), 3.16 (bs, 2H), 2.91-2.73 (m, 2H), 2.22 (s, 3H), 1.36-1.60 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 10.59 (bs, 1H), 8.92 (s, 1H), 8.68 (d, J = 5.2 Hz, 1H), 8.46-8.41 (m, 2H), 7.88- 7.85 (m, 1H), 7.63 (s, 1H), 7.39 (dd, J = 8.0 Hz, 2H), 7.31 (d, J = 6.8 Hz, 2H), 7.29-7.20 (m, 3H), 7.05 (t, J = 8.0 Hz, 1H), 6.93 (t, J = 7.2 Hz, 1H), 5.40 (s, 2H), 4.98 (t, J = 8.0 Hz, 1H), 3.44-3.35 (m, 2H), 3.34-3.31 (m, 2H), 3.11- 3.02 (m, 4H), 2.85-2.78 (m, 2H), 1.90-1.79 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 8.99 (s, 1H), 7.93 (bs, 3H), 7.74 (d, J = 6.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.38- 7.23 (m, 7H), 7.14 (d, J = 6.8 Hz, 2H), 6.91 (t, J = 7.2 Hz, 1H), 5.36 (s, 2H), 4.91 (t, J = 7.6 Hz, 1H), 3.59 (bs, 1H), 3.07-2.91 (m, 3H), 1.51-1.60 (m, 6H), 1.42 (bs, 2H);
1H NMR (400 MHz, DMSO-d6): δ 8.93 (s, 1H), 8.71 (d, J = 4.0 Hz, 1H), 8.45 (d, J = 7.2 Hz, 1H), 8.03 (bs, 3H), 7.96- 7.95 (m, 2H), 7.60 (s, 1H), 7.39 (dd, J = 8.0 Hz, 2H), 7.32- 7.22 (m, 3H), 7.17 (d, J = 7.2 Hz, 2H), 7.07 (t, J = 7.6 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H), 5.36 (q, J = 16.0 Hz, 2H), 4.94 (t, J = 7.2 Hz, 1H), 3.58 (bs, 1H), 3.16-3.02 (m, 3H), 1.76- 1.58 (m, 4H), 1.53-1.40 (m, 4H);
1H NMR (400 MHz, CD3OD): 9.44 (d, J = 2.20 Hz, 1H), 7.52 (d, J = 7.80 Hz, 1H), 7.34 (d, J = 8.38 Hz, 1H), 7.37 (d, J = 8.24 Hz, 1H), 7.31-7.26 (m, 3H), 7.26-7.24 (m, 1H), 7.20-7.16 (m, 2H), 7.13 (t, J = 7.78 Hz, 1H), 7.03 (t J = 7.53 Hz, 1H), 5.36 (bs, 2H), 5.10 (t, J = 7.88 Hz, 1H), 3.20- 3.11 (m, 5H), 3.11-3.03 (m, 2H), 2.60-2.46 (m, 2H), 1.71 (d, J = 11.90 Hz, 1H), 1.59 (d, J = 11.23 Hz, 1H), 1.24-1.17 (m, 2, 1.15-1.08 (m, 2H);,
1H NMR (400 MHz, DMSO-d6): 8.30 (bs, 2H), 7.76 (s, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.36-7.23 (m, 5H), 7.17-7.15 (m, 2H), 7.05-6.97 (m, 2H), 5.36 (s, 2H), 3.35 (bs, 2H), 3.19-3.08 (m, 5H), 2.93 (bs, 2H), 2.78-2.67 (m, 3H), 1.89-1.86 (m, 2H), 1.67-1.59 (m, 2H), 1.48-1.46 (m, 1H), 1.35-1.25 (m, 3H), 1.11 (bs, 5H);
1H NMR (400 MHz, DMSO-d6): δ 8.71 (bs, 1H), 8.29 (bs, 1H), 7.97 (bs, 3H), 7.66 (d, J = 6.4 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.36-7.14 (m, 5H), 7.12 (d, J = 6.8 Hz, 2H), 7.07- 6.97 (m, 2H), 5.32 (q, J = 16.0 Hz, 2H), 3.70-3.61 (m, 1H), 3.41-3.31 (m, 1H), 3.19-3.22 (m, 2H), 3.01 (bs, 1H), 2.79-2.67 (m, 2H), 2.65-2.56 (m, 2H), 1.87-1.74 (m, 2H), 1.64-1.43 (m, 6H), 1.43-1.22 (m, 5H);
1H NMR (400 MHz, CD3OD): δ 7.44 (d, J = 7.84 Hz, 1H), 7.31-7.21 (m, 5H), 7.19-7.12 (m, 5H), 7.06 (t, J = 7.68 Hz, 1H), 7.01-6.91 (m, 2H), 5.34 (bs, 2H), 4.73 (t, J = 8.34 Hz, 1H), 3.10-2.98 (m, 4H), 2.92-2.80 (m, 2H), 2.55-2.42 (m, 2H), 2.28 (bs, 3H), 1.32-1.30 (m, 3H), 1.08-0.947 (m, 2H);
1H NMR (400 MHz, CD3OD): δ 7.35 (d, J = 7.84 Hz, 1H), 7.30-7.22 (m, 4H), 7.17 (bs, 1H), 7.14-7.08 (m, 5H), 7.05 (t, J = 7.58 Hz, 1H), 6.98 (d, J = 6.82 Hz, 1H), 6.91 (t, J = 7.33 Hz, 1H), 5.35 (bs, 2H), 4.72 (t, J = 8.35 Hz, 1H), 3.79-3.72 (m, 1H), 3.18-3.12 (m, 2H), 3.02-2.90 (m, 3H), 2.87-2.81 (m, 1H), 2.26 (bs, 3H), 1.82-1.71 (m, 2H), 1.45-1.36 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 8.47 (bs, 1H), 8.19 (bs, 1H), 7.82 (t, J = 5.6 Hz, 1H), 7.37 (t, J = 8.3 Hz, 2H), 7.29 (s, 1H), 7.15-7.05 (m, 4H), 6.96-6.88 (m, 2H), 4.62 (t, J = 7.9 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.19-3.11 (m, 3H), 3.04-2.94 (m, 2H), 2.89-2.81 (m, 1H), 2.78-2.70 (m, 1H), 2.59-2.52 (m, 2H), 2.23 (s, 3H), 1.70-1.56 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H), 1.18-1.11 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 8.61 (bs, 1H), 8.35 (bs, 1H), 7.78 (t, J = 5.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.31-7.15 (m, 4H), 7.07 (d, J = 8.0 Hz, 2H), 7.06 (t, J = 7.2 Hz, 1H), 6.97 (t, J = 7.2 Hz, 1H), 5.34 (s, 2H) 3.16 (d, J = 6.0 Hz, 2H), 3.03 (q, J = 6.8 Hz, 2H), 2.90 (t, J = 7.6 Hz, 2H), 2.68 (q, J = 12.0 Hz, 2H), 2.40 (t, J = 7.6 Hz, 2H), 1.72 (d, J = 12.0 Hz, 2H), 1.48-1.43 (m, 1H), 1.33-1.17 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 8.44 (bs, 2H), 7.97 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H) 7.25 (s, 1H), 7.13-6.99 (m, 4H), 6.95-6.90 (m, 1H), 6.87 (t, J = 7.2 Hz, 1H), 4.60 (t, J = 8.1 Hz, 1H), 4.01-3.90 (m, 2H), 3.78-3.64 (m, 1H), 3.20-3.04 (m, 2H), 2.95-2.80 (m, 3H), 2.77-2.68 (m, 1H), 2.21 (s, 3H), 1.84-1.30 (m, 10H), 1.20-0.89 (m, 5H);
1H NMR (400 MHz, Methanol-d4): δ 9.16 (s, 1H), 8.24-8.20 (m, 1H), 8.16 (s, 1H), 7.79 (d, J = 6.7 Hz, 1H), 7.41 (s, 5H), 7.20-7.07 (m, 3H), 7.06-7.02 (m, 1H), 5.75 (s, 2H), 3.84- 3.75 (m, 1H), 3.25-3.17 (m, 2H), 3.11-2.93 (m, 4H), 2.27 (s, 3H), 1.93-1.85 (m, 1H), 1.84-1.76 (m, 1H), 1.62-1.50 (m, 1H), 1.48-1.36 (m, 1H), 1.33-1.16 (m, 1H);
1H NMR (400 MHz, DMSO-d6): δ 8.60 (bs, 2H), 8.03 (d, J = 7.7 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.32 (t, J = 3.9 Hz, 2H) 7.14-7.02 (m, 4H), 6.96-6.85 (m, 2H), 4.60 (t, J = 7.9 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.78-3.66 (m, 1H), 3.20- 3.06 (m, 2H), 2.93-2.81 (m, 3H), 2.78-2.69 (m, 1H), 2.23 (s, 3H), 1.75-1.62 (m, 2H), 1.54-1.30 (m, 5H);
1H NMR (400 MHz, DMSO-d6): δ 8.17 (bs, 2H), 7.80 (m, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 7.3 Hz, 1H) 7.25 (s, 1H), 7.14-7.02 (m, 4H), 6.95-6.86 (m, 2H), 4.61 (t, J = 7.9 Hz, 1H), 3.95 (d, J = 7.2 Hz, 2H), 3.19-3.09 (m, 2H), 3.08-2.98 (m, 1H), 2.97-2.80 (m, 2H), 2.74-2.64 (m, 1H), 2.61-2.51 (m, 2H), 2.21 (s, 3H), 1.82-1.45 (m, 8H), 1.25- 0.90 (m, 10H);
1H NMR (400 MHz, DMSO-d6): δ 8.86 (bs, 1H), 8.77 (bs, 1H), 8.66 (bs, 1H), 8.53 (bs, 1H), 8.32 (s, 1H), 8.04 (s, 1H), 7.82 (s, 1H), 7.57 (s, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.32- 7.19 (m, 5H), 7.05 (t, J = 7.2 Hz, 1H), 6.93 (t, J = 7.2 Hz, 1H), 5.39 (s, 2H), 4.89 (t, J = 6.8 Hz, 1H), 3.14 (bs, 2H), 3.01-2.97 (m, 4H), 2.66-2.60 (m, 3H), 1.68-1.60 (m, 2H), 1.23-1.16 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 9.13 (bs, 1H), 9.03 (bs, 1H), 8.76 (bs, 1H), 8.50 (bs, 1H), 7.93 (s, 2H), 7.39-7.23 (m, 5H), 7.22-7.11 (m, 3H), 7.05-6.95 (m, 1H), 5.60-5.43 (m, 2H), 4.76 (t, J = 7.8 Hz, 1H), 3.21-3.10 (m, 2H), 3.05-2.74 (m, 5H), 2.69-2.58 (m, 2H), 2.25 (s, 3H), 1.68-1.54 (m, 2H), 1.30-1.00 (m, 5H);
1H NMR (400 MHz, DMSO-d6): δ 8.90 (s, 1H), 8.70 (bs, 2H), 8.05 (d, J = 7.2 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.39- 7.36 (m, 3H), 7.30-7.15 (m, 3H), 7.05 (d, J = 7.6 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.92 (t, J = 7.2 Hz, 1H), 5.35 (s, 2H), 4.91 (t, J = 7.6 Hz, 1H), 3.50-3.46 (m, 1H), 3.12 (bs, 2H), 2.99-2.37 (m, 4H), 1.72-1.59 (m, 2H), 1.49- 1.41 (m, 2H);
1H NMR (400 MHz, Methanol-d4): δ 9.15 (s, 1H), 8.24-8.20 (m, 1H), 8.12 (s, 1H), 7.82 (d, J = 6.8 Hz, 1H), 7.44-7.38 (m, 5H), 7.22-7.11 (m, 3H), 7.07-7.03 (m, 1H), 5.75 (s, 2H), 3.09-2.94 (m, 4H), 2.86-2.75 (m, 2H), 2.29 (s, 3H), 1.87- 1.77 (m, 2H), 1.40-1.34 (m, 4H), 1.32-1.25 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 8.88-8.26 (m, 5H), 8.00 (bs, 1H), 7.59 (bs, 1H), 7.37-7.12 (m, 8H) 7.02-6.96 (m, 1H), 5.62 (bs, 2H), 5.00 (t, J = 7.8 Hz, 1H), 3.20-3.10 (m, 2H), 3.07-2.92 (m, 2H), 2.91-2.76 (m, 2H), 2.70-2.55 (m, 2H), 2.25 (s, 3H), 1.61 (t, J = 10.3 Hz, 2H), 1.31-1.24 (m, 1H), 1.22-1.05 (m, 4H);
1H NMR 400 MHz; DMSO-d6): δ 8.77 (brs, 1H), 8.64 (d, J = 5.0 Hz, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.04-7.88 (m, 4H), 7.81 (t, J = 7.2 Hz, 1H), 7.39 (s, 1H), 7.38-7.32 (m, 2H), 7.31-7.22 (m, 3H), 7.18-7.08 (m, 3H), 7.01-6.95 (m, 1H), 5.45-5.34 (m, 2H), 5.04 (t, J = 7.7 Hz, 1H), 3.05-2.93 (m, 4H), 1.84-1.73 (m, 2H), 1.72-1.63 (m, 2H), 1.46-1.27 (m, 2H), 1.24-1.04 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 7.87-7.84 (m, 3H), 7.73 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.32-7.22 (m, 3H), 7.21-7.15 (m, 3H), 7.12-7.05 (m, 1H), 7.02-6.96 (m, 1H), 5.33 (s, 2H), 3.47-3.42 (m, 1H), 2.91 (t, J = 7.5 Hz, 3H), 2.39 (t, J = 7.5 Hz, 2H), 1.94-1.86 (m, 2H), 1.80-1.72 (m, 2H), 1.42-1.27 (m, 2H), 1.19-1.06 (m, 2H);
1H NMR (400 MHz, Methanol-d4): δ 8.95-8.91 (m, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.22-7.20 (m, 1H), 7.14-7.06 (m, 2H), 6.99-6.93 (m, 1H), 5.00 (t, J = 8.0 Hz, 1H), 3.94 (d, J = 7.2 Hz, 2H), 3.82-3.71 (m, 1H), 3.16-3.07 (m, 2H), 3.04-2.87 (m, 3H), 1.96-1.80 (m, 2H), 1.76-1.65 (m, 4H), 1.63-1.55 (m, 2H), 1.53-1.28 (m, 3H), 1.25-1.15 (m, 3H), 1.11-0.96 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 8.59-8.74 (m, 2H), 7.97 (d, J = 7.4, 1H), 7.54 (d, J = 7.8, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.33-7.27 (m, 2H), 7.26-7.21 (m, 2H), 7.19-7.15 (m, 2H), 7.11-7.06 (m, 1H), 7.02-6.97 (m, 1H), 5.34 (s, 2H), 3.87-3.76 (m, 1H), 3.23-3.16 (m, 2H), 2.96-2.90 (m, 4H), 2.43 (t, J = 7.6 Hz, 2H), 1.85-1.77 (m, 2H), 1.59-1.46 (m, 2H);
1H NMR (400 MHz, Methanol-d4): δ 7.36 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.18-7.05 (m, 5H), 6.99 (d, J = 6.9 Hz, 1H), 6.95-6.89 (m, 1H), 4.72 (t, J = 8.1 Hz, 1H), 3.96 (d, J = 7.2 Hz, 2H), 3.43-3.35 (m, 2H), 3.09-3.02 (m, 1H), 3.01-2.96 (m, 2H), 2.95-2.87 (m, 1H), 2.76 (s, 3H), 2.74 (s, 3H), 2.27 (s, 3H), 1.89-1.78 (m, 1H), 1.77-1.64 (m, 3H), 1.63-1.54 (m, 2H), 1.26-1.17 (m, 3H), 1.08-0.96 (m, 2H);
1H NMR (400 MHz, Methanol-d4): δ 7.30 (t, J = 8.8 Hz, 2H), 7.14-7.04 (m, 5H), 6.96 (t, J = 7.5 Hz, 1H), 6.91-6.86 (m, 1H), 4.69 (t, J = 8.1 Hz, 1H), 3.96 (d, J = 7.2 Hz, 2H), 3.04-2.92 (m, 2H), 2.84-2.75 (m, 1H), 2.25 (s, 3H), 2.00- 1.91 (m, 2H), 1.90-1.81 (m, 1H), 1.80-1.65 (m, 5H), 1.64- 1.54 (m, 2H), 1.45-1.32 (m, 2H), 1.27-1.17 (m, 4H), 1.16- 0.95 (m, 4H;
1H NMR (400 MHz, DMSO-d6): δ 8.75 (bs, 3H), 8.27 (bs, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.11-7.06 (m, 2H), 6.95 (t, J = 7.2 Hz, 1H), 3.93 (d, J = 7.2 Hz, 1H), 3.66-3.69 (m, 2H), 3.35- 3.30 (m, 1H), 3.33-3.07 (m, 4H), 2.91-2.67 (m, 5H), 1.86- 1.75 (m, 4H), 1.49-1.64 (m, 9H), 1.39-1.33 (m, 3H), 1.21-0.95 (m, 5H);
1H NMR (400 MHz, DMSO-d6): δ 8.75 (bs, 1H), 8.27 (bs, 1H), 7.94 (bs, 3H), 7.67 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.24-7.06 (m, 2H), 6.95 (t, J = 7.2 Hz, 1H), 3.92 (s, 2H), 3.34-3.18 (m, 3H), 2.87- 2.69 (m, 4H), 1.90-1.83 (m, 8H), 1.74-1.45 (m, 6H), 1.33- 1.24 (m, 4H), 1.12-0.95 (m, 8H);
1H NMR (400 MHz, DMSO-d6): δ 10.24 (bs, 1H), 8.72 (bs, 1H), 8.25 (bs, 2H), 7.53 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.15 (s, 1H), 7.07 (t, J = 7.2 Hz, 1H), 6.98 (t, J = 7.2 Hz, 1H), 3.95 (s, 2H), 3.32-3.17 (m, 4H), 2.95-2.93 (m, 2H), 2.79-2.72 (m, 2H), 2.63 (s, 6H), 2.62-2.58 (m, 2H), 1.87-1.84 (m, 2H), 1.76 (bs, 1H), 1.64-1.49 (m, 6H), 1.29 (t, J = 8.0 Hz, 2H), 1.13-0.95 (m, 6H);
1H NMR (400 MHz, DMSO): δ 8.45 (bs, 1H), 8.36 (bs, 1H), 7.96 (d, J = 9.0 Hz, 1H), 7.37-7.27 (m, 3H), 7.12-7.03 (m, 4H), 6.94-6.89 (m, 2H), 4.60 (t, J = 8.2 Hz, 1H), 4.20- 4.07(m, 2H), 3.74-3.69 (m, 1H), 3.17-3.07 (m, 2H), 2.94- 2.67 (m, 4H), 2.22 (s, 3H), 1.79-1.59 (m, 9H), 1.50-1.40 (m, 2H), 1.23-1.09 (m, 4H), 1.00-0.87 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 8.47 (bs, 1H), 8.17 (bs, 1H), 7.81 (t, J = 6.3 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H), 7.13-7.04 (m, 4H), 6.94-6.88 (m, 2H), 4.61 (t, J = 7.7 Hz, 1H), 4.16-4.09 (m, 2H), 3.20-3.14 (m, 2H), 3.05- 2.92 (m, 2H), 2.86-2.81 (m, 1H), 2.75-2.65 (m, 1H), 2.22 (s, 3H), 1.78-1.60 (m, 9H), 1.22-1.06 (m, 10H), 0.99-0.88 (m, 3H).
1H NMR 400 MHz; DMSO-d6): δ 7.82-7.64 (m, 4H), 7.39 (d, J = 8.6 Hz, 1H), 7.32-7.25 (m, 2H), 7.13-7.00 (m, 4H), 6.94-6.84 (m, 2H), 4.60 (t, J = 8.0 Hz, 1H), 4.03 (d, J = 7.4 Hz, 2H), 3.40-3.34 (m, 1H), 2.98-2.79 (m, 2H), 2.71-2.62 (m, 1H), 2.39-2.29 (m, 1H), 2.21 (s, 3H), 1.90-1.79 (m, 2H), 1.69-1.43 (m, 8H), 1.34-1.20 (m, 4H), 1.18-1.00 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 8.41 (bs, 2H), 7.97 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.14-7.01 (m, 4H), 6.97-6.84 (m, 2H), 4.61 (t, J = 7.9 Hz, 1H), 4.11-3.97 (m, 2H), 3.78-3.68 (m, 1H), 3.21-3.08 (m, 2H), 2.94-2.82 (m, 3H), 2.79-2.69 (m, 1H), 2.38-2.31 (m, 1H), 2.22 (s, 3H), 1.72-1.55 (m, 6H), 1.53-1.45 (m, 3H), 1.43-1.34 (m, 1H), 1.30-1.22 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 7.76 (d, J = 8.0 Hz, 1H), 7.71 (bs, 3H), 7.35 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 10.3 Hz, 2H), 7.11-7.03 (m, 4H), 6.93-6.86 (m, 2H), 4.60 (t, J = 8.2 Hz, 1H), 4.13 (t, J = 7.1 Hz, 2H), 3.38-3.33 (m, 1H), 2.94- 2.78 (m, 2H), 2.70-2.64 (m, 1H), 2.21 (s, 3H), 1.89-1.78 (m, 3H), 1.70-1.57 (m, 8H), 1.33-1.21 (m, 2H), 1.21-1.02 (m, 6H), 0.98-0.88 (m, 2H).
1H NMR 400 MHz; DMSO-d6): δ 7.84 (bs, 3H), 7.72 (d, J = 6.2 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.26 (s, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.08-7.01 (m, 3H), 6.92 (d, J = 7.5 Hz, 1H), 6.87 (t, J = 7.2 Hz, 1H), 4.61 (t, J = 7.9 Hz, 1H), 4.02-3.89 (m, 2H), 3.63-3.54 (m, 1H), 3.10-2.98 (m, 1H), 2.96-2.87 (m, 1H), 2.79-2.70 (m, 1H), 2.21 (s, 3H), 1.81-1.36 (m, 14H), 1.20-1.04 (m, 3H), 1.03- 0.90 (m, 2H).
1H NMR 400 MHz; DMSO-d6): δ 8.81 (bs, 2H), 8.00 (d, J = 7.4 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 7.05 (s, 1H), 6.97 (t, J = 7.4 Hz, 1H), 3.92 (d, J = 7.1 Hz, 2H), 3.86-3.78 (m, 1H), 3.25- 3.13 (m, 2H), 3.01-2.83 (m, 4H), 2.42 (t, J = 7.5 Hz, 2H), 1.90-1.44 (m, 10H), 1.19-0.89 (m, 5H).
1H NMR 400 MHz; DMSO-d6): δ 7.92 (bs, 3H), 7.73 (d, J = 7.4 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 7.04 (s, 1H), 6.97 (t, J = 7.4 Hz, 1H), 3.91 (d, J = 7.1 Hz, 2H), 3.51-3.40 (m, 1H), 3.01- 2.82 (m, 3H), 2.38 (t, J = 7.4 Hz, 2H), 1.97-1.86 (m, 2H), 1.82-1.56 (m, 6H), 1.54-1.45 (m, 2H), 1.41-1.28 (m, 2H), 1.22-1.06 (m, 5H), 1.02-0.89 (m, 2H).
1H NMR 400 MHz; DMSO-d6): δ 8.74 (bs, 1H), 8.49 (bs, 1H), 7.80 (d, J = 5.2 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 7.06 (s, 1H), 6.97 (t, J = 7.4 Hz, 1H), 3.92 (d, J = 7.1 Hz, 2H), 3.19 (d, J = 12.2 Hz, 2H), 3.05 (q, J = 6.7 Hz, 2H), 2.89 (t, J = 7.4 Hz, 2H), 2.72 (q, J = 12.2 Hz, 2H), 2.40 (t, J = 8.2 Hz, 2H), 1.80-1.39 (m, 9H), 1.35-1.18 (m, 4H), 1.16-1.05 (m, 3H), 1.04-0.88 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 8.41 (bs, 1H), 8.35 (bs, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.42-7.38 (m, 1H), 7.34 (s, 1H), 7.13-7.04 (m, 3H), 7.0-6.86 (m, 3H), 4.53 (t, J = 8.0 Hz, 1H), 3.99-3.91 (m, 2H), 3.75-3.68 (m, 1H), 3.17- 2.91 (m, 2H), 2.89-2.78 (m, 3H), 2.73-2.70 (m, 1H), 2.22 (s, 3H), 1.76-1.61 (m, 6H), 1.51-1.31 (m, 4H), 1.38- 0.94 (m, 5H);
1H NMR (400 MHz, DMSO-d6): δ 8.57 (bs, 1H), 8.28 (bs, 1H), 7.81 (t, J = 6.0 Hz, 1H), 7.41-7.38 (m, 1H), 7.14 (s, 1H), 7.13-7.11 (m, 3H), 7.07 (d, J = 6.4 Hz, 1H), 6.95- 6.86 (m, 2H), 4.54 (t, J = 8.0 Hz, 1H), 3.94 (d, J = 7.2 Hz, 2H), 3.17-3.14 (m, 2H), 2.80-3.05 (m, 3H), 2.74-2.72 (m, 1H), 2.68-2.59 (m, 2H), 2.22 (s, 3H), 1.77-1.60 (m, 6H), 1.51-1.47 (m, 2H), 1.24-1.11 (m, 8H), 1.0-0.94 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 8.49 (bs, 1H), 8.20 (bs, 1H), 7.83-7.80 (m, 1H), 7.46-7.45 (m, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.32 (s, 1H), 7.17-7.12 (m, 2H), 7.07 (d, J = 7.8 Hz, 2H), 6.95 (d, J = 7.6 Hz, 1H), 4.59 (t, J = 8.1 Hz, 1H), 3.96 (d, J = 7.55 Hz, 1H), 3.18-3.15 (m, 2H), 3.05-2.99 (m, 2H), 2.95-2.87 (m, 1H), 2.84-2.79 (m, 1H), 2.74-2.51 (m, 3H), 2.22 (s, 3H), 1.78-1.43 (m, 8H), 1.23-0.90 (m, 10H).
1H NMR (400 MHz, DMSO-d6): δ 8.45 (bs, 2H), 7.98-7.96 (m, 1H), 7.42-7.39 (m, 2H), 7.33 (s, 1H), 7.17-7.10 (m, 2H), 7.06-7.04 (m, 2H), 6.95 (d, J = 7.1, 1H), 4.59 (t, J = 7.9 Hz, 1H), 4.00-3.93 (m, 2H), 3.75-3.67 (m, 1H), 3.18- 3.07 (m, 2H), 2.93-2.59 (m, 4H), 2.23 (s, 3H), 1.74-1.57 (m, 6H), 1.51-1.36 (m, 4H), 1.16-1.06 (m, 3H), 1.00-0.92 (m, 2H).
