Patent Grant
8501767
This application is a U.S. national stage entry under 35 U.S.C. §371 of International Patent Application PCT/IB2009/054021 filed 15, Sep. 2009, which claims priority to South African Patent Application No. 2008/07954, entitled COMPOUNDS AND COMPOSITIONS HAVING ACTIVITY AGAINST THE ENZYME HIV-1 REVERSE TRANSCRIPTASE, filed 16, Sep. 2008, all of which are incorporated herein by reference in their entirety.
THIS INVENTION relates to compounds and compositions having activity against the enzyme HIV-1 reverse transcriptase.
Highly active antiretroviral treatment (HAART) is a treatment regimen for HIV-AIDS sufferers which combines a cocktail of antiretroviral drugs chosen from a number of different classes. One of these classes comprises the non-nucleoside reverse transcriptase inhibitors (NNRTIs). These drugs act by inhibiting the enzyme HIV-1 reverse transcriptase. This enzyme is a validated target for the development of anti-HIV drugs. There are a number of NNRTIs that are FDA approved and one of these drugs generally forms part of the first-line treatment regimen against HIV-AIDS. There are a number of advantages associated with this class. One of the advantages is the excellent selectivity index (ratio of 50% cytotoxic concentration to 50% antivirally effective concentration) displayed by these drugs, which is usually of the order of 10,000-100,000. This high selectivity makes the NNRTI class the least toxic of the clinically approved antiretrovirals and makes these drugs suitable for use in the prevention of mother to child transmission. The reason for the high selectivity is the fact that NNRTIs only recognise and bind to HIV-1 reverse transcriptase, not to any other RTs or DNA or RNA polymerases. These drugs act by binding to a lipophilic, non-substrate binding pocket located about 10 Å from the substrate binding site. This binding results in conformational changes within the reverse transcriptase catalytic site that leads to a dramatic slowing down of the catalytic activity. The allosteric inhibitors of reverse transcriptase (RT) possess very different structural characteristics and as many as 50 diverse structural classes have been found to have activity against reverse transcriptase. The first generation of NNRTIs (exemplified by nevirapine and delavirdine) is sensitive to the development of drug resistance and even a single amino acid mutation in the NNRTI binding region of RT confers a high level of drug resistance. There is accordingly a requirement for NNRTIs which can inhibit as many different RT mutants as possible.
The applicant is aware of PCT/US2008/082531 entitled “Non-nucleoside reverse transcriptase inhibitors” (filed on 5 Nov. 2008) which claims the priority of U.S. Ser. No. 60/986,990 (filed on 9 Nov. 2007). The generic structure disclosed in this document covers a very large number of compounds. The document specifically discloses about 11600 compounds. However, inhibition data are provided for only about 30 compounds. The generic disclosure of the present application covers a substantially smaller number of compounds and those compounds of PCT/US2008/082531 which fall within the scope of the generic structure of the present application have been excluded by the introduction of provisos.
According to a first aspect of the invention there is provided a compound selected from compounds of the formula A or B
in which, for formula A,
R is cycloalkyl and R1 is substituted aryl.
The alkyl and branched alkyl groups of R1 may be optionally substituted by one or more heteroatoms. The heteroatoms may be oxygen, nitrogen or sulphur. For example the alkyl group may be substituted by a thiomethyl group. The substituted alkyl group may, therefore, be a 2-thiomethylethyl group. The phenyl group may optionally be substituted by one or more substituents selected from halogen, OH, alkyl, alkoxy, cyano, amino, substituted alkyl, halo or nitro. The heteroaryl group may be an O, N or S heteroaryl group and may, for example, be selected from oxazolyl, isoxazolyl, substituted isoxazolyl, furanyl, and thiophenyl groups.
The halogen may be selected from one or more of F, Cl and Br.
The cycloalkyl group may be selected from C3-C6 cycloalkyl groups and adamantane. For example, the cycloalkyl group may be a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or tetrahydrofuranyl group.
The alkyl and branched alkyl groups may be selected from C2 to C12 alkyl and branched alkyl groups. Preferred alkyl and branched alkyl groups include 2-pentyl, 1-butyl, 2-propyl, 2-butyl and 1-pentyl and 1-octyl.
Examples of preferred compounds of the invention, of formula A are compounds in which:
(a) R is selected from ethyl, 2-morpholinoethyl, 1-butyl, 2-pentyl, 1-pentyl, 1,1,3,3-tetramethylbutyl, isopropyl, cyclohexyl, cyclopropyl, 4-(3,4-dichlorophenoxy)butyl, 1-adamantyl, 4-methoxyphenyl, 2-naphthyl, benzyl, 4-chlorobenzyl, 2-chloro-6-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, cyclopentyl;
(b) R1 is selected from ethyl, 2-(methylthio)ethyl, 1-propyl, 2-butyl, 2-methyl-1-propyl, 2,2-dimethyl-1-propyl, cyclopropyl, cyclopentyl, cyclohexyl, 1-pentyl, 2-pentyl, 3-pentyl, tert-butyl, isopropyl, isobutyl, 1-octyl, 1-phenylethyl, 2-hydroxyphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-nitrophenyl, 2-fluorophenyl, 4-fluorophenyl, 3-ethoxy-4-hydroxy-phenyl, 4-dimethylaminophenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxy-4-hydroxyphenyl, 4-benzyloxyphenyl, 2,4-dimethoxyphenyl, 4-hydroxy-3-methoxy-phenyl, 3-hydroxy-4-methoxy-phenyl, 2,3,6-trichlorophenyl, 2-fluoro-(3-methoxy)phenyl, 3-chloro-2-fluoro-phenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 4-chloro-3-fluoro-phenyl, 2-chloro-6-fluoro-5-methyl-phenyl, 3-(5-methyl)isoxazolyl, 2-(5-hydroxymethyl)furanyl, 2-furanyl, 2-(5-chloro)furanyl, 2-(5-ethyl)thienyl, 2-(3-methyl)thienyl, 2,4,5-trifluorophenyl, 3-(2,5-dimethoxy)tetrahydrofuranyl, 4-cyanophenyl, 3-cyanophenyl, norpinenyl;
(c) R2 is selected from H, benzyloxy, methyl, chloro;
(d) R3 is selected from H, methyl, chloro;
(e) R4 is selected from H, chloro, fluoro, methyl, bromo, nitrile, 2-methylphenyl, 4-methoxyphenyl,
(f) R5 is selected from H, methyl, chloro, bromo, 2-methylphenyl, phenyloxy, 4-methoxyphenyl, ethoxy, cyano;
(g) R6 is selected from H, ethyl, acetyl,
(h) R4 and R5 together form an aromatic ring.
(i) R2 and R3 together form an aromatic ring.
According to a second aspect of the invention there is provided a composition for use in treating a subject who has been infected with HIV, the composition including a compound selected from compounds of formula A or B as described above.
According to a third aspect of the invention there is provided a substance or composition for use in a method of treating a subject who has been infected by HIV, the substance or composition including a compound selected from compounds of formula A or B as described above.
According to a fourth aspect of the invention, there is provided the use of a compound selected from compounds of formula A or B as described above in the manufacture of a medicament for the treatment of a subject infected with HIV.
The compounds of the invention have been found to have activity against the enzyme reverse transcriptase in the μ-molar range. In addition these compounds have been found to be active against HIV in the whole cell PBMC or MAGI anti-HIV assay in the μM to nM range.
According to a fifth aspect of the invention there is provided a method of treating a subject who has been infected by HIV, the method including administering to a subject in need of treatment a compound selected from compounds of formula A or B as described above.
The compounds of the invention can readily be prepared in one step by an acid-catalysed three-component coupling reaction as shown in Scheme 1 in which a 2-aminopyridine or a substituted 2-aminopyridine, in which R, R1, R2, R3, R4 and R5 are as hereinbefore described, is reacted with an aldehyde and an isonitrile in the presence of montmorillonite K-10 clay or any other suitable acid catalyst at 95-100° C. for 5-8 hours under conventional heating or 15-30 min under microwave irradiation. The product is generally isolated by column chromatography.
Thus according to a sixth aspect of the invention, there is provided a method of synthesising a compound selected from compounds of formula A or B as described above, which includes the step of condensing a 2-aminopyridine or a substituted 2-aminopyridine of the formula
or 2-aminopyrimidine with an aldehyde of the formula R1CHO and an isocyanide of the formula RNC in which R, R1, R2, R3, R4, R5 and R6 are as described above.
Examples of the compounds of the invention are set out in Scheme 2.
The invention is now described, by way of example with reference to the following Examples.
All compounds were prepared by one of four methods
The appropriate 2-aminopyridine (1.33 mmol), aldehyde (1.33 mmol) and isocyanide (1.36 mmol) in dioxane (2.5 ml) were heated in the presence of montmorillonite K-10 clay (250 mg) for 5-8 h at 95-100° C. After reaction, the liquid was filtered from the clay and the clay was rinsed with dioxane or ethyl acetate (2×2.5 ml). The solvent was removed in vacuo and the residue purified by column chromatography (elution hexane:ethyl acetate) to afford the required product.
Method 1 applies to compounds: 1-15, 17-31, 33-41, 43, 49-64, 67-77, 106-110, 112-115 and 117-183.
As for method 1, but instead of heating, the reaction was stirred at room temperature for 48 h.
Method 2 applies to compounds: 45-47
As for method 1, but instead of conventional heating, reaction components were reacted under microwave irradiation at 150 W and 100° C. for 15-30 min in a sealed pressure tube.
Method 3 applies to compounds: 42, 44, 48, 65, 66, 78-105, 111, 116, 186-194. In the case of the pyrimidine 193, the appropriate 2-aminopyrimidine (1.33 mmol) and aldehyde (2.66 mmol) were microwaved at 150 W power and 150° C. for 35 min without solvent. Isocyanide (1.60 mmol), dioxane (1.5 ml) and montmorillonite K-10 clay (250 mg) were then added and irradiated at 150 W and 100° C. for 25 min. After reaction, the liquid was filtered from the clay and the clay was rinsed with dioxane or ethyl acetate.
The solvent was removed in vacuo and the residue purified by column chromatography (elution ethyl acetate) to afford the required product.
Imidazo[1,2-a]pyridines prepared by method 1 or 3 were further modified to produce compounds 16, 32, 184 and 185. Preparations are described below.
N-butyl-2-isopropylimidazo[1,2-a]pyridin-3-amine 5 (250 mg, 1.08 mmol) was reacted with acetyl chloride (2 eq., 2.16 mmol, 154 μl) in the presence of K2CO3 (2 eq., 2.16 mmol, 299 mg) in acetonitrile (10 ml) at room temperature. The reaction progress was monitored by TLC. Purification of the product was achieved by column chromatography, eluting with ethyl acetate:hexane.
N-butyl-N-(2-isopropylimidazo[1,2-a]pyridin-3-yl)acetamide 16 (287 mg, 1.05 mmol) was reacted with LiAlH4 (2 eq., 2.10 mmol, 80 mg) in THF (10 ml) at room temperature. Progress of the reaction was monitored by TLC. Aqueous NaOH solution was used to quench the reaction. Solids were filtered and washed with ethyl acetate and the product was purified by column chromatography, eluting with ethyl acetate.
Phenol (40.43 mg, 0.687 mmol) was dissolved in DMF (5 ml) and sodium metal (10.31 mg, 0.687 mmol) was added portion-wise. 5-Bromo-2-(2-chlorophenyl)-N-cyclohexylimidazo[1,2-a]pyridin-3-amine 42 (139.1 mg, 0.344 mmol) was added to this sodium phenoxide solution and heated at 90° C. for 4 h. The reaction was quenched with water and extracted into ethyl acetate. The product was purified by column chromatography, elution ethyl acetate:hexane.
5-bromo-2-(2-chlorophenyl)-N-cyclohexylimidazo[1,2-a]pyridin-3-amine 42 (152 mg, 0.376 mmol) was added to sodium ethoxide [generated in situ by addition of sodium metal (17.32 mg) to absolute ethanol (10 ml)]. The mixture was heated under reflux for 8 h. Excess solvent was removed in vacuo and the resultant mixture was treated with water before been extracted into ethyl acetate, dried over magnesium sulphate and filtered. Excess solvent was removed under reduced pressure to give an oil that was purified by column chromatography, eluting with hexane:ethyl acetate.
The analytical data of compounds 1-194 are set out below.
1H NMR (200 MHz, CDCl3) δ 8.05-7.94 (m, 1H), 7.46-7.33 (m, 1H), 7.01 (ddd, J=1.3, 6.7, 9.0, 1H), 6.69 (td, J=1.0, 6.7, 1H), 3.07-2.67 (m, 2H), 2.11-1.82 (m, 3H), 1.82-1.67 (m, 2H), 1.67-1.48 (m, 1H), 1.41-1.10 (m, 5H), 1.05 (dt, J=4.1, 5.2, 2H), 1.01-0.85 (m, 2H).
13C NMR (50 MHz, CDCl3) δ 141.22, 140.49, 124.82, 122.67, 121.94, 116.62, 110.82, 57.24, 34.37, 25.85, 24.94, 8.18, 7.73.
HRMS (ESI): m/z 256.1810 (M+H)+; calc. for C16H22N3: 256.1814.
1H NMR (200 MHz, CDCl3) δ 8.10-7.94 (m, 1H), 7.48-7.38 (m, 1H), 7.06 (ddd, J=1.3, 6.6, 9.0, 1H), 6.72 (td, J=1.1, 6.8, 1H), 3.20-2.78 (m, 6H), 2.18-2.00 (m, 3H), 1.76 (ddt, J=6.2, 10.2, 18.4, 5H), 1.41-1.03 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 141.43, 137.54, 125.25, 123.10, 122.53, 116.90, 111.11, 57.16, 34.43, 34.35, 27.81, 25.79, 24.91, 15.87.
HRMS (ESI): m/z 290.1684 (M+H)+; calc. for C16H24N3S: 290.1691.
1H NMR (200 MHz, CDCl3) δ 8.14-7.93 (m, 1H), 7.48 (dt, J=1.3, 9.5, 1H), 7.04 (ddd, J=1.2, 6.7, 8.8, 1H), 6.71 (td, J=1.1, 6.9, 1H), 3.10-2.63 (m, 2H), 2.12-1.48 (m, 9H), 1.48-1.06 (m, 10H), 1.06-0.90 (m, 2H), 0.85 (t, J=7.3, 3H).
13C NMR (50 MHz, CDCl3) δ 143.77, 141.75, 124.39, 123.01, 122.71, 117.13, 111.12, 57.58, 34.55, 34.51, 33.63, 30.16, 26.09, 25.23, 25.15, 21.07, 12.87.
HRMS (ESI): m/z 272.2127 (M+H)+; calc. for C17H26N3: 272.2127.
1H NMR (200 MHz, CDCl3) δ 8.01 (d, J=6.9, 1H), 7.52 (d, J=9.1, 1H), 7.18-7.05 (m, 1H), 6.78 (td, J=0.7, 6.8, 1H), 6.63-6.55 (m, 1H), 4.79-3.86 (m, 1H), 3.17-2.91 (m, 1H), 2.48 (s, 3H), 2.03-1.46 (m, 5H), 1.46-0.91 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 168.61, 159.55, 141.64, 129.39, 123.54, 123.02, 117.87, 111.94, 100.67, 56.38, 34.07, 25.70, 25.08, 12.21.
HRMS (ESI): m/z 297.1701 (M+H)+; calc. for C17H21N4O: 297.1715.
1H NMR (200 MHz, CDCl3) δ 7.92 (d, J=6.8, 1H), 7.56-7.30 (m, 1H), 6.97 (ddd, J=0.9, 6.7, 8.6, 1H), 6.64 (td, J=0.6, 6.7, 1H), 3.24-2.97 (m, 1H), 2.90 (t, J=6.8, 3H), 1.65-1.34 (m, 4H), 1.30 (d, J=6.9, 6H), 0.87 (t, J=7.1, 3H).
13C NMR (50 MHz, CDCl3) δ 143.98, 141.19, 124.52, 122.64, 122.08, 117.08, 110.96, 48.96, 32.90, 26.45, 22.80, 20.22, 13.92.
HRMS (ESI): m/z 232.1808 (M+H)+; calc. for C14H22N3: 232.1814.
1H NMR (200 MHz, CDCl3) δ 8.02 (d, J=6.8, 1H), 7.49 (d, J=8.9, 1H), 7.07-6.95 (m, 1H), 6.72 (dd, J=3.7, 9.7, 1H), 3.31-3.01 (m, 1H), 2.85 (ddd, J=5.2, 7.7, 10.2, 2H), 2.00-1.51 (m, 5H), 1.36 (d, J=6.9, 6H), 1.22 (dt, J=7.3, 12.7, 5H).
13C NMR (50 MHz, CDCl3) δ 144.66, 141.40, 123.06, 122.76, 122.44, 117.00, 110.94, 57.23, 34.30, 26.20, 25.85, 24.95, 22.83.
HRMS (ESI): m/z 258.1963 (M+H)+; calc. for C16H24N3: 258.1970.
1H NMR (200 MHz, CDCl3) δ 8.11-7.98 (m, 1H), 7.51-7.34 (m, 1H), 7.00 (ddd, J=0.7, 2.1, 9.5, 1H), 3.26-2.99 (m, 1H), 2.99-2.65 (m, 2H), 2.11-1.52 (m, 5H), 1.48-1.28 (m, 6H), 1.28-1.07 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 146.07, 139.73, 124.02, 123.66, 120.39, 119.45, 117.36, 57.23, 34.26, 26.28, 25.78, 24.91, 22.72.
HRMS (ESI): m/z 292.1581 (M+H)+; calc. for C16H23N3Cl: 292.1581.
1H NMR (200 MHz, CDCl3) δ 8.17 (dt, J=1.0, 6.9, 1H), 7.70 (dd, J=3.0, 6.4, 1H), 7.62-7.52 (m, 1H), 7.52-7.29 (m, 3H), 7.16 (ddd, J=1.1, 6.6, 9.0, 1H), 6.82 (td, J=0.9, 6.7, 1H), 3.29 (d, J=6.7, 1H), 2.68 (s, 1H), 1.88-1.31 (m, 5H), 1.30-0.77 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 141.56, 135.04, 133.98, 132.56, 129.42, 129.07, 126.86, 126.33, 123.66, 122.83, 117.52, 111.55, 56.41, 33.87, 25.67, 24.60.
HRMS (ESI): m/z 326.1440 (M+H)+; calc. for C19H21N3Cl: 326.1424.
1H NMR (200 MHz, CDCl3) δ 8.01 (d, J=6.8, 1H), 7.45 (d, J=9.2, 1H), 7.17-6.89 (m, 1H), 6.71 (t, J=6.8, 1H), 2.75 (m+dd, J=7.6, 15.1, 4H), 2.08-1.46 (m, 5H), 1.34 (t, J=7.5, 3H), 1.27-1.02 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 141.52, 140.82, 124.27, 123.22, 122.67, 117.02, 111.34, 57.42, 34.55, 26.09, 25.18, 20.74, 14.26.
HRMS (ESI): m/z 244.1809 (M+H)+; calc. for C15H22N3: 244.1814.
1H NMR (200 MHz, CDCl3) δ 8.15 (d, J=6.7, 1H), 7.47 (d, J=9.0, 1H), 7.17-6.91 (m, 1H), 6.68 (t, J=6.7, 1H), 3.32-2.96 (m, 1H), 2.96-2.37 (m, 1H), 1.35 (d, J=6.8, 6H), 1.15 (d, J=8.1, 6H), 1.07 (d, J=10.9, 10H).
13C NMR (50 MHz, CDCl3) δ 146.77, 142.18, 123.36, 122.99, 121.43, 116.91, 110.57, 59.26, 56.93, 31.97, 31.82, 29.23, 26.12, 22.89.
HRMS (ESI): m/z 288.2426 (M+H)+; calc. for C18H30N3: 288.2440.