1H NMR (400 MHz, Methanol-d4): δ 7.36-7.32 (m, 2H), 7.16 (s, 1H), 7.14-7.07 (m, 4H), 7.00-6.96 (m, 1H), 6.93- 6.88 (m, 1H), 4.69 (t, J = 8.0 Hz, 1H), 4.01 (d, J = 6.7 Hz, 2H), 3.84-3.75 (m, 1H), 3.22-3.12 (m, 2H), 3.04-2.93 (m, 3H), 2.91-2.83 (m, 1H), 2.27 (s, 3H), 1.89-1.76 (m, 2H), 1.55-1.34 (m, 2H), 1.31-1.22 (m, 1H), 0.61-0.54 (m, 2H), 0.39-0.34 (m, 2H);
1H NMR (400 MHz, Methanol-d4): δ 7.36-7.31 (m, 2H), 7.16-7.06 (m, 5H), 6.99-6.95 (m, 1H), 6.90 (t, J = 7.7 Hz, 1H), 4.68 (t, J = 8.0 Hz, 1H), 4.01 (d, J = 6.7 Hz, 2H), 3.02- 2.93 (m, 2H), 2.85-2.78 (m, 1H), 2.26 (s, 3H), 1.98-1.91 (m, 2H), 1.80-1.66 (m, 2H), 1.45-1.32 (m, 2H), 1.31-1.19 (m, 2H), 1.18-1.00 (m, 2H) 0.58-0.54 (m,. 2H), 0.38-0.34 (m,. 2H);
1H NMR (400 MHz, DMSO-d6): δ 7.95 (d, J = 7.6 Hz, 1H), 7.80 (bs, 3H), 7.38 (d, J = 4.4 Hz, 1H), 7.33 (s, 1H), 7.09 (t, J = 7.2 Hz, 1H), 7.06 (bs, 1H), 7.03 (bs, 1H), 6.97 (dd, J = 10.0, 2.4 Hz, 1H), 6.98-6.86 (m, 2H), 4.53 (t, J = 8.0 Hz, 1H), 3.94 (d, J = 7.2 Hz, 2H), 2.92-2.80 (m, 2H), 2.68- 2.65 (m, 1H), 2.21 (s, 3H), 1.90-1.84 (m, 2H), 1.75-1.52 (m, 6H), 1.46 (t, J = 12.4 Hz, 2H), 1.33-1.25 (m, 3H), 1.28- 0.94 (m, 7H);
1H NMR (400 MHz, DMSO-d6): δ 7.76 (d, J = 8.0 Hz, 1H), 7.71 (bs, 3H), 7.42-7.38 (m, 2H), 7.32 (s, 1H), 7.17-7.10 (m, 2H), 7.05-7.03 (m, 2H), 6.94 (d, J = 7.4 Hz, 1H), 4.58 (t, J = 8.7 Hz, 1H), 3.96 (d, J = 6.7 Hz, 2H), 3.37-3.32 (m, 1H), 2.95-2.88 (m, 1H), 2.84-2.78 (m, 1H), 2.68-2.62 (m, 1H), 2.22 (s, 3H), 1.88-1.82 (m, 2H), 1.77-1.58 (m, 6H), 1.51- 1.41 (m, 2H), 1.34-1.23 (m, 2H), 1.16-0.93 (m, 7H).
1H NMR (400 MHz, DMSO-d6): δ 7.82-7.69 (m, 4H), 7.40- 7.32 (m, 2H), 7.26 (s, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 6.39 (m, 2H), 6.27-6.24 (m, 1H), 4.58 (t, J = 7.7 Hz, 1H), 3.99-3.93 (m, 2H), 3.65 (s, 6H), 2.98-2.88 (m, 1H), 2.87-2.78 (m, 1H), 2.72-2.63 (m, 1H), 1.92-1.83 (m, 2H), 1.81-1.60 (m, 6H), 1.57-1.45 (m, 3H), 1.36-1.23 (m, 2H), 1.21-1.06 (m, 5H), 1.05-0.93 (m, 2H);
1H NMR (400 MHz, Methanol-d4): δ 7.43 (d, J = 7.7 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.22 (s, 1H), 7.17-7.09 (m, 4H), 7.00-6.92 (m, 2H), 4.75-4.70 (m, 1H), 4.01 (t, J = 6.7 Hz, 2H), 3.22-3.11 (m, 3H), 3.03-2.96 (m, 1H), 2.89- 2.82 (m, 1H), 2.53-2.43 (m, 1H), 2.42-2.33 (m, 1H), 2,28 (s, 3H), 1.81-1.74 (m, 1H), 1.67-1.59 (m, 1H), 1.40-1.34 (m, 2H), 1.28-1.22 (m, 2H), 1.20-1.08 (m, 2H), 1.06-0.96 (m, 1H), 0.61-0.55 (m, 2H), 0.42-0.35 (m, 2H);
1H NMR (400 MHz; DMSO-d6): δ 7.88 (bs, 3H), 7.80 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.31-7.17 (m, 6H), 7.14-7.08 (m, 1H), 7.07-7.00 (m, 1H), 6.89-6.82 (m, 1H), 4.64 (t, J = 7.8 Hz, 1H), 4.00-3.88 (m, 2H), 3.42-3.34 (m, 1H), 2.96-2.81 (m, 2H), 2.73-2.62 (m, 1H), 1.93-1.46 (m, 10H), 1.36-1.22 (m, 2H), 1.20-0.91 (m, 7H).
1H NMR (400 MHz, Methanol-d4): δ 7.56 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.11-7.06 (m, 1H), 7.01-6.93 (m, 2H), 3.96-3.90 (m, 2H), 3.23-3.19 (m, 1H), 2.95-2.86 (m, 1H), 2.71-2.63 (m, 1H), 2.56-2.47 (m, 1H), 2.06-1.98 (m, 1H), 1.96-1.89 (m, 1H), 1.86-1.78 (m, 2H), 1.77-1.65 (m, 4H), 1.63-1.55 (m, 2H), 1.40-1.28 (m, 4H), 1.27-1.16 (m, 4H), 1.14-1.08 (m, 1H), 1.07-1.00 (m, 2H), 0.96 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H);
1H NMR (400 MHz, Methanol-d4): δ 7.57 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.13-7.08 (m, 1H), 7.02-6.94 (m, 2H), 3.97-3.91 (m, 3H), 3.86-3.81 (m, 1H), 3.27-3.20 (m, 2H), 2.94-2.78 (m, 2H), 2.74-2.67 (m, 1H), 2.55-2.48 (m, 2H), 1.98-1.88 (m, 2H), 1.87-1.76 (m, 4H), 1.75-1.64 (m, 3H), 1.63-1.55 (m, 2H), 1.44-1.31 (m, 4H), 1.30-1.17 (m, 5H), 1.16-0.97 (m, 3H), 0.89-0.77 (m, 1H);
1H NMR (400 MHz, DMSO-d6): δ 7.75 (d, J = 7.6 Hz, 1H), 7.67 (bs, 3H), 7.36 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.25 (s, 1H), 7.02 (dt, J = 8.0, 1.2 Hz, 1H), 6.86 (dt, J = 7.6, 0.8 Hz, 1H), 6.64 (s, 1H), 6.58 (s, 1H), 6.50 (s, 1H), 4.45 (t, J = 8.0 Hz, 1H), 3.94 (d, J = 7.2 Hz, 2H), 3.4 (s, 3H), 3.39-3.34 (m, 1H), 2.93-2.79 (m, 1H), 2.67-2.65 (m, 1H), 2.64-2.62 (m, 1H), 2.18 (s, 3H), 1.90-1.84 (m, 3H), 1.78-1.48 (m, 7H), 1.29-1.23 (m, 2H), 1.12-0.96 (m, 7H);
1H NMR (400 MHz, DMSO-d6): δ 7.78 (d, J = 8.0 Hz, 1H), 7.69 (bs, 3H), 7.29 (d, J = 8.0 Hz, 1H), 7.85-7.22 (m, 4H), 7.08-7.04 (m, 2H), 6.88 (t, J = 7.2 Hz, 1H), 4.63 (t, J = 8.0 Hz, 1H), 3.32-3.31 (m, 1H), 3.94 (dd, J = 7.2, 2.0 Hz, 2H), 2.94-2.74 (m, 2H), 2.72-2.69 (m, 1H), 1.90-1.83 (m, 3H), 1.76-1.48 (m, 7H), 1.33-1.24 (m, 2H), 1.23-0.97 (m, 7H);
1H NMR (400 MHz; DMSO-d6): δ 7.97-7.76 (m, 4H), 7.39 (d, J = 8.2 Hz, 1H), 7.33-7.27 (m, 2H), 7.27-7.21 (m, 3H), 7.20-7.14 (m, 1H), 7.09-7.02 (m, 1H), 6.93-6.86 (m, 1H), 4.66 (t, J = 7.8 Hz, 1H), 3.96 (d, J = 6.9 Hz, 2H), 3.42-3.34 (m, 1H), 2.96-2.80 (m, 2H), 2.77-2.68 (m, 1H), 1.95-1.82 (m, 2H), 1.82-1.44 (m, 8H), 1.37-0.90 (m, 9H).
1H NMR 400 MHz; DMSO-d6): δ 7.89-7.62 (m, 4H), 7.41 (d, J = 8.2 Hz, 1H), 7.37-7.31 (m, 3H), 7.26 (d, J = 2.3 Hz, 2H), 7.11-7.04 (m, 1H), 6.95-6.88 (m, 1H), 4.67 (t, J = 8.2 Hz, 1H), 4.03-3.91 (m, 2H), 3.43-3.34 (m, 1H), 2.99-2.72 (m, 3H), 1.93-1.82 (m, 2H), 1.82-1.43 (m, 8H), 1.37-1.22 (m, 2H), 1.21-0.92 (m, 7H).
1H NMR (400 MHz; DMSO-d6): δ 7.92-7.67 (m, 4H), 7.38 (d, J = 8.2 Hz, 1H), 7.34-7.21 (m, 3H), 7.13-6.98 (m, 3H), 6.97-6.85 (m, 2H), 4.67 (t, J = 7.8 Hz, 1H), 4.04-3.90 (m, 2H), 3.42-3.32 (m, 1H), 2.98-2.79 (m, 2H), 2.77-2.68 (m, 1H), 1.93-1.44 (m, 10H), 1.36-1.22 (m, 2H), 1.20-0.91 (m, 7H).
1H NMR (400 MHz; DMSO-d6): δ 8.78 (bs, 1H), 8.63 (d, J = 5.0 Hz, 1H), 8.24 (d, J = 8.2 Hz, 1H), 8.03-7.86 (m, 4H), 7.78 (t, J = 6.9 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.40-7.34 (m, 2H), 7.13-7.04 (m, 1H), 6.92 (t, J = 7.3 Hz, 1H), 4.86 (t, J = 7.8 Hz, 1H), 4.04-3.90 (m, 2H), 3.39-3.29 (m, 1H), 2.99- 2.83 (m, 2H), 1.94-1.83 (m, 2H), 1.82-1.46 (m, 8H), 1.37- 1.24 (m, 2H), 1.21-0.91 (m, 8H).
1H NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 8.15-7.93 (m, 3H), 7.54 (d, J = 8.6 Hz, 2H), 7.39-7.29 (m, 5H), 7.16- 7.09 (m, 3H), 7.05 (t, J = 7,7 Hz, 1H), 6.96-6.87 (m, 2H), 4.72 (t, J = 7.9 Hz, 1H), 4.04-3.89 (m, 4H), 3.20-3.10 (m, 1H), 3.01-2.91 (m, 1H), 2.22 (s, 3H), 1.78-1.66 (m, 1H), 1.61-1.42 (m, 5H), 1.12-1.00 (m, 3H), 0.99-0.83 (m, 2H);
1H NMR (400 MHz, Methanol-d4): δ 7.33-7.27 (m, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.10-7.02 (m, 4H), 6.88 (t, J = 7.6 Hz, 1H), 4.68 (t, J = 7.9 Hz, 1H), 3.94 (d, J = 7.1 Hz, 2H), 2.99-2.91 (m, 2H), 2.83-2.76 (m, 1H), 2.26 (s, 3H), 1.99- 1.91 (m, 2H), 1.88-1.80 (m, 1H), 1.78-1.65 (m, 5H), 1.64- 1.55 (m, 2H), 1.47-1.31 (m, 3H), 1.24-1.17 (m, 3H), 1.16- 0.97 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 8.91 (s, 1H), 8.38 (bs, 1H), 8.01-7.91 (m, 3H), 7.83-7.75 (m, 4H), 7.62 (t, J = 7.4 Hz, 1H), 7.42-7.35 (m, 3H), 7.04 (t, J = 7.2 Hz, 1H), 6.85 (t, J = 8.0 Hz, 1H), 4.90 (t, J = 8.0 Hz, 1H), 3.97 (dd, J = 7.2, 3.2 Hz, 2H), 3.36-3.31 (m, 1H), 3.04-2.89 (m, 3H), 1.90-1.77 (m, 4H), 1.65-1.61 (m, 4H), 1.53-1.51 (m, 2H), 1.36-1.23 (m, 2H), 1.20-1.18 (m, 4H), 1.14- 0.94 (m, 3H);
1H NMR (400 MHz, DMSO-d6): δ 7.81 (s, 1H), 7.79 (bs, 3H), 7.40-7.29 (m, 5H), 7.18 (s, 1H), 7.18-7.04 (m, 2H), 6.91-6.87 (m, 1H), 4.69 (t, J = 8.0 Hz, 1H), 3.95 (dd, J = 7.0, 2.4 Hz, 2H), 2.95-2.83 (m, 2H), 2.79-2.73 (m, 1H), 1.85-1.79 (m, 2H), 1.78-1.74 (m, 1H), 1.64-1.60 (m, 4H), 1.54-1.47 (m, 2H), 1.33-1.22 (m, 3H), 1.17-1.11 (m, 5H), 1.04-0.95 (m, 3H);
1H NMR (400 MHz, DMSO-d6): δ 7.91 (bs, 3H), 7.74-7.71 (m, 2H), 7.51-7.42 (m, 3H), 7.41-7.27 (m, 2H), 7.13-7.05 (m, 2H), 3.94 (d, J = 7.0 Hz, 2H), 3.51-3.43 (m, 1H), 3.00- 2.89 (m, 3H), 2.43-2.37 (m, 5H), 1.95-1.85 (m, 2H), 1.81- 1.71 (m, 3H), 1.70-1.57 (m, 3H), 1.56-1.46 (m, 2H), 1.41- 1.27 (m, 2H), 1.19-1.06 (m, 5H), 1.04-0.91 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 8.37 (bs, 4H), 7.71(t, J = 5.6 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.11 (s, 1H), 7.06 (dt, J = 8.0, 0.8 Hz, 1H), 6.96 (t, J = 7.0 Hz, 1H), 3.87 (h, J = 8.0 Hz, 2H), 3.31-3.30 (m, 1H), 3.21-3.09 (m, 4H), 2.80-2.94 (m, 3H), 2.77-2.66 (m, 3H), 1.87-1.74 (m, 3H), 1.73-1.50 (m, 9H), 1.38-1.25 (m, 3H), 1.12 (bs, 8H), 1.0-0.94 (m, 2H),
1H NMR (400 MHz, Methanol-d4): δ 7.28 (d, J = 8.8 Hz, 2H), 7.13-7.05 (m, 5H), 6.95 (d, J = 6.8 Hz, 1H), 6.86 (t, J = 7.2 Hz, 1H), 4.66 (t, J = 8.0 Hz, 1H), 3.94 (d, J = 7.2 Hz, 2H), 3.53-3.49 (m, 1H), 3.08-3.13 (m, 1H), 2.98-2.93 (m, 1H), 2.77 (s, 6H), 2.25 (s, 3H), 2.02-1.98 (m, 2H), 1.85- 1.48 (m, 10H), 1.38-1.21 (m, 5H), 1.09-1.01 (m, 3H);.
1H NMR (400 MHz, Methanol-d4): δ 7.31 (d, J = 9.0 Hz, 2H), 7.12-7.06 (m, 2H), 6.94-6.89 (m, 2H), 6.76 (d, J = 9.9 Hz, 1H), 6.70 (d, J = 9.7 Hz, 1H), 4.70 (t, J = 8.0 Hz, 1H), 3.97 (d, J = 7.2 Hz, 2H), 3.54-3.46 (m, 1H), 3.04-2.91 (m, 2H), 2.83-2.76 (m, 1H), 2.27 (s, 3H), 2.01-1.93 (m, 2H), 1.90-1.82 (m, 1H), 1.81-1.70 (m, 4H), 1.69-1.65 (m, 1H), 1.64-1.55 (m, 2H), 1.46-1.34 (m, 2H), 1.30-1.17 (m, 4H), 1.15-0.99 (m, 3H);
1H NMR (400 MHz, Methanol-d4): δ 7.74 (d, J = 7.6 Hz, 1H), 7.68 (bs, 3H), 7.26 (d, J = 8.8 Hz, 1H), 7.20 (s, 1H), 7.13-7.03 (m, 3H), 6.93 (d, J = 7.3 Hz, 1H), 6.77-6.73 (m, 1H), 6.72-6.67 (m, 1H), 4.55 (t, J = 7.8 Hz, 1H), 3.90 (d, J = 7.0 Hz, 2H), 3.65 (s, 3H), 2.98-2.89 (m, 1H), 2.87-2.79 (m, 1H), 2.69-2.61 (m, 1H), 2.22 (s, 3H), 1.89-1.82 (m, 2H), 1.79-1.70 (m, 1H), 1.69-1.58 (m, 5H), 1.56-1.45 (m, 2H), 1.35-1.22 (m, 3H), 1.19-1.06 (m, 5H), 1.01-0.92 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 7.80 (bs, 4H), 7.55-7.50 (m, 3H), 7.47 (d, J = 7.4 Hz, 1H), 7.41 (t, J = 7.4 Hz, 2H), 7.37-7.32 (m, 1H), 7.30-7.23 (m, 2H), 7.14-7.03 (m, 3H), 6.94-6.87 (m, 1H), 4.68 (t, J = 7.9 Hz, 1H), 3.98 (d, J = 7.2 Hz, 2H), 3.70-3.53 (m, 1H), 3.40-3.32 (m, 1H), 3.16-3.06 (m, 1H), 2.99-2.79 (m, 2H), 2.76-2.61 (m, 1H), 2.21 (s, 3H), 1.89-1.81 (m, 2H), 1.69-1.60 (m, 4H), 1.56-1.50 (m, 1H), 1.30-1.23 (m, 7H), 1.17-1.07 (m, 3H).
1H NMR (400 MHz, DMSO-d6): δ 7.89-7.75 (m, 4H), 7.46- 7.39 (m, 2H), 7.29 (d, J = 7.6 Hz, 1H), 7.14-7.0 (m, 4H), 6.95-6.85 (m, 2H), 4.77-4.65 (m, 2H), 3.46-3.34 (m, 1H), 2.98-2.82 (m, 2H), 2.71-2.62 (m, 1H), 2.22 (s, 3H), 1.93-1.82 (m, 2H), 1.71-1.59 (m, 2H), 1.45 (dd, J = 19.2, 6.4 Hz, 6H), 1.38-1.21 (m, 3H), 1.20-1.02 (m, 3H);
1H NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H), 7.40-7.30 (m, 6H), 7.14-7.10 (m, 3H), 7.08-7.01 (m, 2H), 6.96- 6.86 (m, 3H), 6.80 (d, J = 8.0 Hz, 1H), 4.71 (t, J = 7.6 Hz, 1H), 4.02-3.87 (m, 2H), 3.13-2.97 (m, 5H), 2.91-2.83 (m, 1H), 2.22 (s, 3H), 1.54-1.37 (m, 11H), 1.07-0.78 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 7.96-7.77 (m, 5H), 7.39 (t, J = 8.8 Hz, 2H), 7.26 (s, 1H), 7.19 (d, J = 6.8 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.94 (t, J = 7.3 Hz, 1H), 6.20 (s, 1H), 6.06-6.00 (m, 1H), 4.44 (t, J = 7.8 Hz, 1H), 3.99-3.93 (m, 2H), 2.99-2.90 (m, 1H), 2.85-2.65 (m, 3H), 1.92-1.85 (m, 2H), 1.79-1.70 (m, 2H), 1.69-1.58 (m, 4H), 1.57-1.47 (m, 2H), 1.37-1.28 (m, 2H), 1.18-1.08 (m, 5H), 1.04-0.94 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 7.61 (bs, 3H), 7.40- 7.28 (m, 4H), 7.17-7.01 (m, 5H), 6.98-6.85 (m, 3H), 4.72 (t, J = 8.8 Hz, 1H), 4.08-3.82 (m, 2H), 3.22-3.07 (m, 1H), 3.0-2.88 (m, 1H), 2.22 (s, 3H), 1.92-1.62 (m, 5H), 1.60-1.34 (m, 8H), 1.30-1.20 (m, 2H), 1.05-0.94 (m, 4H), 0.93-0.82-(m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 7.83-7.73 (m, 4H), 7.38 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 7.13 (t, J = 7.9 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 6.90-6.81 (m, 2H), 6.80-6.77 (m, 1H), 6.71-6.66 (m, 1H), 4.62 (t, J = 7.9 Hz, 1H), 3.95 (d, J = 7.1 Hz, 2H), 3.67 (s, 3H), 3.41- 3.35 (m, 1H), 2.98-2.90 (m, 1H), 2.89-2.81 (m, 1H), 2.72- 2.65 (m, 1H), 1.90-1.82 (m, 2H), 1.81-1.72 (m, 1H), 1.70- 1.59 (m, 5H), 1.58-1.47 (m, 2H), 1.34-1.22 (m, 2H), 1.19- 1.07 (m, 5H), 1.06-0.95 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 9.25 (bs, 2H), 7.95 (bs, 3H), 7.43-7.30 (m, 5H), 7.18 (bs, 1H), 7.08 (dt, J = 8.0, 0.8 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 4.36 (t, J = 7.6 Hz, 1H), 3.98 (d, J = 7.6 Hz, 2H), 3.07-3.04 (m, 3H), 2.94- 2.91 (m, 1H), 2.50-2.49 (m, 1H), 2.33-2.33 (m, 1H), 1.95- 1.81 (m, 4H), 1.80-1.77 (m, 1H), 1.64-1.60 (m, 3H), 1.52-1.49 (m, 2H), 1.40-1.29 (m, 4H), 1.17-1.11 (m, 3H), 1.02-0.97 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 7.73 (s, 3H), 7.58 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.02-6.91 (m, 3H), 3.92 (d, J = 7.0 Hz, 2H), 2.96-2.85 (m, 1H), 2.47-2.30 (m, 4H), 1.90-1.70 (m, 5H), 1.68-1.59 (m, 6H), 1.55-1.44 (m, 5H), 1.33-1.21 (m, 2H), 1.17-1.07 (m, 6H), 1.01-0.80 (m, 6H);
1H NMR (400 MHz, DMSO-d6): δ 9.31 (bs, 2H), 8.87 (bs, 2H), 7.54 (d, J = 1.8 Hz, 1H), 7.42 (d, J = 7.4 Hz, 2H), 7.21-7.11 (m, 4H), 6.99 (d, J = 7.2 Hz, 1H), 4.29 (t, J = 7.5 Hz, 1H), 3.99 (d, J = 6.6 Hz, 2H), 3.35, 3.28 (m, 2H), 3.03- 2.69 (m, 4H), 2.44-2.27 (m, 2H), 2.25 (s, 3H), 2.11-2.08 (m, 2H), 1.79-1.74 (m, 3H), 1.71-1.54 (m, 3H), 1.51-1.42 (m, 2H), 1.40-0.75 (m, 6H).
1H NMR (400 MHz, DMSO-d6) δ 9.08 (bs, 2H), 8.06 (bs, 3H), 7.48-7.34 (m, 3H), 7.20-7.02 (m, 4H), 7.01-6.86 (m, 2H), 4.26 (t, J = 7.6 Hz, 1H), 4.06 (d, J = 7.6 Hz, 2H), 3.03- 2.72 (m, 4H), 2.43-2.27 (m, 2H), 2.24 (s, 3H), 2.09-1.92 (m, 4H), 1.70-1.17 (m, 13H).
1H NMR (400 MHz, DMSO-d6): δ 8.53 (s, 1H), 7.78-7.69 (m, 4H), 7.18-7.07 (m, 3H), 7.04-6.97 (m, 2H), 6.92 (d, J = 7.4 Hz, 1H), 6.60-6.53 (m, 2H), 4.48 (t, J = 7.8 Hz, 1H), 3.86 (d, J = 7.0 Hz, 2H), 3.00-2.88 (m, 1H), 2.83-2.75 (m, 1H), 2.64-2.57 (m, 1H), 2.22 (s, 3H), 1.90-1.81 (m, 2H), 1.75-1.59 (m, 6H), 1.56-1.47 (m, 2H), 1.36-1.23 (m, 3H), 1.19-1.09 (m, 4H), 1.06-0.91 (m, 3H);
1H NMR (400 MHz, DMSO-d6): δ 7.76 (t, J = 5.6 Hz, 1H), 7.70 (bs, 3H), 7.36 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 7.11-7.02 (m, 4H), 6.98 (d, J = 7.2 Hz, 1H), 6.85 (dt, J = 8.0, 0.8 Hz, 1H), 4.57 (t, J = 8.0 Hz, 1H), 4.0-3.93 (m, 2H), 2.92-2.82 (m, 2H), 2.76-2.76 (m, 4H), 2.21 (s, 3H), 1.82-1.78 (m, 1H), 1.77-1.61 (m, 5H), 1.53- 1.36 (m, 5H), 1.11 (bs, 4H), 1.01-0.95 (m, 2H), 0.85- 0.62 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 7.66 (bs, 3H), 7.38-7.27 (m, 3H), 7.11-7.09 (m, 3H), 7.02 (t, J = 7.2 Hz, 1H), 6.92- 6.86 (m, 2H), 4.61 (t, J = 7.6 Hz, 1H), 4.26 (t, J = 13.4 Hz, 1H), 4.01 (bs, 1H), 3.94 (d, J = 7.2 Hz, 2H), 3.11-3.01 (m, 2H), 2.89-2.78 (m, 1H), 2.67-2.4 (m, 2H), 2.49-2.31 (m, 1H), 2.21 (s, 3H), 1.79-1.49 (m, 9H), 1.11 (bs, 3H), 0.98-0.58 (m, 4H);
1H NMR (400 MHz, DMSO-d6): δ 8.98 (bs, 2H), 7.96 (bs, 3H), 7.68-7.64 (m, 2H), 7.54-7.37 (m, 5H), 7.06 (t, J = 7.5 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 4.48 (t, J = 7..5 Hz, 1H), 3.99 (d, J = 6.6 Hz, 2H), 2.95-2.82 (m, 4H), 2.39- 2.35 (m, 1H), 2.04-1.99 (m, 4H), 1.83-1.79 (m, 1H), 1.63 (bs, 4H), 1.37-1.25 (m, 5H), 1.13-0.82 (m, 6H).
1H NMR (400 MHz, DMSO-d6): δ 7.53 (d, J = 1.86 Hz, 1H), 7.40-7.48 (m, 2H), 7.31 (bs, 3H), 7.28-7.09 (m, 6H), 6.99 (d, J = 7.3 Hz, 1H), 4.28 (t, J = 7.8 Hz, 1H), 3.99 (d, J = 7.2 Hz, 2H), 3.05 (d, J = 7.3 Hz, 1H), 2.99-2.83 (m, 3H), 2.81-2.71 (m, 1H), 2.37-2.27 (m, 1H), 2.24 (s, 3H), 2.11- 1.90 (m, 4H), 1.85-1.73 (m, 1H), 1.70-1.55 (m, 3H), 1.48- 1.45 (m, 2H), 1.41-1.30 (m, 3H), 1.20-1.10 (m, 4H), 1.03- 0.91 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 9.51-8.86 (m, 2H), 8.09 (bs, 3H), 7.52 (s, 1H), 7.47-7.28 (m, 5H), 7.09 (t, J = 7.5 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 4.54-4.42 (m, 1H), 4.00 (d, J = 6.2 Hz, 2H), 3.06-2.72 (m, 4H), 2.42-2.27 (m, 1H), 2.17-1.91 (m, 4H), 1.87-1.73 (m, 1H), 1.71-1.22 (m, 10H), 1.20-0.90 (m, 5H).