1H NMR (200 MHz, CDCl3) δ 7.98 (d, J=6.8, 1H), 7.48 (d, J=9.0, 1H), 7.04 (dd, J=6.5, 8.5, 1H), 6.71 (t, J=6.9, 1H), 3.20-3.05 (m, 2H), 2.96 (t, J=7.0, 2H), 1.58 (ddd, J=3.7, 7.9, 14.3, 2H), 1.42-1.10 (m, 10H), 0.90 (t, J=7.0, 3H).
13C NMR (50 MHz, CDCl3) δ 143.89, 141.17, 124.52, 122.69, 122.08, 117.05, 111.00, 49.25, 30.50, 29.23, 26.44, 22.79, 22.55, 14.02.
HRMS (ESI): m/z 246.1950 (M+H)+; calc. for C15H24N3: 246.1970.
1H NMR (200 MHz, CDCl3) δ 8.09 (d, J=6.9, 1H), 7.74-7.60 (m, 1H), 7.60-7.37 (m, 2H), 7.20-7.03 (m, 1H), 6.98 (d, J=8.2, 1H), 6.75 (t, J=7.1, 1H), 4.35-4.04 (m, 3H), 3.36-2.68 (m, 2H), 1.95-1.52 (m, 5H), 1.45 (t, J=6.9, 3H), 1.37-0.97 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 146.08, 145.42, 141.38, 136.83, 126.87, 124.06, 123.53, 122.54, 119.92, 117.13, 114.30, 111.34, 111.17, 64.60, 56.83, 34.24, 25.79, 24.85, 15.00.
HRMS (ESI): m/z 352.2025 (M+H)+; calc. for C21H26N3O2: 352.2025.
1H NMR (200 MHz, CDCl3) δ 7.73 (d, J=8.7, 2H), 7.55 (d, J=8.2, 1H), 7.46-7.07 (m, 3H), 6.94 (dd, J=2.3, 8.8, 1H), 6.73 (d, J=1.4, 1H), 6.26 (s, 1H), 5.58 (s, 1H), 2.62 (s, 3H), 2.33 (s, 3H), 1.94 (ddd, J=5.1, 8.5, 13.5, 1H), 1.16-0.97 (m, 2H), 0.87 (ddd, J=3.8, 6.3, 11.8, 2H).
13C NMR (50 MHz, CDCl3) δ 145.76, 145.18, 144.78, 135.27, 134.89, 134.43, 129.52, 128.25, 127.63, 126.48, 126.12, 122.70, 118.67, 116.19, 115.53, 113.68, 107.06, 20.93, 18.76, 7.83, 7.54.
HRMS (ESI): m/z 328.1803 (M+H)+; calc. for C22H22N3: 328.1814.
1H NMR (200 MHz, CDCl3) δ 8.14-8.05 (m, 1H), 7.97 (d, J=8.9, 2H), 7.51 (dd, J=0.5, 8.9, 1H), 7.17-7.04 (m, 1H), 6.98 (d, J=8.9, 2H), 6.74 (td, J=0.9, 6.7, 1H), 3.84 (s, 3H), 3.40 (td, J=7.2, 13.1, 1H), 3.16-2.79 (m, 1H), 1.08 (d, J=6.3, 6H).
13C NMR (50 MHz, CDCl3) δ 158.95, 141.59, 138.21, 128.31, 127.21, 123.61, 122.54, 117.22, 113.95, 111.34, 55.28, 49.12, 23.45.
HRMS (ESI): m/z 282.1602 (M+H)+; calc. for C17H20N3O: 282.1606.
1H NMR (200 MHz, CDCl3) δ 7.05 (s, 1H), 6.20 (s, 1H), 2.83 (s, 3H), 2.61 (dd, J=8.7, 16.6, 4H), 2.28 (s, 3H), 1.98-1.50 (m, 7H), 1.16 (s, 5H), 0.98 (t, J=7.3, 3H).
13C NMR (50 MHz, CDCl3) δ 143.53, 140.95, 135.08, 133.70, 125.46, 115.34, 113.67, 59.57, 33.61, 29.74, 26.01, 25.17, 22.71, 20.77, 19.51, 14.33.
HRMS (ESI): m/z 286.2284 (M+H)+; calc. for C18H28N3: 286.2283.
1H NMR (200 MHz, DMSO-d6) δ 8.13 (d, J=6.3, 1H), 7.55 (d, J=9.3, 1H), 7.45-7.19 (m, 1H), 6.96 (t, J=6.7, 1H), 3.73-3.26 (m, 11H), 3.10-2.78 (m, 1H), 2.65-2.42 (m, 1H), 1.73 (s, 1H), 1.63 (s, 2H), 1.54-1.32 (m, 3H), 1.26 (t, J=6.7, 6H), 0.82 (t, J=6.9, 3H).
13C NMR (50 MHz, DMSO-d6) δ 175.26, 171.14, 170.96, 146.57, 141.97, 124.82, 122.51, 118.46, 116.80, 112.58, 47.01, 30.61, 29.99, 25.61, 24.08, 22.44, 22.01, 21.82, 21.74, 20.74, 19.56, 13.59.
1H NMR (200 MHz, DMSO-d6) δ 8.13-7.79 (m, 3H), 7.55 (dd, J=8.8, 14.7, 1H), 7.39-7.16 (m, 1H), 7.04-6.83 (m, 3H), 6.76 (d, J=8.8, 2H), 6.45 (d, J=8.8, 2H), 3.77 (s, 3H), 3.64 (s, 3H).
13C NMR (50 MHz, DMSO-d6) δ 158.66, 152.22, 141.40, 139.19, 139.12, 137.35, 127.65, 126.18, 124.64, 122.81, 116.70, 114.97, 113.79, 113.41, 111.83, 55.19, 55.03.
HRMS (ESI): m/z 346.1548 (M+H)+; calc. for C21H20N3O2: 346.1556.
1H NMR (200 MHz, CDCl3) δ 7.99 (d, J=6.8, 1H), 7.52 (d, J=8.9, 1H), 7.35 (s, 5H), 7.19-6.97 (m, 1H), 6.72 (t, J=6.7, 1H), 4.15 (d, J=3.7, 2H), 3.35-3.17 (m, 1H), 3.17-2.94 (m, 1H), 1.33 (d, J=6.9, 6H).
13C NMR (50 MHz, CDCl3) δ 144.54, 141.34, 139.39, 128.60, 128.22, 127.54, 123.84, 122.89, 122.05, 117.14, 111.10, 53.33, 26.49, 22.74.
HRMS (ESI): m/z 266.1637 (M+H)+; calc. for C17H20N3: 266.1657.
1H NMR (200 MHz, CDCl3) δ 8.01 (d, J=7.3, 1H), 7.49 (d, J=9.0, 1H), 7.17-6.92 (m, 1H), 6.71 (t, J=6.8, 1H), 3.34-3.03 (m, 1H), 3.02-2.64 (m, 2H), 2.12-1.82 (m, 8H), 1.82-1.44 (m, 5H), 1.44-1.00 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 142.71, 141.52, 124.07, 122.63, 122.31, 116.99, 110.83, 57.19, 37.61, 34.33, 33.53, 26.04, 25.88, 25.00.
HRMS (ESI): m/z 284.2125 (M+H)+; calc. for C18H26N3: 284.2127.
1H NMR (200 MHz, CDCl3) δ 7.93-7.79 (m, 1H), 7.73 (d, J=8.7, 2H), 7.69-7.58 (m, 1H), 7.51 (d, J=8.1, 1H), 7.43-7.12 (m, 3H), 6.95 (dd, J=2.4, 8.8, 1H), 6.72 (td, J=1.1, 6.8, 1H), 6.66 (d, J=2.2, 1H), 5.73 (s, 1H), 3.37-3.03 (m, 1H), 1.37 (d, J=6.9, 6H).
13C NMR (50 MHz, CDCl3) δ 148.20, 143.18, 142.59, 134.74, 129.56, 128.42, 127.63, 126.54, 126.07, 124.12, 122.90, 122.44, 117.36, 116.97, 116.27, 111.68, 106.69, 26.79, 22.31.
HRMS (ESI): m/z 302.1640 (M+H)+; calc. for C20H20N3: 302.1657.
1H NMR (200 MHz, CDCl3) δ 8.09-7.90 (m, 1H), 7.53-7.37 (m, 1H), 7.15-6.95 (m, 1H), 6.80-6.64 (m, 1H), 5.40-4.99 (m, 2H), 3.81-3.62 (m, 1H), 3.44 (dd, J=4.2, 10.4, 6H), 3.04 (dd, J=5.3, 10.8, 1H), 2.85 (td, J=5.5, 9.5, 1H), 2.72-2.41 (m, 1H), 2.41-2.19 (m, 1H), 1.99-1.37 (m, 5H), 1.17 (dq, J=7.5, 13.3, 5H).
13C NMR (50 MHz, CDCl3) δ 147.44, 141.52, 138.14, 137.54, 136.67, 125.76, 123.16, 122.83, 122.49, 122.25, 117.18, 117.03, 116.85, 113.69, 111.51, 111.17, 109.68, 109.13, 105.97, 105.38, 104.83, 104.50, 57.13, 57.08, 56.13, 55.74, 54.92, 42.71, 41.75, 38.71, 36.36, 34.34, 34.18, 34.11, 25.73, 25.01, 24.89, 24.85.
HRMS (ESI): m/z 346.2094 (M+H)+; calc. for C19H28N3O3: 346.2131.
1H NMR (200 MHz, CDCl3) δ 7.96-7.76 (m, 1H), 7.36 (dd, J=5.0, 9.7, 1H), 6.99-6.70 (m, 1H), 3.22-2.93 (m, 1H), 2.77 (s, 2H), 1.92-1.41 (m, 5H), 1.28 (d, J=6.9, 6H), 1.22-0.87 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 155.15, 150.48, 146.47, 138.82, 138.11, 124.36, 117.28, 117.10, 114.49, 113.97, 109.17, 108.35, 57.01, 34.11, 26.20, 25.63, 24.75, 22.61.
HRMS (ESI): m/z 276.1858 (M+H)+; calc. for C16H23N3F: 276.1876.
1H NMR (200 MHz, CDCl3) δ 7.11 (s, 1H), 6.20 (s, 1H), 3.08 (dt, J=6.9, 13.7, 1H), 2.83 (s, 3H), 2.64 (s, 1H), 2.26 (s, 3H), 1.89-1.51 (m, 5H), 1.32 (d, J=6.9, 6H), 1.26-0.97 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 146.49, 143.95, 135.39, 133.92, 124.12, 115.64, 115.61, 114.12, 114.09, 59.82, 33.80, 26.27, 26.19, 25.45, 22.99, 21.03, 19.85.
HRMS (ESI): m/z 286.2277 (M+H)+; calc. for C18H28N3: 286.2283.
1H NMR (200 MHz, CDCl3) δ 8.04-7.91 (m, 1H), 7.48-7.34 (m, 1H), 7.14-6.92 (m, 1H), 6.83-6.60 (m, 1H), 3.03 (t, J=7.1, 3H), 1.99 (ddd, J=5.2, 8.4, 13.5, 1H), 1.74-1.49 (m, 2H), 1.49-1.17 (m, 4H), 1.15-1.00 (m, 2H), 1.00-0.75 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 141.31, 139.89, 126.43, 122.93, 121.98, 116.99, 111.18, 49.36, 30.81, 29.51, 22.83, 14.30, 8.33, 7.81.
HRMS (ESI): m/z 244.1819 (M+H)+; calc. for C15H22N3: 244.1814.
1H NMR (200 MHz, CDCl3) δ 7.66 (dd, J=1.0, 6.7, 1H), 7.62-7.45 (m, 2H), 7.45-7.20 (m, 3H), 6.65-6.44 (m, 1H), 6.44-6.20 (m, 1H), 5.41 (s, 2H), 3.32-3.05 (m, 1H), 3.05-2.58 (m, 2H), 2.03-1.54 (m, 5H), 1.42 (d, J=6.9, 6H), 1.35-1.05 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 147.73, 144.20, 137.20, 128.73, 127.95, 127.19, 124.30, 116.01, 110.72, 102.01, 70.82, 57.54, 34.55, 26.83, 26.13, 25.23, 23.07.
HRMS (ESI): m/z 364.2351 (M+H)+; calc. for C23H30N3O: 364.2389.
1H NMR (200 MHz, CDCl3) δ 7.98 (d, J=8.6, 2H), 7.87-7.57 (m, 4H), 7.57-7.10 (m, 4H), 6.99 (dd, J=2.3, 8.7, 1H), 6.86 (d, J=8.6, 2H), 6.78-6.63 (m, 2H), 5.93 (s, 1H), 3.78 (s, 3H).
13C NMR (50 MHz, CDCl3) δ 159.65, 143.04, 142.80, 139.81, 138.46, 135.12, 130.15, 128.87, 128.59, 127.94, 126.87, 126.47, 126.27, 125.11, 123.31, 122.93, 117.65, 116.66, 114.29, 112.25, 107.30, 55.47.
HRMS (ESI): m/z 366.1577 (M+H)+; calc. for C24H20N3O: 366.1606.
1H NMR (200 MHz, CDCl3) δ 8.00-7.85 (m, 3H), 7.60-7.45 (m, 1H), 7.40-7.25 (m, 5H), 7.15-6.95 (m, 3H), 6.75-6.65 (m, 1H), 4.20 (d, 2H), 3.85 (s, 3H), 3.50-3.35 (m, 1H).
13C NMR (50 MHz, CDCl3) δ 159.02, 156.38, 141.43, 139.05, 129.60, 128.58, 128.23, 128.17, 128.09, 127.53, 123.59, 122.14, 117.21, 114.04, 111.37, 55.26, 52.37.
HRMS (ESI): m/z 330.1591 (M+H)+; calc. for C21H20N3O: 330.1606.
1H NMR (200 MHz, CDCl3) δ 8.18-7.78 (m, 1H), 7.57-7.26 (m, 1H), 7.10-6.82 (m, 1H), 6.63 (td, J=0.9, 6.7, 1H), 6.11 (ddd, J=1.3, 3.2, 4.7, 1H), 3.06 (td, J=1.3, 5.8, 1H), 3.01-2.72 (m, 2H), 2.61-2.30 (m, 3H), 2.25-2.03 (m, 1H), 1.92-1.44 (m, 5H), 1.32 (s, 3H), 1.30-1.01 (m, 6H), 0.90 (s, 3H).
13C NMR (50 MHz, CDCl3) δ 141.98, 138.46, 137.13, 123.36, 122.70, 121.85, 117.41, 111.35, 57.61, 44.20, 41.16, 38.12, 34.50, 34.39, 32.50, 32.12, 26.63, 26.10, 25.21, 21.54.
HRMS (ESI): m/z 336.2413 (M+H)+; calc. for C22H30N3: 336.2440.
1H NMR (200 MHz, CDCl3) δ 8.06-7.92 (m, 1H), 7.45-7.36 (m, 1H), 7.02 (ddd, J=1.3, 6.7, 9.0, 1H), 6.70 (td, J=1.1, 6.8, 1H), 3.25-2.79 (m, 3H), 1.99 (ddd, J=5.1, 8.3, 10.0, 1H), 1.73-1.31 (m, 5H), 1.15-0.73 (m, 6H).
13C NMR (50 MHz, CDCl3) δ 141.04, 139.62, 126.15, 122.71, 121.72, 116.72, 110.95, 48.81, 32.95, 20.22, 13.95, 8.05, 7.56.
HRMS (ESI): m/z 230.1646 (M+H)+; calc. for C14H20N3: 230.1657.
1H NMR (200 MHz, CDCl3) δ 7.87-7.75 (m, 1H), 7.64-7.50 (m, 1H), 7.23-7.02 (m, 1H), 6.90-6.61 (m, 3H), 6.56-6.31 (m, 2H), 5.23 (s, 1H), 3.73 (s, 3H), 3.27-3.01 (m, 1H), 1.32 (d, J=6.9, 6H).
13C NMR (50 MHz, CDCl3) δ 153.24, 147.91, 142.37, 139.29, 123.85, 122.40, 117.83, 117.46, 115.05, 114.08, 111.51, 55.70, 26.70, 22.33.
HRMS (ESI): m/z 282.1582 (M+H)+; calc. for C17H20N3O: 282.1606.
1H NMR (200 MHz, CDCl3) δ 8.01 (d, J=6.8, 1H), 7.44 (d, J=8.4, 1H), 7.12-6.92 (m, 1H), 6.70 (t, J=6.7, 1H), 2.98-2.77 (m, 2H), 2.77-2.58 (m, 2H), 1.95-1.48 (m, 7H), 1.48-1.00 (m, 15H), 0.98-0.72 (m, 3H).
13C NMR (50 MHz, CDCl3) δ 141.35, 139.73, 124.40, 122.69, 122.37, 116.85, 110.89, 57.21, 34.33, 31.91, 29.85, 29.67, 29.50, 29.29, 27.51, 25.86, 24.93, 22.68, 14.09.
HRMS (ESI): m/z 328.2747 (M+H)+; calc. for C21H34N3: 328.2753.
1H NMR (200 MHz, CDCl3) δ 7.99 (d, J=6.8, 1H), 7.49 (d, J=9.0, 1H), 7.12-6.98 (m, 1H), 6.72 (t, J=6.3, 1H), 3.16 (dt, J=7.0, 13.8, 1H), 2.99 (dd, J=6.3, 12.5, 3H), 2.88-2.70 (m, 1H), 1.74-1.40 (m, 5H), 1.38 (d, J=6.9, 7H), 0.95 (t, J=7.0, 4H).
1H NMR (200 MHz, CDCl3) δ 8.14-8.04 (m, 1H), 7.94 (d, J=8.7, 2H), 7.54-7.47 (m, 1H), 7.07 (ddd, J=1.3, 6.6, 8.9, 1H), 6.81 (d, J=8.9, 1H), 6.73 (td, J=0.9, 6.9, 2H), 3.01 (s, 8H), 1.93-1.43 (m, 5H), 1.43-0.93 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 149.65, 141.40, 137.26, 131.84, 127.83, 123.07, 122.78, 122.41, 116.87, 112.33, 110.95, 56.80, 40.42, 34.15, 25.79, 24.83.
1H NMR (200 MHz, CDCl3) δ 8.21 (d, J=6.9, 1H), 7.79 (d, J=8.9, 2H), 7.51 (d, J=9.0, 1H), 7.10 (dd, J=7.2, 8.5, 1H), 6.97 (d, J=8.9, 2H), 6.75 (t, J=6.8, 1H), 3.85 (s, 3H), 3.34-2.95 (m, 1H), 1.60 (s, 2H), 1.04 (s, 9H), 0.96 (s, 6H).
13C NMR (50 MHz, CDCl3) δ 159.21, 142.18, 140.03, 129.78, 128.35, 123.91, 123.70, 123.01, 117.39, 113.94, 111.32, 60.88, 57.35, 55.53, 32.15, 32.02, 29.26.
HRMS (ESI): m/z 352.2379 (M+H)+; calc. for C22H30N3O: 352.2389.
1H NMR (400 MHz, CDCl3) δ 8.07-8.02 (m, 1H), 7.49-7.45 (m, 1H), 7.14-7.08 (m, 1H), 6.80-6.71 (m, 2H), 6.33 (d, 1H), 4.66 (s, 2H), 3.49 (br s, 1H), 2.95-2.90 (m, 2H), 1.87-1.82 (m, 2H), 1.75-1.68 (m, 2H), 1.60-1.55 (m, 1H), 1.35-1.10 (m, 5H).
13C NMR (101 MHz, DMSO-d6) δ 154.38, 148.63, 140.53, 127.56, 125.49, 123.72, 123.10, 116.47, 111.52, 108.47, 106.98, 56.25, 55.81, 33.54, 25.36, 24.48.
HRMS (ESI): m/z 312.1679 (M+H)+; calc. for C18H22N3O2: 312.1712.
1H NMR (200 MHz, CDCl3) δ 8.10-7.93 (m, 1H), 7.41-7.27 (m, 1H), 7.08-6.89 (m, 1H), 3.19-2.57 (m, 2H), 2.07-1.84 (m, 3H), 1.84-1.68 (m, 2H), 1.68-1.45 (m, 1H), 1.44-1.11 (m, 5H), 1.11-0.80 (m, 4H).
13C NMR (50 MHz, CDCl3) δ 141.94, 139.49, 125.32, 123.91, 119.89, 119.36, 116.94, 57.21, 34.34, 25.79, 24.91, 8.20, 7.93.
HRMS (ESI): m/z 290.1408 (M+H)+; calc. for C16H21N3Cl: 290.1424.
1H NMR (200 MHz, CDCl3) δ 8.16 (d, J=7, 1H), 8.10 (m, 2H), 7.60 (m, 2H), 7.14-7.32 (m, 1H), 6.93 (br t, 1H), 4.14 (br s, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.76 (t, 4H), 3.07-3.10 (m, 2H), 2.52-2.58 (m, 2H), 2.44 (t, 4H).
13C NMR (50 MHz, CDCl3) δ 149.6, 148.9, 138.7, 126.2, 126.0, 124.1, 122.5, 119.4, 117.3, 112.0, 111.4, 111.3, 110.0, 67.0, 58.7, 56.4, 56.2, 54.0, 44.3.
1H NMR (200 MHz, CDCl3) δ 7.93 (dt, J=1.0, 6.8, 1H), 7.39 (dt, J=0.9, 9.0, 1H), 6.93 (ddd, J=1.3, 6.7, 9.0, 1H), 6.59 (td, J=1.1, 6.7, 1H), 3.05-2.60 (m, 2H), 1.91-1.38 (m, 6H), 1.26 (d, J=6.9, 3H), 1.22-0.93 (m, 7H), 0.80 (t, J=7.2, 3H).
13C NMR (50 MHz, CDCl3) δ 143.69, 141.28, 123.68, 122.40, 122.21, 116.71, 110.57, 57.10, 39.10, 34.09, 31.11, 25.63, 24.75, 24.68, 20.86, 13.99.
HRMS (ESI): m/z 286.2251 (M+H)+; calc. for C18H28N3: 286.2283.
1H NMR (200 MHz, CDCl3) δ 8.09 (dt, J=1.0, 6.7, 1H), 7.76 (d, J=8.5, 1H), 7.53 (d, J=9.0, 1H), 7.08 (ddd, J=1.3, 6.7, 9.1, 1H), 6.75 (td, J=1.1, 6.8, 1H), 6.67 (dd, J=2.4, 8.5, 1H), 6.58 (d, J=2.2, 1H), 3.87 (s, 6H), 3.70 (s, 3H), 2.87-2.40 (m, 1H), 2.01-1.27 (m, 4H), 1.27-0.75 (m, 4H).
13C NMR (50 MHz, CDCl3) δ 160.67, 156.86, 132.32, 126.71, 123.30, 122.56, 116.96, 111.38, 105.81, 99.31, 67.09, 56.42, 56.12, 55.44, 34.15, 25.74, 24.83.
HRMS (ESI): m/z 352.2012 (M+H)+; calc. for C21H26N3O2: 352.2025.
1H NMR (200 MHz, CDCl3) δ 8.01 (dt, J=1.0, 6.6, 1H), 7.46 (dt, J=1.0, 9.3, 1H), 7.03 (ddd, J=1.3, 6.6, 9.0, 1H), 6.70 (td, J=1.1, 6.8, 1H), 3.11-2.75 (m, 2H), 2.64 (s, 2H), 2.07-1.43 (m, 5H), 1.41-1.07 (m, 5H), 1.00 (s, 9H).
13C NMR (50 MHz, CDCl3) δ 140.88, 137.31, 126.04, 122.44, 122.39, 116.98, 110.75, 56.84, 41.34, 34.50, 33.12, 29.85, 25.83, 24.96.
HRMS (ESI): m/z 286.2247 (M+H)+; calc. for C18H28N3: 286.2283.
1H NMR (200 MHz, CDCl3) δ 8.06-7.96 (m, 1H), 7.51-7.35 (m, 1H), 7.04 (ddd, J=1.3, 6.7, 9.0, 1H), 6.71 (td, J=1.1, 6.8, 1H), 3.14-2.77 (m, 2H), 2.77-2.50 (m, 2H), 1.98-1.47 (m, 7H), 1.47-1.29 (m, 4H), 1.27-1.05 (m, 5H), 0.90 (t, J=6.9, 3H).
13C NMR (50 MHz, CDCl3) δ 141.32, 139.65, 124.40, 122.74, 122.36, 116.81, 110.92, 57.20, 34.32, 32.05, 29.35, 27.43, 25.84, 24.92, 22.57, 14.07.
HRMS (ESI): m/z 286.2270 (M+H)+; calc. for C18H28N3: 286.2283.
1H NMR (400 MHz, CDCl3) δ 7.60 (d, J=2.9, 1H), 7.60-7.57 (m, 1H), 7.54 (d, J=1.8, 1H), 7.52 (d, J=1.8, 1H), 7.50-7.48 (m, 1H), 7.47 (d, J=2.5, 1H), 7.37-7.29 (m, 4H), 7.03-6.96 (m, 3H), 6.94 (t, J=4.1, 1H), 3.28 (d, J=6.2, 2H), 2.97-2.62 (m, 2H), 1.66 (d, J=12.4, 5H), 1.59-1.48 (m, 4H), 1.48-1.35 (m, 2H), 1.16-0.97 (m, 7H), 0.97-0.75 (m, 4H).
13C NMR (101 MHz, CDCl3) δ 143.74, 138.16, 133.87, 133.32, 132.60, 129.50, 129.21, 128.45, 126.64, 123.78, 118.62, 117.34, 112.21, 58.29, 32.70, 25.73, 24.50.
HRMS (ESI): m/z 404.0516 (M+H)+; calc. for C19H20N3ClBr: 404.0529.
1H NMR (200 MHz, CDCl3) δ 8.43-7.97 (m, 3H), 7.64 (td, J=1.5, 7.7, 4H), 7.58-7.48 (m, 2H), 7.39 (td, J=1.3, 7.5, 2H), 7.31-7.21 (m, 2H), 7.21-7.13 (m, 2H), 7.11 (dd, J=1.3, 6.7, 1H), 6.80 (td, J=1.1, 6.7, 2H), 3.42-3.09 (m, 2H), 2.82-2.48 (m, 2H), 1.80-1.33 (m, 12H), 1.21-0.81 (m, 13H).
13C NMR (50 MHz, CDCl3) δ 141.35, 136.12, 132.67, 132.50, 129.26, 127.26, 125.80, 123.51, 122.87, 122.79, 117.53, 111.46, 56.34, 33.80, 25.64, 24.51.
HRMS (ESI): m/z 370.0892 (M+H)+; calc. for C19H21N3Br: 370.0919.
1H NMR (400 MHz, CDCl3) δ 8.12 (dt, J=1.2, 6.9, 1H), 7.79-7.61 (m, 1H), 7.55 (dt, J=1.1, 9.1, 1H), 7.51-7.44 (m, 1H), 7.42-7.28 (m, 2H), 7.14 (ddd, J=1.3, 6.7, 9.1, 1H), 6.82 (td, J=1.1, 6.8, 1H), 3.30 (t, J=6.2, 1H), 2.83 (q, J=6.7, 2H), 1.95-1.64 (m, 1H), 1.42-1.24 (m, 2H), 1.24-1.05 (m, 3H), 0.90-0.60 (m, 3H).
13C NMR (101 MHz, CDCl3) δ 141.47, 133.93, 132.84, 132.60, 129.48, 129.14, 126.87, 123.57, 122.60, 117.69, 111.62, 48.27, 30.02, 28.93, 22.38, 13.90.
HRMS (ESI): m/z 314.1414 (M+H)+; calc. for C18H21N3Cl: 314.1424.
1H NMR (400 MHz, CDCl3) δ 8.08 (dt, J=1.2, 6.8, 1H), 7.97-7.89 (m, 2H), 7.61-7.55 (m, 1H), 7.15 (ddd, J=1.3, 6.7, 9.0, 1H), 6.99-6.94 (m, 2H), 6.82 (td, J=1.1, 6.8, 1H), 3.85 (s, 4H), 3.02 (t, J=7.1, 2H), 1.58 (dt, J=6.9, 14.4, 2H), 1.41 (dq, J=7.2, 14.3, 2H), 0.92 (t, J=7.3, 3H).
13C NMR (101 MHz, CDCl3) δ 159.10, 140.57, 134.37, 128.20, 125.71, 125.54, 124.57, 122.43, 116.53, 114.03, 112.06, 55.22, 47.92, 32.78, 20.18, 13.89.
HRMS (ESI): m/z 296.1735 (M+H)+; calc. for C18H22N3O: 296.1763.
1H NMR (400 MHz, CDCl3) δ 8.06 (dt, J=1.1, 6.8, 1H), 7.95-7.89 (m, 2H), 7.56 (d, J=9.0, 1H), 7.13 (ddd, J=1.3, 6.7, 9.0, 1H), 7.01-6.94 (m, 2H), 6.80 (td, J=1.1, 6.8, 1H), 3.85 (s, 4H), 3.01 (t, J=7.1, 2H), 1.58 (dd, J=7.6, 14.8, 2H), 1.34 (ddd, J=5.1, 9.9, 19.4, 4H), 0.89 (t, J=7.1, 3H).
13C NMR (101 MHz, CDCl3) δ 159.04, 140.79, 134.74, 128.20, 126.10, 125.52, 124.24, 122.35, 116.72, 114.01, 111.85, 55.22, 48.20, 30.36, 29.17, 22.47, 13.97.
HRMS (ESI): m/z 310.1906 (M+H)+; calc. for C19H24N3O: 310.1919.
1H NMR (400 MHz, CDCl3) δ 7.63-7.58 (m, 1H), 7.52-7.46 (m, 2H), 7.38-7.30 (m, 2H), 7.04 (dd, J=7.2, 9.0, 1H), 6.78 (dd, J=1.1, 7.2, 1H), 3.57-3.40 (m, 1H), 3.27 (d, J=5.7, 1H), 1.70-1.46 (m, 2H), 1.46-1.30 (m, 4H), 1.30-1.14 (m, 2H).
13C NMR (101 MHz, CDCl3) δ 143.66, 137.58, 133.63, 133.36, 132.65, 129.50, 129.27, 126.64, 126.37, 126.13, 123.65, 116.80, 114.02, 61.91, 32.48, 22.98.
HRMS (ESI): m/z 346.0865 (M+H)+; calc. for C18H18N3Cl2: 346.0878.
1H NMR (200 MHz, CDCl3) δ 8.08-7.95 (m, 1H), 7.46 (d, J=9.6, 1H), 7.06 (dd, J=2.0, 9.6, 1H), 6.56 (s, 1H), 4.54 (t, J=6.8, 1H), 3.07 (dd, J=6.9, 13.8, 2H), 2.48 (s, 3H), 1.73-1.50 (m, 2H), 1.50-1.22 (m, 2H), 0.92 (t, J=7.2, 3H).
13C NMR (50 MHz, CDCl3) δ 168.93, 159.22, 139.76, 131.08, 124.93, 124.54, 120.57, 120.51, 118.33, 100.50, 47.42, 32.64, 20.13, 13.85, 12.21.
HRMS (ESI): m/z 305.1180 (M+H)+; calc. for C15H18N4ClO: 305.1169.
1H NMR (200 MHz, CDCl3) δ 7.98 (dd, J=0.9, 1.9, 1H), 7.48 (dd, J=0.8, 9.6, 1H), 7.44-7.22 (m, 5H), 7.08 (dd, J=2.0, 9.6, 1H), 6.61-6.54 (m, 1H), 4.80 (t, J=6.4, 1 H), 4.25 (d, J=6.5, 2H), 2.49 (d, J=11.7, 3H).
13C NMR (50 MHz, CDCl3) δ 169.36, 159.09, 140.09, 138.64, 130.45, 128.80, 128.50, 127.88, 125.78, 121.07, 120.93, 118.35, 100.84, 52.22, 12.49.
HRMS (ESI): m/z 339.0979 (M+H)+; calc. for C18H16N4OCl: 339.1013.
1H NMR (200 MHz, CDCl3) δ 7.09 (s, 1H), 6.56 (d, J=0.6, 1H), 6.25 (s, 1H), 3.98 (t, J=7.2, 1H), 3.09-2.73 (m, 5H), 2.45 (s, 3H), 2.26 (s, 3H), 1.76-1.50 (m, 2H), 1.38 (dq, J=7.1, 13.8, 2H), 0.90 (t, J=7.2, 3H).
13C NMR (50 MHz, CDCl3) δ 168.42, 159.50, 143.95, 135.77, 134.93, 132.46, 126.01, 116.10, 114.03, 100.75, 52.08, 31.99, 20.86, 20.19, 18.57, 13.93, 12.10.
HRMS (ESI): m/z 299.1869 (M+H)+; calc. for C17H23N4O: 299.1872.
1H NMR (200 MHz, CDCl3) δ 7.96 (d, J=6.8, 1H), 7.55-7.18 (m, 6H), 7.12-6.97 (m, 1H), 6.77-6.54 (m, 1H), 4.21 (s, 2H), 3.52-2.83 (m, 1H), 1.85 (ddd, J=5.1, 8.3, 9.9, 1H), 1.11-0.97 (m, 2H), 0.91 (dtd, J=2.1, 4.9, 7.3, 2H).
13C NMR (50 MHz, CDCl3) δ 139.53, 128.72, 128.55, 128.28, 127.88, 127.46, 122.92, 121.68, 116.70, 111.00, 107.42, 53.26, 8.00, 7.57.
HRMS (ESI): m/z 264.1477 (M+H)+; calc. for C17H18N3: 264.1501.
1H NMR (200 MHz, CDCl3) δ 8.07 (dd, J=6.7, 1.2, 1H), 7.53 (d, J=9.0, 1H), 7.51 (d, J=1.6, 1H), 7.15 (ddd, J=9.0, 6.7, 1.2, 1H), 6.91 (d, J=3.3, 1H), 6.79 (td, J=6.7, 1.0, 1H), 6.55 (dd, J=3.3, 1.6, 1H), 3.62 (br s, 1H) 2.85-3.10 (m, 1H), 1.50-2.00, 1.05-1.45 (m, 9H).
13C NMR (50 MHz, CDCl3) δ 149.72, 141.56, 141.37, 127.40, 125.45, 124.45, 122.81, 116.90, 111.91, 111.52, 106.98, 57.12, 34.13, 25.76, 25.01.
1H NMR (200 MHz, CDCl3) δ 8.11 (d, J=6.8, 2H), 8.02 (d, J=8.6, 2H), 7.16-7.08 (m, 1H), 7.02-6.98 (d, J=8.6, 2H), 6.80-6.73 (m, 1H), 3.87 (s, 3H), 1.80-1.59 (br m, 10H).
13C NMR (50 MHz, CDCl3) δ 158.3, 141.6, 138.3, 137.1, 128.6, 127.3, 124.3, 123.9, 118.5, 117.3, 116.2, 57.1, 55.5, 34.4, 26.0, 25.1.
1H NMR (200 MHz, CDCl3) δ 8.07 (dd, J=6.4, 1.2, 1H), 7.51 (d, J=8.0, 1H), 7.45 (d, J=0.8, 1H), 7.11 (ddd, J=8.0, 6.4, 1.2, 1H), 6.89 (d, J=3.2, 1H), 6.78 (td, J=6.4, 0.8, 1H), 6.53 (dd, J=3.2, 1.2, 1H), 4.34 (br s, 1H), 3.76 (m 4H), 3.13 (t, J=6.0, 2H), 2.61 (t, J=6.4, 2H), 2.50 (br s, 4H).
13C NMR (50 MHz, CDCl3) δ 150.3, 141.7, 141.3, 126.9, 126.7, 123.9, 122.4, 117.3, 111.6, 111.5, 106.3, 67.0, 58.2, 53.5, 44.3.
1H NMR (200 MHz, CDCl3) δ 8.01 (d, J=6.8, 1H), 7.71 (d, J=1.8, 1H), 7.60-7.48 (m, 2H), 7.12-6.94 (m, 1H), 6.90, (d, J=8.4, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 3.20-2.81 (m, 2H), 1.83-1.21 (br m, 10H).
13C NMR (50 MHz, CDCl3) 149.3, 148.7, 141.6, 136.7, 127.6, 124.4, 123.9, 122.8, 119.7, 117.3, 111.7, 111.4, 110.9, 67.3, 57.0, 56.2, 56.1, 34.5, 26.0, 25.1.
1H NMR (200 MHz, DMSO-d6) δ 8.49-8.22 (m, 2H), 7.45 (d, J=8.8, 1H), 7.21-7.06 (m, 1H), 6.86 (t, J=6.7, 1H), 4.87-4.59 (m, 1H), 3.85 (s, 6H), 3.07-2.81 (m, 1H), 1.86-1.43 (m, 5H), 1.43-0.92 (m, 5H).
13C NMR (50 MHz, DMSO-d6) δ 147.76, 140.11, 135.09, 134.79, 124.95, 124.41, 123.44, 123.03, 116.24, 110.93, 104.05, 56.18, 55.86, 33.58, 25.44, 24.40.
HRMS (ESI): m/z 368.1946 (M+H)+; calc. for C21H26N3O3: 368.1974.
1H NMR (200 MHz, CDCl3) δ 8.10 (d, J=6.8, 1H), 8.01 (d, J=8.8, 2H), 7.59-7.27 (m, 7H), 7.13-7.00 (m, 2H), 6.76 (t, J=6.8, 1H), 5.13 (s, 2H), 2.98 (m, 1H), 1.75 (m, 5H), 1.47-0.97 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 158.10, 141.42, 136.97, 136.56, 129.52, 128.45, 128.28, 127.83, 127.43, 124.05, 123.51, 122.52, 117.07, 114.82, 111.27, 69.99, 56.77, 34.13, 25.73, 24.79.
HRMS (ESI): m/z 412.2364 (M+H)+; calc. for C27H30N3O: 412.2389.
1H NMR (200 MHz, DMSO-d6+CD3OD) δ 8.36 (d, J=6.8, 1H), 8.17 (dd, J=1.7, 8.1, 1H), 7.54 (d, 1H), 7.40-7.15 (m, 2H), 7.10-6.85 (m, 3H), 3.05-2.81 (m, 1H), 1.99-1.44 (m, 5H), 1.44-1.01 (m, 5H).
13C NMR (50 MHz, DMSO-d6+CD3OD) δ 156.77, 141.58, 135.94, 129.75, 129.14, 125.78, 125.08, 123.89, 119.89, 117.86, 116.87, 113.01, 57.65, 34.24, 26.43, 25.54.
HRMS (ESI): m/z 308.1767 (M+H)+; calc. for C19H22N3O: 308.1763.
1H NMR (200 MHz, CDCl3) δ 8.05 (dt, J=1.0, 6.8, 1H), 7.58-7.38 (m, 1H), 7.03 (ddd, J=1.3, 6.6, 9.0, 1H), 6.70 (td, J=1.1, 6.7, 1H), 3.20-2.72 (m, 1H), 2.72-2.42 (m, 1H), 1.99-1.44 (m, 9H), 1.41-1.01 (m, 6H), 0.80 (t, J=7.4, 6H).
13C NMR (50 MHz, CDCl3) δ 142.04, 141.60, 125.60, 122.61, 122.45, 116.96, 110.69, 57.56, 40.98, 34.25, 28.31, 25.86, 24.92, 12.62.
HRMS (ESI): m/z 286.2281 (M+H)+; calc. for C18H28N3: 286.2283.