1H NMR (400 MHz, DMSO-d6): δ 9.21-8.67 (m, 2H), 7.92 (bs, 3H), 7.46-7.27 (m, 4H), 7.23-7.11 (m, 2H), 7.08 (t, J = 7.6 Hz, 1H), 7.03-6.95 (m, 1H), 6.92 (t, J = 7.1 Hz, 1H), 4.37 (t, J = 7.1 Hz, 1H), 4.04-3.92 (m, 2H), 3.03-2.72 (m, 4H), 2.36-2.35 (m, 1H), 2.09-1.91 (m, 4H), 1.85-1.72 (m, 1H), 1.71-1.56 (m, 3H), 1.55-1.46 (m, 2H), 1.45-1.21 (m, 5H), 1.18-1.08 (m, 3H), 1.05-0.90 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 9.02 (bs, 2H), 7.91 (bs, 3H), 7.44-7.38 (m, 5H), 7.28 (s, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 6.90 (t, J = 7.2 Hz, 1H), 4.41 (t, J = 7.2 Hz, 1H), 3.98 (d, J = 6.8 hz, 2H), 2.94-2.81 (m, 4H), 2.32 (t, J = 2.0 Hz, 1H), 1.98-1.80 (m, 4H), 1.79- 1.74 (m, 1H), 1.60-1.49 (m, 5H), 1.34-1.23 (m, 5H), 1.12 (bs, 3H), 1.11-0.96 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 7.86-7.82 (m, 4H), 7.35- 7.23 (m, 3H), 7.13-7.07 (m, 1H), 7.05-7.00 (m, 2H), 6.93 (d, J = 7.4 Hz, 1H), 6.81 (t, J = 7.8 Hz, 1H), 4.59 (t, J = 8.0 Hz, 1H), 4.37-4.20 (m, 2H), 3.00-2.89 (m, 1H), 2.88-2.80 (m, 1H), 2.69-2.60 (m, 1H), 2.20 (s, 3H), 1.90-1.75 (m, 3H), 1.72-1.60 (m, 5H), 1.52-1.45 (m, 2H), 1.35-1.22 (m, 3H), 1.19-0.98 (m, 7H);
1H NMR (400 MHz, DMSO-d6): δ 7.76 (d, J = 7.2 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.46 (bs, 3H), 7.28 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.10 (t, J = 7.3 Hz, 1H), 7.05-6.97 (m, 3H), 6.93 (d, J = 7.3 Hz, 1H), 4.58 (t, J = 7.9 Hz, 1H), 3.97-3.94 (m, 2H), 3.01-2.73 (m, 2H), 2.68-2.59 (m, 1H), 2.20 (s, 3H), 1.91-1.79 (m, 2H), 1.78-1.56 (m, 6H), 1.56-1.42 (m, 2H), 1.40-0.78 (m, 10H).
1H NMR (400 MHz, DMSO-d6): δ 8.60 (bs, 3H), 7.80 (bs, 2H), 7.37 (t, J = 8.8 Hz, 2H), 7.32 (s, 1H), 7.16-7.05 (m, 4H), 6.96 (d, J = 6.8 Hz, 1H), 6.88 (t, J = 7.2 Hz, 1H), 4.20 (t, J = 7.6 Hz, 1H), 3.97 (d, J = 7.2 Hz, 2H), 2.78-2.74 (m, 1H), 2.73-2.71 (m, 3H), 2.66-2.62 (m, 2H), 2.33-2.27 (m, 1H), 2.24 (s, 3H), 1.79-1.75 (m, 5H), 1.65-1.49 (m, 7H), 1.15-1.11 (m, 3H), 1.02-0.85 (m, 7H);
1H NMR (400 MHz, DMSO-d6): δ 7.91-7.85 (m, 1H), 7.83 (bs, 3H), 7.36 (dd, J = 8.0, 2.4 Hz, 1H), 7.29-7.23 (m, 2H), 7.03-7.01 (m, 4H), 6.93-6.85 (m, 2H), 4.58 (dt, J = 7.6, 4.0 Hz, 1H), 3.99-3.90 (m, 2H), 3.48-3.30 (m, 1H), 2.98- 2.92 (m, 1H), 2.90-2.84 (m, 1H), 2.79-2.66 (m, 1H), 2.32 (s, 3H), 1.94-1.90 (m, 1H), 1.84-1.52 (m, 10H), 1.23-0.96 (m, 8H);
1H NMR (400 MHz, DMSO-d6): δ 8.20 (bs, 3H), 7.80- 7.67 (m, 3H), 7.55-7.45 (m, 3H), 7.45 (t, J = 7.6 Hz, 1H), 7.34-7.29 (m, 2H), 5.02 (q, J = 7.2 Hz, 1H), 4.68 (bs, 1H), 4.44 (t, J = 11.2 Hz, 1H), 4.32 (d, J = 7.2 Hz, 2H), 3.61- 3.33 (m, 4H), 2.63 (s, 3H), 2.28-2.17 (m, 3H), 2.08-2.03 (m, 3H), 1.94-1.91 (m, 2H), 1.85-1.82 (m, 2H), 1.68- 1.55 (m, 4H), 1.41-1.39 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 7.80-7.70 (m, 4H), 7.40- 7.31 (m, 2H), 7.23 (s, 1H), 7.13-7.02 (m, 4H), 6.95-6.86 (m, 2H), 4.59 (t, J = 8.0 Hz, 1H), 4.02-3.89 (m, 2H), 2.94-2.81 (m, 2H), 2.80-2.72 (m, 2H), 2.22 (s, 3H), 1.83-1.73 (m, 3H), 1.70-1.54 (m, 4H), 1.53-1.39 (m, 4H), 1.16-1.06 (m, 6H), 1.03-0.95 (m, 2H), 0.81-0.64 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 7.68 (bs, 3H), 7.40-7.24 (m, 3H), 7.15-7.00 (m, 4H), 6.98-6.85 (m, 2H), 4.68-4.58 (m, 1H), 4.34 (t, J = 7.2 Hz, 1H) 4.01-3.90 (m, 3H), 3.17- 3.04 (m, 1H), 3.02-2.93 (m, 1H), 2.90-2.71 (m, 3H), 2.40- 2.30 (m, 1H), 2.22 (s, 3H), 1.83-1.71 (m, 1H), 1.70-1.59 (m, 3H), 1.58-1.47 (m, 4H), 1.46-1.30 (m, 3H), 1.19-1.10 (m, 3H), 1.04-0.94 (m, 2H), 0.85-0.39 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 7.77-7.60 (m, 4H), 7.37 (d, J = 8.7, 1H), 7.33-7.24 (m, 2H), 7.14-7.01 (m, 4H), 6.95- 6.83 (m, 2H), 4.60 (t, J = 7.6 Hz, 1H), 3.95 (d, J = 7.2 Hz, 2H), 3.41-3.35 (m, 1H), 2.89-2.79 (m, 1H), 2.69-2.60 (m, 3H), 2.21 (s, 3H), 1.82-1.60 (m, 8H), 1.57-1.37 (m, 3H), 1.19-1.08 (m, 3H), 1.07-0.91 (m, 6H);
1H NMR (400 MHz, DMSO-d6): δ 7.87 (bs, 3H), 7.80 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 1.7 Hz, 1H), 7.40-7.31 (m, 2H), 7.18-7.14 (m, 1H), 7.14-7.04 (m, 3H), 7.09-7.06 (m, 1H), 6.93 (d, J = 6.9 Hz, 1H), 4.64 (t, J = 7.7 Hz, 1H), 3.99 (d, J = 6.7 Hz, 2H), 3.70 (s, 3H), 3.40- 3.29 (m, 1H), 2.96-2.81 (m, 2H), 2.74-2.65 (m, 1H), 2.20 (s, 3H), 1.91-1.82 (m, 2H), 1.81-1.73 (m, 1H), 1.70-1.50 (m, 7H), 1.35-1.23 (m, 2H), 1.19-0.95 (m, 7H).
1H NMR (400 MHz; DMSO-d6): δ 9.04 (bs, 2H), 8.00 (bs, 3H), 7.40 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.29- 7.20 (m, 2H), 7.18-7.7.03 (m, 4H), 6.90 (t, J = 7.4 Hz, 1H), 4.45 (t, J = 7.0 Hz, 1H), 4.03-3.91 (m, 2H), 3.03-2.80 (m, 4H), 2.38 (s, 3H), 2.34-2.25 (m, 1H), 2.08-1.92 (m, 4H), 1.84-1.72 (m, 1H), 1.69-1.56 (m, 3H), 1.54-1.23 (m, 7H), 1.20-1.06 (m, 3H), 1.04-0.91 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 8.77(d, J = 6.1 Hz, 2H), 8.18 (bs, 2H), 8.03 (bs, 1H), 7.89-7.75 (m, 4H), 7.71 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.41(s, 1H), 7.25- 6.99 (m, 4H), 6.93 (d, J = 6.9 Hz, 1H), 4.79 (t, J = 8.7 Hz, 1H), 4.04 (d, J = 7.2 Hz, 2H), 3.04-2.84 (m, 2H), 2.72-2.63 (m, 2H), 2.21 (s, 3H), 1.96-1.41 (m, 10H), 1.35-1.20 (m, 2H), 1.17-0.97 (m, 7H).
1H NMR(400 MHz, Methanol-d4): δ 7.39-7.29 (m, 2H), 7.19-7.06 (m, 5H), 7.03-6.87 (m, 2H), 3.99-3.93 (m, 2H), 3.64-3.55 (m, 2H), 3.07-3.00 (m, 1H), 2.96-2.86 (m, 1H), 2.85-2.75 (m, 1H), 2.27 (s, 3H), 2.06-1.96 (m, 1H), 1.90- 1.66 (m, 6H), 1.64-1.55 (m, 2H), 1.49-1.20 (m, 8H), 1.10- 0.99 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 7.96, (d, J = 7.6 Hz, 1H), 7.77-7.67 (m, 4H), 7.41 ((d, J = 9.0 Hz, 1H), 7.23-7.18 (m, 2H), 3.95 (d, J = 7.2 Hz, 2H), 3.51-3.41 (m, 3H), 3.03-2.93 (m, 1H), 1.96-1.88 (m, 2H), 1.85-1.77 (m, 2H), 1.76-1.68 (m, 1H), 1.67-1.58 (m, 3H), 1.50-1.40 (m, 2H), 1.37-1.20 (m, 4H), 1.16-1.08 (m, 3H), 1.02-0.88 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 8.89 (bs, 2H), 8.65 (bs, 1H), 8.27 (s, 1H), 7.97-7.91 (m, 4H), 7.72-7.67 (m, 1H), 7.56 (dt, J = 8.0, 1.2 Hz, 1H), 7.44-7.41 (m, 2H), 7.42 (s, 1H), 7.10-7.0 (m, 1H), 6.97-6.89 (m, 1H), 6.49 (s, 1H), 4.57 (t, J = 7.6 Hz, 1H), 3.99 (d, J = 7.2 Hz, 2H), 2.96- 2.76 (m, 5H), 2.08-1.94 (m, 4H), 1.82-1.80 (m, 1H), 1.65- 1.61 (m, 3H), 1.53-1.50 (m, 3H), 1.33-1.24 (m, 4H), 1.03 (bs, 3H), 1.0-0.98 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 8.88 (bs, 3H), 8.00 (bs, 2H), 7.79-7.78 (m, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.31 (s, 1H), 7.24 (dd, J = 8.76 1.86 Hz, 1H), 3.95 (d, J = 6.9 Hz, 2H), 3.18-3.10 (m, 2H), 3.05-3.01 (m, 3H), 2.99-2.90 (m, 1H), 2.06-1.97 (m, 2H), 1.95-1.79 (m, 2H) 1.80-1.70 (m, 1H), 1.68-1.58 (m, 3H), 1.51-1.33 (m, 6H), 1.14-1.08 (m, 3H), 1.03-0.93 (m, 2H);
1H NMR 400 MHz; DMSO-d6): δ 7.76 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.33-7.21 (m, 3H), 7.17 (s, 1H), 7.14-6.98 (m, 6H), 6.90-6.82 (m, 3H), 4.60 (t, J = 7.6 Hz, 1H), 3.95 (d, J = 7.0 Hz, 2H), 2.89-2.77 (m, 1H), 2.73-2.61 (m, 1H), 2.21 (s, 3H), 1.83-1.46 (m, 11H), 1.24-0.96 (m, 10H).
1H NMR (400 MHz, DMSO-d6): δ 7.75 (bs, 3H), 7.70 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 1.7 Hz, 1H), 7.09-6.86 (m, 6H), 6.93 (d, J = 6.9 Hz, 1H), 3.88 (d, J = 6.7 Hz, 2H), 3.61 (t, J = 7.0 Hz, 1H), 3.40-3.29 (m, 1H), 2.96-2.58 (m, 3H) 2.41 (d, J = 7.7 Hz, 2H), 2.18 (s, 3H), 1.90-1.71 (m, 3H), 1.69-1.54 (m, 5H), 1.44-1.41 (m, 2H), 1.29-1.25 (m, 2H), 1.15-0.95 (m, 5H), 0.91-0.81 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 7.76 (t, J = 5.9 Hz, 1H), 7.70 (bs, 3H), 7.44 (d, J = 1.9 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.32 (s, 1H), 7.19-7.02-(m, 4H), 6.95 (d, J = 7.2 Hz, 1H), 4.57 (t, J = 8.2 Hz, 1H), 4.00-3.90 (m, 2H), 2.96-2.56 (m, 6H), 2.22 (s, 3H), 1.80-1.55 (m, 6H), 1.53-1.33 (m, 5H), 1.20-1.03 (m, 4H), 1.02-0.89 (m, 2H), 0.85-0.62 (m, 4H).
1H NMR (400 MHz, Methanol-d4): δ 7.55 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.11 (dt, J = 7.8, 1.2 Hz, 1H), 7.03 (s, 1H), 6.99 (t, J = 7.2 Hz, 1H), 4.54 (s, 1H), 3.96 (d, J = 7.2 Hz, 2H), 3.10-3.04 (m, 1H), 2.89-2.84 (m, 1H), 2.75-2.68 (m, 3H), 2.17-2.11 (m, 2H), 1.99-1.84 (m, 5H), 1.82-1.78 (m, 1H), 1.70-1.69 (m, 2H), 1.65-1.62 (m, 2H), 1.57-1.54 (m, 3H), 1.45-1.43 (m, 1H), 1.39- 1.28 (m, 5H), 1.25-1.11 (m, 5H), 1.09-0.93 (m, 5H);
1H NMR (400 MHz, DMSO-d6): δ 7.76 (d, J = 7.5 Hz, 1H), 7.64 (bs, 3H), 7.53-7.48 (m, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.42-7.28 (m, 5H), 7.15-7.01 (m, 4H), 6.92 (d, J = 7.1 Hz, 1H), 4.65-4.58 (m, 1H), 3.99 (d, J = 7.3 Hz, 2H), 2.96-2.78 (m, 2H), 2.77-2.63 (m, 1H), 2.20 (s, 3H), 1.91-1.73 (m, 3H), 1.71-1.50 (m, 7H), 1.37-0.93 (m, 10H).
1H NMR (400 MHz, DMSO-d6): δ 7.77-7.60 (m, 4H), 7.37 (d, J = 8.7, 1H), 7.33-7.24 (m, 2H), 7.14-7.01 (m, 4H), 6.95- 6.83 (m, 2H), 4.60 (t, J = 7.6 Hz, 1H), 3.95 (d, J = 7.2 Hz, 2H), 3.41-3.35 (m, 1H), 2.89-2.79 (m, 1H), 2.69-2.60 (m, 3H), 2.21 (s, 3H), 1.82-1.60 (m, 8H), 1.57-1.37 (m, 3H), 1.19-1.08 (m, 3H), 1.07-0.91 (m, 6H).
1H NMR (400 MHz, DMSO-d6): δ 7.72 (bs, 2H), 7.94 (bs, 3H), 7.77 (s, 1H), 7.53-7.37 (m, 4H), 7.32 (t, J = 7.6 Hz, 1H), 7.18 (s, 1H), 7.11 (d, J = 7.3 Hz, 1H), 3.98 (d, J = 7.2 Hz, 2H), 3.05-2.87 (m, 4H), 2.82 (t, J = 7.2 Hz, 2H), 2.38 (s, 3H), 2.13-1.92 (m, 6H), 1.83-1.72 (m, 1H), 1.73-1.57 (m, 3H), 1.55-1.45 (m, 2H), 1.43-1.28 (m, 4H), 1.19-1.08 (m, 3H), 1.04-0.92 (m, 2H).
1H NMR (400 MHz, CDCl3): δ 7.40 (d, J = 7.6 Hz, 1H), 7.29 (s, 1H), 7.25-7.08 (m, 4H), 7.0-6.96 (m, 2H), 6.92 (s, 1H), 4.99 (d, J = 8.0 Hz, 1H), 4.64 (t, J = 8.0 Hz, 1H), 3.91-3.89 (m, 2H), 3.62-3.57 (m, 2H), 2.98 (q, J = 7.2 Hz, 1H), 2.77 (q, J = 7.6 Hz, 1H), 2.28 (s, 3H), 1.85-1.78 (m, 1H), 1.71-1.63 (m, 4H), 1.51-1.47 (m, 3H), 1.28- 1.13 (m, 6H), 1.07-0.97 (m, 4H), 0.81-0.73 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 7.63 (d, J = 7.75 Hz, 1H), 7.41-7.36 (m, 1H), 7.29-7.25 (m, 2H), 7.11-7.01 (m, 4H), 6.92-6.85 (m, 2H), 4.60 (t, J = 8.0 Hz, 1H), 4.46 (d, J = 4.4 Hz, 1H), 4.00-3.90 (m, 2H), 2.86-2.80 (m, 1H), 2.67- 2.60 (m, 1H), 2.21 (s, 3H), 1.77-1.70 (m, 3H), 1.68-1.55 (m, 6H), 1.52-1.43 (m, 2H), 1.15-1.06 (m, 6H), 1.04-0.92 (m, 3H).
1H NMR (400 MHz, DMSO-d6): δ 8.84 (bs, 2H), 8.03 (bs, 3H), 7.73 (d, J = 1.8 Hz, 1H), 7.43 (d, J = 8.9 Hz, 1H), 7.31- 7.15 (m, 2H), 3.95 (d, J = 7.2 Hz, 2H), 3.06-2.85 (m, 4H), 2.74 (t, J = 7.3 Hz, 2H), 2.12-1.87 (m, 6H), 1.79-1.68 (m, 1H), 1.68-1.53 (m, 3H), 1.51-1.31 (m, 6H), 1.17-1.04 (m, 3H), 1.01-0.89 (m, 2H).
1H NMR (400 MHz, Methanol-d4): δ 7.36 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.19-7.06 (m, 5H), 6.99 (bs, 1H), 6.94-6.90 (m, 1H), 4.24 (t, J = 5.6 Hz, 1H), 3.97 (d, J = 7.2 Hz, 2H), 3.08-2.90 (m, 2H), 2.55-2.51 (m, 1H), 2.37-2.36 (m, 2H), 2.27 (s, 3H), 1.99-1.97 (m, 3H), 1.85- 1.80 (m, 4H), 1.72-1.66 (m, 2H), 1.59-1.56 (m, 2H), 1.37-1.30 (m, 3H), 1.29-1.19 (m, 5H), 1.04-0.99 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 10.62 (bs, 1H), 8.23 (bs, 3H), 7.42-7.39 (m, 3H), 7.18-7.13 (m, 3H), 7.04 (dt, J = 8.0, 0.8 Hz, 1H), 6.96 (d, J = 6.4 Hz, 1H), 6.89 (t, J = 7.6 Hz, 1H), 4.15 (t, J = 7.6 Hz, 1H), 3.92-4.02 (m, 2H), 3.57- 3.46 (m, 2H), 3.21 (bs, 1H), 3.02-2.85 (m, 4H), 2.52- 2.50 (m, 1H), 2.49-2.46 (m, 2H), 2.04 (bs, 2H), 1.90 (bs, 2H), 1.81-1.76 (m, 1H), 1.65 (bs, 2H), 1.61 (bs, 1H), 1.54- 1.48 (m, 3H), 1.23 (s, 1H), 1.14-1.12 (m, 3H), 1.02- 0.97 (m, 2H).
1H NMR (400 MHz; DMSO-d6): δ 7.80-7.70 (m, 4H), 7.40- 7.34 (m, 2H), 7.30-7.23 (m, 2H), 7.20-7.14 (m, 2H), 7.10 (t, J = 7.3 Hz, 1H), 7.03-7.01 (m, 3H), 6.98 (dt, J = 7.3, 1.0 Hz, 1H), 6.92 (d, J = 7.3 Hz, 1H), 4.61 (t, J = 7.7 Hz, 1H), 3.97 (d, J = 7.0 Hz, 2H), 3.67 (s, 3H), 3.42-3.33 (m, 1H), 2.98-2.76 (m, 2H), 2.73-2.62 (m, 1H), 2.21 (s, 3H), 1.92- 1.49 (m, 10H), 1.36-1.22 (m, 2H), 1.20-0.92 (m, 7H).
1H NMR (400 MHz, DMSO-d6): δ 7.76 (d, J = 7.52 Hz, 1H), 7.71 (bs, 3H), 7.42 (d, J = 8.3 Hz, 1H), 7.29 (s, 1H), 7.27-7.17 (m, 4H), 7.15-6.99 (m, 5H), 6.92 (d, J = 7.1 Hz, 1H), 4.61 (t, 1H, J = 8.1 Hz), 4.24-4.01 (m, 2H), 3.39-3.32 (m, 1H), 2.98-2.77 (m, 2H), 2.74-2.63 (m, 1H), 2.20 (s, 3H), 2.10 (s, 3H), 1.92-1.74 (m, 3H), 1.74-1.51 (m, 7H), 1.33-1.23 (m, 2H), 1.20-1.08 (m, 4H), 1.08-0.95 (m, 3H).
1H NMR (400 MHz, DMSO-d6): δ 8.77 (bs, 2H), 7.86 (bs, 3H), 7.70 (d, J = 1.2 Hz, 1H), 7.41-7.25 (m, 2H), 7.21-7.07 (m, 3H), 7.07-6.49 (m, 2H), 4.30-4.20 (m, 1H), 3.99 (d, J = 6.7 Hz, 2H), 3.03-2.82 (m, 3H), 2.80-2.71 (m, 1H), 2.23 (s, 3H), 2.07-1.90 (m, 4H), 1.83-1.72 (m, 1H), 1.70-1.56 (m, 3H), 1.54-1.21 (m, 7H), 1.18-0.92 (m, 7H).;
1H NMR (400 MHz, DMSO-d6): δ 7.78 (bs, 4H), 7.39 (d, J = 8.6 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H), 7.18 (s, 1H), 7.14- 7.06 (m, 1H), 7.06-6.99 (m, 3H), 6.92 (d, J = 7.3 Hz, 1H), 6.85 (t, J = 7.3 Hz, 1H), 4.61(t, J = 8.0 Hz, 1H), 3.80 (s, 2H), 3.02-2.78 (m, 2H), 2.70-2.56 (m, 1H), 2.20 (s, 3H), 1.96-1.81 (m, 5H), 1.72-1.59 (m, 5H), 1.59-1.46 (m, 9H), 1.38-1.21 (m, 3H), 1.19-1.00 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 7.70-7.65 (m, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.30-7.23 (m, 2H), 7.12-7.00 (m, 4H), 6.94-6.84 (m, 2H), 4.60 (t, J = 7.9 Hz, 1H), 4.14-405 (m, 2H), 4.04-3.92 (m, 3H), 3.89-3.81 (m, 2H), 2.87-2.80 (m, 1H), 2.68-2.62 (m, 1H), 2.21 (s, 3H), 1.82-1.71 (m, 3H), 1.69-1.57 (m, 5H), 1.55-1.47 (m, 2H), 1.28-1.23 (m, 4H), 1.22-1.17 (m, 5H), 1.16-1.09 (m, 5H), 1.05-0.94 (m, 3H).
1H NMR (400 MHz, DMSO-d6): δ 7.39-7.23 (m, 3H), 7.14- 7.01 (m, 4H), 6.95-6.84 (m, 2H), 5.32-5.4 (m, 1H), 4.67- 4.59 (m, 1H), 4.29 (t, J = 14.2 Hz, 1H), 4.15-4.06 (m, 2H), 4.05-3.92 (m, 4H), 3.91-3.82 (m, 2H), 3.20-3.05 (m, 1H), 3.00-2.91 (m, 1H), 2.85-2.73 (m, 2H), 2.39-2.30 (m, 1H), 2.21 (s, 3H), 1.81-1.72 (m, 1H), 1.69-1.59 (m, 3H), 1.57- 1.43 (m, 5H), 1.29-1.18 (m, 9H), 1.16-1.10 (m, 3H), 1.02- 0.93 (m, 2H), 0.77-0.66 (m, 1H).
1H NMR (400 MHz; DMSO-d6): δ 8.99 (bs, 2H), 7.99-7.85 (m, 3H), 7.81 (d, J = 7.5 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 1.3 Hz, 1H), 7.27 (s, 1H), 7.21 (dd, J = 8.8, 1.6 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 7.08-7.03 (m, 2H), 6.93 (d, J = 6.2 Hz, 1H), 6.01-5.95 (m, 1H), 4.64 (t, J = 7.5 Hz, 1H), 3.95 (d, J = 7.2 Hz, 2H), 3.75-3.67 (m, 2H), 2.95-2.81 (m, 2H), 2.70-2.61 (m, 3H), 2.21 (s, 3H), 1.91-1.83 (m, 2H), 1.79-1.71 (m, 1H), 1.70-1.56 (m, 6H), 1.55-1.46 (m, 2H), 1.37-1.22 (m, 3H), 1.19-0.94 (m, 8H).
1H NMR (400 MHz, DMSO-d6): δ 8.93 (bs, 2H), 7.95 (bs, 3H), 7.45 (d, J = 1.3 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.38 (s, 1H), 7.31-7.24 (m, 1H), 7.22-7.11 (m, 5H), 7.06 (d, J = 7.5 Hz, 1H), 7.02-6.95 (m, 2H), 4.27 (t, J = 7.5 Hz, 1H), 4.00 (d, J = 6.9 Hz, 2H), 3.68 (s, 3H), 3.02-2.88 (m, 3H), 2.85-2.72 (m, 1H), 2.36-2.28 (m, 1H), 2.24 (s, 3H), 2.06- 1.92(m, 4H), 1.87-1.76 (m, 1H), 1.71-1.26 (m, 10H), 1.20- 1.10 (m, 3H), 1.07-0.95 (m, 2H).