1H NMR (200 MHz, CDCl3) δ 8.49-8.21 (m, 4H), 8.07 (dt, J=1.0, 6.9, 1H), 7.55 (d, J=8.3, 1H), 7.18 (ddd, J=1.3, 6.7, 9.1, 1H), 6.83 (td, J=1.0, 6.8, 1H), 3.28-2.79 (m, 2H), 2.04-1.47 (m, 5H), 1.47-0.97 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 146.55, 142.06, 141.13, 134.43, 127.26, 126.47, 124.83, 123.80, 122.65, 117.89, 112.23, 57.12, 34.36, 25.66, 24.87.
HRMS (ESI): m/z 337.1670 (M+H)+; calc. for C19H21N4O2: 337.1665.
1H NMR (200 MHz, CDCl3) δ 8.08-7.95 (m, 1H), 7.50-7.36 (m, 1H), 7.03 (ddd, J=1.2, 6.7, 9.0, 1H), 6.70 (td, J=0.9, 6.7, 1H), 3.00-2.69 (m, 2H), 2.58 (d, J=7.1, 2H), 2.20 (dt, J=6.8, 13.4, 1H), 2.04-1.49 (m, 5H), 1.38-1.07 (m, 5H), 0.95 (d, J=6.6, 6H).
13C NMR (50 MHz, CDCl3) δ 141.29, 138.72, 125.17, 122.65, 122.38, 116.83, 110.81, 57.21, 36.67, 34.34, 28.88, 25.83, 24.92, 22.74.
HRMS (ESI): m/z 272.2105 (M+H)+; calc. for C17H26N3: 272.2127.
1H NMR (200 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.26 (d, J=6.9, 1H), 8.03 (d, J=8.6, 2H), 7.41 (d, J=8.9, 1H), 7.28-7.01 (m, 1H), 6.83 (t, J=7.3, 3H), 4.60 (d, J=5.5, 1 H), 3.45-3.38 (m, 1H), 3.00-2.65 (m, 1H), 2.01-1.40 (m, 5H), 1.40-0.85 (m, 5H).
13C NMR (50 MHz, DMSO-d6) δ 154.73, 138.53, 133.82, 126.11, 123.79, 122.44, 121.29, 121.20, 114.42, 113.20, 109.01, 54.45, 31.83, 23.77, 22.78.
HRMS (ESI): m/z 308.1754 (M+H)+; calc. for C19H22N3O: 308.1763.
1H NMR (200 MHz, CDCl3) δ 8.08 (dt, J=1.0, 6.9, 1H), 7.47 (d, J=9.0, 1H), 7.04 (ddd, J=1.3, 6.6, 8.9, 1H), 6.69 (td, J=0.9, 6.7, 1H), 3.17-2.71 (m, 2H), 2.06-1.51 (m, 6H), 1.47 (s, 9H), 1.40-1.02 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 140.10, 138.20, 123.62, 122.89, 116.56, 111.17, 109.72, 58.68, 34.13, 33.19, 30.66, 25.82, 25.05.
HRMS (ESI): m/z 272.2102 (M+H)+; calc. for C17H26N3: 272.2127.
1H NMR (200 MHz, CDCl3) δ 7.88 (d, J=6.9, 1H), 7.50-7.25 (m, 2H), 7.15 (d, J=8.9, 1H), 6.98 (ddd, J=1.0, 6.7, 8.2, 1H), 6.83 (d, J=2.9, 1H), 6.79-6.72 (m, 1H), 6.70-6.50 (m, 2H), 6.47-6.24 (m, 1H), 3.79 (dd, J=7.6, 13.5, 2H), 3.59 (d, J=6.1, 1H), 2.98 (dd, J=6.4, 12.9, 2H), 1.88-1.31 (m, 4H).
13C NMR (50 MHz, CDCl3) δ 157.76, 150.15, 141.52, 141.32, 132.52, 130.38, 129.19, 127.45, 126.16, 123.57, 122.13, 117.09, 116.14, 115.54, 114.26, 111.51, 106.26, 68.07, 48.10, 26.99, 26.46.
HRMS (ESI): m/z 416.0902 (M+H)+; calc. for C21H20N3O2Cl2: 416.0933.
1H NMR (200 MHz, CDCl3) δ 7.88 (dt, J=1.0, 6.8, 1H), 7.37 (br dt, J=9.0, 1H), 7.16 (d, J=8.9, 1H), 6.95 (dd, J=1.2, 6.7, 1H), 6.90 (dd, J=1.3, 6.8, 1H), 6.85 (d, J=2.9, 1 H), 6.71-6.49 (m, 1H), 3.82 (t, J=6.0, 2H), 3.20-2.99 (m, 1H), 2.92 (d, J=6.1, 3H), 1.89-1.44 (m, 4H), 1.27 (d, J=6.9, 6H).
13C NMR (50 MHz, CDCl3) δ 157.76, 144.16, 141.06, 132.51, 129.16, 128.99, 123.96, 122.57, 121.87, 120.40, 116.86, 115.52, 114.26, 110.86, 68.08, 48.68, 27.25, 26.51, 26.25, 22.64.
HRMS (ESI): m/z 392.1259 (M+H)+; calc. for C20H24N3OCl2: 392.1296.
1H NMR (200 MHz, CDCl3) δ 7.96 (d, J=6.8, 2H), 7.52 (d, J=9.0, 2H), 7.18-6.99 (m, 2H), 6.73 (t, J=6.7, 2H), 4.03 (s, 2H), 3.39-3.07 (m, 1H), 3.07-2.81 (m, 1H), 1.23 (d, J=6.9, 6H).
13C NMR (101 MHz, CDCl3) δ 144.68, 141.38, 137.86, 133.42, 129.58, 128.75, 123.52, 123.24, 122.00, 117.17, 111.34, 52.60, 26.43, 22.69.
HRMS (ESI): m/z 300.1241 (M+H)+; calc. for C17H19N3Cl: 300.1268.
1H NMR (200 MHz, CDCl3) δ 7.98 (dt, J=1.1, 6.8, 1H), 7.47-7.34 (m, 1H), 7.04 (ddd, J=1.3, 6.7, 9.1, 1H), 6.76 (d, J=3.4, 1H), 6.69 (td, J=1.0, 6.8, 1H), 6.21 (d, J=3.4, 1H), 3.42 (d, J=6.6, 1H), 3.07-2.73 (m, 1H), 2.01-1.41 (m, 5H), 1.41-0.99 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 149.97, 141.83, 135.16, 127.34, 125.70, 124.15, 122.79, 117.22, 111.66, 108.25, 108.04, 57.38, 34.18, 25.76, 24.95.
HRMS (ESI): m/z 316.1195 (M+H)+; calc. for C17H19N3OCl: 316.1217.
1H NMR (200 MHz, CDCl3) δ 8.07 (dt, J=1.1, 6.9, 1H), 7.50 (d, J=9.0, 1H), 7.41 (d, J=3.6, 1H), 7.10 (ddd, J=1.3, 6.6, 9.0, 1H), 6.92-6.79 (m, 1H), 6.79-6.66 (m, 1H), 3.27-2.97 (m, 2H), 2.90 (dd, J=7.6, 15.1, 2H), 2.09-1.51 (m, 5H), 1.36 (t, J=7.5, 4H), 1.30-1.00 (m, 4H).
13C NMR (50 MHz, CDCl3) δ 147.81, 140.51, 125.43, 125.06, 124.05, 123.45, 122.97, 116.09, 112.42, 57.03, 34.26, 25.74, 24.92, 23.51, 15.86.
HRMS (ESI): m/z 326.1695 (M+H)+; calc. for C19H24N3S: 326.1691.
1H NMR (200 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.30 (d, 1H), 7.80 (s, 1H), 7.65 (d, 1H), 7.45 (d, 1H), 7.15 (t, 1H), 6.95-6.75 (m, 2H), 4.70 (d, 1H), 3.85 (s, 3H), 3.00-2.80 (m, 1H), 1.85-0.95 (m, 10H).
13C NMR (50 MHz, DMSO-d6) δ 147.31, 145.71, 140.23, 135.31, 126.14, 124.33, 123.28, 123.08, 119.41, 116.30, 115.33, 110.96, 110.62, 56.21, 55.49, 33.55, 25.44, 24.43.
HRMS (ESI): m/z 338.1872 (M+H)+; calc. for C20H24N3O2: 338.1869.
1H NMR (200 MHz, CDCl3-CD3OD) δ 8.04 (d, 1H), 7.50-7.25 (m, 3H), 7.15-7.00 (m, 1H), 6.85 (d, 1H), 6.75-6.65 (m, 1H), 3.83 (s, 3H), 3.75-3.45 (m, 1H), 2.95-2.75 (m, 1H), 1.85-0.90 (m, 10H).
13C NMR (50 MHz, CDCl3-DMSO-d6) δ 147.18, 145.94, 140.35, 134.58, 125.63, 125.20, 124.38, 122.77, 118.47, 115.46, 113.79, 112.21, 111.22, 56.50, 55.59, 33.78, 25.46, 24.61.
HRMS (ESI): m/z 338.1873 (M+H)+; calc. for C20H24N3O2: 338.1869.
1H NMR (200 MHz, CDCl3) δ 8.12 (d, J=6.9, 1H), 7.56 (d, J=8.9, 1H), 7.28 (d, J=4.3, 1H), 7.20-7.06 (m, 1H), 6.96 (d, J=5.1, 1H), 6.80 (td, J=0.7, 6.8, 1H), 3.46-3.04 (m, 1H), 3.04-2.76 (m, 1H), 2.47 (s, 3H), 2.02-1.43 (m, 5H), 1.36-0.94 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 141.26, 135.92, 131.79, 130.54, 129.38, 125.91, 124.12, 123.58, 122.66, 117.33, 111.51, 56.75, 33.92, 25.73, 24.74, 15.24.
HRMS (ESI): m/z 312.1534 (M+H)+; calc. for C18H22N3S: 312.1534.
1H NMR (200 MHz, CDCl3) δ 8.22 (d, J=8.2, 2H), 8.08 (dt, J=1.0, 6.0, 1H), 7.68 (d, J=8.3, 2H), 7.60-7.45 (m, 1H), 7.15 (ddd, J=1.2, 6.7, 9.0, 1H), 6.80 (td, J=1.0, 6.7, 1H), 3.29-2.67 (m, 2H), 1.96-1.42 (m, 5H), 1.42-0.91 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 141.75, 138.01, 135.14, 128.46, 126.91, 125.59, 125.31 (dd, J=3.8, 7.6), 124.45, 124.34, 122.64, 117.57, 111.84, 56.94, 34.22, 25.65, 24.81.
HRMS (ESI): m/z 360.1683 (M+H)+; calc. for C20H21N3F3: 360.1688.
1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=6.9, 1H), 7.57 (d, J=9.1, 1H), 7.26-7.05 (m, 3H), 6.82 (dd, J=3.8, 9.7, 1H), 3.02 (s, 1H), 2.82-2.60 (m, 1H), 2.31 (d, J=2.1, 3H), 1.75 (d, J=11.7, 2H), 1.65-1.54 (m, 2H), 1.54-1.40 (m, 1H), 1.22-0.87 (m, 5H).
13C NMR (101 MHz, CDCl3) δ 160.71, 158.24, 141.67, 132.21, 131.55, 131.49, 127.21, 124.60, 124.56, 123.95, 123.77, 123.62, 122.76, 117.77, 111.56, 56.31, 33.76, 25.60, 24.61, 14.54.
HRMS (ESI): m/z 358.1481 (M+H)+; calc. for C20H22N3ClF: 358.1486.
1H NMR (200 MHz, CDCl3) δ 8.06 (d, J=6.8, 1H), 7.97 (dd, J=1.9, 10.9, 1H), 7.91-7.77 (m, 1H), 7.52 (d, J=9.3, 1H), 7.44 (t, J=8.1, 1H), 7.23-7.08 (m, 1H), 6.81 (td, J=0.8, 6.8, 1H), 3.16-2.79 (m, 2H), 1.99-1.42 (m, 6H), 1.42-0.90 (m, 7H).
13C NMR (50 MHz, CDCl3) δ 160.56, 155.65, 141.62, 130.43, 125.07, 124.50, 123.14, 123.07, 122.58, 117.46, 115.11, 114.66, 111.96, 56.91, 34.24, 25.65, 24.83.
HRMS (ESI): m/z 344.1323 (M+H)+; calc. for C19H20N3FCl: 344.1330.
1H NMR (200 MHz, CDCl3) δ 8.35-8.21 (m, 1H), 8.15-8.04 (m, 1H), 8.04-7.90 (m, 1H), 7.61-7.47 (m, 1H), 7.43 (ddd, J=1.1, 1.9, 7.9, 1H), 7.29 (dd, J=5.4, 10.3, 1H), 7.13 (ddd, J=1.3, 6.7, 9.0, 1H), 6.79 (td, J=1.1, 6.8, 1H), 3.29-2.66 (m, 2H), 1.69 (M, 6H), 1.41-0.74 (m, 7H).
13C NMR (50 MHz, CDCl3) δ 141.62, 136.60, 131.01, 130.03, 129.98, 129.89, 125.34, 124.13, 122.69, 122.63, 117.46, 111.72, 56.97, 34.25, 25.70, 24.82.
HRMS (ESI): m/z 370.0911 (M+H)+; calc. for C19H21N3Br: 370.0919.
1H NMR (200 MHz, CDCl3) δ 8.09-8.00 (m, 1H), 7.94 (d, J=8.6, 2H), 7.58-7.43 (m, 3H), 7.10 (ddd, J=1.3, 6.7, 9.0, 1H), 6.75 (td, J=1.1, 6.8, 1H), 3.01 (s, 2H), 1.93-1.39 (m, 5H), 1.16 (s, 5H).
13C NMR (50 MHz, CDCl3) δ 141.57, 135.62, 133.46, 131.43, 128.49, 124.83, 123.98, 122.55, 121.09, 117.33, 111.58, 56.77, 34.32, 25.66, 24.76.
HRMS (ESI): m/z 370.0926 (M+H)+; calc. for C19H21N3Br: 370.0919.
1H NMR (200 MHz, CDCl3) δ 8.26-8.03 (m, 1H), 7.77-7.61 (m, 1H), 7.61-7.50 (m, 1H), 7.50-7.41 (m, 1H), 7.41-7.21 (m, 2H), 7.12 (ddd, J=1.1, 6.7, 8.9, 1H), 6.78 (td, J=0.7, 6.7, 1H), 3.33-3.03 (m, 1H), 3.03-2.74 (m, 1H), 1.44-0.99 (m, 4H), 0.84 (d, J=6.3, 3H), 0.75 (dd, J=6.2, 7.4, 3H).
13C NMR (50 MHz, CDCl3) δ 141.51, 134.02, 132.58, 132.41, 129.29, 129.23, 128.97, 126.73, 123.51, 123.37, 122.63, 117.43, 111.41, 53.14, 39.54, 20.79, 18.85, 13.93.
HRMS (ESI): m/z 314.1402 (M+H)+; calc. for C18H21N3Cl: 314.1424.
1H NMR (200 MHz, CDCl3) δ 8.12-7.92 (m, 1H), 7.59-7.40 (m, 1H), 7.05 (ddd, J=1.2, 6.7, 8.9, 1H), 6.71 (dd, J=0.8, 13.6, 1H), 3.25-2.98 (m, 2H), 2.95-2.56 (m, 1H), 1.63-1.40 (m, 3H), 1.37 (dd, J=2.9, 6.9, 6H), 1.06 (d, J=6.3, 2H), 0.93 (dd, J=5.5, 8.4, 3H).
13C NMR (50 MHz, CDCl3) δ 144.92, 141.51, 123.23, 122.69, 122.36, 117.07, 110.92, 53.66, 40.03, 26.24, 22.73, 21.01, 19.45, 14.24.
HRMS (ESI): m/z 246.1967 (M+H)+; calc. for C15H24N3: 246.1970.
1H NMR (400 MHz, CDCl3) δ 8.13 (d, J=1.8, 1H), 7.75-7.64 (m, 1H), 7.52-7.42 (m, 2H), 7.42-7.29 (m, 4H), 7.24 (d, J=1.8, 1H), 3.29 (s, 1H), 2.66 (dd, J=7.7, 11.3, 1 H), 2.01-0.74 (m, 29H).
13C NMR (101 MHz, CDCl3) δ 137.08, 133.13, 132.79, 132.67, 129.64, 129.60, 129.40, 128.19, 127.05, 123.79, 123.63, 119.68, 119.25, 67.07, 56.46, 33.79, 25.53, 24.49.
HRMS (ESI): m/z 394.0643 (M+H)+; calc. for C19H19N3Cl3: 394.0645.
1H NMR (400 MHz, CDCl3) δ 8.13 (d, J=1.8, 1H), 7.71-7.67 (m, 1H), 7.48-7.44 (m, 1H), 7.38-7.33 (m, 2H), 7.24 (d, J=1.8, 1H), 3.33 (d, J=29.8, 1H), 2.66 (s, 1H), 1.77-1.60 (m, 3H), 1.51 (dd, J=14.4, 43.3, 2H), 1.12-0.97 (m, 5H).
13C NMR (101 MHz, CDCl3) δ 154.41, 152.06, 139.17, 136.70, 133.59, 132.41, 129.50, 129.33, 127.59, 127.57, 127.01, 118.12, 118.03, 115.96, 115.70, 109.51, 109.10, 56.28, 33.81, 25.55, 24.55.
HRMS (ESI): m/z 344.1299 (M+H)+; calc. for C19H20N3ClF: 344.1330.
1H NMR (200 MHz, CDCl3) δ 8.25-8.11 (m, 1H), 7.75-7.56 (m, 1H), 7.55-7.39 (m, 2H), 7.39-7.25 (m, 2H), 7.10 (ddd, J=1.2, 1.9, 9.5, 1H), 3.27 (d, J=6.8, 1H), 2.80-2.46 (m, 1H), 1.82-1.34 (m, 5H), 1.23-0.76 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 139.84, 136.39, 133.58, 132.56, 132.38, 129.44, 129.27, 126.88, 126.72, 124.94, 120.67, 120.08, 117.96, 56.36, 33.79, 25.58, 24.52.
HRMS (ESI): m/z 360.1019 (M+H)+; calc. for C19H20N3Cl2: 360.1034.
1H NMR (200 MHz, CDCl3) δ 8.16 (dt, J=1.2, 7.3, 1H), 7.63 (d, J=8.3, 1H), 7.58-7.41 (m, 2H), 7.42-7.30 (m, 1H), 7.15 (ddd, J=1.3, 6.7, 9.1, 1H), 6.82 (t, J=6.8, 1H), 3.33 (dt, J=5.7, 11.0, 1H), 3.14 (d, J=6.2, 1H), 1.75-1.37 (m, 6H), 1.37-1.04 (m, 2H).
13C NMR (50 MHz, CDCl3) δ 141.65, 134.28, 134.07, 133.27, 133.21, 132.75, 129.24, 127.27, 127.06, 123.97, 122.72, 117.53, 111.72, 59.36, 33.27, 23.29.
HRMS (ESI): m/z 346.0889 (M+H)+; calc. for C18H18N3Cl2: 346.0878.
1H NMR (400 MHz, CDCl3) δ 8.05 (dt, J=1.1, 6.9, 1H), 8.00-7.89 (m, 2H), 7.61-7.44 (m, 3H), 7.12 (ddd, J=1.3, 6.7, 9.0, 1H), 6.76 (td, J=1.1, 6.8, 1H), 3.72-3.47 (m, 1H), 2.99 (d, J=3.9, 1H), 1.83-1.60 (m, 4H), 1.60-1.49 (m, 2H), 1.49-1.35 (m, 2H).