1H NMR 400 MHz; DMSO-d6): δ 7.80 (bs, 3H), 7.70 (d, J = 7.5 Hz, 1H), 7.53 (d, J = 1.3 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.33-7.26 (m, 2H), 7.21 (dd, J = 8.5, 1.6 Hz, 1H),7.12- 7.04 (m, 2H), 7.01 (dt, J = 7.5, 0.9 Hz, 1H), 3.93 (d, J = 6.9 Hz, 2H), 3.75 (s, 3H), 3.51-3.37 (m, 1H), 2.99-2.85 (m, 3H), 2.38 (t, J = 7.5 Hz, 2H), 1.94-1.83(m, 2H), 1.82-1.49 (m, 8H), 1.40-1.25 (m, 2H), 1.20-1.06 (m, 5H), 1.05-0.94 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 7.78 (bs, 3H), 7.72 (d, J = 7.6 Hz, 1H), 7.62-7.54 (m, 2H), 7.51-7.43 (m, 4H), 7.23- 7.19 (m, 1H), 7.12 (s, 1H), 3.96 (d, J = 6.8 Hz, 2H), 3.50- 3.38 (m, 1H), 2.91 (t, J = 7.5 Hz, 3H), 2.39 (t, J = 7.5 Hz, 2H), 1.91-1.82 (m, 2H), 1.82-1.71 (m, 3H), 1.70-1.48 (m, 5H), 1.39-1.23 (m, 2H), 1.20-1.06 (m, 5H), 1.06-0.93 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 9.02 (bs, 2H), 7.98 (bs, 3H), 7.42 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 7.19-7.09 (m, 3H), 7.08-7.01 (m, 1H), 6.97 (d, J = 7.1 Hz, 1H), 6.88 (t, J = 7.1 Hz, 1H), 4.27(t, J = 7.9 Hz, 1H), 3.85 (s, 2H), 3.02-2.87 (m, 3H), 2.86-2.74 (m, 1H), 2.35-2.28 (m, 1H), 2.23 (s, 3H), 2.04-1.89 (m, 7H), 1.71- 1.59 (m, 3H), 1.58-1.46 (m, 10H), 1.42-1.28 (m, 4H).
1H NMR (400 MHz, DMSO-d6): δ 7.91 (d, J = 7.6 Hz, 1H), 7.67-7.57 (m, 3H), 7.54-7.50 (m, 2H), 7.49-7.45 (m, 4H), 7.23-7.19 (m, 2H), 3.99 (d, J = 7.0 Hz, 2H), 3.47 (s, 3H), 2.98-2.89 (m, 1H), 1.93-1.86 (m, 2H), 1.84-1.74 (m, 3H), 1.70-1.64 (m, 2H), 1.63-1.54 (m, 3H), 1.38-1.27 (m, 2H), 1.25-1.13 (m, 5H), 1.06-0.96 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 7.91 (d, J = 7.6 Hz, 1H), 7.75 (bs, 3H), 7.47 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.29- 7.25 (m, 1H), 7.25-7.19 (m, 3H), 7.18 (s, 1H), 7.06 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 3.97 (d, J = 7.2 Hz, 2H), 3.50-3.40 (m, 3H), 2.97-2.91 (m, 1H), 2.25 (s, 3H), 1.96-1.94 (m, 2H), 1.90-1.88 (m, 3H), 1.79-1.55 (m, 5H), 1.38-1.29 (m, 2H), 1.37-1.11 (m, 5H), 1.04-0.98 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 7.81 (d, J = 1.2 Hz, 1H) 7.77 (s, 1H), 7.75 (bs, 3H), 7.60 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.42 (dd, J = 8.4, 1.6 Hz, 1H), 7.15-7.07 (m, 3H), 6.94 (d, J = 7.2 Hz, 1H), 4.63 (t, J = 8.0 Hz, 1H), 4.02 (d, J = 6.8 Hz, 2H), 2.94-2.83 (m, 2H), 2.70-2.66 (m, 1H), 2.22 (s, 3H), 2.0-1.99 (m, 2H), 1.86-1.84 (m, 1H), 1.61 (bs, 4H), 1.44-1.14 (m, 2H), 1.33-1.22 (m, 4H), 1.17- 0..98 (m, 5H), 0.96-0.84 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 7.80 (bs, 4H), 7.70 (d, J = 7.5 Hz, 1H), 7.53 (d, J = 1.3 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.33-7.26 (m, 2H), 7.21 (dd, J = 8.5, 1.6 Hz, 1H),7.12- 7.04 (m, 2H), 7.01 (dt, J = 7.5, 0.9 Hz, 1H), 3.93 (d, J = 6.9 Hz, 2H), 3.75 (s, 3H), 3.51-3.37 (m, 1H), 2.99-2.85 (m, 3H), 2.38 (t, J = 7.5 Hz, 2H), 1.94-1.83(m, 2H), 1.82-1.49 (m, 8H), 1.40-1.25 (m, 3H), 1.20-1.06 (m, 6H), 1.05-0.94 (m, 2H).
1H NMR 400 MHz; DMSO-d6): δ 7.92-7.69 (m, 4H), 7.36 (d, J = 8.3 Hz, 1H), 7.31-7.23 (m, 2H), 7.14-6.98 (m, 4H), 6.92 (d, J = 7.5 Hz, 1H), 6.87 (t, J = 7.3 Hz, 1H), 4.60 (t, J = 8.0 Hz, 1H), 3.93 (d, J = 7.5 Hz, 2H), 3.43-3.33 (m, 1H), 2.97-2.78 (m, 2H), 2.71-2.58 (m, 1H), 2.20 (s, 3H), 2.07- 1.93 (m, 1H), 1.92-1.82 (m, 2H), 1.71-1.40 (m, 10H), 1.38- 1.04 (m, 8H).
1H NMR (400 MHz, DMSO-d6): δ 8.00 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 1.8 Hz, 1H), 7.82-7.61 (m, 4H), 7.60-7.50 (m, 3H), 7.48-7.43 (m, 1H), 7.31-7.27 (m, 1H), 7.21 (s, 1H), 3.99 (d, J = 7.1 Hz, 2H), 3.51 (s, 2H), 3.50-3.41 (m, 1H), 3.00-2.89 (m, 1H), 1.93-1.86 (m, 2H), 1.85-1.77 (m, 2H), 1.68-1.58 (m, 3H), 1.55-1.49 (m, 2H), 1.39-1.20 (m, 5H), 1.16-0.96 (m, 5H).
1H NMR (400 MHz, DMSO-d6): δ 8.87 (bs, 2H), 8.76 (bs, 1H), 7.97 (s, 2H), 7.67 (s, 1H), 7.60-7.54 (m, 2H), 7.51-7.47 (m, 3H), 7.34-7.23 (m, 2H), 3.99 (d, J = 7.0 Hz, 2H), 3.20- 3.13 (m, 2H), 3.11-3.04 (m, 3H), 2.99-2.92 (m, 1H), 2.17- 2.10 (m, 2H), 2.04-1.97 (m, 2H), 1.84-1.75 (m, 1H), 1.70- 1.65 (m, 2H), 1.63-1.54 (m, 2H), 1.48-1.31 (m, 5H), 1.19- 1.12 (m, 3H), 1.06-0.97 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 8.78 (bs, 2H), 7.95 (bs, 3H), 7.87 (d, J = 1.4 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.63 (s, 1H), 7.60-7.51 (m, 2H), 7.49-7.42 (m, 1H), 7.31-7.26 (m, 1H), 7.22 (s, 1H), 3.99 (d, J = 6.9 Hz, 2H), 3.02-2.88 (m, 4H), 2.83 (t, J = 6.9 Hz, 2H), 2.15-1.93 (m, 6H), 1.86-1.74 (m, 1H), 1.72-1.57 (m, 3H), 1.55-1.47 (m, 2H), 1.45-1.28 (m, 4H), 1.21-1.07 (m, 3H), 1.05-0.93 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 8.88 (bs, 2H), 7.96 (bs, 3H), 7.52 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.30-7.28 (m, 2H), 7.25-7.22 (m, 3H), 7.10 (dd, J = 8.4, 1.6 Hz, 1H), 3.97 (d, J = 7.2 Hz, 2H), 3.14 (bs, 1H), 3.09-2.96 (m, 4H), 2.27 (s, 3H), 2.13 (bs, 1H), 2.11 (bs, 1H), 2.01 (bs, 1H), 1.98 (bs, 1H), 1.79-1.77 (m, 1H), 1.67-1.55 (m, 5H), 1.47-1.31 (m, 5H), 1.23-1.13 (m, 3H), 1.03-0.96 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 9.19 (bs, 1H), 9.10 (bs, 1H), 8.06 (bs, 3H), 7.49-7.32 (m, 3H), 7.22-7.02 (m, 4H), 6.96 (d, J = 6.5 Hz, 1H), 6.90 (t, J = 7.8 Hz, 1H), 4.27 (t, J = 7.8 Hz, 1H), 3.96 (d, J = 7.5 Hz, 2H), 3.04-2.70 (m, 4H), 2.38-2.27 (m, 1H), 2.23 (s, 3H), 2.10-1.94 (m, 5H), 1.69- 1.25 (m, 15H), 1.24-1.13 (m, 2H).
1H NMR 400 MHz; DMSO-d6): δ 10.28 (bs, 1H), 8.61 (bs, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 7.09 (t, J = 7.5 Hz, 1H), 7.06-6.99 (m, 3H), 6.91 (d, J = 7.3 Hz, 1H), 6.89-6.82 (m, 1H), 4.60 (t, J = 8.0 Hz, 1H), 3.95 (d, J = 7.0 Hz, 2H), 3.41- 3.31 (m, 1H), 2.89-2.76 (m, 1H), 2.70-2.59 (m, 1H), 2.20 (s, 3H), 1.93-1.70 (m, 2H), 1.69-1.47 (m, 9H), 1.41-1.29 (m, 2H), 1.17-0.93 (m, 7H).
1H NMR (400 MHz, DMSO-d6): δ 8.80 (d, J = 8.8 Hz, 2H), 8.36-8.17 (m, 3H), 8.04 (d, J = 7.5 Hz, 1H,), 7.95-7.70 (m, 4H), 7.64 (d, J = 7.8 Hz, 1H), 7.28 (s, 1H), 4.03 (d, J = 7.0 Hz, 2H), 3.56 (s, 2H), 3.02-2.87 (m, 1H), 1.98-1.71 (m, 5H), 1.71-1.46 (m, 5H), 140-1.07 (m, 8H), 1.06-0.92 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, J = 8.1 Hz, 1H), 7.97-7.88 (m, 2H), 7.75 (bs, 3H), 7.33 (d, J = 7.0 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H),7.18-7.07 (m, 4H), 6.96 (d, J = 7.0 Hz, 1H), 4.66-4.58 (m, 1H), 3.47-3.36 (m, 1H), 3.06-2.86 (m, 2H), 2.73-2.61 (m, 1H), 2.23 (s, 3H), 1.98-1.67 (m, 9H), 1.61-1.45 (m, 4H), 1.37-1.08 (m, 6H).
1H NMR (400 MHz, DMSO-d6): δ 7.87-7.68 (m, 4H), 7.67 (d, J = 1.9 Hz, 1H), 7.39 (d, J = 9.5 Hz, 1H), 7.21-7.17 (m, 1H), 7.12 (s, 1H), 3.92 (d, J = 7.2 Hz, 2H), 3.49-3.39 (m, 1H), 2.99-2.80 (m, 3H), 2.35-2.31(m, 2H), 1.95-1.83 (m, 2H), 1.81-1.71 (m, 2H), 1.68-1.57 (m, 3H), 1.51-1.20 (m, 5H), 1.19-1.06 (m, 5H), 0.97-0.84 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 9.08 (bs, 2H), 8.00 (bs, 3H), 7.92 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.64-7.53 (m, 3H), 7.51-7.46 (m, 1H), 7.33-7.29 (m, 2H), 3.99 (d, J = 6.9 Hz, 2H,), 3.25-3.10 (m, 4H), 3.06-2.90 (m, 2H), 2.15 (d, J = 10.2, 2H), 2.01 (d, J = 10.2 Hz, 2H), 1.86-1.72 (m, 1H), 1.71-1.29 (m, 9H), 1.20-1.08 (m, 3H), 1.06-0.94 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 8.55 (bs, 1H), 8.28 (bs, 1H), 7.50-7.25 (m, 3H), 7.21-7.08 (m, 4H), 6.99-6.92 (m, 1H), 4.63 (dd, J1 = 6.6 Hz, J2 = 6.6 Hz, 1H), 4.49-4.01 (m, 1H), 3.96 (d, J = 7.1 Hz, 2H), 3.29-3.05 (m, 3H), 3.04-2.84 (m, 3H), 2.78-2.54 (m, 3H), 2.22 (d, J = 3.7 Hz, 3H), 1.88- 1.37 (m, 10H), 1.21-1.05 (m, 3H), 1.03-0.87 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 8.51 (bs, 2H), 7.19-7.40 (m, 3H), 7.01-7.17 (m, 4H), 6.82-6.96 (m, 2H), 4.62-4.69 (m, 1H), 4.10-3.99 (m, 1H), 3.95 (d, J = 6.8 Hz, 1H,), 3.17- 3.29 (m, 3H), 2.80-3.14 (m, 4H), 2.54-2.79 (m, 3H), 2.21 (d, J = 3.6 Hz, 3H,), 1.27-1.90 (m, 10H), 0.88-1.21 (m, 5H).
1H NMR (400 MHz, DMSO-d6): δ 8.82 (bs, 2H), 8.08 (t, J = 6.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.25 (s, 1H), 7.13-7.02 (m, 4H), 6.94-6.86 (m, 2H), 4.59 (t, J = 8.0 Hz, 1H), 3.97-3.87 (m, 3H), 3.60-3.55 (m, 2H), 3.12-2.95 (m, 2H), 2.93-2.76 (m, 4H), 2.21 (s, 3H), 1.90-1.48 (m, 6H), 1.26-1.23 (m, 2H), 1.13-1.11 (m, 3H), 1.01-0.95 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 8.79 (bs, 2H), 8.08 (t, J = 6.0 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.34 (s, 1H), 7.17-7.12 (m, 2H), 7.05-7.09 (m, 2H), 6.94 (d, J = 7.2 Hz, 1H), 4.57 (t, J = 8.0 Hz, 1H), 3.98- 3.88 (m, 2H), 3.62-3.53 (m, 2H), 3.12-3.06 (m, 1H), 3.02- 2.92 (m, 2H), 2.90-2.76 (m, 3H), 2.22 (s, 3H), 1.81- 1.60 (m, 4H), 1.48-1.45 (m, 2H), 1.27-1.23 (m, 4H), 1.18- 1.10 (m, 2H), 1.05-0.94 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 8.49 (bs, 2H), 7.97 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 7.12-7.04 (m, 4H), 6.94-6.87 (m, 2H), 4.59 (t, J = 8.0 Hz, 1H), 4.04 (d, J = 7.2 Hz, 2H), 3.73- 3.68 (m, 1H), 3.17-3.08 (m, 2H), 2.91-2.73 (m, 2H), 2.67- 2.66 (m, 1H), 2.21 (s, 3H), 1.95-1.81 (m, 2H), 1.78- 1.61 (m, 4H), 1.58-1.50 (m, 2H), 1.48-1.45 (m, 1H), 1.42- 1.41 (m, 1H), 1.38-1.22 (m, 4H);
1H NMR 400 MHz; DMSO-d6): δ 8.62 (bs, 2H), 8.01 (d, J = 7.5 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.33-7.23 (m, 2H), 7.17-6.99 (m, 4H), 6.96-6.82 (m, 2H), 4.61 (t, J = 7.8 Hz, 1H), 4.02 (d, J = 7.1 Hz, 2H), 3.87-3.77 (m, 2H), 3.76-3.66 (m, 1H), 3.26-3.06 (m, 4H), 2.96-2.81 (m, 3H), 2.79-2.68 (m, 1H), 2.21 (s, 3H), 2.09-1.93 (m, 1H), 1.77-1.61 (m, 2H), 1.53-1.22 (m, 6H).
1H NMR 400 MHz; DMSO-d6): δ 8.49 (bs, 2H), 7.99 (d, J = 7.6 Hz, 1H), 7.51-7.39 (m, 2H), 7.35 (s, 1H), 7.21-7.00 (m, 4H), 6.95 (d, J = 7.6 Hz, 1H), 4.59 (t, J = 8.2 Hz, 1H), 4.03 (d, J = 7.3 Hz, 2H), 3.86-3.77 (m, 2H), 3.76-3.62 (m, 1H), 3.25-3.07 (m, 4H), 2.96-2.78 (m, 3H), 2.77-2.67 (m, 1H), 2.22 (s, 3H), 2.06-1.92 (m, 1H), 1.75-1.60 (m, 2H), 1.51-1.22 (m, 6H).
1H NMR (400 MHz, DMSO-d6): δ 8.41 (bs, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 4.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 4.0, 8.0 Hz, 1H), 7.16 (s, 1H), 4.02 (d, J = 8.0 Hz, 2H), 3.78-3.76 (m, 1H), 3.41-3.38 (m, 2H), 3.17- 3.14 (m, 3H), 2.93-2.83 (m, 3H), 2.38 (t, J = 8.0 Hz, 2H), 2.02-1.92 (m, 2H), 1.85-1.18 (m, 9H);
1H NMR (400 MHz, DMSO-d6): δ 8.48 (bs, 2H), 7.98 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.44 (d, J = 4.0 Hz, 1H), 7.36 (s, 1H), 7.18 (dd, J = 4.0, 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 4.59 (t, J = 8.0 Hz, 1H), 4.06 (d, J = 8.0 Hz, 2H), 3.72-3.69 (m, 1H), 3.16-3.09 (m, 2H), 2.88-2.74 (m, 4H), 2.22 (s, 3H), 1.98-1.90 (m, 3H), 1.77-1.67 (m, 4H), 1.55- 1.38 (m, 4H), 1.24-1.17 (m, 2H);
1H NMR (400 MHz, Methanol-d4): δ 7.37 (d, J = 8.0, 0.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.17-7.08 (m, 5H), 6.99 (d, J = 6.8 Hz, 1H), 6.90 (t, J = 7.6 Hz, 1H), 4.23 (t, J = 8.0 Hz, 1H), 4.16-4.09 (m, 2H), 3.96 (d, J = 7.2 Hz, 2H), 3.80 (t, J = 12.0 Hz, 1H), 3.70-3.61 (m, 1H), 3.40-3.35 (m, 1H), 3.20-3.10 (m, 4H), 3.07-2.97 (m, 2H), 2.60-2.56 (m, 1H), 2.44-2.41 (m, 1H), 2.27 (s, 3H), 1.87-1.82 (m, 1H), 1.71-1.58 (m, 5H), 1.26-1.20 (m, 3H), 1.04-0.98 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 9.27 (bs, 2H), 8.92 (bs, 2H), 7.53 (d, J = 1.6 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.36 (s, 1H), 7.17 (dd, J = 8.4, 2.0 Hz, 2H), 7.13-7.10 (m, 2H), 6.99 (d, J = 7.2 Hz, 1H), 4.22 (t, J = 8.0 Hz, 1H), 4.08 (t, J = 8.8 Hz, 1H), 4.01-3.94 (m, 3H), 3.77-3.71 (m, 1H), 3.22-3.11 (m, 3H), 3.0-2.89 (m, 3H), 2.85-2.77 (m, 2H), 2.45-2.41 (m, 1H), 2.24-2.20 (m, 1H), 2.21 (s, 3H), 1.73-1.71 (m, 1H), 1.72-1.60 (m, 3H), 1.46 (bs, 2H), 1.16-1.12 (m, 3H), 01.0-0.95 (m, 2H);
1H NMR (400 MHz, DMSO-d6): δ 9.20-8.56 (bs, 4H), 7.80 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.33 (s, 1H), 7.26 (dd, J = 6.8, 1.9 Hz, 1H), 4.06 (d, J = 6.8 Hz, 2H), 3.32-3.41 (m, 3H), 3.79-320 (m, 6H), 2.25-2.11-(m, 2H), 2.06-1.18 (m, 3H), 1.84-1.49 (m, 6H), 1.32-1.19 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 10.98 (bs, 1H), 8.91 (bs, 1H), 8.66 (bs, 1H), 7.60-7.51 (m, 2H), 7.43 (d, J = 8.6 Hz, 1H), 7.23-7.10 (m, 4H), 7.02-6.96 (d, J = 5.6 Hz, 1H), 4.28- 4.18 (m, 1H), 3.98 (d, J = 7.2 Hz, 2H), 3.59-3.45 (m, 1H), 3.41-3.28 (m, 2H), 3.17-2.81 (m, 4H), 2.69 (m, 3H), 2.47- 2.29 (m, 2H), 2.25 (m, 3H), 2.19-2.01 (m, 2H), 1.94-1.71 (m, 3H), 1.71-1.55 (m, 3H), 1.54-1.42 (m, 2H), 1.21-0.92 (m, 5H).
1H NMR (400 MHz, DMSO-d6): δ 9.08 (bs, 2H), 8.03 (bs, 3H), 7.43-7.34 (m, 3H), 7.20-7.10 (m, 3H), 7.09-7.03 (m, 1H), 6.99-6.94 (m, 1H), 6.90 (t, J = 7.2 Hz, 1H), 4.26 (t, J = 7.6 Hz, 1H), 3.98 (d, J = 6.9 Hz, 2H), 3.01-2.86 (m, 3H), 2.84-2.72 (m, 1H), 2.48-2.40 (m, 1H), 2.37-2.27 (m, 1H), 2.23 (s, 3H), 2.09-1.93 (m, 4H), 1.86-1.72 (m, 1H), 1.71- 1.55 (m, 3H), 1.54-1.29 (m, 6H), 1.21-1.06 (m, 3H), 1.05- 0.89 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 9.92-8.63 (m, 4H), 7.72- 7.38 (m, 3H), 7.35-6.83 (m, 5H), 4.44-4.21 (m, 1H), 4.19 (m, 2H), 3.93-3.71 (m, 2H), 3.26-3.12 (m, 6H), 3.03-2.70 (m, 4H), 2.40-1.62 (m, 9H), 1.50-1.03 (m, 4H).
1H NMR (400 MHz, DMSO-d6): δ 8.91 (bs, 4H), 7.74 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.25 (s, 1H), 7.23 (dd, J = 4.0, 8.0 Hz, 1H), 4.05 (d, J = 8.0 Hz, 2H), 3.01-2.85 (m, 5H), 2.74 (t, J = 8.0 Hz, 2H), 2.15-2.12 (m, 3H), 1.96-1.90 (m, 5H), 1.78-1.53 (m, 7H), 1.26-1.23 (m, 2H).
1H NMR (400 MHz, CDCl3): δ 7.52 (dd, J = 4.0, 8.0 Hz, 1H), 7.23-7.21 (m, 1H), 7.18-7.13 (m, 2H), 7.08 (s, 1H), 7.06-7.02 (m, 2H), 6.90 (d, J = 8.0 Hz, 1H), 5.56 (s, 1H), 5.19 (t, J = 8.0 Hz, 1H), 4.64-4.60 (m, 1H), 4.13-4.11 (m, 1H), 3.90-3.82 (m, 2H), 3.18-3.14 (m, 1H), 3.02-2.76 (m, 3H), 2.48-2.44 (m, 1H), 2.30 (s, 3H), 1.86-1.67 (m, 6H), 1.47-1.44 (m, 1H), 1.19-1.14 (m, 3H), 1.00-0.94 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 12.32 (bs, 1H), 8.39 (bs, 2H), 8.05-7.95 (m, 2H), 7.73-7.65 (m, 1H), 7.53-7.45 (m, 1H), 7.42-7.35 (m, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.09-7.02 (m, 2H), 6.95 (d, J = 7.6 Hz, 1H), 4.72-4.63 (m, 1H), 4.07- 3.93 (m, 2H), 3.77-3.65 (m, 1H), 3.23-3.05 (m, 2H), 2.97- 2.70 (m, 4H), 2.21 (s, 3H), 1.80-1.70 (m, 2H), 1.69-1.59 (m, 3H), 1.55-1.44 (m, 3H), 1.42-1.33 (m, 1H), 1.25-1.12 (m, 4H), 1.04-0.93 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 8.01 (d, J = 4.0 Hz, 1H), 7.73 (d, J = 4.0 Hz, 1H), 7.51 (dd, J = 4.0, 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.19 (dd, J = 4.0, 8.0 Hz, 1H), 7.16 (s, 1H), 6.37 (d, J = 8.0 Hz, 1H), 3.92 (d, J = 8.0 Hz, 2H), 2.96 (t, J = 8.0 Hz, 2H), 2.55 (t, J = 8.0 Hz, 2H), 1.69-1.68 (m, 1H), 1.58-1.56 (m, 3H), 1.45-1.42 (m, 2H), 1.06-1.04 (m, 3H), 0.94-0.89 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 7.92-7.73 (m, 4H), 7.46- 7.36 (m, 2H), 7.28-7.22 (m, 1H), 7.13-7.08 (m, 1H), 7.06- 6.98 (m, 3H), 6.91 (d, J = 6.9 Hz, 1H), 6.85 (t, J = 7.3 Hz, 1H), 4.64-4.60 (m, 1H), 4.33-4.23 (m, 1H), 2.92-2.83 (m, 2H), 2.68-2.57 (m, 3H), 2.20 (d, J = 10.7 Hz, 3H), 1.91-1.80 (m, 3H), 1.76-1.66 (m, 3H), 1.62-1.55 (m, 2H), 1.47 (t, J = 6.3 Hz, 3H), 1.34-1.21 (m, 3H), 1.16-1.02 (m, 6H), 0.87- 0.76 (m, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.9-1.05 (m, 2H), 1.05- 1.21 (m, 3H), 1.3-1.4 (m, 2H), 1.45-1.55 (m, 2H), 1.55-1.6 (m, 2H), 1.95-2.05 (m, 1H), 2.85-2.95 (m, 4H), 3.25 (d, J = 12.56 Hz, 2H), 4.02 (d, J = 7.09 Hz, 2H), 4.28 (s, 2H), 7.10 (t, J = 7.22 Hz, 1H), 7.19 (t, J = 7.65 Hz, 1H), 7.51 (d, J = 7.65 Hz, 1H), 7.6 (s, 1H), 7.78 (d, J = 7.89 Hz, 1H), 8.85(brs, 1H), 9.0(brs, 1H), 9.15 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 0.98-1.12 (m, 2H), 1.12- 1.23(m, 3H), 1.26-1.41(m, 3H) 1.50 (m, 2H) 1.60-1.75 (m, 3H), 1.75-1.90 (m, 2H), 2.02-2.15 (m, 2H), 2.68 (s, 3H), 2.82-2.88 (m, 3H), 2.88-3.22 (m, 1H), 3.23 (d, J = 11.29 Hz, 2H), 4.01-4.1(m, 2H), 4.41-4.49 (m, 2H), 7.11-7.22 (m, 2H), 7.55 (d, J = 8.15 Hz, 1H), 7.69(s, 1H), 7.80(d, J = 7.78 Hz, 1H), 8.82 (brs, 1H), 8.98 (brs, 1H), 10.27 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.98-1.03 (m, 2H), 1.12- 1.18(m, 5H), 1.20-1.47(m, 6H), 1.50 (d, , J = 10.63 Hz, 2H), 1.60-1.65 (m, 3H), 1.80-1.81 (m, 1H), 1.86-1.96 (m, 1H), 1.99-2.14 (m, 1H), 2.1-2.2 (m, 1H), 2.82-2.99 (m, 4H), 3.11-3.14 (m, 2H), 3.14-3.18(m, 2H), 3.18-3.29 (m, 2H), 4.05-4.06 (m, 2H), 4.50 (s 2H), 7.17(t, J = 7.64 Hz, 1H), 7.2(t, J = 7.78 Hz, 1H), 7.55(d, J = 8.20 Hz, 1H), 7.66 (s, 1H), 7.75(d, J = 7.90 Hz, 1H), 8.81 (brs, 1H), 9.02 (brs, 1H), 10.16 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.85-1.0 (m, 7H), 1.11- 1.20(m, 4H) 1.23(s, 2H) 1.46-1.49 (m, 3H) 1.58-1.63 (m, 4H), 1.63-1.74 (m, 4H), 2.20 (m, 4H), 2.32 (m, 3H), 2.43- 2.50 (m, 3H), 2.88 (brs, 2H), 3.64 (s, 2H), 3.95(d, J = 7.06 Hz, 2H), 6.96 (t, J = 7.55 Hz, 1H), 7.11 (t, J = 7.03 Hz, 1H), 7.18 (brs, 1H), 7.40(d, J = 8.18 Hz, 1H), 7.58 (d, J = 8.15 Hz, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.99-1.10 (m, 2H), 1.12- 1.35 (m, 4H), 1.35-1.44(m, 2H), 1.52 (d, J = 11.77 Hz, 2H), 1.59-1.75 (m, 3H), 1.77-1.89 (m, 1H), 1.92 (d, J = 13.97 Hz, 2H), 2.0-2.32 (m, 1H), 2.79-2.87 (m, 4H), 3.24-3.33 (m, 2H), 3.87 (s, 3H), 4.08(d, J = 7.07 Hz, 2H), 4.34 (brs, 2H), 7.64 (d, J = 8.73 Hz, 1H), 7.79 (s, 1H), 7.80(d, J = 1.20 Hz, 1H), 8.50 (s, 1H), 8.80 (brs, 1H), 8.81-9.11 (m, 3H).
1H NMR (400 MHz, DMSO-d6): δ 0.84-1.01 (m, 2H), 1.09- 1.23 (m, 4H), 1.35-1.44(m, 2H), 1.52 (d, J = 11.45 Hz, 2H), 1.53-1.69 (m, 3H), 1.70-1.83 (m, 2H), 1.92 (d, J = 12.63 Hz, 2H), 2.03 (brs, 1H), 2.79-2.87 (m, 4H), 3.24 (d, J = 12.09 Hz, 2H), 4.06 (d, J = 6.99 Hz, 2H), 4.32 (s, 2H), 7.59 (d, J = 8.73 Hz, 1H), 7.69 (s, 1H), 7.77 (d, J = 8.63 Hz, 1H), 8.45 (s, 1H), 8.97 (brs, 3H), 12.45 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.66-1.85 (m, 9H), 1.92 (brs, 1H), 2.05-2.12 (m, 2H), 2.24 (s, 5H), 2.33-2.40 (m, 1H), 2.75-2.81 (m, 2H), 2.92-2.94 (m, 2H), 3.13 (brs, 5H), 3.43 (d, 2H), 4.23 (t, J = 7.16 Hz, 1H), 4.65-4.67 (m, 1H), 6.95-6.99 (m, 2H), 7.10-7.19 (m, 4H), 7.33 (s, 1H), 7.45 (d, J = 7.91 Hz, 1H), 7.52 (d, J = 8.08 Hz, 1H), 7.95 (brs, 2H), 8.70 (brs, 2H), 8.80-8.98 (m, 3H).
1H NMR (400 MHz, DMSO-d6): δ 1.69-1.97 (m, 10H), 2.0- 2.05 (m, 2H), 2.24 (s, 3H), 2.32-2.35 (m, 2H), 2.56-2.58 (m, 1H), 3.15-3.24 (m, 3H), 3.57 (t, J = 11.18 Hz, 2H), 3.99-4.01 (m, 2H), 4.25 (t, J = 7.40 Hz, 1H), 4.60 (t, J = 10.82 Hz, 1H), 6.92 (t, J = 7.21 Hz, 1H), 6.96 (d, J = 5.96 Hz, 1H), 7.07 (t, J = 7.64 Hz, 1H), 7.14 (s, 3H), 7.39 (d, J = 7.98 Hz, 1H), 7.51 (d, J = 8.03 Hz, 1H), 7.59 (s, 1H), 8.02 (brs, 3H), 8.94 (brs, 1H), 8.99 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.20-1.32 (m, 1H), 1.52- 1.55 (m, 2H), 1.62-1.90 (m, 13H), 1.95-2.06 (m, 2H), 2.24 (s, 3H), 2.33-2.35 (m, 1H), 2.81(m, 1H), 2.91(m, 1H), 3.16(m, 1H), 3.23 (m, 1H), 4.22-4.32 (m, 2H), 6.90 (t, J = 7.26 Hz, 1H), 6.96 (d, J = 6.14 Hz, 1H), 7.05 (t, J = 7.45 Hz, 1H), 7.14-7.17 (m, 3H), 7.39 (d, J = 7.91 Hz, 1H), 7.45 (d, J = 8.27 Hz, 1H), 7.53 (s, 1H), 8.01 (brs, 3H), 8.93 (brs, 1H), 8.98 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.25 (m, 1H), 1.46- 1.55 (m, 2H), 1.70-1.83 (m, 8H), 1.94 (m, 2H), 2.095 (d, J = 12.72 Hz, 2H), 2.24 (s, 3H), 2.31-2.49(m, 1H), 2.65-2.89(m, 4H), 3.33(m, 1H), 4.23-4.32 (m, 2H), 6.90 (t, J = 7.28 Hz, 1H), 6.96 (d, J = 6.92 Hz, 1H), 7.06 (t, J = 7.49 Hz, 1H), 7.11-7.17 (m, 3H), 7.39 (d, J = 7.95 Hz, 1H), 7.45 (d, J = 8.30 Hz, 1H), 7.52 (s, 1H), 8.81 (brs, 1H), 8.94 (brs, 1H), 9.32 (brs, 1H). 9.34 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.32 (m, 2H), 1.48- 1.52 (m, 2H), 1.73-1.83 (m, 3H), 1.86-1.89 (m, 2H), 1.94- 1.97 (m, 2H), 2.24 (s, 3H), 2.72-2.82 (m, 1H), 2.85-2.86 (m, 2H), 2.95-3.01 (m, 2H), 4.21-4.32(m, 2H), 6.90 (t, J = 7.12 Hz, 1H), 6.97 (d, J = 7.38 Hz, 1H), 7.06 (t, J = 7.40 Hz, 1H), 7.13-7.17 (m, 3H), 7.38 (d, J = 8.02 Hz, 1H), 7.45 (d, J = 9.74 Hz, 2H), 7.86 (brs, 3H), 8.86 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 9.28 (brs, 1H), 9.17 (brs, 1H), 8.96 (brs, 2H), 8.30 (brs, 3H), 8.12 (brs, 1H), 7.66 (s, 1H), 7.51 (d, J = 8.47 Hz, 1H), 7.46 (s, 1H), 7.21 (d, J = 8.47 Hz, 1H), 7.18-7.14 (m, 3H), 6.97 (d, J = 5.88 Hz, 1H), 4.23- 4.19 (m, 1H), 4.10-4.01 (m, 4H), 3.79 (d, J = 10.73 Hz, 2H), 3.21-3.10 (m, 4H), 2.95-2.84 (m, 2H), 2.72-2.65 (m, 1H), 2.40-2.38 (m, 1H), 2.24 (s, 3H), 2.10-1.98 (m, 3H), 1.90-1.60 (m, 6H), 1.85-1.20 (m, 4H)
1H NMR (400 MHz, DMSO-d6): δ 8.97 (brs, 2H), 9.17 (brs, 1H), 8.01 (brs, 3H), 7.94 (s, 1H), 7.69 (d, J = 8.73 Hz, 1H), 7.65 (s, 1H), 7.44 (d, J = 8.54 Hz, 1H), 7.20-7.15 (m, 3H), 6.99 (d, J = 5.73 Hz, 1H), 4.36-4.33 (m, 1H), 4.15-4.10 (m, 2H), 3.80 (d, J = 10.23 Hz, 2H), 3.22-3.16 (m, 4H), 2.89 (brs 1H), 2.80 (brs, 1H), 2.36-2.34 (m, 1H), 2.24 (s, 3H), 2.10-1.9
(m, 1H), 1.90-1.60 (m, 8H), 1.41-1.20 (m, 4H).
1H NMR (400 MHz, DMSO-d6): δ 1.40-1.46 (m, 2H), 1.48- 1.52 (m, 2H), 1.62-1.84 (m, 10H), 2.11 (m, 1H), 2.24 (s, 3H), 2.31-2.34 (m, 1H), 2.73-2.82 (m, 3H), 2.93 (m, 1H), 3.14 (m, 1H), 3.23(d, J = 11.9 Hz, 3H), 4.08(d, J = 6.85 Hz, 2H), 4.25(t, 4H), 6.92 (t, J = 7.24 Hz, 1H), 6.96 (d, J = 7.30 Hz, 1H), 7.06-7.17 (m, J = 7.40 Hz, 4H), 7.38-7.45 (m, 3H), 8.05 (brs, 1H), 8.60 (brs, 1H), 8.79 (brs, 1H), 9.02 (brs, 1H), 9.11 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.40-1.43 (m, 2H), 1.62- 1.63 (m, 2H), 1.92-2.01 (m, 2H), 2.24 (s, 3H), 2.77-3.94 (m, 8H), 3.23 (d, J = 11.51 Hz, 2H), 4.08 (d, J = 6.41 Hz, 2H), 4.25 (t, J = 7.73 Hz, 1H), 6.92 (t, J = 7.34 Hz, 1H), 6.97 (d, J = 7.32 Hz, 1H), 7.06-7.18 (m, 4H), 7.38-7.45 (m, 3H), 7.99 (brs, 3H), 8.56 (brs, 1H), 8.77 (brs, 1H), 9.13 (brs, 1H), 9.14 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.40-1.43 (m, 2H), 1.64 (d, J = 13.71 Hz, 2H), 1.82-1.92 (m, 2H), 2.12 (d, J = 12.92 Hz, 3H), 2.24 (s, 3H), 2.31-2.34 (m, 1H), 2.80-2.89 (m, 7H), 3.23 (d, J = 11.20 Hz, 3H), 4.08 (d, J = 6.81 Hz, 1H), 4.27 (t, J = 7.84 Hz, 1H), 6.90-6.98 (m, 2H), 7.07-7.18 (m, 4H), 7.39-7.45 (m, 3H), 8.61 (brs, 1H), 8.81 (brs, 1H), 8.96 (brs, 1H), 9.02 (brs, 1H), 9.43 (brs, 1H), 9.46 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 9.44-9.32 (m, 2H), 8.91- 8.75 (m, 2H), 7.95 (s, 1H), 7.70 (d, J = 8.51 Hz, 1H), 7.62 (s, 1H), 7.45 (d, J = 8.50 Hz, 1H), 7.21-7.16 (m, 3H), 7.00 (d, J = 6.54 Hz, 1H), 4.36(t, J = 7.55 Hz, 1H), 4.11 (d, J = 4.76 Hz, 2H), 3.80 (d, J = 10.25 Hz, 2H), 3.33- 3.20 (m, 4H), 2.66-2.8
(m, 5H), 2.35-2.32 (m, 1H), 2.25 (s, 3H), 2.15-2.05 (m, 3H), 1.85-1.72 (m, 2H), 1.39-1.23 (m, 4H).
1H NMR (400 MHz, DMSO-d6): δ 1.79-1.85 (m, 2H), 2.10 (m, 4H), 2.24 (s, 3H), 2.29-2.40 (m, 3H), 2.55 (m, 1H), 2.72-2.89 (m, 4H), 3.11-3.13(m, 2H), 3.31-3.47 (m, 11H), 4.29 (t, J = 8.0 Hz, 1H), 4.68 (t, J = 11.80 Hz, 1H), 6.93- 6.98 (m, 2H), 7.09-7.19 (m, 4H), 7.35 (s, 1H), 7.45(d, J = 7.19 Hz, 1H), 7.54 (d, J = 8.28 Hz, 1H), 8.87-8.89 (m, 1H), 9.10 (brs, 1H), 9.49 (brs, 1H), 9.55(brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.37 (m, 5H), 1.87- 1.90 (m, 2H), 2.00-2.02 (m, 1H), 2.24 (s, 3H), 2.72-2.74 (m, 1H), 2.85-2.90 (m, 3H), 2.94-2.96 (m, 2H), 3.20 (t, J = 10.39 Hz, 2H), 3.81 (d, J = 11.28 Hz, 2H), 4.11(d, J = 6.92 Hz, 2H), 4.34 (t, J = 7.91 Hz, 1H), 7.0 (d, J = 6.8 Hz, 1H), 7.15-7.21 (m, 3H), 7.44 (d, J = 8.53 Hz, 1H), 7.58(s, 1H), 7.69 (d, J = 8.56 Hz, 1H), 7.90 (brs, 3H), 7.92 (s, 1H), 8.96 (brs, 1H), 8.99 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.96-1.12 (m, 5H), 1.50 (d, J = 11.11 Hz, 2H), 1.59-1.83 (m, 12H), 2.61-2.63 (m, 1H), 2.81-2.98 (m, 3H), 3.15-3.32 (m, 2H), 3.93-4.02 (m, 2H), 4.65 (t, J = 7.13 Hz, 1H), 6.94 (t, J = 7.62 Hz, 1H), 7.09 (t, J = 7.69 Hz, 1H), 7.45 (d, J = 8.17 Hz, 2H), 7.53 (s, 1H), 7.77 (m, 1H), 8.08 (brs, 3H), 8.27 (brs, 1H), 8.65 (d, J = 4.63 Hz, 1H), 8.87 (brs, 1H), 9.17 (brs, 1H), 9.25 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.96-1.12 (m, 5H), 1.50 (d, J = 12.17 Hz, 3H), 1.59-1.64 (m, 3H), 2.13 (d, J = 12.79 Hz, 2H), 2.52-2.59 (m, 1H), 2.71-2.89 (m, 3H), 2.90-2.99 (m, 2H), 3.35-3.49 (m, 3H), 3.97-3.98 (m, 2H), 4.65 (t, J = 7.13 Hz, 1H), 6.94 (t, J = 7.16 Hz, 1H), 7.10 (t, J = 7.18 Hz, 1H), 7.40-7.44 (m, 2H), 7.51 (s, 1H), 7.78 (s, 1H), 8.27 (s, 1H), 8.66 (d, J = 4.46 Hz, 1H), 8.87 (brs, 2H), 9.05 (brs, 1H), 9.55 (brs, 1H), 9.66 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.99-1.49 (m, 7H), 1.60- 1.80 (m, 6H), 1.97 (m, 2H), 2.89-2.95 (m, 6H), 3.98 (s, 2H), 4.78 (s, 1H), 6.93 (s, 1H), 7.09 (s, 1H), 7.42-7.51 (m, 3H), 7.82 (s, 1H), 8.10 (brs, 3H), 8.33 (bs, 1H), 8.68 (s, 1H), 8.90 (brs, 1H), 9.40 (brs, 1H), 9.50 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.91-1.94 (m, 2H), 2.10 (d, J = 10.37 Hz, 2H), 2.25-2.31 (m, 5H), 2.34-2.40 (m, 1H), 2.87-2.95 (m, 5H), 3.12 (s, 2H), 3.42 (d, J = 12.00 Hz, 2H), 4.27 (t, J = 7.40 Hz, 1H), 4.68 (t, J = 11.80 Hz, 1H), 6.93-6.98 (m, 2H), 7.09-7.19 (m, 4H), 7.34 (s, 1H), 7.44 (d, J = 7.97 Hz, 1H), 7.54 (d, J = 8.16 Hz, 1H), 8.02 (brs, 3H), 9.06 (brs, 1H), 9.17 (brs, 1H), 9.20 (brs, 1H), 9.26 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.94 (s, 1H), 1.23-1.26 (m, 1H), 1.40 (d, J = 7.69 Hz, 1H), 1.57-1.59 (m, 3H), 1.79-1.89 (m, 3H), 2.11-2.16 (m, 3H), 2.24(s, 3H), 2.35(d, J = 23.61 Hz, 1H), 4.29-4.31 (m, 1H), 4.88 (s, 1H), 6.90-6.97 (m, 2H), 7.07 (t, J = 7.79 Hz, 1H), 7.11-7.17 (m, 3H), 7.37- 7.40 (m, 1H), 7.44 (d, J = 8.23 Hz, 1H), 7.60-7.66 (m, 1H), 8.86 (brs, 1H), 9.23 (brs, 1H), 9.36 (brs, 1H), 9.40 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.92 (s, 1H), 1.22 (t, J = 10.85 Hz, 1H), 1.40 (d, J = 9.03 Hz, 1H), 1.55 (s, 3H), 1.65- 1.96 (m, 12H), 2.14 (t, J = 11.05 Hz, 1H), 2.65 (s, 1H), 2.78-2.95 (m, 4H), 3.16-3.22 (m, 2H), 4.71 (t, J = 8.09 Hz, 1H), 4.88 (d, J = 5.65 Hz, 1H), 6.96 (t, J = 7.54 Hz, 1H), 7.10 (t, J = 7.62 Hz, 1H), 7.42-7.48 (m, 2H), 7.83 (t, J = 7.12 Hz, 1H), 7.87 (s, 1H), 8.10 (brs, 3H), 8.37 (d, J = 7.41 Hz, 1H), 8.67(d, J = 5.07 Hz, 1H), 8.95 (s, 1H), 9.24 (brs, 1H), 9.44 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.92-0.97 (m, 1H), 1.23 (m, 1H), 1.40 (d J = 8.80 Hz, 1H), 1.53-1.57 (m 1H), 1.66- 1.68 (m, 2H), 1.85-1.95 (m, 3H), 2.15 (s, 1H), 2.38 (s, 1H), 2.57 (s, 1H), 2.72-2.74 (m, 1H), 2.87-3.05 (m, 4H), 3.26- 3.41 (m, 4H), 4.74 (t, J = 6.5 Hz, 1H), 4.88 (d, J = 11.51 Hz, 1H) 6.93 (t, J = 7.45 Hz, 1H), 7.11 (t, J = 7.56 Hz, 1H), 7.43-7.49 (m, 2H), 7.82-7.87 (m, 2H), 8.38 (d, J = 6.93 Hz, 1H), 8.86-8.90 (m, 1H), 8.96 (s, 1H), 9.08 (s, 1H), 9.08 (s, 1H), 9.61 (brs, 1H), 9.82 (brs, 1H).
1H NMR (400 MHz, DMSO-d6) δ 9.65 (brs, 1H), 9.55 (brs, 1H), 9.11 (brs, 1H), 8.89 (brs, 2H), 8.72-8.70 (m, 1H), 7.96 (s 1H), 7.70-7.69 (m, 2H), 7.47 (d, J = 8.34 Hz, 1H), 7.19-7.17 (m, 3H), 7.01-6.99 (m, 1H), 4.38 (t, J = 7.42 Hz, 1H), 4.16 (d, J = 6.49 Hz, 2H), 3.33-3.32 (m, 1H), 3.22 (d, J = 12.35 Hz
2H), 2.86-2.66 (m, 6H), 2.40- 2.32 (m, 1H), 2.26 (s, 3H), 2.15
2.11 (m, 3H), 1.84- 1.81(m, 2H), 1.64-1.62 (m, 2H), 1.46-1.38
(m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 9.33 (brs, 1H), 9.25 (brs, 1H), 8.86 (brs, 1H), 8.66 (brs, 1H), 8.03 (s, 3H), 7.94 (s, 1H), 7.69-7.65 (m, 2H), 7.46(d, J = 8.38 Hz, 1H), 7.21-7.16 (m, 3H), 7.0 (d, J = 6.33 Hz, 1H), 4.36 (t, J = 7.64 Hz, 1H), 4.15 (d, J = 6.8 Hz, 2H), 3.22 (d, J = 10.97 Hz, 2H), 2.95-2.76 (m, 9H), 2.36-2.34 (m, 1H), 2.25 (s, 3H), 2.13-2.11 (m, 1H), 1.91 1.95 (m, 2H), 1.64-1.59 (m, 2H), 1.46-1.40 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 0.94 (m, 1H), 1.40 (d, J = 9.68 Hz, 1H), 1.53 (s, 1H), 1.68 (d, J = 8.65 Hz, 2H), 1.92 (s, 3H), 2.14 (s, 1H), 2.38 (s, 1H), 2.57 (s, 1H), 2.66 (s, 1H), 2.87-2.96 (m, 7H), 4.65 (s, 1H), 4.87 (t, J = 5.11 Hz, 1H), 6.96 (t, J = 7.35 Hz, 1H), 7.10 (t, J = 7.48 Hz, 1H), 7.46 (t, J = 10.20 Hz, 2H), 7.72 (brs, 1H), 7.77 (brs, 1H), 7.98 (brs, 3H), 8.26 (brs, 1H), 8.60 (brs, 1H), 8.90 (brs, 1H), 9.26 (brs, 1H), 9.37 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.25-1.39 (m, 1H), 1.49- 1.52 (m, 2H), 1.74-1.86 (m, 7H), 1.95 (d, J = 10.62 Hz, 2H), 2.13 (d, J = 12.81 Hz, 2H), 2.65 (s, 1H), 2.83-2.86 (m, 5H), 3.32-3.37 (m, 5H), 4.31(t, J = 11.87 Hz, 1H), 4.65 (t, J = 7.12 Hz, 1H), 6.94 (t, J = 7.66 Hz, 1H), 7.09 (t, J = 7.82 Hz, 1H), 7.47 (dd, J1,2 = 8.0 Hz, J1,3 = 16.40 Hz, 2H), 7.69 (brs, 1H), 7.77 (brs, 1H), 8.27 (brs, 3H), 8.64 (d, J = 4.60 Hz, 2H), 8.82 (brs, 1H), 8.89 (brs, 1H), 8.97 (s, 1H), 9.51 (brs, 1H), 9.69 (1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.52 (m, 8H), 1.71- 1.74 (m, 3H), 1.85 (d, J = 13.89 Hz, 2H), 2.03 (s, 1H), 2.49-2.50 (m, 1H), 2.83-2.94 (m, 5H), 4.31 (t, J = 11.15 Hz, 1H), 4.31(t, J = 11.15 Hz, 1H), 4.34 (m, 1H), 6.94 (t, J = 7.43 Hz, 1H), 7.09 (t, J = 7.42 Hz, 1H), 7.46 (dd, J1,2 = 7.88 Hz, J1,3 = 18.29 Hz, 2H), 7.61-7.65 (m, 1H), 7.99 (brs, 1H), 8.58 (brs, 1H), 8.84 (s, 1H), 9.12 (brs, 1H), 9.27 (1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.31 (m, 2H), 1.48- 1.52 (m, 2H), 1.55-1.86 (m, 5H), 2.49-2.59 (m, 1H), 2.87- 2.96 (m, 7H), 4.31 (t, J = 10.54 Hz, 1H), 4.66 (s, 1H), 6.94 (t, J = 7.20 Hz, 1H), 7.09 (t, J = 8.03 Hz, 1H), 7.47 (dd, J1,2 = 7.78 Hz, J1,3 = 13. 0 Hz, 2H), 7.67 (s, 1H), 7.78 (brs, 1H), 8.01 (brs, 1H), 8.30 (brs, 1H), 8.65 (brs, 1H), 8.90 (brs, 1H), 9.27 (1H), 9.38 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 9.32 (brs, 1H), 9.15 (brs, 1H), 8.10 (s, 3H), 7.52 (s, 1H), 7.44 (s, 1H), 7.43 (d, J = 8.21 Hz, 1H), 7.38 (d, J = 7.82 Hz, 1H), 7.16-7.13 (m, 3H), 7.06 (t J = 7.59 Hz, 1H), 6.96-6.94 (m, 1H), 6.90 (t, J = 7.55 Hz, 1H
4.86-4.83 (m, 1H), 4.25 (t, J = 7.35 Hz, 1H), 3.0-2.91 (m, 3H), 2.81-2.73 (m, 1H), 2.60-2.55 (m, 1H), 2.35-2.30 (m, 1H
2.23 (s, 3H), 1.87-1.70 (m, 2H), 1.44-1.29 (m, 4H).