13C NMR (101 MHz, CDCl3) δ 141.63, 135.83, 133.49, 131.45, 128.62, 125.49, 124.10, 122.47, 121.18, 117.44, 111.67, 59.06, 33.46, 23.57.
HRMS (ESI): m/z 356.0727 (M+H)+; calc. for C18H19N3Br: 356.0762.
1H NMR (400 MHz, CDCl3) δ 8.31-8.28 (m, 1H), 8.09 (d, J=6.8, 1H), 8.04-7.97 (m, 1H), 7.52 (dt, J=3.5, 7.8, 1H), 7.43 (ddd, J=0.9, 1.9, 7.9, 1H), 7.32-7.24 (m, 1H), 7.17-7.11 (m, 1H), 6.79 (td, J=0.8, 6.8, 1H), 3.66 (t, J=10.3, 1H), 3.01 (s, 1H), 1.88-1.65 (m, 4H), 1.65-1.53 (m, 2H), 1.53-1.39 (m, 2H).
13C NMR (101 MHz, CDCl3) δ 141.71, 136.63, 135.41, 130.13, 130.10, 130.06, 129.94, 125.80, 125.52, 124.26, 122.70, 122.55, 117.61, 111.82, 59.24, 33.56, 23.61.
HRMS (ESI): m/z 356.0774 (M+H)+; calc. for C18H19N3Br: 356.0762.
1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=6.7, 1H), 7.96 (d, J=10.9, 1H), 7.85 (d, J=8.4, 1H), 7.51 (d, J=9.0, 1H), 7.42 (t, J=8.0, 1H), 7.20-7.07 (m, 1H), 6.79 (t, J=6.7, 1H), 3.88-3.40 (m, 1H), 2.97 (d, J=3.8, 1H), 1.87-1.62 (m, 4H), 1.62-1.52 (m, 2H), 1.52-1.35 (m, 2H).
13C NMR (101 MHz, CDCl3) δ 159.39, 156.93, 141.73, 135.29, 135.22, 134.97, 130.38, 125.70, 124.44, 123.27, 123.23, 122.49, 119.51, 119.33, 117.62, 115.13, 114.90, 111.92, 59.12, 33.54, 23.61.
HRMS (ESI): m/z 330.1173 (M+H)+; calc. for C18H18N3FCl: 330.1173.
1H NMR (400 MHz, CDCl3) δ 8.23-8.08 (m, 1H), 7.56 (ddd, J=1.0, 1.9, 9.1, 1H), 7.23-7.06 (m, 3H), 6.87-6.72 (m, 1H), 3.54-3.27 (m, 1H), 2.96 (d, J=6.4, 1H), 2.39-2.21 (m, 3H), 1.72-1.51 (m, 4H), 1.51-1.37 (m, 2H), 1.37-1.16 (m, 2H).
13C NMR (101 MHz, CDCl3) δ 160.78, 158.31, 141.64, 132.36, 132.32, 131.52, 131.45, 129.80, 127.90, 124.58, 124.54, 123.93, 123.74, 123.57, 122.61, 122.11, 121.92, 117.83, 111.52, 59.33, 33.16, 23.24, 14.48, 14.44.
HRMS (ESI): m/z 344.1328 (M+H)+; calc. for C19H20N3FCl: 344.1330.
1H NMR (400 MHz, CDCl3) δ 8.21 (d, J=8.0, 2H), 8.07 (d, J=6.9, 1H), 7.67 (d, J=7.9, 2H), 7.53 (d, J=9.1, 1H), 7.15 (dd, J=7.2, 8.5, 1H), 6.79 (t, J=6.8, 1H), 3.75-3.50 (m, J=9.6, 1H), 3.04 (d, J=3.2, 1H), 1.87-1.62 (m, 4H), 1.62-1.51 (m, 2H), 1.50-1.36 (m, 2H).
13C NMR (101 MHz, CDCl3) δ 141.81, 138.09, 138.08, 135.39, 129.07, 128.75, 127.10, 126.25, 125.69, 125.33, 125.29, 125.25, 125.22, 124.40, 122.56, 117.66, 111.89, 59.20, 33.51, 23.57.
HRMS (ESI): m/z 346.1525 (M+H)+; calc. for C19H19N3F3: 346.1531.
1H NMR (400 MHz, CDCl3) δ 8.14 (ddd, J=0.9, 1.6, 6.9, 1H), 7.64-7.60 (m, 1H), 7.56-7.52 (m, 1H), 7.51-7.48 (m, 1H), 7.38-7.33 (m, 1H), 7.19-7.12 (m, 1H), 6.81 (tt, J=1.8, 9.2, 1H), 3.19 (d, J=6.0, 1H), 2.67 (dd, J=3.8, 9.0, 1H), 1.65 (t, J=11.2, 2H), 1.59 (dd, J=4.6, 8.9, 2H), 1.53-1.42 (m, 1H), 1.17-0.92 (m, 6H).
13C NMR (101 MHz, CDCl3) δ 141.75, 134.27, 134.14, 133.34, 133.14, 132.80, 129.29, 127.33, 126.44, 123.93, 122.89, 117.57, 111.70, 56.43, 33.89, 25.62, 24.58.
HRMS (ESI): m/z 360.1025 (M+H)+; calc. for C19H20N3Cl2: 360.1034.
1H NMR (400 MHz, CDCl3) δ 8.39-8.34 (m, 1H), 7.75-7.68 (m, 1H), 7.52 (ddd, J=5.0, 6.0, 11.0, 1H), 7.48-7.43 (m, 1H), 7.40-7.29 (m, 2H), 7.17-7.11 (m, 1H), 6.82-6.75 (m, 1H), 3.28-3.11 (m, 1H), 1.95-1.83 (m, 3H), 1.52 (d, J=12.2, 3H), 1.42 (t, J=10.7, 9H).
13C NMR (101 MHz, CDCl3) δ 142.21, 137.82, 134.92, 132.85, 132.46, 129.45, 129.04, 126.94, 124.04, 123.94, 123.77, 117.36, 111.21, 55.83, 43.49, 36.17, 29.61.
HRMS (ESI): m/z 378.1731 (M+H)+; calc. for C23H25N3Cl: 378.1737.
1H NMR (400 MHz, CDCl3) δ 8.30 (dt, J=7.3, 15.7, 1H), 7.50 (dt, J=6.1, 12.2, 1H), 7.16-7.07 (m, 1H), 6.80-6.70 (m, 1H), 6.63-6.56 (m, 1H), 4.17-3.98 (m, 1H), 2.60-2.40 (m, 3H), 1.98 (d, J=20.6, 2H), 1.82-1.70 (m, 5H), 1.62-1.47 (m, 5H).
13C NMR (101 MHz, CDCl3) δ 168.66, 159.46, 142.39, 128.08, 126.54, 124.33, 124.13, 117.50, 111.52, 101.16, 57.60, 43.42, 36.20, 29.78, 12.20.
HRMS (ESI): m/z 349.2013 (M+H)+; calc. for C21H25N4O: 349.2028.
1H NMR (400 MHz, CDCl3) δ 8.19-8.13 (m, 1H), 7.56 (t, J=10.7, 1H), 7.41-7.29 (m, 1H), 7.19-7.11 (m, 1H), 7.06-6.97 (m, 2H), 6.87-6.75 (m, 1H), 3.48-3.32 (m, 1H), 3.07 (d, J=6.1, 1H), 1.73-1.53 (m, 4H), 1.53-1.38 (m, 2H), 1.38-1.24 (m, 2H).
13C NMR (101 MHz, CDCl3) δ 162.09, 162.02, 159.61, 159.54, 142.02, 129.83, 129.72, 129.62, 128.46, 126.59, 123.80, 122.64, 117.88, 111.75, 111.69, 111.66, 111.56, 111.49, 59.42, 33.23, 23.24.
HRMS (ESI): m/z 314.1462 (M+H)+; calc. for C18H18N3F2: 314.1469.
1H NMR (400 MHz, CDCl3) δ 8.28 (dt, J=1.2, 7.0, 1H), 7.51 (dt, J=1.1, 9.1, 1H), 7.27 (d, J=4.8, 1H), 7.12 (ddd, J=1.3, 6.6, 9.0, 1H), 6.93 (d, J=5.1, 1H), 6.76 (td, J=1.1, 6.8, 1H), 3.01 (s, 1H), 2.36 (s, 3H), 1.94 (s, 3H), 1.67-1.34 (m, 12H).
13C NMR (101 MHz, CDCl3) δ 142.08, 135.20, 131.03, 130.16, 127.25, 124.57, 123.81, 123.58, 120.05, 117.31, 111.16, 56.25, 43.44, 36.19, 29.68, 15.17.
HRMS (ESI): m/z 364.1836 (M+H)+; calc. for C22H26N3S: 364.1847.
1H NMR (400 MHz, CDCl3) δ 8.66 (ddd, J=6.1, 6.6, 12.7, 1H), 8.18 (d, J=7.4, 1H), 7.78 (dd, J=1.8, 7.6, 1H), 7.73-7.67 (m, 1H), 7.62-7.50 (m, 2H), 7.48-7.44 (m, 1H), 7.42-7.36 (m, 1H), 7.36-7.29 (m, 1H), 7.05 (t, J=5.0, 1H), 3.23 (s, 1H), 1.90 (s, 3H), 1.66 (d, J=2.9, 3H), 1.51 (s, 2H), 1.46 (d, J=2.4, 8H).
13C NMR (101 MHz, CDCl3) δ 139.64, 135.61, 134.88, 132.95, 132.50, 129.60, 129.57, 129.39, 128.86, 128.28, 127.80, 127.76, 127.00, 126.76, 123.88, 122.79, 121.30, 111.80, 55.63, 43.50, 36.12, 29.58.
HRMS (ESI): m/z 428.1896 (M+H)+; calc. for C27H27N3Cl: 428.1894.
1H NMR (200 MHz, CDCl3) δ 7.71-7.55 (m, 1H), 7.55-7.42 (m, 1H), 7.42-7.29 (m, 2H), 7.25 (d, J=4.3, 2H), 3.18 (s, 3H), 2.55 (s, 1H), 1.53 (d, J=17.9, 5H), 1.16-0.65 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 142.05, 138.18, 137.93, 135.11, 134.05, 132.69, 132.49, 129.40, 129.23, 128.26, 126.90, 116.25, 109.91, 58.69, 33.04, 25.68, 24.68, 17.94.
HRMS (ESI): m/z 418.0676 (M+H)+; calc. for C20H22N3ClBr: 418.0686.
1H NMR (400 MHz, CDCl3) δ 8.65-8.55 (m, 1H), 7.68-7.63 (m, 1H), 7.61 (ddd, J=0.9, 3.4, 9.3, 1H), 7.53-7.46 (m, 1H), 7.43-7.32 (m, 2H), 7.27-7.19 (m, 1H), 3.53-3.13 (m, 1H), 2.86-2.55 (m, 1H), 1.60 (dd, J=23.5, 47.2, 5H), 1.20-0.95 (m, 5H).
13C NMR (101 MHz, CDCl3) δ 140.47, 137.48, 132.83, 132.57, 132.30, 129.76, 129.62, 129.36, 127.41, 127.07, 123.24, 118.50, 117.05, 97.81, 56.58, 33.76, 25.44, 24.45.
HRMS (ESI): m/z 351.1361 (M+H)+; calc. for C20H20N4Cl: 351.1376.
1H NMR (400 MHz, CDCl3) δ 9.44 (dt, J=5.7, 11.5, 1H), 7.74 (dt, J=4.5, 9.0, 1H), 7.71-7.65 (m, 1H), 7.62-7.55 (m, 1H), 7.52-7.47 (m, 1H), 7.46-7.40 (m, 3H), 7.39-7.36 (m, 1H), 7.36-7.33 (m, 1H), 3.60-3.39 (m, 1H), 2.86-2.67 (m, 1H), 1.74 (dd, J=12.6, 18.3, 2H), 1.60-1.36 (m, 3H), 1.11-0.86 (m, 5H).
13C NMR (101 MHz, CDCl3) δ 140.68, 134.79, 132.65, 131.29, 129.57, 129.44, 129.34, 129.05, 128.43, 127.66, 127.36, 127.01, 125.69, 124.42, 124.33, 117.52, 117.11, 56.59, 33.10, 25.58, 24.62.
HRMS (ESI): m/z 376.1576 (M+H)+; calc. for C23H23N3Cl: 376.1581.
1H NMR (400 MHz, CDCl3) δ 8.22-8.08 (m, 1H), 7.74-7.59 (m, 1H), 7.53-7.41 (m, 1H), 7.41-7.27 (m, 2H), 7.03 (dd, J=1.1, 1.8, 1H), 3.22 (d, J=6.9, 1H), 2.72-2.61 (m, 1H), 2.60 (s, 3H), 1.73-1.40 (m, 6H), 1.17-0.82 (m, 6H).
13C NMR (101 MHz, CDCl3) δ 140.39, 135.51, 133.81, 132.77, 132.61, 129.42, 129.25, 128.52, 126.99, 126.84, 125.82, 120.85, 106.62, 56.38, 33.80, 25.59, 24.53, 16.43.
HRMS (ESI): m/z 418.0676 (M+H)+; calc. for C20H22N3ClBr: 418.0686.
1H NMR (400 MHz, CDCl3) δ 8.33-8.21 (m, 1H), 7.70-7.56 (m, 1H), 7.52-7.45 (m, 1H), 7.45-7.40 (m, 1H), 7.40-7.29 (m, 2H), 7.20 (dd, J=1.9, 9.5, 1H), 3.25 (d, J=6.9, 1H), 2.66 (dd, J=3.4, 6.5, 1H), 1.75-1.62 (m, 2H), 1.61-1.52 (m, 2H), 1.52-1.39 (m, 1H), 1.18-0.86 (m, 5H).
13C NMR (101 MHz, CDCl3) δ 139.99, 136.23, 133.61, 132.62, 132.46, 129.52, 129.35, 127.06, 126.97, 126.62, 123.02, 118.30, 106.65, 56.41, 33.81, 25.58, 24.53.
HRMS (ESI): m/z 404.0512 (M+H)+; calc. for C19H20N3ClBr: 404.0529.
1H NMR (400 MHz, CDCl3) δ 8.30-8.09 (m, 1H), 7.43 (dt, J=1.1, 9.0, 1H), 7.04 (ddd, J=1.3, 6.6, 9.0, 1H), 6.69 (td, J=1.1, 6.8, 1H), 2.77-2.70 (m, 2H), 2.05 (d, J=8.4, 3H), 1.79 (dt, J=7.7, 15.7, 2H), 1.72 (d, J=2.5, 6H), 1.64 (d, J=12.3, 3H), 1.57 (d, J=12.3, 3H), 1.45-1.17 (m, 11H), 0.87 (t, J=6.9, 3H).
13C NMR (101 MHz, CDCl3) δ 141.92, 141.67, 123.26, 122.92, 122.06, 116.66, 110.52, 55.48, 44.01, 36.27, 31.87, 29.91, 29.73, 29.54, 29.46, 29.25, 27.98, 22.65, 14.06.
HRMS (ESI): m/z 380.3053 (M+H)+; calc. for C25H38N3: 380.3066.
1H NMR (400 MHz, CDCl3) δ 8.17 (dt, J=1.1, 6.9, 1H), 7.64 (ddd, J=1.3, 4.4, 9.5, 2H), 7.59-7.49 (m, 1H), 7.40 (ddd, J=0.6, 1.2, 7.5, 1H), 7.27-7.20 (m, 1H), 7.18-7.08 (m, 1H), 6.80 (ddd, J=0.6, 1.0, 6.7, 1H), 3.46-3.27 (m, 1H), 3.21 (d, J=6.4, 1H), 1.68-1.48 (m, 4H), 1.48-1.35 (m, 2H), 1.35-1.13 (m, 2H).
13C NMR (101 MHz, CDCl3) δ 141.31, 136.72, 136.11, 132.69, 132.53, 129.32, 127.29, 126.48, 123.65, 122.88, 122.68, 117.54, 111.55, 59.30, 33.16, 23.19.
HRMS (ESI): m/z 356.0768 (M+H)+; calc. for C18H19N3Br: 356.0762.
1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=6.9, 1H), 7.67-7.49 (m, 1H), 7.49-7.36 (m, 2H), 7.33-7.21 (m, 1H), 7.19-7.03 (m, 1H), 6.81 (dd, J=3.6, 10.3, 1H), 3.50-3.32 (m, 1H), 2.84 (d, J=6.0, 1H), 1.72-1.53 (m, 4H), 1.53-1.40 (m, 2H), 1.40-1.27 (m, 2H).
13C NMR (101 MHz, CDCl3) δ 141.46, 136.35, 132.97, 129.88, 128.01, 127.38, 123.61, 122.70, 117.89, 111.60, 59.41, 33.29, 23.34.
HRMS (ESI): m/z 346.0877 (M+H)+; calc. for C18H18N3Cl2: 346.0878.
1H NMR (400 MHz, CDCl3) δ 8.18 (dt, J=1.2, 6.9, 1H), 7.39 (dt, J=1.1, 9.0, 1H), 7.03 (ddt, J=1.2, 6.7, 9.0, 1H), 6.68 (td, J=1.1, 6.8, 1H), 2.77 (s, 1H), 2.19-1.93 (m, 4H), 1.77 (d, J=2.5, 6H), 1.61 (q, J=12.2, 6H), 1.13-1.03 (m, 2H), 0.99-0.91 (m, 2H).
13C NMR (101 MHz, CDCl3) δ 142.47, 141.73, 122.88, 122.75, 122.49, 116.39, 110.46, 55.60, 43.98, 36.27, 29.73, 8.87, 8.18.
HRMS (ESI): m/z 308.2128 (M+H)+; calc. for C20H26N3: 308.2127.
1H NMR (400 MHz, CDCl3) δ 7.63-7.56 (m, 1H), 7.49 (dddd, J=1.3, 1.8, 4.5, 5.0, 2H), 7.39-7.30 (m, 2H), 7.08-6.99 (m, 1H), 6.80-6.73 (m, 1H), 3.31 (d, J=6.8, 1H), 2.81 (s, 1H), 1.67 (d, J=12.5, 2H), 1.52 (s, 2H), 1.45 (s, 1H), 1.06 (t, J=10.4, 3H), 0.89 (d, J=10.1, 2H).
13C NMR (101 MHz, CDCl3) δ 143.62, 137.52, 133.65, 133.24, 132.59, 129.49, 129.25, 128.24, 126.67, 125.99, 123.55, 116.77, 114.06, 58.58, 32.78, 25.67, 24.50.
HRMS (ESI): m/z 360.1014 (M+H)+; calc. for C19H20N3Cl2: 360.1034.
1H NMR (400 MHz, CDCl3) δ 8.66 (d, J=8.0, 1H), 7.99 (dd, J=1.3, 7.3, 1H), 7.75-7.63 (m, 3H), 7.63-7.56 (m, 1H), 7.56-7.48 (m, 1H), 7.42 (ddd, J=1.4, 4.5, 7.6, 1 H), 7.32-7.18 (m, 1H), 7.06 (d, J=7.3, 1H), 3.29 (d, J=6.9, 1H), 2.70 (s, 1H), 1.79-1.64 (m, 2H), 1.57 (s, 2H), 1.51-1.42 (m, 1H), 1.17-0.97 (m, 4H), 0.95-0.75 (m, 1H).
13C NMR (101 MHz, CDCl3) δ 138.83, 136.11, 134.54, 132.88, 132.55, 129.39, 129.25, 127.85, 127.74, 127.62, 127.50, 126.87, 123.95, 123.13, 122.73, 120.43, 112.28, 56.86, 33.75, 25.62, 24.53.
HRMS (ESI): m/z 420.1063 (M+H)+; calc. for C23H23N3Br: 420.1075.