1H NMR (400 MHz, DMSO-d6): δ 9.57 (brs, 1H), 9.43 (brs, 1H), 9.04-9.10 (m, 1H), 8.90-8.82 (m, 1H), 7.52 (s, 1H), 7.43 (d, J = 8.28 Hz, 1H), 7.39 (d, J = 7.88 Hz, 1H), 7.17-7.12 (m, 3H), 7.06 (t, J = 7.57 Hz, 1H), 6.96-6.94 (m, 1H), 6.90 (t, J = 7.53 Hz, 1H), 4.85 (t, J = 7.05 Hz, 1H), 4.26 (t, J = 7.87 Hz, 1H), 3.42-3.30 (m, 3H), 2.89-2.80 (m, 4H), 2.59-2.53 (m, 1H 2.38-2.30 (m, 1H), 2.24 (s, 3H), 2.18-2.10 (m, 4H), 1.92-1.80
(m, 6H), 1.72-1.69 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 9.16 (brs, 1H), 8.10 (brs, 1H), 7.94 (s, 1H), 7.43 (d, J = 8.26 Hz, 1H), 7.37 (d, J = 7.92 Hz, 1H), 7.13-7.17 (m, 3H), 7.06 (t, J = 7.61 Hz, 1H), 6.95 (d J = 6.69 Hz, 1H), 6.90 (t, J = 7.44 Hz, 1H), 4.84 (t, J = 6.82 Hz, 1H), 4.24 (t, J = 7.55 Hz, 1H), 2.94 (t, J = 7.17 Hz, 2H), 2.87(t, J = 7.33 Hz, 2H), 2.79-2.72 (m, 1H), 2.38-2.32 (m, 1H), 2.24 (s, 3H), 2.19-2.10 (m, 2H), 1.98- 1.82 (m, 6H), 1.75
1.66 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.31 (m, 1H), 1.46- 1.52 (m, 2H), 1.70-1.85 (m, 7H), 1.96 (d, J = 11.08 Hz, 2H), 2.14 (d, J = 11.06 Hz, 2H), 2.65 (s, 1H), 3.32-3.37(m, 4H), 4.32 (t, J = 11.18 Hz, 1H), 4.76 (t, J = 6.37 Hz, 1H), 6.95 (t, J = 7.41 Hz, 1H), 7.10 (t, J = 7.78 Hz, 1H), 7.47 (dd, J1,2 = 7.78 Hz, J1,3 = 21.01 Hz, 2H), 7.78 (s, 1H), 7.94 (d, J = 4.67 Hz, 2H), 8.75 (d, J = 5.97 Hz, 2H), 8.82 (brs, 1H), 9.06 (brs, 1H), 9.66 (brs, 1H), 9.81 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.87-0.91 (m, 1H), 1.22- 1.25 (m, 1H), 1.32-1.55 (m, 6H), 1.65-1.74 (m, 2H), 1.98 (d, J = 11.59 Hz, 3H), 2.07-2.17 (m, 3H), 2.37 (s, 1H), 2.65 (s, 1H), 2.71-2.80 (m, 1H), 2.91 (brs, 4H), 4.84 (t, J = 6.69 Hz, 1H), 4.88-4.89 (m, 1H), 6.94-6.98 (m, 1H), 7.10 (t, J = 7.35 Hz, 1H), 7.40-7.49 (m, 2H), 7.94 (dd, J1,2 = 6.788 Hz, J1,3 = 14.01 Hz, 2H), 8.0 (d, J = 5.74 Hz, 1H), 8.12 (s, 3H), 8.75-8.78 (m, 2H), 9.45 (brs, 1H), 9.68 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.87-0.91 (m, 1H), 1.22 (t, J = 10.76 Hz, 1H), 1.40 (d, J = 9.18 Hz, 1H), 1.55 (brs, 1H), 1.66 (d, J = 9.70 Hz, 1H), 1.70-1.75 (m, 1H), 1.84-2.01 (m, 4H), 2.14 (brs, 3H), 2.37 (s, 1H), 2.48-2.57(m, 2H), 2.74-2.94 (m, 6H), 3.31-3.37 (m, 4H), 4.79-4.90 (m, 2H), 6.97 (t, J = 7.45 Hz, 1H), 7.11 (t, J = 7.32 Hz, 1H), 7.41- 7.49 (m, 2H), 7.91 (s, 1H), 7.95 (d, J = 5.74 Hz, 5.75, 1H), 8.0 (d, J = 6.31 Hz, 1H), 8.76-8.85 (m, 2H), 8.87 (brs, 1H), 9.12 (brs, 1H), 9.73 (brs, 1H), 9.91 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.91 (brs, 1H), 1.22 (m, 1H), 1.40 (d, J = 9.30 Hz, 1H), 1.57 (brs, 1H), 1.66 (d, J = 9.54 Hz, 2H), 1.94-1.96 (m, 2H), 2.14 (t, J = 11.25 Hz, 1H), 2.37 (s, 1H), 2.55-2.59 (m, 1H), 2.70-2.74 (m, 1H), 2.88-2.98 (m, 7H), 4.75-4.81 (m, 1H), 4.88-4.89 (m, 1H), 6.97 (t, J = 7.64 Hz, 1H), 7.10 (t, J = 7.37 Hz, 1H), 7.42- 7.49 (m, 2H), 7.87 (d, J = 8.37 Hz, 1H), 7.92 (d, J = 5.58 Hz, 1H), 7.97 (d, J = 5.76 Hz, 1H), 8.04 (brs, 1H), 8.75 (t, J = 6.19 Hz, 2H), 9.41 (brs, 1H), 9.55 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.23-1.26 (m, 1H), 1.49- 1.52 (m, 2H), 1.70-1.87 (m, 5H), 1.94-1.97 (m, 4H), 2.54- 2.62 (m, 1H), 2.88-2.98 (m, 7H), 4.29-4.35 (m, 1H), 4.74- 4.76 (m, 1H), 6.95 (t, J = 7.28 Hz, 1H), 7.10 (t, J = 7.43 Hz, 1H), 7.44 (d, J = 7.97 Hz, 1H), 7.50 (d, J = 8.38 Hz, 1H), 7.73 (s, 1H), 7.94 (brs, 2H), 8.03 (brs, 3H), 8.75 (d, J = 5.24 Hz, 1H), 9.38 (brs, 1H), 9.47 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.38 (m, 3H), 1.46- 1.52 (m, 4H), 1.55-1.84 (m, 5H), 1.86-1.97 (m, 4H), 2.06 (s, 1H), 2.45 (m, 1H), 2.60-2.64 (m, 1H), 2.91 (brs, 4H), 4.32 (t, J = 11.27 Hz, 1H), 4.75-4.77 (m, 1H), 6.95 (t, J = 7.40 Hz, 1H), 7.10 (t, J = 7.63 Hz, 1H), 7.44 (d, J = 7.95 Hz, 1H), 7.50 (d, J = 8.36 Hz, 1H), 7.76 (s, 1H), 7.97 (brs, 2H), 8.09 (brs, 3H), 8.76 (d, J = 5.74 Hz, 1H), 9.38 (brs, 1H), 9.53 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.91-0.96 (m, 1H), 1.22- 1.32 (m, 2H), 1.39 (d, J = 9.30 Hz, 1H), 1.56-1.58 (m, 1H), 1.66 (d, J = 9.01 Hz, 2H), 1.85-1.97 (m, 3H), 2.12-2.18 (m, 1H), 2.23 (s, 3H), 2.43-2.49 (m, 2H), 2.60-2.65 (m, 2H), 2.87-2.95 (m, 7H), 4.28 (t, J = 7.79 Hz, 1H), 4.84-4.89 (m, 1H), 6.91 (t, J = 7.49 Hz, 1H), 6.96 (d, J = 6.89 Hz, 1H), 7.06 (t, J = 7.81 Hz, 1H), 7.12-7.14 (m, 3H), 7.37 (d, J = 7.96 Hz, 1H), 7.43 (d, J = 8.28 Hz, 1H), 7.61 (s, 1H), 8.02 (brs, 3H), 9.19-9.36 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 9.19 (brs, 1H), 8.0 (brs, 1H), 7.45-7.42 (m, 2H), 7.30 (d, J = 7.89 Hz, 1H), 7.19 (d, J = 7.29 Hz, 1H), 7.14 (d, J = 6.95 Hz, 1H), 7.11-7.04 (m, 3H), 6.89 (t, J = 7.43 Hz, 1H), 4.84 (t, J = 6.59 Hz, 1H), 4.44 (t, J =
7.41 Hz, 1H), 2.99-2.82 (m, 6H), 2.40 (s, 3H), 2.25-2.30 (s, 1H), 2.19-2.10 (m, 2H), 1.96-1.80 (m, 6H), 1.72-1.63 (m, 2H)
1.22 (s, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.25-1.32 (m, 1H), 1.45- 1.56 (m, 2H), 1.69-1.89 (m, 5H), 1.91-1.97 (m, 3H), 2.31- 2.37 (m, 1H), 2.76 (brs, 1H), 2.85-2.96 (m, 5H), 4.26-4.32 (m, 2H), 6.89 (t, J = 7.35 Hz, 1H), 7.05 (d, J = 7.30 Hz, 1H), 7.14 (t, J = 7.23 Hz, 1H), 7.26 (t, J = 7.43 Hz, 2H), 7.32-7.38 (m, 2H), 7.45 (d, J = 8.31 Hz, 1H), 7.53 (s, 1H), 8.03 (brs, 3H), 9.21 (brs, 1H), 9.27 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.25-1.32 (m, 1H), 1.46- 1.54 (m, 2H), 1.70-1.89 (m, 5H), 1.91-1.96 (m, 4H), 2.31- 2.40 (m, 1H), 2.76 (brs, 1H), 2.87-2.95 (m, 5H), 4.27-4.36 (m, 1H), 4.38 (t, J = 7.57 Hz, 1H), 6.93 (t, J = 7.57 Hz, 1H), 6.96-7.00 (m, 1H), 7.06 (t, J = 7.11 Hz, 1H), 7.14-7.20 (m, 2H), 7.28-7.34 (m, 1H), 7.39 (d, J = 7.90 Hz, 1H), 7.46 (d, J = 8.33 Hz, 1H), 7.57 (s, 1H), 8.01 (brs, 3H), 9.17 (brs, 1H), 9.26 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.31 (m, 1H), 1.44- 1.54 (m, 2H), 1.69-1.77 (m, 3H), 1.83 (d, J = 12.2 Hz, 2H), 1.92 (m, 4H), 2.24-2.31 (m, 1H), 2.40 (s, 3H), 2.85-2.95 (m, 6H), 4.29 (t, J = 11.59 Hz, 1H), 4.44 (t, J = 7.07 Hz, 1H), 6.89 (t, J = 7.38 Hz, 1H), 7.04-7.11 (m, 3H), 7.14 (d, J = 7.17 Hz, 2H), 7.19 (d, J = 7.37 Hz, 1H), 7.30 (d, J = 7.86 Hz, 1H), 7.44-7.46 (m, 2H), 7.99 (brs, 3H), 9.17 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 0.96-0.98 (m, 2H), 1.12- 1.24 (m, 3H), 1.26-1.29 (m, 1H), 1.49 (brs, 2H), 1.59-1.64 (m, 3H), 1.74 (brs, 2H), 1.93 (brs, 2H), 2.22 (s, 3H), 2.70- 2.74 (m, 2H), 2.87-3.09 (m, 7H), 3.58 (s, 1H), 3.97 (d, J = 5.06 Hz, 2H), 4.25 (t, J = 6.95 Hz, 1H), 6.89 (t, J = 7.32 Hz, 1H), 6.96 (d, J = 5.52 Hz, 1H), 7.0 (t, J = 7.71 Hz, 1H), 7.11-7.15 (m, 3H), 7.36-7.45 (m, 3H), 8.02 (brs, 3H), 9.23 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.32 (m, 1H), 1.45- 1.51 (m, 2H), 1.54-1.86 (m, 5H), 1.95 (d, J = 7.45 Hz, 2H), 2.24 (s, 3H), 2.31 (s, 1H), 2.37-2.43 (m, 1H), 2.85-2.87 (m, 1H), 2.94 (brs, 1H), 3.14 (s, 4H), 4.25-4.32 (m, 2H), 6.90 (t, J = 7.44 Hz, 1H), 6.97 (d, J = 6.47 Hz, 1H), 7.07 (t, J = 7.89 Hz, 1H), 7.14-7.17 (m, 3H), 7.39 (d, J = 7.86 Hz, 1H), 7.45 (d, J = 8.02 Hz, 1H), 7.51 (s, 1H), 8.19 (brs, 3H), 9.36 (brs, 1H), 9.44 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.32 (m, 1H), 1.45- 1.55 (m, 2H), 1.70-1.82 (m, 3H), 1.86 (d, J = 14.80 Hz, 2H), 1.86-1.96 (m, 4H), 2.35-2.37 (m, 1H), 2.52-2.57 (m, 1H), 2.78 (brs, 1H), 2.86-2.88 (m, 3H), 2.94 (t, J = 6.65 Hz, 1H), 4.27-4.33 (m, 1H), 4.43 (t, J = 7.75 Hz, 1H), 6.92 (t, J = 7.47 Hz, 1H), 7.07 (t, J = 7.78 Hz, 1H), 7.15 (d, J = 7.56 Hz, 1H), 7.33 (s, 1H), 7.36-7.43 (m, 3H), 7.47 (d, J = 8.34 Hz, 1H), 7.59 (s, 1H), 7.98 (brs, 3H), 9.11 (brs, 1H), 9.20 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.32 (m, 1H), 1.49- 1.52 (m, 2H), 1.70-1.84 (m, 6H), 1.93-1.95 (m, 4H), 2.34- 2.37 (m, 1H), 2.77 (brs, 1H), 2.87 (brs, 3H), 2.96 (brs, 2H), 4.27-4.33 (m, 1H), 4.42-4.43 (m, 1H), 6.94 (t, J = 6.26 Hz, 1H), 7.04 (t, J = 7.74 Hz, 1H), 7.40 (s, 4H), 7.48 (d, J = 8.32 Hz, 1H), 7.99 (brs, 3H), 9.14 (brs, 1H), 9.26 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.32 (m, 1H), 1.45- 1.58 (m, 6H), 1.70-1.79 (m, 3H), 1.84 (d, J = 12.33 Hz, 2H), 1.95 (d, J = 10.46 Hz, 2H), 2.24 (s, 3H), 2.28-2.33 (m, 1H), 2.76-2.78 (m, 3H), 2.87 (brs, 3H), 4.22 (t, J = 7.63 Hz, 1H), 4.26-4.32 (m, 1H), 6.90 (t, J = 7.28 Hz, 1H), 6.96 (d, J = 6.70 Hz, 1H), 7.05 (d, J = 7.61 Hz, 1H), 7.11-7.17 (m, 3H), 7.38 (d, J = 7.89 Hz, 1H), 7.45 (d, J = 8.23 Hz, 1H), 7.78 (s, 1H), 7.85 (brs, 3H), 8.86 (brs, 1H), 8.91 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 9.06-9.15 (m, 2H), 7.95 (s 3H), 7.70 (s, 1H), 7.65-7.62 (m, 2H), 7.53-7.51 (m, 2H), 7.47
(d, J = 8.26 Hz, 1H), 7.38 (d, J = 7.88 Hz, 1H), 7.08 (t, J = 7.51 Hz, 1H), 6.92 (t, J = 7.44 Hz, 1H), 4.50 (t, J = 7.52 Hz, 1H), 4.31 (t, J = 11.33 Hz, 1H), 3.0- 2.92 (m, 2H), 2.90-2.85 (m, 3H), 2.82-2.73 (m, 1H), 2.60-2.55 (m, 1H), 2.40-2.35 (m,
1H), 2.0-1.70 (m, 9H), 1.56-1.46 (m, 2H), 1.33-1.29 (m, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.32 (m, 1H), 1.48- 1.51 (m, 2H), 1.74-1.80 (brs, 3H), 1.85 (d, J = 12.15 Hz, 2H), 1.95 (d, J = 11.70 Hz, 2H), 2.21 (s, 1H), 2.24 (s, 3H), 2.53-2.56 (m, 2H), 2.72-2.77 (m, 1H), 4.21 (t, J = 7.70 Hz, 1H), 4.29 (t, J = 10.90 Hz, 1H), 6.90 (t, J = 7.14 Hz, 1H), 6.96 (d, J = 6.81 Hz, 1H), 7.06 (t, J = 7.17 Hz, 1H), 7.10- 7.18 (m, 3H), 7.68 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 1.07 (t, J = 6.96 Hz, 1H), 1.22-132 (m, 1H), 1.45-1.58 (m, 4H), 1.70-1.86 (m, 5H), 1.94-2.03 (m, 4H), 2.24 (s, 3H), 2.31-2.35 (m, 1H), 2.80 (brs, 1H), 2.90 (brs, 1H), 2.98 (t, J = 12.69 Hz, 2H), 3.36 (brs, 1H), 3.91 (d, J = 12.87 Hz, 1H), 4.26-4.28 (m, 2H), 6.90 (t, J = 7.26 Hz, 1H), 6.94 (d, J = 17.87 Hz, 1H), 7.05 (t, J = 7.33 Hz, 1H), 7.13 (s, 3H), 7.39 (d, J = 7.76 Hz, 1H), 7.44 (d, J = 8.28 Hz, 1H), 7.52-7.55 (m, 5H), 9.41 (brs, 1H), 9.53 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.81-0.85 (m, 1H), 1.22- 1.34 (m, 4H), 1.47-1.50 (m, 4H), 1.61-1.64 (m, 1H), 1.69- 1.77 (m, 3H), 1.86 (s, 4H), 1.93-1.94 (m, 5H), 2.04 (s, 2H), 2.21 (s, 1H), 2.23 (s, 3H), 2.39 (s, 1H), 2.94-3.02 (m, 2H), 3.06-3.17 (m, 1H), 3.76 (t, J = 11.71 Hz, 1H), 4.06-4.10 (m, 1H), 4.23-4.32 (m, 2H), 4.40 (d, J = 13.32 Hz, 1H), 6.85- 6.94 (m, 2H), 7.00-7.06 (m, 1H), 7.10-7.14 (m, 2H), 7.17 (d, J = 6.62 Hz, 1H), 7.39 (d, J = 7.86 Hz, 1H), 7.40-7.43 (m, 2H), 7.54 (d, J = 2.83 Hz, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.28 (m, 2H), 1.44- 1.54 (m, 2H), 1.69-1.94 (m, 5H), 1.91-1.94 (m, 4H), 2.24 (s, 3H), 2.74 (br s, 1H), 2.86-2.94 (m, 5H), 4.24-4.30 (m, 2H), 6.98 (d, J = 7.23 Hz, 1H), 7.12-7.16 (m, 4H), 7.47 (d, J = 8.79 Hz, 1H), 7.52 (s, 1H), 7.61 (s, 1H), 8.02 (brs, 3H), 9.18 (brs, 1H), 9.24 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.21-1.33 (m, 1H), 1.49- 1.52 (m, 2H), 1.70-1.90 (m, 6H), 1.92-1.94 (m, 4H), 2.34- 2.35 (m, 1H), 2.65-2.77 (m, 1H), 2.88-2.96 (m, 5H), 4.27- 4.33 (m, 1H), 4.37 (t, J = 7.55 Hz, 1H), 6.92 (t, J = 7.35 Hz, 1H), 7.07 (t, J = 7.41 Hz, 1H), 7.20-7.23 (m, 1H), 7.28- 7.32 (m, 2H), 7.38 (d, J = 7.42 Hz, 2H), 7.46 (d, J = 8.28 Hz, 1H), 7.58 (s, 1H), 7.97 (br s, 3H), 9.10 (br s, 1H), 9.19 (br s, 1H).
1H NMR (400 MHz, DMSO-d6) δ 9.25-9.07 (m, 2H), 8.25- 8.04 (m, 3H), 7.74 (s, 1H), 7.60 (s, 1H), 7.30 (d, J = 8.29 Hz, 1H), 7.16-7.04 (m, 3H), 7.03 (d, J = 8.27 Hz, 1H), 6.96 (d, J = 6.7 Hz, 1H), 4.39-4.32(m,, 1H), 4.24 (t, J = 6.95 Hz, 1H), 2.9
-2.85 (m, 5H), 2.84-2.74 (m, 1H), 2.38-2.30 (m, 1H), 2.23(s, 3H), 2.0-1.9 (m, 4H), 1.80-1.62 (m, 5H), 1.55-1.43 (m, 2H), 1.33-1.20 (m, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.34 (m, 3H), 1.42- 1.52 (m, 4H), 1.70-1.86 (m, 4H), 1.81-1.83 (m, 2H), 1.91- 1.93 (m, 2H), 2.22 (brs, 1H), 2.31 (s, 4H), 3.08 (s, 1H), 4.16 (t, J = 7.39 Hz, 1H), 4.27 (t, J = 11.80 Hz, 1H), 6.86 (d, J = 7.07 Hz, 1H), 6.88-6.91 (m, 1H), 7.02 (t, J = 7.97 Hz, 1H), 7.09 (brs, 3H), 7.34-7.42 (m, 3H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.28 (m, 2H), 1.43- 1.53 (m, 2H), 1.65-1.71 (m, 3H), 1.83 (d, J = 13.33 Hz, 2H), 1.90-1.97 (m, 6H), 2.73 (t, J = 7.48 Hz, 2H), 2.88-2.96 (m, 6H), 4.25-4.31 (m, 1H), 7.21 (dd, J1,2 = 1.80 Hz, J1,3 = 8.80 Hz, 1H), 7.48 (d, J = 8.86 Hz, 1H), 7.72 (d, J = 1.71 Hz, 1H), 7.93 (brs, 3H), 8.82 (brs, 1H), 8.84 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.30 (m, 2H), 1.49- 1.55 (m, 2H), 1.71-1.78 (m, 3H), 1.85 (d, J = 13.29 Hz, 2H), 1.94-2.02 (m, 6H), 2.38 (s, 4H), 2.81 (t, J = 7.48 Hz, 2H), 2.89-2.95 (m, 7H), 4.30 (t, J = 11.52 Hz, 1H), 7.10 (d, J = 7.21 Hz, 1H), 7.30 (d, J = 7.70 Hz, 1H), 7.34 (s, 1H), 7.39 (d, J = 8.49 Hz, 1H), 7.45 (d, J = 7.62 Hz, 1H), 7.49 (s, 1H), 7.54 (d, J = 8.42 Hz, 1H), 7.73 (s, 1H), 7.97 (brs, 3H), 8.93 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 1.00-1.10 (m, 2H), 1.22- 1.32 (m, 4H), 1.44-1.54 (m, 2H), 1.70-1.89 (m, 10H), 1.94 (d, J = 11.64 Hz, 2H), 2.24 (s, 4H), 2.37-2.38 (m, 1H), 2.71 (t, J = 11.52 Hz, 1H), 2.90-2.65 (m, 2H), 3.15-3.20 (m, 1H), 4.17 (t, J = 7.82 Hz, 1H), 4.28 (t, J = 11.46 Hz, 1H), 5.29 (s, 1H), 5.75 (d, (t, J = 4.52 Hz, 1H), 6.90 (t, J = 7.41 Hz, 1H), 6.93-6.95 (m, 1H), 7.05 (t, J = 7.75 Hz, 1H), 7.13 (d, J = 5.57 Hz, 3H), 7.41 (dd, J1,2 = 7.04 Hz, J1,3 = 14.93 Hz, 2H), 7.48 (s, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.27 (m, 2H), 1.44- 1.54 (m, 2H), 1.73-1.95 (m, 11H), 2.25 (s, 4H), 2.76-2.89 (m, 9H), 4.28 (brs, 1H), 7.06-7.52 (m, 8H), 8.05 (s, 3H), 9.02 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.32 (m, 1H), 1.48- 1.51 (m, 2H), 1.70-1.87 (m, 5H), 1.94-1.96 (m, 6H), 2.24 (s, 3H), 2.63-2.65 (m, 1H), 2.88 (brs, 5H), 3.19 (m, 1H), 3.22 (brs, 5H), 4.18-4.20 (m, 1H), 4.21-4.30 (m, 1H), 6.91 (t, J = 7.48 Hz, 1H), 6.96 (d, J = 5.60 Hz, 1H), 7.07 (t, J = 7.55 Hz, 1H), 7.15-7.17 (m, 3H), 7.44 (dd, J = 6.80 Hz, 2H), 7.68 (s, 1H), 8.08 (brs, 6H), 11.19 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.31 (m, 2H), 1.44- 1.53 (m, 2H), 1.59-1.62 (m, 2H), 1.73-1.77 (m, 3H), 1.84 (d, J = 12.82 Hz, 1H), 1.94 (d, J = 11.13 Hz, 1H), 2.17 (s, 7H), 2.28 (s, 3H), 2.31-2.33 (m, 4H), 3.16-3.25 (m, 4H), 4.20 (t, J = 7.41 Hz, 1H), 4.27 (t, , J = 11.55 Hz, 1H), 6.87 (t, J = 7.46 Hz, 1H), 6.91 (d, J = 6.48 Hz, 2H), 7.03 (t, J = 7.35 Hz, 1H), 7.10-7.13 (m, 3H), 7.34 (d, J = 7.79 Hz, 1H), 7.42 (s, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.31 (m, 2H), 1.44- 1.50 (m, 4H), 1.69-1.85 (m, 3H), 1.84 (d, J = 12.31 Hz, 2H), 1.93 (d, J = 10.88 Hz, 2H), 2.06-2.08 (m, 2H), 2.22 (s, 4H), 2.41-2.43 (m, 4H), 2.76 (t, J = 6.67 Hz, 2H), 4.14 (t, J = 7.24 Hz, 1H), 4.26 (t, J = 11.18 Hz, 1H), 6.86 (d, J = 7.23 Hz, 1H), 6.90 (t, J = 5.05 Hz, 1H), 7.07 (t, J = 7.54 Hz, 1H), 7.01-7.10 (m, 4H), 7.33-7.42 (m, 5H), 7.81 (t, J = 5.32 Hz, 1H).
1H NMR (400 MHz, DMSO-d6): δ 7.43-7.34 (m, 3H), 7.15- 7.09 (m, 3H), 7.03 (t, J = 7.41 Hz, 1H), 6.96-6.85 (m, 2H), 4.32-4.25 (m, 1H), 4.17 (t, J = 7.21 Hz, 1H), 2.40-2.32 (m, 6H), 2.22 (s, 4H), 2.10-2.05 (m, 1H), 1.98-1.91 (m, 2H), 1.89- 1.80 (m, 2H), 1.78-1.70 (m, 3H), 1.63 (s, 4H), 1.54-1.45 (m, 4H), 1.36-1.20 (m, 3H).
1H NMR (400 MHz, DMSO-d6): δ 1.10-1.28 (m, 3H), 1.44- 1.51 (m, 4H), 1.62-1.68 (m, 6H), 1.81 (d, J = 11.59 Hz, 2H), 1.90 (d, J = 10.36 Hz, 2H), 2.09 (brs, 1H), 2.19 (s, 4H), 2.32-2.36 (m, 2H), 4.10-4.12 (m, 1H), 4.22 (brs, 1H), 6.84- 6.91 (m, 2H), 7.00-7.09 (m, 3H), 7.32-7.39 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.32 (m, 2H), 1.46- 1.55 (m, 2H), 1.70-1.86 (m, 6H), 1.95 (d, J = 6.68 Hz, 5H), 2.24 (s, 4H), 2.31 (s, 1H), 2.72 (t, J = 3.38 Hz, 2H), 2.95 (d, J = 6.07 Hz, 6H), 4.22-4.32 (m, 2H), 6.90 (t, J = 7.33 Hz, 1H), 6.96 (d, J = 6.64 Hz, 1H), 7.05 (t, J = 7.79 Hz, 1H), 7.11-7.17 (m, 3H), 7.38 (d, J = 7.71 Hz, 1H),), 7.45 (d, J = 8.29 Hz, 1H), 7.49 (s, 1H), 8.78 (brs, 2H), 9.05 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.32 (m, 2H), 1.46- 1.55 (m, 2H), 1.73-1.81 (m, 3H), 1.83 (d, J = 13.85 Hz, 3H), 1.93 (s, 6H), 2.58 (s, 1H), 2.66 (s, 1H), 2.88 (s, 2H), 2.96 (brs, 4H), 4.30 (t, J = 11.39 Hz, 1H), 2.52 (s, 1H), 6.90 (t, J = 7.41 Hz, 1H), 7.07 (t, J = 7.49 Hz, 1H), 7.38 (t, J = 8.05 Hz, 1H), 7.49 (t, J = 8.25 Hz, 1H), 7.65 (s, 1H), 7.84-8.00 (m, 5H), 8.33 (brs, 1H), 8.50 (s, 1H), 8.56 (brs, 1H), 9.15 (brs, 1H), 9.47 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.28 (m, 2H), 1.46- 1.56 (m, 2H), 1.69-1.78 (m, 3H), 1.85 (d, J = 18.50 Hz, 3H), 1.90-1.96 (m, 4H), 2.00-2.07 (m, 2H), 2.81-2.97 (m, 8H), 4.30-4.35 (m, 1H), 7.28 (d, J = 8.09 Hz, 1H), 7.38 (s, 1H), 7.45 (dd, J1,2 = 1.40 Hz, J1,3 = 8.68 Hz,), 7.54-7.59 (m, 2H), 7.62 (s, 1H), 7.74 (d, J = 7.83 Hz, 1H), 7.87 (d, J = 1.19 Hz, 1H), 8.01 (brs, 3H), 9.00 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 0.85-0.88 (m, 2H), 0.98- 1.44 (m, 4H), 1.47-1.65 (m, 7H), 1.68-1.74 (m, 4H), 1.81- 1.85 (m, 4H), 1.94 (s, 2H), 2.08 (s, 2H), 2.49-2.84 (m, 7H), 4.24-4.27 (m, 1H), 6.96 (t, J = 7.57 Hz, 1H), 7.07 (t, J = 7.38 Hz, 1H), 7.28 (s, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 7.91 Hz, 1H), 7.95 (br s, 3H), 8.92 (br s, 2H).