1H NMR (200 MHz, CDCl3) δ 8.15 (d, J=7.1, 1H), 7.69 (d, J=2.5, 1H), 7.52 (d, J=9.1, 1H), 7.46-7.06 (m, 5H), 6.84 (d, J=6.7, 1H), 2.25-2.07 (m, 5H), 1.83-1.43 (m, 12H), 1.41-0.96 (m, 25H), 0.96-0.73 (m, 16H).
13C NMR (50 MHz, CDCl3) δ 138.21, 132.79, 132.26, 130.77, 130.64, 130.58, 129.45, 129.10, 128.52, 124.09, 122.92, 117.54, 111.80, 56.52, 33.93, 31.59, 24.61.
HRMS (ESI): m/z 360.1037 (M+H)+; calc. for C19H20N3Cl2: 360.1034.
1H NMR (400 MHz, CDCl3) δ 8.15 (dt, J=1.0, 6.9, 1H), 7.60 (d, J=8.3, 1H), 7.51 (dt, J=0.9, 9.0, 1H), 7.48 (d, J=2.1, 1H), 7.34-7.30 (m, 1H), 7.14 (ddd, J=1.2, 6.7, 9.0, 1H), 6.79 (td, J=0.9, 6.7, 1H), 3.39-3.27 (m, 1H), 3.20 (s, 1H), 1.68-1.48 (m, 4H), 1.48-1.34 (m, 2H), 1.34-1.17 (m, 2H).
13C NMR (101 MHz, CDCl3) δ 141.30, 134.09, 133.50, 133.02, 132.97, 132.30, 129.01, 127.05, 126.87, 123.99, 122.53, 117.06, 111.62, 58.99, 32.94, 22.99.
HRMS (ESI): m/z 314.1473 (M+H)+; calc. for C18H18N3F2: 314.1469.
1H NMR (200 MHz, CDCl3) δ 8.21-8.10 (m, 1H), 8.07 (d, J=6.9, 1H), 8.01-7.82 (m, 1H), 7.52 (d, J=9.1, 1H), 7.43-7.20 (m, 2H), 7.20-7.02 (m, 1H), 6.78 (t, J=6.8, 1 H), 3.20-2.75 (m, 2H), 1.99-1.42 (m, 6H), 1.42-0.92 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 141.55, 136.30, 135.18, 134.39, 129.55, 127.06, 127.02, 125.17, 124.86, 124.08, 122.60, 117.40, 111.66, 56.90, 34.19, 25.67, 24.78.
HRMS (ESI): m/z 326.1423 (M+H)+; calc. for C19H21N3Cl: 326.1424.
1H NMR (200 MHz, CDCl3) δ 8.15 (d, J=6.9, 1H), 7.56 (d, J=9.1, 1H), 7.48-7.35 (m, 2H), 7.28 (dd, J=6.6, 8.8, 1H), 7.21-7.02 (m, 1H), 6.81 (td, J=0.7, 6.7, 1H), 3.03-2.55 (m, 2H), 1.93-1.40 (m, 8H), 1.39-0.96 (m, 14H), 0.96-0.65 (m, 8H).
13C NMR (50 MHz, CDCl3) δ 141.53, 136.31, 133.06, 129.85, 128.90, 128.00, 126.72, 123.56, 122.85, 117.83, 111.55, 56.58, 33.84, 25.69, 24.60.
HRMS (ESI): m/z 360.1042 (M+H)+; calc. for C19H20N3Cl2: 360.1034.
1H NMR (400 MHz, CDCl3) δ 8.13 (dt, J=1.2, 6.9, 1H), 7.57 (dt, J=1.1, 9.1, 1H), 7.34 (tt, J=6.4, 8.3, 1H), 7.14 (ddd, J=1.3, 6.6, 9.1, 1H), 7.03 (t, J=8.1, 2H), 6.80 (td, J=1.1, 6.8, 1H), 3.12 (s, 1H), 2.71 (s, 1H), 1.84-1.66 (m, 2H), 1.66-1.54 (m, 2H), 1.54-1.42 (m, 1H), 1.21-0.92 (m, 6H).
13C NMR (101 MHz, CDCl3) δ 161.92, 161.85, 159.44, 159.37, 141.97, 129.75, 129.64, 129.54, 127.74, 126.45, 123.75, 122.71, 117.69, 111.72, 111.59, 111.46, 56.40, 33.87, 25.53, 24.64.
HRMS (ESI): m/z 328.1630 (M+H)+; calc. for C19H20N3F2: 328.1625.
1H NMR (400 MHz, CDCl3) δ 8.66 (ddd, J=0.7, 1.3, 2.6, 1H), 8.04-7.94 (m, 2H), 7.70 (dd, J=0.9, 8.0, 1H), 7.66-7.57 (m, 1H), 7.54 (ddd, J=1.4, 7.2, 7.7, 1H), 7.40-7.27 (m, 2H), 7.20-7.12 (m, 1H), 7.05 (d, J=7.2, 1H), 3.49 (s, 1H), 2.72 (s, 1H), 1.78 (s, 2H), 1.62 (s, 2H), 1.51 (s, 1H), 1.10 (d, J=7.7, 5H).
13C NMR (101 MHz, CDCl3) δ 160.62, 158.21, 139.52, 131.50, 129.37, 128.88, 128.79, 127.86, 127.82, 126.90, 124.76, 123.94, 122.75, 120.52, 119.88, 115.68, 115.45, 112.25, 57.26, 33.96, 25.63, 24.83.
HRMS (ESI): m/z 360.1857 (M+H)+; calc. for C23H23N3F: 360.1876.
1H NMR (200 MHz, CDCl3) δ 7.91 (d, J=6.8, 1H), 7.46 (d, J=9.0, 1H), 7.25 (d, J=6.8, 1H), 7.17-7.00 (m, 1H), 6.93 (d, J=7.1, 1H), 6.77 (dd, J=6.7, 14.2, 2H), 5.87 (s, 1H), 2.85 (s, 1H), 1.79-1.49 (m, 3H), 1.16-0.85 (m, 2H), 0.85-0.54 (m, 2H).
13C NMR (50 MHz, CDCl3) δ 142.56, 141.29, 139.91, 130.63, 128.32, 127.15, 123.48, 123.38, 121.58, 121.34, 120.13, 116.68, 111.66, 18.16, 7.62, 7.17.
HRMS (ESI): m/z 298.1123 (M+H)+; calc. for C17H17N3Cl: 298.111.
1H NMR (200 MHz, CDCl3) δ 8.15 (d, J=6.9, 1H), 7.92 (td, J=2.3, 7.6, 1H), 7.54 (d, J=9.1, 1H), 7.22 (m, 4H), 6.79 (t, J=6.7, 1H), 3.45 (t, J=7.8, 1H), 2.91-2.46 (m, 1H), 1.88-1.34 (m, 5H), 1.21-0.83 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 141.74, 131.58, 131.49, 129.15, 128.98, 124.60, 124.54, 123.65, 122.88, 117.38, 115.76, 115.29, 111.44, 56.65, 34.01, 25.66, 24.79.
HRMS (ESI): m/z 310.1724 (M+H)+; calc. for C19H21N3F: 310.1720.
1H NMR (400 MHz, CDCl3) δ 8.13 (t, J=1.9, 1H), 8.04 (dt, J=1.1, 6.9, 1H), 7.94 (dt, J=1.4, 7.7, 1H), 7.50 (dt, J=1.0, 9.0, 1H), 7.33 (t, J=7.8, 1H), 7.25 (ddd, J=1.1, 2.1, 8.0, 1H), 7.15-7.07 (m, 1H), 6.75 (td, J=1.1, 6.8, 1H), 3.70-3.52 (m, 1H), 3.03 (d, J=3.2, 1H), 1.84-1.61 (m, 4H), 1.59-1.49 (m, 2H), 1.49-1.32 (m, 2H).
13C NMR (101 MHz, CDCl3) δ 141.48, 136.13, 135.21, 134.29, 129.53, 127.09, 126.98, 125.72, 124.90, 124.28, 122.49, 117.31, 111.74, 59.01, 33.40, 23.49.
HRMS (ESI): m/z 312.1273 (M+H)+; calc. for C18H19N3Cl: 312.1268.
1H NMR (400 MHz, CDCl3) δ 8.08 (dt, J=1.2, 6.9, 1H), 8.04-7.98 (m, 2H), 7.52 (dt, J=1.0, 9.1, 1H), 7.42-7.37 (m, 2H), 7.14 (ddd, J=1.3, 6.7, 9.0, 1H), 6.79 (td, J=1.1, 6.8, 1H), 3.62 (s, 1H), 3.02 (s, 1H), 1.83-1.62 (m, 4H), 1.62-1.50 (m, 2H), 1.50-1.38 (m, 2H).
13C NMR (101 MHz, CDCl3) δ 141.49, 135.58, 133.05, 132.74, 128.58, 128.33, 125.47, 124.38, 122.54, 117.29, 111.85, 59.05, 33.45, 23.56.
HRMS (ESI): m/z 312.1273 (M+H)+; calc. for C18H19N3Cl: 312.1268.
1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J=0.9, 9.0, 1H), 7.62 (dt, J=3.1, 5.4, 1H), 7.54-7.47 (m, 1H), 7.45-7.34 (m, 3H), 7.17 (dd, J=7.1, 8.9, 1H), 3.33 (d, J=7.1, 1H), 2.79 (d, J=3.3, 1H), 1.73 (d, J=10.2, 2H), 1.55 (d, J=3.8, 3H), 1.44 (d, J=13.8, 1H), 1.04 (dd, J=10.2, 19.7, 5H).
13C NMR (101 MHz, CDCl3) δ 141.06, 138.44, 133.09, 132.37, 129.80, 129.66, 128.09, 127.08, 124.31, 124.30, 122.94, 121.90, 113.97, 108.02, 57.24, 32.67, 25.60, 24.54.
1H NMR (200 MHz, CDCl3) δ 7.78 (d, J=6.8, 1H), 7.56 (d, J=9.0, 1H), 7.25-7.11 (m, 1H), 7.06 (t, J=8.0, 1H), 6.86-6.61 (m, 2H), 6.51 (t, J=2.0, 1H), 6.37 (dd, J=2.2, 8.1, 1H), 5.81 (s, 1H), 3.27-2.83 (m, 1H), 1.29 (d, J=6.9, 6H).
13C NMR (50 MHz, CDCl3) δ 148.27, 146.94, 142.60, 135.34, 130.53, 124.27, 122.19, 119.44, 117.33, 116.27, 113.16, 111.83, 111.28, 26.71, 22.22.
HRMS (ESI): m/z 286.1118 (M+H)+; calc. for C16H17N3Cl: 286.111.
1H NMR (200 MHz, CDCl3) δ 8.23-8.13 (m, 1H), 7.76-7.62 (m, 1H), 7.62-7.42 (m, 2H), 7.42-7.23 (m, 2H), 7.15 (ddd, J=1.3, 6.8, 9.1, 1H), 6.81 (td, J=1.0, 6.8, 1H), 3.34 (dt, J=5.0, 10.2, 1H), 3.21 (d, J=6.4, 1H), 2.21-1.82 (m, 1H), 1.72-1.04 (m, 7H).
13C NMR (50 MHz, CDCl3) δ 141.55, 134.01, 132.66, 132.57, 129.44, 129.11, 127.00, 126.87, 123.74, 122.71, 117.56, 111.60, 59.42, 33.24, 23.28.
HRMS (ESI): m/z 312.1270 (M+H)+; calc. for C18H19N3Cl: 312.1268.
1H NMR (200 MHz, CDCl3) δ 8.02 (dd, J=1.1, 6.8, 1H), 7.56 (d, J=9.0, 1H), 7.26 (d, J=7.8, 1H), 7.20-6.99 (m, 1H), 6.93 (d, J=6.7, 1H), 6.88-6.63 (m, 2H), 5.77 (s, 1H), 2.85 (dt, J=6.9, 13.8, 1H), 1.61 (s, 3H), 1.23 (dd, J=7.3, 14.5, 6H).
13C NMR (50 MHz, CDCl3) δ 146.67, 141.52, 140.23, 130.59, 128.13, 127.27, 123.44, 123.32, 122.01, 121.38, 118.58, 117.02, 111.81, 26.15, 21.73 (br), 18.03.
HRMS (ESI): m/z 300.1271 (M+H)+; calc. for C17H19N3Cl: 300.1268.
1H NMR (200 MHz, CDCl3) δ 8.14-7.91 (m, 1H), 7.52 (d, J=9.0, 1H), 7.26 (d, J=6.1, 1H), 7.21-7.03 (m, 1H), 6.94 (d, J=7.1, 1H), 6.81 (t, J=7.6, 2H), 5.76 (s, 1H), 2.50 (dd, J=7.6, 15.1, 2H), 1.62 (s, 3H), 1.14 (t, J=7.6, 3H).
13C NMR (50 MHz, CDCl3) δ 142.86, 141.53, 140.10, 130.61, 128.49, 127.27, 123.58, 123.46, 122.01, 121.58, 119.58, 117.02, 111.86, 20.34, 18.11, 12.84.
HRMS (ESI): m/z 286.1117 (M+H)+; calc. for C16H17N3Cl: 286.1111.
1H NMR (400 MHz, CDCl3) δ 8.16 (dt, J=1.2, 6.9, 1H), 7.67 (d, J=2.6, 1H), 7.49 (dt, J=1.1, 9.1, 1H), 7.39 (d, J=8.6, 1H), 7.29 (dd, J=2.6, 8.6, 1H), 7.17 (ddd, J=1.3, 6.7, 9.1, 1H), 6.82 (tt, J=3.2, 6.5, 1H), 3.37 (d, J=25.1, 1H), 3.18 (s, 1H), 2.02-1.88 (m, 1H), 1.70-1.50 (m, 4H), 1.50-1.37 (m, 2H), 1.37-1.19 (m, 2H).
13C NMR (101 MHz, CDCl3) δ 141.47, 135.21, 132.65, 132.04, 130.71, 130.45, 129.10, 128.93, 128.48, 124.32, 122.70, 117.19, 111.87, 59.24, 33.10, 23.10.
HRMS (ESI): m/z 346.0878 (M+H)+; calc. for C18H18N3Cl2: 346.0878.
1H NMR (400 MHz, CDCl3) δ 8.14 (dt, J=1.1, 6.9, 1H), 7.57 (dt, J=1.1, 9.1, 1H), 7.35 (tt, J=6.4, 8.4, 1H), 7.15 (ddd, J=1.3, 6.6, 9.1, 1H), 7.03 (t, J=8.1, 1H), 6.81 (td, J=1.1, 6.8, 1H), 3.11 (s, 1H), 2.67 (m, 1H), 1.75 (m, 2H), 1.69-1.56 (m, 2H), 1.56-1.38 (m, 1H), 1.07 (m, 5H).
13C NMR (101 MHz, CDCl3) δ 161.95, 161.88, 159.48, 159.41, 142.03, 129.69, 123.82, 122.76, 117.76, 111.78, 111.65, 111.52, 56.46, 34.04, 25.58, 24.70.
HRMS (ESI): m/z 346.1534 (M+H)+; calc. for C19H19N3F3: 346.1531.
1H NMR (200 MHz, CDCl3) δ 8.15 (d, J=6.9, 1H), 7.92 (td, J=2.2, 7.5, 1H), 7.53 (d, J=9.0, 1H), 7.29 (ddd, J=4.8, 8.8, 13.0, 2H), 7.13 (dd, J=9.4, 16.2, 2H), 6.75 (t, J=6.3, 1H), 3.55-3.15 (m, 2H), 1.77-1.09 (m, 8H).
13C NMR (50 MHz, CDCl3) δ 161.82, 156.95, 141.45, 131.43, 131.35, 129.31, 129.14, 124.53, 124.46, 124.17, 122.70, 116.93, 115.65, 115.18, 111.70, 59.30, 33.09, 23.16.
HRMS (ESI): m/z 296.1566 (M+H)+; calc. for C18H19N3F: 296.1563.
1H NMR (200 MHz, CDCl3) δ 8.07-7.97 (m, 1H), 7.53-7.43 (m, 1H), 7.04 (ddd, J=1.2, 6.5, 8.9, 1H), 6.71 (td, J=0.8, 6.6, 1H), 3.02-2.59 (m, 2H), 2.03-1.51 (m, 13H), 1.51-1.00 (m, 8H).
13C NMR (50 MHz, CDCl3) δ 144.01, 141.36, 138.21, 122.68, 122.43, 116.98, 110.93, 57.21, 36.47, 34.28, 33.02, 26.91, 26.04, 25.86, 24.95.
HRMS (ESI): m/z 298.2261 (M+H)+; calc. for C19H28N3: 298.2283.
1H NMR (200 MHz, CDCl3) δ 8.13-7.92 (m, 2H), 7.52 (dt, J=1.0, 9.1, 1H), 7.22-6.97 (m, 2H), 6.77 (td, J=1.1, 6.8, 1H), 3.31-2.47 (m, 2H), 1.93-1.40 (m, 4H), 1.40-0.86 (m, 4H).
13C NMR (50 MHz, CDCl3) δ 164.7, 160.0, 142.1, 131.3, 129.6, 129.4, 124.9, 124.0, 123.4, 117.9, 116.4, 115.7, 112.2, 57.3, 35.3, 26.1, 25.0.
HRMS (ESI): m/z 310.1721 (M+H)+; calc. for C19H21N3F: 310.1720.
1H NMR (200 MHz, CDCl3) δ 7.89 (dd, J=0.9, 7.0, 1H), 6.83 (d, J=6.8, 1H), 6.61 (t, J=6.8, 1H), 3.01-2.65 (m, 2H), 2.57 (s, 3H), 2.05-1.52 (m, 15H), 1.52-1.32 (m, 4H), 1.32-1.02 (m, 6H).
13C NMR (50 MHz, CDCl3) δ 143.45, 138.22, 126.60, 123.69, 121.57, 120.35, 110.81, 57.34, 37.09, 34.29, 32.90, 26.95, 25.96, 25.89, 24.99, 16.93.
HRMS (ESI): m/z 312.2404 (M+H)+; calc. for C20H30N3: 312.2440.
1H NMR (200 MHz, CDCl3) δ 7.89 (d, J=7.2, 1H), 7.23 (s, 1H), 6.54 (dd, J=1.3, 6.8, 1H), 2.98-2.55 (m, 2H), 2.35 (s, 3H), 1.96-1.66 (m, 10H), 1.66-1.48 (m, 3H), 1.48-1.30 (m, 3H), 1.30-1.00 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 137.08, 133.51, 128.81, 126.28, 121.76, 115.49, 113.53, 57.35, 36.49, 34.25, 33.00, 26.94, 26.06, 25.89, 24.96, 21.23.
HRMS (ESI): m/z 312.2409 (M+H)+; calc. for C20H30N3: 312.2440.
1H NMR (200 MHz, CDCl3) δ 7.77 (s, 1H), 7.37 (d, J=9.1, 1H), 6.89 (dd, J=1.7, 9.1, 1H), 2.97-2.78 (m, 2H), 2.31 (s, 3H), 2.06-1.49 (m, 13H), 1.34 (m, 8H).
13C NMR (50 MHz, CDCl3) δ 143.91, 140.49, 125.77, 123.03, 120.41, 120.11, 116.36, 57.13, 36.46, 34.26, 33.04, 26.94, 26.06, 25.88, 24.97, 18.38.
HRMS (ESI): m/z 312.2408 (M+H)+; calc. for C20H30N3: 312.2440.
1H NMR (200 MHz, CDCl3) δ 7.32 (d, J=8.2, 1H), 7.07-6.74 (m, 1H), 6.34 (d, J=6.8, 1H), 2.88 (s, 3H), 2.70 (m, 2H), 2.00-1.53 (m, 13H), 1.52-0.98 (m, 8H).
13C NMR (50 MHz, CDCl3) δ 146.00, 143.08, 135.88, 124.67, 122.94, 115.28, 112.64, 59.65, 36.23, 33.44, 32.87, 26.93, 25.96, 25.15, 19.76.