1H NMR (400 MHz, DMSO-d6): δ 9.38-9.30 (m, 2H), 8.00- 7.70 (m, 5H), 7.71 (d, J = 8.61 Hz, 1H), 7.44-7.42 (m, 4H), 7.18 (brs, 1H), 4.55 (t, J = 7.40 Hz, 1H), 4.42-4.39 (m, 1H), 3.10-2.77 (m, 6H), 2.60-2.55 (m, 1H), 2.43-2.38 (m, 1H), 1.95-1.93 (m, 4H), 1.86-1.81 (m, 4H), 1.77-1.73 (m, 1H), 1.59-1.42 (m, 2H), 1.35-1.20 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 1.08 (t, J = 7.02 Hz, 1H), 1.22-1.32 (m, 3H), 1.43-1.52 (m, 3H), 1.70-1.79 (m, 3H), 1.85 (d, J = 11.70 Hz, 2H), 1.90-1.97 (m, 7H), 2.80 (brs, 1H), 2.91-3.02 (m, 2H), 3.26 (brs, 2H), 3.31(s, 1H), 3.85 (d, J = 13.06 Hz, 1H), 4.22-4.32 (m, 2H), ), 4.38 (d, J = 12.34 Hz, 1H), 6.90 (t, J = 7.47 Hz, 1H), 6.96 (d, J = 6.53 Hz, 1H), 7.06 (t, J = 7.38 Hz, 1H), 7.14-7.17 (m, 3H), 7.39 (d- J = 7.81 Hz, 1H), 7.45 (d, J = 8.23 Hz, 1H), 7.50 (s, 1H), 8.97 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.32 (m, 3H), 1.45- 1.55 (m, 2H), 1.70-1.76 (m, 3H), 1.85 (d, J = 11.84 Hz, 4H), 1.90-1.97 (m, 2H), 2.24 (s, 4H), 2.59 (s, 1H), 2.80 (brs, 1H), 2.92 (brs, 1H), 3.21 (brs, 1H), 3.94 (d, J = 12.95 Hz, 2H), 4.22-4.32 (m, 2H), 6.91 (t, J = 7.40 Hz, 1H), 6.96 (d, J = 6.87 Hz, 1H), 7.06 (t, J = 7.77 Hz, 1H), 7.11-7.18 (m, 3H), 7.39 (d, , J = 7.84 Hz, 1H), 7.45 (d, J = 6.09 Hz, 1H), 8.68 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 0.96-1.1 (m, 2H), 1.12- 1.22 (m, 3H), 1.50 (t, J = 11.26 Hz, 2H), 1.59-1.64 (m, 3H), 1.70-1.77 (m, 1H), 1.94 (t, J = 6.82 Hz, 2H), 2.01 (t, J = 7.69 Hz, 1H), 2.37 (s, 3H), 2.79 (t, J = 7.33 Hz, 2H), 2.89- 2.95 (m, 6H), 3.96 (d, J = 6.94 Hz, 2H), 7.10 (d, J = 7.39 Hz, 1H), 7.14 (s, 1H), 7.31 (t, J = 7.55 Hz, 1H), 7.39 (d, J = 8.07 Hz, 1H), 7.44-7.49 (m, 3H), 7.77 (s, 1H), 8.03 (br s, 3H), 9.01 (br s, 2H).
1H NMR (400 MHz, DMSO-d6): δ 8.10 (brs, 1H), 7.80 (brs, 1H), 7.68-7.61 (m, 2H), 7.51 (d, J = 8.69 Hz, 1H), 7.40-7.34 (m, 3H), 7.13-7.07 (m, 2H), 4.34 (t, J = 11.72 Hz, 1H), 2.85- 2.81 (m, 2H), 2.74-2.70 (m, 2H), 2.29-2.25 (m, 2H), 2.00- 1.9 (m, 2H), 1.89 (s, 1H), 1.87-1.72 (m, 7H), 1.54-1.45 (m, 2H), 1.32-1.22 (m, 4H).
1H NMR (400 MHz, DMSO-d6): δ 0.96-1.05 (m, 4H), 1.22- 1.32 (m, 2H), 1.44-1.54 (m, 2H), 1.70-1.76 (m, 7H), 1.85 (d, J = 13.03 Hz, 2H), 1.90-1.97 (d, J = 12.19 Hz, 2H), 2.06- 2.12 (m, 1H), 2.23 (s, 4H), 2.57 (s, 1H), 3.19 (brs, 1H), 4.17 (t, J = 7.73 Hz, 1H), 4.27 (t, J = 11.46 Hz, 1H), 5.75 (d, J = 7.91 Hz, 1H), 6.88 (t, J = 7.35 Hz, 1H), 6.92 (d, J = 6.36 Hz, 1H), 7.03 (t, J = 7.77 Hz, 1H), 7.10-7.14 (m, 3H), 7.35- 7.45 (d, 3H).
1H NMR (400 MHz, DMSO-d6): δ 0.82-0.91 (m, 2H), 1.06 (t, 3H), 1.22-1.47 (m, 6H), 1.51-1.82 (m, 14H), 1.93 (s, 6H), 2.07-2.09 (m, 2H), 2.53-2.59 (m, 1H), 2.76 (t, J = 6.62 Hz, 2H), 2.88 (brs, 2H), 4.27 (t, J = 11.16 Hz, 1H), 6.96 (t, J = 7.32 Hz, 1H), 7.07 (t, J = 7.43 Hz, 1H), 7.30 (s, 1H), 7.45 (d, J = 8.25 Hz, 1H), 7.51 (d, J = 7.79 Hz, 1H) 8.01 (br s, 3H), 8.82 (br s, 1H), 8.99 (br s, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.35 (m, 2H), 1.48- 1.51 (m, 2H), 1.70 (d, J = 9.98 Hz, 2H), 1.83-1.96 (m, 9H), 2.25 (s, 4H), 2.87-2.96 (m, 7H), 4.35-4.40 (m, 2H), 6.99- 7.04 (m, 2H), 7.16 (s, 4H), 7.41 (d, J = 7.93 Hz, 1H), 7.69 (d, J = 7.77 Hz, 1H), 7.79 (s, 1H), 7.91 (s, 1H), 8.03 (brs, 3H), 9.22 (brs,, 2H).
1H NMR (400 MHz, DMSO-d6): δ 0.95-1.04 (m, 1H), 1.14- 1.35 (m, 3H), 1.38-1.59 (m, 6H), 1.63-1.94 (m, 11H), 2.12 (d, J = 12.40 Hz, 1H), 2.56-2.66 (m, 5H), 2.77 (t, J = 11.74 Hz, 1H), 4.25 (t, J = 11.58 Hz, 1H), 7.17 (d, J = 8.73 Hz, 1H), 7.24 (d, J = 9.75 Hz, 1H), 7.45 (d, J = 8.75 Hz, 1H), 7.68 (s, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.05-1.17 (m, 2H), 1.20- 1.35 (m, 4H), 1.31-1.50 (m, 4H), 1.53-1.58 (m, 2H), 1.60- 1.72 (m, 4H), 1.80 (d, J = 11.45 Hz, 3H), 1.89 (d, J = 11.68 Hz, 4H), 2.16 (d, J = 11.96 Hz, 1H), 2.33 (s, 3H), 2.64 (d, J = 6.58 Hz, 5H), 2.80-8.86 (m, 1H), 4.23 (t, J = 11.13 Hz, 1H), 7.08 (d, J = 7.44 Hz, 1H), 7.17 (s, 1H), 7.27-7.41 (m, 4H), 7.48 (d, J = 8.60 Hz, 1H), 7.70 (s, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.88-0.88 (m, 2H), 0.98- 1.27 (m, 5H), 1.47-1.62 (m, 7H), 1.65-1.92 (m, 11H), 2.07- 2.10 (m, 2H), 2.70 (brs, 1H), 2.84 (brs, 5H), 4.40 (t, J = 11.65 Hz, 1H), 7.43 (t, J = 8.74 Hz, 1H), 7.54 (s, 1H), 7.70 (d, J = 8.63 Hz, 1H), 7.92 (brs, 3H), 8.09 (s, 1H), 8.85 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 0.88-0.92 (m, 2H), 0.96- 1.16 (m, 3H), 1.21-1.30 (m, 3H), 1.32 (s, 1H), 1.39-1.60 (m, 8H), 1.63-1.71 (m, 4H),), 1.75-1.84 (m, 4H), 1.88 (d, J = 13.68 Hz, 2H), 2.28-2.31 (m, 2H), 2.42 (d, J = 5.59 Hz, 2H), 2.60 (brs, 2H), 2.70-2.71 (m, 1H), 4.25 (t, J = 11.71 Hz, 1H), 6.93 (t, J = 7.25 Hz, 1H), 7.05 (t, J = 7.44 Hz, 1H), 7.15 (s, 1H), 7.54 (s, 1H), 7.42 (d, J = 8.25 Hz, 1H), 7.48 (d, J = 7.86 Hz, 1H).
1H NMR (400 MHz, DMSO-d6) δ 9.10 (brs, 1H), 9.05-8.98 (m, 3H), 7.86 (s, 1H), 7.57 (d, J = 8.75 Hz, 1H), 7.51 (s, 1H), 7.47 (d, J = 7.82 Hz, 1H), 7.43-7.41 (m, 2H), 7.31 (t, J = 7.57 Hz, 1H), 7.10 (d, J = 7.25 Hz, 1H), 4.31 (t, J = 11.54 Hz, 1H)
3.14 (s, 4H), 3.08-3.01 (m, 2H), 2.95- 2.86 (m, 2H), 2.37 (s, 3H), 1.96 (d, J = 8.87 Hz, 4H), 1.85 (d, J = 13.01 Hz, 2H), 1.80-1.66 (m, 3H), 1.50 (q, J = 25.47, 12.29 Hz, 2H), 1.25-1.20 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.30 (m, 2H), 1.45- 1.55 (m, 2H), 1.70-1.86 (m, 7H), 1.95 (d, J = 11.59 Hz, 2H), 2.37 (s, 3H), 2.58-2.66 (m, 4H), 2.72-2.82 (m, 3H), 3.66 (brs, 1H), 4.29 (t, J = 11.84 Hz, 1H), 7.09 (d, J = 7.45 Hz, 1H), 7.26 (s, 1H), 7.31 (t, J = 7.46 Hz, 1H), 7.38 (t, J = 8.11 Hz, 1H), 7.43 (d, J = 7.76 Hz, 1H), 7.46 (s, 1H), 7.52 (d, J = 8.52 Hz, 1H), 7.72 (s, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.34 (m, 4H), 1.45- 1.55 (m, 2H), 1.70-1.80 (m, 3H), 1.84 (d, J = 12.87 Hz, 2H), 1.95 (d, J = 10.64 Hz, 2H), 2.17-2.18 (m, 1H), 2.23 (s, 3H), 2.31-2.32 (m, 1H), 2.53-2.56 (m, 1H), 2.62-2.71 (m, 4H), 2.87 (d, J = 11.19 Hz. 1H), 3.76 (brs, 1H), 4.18 (t, J = 7.73 Hz, 1H), 4.25-4.31 (m, 1H), 6.80 (brs, 1H), 6.87-6.94 (m, 3H), 7.04 (t, J = 7.76 Hz, 1H), 7.09-7.15 (m, 3H), 7.37 (d, J = 7.88 Hz, 1H), 7.40 (s, 1H), 7.43 (d, J = 8.29 Hz, 1H), 7.46 (s, 1H), 7.52 (d, J = 8.52 Hz, 1H), 7.72 (s, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.32 (m, 2H), 1.46- 1.55 (m, 2H), 1.70-1.85 (m, 7H), 1.95 (brs, 2H), 2.24 (s, 3H), 2.28-2.29 (m, 1H), 2.40-2.42 (m, 1H), 2.76-2.85 (m, 3H), 2.89-2.98 (m, 1H), 4.28-4.40 (m, 2H), 6.98 (d, J = 7.27 Hz, 1H), 7.02-7.12 (m, 2H), 7.17 (t, J = 7.51 Hz, 1H), 7.54-7.60 (m, 2H), 7.68 (d, J = 8.81 Hz, 1H), 7.87 (brs, 2H), 8.07 (s, 1H), 12.41 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 1.20-1.32 (m, 3H), 1.43- 1.54 (m, 2H), 1.68-1.85 (m, 5H), 1.95 (d, J = 13.28 Hz, 2H), 2.16-2.20 (m, 1H), 2.22 (s, 3H), 2.32-2.38 (m, 1H), 3.20- 3.26 (m, 1H), 3.35-3.42 (m, 2H), 3.43-3.62 (m, 4H), 4.16- 4.-4.19 (m, 1H), 4.21-4.34 (m, 2H), 4.49 (d, J = 5.04 Hz, 1H), 4.53 (d, J = 5.90 Hz, 1H), 4.61-4.66 (m, 1H), 4.69 (d, J = 5.36 Hz, 1H), 6.85-6.93 (m, 2H), 7.03 (t, J = 8.00 Hz, 1H), 7.09-7.13 (m, 3H), 7.34 (d, J = 7.92 Hz, 1H), 7.41- 7.44 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 0.96-1.02 (m, 1H), 1.14- 1.34 (m, 4H), 1.39-1.55 (m, 6H), 1.56-1.94 (m, 11H), 2.13 (d, J = 11.51 Hz, 1H), 2.57-2.60 (m, 4H), 2.81-2.86 (m, 2H), 3.16-3.23 (m, 1H), 4.36 (t, J = 11.44 Hz, 1H), 7.42 (d, J = 11.48 Hz, 2H), 7.67 (d, J = 8.64 Hz, 1H), 8.09 (d, J = 7.18 Hz, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.21-1.32 (m, 3H), 1.44- 1.53 (m, 2H), 1.69-1.79 (m, 3H), 1.84 (d, J = 13.17 Hz, 2H), 1.93 (d, J = 11.39 Hz, 2H), 2.06-2.10 (m, 1H), 2.19-2.22 (m, 1H), 2.24 (s, 3H), 2.40 (brs, 3H), 4.16 (brs, 1H), 4.24-4.30 (m, 1H), 6.87 (t, J = 7.42 Hz, 1H), 6.91(d, J = 5.12 Hz, 1H), 7.02 (t, J = 7.35 Hz, 1H), 7.09-7.12 (m, 3H), 7.35 (d, J = 7.87 Hz, 1H), 7.41 (d, J = 8.52 Hz, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.21-1.34 (m, 7H), 1.48- 1.51 (m, 2H), 1.70-1.76 (m, 3H), 1.84 (d, J = 13.22 Hz, 2H), 1.95 (d, J = 9.62 Hz, 2H), 2.24 (s, 4H), 2.40 (brs, 1H), 2.71 (brs, 1H), 2.93 (brs, 2H), 3.467-3.56 (m, 5H), 3.69 (brs, 1H), 3.83 (brs, 1H), 4.18 (t, J = 7.94 Hz, 1H), 4.26-4.31 (m, 1H), 4.45 (brs, 1H), 4.88 (brs, 1H), 6.88 (t, J = 7.60 Hz, 1H), 6.95(d, J = 6.73 Hz, 1H), 7.05 (t, J = 7.15 Hz, 1H), 7.09- 7.16 (m, 3H), 7.35 (d, J = 8.09 Hz, 1H), 7.42-7.45 (m, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.24-1.40 (m, 7H), 1.45- 1.55 (m, 2H), 1.70-1.79 (m, 3H), 1.84 (d, J = 13.11 Hz, 2H), 1.94-2.03 (m, 7H), 2.24 (s, 3H), 2.25-2.29 (m, 1H), 2.78 (brs, 1H), 2.91-2.96 (m, 3H), 4.23 (t, J = 7.58 Hz, 1H), 4.29-4.32 (m, 1H), 6.90 (t, J = 7.39 Hz, 1H), 6.96 (d, J = 6.64 Hz, 1H), 7.05 (t, J = 7.76 Hz, 1H), 7.12-7.17 (m, 3H), 7.39 (d, J = 7.84 Hz, 1H), 7.45 (d, J = 8.24 Hz, 1H), 7.50 (s, 1H), 7.92-8.02 (m, 3H), 8.94 (brs, 1H), 9.04 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.54 (m, 9H), 1.70- 1.86 (m, 5H), 1.93-2.04 (m, 6H), 2.32-2.36 (m, 1H), 2.54- 2.56 (m, 1H), 2.72-3.06 (m, 4H), 4.27-4.33 (m, 1H), 4.45 (t, J = 7.55 Hz, 1H), 6.91 (t, J = 7.33 Hz, 1H), 7.06 (t, J = 7.47 Hz, 1H), 7.14 (d, J = 6.54 Hz, 1H), 7.34-7.41 (m, 4H), 7.46 (d, J = 8.27 Hz, 1H), 7.64 (s, 1H), 8.11 (s, 3H), 9.21 (brs, 1H), 9.336 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.34 (m, 2H), 1.45- 1.54 (m, 2H), 1.69-1.86 (m, 6H), 1.96 (d, J = 10.84 Hz, 2H), 2.24 (s, 3H), 2.35-2.38 (m, 1H), 2.84-2.88 (m, 1H), 2.35- 2.38 (m, 1H), 2.96 (brs, 1H), 3.12-3.17 (m, 4H), 3.80 (brs, 1H), 4.25-4.32 (m, 1H), 6.90 (t, J = 7.36 Hz, 1H), 6.97(d, J = 6.45 Hz, 1H), 7.06 (t, J = 7.38 Hz, 1H), 7.12-7.18 (m, 1H), 7.39 (d, J = 7.90 Hz, 1H), 7.45 (d, J = 8.33 Hz, 1H), 7.52 (d, J = 2.60 Hz, 1H), 8.31-8.75 (brs, 6H), 9.50 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.31 (m, 1H), 1.36- 1.43 (m, 2H), 1.48-1.66 (m, 6H), 1.68-2.00 (m, 14H), 2.14 (brs, 4H), 2.14 (s, 4H), 2.93 (brs, 2H), 3.14 (brs, 1H), 3.55 (brs, 1H), 4.30 (t, J = 11.65 Hz, 1H), 7.10 (d, J = 7.30 Hz, 1H), 7.24 (s, 1H), 7.29-7.33(m, 2H), 7.39 (d, J = 8.36 Hz, 1H), 7.44 (d, J = 7.92 Hz, 1H), 7.49 (s, 1H), 7.54 (t, J = 8.61 Hz, 1H), 7.81 (d, J = 12.40 Hz, 1H), 8.08 (brs, 3H),), 8.78 (brs, 1H), 8.95 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.32 (m, 2H), 1.45- 1.60 (m, 5H), 1.63-1.86 (m, 8H), 1.94 (d, J = 10.99 Hz, 4H), 2.14 (brs, 3H), 2.38 (s, 3H), 2.88-2.98 (m, 3H), 3.30 (s, 2H), 3.50 (brs, 1H), 4.30 (t, J = 11.58 Hz, 1H), 7.10 (d, J = 7.47 Hz, 1H), 7.24 (s, 1H), 7.38 (t, J = 8.44 Hz, 1H), 7.44 (d, J = 7.65 Hz, 1H), 7.49 (s, 1H), 7.53-7.55 (m, 1H), 7.79 (s, 1H), 8.87 (brs, 3H).
1H NMR (400 MHz, DMSO-d6): δ 1.21-1.52 (m, 12H), 1.56-1.78 (m, 4H), 1.84 (d, J = 13.00 Hz, 2H), 1.93-1.99 (m, 6H), 2.12 (brs, 3H), 2.36-2.39 (m, 1H), 2.95-3.0 (m, 2H), 3.18-3.19 (m, 1H), 3.45-3.53 (m, 1H), 4.33 (t, J = 11.57 Hz, 1H), 7.28 (s, 1H), 7.30 (s, 1H), 7.44 (d, J = 8.65 Hz, 1H), 7.55-7.60 (m, 3H), 7.73 (d, J = 7.63 Hz, 1H), 7.86 (s, 1H), 7.97 (brs, 3H), 8.69 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 1.21-1.32 (m, 3H), 1.35- 1.52 (m, 11H), 1.63-1.72 (m, 4H), 1.78-1.89 (m, 6H), 1.93- 2.00 (m, 6H), 2.07 (d, J = 10.01 Hz, 2H), 2.74 (t, J = 7.28 Hz, 2H), 2.94 (brs, 4H), 4.21 (t, J = 12.00 Hz, 1H), 6.98 (d, J = 8.19 Hz, 1H), 7.22 (s, 1H), 7.36 (t, J = 8.58 Hz, 1H), 7.98 (brs, 3H), 8.77 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.32 (m, 3H), 1.35- 1.50 (m, 7H), 1.64-1.72 (m, 5H), 1.78-1.90 (m, 7H), 1.92- 1.99 (m, 7H), 2.72 (t, J = 7.07 Hz, 2H), 2.86-2.90 (m, 4H), 2.96 (t, J = 6.01 Hz, 2H), 4.21 (t, J = 11.86 Hz, 1H), 6.98 (d, J = 8.28 Hz, 1H), 7.23 (s, 1H), 7.31 (s, 1H), 7.35 (d, J = 8.61 Hz, 1H), 8.09 (brs, 3H), 8.93 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 1.23-1.47 (m, 6H), 1.50- 1.54 (m, 2H), 1.69-1.72 (m, 3H), 1.81-1.86 (m, 3H), 1.90- 1.97 (m, 7H), 2.36-2.39 (m, 1H), 2.74-2.78 (m, 1H), 2.87- 2.97 (m, 4H), 3.69 (s, 3H), 4.30 (t, J = 7.64 Hz, 1H), 4.35- 4.41 (m, 1H), 6.98 (d, J = 5.78 Hz, 1H), 6.90-6.94 (m, 2H), 7.21 (t, J = 7.80 Hz, 1H), 7.42 (d, J = 8.64 Hz, 1H), 7.67(s, 1H), 7.69(s, 1H), 7.93 (s, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.20-1.30 (m, 2H), 1.45- 1.54 (m, 2H), 1.68-1.77 (m, 5H), 1.81-1.85 (m, 3H), 1.91 (d, J = 10.91 Hz, 2H), 2.06-2.09 (m, 2H), 2.74-2.95 (m, 5H), 3.28-3.34 (m, 3H), 3.69 (s, 3H), 4.32 (t, J = 7.51 Hz, 1H), 4.35-4.41 (m, 1H), 6.75 (d, J = 6.41 Hz, 1H), 6.90-6.94 (m, 2H), 7.21 (t, J = 7.88 Hz, 1H), 7.42 (d, J = 8.37 Hz, 1H), 7.67 (s, 1H), 7.69 (s, 1H), 7.93 (s, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.21-1.32 (m, 2H), 1.48- 1.55 (m, 2H), 1.69-1.72 (m, 1H), 1.75-1.85 (m, 4H), 1.88- 1.94 (m, 4H), 2.35-2.39 (m, 1H), 2.74 (brs, 2H), 2.87(brs, 3H), 2.95 (brs, 2H), 3.71 (s, 3H), 4.35-4.44 (m, 2H), 6.76 (d, J = 9.43 Hz, 1H), 6.93 (s, 1H), 6.95 (s, 1H), 7.21 (t, J = 8.35 Hz, 1H), 7.43 (d, J = 8.57 Hz, 1H), 7.72 (d, J = 8.63 Hz, 1H), 7.76 (s, 1H), 7.94 (brs, 3H), 9.05 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 1.19-1.38 (m, 5H), 1.41- 1.54 (m, 5H), 1.70-1.75 (m, 6H), 1.83 (t, J = 12.26 Hz, 2H), 1.90-1.98 (m, 4H), 2.09-2.20 (m, 3H), 2.38 (s, 1H), 2.90 (t, J = 13.07 Hz,, 2H), 2.98-3.01 (m, 1H), 3.35 (m, 2H), 3.49- 3.52 (m, 1H), 4.30 (t, J = 11.70 Hz, 1H), 7.27-7.32 (m, 2H), 7.42 (d, J = 8.59 Hz, 1H), 7.54-7.58 (m, 3H), 7.71 (d, J = 7.78 Hz, 1H), 7.83-7.85 (m, 1H).
1H NMR (400 MHz, DMSO-d6): δ 9.05-9.02 (m, 2H), 8.80- 8.74 (m, 2H), 7.89-7.88 (m, 1H), 7.74 (d, J = 7.88 Hz, 1H), 7.61-7.45 (m, 3H), 7.44 (d, J = 8.36 Hz, 1H), 7.30-7.28 (m, 2H), 4.33 (t, J = 11.56 Hz, 1H), 3.59-3.52 (m, 2H), 2.42- 2.38 (m, 1H), 2.25-2.10 (m, 3H), 2.0-1.90 (m, 4H), 1.89-1.80 (m, 5H), 1.75-1.62(m, 3H), 1.60-1.40 (m, 6H), 1.32-1.30 (m, 1H)
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.28 (m, 2H), 1.47- 1.54 (m, 2H), 1.50-1.85 (m, 5H), 1.92 (brs, 2H), 2.24 (s, 3H), 2.79 (brs, 2H), 2.93 (brs, 3H), 3.15-3.24 (m, 4H), 3.77 (t, J = 11.59 Hz, 2H), 3.96 (d, J = 11.81 Hz, 2H), 4.22-4.30 (m, 2H), 6.98 (d, J = 6.49 Hz, 1H), 7.11 (s, 2H), 7.16 (d, J = 7.50 Hz, 2H), 7.47 (d, J = 8.61 Hz, 1H), 7.52 (s, 1H), 7.57 (s, 1H), 8.99 (brs, 1H), 9.44 (brs, 1H), 9.57 (brs, 1H), (brs, 1H), 9.72 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.83-0.97 (m, 2H), 1.00- 1.03 (m, 1H), 1.08-1.32 (m, 4H), 1.45-1.60 (m, 6H), 1.65- 1.92 (m, 12H), 1.96-2.14 (m, 4H), 2.71-2.88 (m, 4H), 3.20 (brs, 1H), 3.28 (brs, 1H), 4.40 (t, J = 11.73 Hz, 1H), 7.43 (d, J = 8.22 Hz, 1H), 7.58 (s, 1H), 7.70 (d, J = 8.68 Hz, 1H), 8.08 (s, 1H), 8.81 (brs, 1H), 8.90 (brs, 1H), 9.13 (brs, 1H), (brs, 1H), 9.28 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.83-0.88 (m, 2H), 0.98- 1.04 (m, 1H), 1.08-1.16 (m, 2H), 1.19-1.32 (m, 6H), 1.36- 1.58 (m, 6H), 1.66-1.74 (m, 4H), 1.77-1.82 (m, 4H), 1.92 (brs, 6H), 1.82 (m, 4H), 2.05-2.09 (m, 2H), 2.75 (brs, 1H), 2.82-2.90 (m, 3H), 4.40 (t, J = 11.99 Hz, 1H), 7.44 (d, J = 8.63 Hz, 1H), 7.53 (s, 1H), 7.71 (d, J = 8.68 Hz, 1H), 7.88 (brs, 3H), 8.08 (s, 1H), 8.90 (brs, 1H), 8.59 (brs, 1H), (brs, 1H), 8.73 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.30 (m, 6H), 1.33- 1.54 (m, 2H), 1.65-1.71 (m, 3H), 1.84 (d, J = 11.84 Hz, 2H), 1.91-2.06 (m, 8H), 2.22 (s, 3H), 2.70-2.88 (m, 5H), 2.98 (dd, J1,2 = 6.6.92 Hz, J1,3 = 13.20 Hz, 1H), 3.25 (brs, 1H), 4.24-4.30 (m, 1H), 6.92-7.01 (m, 4H), 7.10 (t, J = 7.45 Hz, 1H), 7.34 (s, 1H), 7.47 (d, J = 8.28 Hz, 1H), 7.62 (d, J = 7.81 Hz, 1H), 7.99 (brs, 3H), 8.59 (brs, 1H), 8.86 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.42 (m, 5H), 1.46- 1.56 (m, 2H), 1.70-1.87 (m, 5H), 1.95-2.04 (m, 6H), 2.24 (s, 3H), 2.24 (s, 3H), 2.42-2.46 (m, 1H), 2.79 (brs, 1H), 2.92 (brs, 3H), 3.73 (s, 3H), 4.30-4.37 (m, 2H), 6.24 (s, 1H), 6.92-9.98 (m, 1H), 7.14-7.18 (m, 4H), 7.42 (d, J = 1.59 Hz, 1H), 7.49 (s, 1H), 7.27 (d, J = 8.56 Hz, 1H), 7.61 (s, 1H), 7.99 (brs, 3H), 9.03 (brs, 1H), 9.14 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 941-9.30 (m, 2H), 8.17- 8. (m, 5H), 7.57 (d, J = 7.05 Hz, 1H), 7.37 (d, J = 9.9 Hz, 3H), 7.26 (d, J = 6.85 Hz, 1H), 7.16 (S, 1H), 4.54-4.47 (m, 2H), 2.99-2.80 (m, 7H), 1.94-1.70 (m, 10H), 1.60-1.42 (m, 2H), 1.40-1.22 (m, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.33 (m, 1H), 1.48- 1.57 (m, 2H), 1.72 (d, J = 12.67 Hz, 1H), 1.77-1.87 (m, 4H), 1.91-1.97 (m, 4H), 2.25 (s, 3H), 2.24 (s, 3H), 2.43-2.46 (m, 1H), 2.86-2.87 (m, 1H), 2.89-2.92 (m, 3H), 2.94-2.96 (m, 2H), 4.40 (t, J = 11.78 Hz, 1H), 4.48 (t, J = 8.11 Hz, 1H), 6.98 (d, J = 7.29 Hz, 1H), 7.16-7.24 (m, 3H), 7.66 (s, 1H), 7.70-7.75 (m, 1H), 7.96 (brs, 3H), 8.19(s, 1H), 8.25 (brs, 2H), 8.78 (d, J = 5.94 Hz, 1H), 9.21 (brs, 1H), 9.31(brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.84-0.87 (m, 2H), 0.97- 1.03 (m, 1H), 1.08-1.14 (m, 2H), 1.17-1.30 (m, 2H), 1.48- 1.57 (m, 6H), 1.64-1.68 (m, 3H), 1.76-1.79 (m, 4H), 1.81- 1.92 (m, 2H), 1.95-2.21 (m, 4H), 2.62 (brs, 1H), 2.77 (brs, 1H), 2.98 (s, 1H), 3.16 (brs, 1H), 3.78 (brs, 1H), 4.40-4.42 (m, 1H), 7.43 (d, J = 8.44 Hz, 1H), 7.57 (d, J = 7.13 Hz, 1H), 7.70 (d, J = 8.61 Hz, 1H), 8.09 (s, 1H), 9.01 (brs, 1H), 9.30 (brs, 2H), 9.48 (brs, 1H), 9.61(brs, 1H).