HRMS (ESI): m/z 312.2428 (M+H)+; calc. for C20H30N3: 312.2440.
1H NMR (200 MHz, CDCl3) δ 8.03 (dd, J=0.8, 6.7, 1H), 7.47 (dd, J=0.9, 9.0, 1H), 7.13-6.90 (m, 1H), 6.70 (t, J=6.7, 1H), 3.59 (m, 1H), 3.00-2.49 (m, 1H), 2.25-0.94 (m, 19H).
13C NMR (50 MHz, CDCl3) δ 144.25, 141.35, 123.99, 122.73, 122.30, 117.01, 110.94, 59.92, 36.53, 33.53, 33.00, 26.91, 26.03, 23.60.
HRMS (ESI): m/z 284.2106 (M+H)+; calc. for C18H26N3: 284.2127.
1H NMR (200 MHz, CDCl3) δ 7.91 (d, J=6.3, 1H), 6.84 (d, J=6.8, 1H), 6.62 (t, J=6.7, 1H), 3.59 (m, 1H), 2.99-2.64 (m, 1H), 2.57 (s, 3H), 2.16-0.77 (m, 19H).
13C NMR (50 MHz, CDCl3) δ 143.58, 126.58, 124.38, 123.88, 121.70, 120.19, 110.86, 60.00, 37.06, 33.52, 32.84, 26.92, 25.94, 23.60, 16.88.
HRMS (ESI): m/z 298.2234 (M+H)+; calc. for C19H28N3: 298.2283.
1H NMR (200 MHz, CDCl3) δ 7.92 (d, J=6.5, 1H), 7.26 (d, J=6.4, 1H), 6.57 (t, J=6.6, 1H), 2.88-2.61 (m, 1H), 2.29 (s, 3H), 2.08-1.31 (m, 12H), 1.31-1.00 (m, 7H).
13C NMR (50 MHz, CDCl3) δ 144.2, 142.6, 134.4, 123.3, 122.6, 116.1, 115.3, 60.8, 37.4, 35.38, 34.3, 27.2, 26.5, 25.7, 21.6.
HRMS (ESI): m/z 298.2247 (M+H)+; calc. for C19H28N3: 298.2283.
1H NMR (200 MHz, CDCl3) δ 7.81 (s, 1H), 7.42 (d, J=9.1, 1H), 6.92 (d, J=9.3, 1H), 3.69-3.48 (m, 1H), 2.91-2.58 (m, 1H), 2.32 (s, 3H), 2.00-0.98 (m, 19H).
13C NMR (50 MHz, CDCl3) δ 143.87, 140.64, 139.16, 138.19, 125.96, 123.66, 120.80, 119.99, 116.31, 114.35, 59.76, 36.47, 33.48, 32.97, 29.29, 26.92, 26.02, 25.64, 23.60, 18.33.
HRMS (ESI): m/z 298.2250 (M+H)+; calc. for C19H28N3: 298.2283.
1H NMR (200 MHz, CDCl3) δ 7.36 (t, J=7.4, 1H), 7.03-6.78 (m, 1H), 6.35 (t, J=7.3, 1H), 4.01-3.24 (m, 4H), 2.92 (s, 2H), 2.71-2.50 (m, 2H), 2.50-2.07 (m, 4H), 2.04-0.96 (m, 27H).
13C NMR (50 MHz, CDCl3) δ 145.55, 136.00, 125.97, 123.29, 122.79, 122.74, 115.31, 115.22, 115.09, 112.86, 112.52, 112.28, 62.69, 36.24, 32.94, 32.89, 26.99, 26.87, 26.01, 23.71, 19.74.
HRMS (ESI): m/z 298.2251 (M+H)+; calc. for C19H28N3: 298.2283.
1H NMR (200 MHz, CDCl3) δ 8.06-7.95 (m, 1H), 7.58-7.44 (m, 1H), 7.44-7.11 (m, 5H), 7.05 (ddd, J=1.2, 6.7, 8.8, 1H), 6.71 (t, J=6.7, 1H), 4.33 (q, J=7.1, 1H), 2.87-2.28 (m, 2H), 1.98-1.43 (m, 8H), 1.43-0.78 (m, 6H).
13C NMR (50 MHz, CDCl3) δ 145.64, 142.00, 141.09, 128.41, 128.35, 127.97, 127.43, 126.01, 122.77, 122.43, 117.07, 111.08, 57.20, 37.99, 34.13, 25.75, 24.90, 24.80, 21.71.
HRMS (ESI): m/z 320.2073 (M+H)+; calc. for C21H26N3: 320.2127.
1H NMR (200 MHz, CDCl3) δ 7.98-7.83 (m, 1H), 7.62-7.10 (m, 5H), 6.95-6.83 (m, 1H), 6.64 (t, J=6.8, 1H), 4.42 (q, J=7.1, 1H), 2.65 (s, 3H), 2.52-2.23 (m, 1H), 1.84 (d, J=7.2, 3H), 1.77-1.47 (m, 5H), 1.36-0.90 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 145.60, 141.51, 141.35, 128.28, 127.57, 126.75, 125.95, 124.79, 121.56, 120.39, 110.91, 57.38, 38.31, 34.02, 25.79, 24.92, 21.71, 16.74.
HRMS (ESI): m/z 334.2242 (M+H)+; calc. for C22H28N3: 334.2283.
1H NMR (200 MHz, CDCl3) δ 7.92 (m, 1H), 7.42-7.14 (m, 6H), 6.65 (dd, 1H), 4.32 (q, 1H), 2.78 (s, 1H), 2.31 (s, 1H), 1.83 (d, 3H), 1.88-1.54 (m, 5H), 1.29-1.04 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 146.8, 142.0, 134.7, 129.3, 128.4, 128.0, 127.5, 126.8, 123.1, 121.8, 116.7, 115.6, 59.8, 39.5, 34.8, 26.6, 25.3, 23.9, 22.2.
HRMS (ESI): m/z 334.2255 (M+H)+; calc. for C22H28N3: 334.2283.
1H NMR (200 MHz, CDCl3) δ 7.84-7.67 (m, 1H), 7.54-7.00 (m, 6H), 6.99-6.78 (m, 1H), 4.30 (q, J=7.1, 1H), 2.89-2.44 (m, 2H), 2.30 (s, 3H), 1.74 (d, J=3.7, 3H), 1.72-1.48 (m, 6H), 1.44-0.83 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 159.24, 145.78, 141.86, 140.19, 128.31, 127.41, 125.93, 125.85, 120.57, 120.08, 116.43, 57.10, 37.98, 34.09, 25.76, 24.91, 21.72, 18.32.
HRMS (ESI): m/z 334.2257 (M+H)+; calc. for C22H28N3: 334.2283.
1H NMR (200 MHz, CDCl3) δ 7.59-7.02 (m, 8H), 6.92 (dd, J=6.8, 8.9, 1H), 6.42-6.29 (m, 1H), 4.30 (q, J=7.1, 1H), 3.68 (s, 1H), 2.84 (s, 3H), 1.76 (d, J=7.2, 3H), 1.72-1.46 (m, 4H), 1.46-0.83 (m, 6H).
13C NMR (50 MHz, CDCl3) δ 145.91, 143.89, 142.83, 136.00, 128.24, 127.41, 125.83, 123.11, 115.40, 112.92, 59.27, 37.67, 33.57, 33.44, 25.88, 25.18, 24.95, 21.97, 19.81.
HRMS (ESI): m/z 334.2255 (M+H)+; calc. for C22H28N3: 334.2283.
1H NMR (200 MHz, CDCl3) δ 8.08-7.90 (m, 1H), 7.60-7.43 (m, 1H), 7.43-7.11 (m, 5H), 7.06 (ddd, J=1.4, 6.7, 9.0, 1H), 6.71 (td, J=1.2, 6.8, 1H), 4.35 (q, J=7.1, 1H), 3.61-3.22 (m, 1H), 2.65-1.98 (m, 2H), 1.86-1.75 (m, 3H), 1.75-1.05 (m, 9H).
13C NMR (50 MHz, CDCl3) δ 145.64, 142.08, 141.11, 128.74, 128.34, 127.42, 122.79, 122.28, 117.18, 111.11, 59.75, 37.93, 33.57, 33.41, 23.55, 21.77.
HRMS (ESI): m/z 306.1950 (M+H)+; calc. for C20H24N3: 306.1970.
1H NMR (200 MHz, CDCl3) δ 7.91 (d, J=7.3, 1H), 7.51-7.10 (m, 5H), 6.89 (d, J=6.8, 1H), 6.65 (t, J=6.7, 1H), 4.43 (q, J=7.2, 1H), 3.44 (dt, J=5.1, 10.2, 1H), 2.65 (s, 3H), 1.83 (d, J=7.2, 3H), 1.79-1.11 (m, 8H).
13C NMR (50 MHz, CDCl3) δ 145.54, 141.38, 128.27, 127.54, 126.79, 125.94, 125.54, 121.71, 120.22, 111.01, 59.93, 38.19, 33.46, 33.36, 23.57, 21.75, 16.74.
HRMS (ESI): m/z 320.2105 (M+H)+; calc. for C21H26N3: 320.2127.
1H NMR (200 MHz, CDCl3) δ 7.89 (d, J=6.9, 1H), 7.52-7.01 (m, 5H), 6.54 (dd, J=1.6, 6.9, 1H), 4.32 (q, J=7.2, 1H), 3.45 (dt, J=5.6, 11.0, 1H), 2.35 (s, 3H), 1.77 (d, J=7.2, 3H), 1.73-1.44 (m, 5H), 1.44-1.04 (m, 3H).
13C NMR (50 MHz, CDCl3) δ 145.76, 141.63, 141.59, 133.64, 128.30, 127.43, 125.92, 124.63, 121.61, 115.65, 113.71, 59.86, 37.88, 33.51, 33.38, 23.57, 21.75, 21.19.
HRMS (ESI): m/z 320.2121 (M+H)+; calc. for C21H26N3: 320.2127.
1H NMR (200 MHz, CDCl3) δ 7.81-7.73 (m, 1H), 7.55-7.06 (m, 5H), 6.91 (dd, J=1.7, 9.1, 1H), 4.32 (q, J=7.2, 1H), 3.58-3.31 (m, 1H), 2.30 (s, 3H), 1.77 (d, J=7.2, 3H), 1.72-1.09 (m, 8H).
13C NMR (50 MHz, CDCl3) δ 145.81, 141.83, 140.20, 138.23, 128.37, 127.46, 127.31, 126.00, 120.72, 120.02, 116.59, 59.67, 37.97, 33.60, 23.62, 21.83, 18.40.
HRMS (ESI): m/z 320.2095 (M+H)+; calc. for C21H26N3: 320.2127.
1H NMR (200 MHz, CDCl3) δ 7.46-7.03 (m, 6H), 6.93 (dd, J=6.9, 8.9, 1H), 6.36 (d, J=6.7, 1H), 4.34 (q, J=7.1, 1H), 3.49 (dt, J=5.7, 11.2, 1H), 2.85 (s, 3H), 1.77 (d, J=7.2, 3H), 1.73-1.07 (m, 8H).
13C NMR (50 MHz, CDCl3) δ 145.96, 143.65, 142.86, 136.02, 128.27, 127.42, 127.01, 125.86, 123.16, 115.49, 112.93, 62.31, 37.53, 33.15, 32.74, 23.74, 23.61, 22.04, 19.68.
HRMS (ESI): m/z 320.2106 (M+H)+; calc. for C21H26N3: 320.2127.
1H NMR (200 MHz, CDCl3) δ 8.23-8.07 (m, 1H), 7.62-7.50 (m, 1H), 7.47 (d, J=8.7, 1H), 7.36 (d, J=8.7, 1H), 7.18 (dd, J=1.3, 6.7, 1H), 6.82 (td, J=0.9, 6.7, 1H), 2.77 (m, 2H), 1.85-1.35 (m, 3H), 1.35-0.71 (m, 3H).
13C NMR (50 MHz, CDCl3) δ 141.56, 134.79, 134.48, 133.04, 131.85, 130.54, 128.27, 126.61, 123.79, 122.90, 117.81, 111.69, 56.63, 33.84, 25.63, 24.58.
HRMS (ESI): m/z 394.0645 (M+H)+; calc. for C19H19N3Cl3: 394.0645.
1H NMR (200 MHz, CDCl3) δ 8.29-8.03 (m, 1H), 7.60-7.39 (m, 2H), 7.33-7.05 (m, 2H), 6.97 (td, J=1.6, 8.2, 1H), 6.77 (td, J=1.1, 6.8, 1H), 3.93 (s, 3H), 3.72-3.26 (m, 1H), 2.91-2.54 (m, 1H), 1.94-1.36 (m, 5H), 1.33-0.81 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 152.17, 148.23, 147.99, 147.32, 142.22, 127.26, 124.54, 123.96, 123.56, 117.67, 112.66, 111.74, 56.95, 56.67, 34.31, 25.93, 25.14.
HRMS (ESI): m/z 340.1824 (M+H)+; calc. for C20H23N3OF: 340.1825.
1H NMR (200 MHz, CDCl3) δ 8.27-8.03 (m, 1H), 7.81 (ddd, J=1.8, 6.6, 8.4, 1H), 7.64-7.47 (m, 1H), 7.40 (ddd, J=1.8, 7.1, 8.0, 1H), 7.31-7.03 (m, 2H), 6.80 (td, J=1.2, 6.8, 1H), 3.56-3.17 (m, 1H), 2.87-2.50 (m, 1H), 1.89-1.33 (m, 5H), 1.10 (d, J=7.0, 5H).
13C NMR (50 MHz, CDCl3) δ 157.31, 152.40, 142.05, 129.94, 129.87, 129.58, 127.10, 124.93, 124.84, 124.01, 122.99, 117.47, 111.64, 56.74, 34.04, 25.62, 24.79.
HRMS (ESI): m/z 344.1329 (M+H)+; calc. for C19H20N3FCl: 344.1330.
1H NMR (200 MHz, CDCl3) δ 8.13-7.98 (m, 3H), 7.53 (d, J=9.0, 1H), 7.46-7.37 (m, 2H), 7.14 (dd, J=7.8, 9.1, 1H), 6.79 (t, J=6.8, 1H), 3.13-2.84 (m, 2H), 1.95-1.46 (m, 6H), 1.22 (m, 4H).
13C NMR (50 MHz, CDCl3) δ 141.65, 133.09, 132.93, 128.58, 128.26, 123.99, 122.60, 117.45, 111.62, 56.87, 34.23, 25.72, 24.82.
HRMS (ESI): m/z 326.1422 (M+H)+; calc. for C19H21N3Cl: 326.1424.
1H NMR (200 MHz, CDCl3) δ 8.28-7.99 (m, 1H), 7.85-7.71 (m, 1H), 7.66-7.40 (m, 4H), 7.13 (ddd, J=1.3, 6.7, 9.0, 1H), 6.80 (td, J=1.1, 6.8, 1H), 3.28-2.83 (m, 1H), 2.66 (m, 1H), 1.90-1.35 (m, 5H), 1.23-0.80 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 141.06, 138.17, 135.28, 132.83, 131.21, 128.11, 126.85, 126.14 (q, J=5.1, 1H), 123.49, 122.77, 121.40, 117.59, 111.50, 56.25, 33.81, 25.63, 24.51.
HRMS (ESI): m/z 360.1688 (M+H)+; calc. for C20H21N3F3: 360.1688.
1H NMR (200 MHz, CDCl3) δ 8.21-7.90 (m, 3H), 7.55 (dt, J=1.0, 9.1, 1H), 7.22-6.97 (m, 3H), 6.78 (td, J=1.0, 6.8, 1H), 3.63 (m, 1H), 1.93-1.27 (m, 9H).
13C NMR (50 MHz, CDCl3) δ 164.68, 159.78, 141.48, 138.21, 129.01, 128.85, 124.17, 122.53, 117.36, 115.57, 115.15, 111.77, 59.20, 33.55, 23.64.
HRMS (ESI): m/z 296.1560 (M+H)+; calc. for C18H19N3F: 296.1563.
1H NMR (200 MHz, CDCl3) δ 8.03 (d, J=6.8, 1H), 7.45 (d, J=9.0, 1H), 7.05 (ddd, J=1.2, 6.5, 8.7, 1H), 6.71 (td, J=1.0, 6.8, 1H), 3.71-3.45 (m, 1H), 2.88-2.51 (m, 2H), 1.92-1.67 (m, 7H), 1.67-1.42 (m, 5H), 1.42-1.11 (m, 10H), 0.87 (m, 2H).
13C NMR (50 MHz, CDCl3) δ 141.31, 139.81, 126.46, 122.81, 122.24, 116.83, 110.95, 59.79, 33.55, 31.90, 29.86, 29.67, 29.49, 29.28, 27.51, 23.60, 22.67, 14.08.
HRMS (ESI): m/z 314.2595 (M+H)+; calc. for C20H32N3: 314.2596.
1H NMR (200 MHz, CDCl3) δ 8.21-8.10 (m, 1H), 7.59-7.50 (m, 1H), 7.50-7.41 (m, 1H), 7.41-7.33 (m, 1H), 7.16 (ddd, J=1.0, 6.5, 8.0, 1H), 6.82 (td, J=0.8, 6.7, 1H), 3.56-3.28 (m, 2H), 2.79 (d, J=5.6, 1H), 1.79-1.40 (m, 7H), 1.40-1.04 (m, 4H).
13C NMR (50 MHz, CDCl3) δ 148.09, 141.46, 137.64, 134.80, 134.78, 134.50, 131.85, 130.56, 130.01, 128.88, 128.25, 127.27, 123.88, 122.73, 117.79, 114.22, 111.76, 107.50, 59.43, 33.38, 23.41.
HRMS (ESI): m/z 380.0490 (M+H)+; calc. for C18H17N3Cl3: 380.0488.
1H NMR (200 MHz, CDCl3) δ 8.14 (d, J=6.9, 1H), 7.65-7.35 (m, 2H), 7.26-7.03 (m, 2H), 6.95 (td, J=1.6, 8.2, 1H), 6.75 (t, J=6.8, 1H), 3.91 (s, 3H), 3.53-3.22 (m, 2H), 1.76-1.07 (m, 8H).
13C NMR (50 MHz, CDCl3) δ 151.87, 147.84, 147.60, 147.01, 141.78, 131.51, 127.51, 124.16, 124.07, 123.62, 122.67, 117.29, 112.37, 111.37, 59.40, 56.29, 33.13, 23.24.
HRMS (ESI): m/z 326.1668 (M+H)+; calc. for C19H21N3OF: 326.1669.
1H NMR (200 MHz, CDCl3) δ 8.18-7.92 (m, 1H), 7.49 (m, 1H), 7.14-6.94 (m, 1H), 6.82-6.61 (m, 1H), 3.80-3.47 (m, 1H), 3.32-3.02 (m, 1H), 2.90-2.66 (m, 1H), 1.93-1.68 (m, 4H), 1.68-1.43 (m, 4H), 1.38 (d, J=9.0, 6H).
13C NMR (50 MHz, CDCl3) δ 160.21, 155.76, 138.10, 126.18, 116.34, 105.78, 105.24, 58.19, 37.28, 37.04, 34.17, 25.09, 18.18, 17.96.
HRMS (ESI): m/z 244.1812 (M+H)+; calc. for C15H22N3: 244.1814.
1H NMR (200 MHz, CDCl3) δ 8.23 (d, 1H), 7.92-7.86 (m, 1H), 7.55 (d, 1H), 7.48-7.30 (d, 1H), 7.28-7.07 (m, 2H), 6.92-6.76 (m, 1H), 6.56-3.22 (m, 2H), 1.80-1.12 (m, 8H).
13C NMR (50 MHz, CDCl3) δ 157.39, 152.48, 142.01, 138.19, 129.87, 129.62, 127.73, 124.93, 124.50, 124.08, 122.87, 117.52, 111.50, 59.58, 33.30, 23.31.