1H NMR (400 MHz, DMSO-d6) δ 9.57 (brs, 1H), 9.39 (brs, 1H), 8.95 (brs, 1H), 8.80 (brs, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.61-7.52 (m, 1H), 7.41-7.32 (m, 3H), 7.30-7.21 (m, 1H), 7.20-7.10 (m, 1H), 4.60-4.42 (m, 2H), 3.55-3.40 (m, 1H), 3.10-2.98 (m, 1H), 2.92-2.80 (m, 5H), 2.15-2.02 (m, 4H), 2.0
1.90 (m, 3H), 1.88-1.70 (m, 8H), 1.60- 1.45 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 9.11 (brs, 1H), 8.94 (brs, 1H), 8.18 (s, 1H), 7.96-7.93 (m, 4H), 7.59 (d, J = 8.28 Hz, 1H) 7.43-7.38 (m, 3H), 7.28 (d, J = 8.33 Hz, 1H), 7.16 (d, J = 8.22 Hz, 1H), 4.53-4.47 (m, 1H), 2.97-2.94 (m, 3H), 2.88-2.82 (m,
2H), 2.32-2.30 (m, 1H), 2.10-1.90 (m, 7H), 1.88-1.70 (m, 5H
1.60-1.45 (m, 2H), 1.40-1.22 (m, 6H).
1H NMR (400 MHz, DMSO-d6): δ 0.79-0.97 (m, 6H), 1.13- 1.32 (m, 4H), 1.34-1.37 (m, 1H), 1.44-1.50 (m, 3H), 1.72 (t, J = 12.25 Hz, 3H), 1.79-1.86 (m, 4H), 1.92 (brs, 2H), 2.01- 2.0392 (m, 2H), 2.56-2.59 (m, 1H), 2.75 (brs, 1H), 2.85 (brs, 3H), 2.93-2.98 (m, 1H), 4.28 (t, J = 11.83 Hz, 1H), 6.97 (t, J = 7.30 Hz, 1H), 7.10 (t, J = 7.44 Hz, 1H), 7.34 (s, 1H), 7.48 (dd, J1,2 = 7.12 Hz, J1,3 = Hz, 14.82 Hz, 2H), 7.90 (brs, 3H), 8.77 (brs, 1H), 8.89 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.79-0.96 (m, 6H), 1.00- 1.22 (m, 14H), 1.50-1.1.57 (m, 5H), 1.65-1.73 (m, 4H), 1.75-1.87 (m, 3H), 2.01-2.11 (m, 2H), 2.56-2.59 (m, 1H), 2.73-2.74 (m, 2H), 2.82-2.86 (m, 4H), 4.06-4.15 (m, 2H), 6.97 (t, J = 6.97 Hz, 1H), 7.09 (t, J = 7.36 Hz, 1H), 7.14 (s, 1H), 7.40 (d, J = 8.26 Hz, 1H), 7.53 (d, J = 7.91 Hz, 1H), 7.88 (brs, 3H), 8.77 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.29 (m, 1H), 1.44- 1.54 (m, 2H), 1.65-1.71 (m, 5H), 1.83 (d, J = 10.10 Hz, 2H), 1.89-2.06 (m, 6H), 2.22 (s, 3H), 2.66-2.69 (m, 1H), 2.80- 2.86 (m, 6H), 2.97-3.08 (m, 4H), 3.13 (brs, 1H), 3.26 (s, 2H), 4.25-4.30 (m, 1H), 6.92-7.01 (m, 4H), 7.08-7.13 (m, 2H), 7.35 (s, 1H), 7.47 (d, J = 8.16 Hz, 1H), 7.63 (d, J = 7.83 Hz, 1H), 8.77 (brs, 3H), 9.03 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.22-1.26 (m, 1H), 1.47- 1.53 (m, 2H), 1.69-1.71 (m, 4H), 1.81-1.88 (m, 6H), 1.99- 2.01 (m, 2H), 2.21 (s, 3H), 2.66-2.83 (m, 9H), 2.96-3.01 (m, 2H), 3.05-3.06 (m, 1H), 3.13-3.14 (m, 1H), 3.23 (brs, 1H), 4.26-4.29 (m, 1H), 6.95-7.00 (m, 4H), 7.09 (t, J = 7.22 Hz, 2H), 7.36 (s, 1H), 7.45 (d, J = 8.11 Hz, 1H), 7.61 (d, J = 7.74 Hz, 1H), 7.98 (s, 1H), 8.08 (brs, 3H), 8.86 (brs, 1H). 9.11 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.20-1.27 (m, 4H), 1.31- 1.53 (m, 9H), 1.61-1.67 (m, 6H), 1.76-1.82 (m, 8H), 1.87- 1.98 (m, 4H), 2.03 (d, J = 11.66 Hz, 1H), 2.77-2.94 (m, 6H), 2.97 (brs, 1H), 3.13 (brs, 1H), 3.18 (brs, 1H), 4.18 (t, J = 11.51 Hz, 1H), 6.96 (d, J = 8.24 Hz, 1H), 7.11 (s, 1H), 7.29- 7.33 (m, 2H).
1H NMR (400 MHz, DMSO-d6): δ 0.84-0.88 (m, 2H), 0.97- 1.22 (m, 5H), 1.40-1.47 (m, 2H), 1.50-1.57 (m, 10H), 1.61- 1.63 (m, 2H), 1.72-1.87 (m, 2H), 1.99-2.04 (m, 5H), 2.32 (s, 1H), 2.40-2.42 (m, 2H), 2.62-2.70 (m, 3H), 3.16 (s, 1H), 4.70 (d, J = 6.53 Hz, 2H), 5.01(s, 1H), 5.27 (t, J = 6.38 Hz, 1H), 6.94 (t, J = 7.32 Hz, 1H), 7.01 (s, 1H), 7.06 (t, J = 7.47 Hz, 1H), 7.30 (d, J = 7.99 Hz, 1H), 7.50 (t, J = 7.89 Hz, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.03-0.05 (m, 1H), 0.16- 0.18 (m, 1H), 0.31-0.32 (m, 1H), 0.51-0.52 (m, 1H), 1.12 (brs, 1H), 1.19-1.26 (m, 1H), 1.41-1.51 (m, 2H), 1.63-1.69 (m, 3H), 1.80-1.82 (m, 4H), 1.91 (d, J = 10.45 Hz, 2H), 2.08-2.10 (m, 2H), 2.20-2.25 (m, 1H), 2.74-2.82 (m, 3H), 2.88 (t, J = 7.34 Hz, 3H), 3.13 (s, 5H), 4.23 (t, J = 12.23 Hz, 1H), 6.96 (t, J = 7.49 Hz, 1H), 7.08 (t, J = 7.15 Hz, 1H), 7.26 (s, 1H), 7.29 (t, J = 6.69 Hz, 1H), 7.43 (d, J = 8.34 Hz, 1H), 7.53 (d, J = 7.88 Hz, 1H).
1H NMR (400 MHz, DMSO-d6): δ 1.01-1.06 (m, 1H), 1.19- 1.23 (m, 2H), 1.26-1.70 (m, 7H), 1.73-1.76 (m, 3H), 1.82- 1.95 (m, 9H), 2.02-2.10 (m, 2H), 2.13-2.24 (m, 1H), 2.66- 2.75 (m, 2H), 2.83 (brs, 4H), 4.24-4.30 (m, 1H), 6.96 (t, J = 7.41 Hz, 1H), 7.08 (t, J = 7.29 Hz, 1H), 7.30 (s, 1H), 7.45 (d, J = 8.28 Hz, 1H), 7.55 (d, J = 7.88 Hz, 1H), 7.96 (brs, 3H), 8.85 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 0.97-1.03 (m, 1H), 1.13- 1.22 (m, 3H), 1.45-1.50 (m, 2H), 1.53-1.66 (m, 3H), 1.80- 1.81 (m, 1H), 1.91-1.97 (m, 2H), 2.24 (s, 3H), 2.31-2.39 (m, 2H), 2.77 (brs, 1H), 2.88-2.95 (m, 1H), 4.04-4.10 (m, 1H), 4.45 (t, J = 7.53 Hz, 1H), 6.99 (d, J = 6.45 Hz, 1H), 7.14- 7.21 (m, 3H), 7.66 (d, J = 9.13 Hz, 1H), 7.71 (s, 1H), 7.96 (dd, J1,2 = 8.28 Hz, J1,3 = 9.13 Hz, 1H), 8.03 (brs, 3H), 8.34 (s, 1H), 9.22 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 0.93-1.02 (m, 2H), 1.11- 1.22 (m, 5H), 1.26-1.39 (m, 4H), 1.46-1.49 (m, 2H), 1.55- 1.75 (m, 3H), 1.80-1.82 (m, 1H), 1.91-2.04 (m, 4H), 2.24 (s, 3H), 2.79 (brs, 1H), 2.88-2.99 (m, 3H), 4.09 (d, J = 6.88 Hz, 1H), 4.43 (t, J = 8.00 Hz, 1H), 7.00 (d, J = 6.47 Hz, 1H), 7.14-7.22 (m, 3H), 7.66-7.68 (m, 2H), 7.95 (brs, 3H), 7.97 (d, J = 9.16 Hz, 1H), 8.35 (s, 1H), 8.90 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 0.78-0.86 (m, 9H), 1.17- 1.25 (m, 13H), 1.27-1.39 (m, 2H), 1.47-1.48 (m, 1H), 1.70- 1.73 (m, 2H), 1.89-1.93 (m, 2H), 2.05-2.07 (m, 2H), 2.57 (brs, 1H), 2.72 (brs, 1H), 2.80-2.96 (m, 5H), 4.03-4.17 (m, 2H), 6.96 (t, J = 7.49 Hz, 1H), 7.08 (t, J = 7.43 Hz, 1H), 7.26 (s, 1H), 7.39 (d, J = 8.19 Hz, 1H), 7.51 (d, J = 7.86 Hz, 1H), 8.15 (brs, 3H), 9.18 (brs, 1H), 9.22 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.78-0.88 (m, 5H), 0.97- 1.03 (m, 1H), 1.17-1.25 (m, 13H), 1.47-1.57 (m, 5H), 1.65- 1.75 (m, 3H), 1.84 (brs, 3H), 2.02-2.12 (m, 2H), 2.71 (brs, 1H), 2.84 (brs, 5H), 4.14-4.23 (m, 2H), 7.40-7.45 (m, 2H), 7.63 (d, J = 8.56 Hz, 1H), 7.92 (brs, 3H), 8.10 (s, 1H), 8.87 (brs, 2H).
1H NMR (400 MHz, DMSO-d6): δ 0.84-1.01 (m, 2H), 1.12- 1.23 (m, 4H), 1.46-1.52 (m, 2H), 1.54-1.69 (m, 3H), 1.76- 1.98 (m, 3H), 2.06 (t, J = 11.78 Hz, 2H), 2.24 (s, 3H), 2.49 (brs, 1H), 2.57 (brs, 1H), 2.85-3.09 (m, 4H), 3.22 (brs, 1H), 3.35-3.37 (m, 1H), 4.03-4.13 (m, 2H), 4.34 (t, J = 7.31 Hz, 1H), 7.00 (d, J = 6.29 Hz, 1H), 7.15-7.21 (m, 3H), 7.66 (d, J = 9.05 Hz, 1H), 7.71 (s, 1H), 7.96 (d, J = 9.12 Hz, 1H), 8.18 (brs, 3H), 8.34 (s, 1H), 10.57 (brs, 1H).
1H NMR (400 MHz, DMSO-d6): δ 0.83-0.98 (m, 2H), 1.00- 1.26 (m, 5H), 1.46-1.57 (m, 5H), 1.62-1.91 (m, 11H), 2.04- 2.10 (m, 2H), 2.55 (s, 1H), 2.66-2.85 (m, 6H), 4.28 (t, 1H), 7.18 (d, J = 8.58 Hz, 1H), 7.38 (s, 1H), 7.47 (d, J = 8.76 Hz, 1H), 7.67 (s, 1H), 8.00 (brs, 3H), 8.99 (brs, 2H).
1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.90 (s, 1H), 8.00 (s, 2H) 7.92 (s, 3H) 7.84 (s, 2H) 7.72 (d, J = 8.8 Hz, 2H), 7.48-7.40 (m, 6H), 7.18 (d, J = 6.4 Hz, 2H), 4.51 (t, J = 7.6 Hz, 2H), 4.42 (s, 1H), 2.96 (s, 2H), 2.82 (s, 2H), 2.00 (s, 3H), 1.94 (s, 4H), 1.83 (t, J = 13.1 Hz, 6H), 1.76 (s, 1H), 1.72 (d, J = 11.8 Hz, 3H), 1.50 (d, J = 13.0 Hz, 3H), 1.37- 1.26 (m, 6H).
1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.23 (s, 2H), 7.99 (d, J = 28.0 Hz, 1H), 7.90 (s, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.56-7.34 (m, 3H), 7.18 (s, 1H), 4.50-4.20 (m, 2H), 3.55 (d, J = 2.0 Hz, 4H), 3.37 (s, 9H), 2.76 (dd, J = 70.3, 27.2 Hz, 5H), 2.06 (d, J = 13.1 Hz, 3H), 1.96-1.66 (m, 7H), 1.51 (d, J = 13.8 Hz, 2H), 1.25 (d, J = 21.8 Hz, 3H), 0.84 (d, J = 7.4 Hz, 2H).
1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.91 (s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.08-7.91 (m, 4H), 7.88-7.61 (m, 3H), 7.18 (d, J = 10.2 Hz, 4H), 7.00 (d, J = 6.9 Hz, 1H), 4.43 (q, J = 9.0, 8.0 Hz, 4H), 3.56 (s, 4H), 2.87 (d, J = 53.8 Hz, 6H), 2.25 (s, 6H), 1.98 (d, J = 24.8 Hz, 6H), 1.77 (d, J = 53.6 Hz, 5H), 1.52 (d, J = 13.2 Hz, 3H), 1.31 (dd, J = 24.7, 12.5 Hz, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.91 (s, 3H), 7.49 (dd, J = 9.0, 4.5 Hz, 1H), 7.42-7.15 (m, 3H), 6.93 (t, J = 9.0 Hz, 2H), 4.27 (d, J = 12.4 Hz, 3H), 2.91 (s, 3H), 2.04 (d, J = 7.9 Hz, 2H), 1.92 (d, J = 10.8 Hz, 5H), 1.78-1.49 (m, 9H), 1.39 (d, J = 66.0 Hz, 8H), 1.25 (d, J = 21.8 Hz, 5H), 1.14-0.63 (m, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.83 (d, J = 11.8 Hz, 1H) 8.11 (s, 2H) 8.00 (s, 3H), 7.74 (d, J = 8.7 Hz, 2H), 7.58 (s, 2H), 7.49 (d, J = 8.6 Hz, 2H), 4.70 (s, 1H), 2.88 (s, 3H), 2.73 (s, 1H), 2.19 (s, 3H), 2.16-2.05 (m, 7H), 2.00 (s, 5H), 1.95 (s, 2H), 1.93 (d, J = 8.8 Hz, 4H), 1.79 (d, J = 12.4 Hz, 2H), 1.67 (d, J = 11.7 Hz, 2H), 1.56 (s, 3H), 1.39-1.27 (m, 6H), 1.14 (t, J = 14.1 Hz, 4H), 0.99 (d, J = 12.7 Hz, 2H), 0.84 (d, J = 12.4 Hz, 4H).
1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.70 (s, 1H), 7.96 (s, 3H), 7.67 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.27-7.12 (m, 1H), 4.29- 3.94 (m, 2H), 3.56 (s, 3H), 3.16 (s, 1H), 2.89 (d, J = 10.9 Hz, 2H), 2.74 (d, J = 16.8 Hz, 2H), 1.99 (d, J = 49.4 Hz, 5H), 1.86-1.33 (m, 12H), 1.35-0.64 (m, 10H).
1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.76 (d, J = 17.1 Hz, 2H), 7.51-7.40 (m, 2H), 7.28 (s, 1H), 7.19 (d, J = 8.7 Hz, 2H), 4.27 (s, 1H), 3.03 (s, 3H), 2.91 (s, 2H), 2.15 (s, 2H), 2.08-1.96 (m, 5H), 1.89 (s, 3H), 1.82 (d, J = 13.0 Hz, 5H), 1.69 (d, J = 12.1 Hz, 4H), 1.51 (dd, J = 27.1, 11.6 Hz, 7H), 1.24 (s, 1H).
1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.74 (d, J = 40.5 Hz, 1H), 7.67 (s, 1H), 7.40 (t, J = 7.3 Hz, 4H), 7.13 (d, J = 6.8 Hz, 1H), 4.40 (d, J = 9.7 Hz, 2H), 2.79 (d, J = 9.0 Hz, 3H), 2.64 (s, 3H), 2.35 (s, 1H), 2.24 (s, 1H), 1.78 (q, J = 31.6, 29.3 Hz, 8H), 1.48 (q, J = 13.5 Hz, 2H), 1.27 (q, J = 12.7, 11.8 Hz, 1H).
1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.80 (s, 1H), 7.70 (s, 1H), 7.41 (m, 4H), 7.16 (s, 1H), 4.42 (s, 2H), 3.89 (s, 6H), 1.87 (d, J = 38.1 Hz, 8H), 1.27 (s, 2H).
1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 9.6 Hz, 3H), 7.16 (s, 1H), 4.41 (s, 2H), 1.82 (t, J = 41.2 Hz, 8H), 1.49 (s, 2H), 1.25 (d, J = 22.2 Hz, 1H).
1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.79 (s, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.52-7.28 (m, 4H), 7.15 (s, 1H), 4.42 (d, J = 7.2 Hz, 2H), 2.83 (t, J = 7.2 Hz, 2H), 2.67 (s, 2H), 2.30 (s, 3H), 2.01 (br s, 1H), 2.02-1.59 (m, 8H), 1.50 (d, J = 13.5 Hz, 5H), 1.37 (s, 2H), 1.26 (d, J = 13.7 Hz, 2H).
1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 18.7 Hz, 3H), 7.74 (d, J = 39.2 Hz, 1H), 7.67 (s, 1H), 7.54-7.29 (m, 7H), 7.13 (s, 1H), 4.40 (d, J = 17.1 Hz, 2H), 2.86 (s, 2H), 2.70 (s, 2H), 2.38 (s, 1H), 2.24 (s, 1H), 1.89 (s, 2H), 1.75 (dq, J = 27.5, 13.0 Hz, 5H), 1.48 (d, J = 13.5 Hz, 2H), 1.23 (d, J = 12.6 Hz, 1H).
1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.79-7.65 (m, 2H), 7.51-7.36 (m, 4H), 7.18 (d, J = 6.9 Hz, 1H), 6.00 (s, 3H), 4.44 (d, J = 9.1 Hz, 2H), 2.83 (t, J = 7.6 Hz, 4H), 1.91 (t, J = 16.8 Hz, 3H), 1.88-1.68 (m, 6H), 1.56-1.43 (m, 2H), 1.26 (td, J = 33.8, 30.5, 22.8 Hz, 2H).
indicates data missing or illegible when filed
Anti-Infective Activity of the Synthesised Compounds
The compounds as disclosed by the present application have anti-infective activity.
Initial minimal inhibitory concentration (MIC) tests were made on two bacterial strains:
The results of these tests are shown in Table XIII.
The MIC of selected compounds was determined against a number of additional strains:
Enterococcus faecalis (ATCC29212)
Pseudomonas aeruginosa (ATCC27853)
Staphylococcus aureus subsp. aureus (ATCC29213)
Klebsiella pneumoniae subsp. pneumoniae (ATCC13883)
Streptococcus pneumoniae (ATCC33400)
Haemophilus influenzae (ATCC49766)
Neisseria meningitidis (ATCC13077)
Listeria monocytogenes (ATCC15313)
Legionella pneumophila subsp. pneumophila (ATCC33152)
Mycobacterium bovis BCG (ATCC19210)
The results of these tests are shown in Table XIV.
Minimal Inhibitory Concentration (MIC)
MIC values were determined using the standard broth microdilution procedure based on the guidelines by the Clinical and Laboratory Standards Institute (CLSI). Briefly, the compounds were dissolved in DMSO to 10 mM. They were diluted in cation-adjusted Mueller-Hinton broth (CAMHB) to four times the highest concentration tested. A serial two-fold dilution in CAMHB was done in microdilution plates. The inoculum of bacterial strain to be tested was prepared by making a suspension of colonies from an 18 to 24 hours old plate in CAMHB. The inoculum was diluted so that, after inoculation, each well contained approximately 5×105 CFU/mL. To a volume of 50 μl compound in CA 3 an equal volume of inoculum was added. The tray was sealed in a plastic bag and incubated at 35° C. for 16 to 20 hours. To aid in the detection of growth the dye resazurin was added to a final concentration 0.001% and incubated at room temperature for 1 h. Reduction of resazurin, and therefore bacterial growth, was seen as a change from blue to pink. The MIC is the lowest concentration of compound that completely inhibits growth of the organism. The method used is described in detail in: Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard—Ninth Edition. CLSI document M07-A9. Wayne, Pa.: Clinical and Laboratory Standards Institute; 2012.
Inhibition of Bacterial RNaseP Activity.
The assay is based on how much the cleavage of the model substrate pATSerUG by E. coli RNase P RNA, M1 RNA, is inhibited by the compound.
The substrate pATSerUG is a 45 nt long model substrate encompassing the 5′ leader, the amino acid acceptor stem and the T-stem/loop structure of the E. coli tRNASerSu1 precursor. It was purchased from Dharmacon/GE Healthcare, and labelled with 32P at the 5′ end with [γ-32P]ATP according to standard procedures, and purified by electrophoresis on a denaturing polyacrylamide gel.
The M1 RNA was generated by T7 in vitro transcription using a PCR product with the M1 RNA gene as template.
The compound to be tested was dissolved in assay buffer (see below). Assay buffer was added to a theoretical concentration of up to 10 mM. After vortexing and incubation at room temperature for 30 minutes the undissolved compound was removed by centrifugation (17,000×g 10 min). The concentration of compound in the supernatant was determined spectroscopically by measuring the absorbance at a wavelength where the compound had an absorbance maximum. The calibration curve was made from known concentrations of the compound dissolved in DMSO.
The cleavage reaction was performed in assay buffer (50 mM Tris-HCl, pH 7.9, 1 m MNH4Cl, 10 mM MgCl2, 5% PEG6000, 10 mM spermidine).
M1 RNA was diluted to 10 times the concentration to be used in assay buffer and preincubated at 37° C. for 10 min to allow proper folding. The final concentration of M1 RNA was determined for each batch of enzyme, and was the concentration that gave approximately 50% cleavage of the substrate in a 10 min reaction. The folded M1 RNA was mixed with the compound to be tested in a total volume of 9 μl and incubated for an additional 10 min at 37° C. The substrate was preheated separately for 5 min at 37° C. The reaction was started by the addition of 1 μl substrate to the M1 RNA-compound mixture. After 10 min incubation at 37° C. the reaction was stopped by the addition of 20 μl stop solution (10 M urea, 100 mM EDTA, 0.05% bromophenol blue, 0.05% xylene cyanol). The reactions were then heated to 95° C. for 3 min, chilled on ice, the cleavage products were seperated on denaturing 20% polyacrylamide (7 M urea/TBE) gels and detected using a Phosphoimager. The signals were quantitated using the softwares QuantityOne or ImageLab.
Initial Screening for Inhibition of RNase P Activity
To test if any inhibition could be detected for the compound an initial inhibition of RNase P activity was determined. The maximum amount of compound was used, i.e. 8 μl of the supernatant from freshly dissolved compound in assay buffer in a 10 μl cleavage reaction. The degree of inhibition was judged from the normalised cleavage (the ratio between cleavage with compound divided by cleavage without compound). If this ratio was <0.5, the IC50 value was determined (Table XIII).
IC50 Determination.
About 8 different concentrations, generally ranging from maximum concentration for the compound down to 8000 times diluted, were tested for cleavage. The IC50 values and Hill slopes were calculated using the software GraphPad Prism. The determined IC50 values are listed in Table XIV.
E. coli
S. aureus
S. aureus
S. aureus
S. aureus
S. aureus
E. faecalis
E. faecium
S. pneumoniae
M. phlei
M. fortuitum
E. coli
E. coli
K. pneumoniae
H. influenzae
A. baumannii
P. aeruginosa
P. aeruginosa
N. gonorrhoeae
H. pylori
| Number | Date | Country | Kind |
|---|---|---|---|
| 1751369-8 | Nov 2017 | SE | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/SE2018/051126 | 11/5/2018 | WO | 00 |