HRMS (ESI): m/z 330.1173 (M+H)+; calc. for C18H18N3FCl: 330.1173.
1H NMR (200 MHz, CDCl3) δ 8.06 (dt, J=1.0, 6.8, 1H), 7.49 (d, J=9.1, 1H), 7.04 (ddd, J=1.2, 6.6, 8.9, 1H), 6.71 (td, J=0.9, 6.8, 1H), 3.64 (dt, J=5.3, 10.8, 1H), 3.02-2.73 (m, 1H), 2.62 (ddd, J=6.4, 8.2, 14.6, 1H), 1.96-1.68 (m, 8H), 1.68-1.41 (m, 4H), 1.37 (d, J=6.8, 1H), 0.82 (t, J=7.4, 6H).
13C NMR (50 MHz, CDCl3) δ 142.09, 141.51, 126.28, 122.65, 122.26, 116.94, 110.72, 60.03, 40.98, 33.58, 28.25, 23.65, 12.60.
HRMS (ESI): m/z 272.2125 (M+H)+; calc. for C17H26N3: 272.2127.
1H NMR (200 MHz, CDCl3) δ 8.13 (d, J=6.9, 1H), 7.78 (d, J=7.5, 1H), 7.66-7.41 (m, 4H), 7.23-7.03 (m, 1H), 6.81 (td, J=0.9, 6.7, 1H), 3.52-3.21 (m, 1H), 3.06-2.78 (m, 1H), 1.40 (m, 8H).
13C NMR (50 MHz, CDCl3) δ 141.03, 135.34, 132.87, 131.23, 129.95, 128.14, 126.72, 126.17 (q, J=5.1), 123.60, 122.64, 121.42, 117.65, 111.59, 59.16, 33.33, 23.35.
HRMS (ESI): m/z 346.1531 (M+H)+; calc. for C19H19N3F3: 346.1531.
1H NMR (200 MHz, CDCl3) δ 8.15-8.06 (m, 1H), 7.52 (dt, J=1.0, 9.0, 1H), 7.26 (d, J=5.1, 1H), 7.11 (ddd, J=1.3, 6.7, 9.0, 1H), 6.94 (d, J=5.1, 1H), 6.77 (td, J=1.1, 6.8, 1H), 3.82-3.25 (m, 1H), 3.22-2.92 (m, 1H), 2.43 (s, 4H), 1.88-1.56 (m, 5H), 1.55-1.31 (m, 4H).
13C NMR (50 MHz, CDCl3) δ 141.36, 135.77, 130.47, 129.73, 126.57, 124.33, 124.21, 123.50, 122.49, 117.47, 111.46, 59.35, 33.32, 23.50.
HRMS (ESI): m/z 298.1383 (M+H)+; calc. for C17H20N3S: 298.1378.
1H NMR (200 MHz, CDCl3) δ 8.01 (d, J=6.7, 1H), 7.40 (d, J=8.9, 1H), 7.21-6.91 (m, 1H), 6.91-6.47 (m, 1H), 3.85-3.53 (m, 1H), 3.14-2.48 (m, 1H), 2.21-1.69 (m, 4H), 1.69-1.40 (m, 4H), 1.23-0.79 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 141.47, 140.87, 138.47, 123.06, 122.12, 116.94, 111.17, 60.15, 33.82, 23.86, 8.45, 8.00.
HRMS (ESI): m/z 242.1659 (M+H)+; calc. for C15H20N3: 242.1657.
1H NMR (200 MHz, CDCl3) δ 8.13-7.98 (m, 1H), 7.57-7.42 (m, 1H), 7.14-6.98 (m, 1H), 6.85-6.59 (m, 1H), 4.55-3.84 (m, 1H), 3.61 (m, 1H), 2.86 (m, 1H), 2.11-1.40 (m, 11H), 1.34 (d, J=6.9, 3H), 0.85 (t, J=7.4, 2H).
13C NMR (50 MHz, CDCl3) δ 143.56, 141.42, 124.80, 122.89, 122.29, 116.86, 110.94, 59.92, 33.54, 33.51, 29.84, 23.58, 20.73, 12.61.
HRMS (ESI): m/z 258.1970 (M+H)+; calc. for C16H24N3: 258.1970.
1H NMR (200 MHz, CDCl3) δ 8.14-7.93 (m, 1H), 7.48 (m, 1H), 7.04 (ddd, J=1.2, 6.7, 8.8, 1H), 6.71 (td, J=1.1, 6.9, 1H), 3.10-2.63 (m, 2H), 2.12-1.48 (m, 8H), 1.48-1.06 (m, 8H), 0.85 (t, J=7.3, 3H).
13C NMR (50 MHz, CDCl3) δ 143.77, 141.75, 124.39, 123.01, 122.71, 117.13, 111.12, 57.58, 34.55, 33.63, 30.16, 26.09, 25.23, 21.07, 12.87.
HRMS (ESI): m/z 272.2127 (M+H)+; calc. for C17H26N3: 272.2127.
1H NMR (200 MHz, CDCl3) δ 8.30 (s, 1H), 7.71-7.54 (m, 1H), 7.52-7.12 (m, 4H), 3.22 (d, J=5.6, 1H), 2.78-2.51 (m, 1H), 2.45 (s, 3H), 1.87-1.33 (m, 5H), 1.23-0.78 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 140.87, 135.76, 134.14, 133.78, 132.60, 132.42, 129.45, 129.16, 126.86, 125.74, 122.98, 116.60, 110.69, 56.52, 33.79, 25.64, 24.56, 22.53.
HRMS (ESI): m/z 418.0686 (M+H)+; calc. for C20H22N3ClBr: 418.0686.
1H NMR (200 MHz, CDCl3) δ 7.91 (s, 1H), 7.74-7.54 (m, 1H), 7.52-7.40 (m, 2H), 7.40-7.18 (m, 2H), 6.98 (dd, J=1.7, 9.2, 1H), 3.40-3.07 (m, 1H), 2.82-2.51 (m, 1H), 2.35 (s, 3H), 1.91-1.31 (m, 5H), 1.23-0.80 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 140.71, 135.00, 134.20, 132.48, 129.31, 128.86, 126.74, 125.92, 121.02, 120.30, 116.84, 56.26, 33.80, 25.64, 24.55, 18.37.
HRMS (ESI): m/z 340.1582 (M+H)+; calc. for C20H23N3Cl: 340.1581.
1H NMR (200 MHz, CDCl3) δ 8.11 (d, 1H), 7.72-7.68 (m, 1H), 7.53-7.26 (m, 4H), 6.72 (dd, 1H), 3.24 (s, 1H), 2.78 (s, 1H), 2.45 (s, 3H), 1.80-1.42 (m, 5H), 1.23-0.97 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 142.4, 135.2, 134.4, 134.7, 133.9, 130.2, 129.3, 127.7, 126.2 123.3, 116.6, 115.3, 57.4, 34.7, 26.4, 25.2, 21.8.
HRMS (ESI): m/z 340.1581 (M+H)+; calc. for C20H23N3Cl: 340.1581.
1H NMR (200 MHz, CDCl3) δ 7.92 (s, 1H), 7.73-7.67 (m, 1H), 7.58-7.22 (m, 4H), 7.03-6.92 (dd, 1H), 3.37 (s, 1H), 2.72 (s, 1H), 2.38 (s, 3H), 1.85-1.42 (m, 5H), 1.22-1.08 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 146.1, 142.8, 141.3, 139.5, 135.9, 133.3, 130.2, 129.6, 127.2, 122.7, 121.3, 118.6, 57.0, 34.2, 26.5, 25.9, 19.5.
HRMS (ESI): m/z 340.1581 (M+H)+; calc. for C20H23N3Cl: 340.1581.
1H NMR (200 MHz, CDCl3) δ 7.71-7.68 (m, 1H), 7.52-7.26 (m, 4H), 7.12-7.08 (m, 1H), 6.53-6.46 (d, 1H), 3.25-3.18 (m, 1H), 3.03 (s, 3H), 2.65 (s, 1H), 1.80-1.45 (m, 5H), 1.26-0.81 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 143.15, 137.29, 136.64, 134.56, 132.65, 132.48, 129.22, 128.87, 128.05, 126.71, 123.78, 115.74, 113.16, 58.72, 33.39, 25.67, 24.95, 19.84.
HRMS (ESI): m/z 340.1581 (M+H)+; calc. for C20H23N3Cl: 340.1581.
1H NMR (200 MHz, CDCl3) δ 8.31 (s, 1H), 7.65 (dd, J=2.5, 6.9, 1H), 7.53-7.11 (m, 4H), 3.50-3.25 (m, 1H), 3.24-3.07 (m, 1H), 2.44 (s, 3H), 1.77-1.04 (m, 8H).
13C NMR (50 MHz, CDCl3) δ 140.72, 135.51, 134.08, 133.66, 132.60, 132.36, 129.39, 129.15, 126.81, 126.38, 122.80, 116.51, 110.69, 59.33, 33.13, 23.20, 22.47.
HRMS (ESI): m/z 404.0528 (M+H)+; calc. for C19H20N3ClBr: 404.0529.
1H NMR (200 MHz, CDCl3) δ 7.98-7.90 (m, 1H), 7.67 (dd, J=2.2, 7.2, 1H), 7.52-7.38 (m, 2H), 7.38-7.28 (m, 2H), 7.00 (dd, J=1.8, 9.2, 1H), 3.49-2.94 (m, 2H), 2.36 (s, 3H), 1.73-0.94 (m, 8H).
13C NMR (50 MHz, CDCl3) δ 142.02, 135.00, 134.23, 132.63, 132.55, 129.39, 128.97, 126.87, 126.82, 121.16, 120.27, 116.94, 108.37, 59.32, 33.22, 23.28, 18.24
HRMS (ESI): m/z 326.1422 (M+H)+; calc. for C19H21N3Cl: 326.1424.
1H NMR (200 MHz, CDCl3) δ 8.05 (d, J=6.9, 1H), 7.75-7.60 (m, 1H), 7.46 (dd, J=2.1, 7.2, 1H), 7.41-7.16 (m, 3H), 6.64 (dd, J=1.5, 7.0, 1H), 3.49-3.01 (m, 2H), 2.40 (s, 3H), 1.72-1.10 (m, 8H).
13C NMR (50 MHz, CDCl3) δ 142.19, 138.27, 134.80, 134.49, 132.88, 132.79, 129.65, 129.28, 129.20, 127.06, 122.22, 116.13, 114.50, 59.76, 33.45, 23.54, 21.56.
HRMS (ESI): m/z 326.1422 (M+H)+; calc. for C19H21N3Cl: 326.1424.
1H NMR (200 MHz, CDCl3) δ 8.03 (ddd, J=0.5, 1.0, 2.4, 1H), 7.74-7.64 (m, 1H), 7.50-7.42 (m, 1H), 7.41-7.26 (m, 2H), 6.94 (d, J=6.7, 1H), 6.72 (t, J=6.7, 1H), 3.47-3.25 (m, 1H), 3.26-3.00 (m, 1H), 2.62 (s, 3H), 1.71-1.41 (m, 6H), 1.41-1.01 (m, 3H).
13C NMR (50 MHz, CDCl3) δ 141.93, 138.20, 134.64, 134.32, 132.84, 132.75, 129.35, 129.00, 127.31, 126.90, 122.49, 120.58, 111.62, 59.43, 33.26, 23.29, 16.71.
HRMS (ESI): m/z 326.1424 (M+H)+; calc. for C19H21N3Cl: 326.1424.
1H NMR (200 MHz, CDCl3) δ 7.76-7.61 (m, 1H), 7.56-7.21 (m, 4H), 7.01 (dd, J=6.9, 8.9, 1H), 6.49 (d, J=8.6, 1H), 3.37-3.00 (m, 2H), 2.97 (s, 3H), 1.71-1.28 (m, 6H), 1.28-0.93 (m, 2H).
13C NMR (50 MHz, CDCl3) δ 143.47, 138.45, 137.04, 134.89, 133.05, 132.97, 132.86, 129.60, 129.29, 127.11, 124.22, 116.12, 113.55, 62.36, 32.95, 23.56, 20.16.
HRMS (ESI): m/z 326.1426 (M+H)+; calc. for C19H21N3Cl: 326.1424.
1H NMR (200 MHz, CDCl3) δ 8.18 (s, 1H), 7.33 (s, 1H), 3.69-3.44 (m, 1H), 3.27-2.96 (m, 1H), 2.88-2.53 (m, 1H), 2.41 (s, 3H), 1.97-1.38 (m, 8H), 1.34 (d, J=6.8, 6H).
13C NMR (50 MHz, CDCl3) δ 145.57, 133.02, 123.33, 122.61, 116.30, 109.91, 109.74, 59.91, 33.56, 26.32, 23.61, 22.73, 22.44.
HRMS (ESI): m/z 336.1077 (M+H)+; calc. for C16H23N3Br: 336.1075.
1H NMR (200 MHz, CDCl3) δ 7.86-7.74 (m, 1H), 7.39 (d, J=9.1, 1H), 6.90 (dd, J=1.8, 9.1, 1H), 3.71-3.41 (m, 1H), 3.29-3.00 (m, 1H), 2.31 (s, 3H), 1.91-1.41 (m, 8H), 1.36 (d, J=6.9, 6H).
13C NMR (50 MHz, CDCl3) δ 144.70, 140.54, 125.88, 123.17, 120.44, 120.04, 116.42, 59.75, 33.55, 26.23, 23.64, 22.85, 18.37.
HRMS (ESI): m/z 258.1972 (M+H)+; calc. for C16H24N3: 258.1970.
1H NMR (200 MHz, CDCl3) δ 7.91 (d, J=7.1, 1H), 7.24 (s, 1H), 6.54 (dd, J=1.4, 7.1, 1H), 3.68-3.46 (m, 1H), 3.24-2.99 (m, 1H), 2.35 (s, 3H), 1.90-1.40 (m, 8H), 1.36 (d, J=6.9, 6H).
13C NMR (50 MHz, CDCl3) δ 144.35, 141.78, 133.46, 121.96, 121.53, 115.42, 113.42, 59.85, 33.41, 26.15, 23.52, 22.71, 21.09.
HRMS (ESI): m/z 258.1969 (M+H)+; calc. for C16H24N3: 258.1970.
1H NMR (200 MHz, CDCl3) δ 8.00-7.82 (m, 1H), 6.97-6.75 (m, 1H), 6.62 (t, J=6.8, 1H), 3.72-3.43 (m, 1H), 3.33-2.99 (m, 1H), 2.58 (s, 3H), 1.93-1.67 (m, 4H), 1.67-1.43 (m, 4H), 1.39 (d, J=6.9, 6H).
13C NMR (50 MHz, CDCl3) δ 144.27, 141.65, 126.67, 124.17, 121.68, 120.23, 110.86, 59.99, 33.59, 26.71, 23.65, 22.82, 16.87.
HRMS (ESI): m/z 258.1969 (M+H)+; calc. for C16H24N3: 258.1970.
1H NMR (200 MHz, CDCl3) δ 7.35 (d, J=8.9, 1H), 6.91 (dd, J=6.8, 9.0, 1H), 6.39-6.30 (m, 1H), 3.63-3.38 (m, 1H), 3.15 (q, J=6.8, 1H), 2.96-2.76 (m, 3H), 1.93-1.67 (m, 4H), 1.67-1.41 (m, 4H), 1.41-1.26 (m, 6H).
13C NMR (50 MHz, CDCl3) δ 146.39, 143.09, 135.91, 123.02, 115.29, 115.29, 112.63, 62.55, 32.91, 25.88, 23.65, 22.75, 19.68.
HRMS (ESI): m/z 258.1971 (M+H)+; calc. for C16H24N3: 258.1970.
1H NMR (200 MHz, CDCl3) δ 8.17 (s, 1H), 7.33 (s, 1H), 3.08 (q, J=6.7, 1H), 2.96-2.59 (m, 2H), 2.41 (s, 3H), 2.02-1.46 (m, 6H), 1.34 (d, J=6.9, 6H), 1.29-1.07 (m, 4H).
13C NMR (50 MHz, CDCl3) δ 145.76, 138.45, 133.21, 122.96, 116.48, 110.14, 100.21, 57.62, 34.47, 26.54, 26.07, 25.16, 22.97, 22.68.
HRMS (ESI): m/z 350.1236 (M+H)+; calc. for C17H25N3Br: 350.1232.
1H NMR (200 MHz, CDCl3) δ 7.78 (s, 1H), 7.38 (d, J=9.2, 1H), 6.89 (dd, J=1.7, 9.1, 1H), 3.23-3.00 (m, 1H), 2.97-2.74 (m, 1H), 2.31 (s, 3H), 1.98-1.47 (m, 5H), 1.35 (d, J=6.9, 6H), 1.22-1.09 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 144.63, 140.56, 138.22, 125.82, 120.41, 120.14, 116.41, 57.17, 34.30, 26.22, 25.89, 24.98, 22.86, 18.39.
HRMS (ESI): m/z 272.2126 (M+H)+; calc. for C17H26N3: 272.2127.
1H NMR (200 MHz, CDCl3) δ 8.00-7.79 (m, 1H), 7.26 (s, 1H), 6.55 (dd, J=1.5, 7.0, 1H), 3.23-2.93 (m, 2H), 2.93-2.73 (m, 1H), 2.35 (s, 3H), 1.99-1.44 (m, 5H), 1.35 (d, J=6.9, 6H), 1.30-0.99 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 144.44, 142.08, 139.90, 133.86, 122.00, 115.73, 113.81, 57.62, 34.51, 26.47, 26.14, 25.20, 23.03, 21.47.
HRMS (ESI): m/z 272.2126 (M+H)+; calc. for C17H26N3: 272.2127.
1H NMR (200 MHz, CDCl3) δ 7.89 (d, J=6.8, 1H), 7.02-6.73 (m, 1H), 6.61 (t, J=6.7, 1H), 3.28-3.04 (m, 1H), 2.98-2.66 (m, 2H), 2.57 (s, 3H), 1.97-1.50 (m, 5H), 1.38 (d, J=6.9, 6H), 1.31-1.04 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 153.93, 144.41, 141.95, 126.89, 121.84, 120.62, 111.05, 57.61, 34.57, 26.94, 26.14, 25.24, 23.08, 17.13.
HRMS (ESI): m/z 272.2123 (M+H)+; calc. for C17H26N3: 272.2127.
1H NMR (200 MHz, CDCl3) δ 7.36 (d, J=8.8, 1H), 6.92 (dd, J=6.7, 8.9, 1H), 6.42-6.29 (m, 1H), 3.24-3.00 (m, 1H), 2.89 (s, 3H), 1.97-1.51 (m, 5H), 1.35 (d, J=6.9, 6H), 1.31-0.97 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 144.26, 141.87; 139.92, 138.47, 123.30, 115.64, 112.96, 59.90, 33.82, 26.27, 26.23, 25.46, 23.01, 20.09.
HRMS (ESI): m/z 272.2128 (M+H)+; calc. for C17H26N3: 272.2127.
1H NMR (200 MHz, CDCl3) δ 7.68-7.49 (m, 2H), 7.49-7.34 (m, 1H), 7.34-7.20 (m, 2H), 7.14 (dd, J=6.8, 9.1, 1H), 7.03-6.84 (m, 1H), 6.65 (td, J=1.2, 7.6, 1H), 6.52 (d, J=6.7, 1H), 6.19 (s, 1H), 6.09 (dd, J=1.1, 8.3, 1H), 2.67 (s, 3H).
13C NMR (50 MHz, CDCl3) δ 144.65, 143.60, 140.64, 138.21, 136.14, 133.24, 132.70, 131.97, 129.61, 129.48, 129.38, 127.82, 126.70, 125.31, 119.47, 118.64, 116.22, 113.90, 113.60, 18.59.
HRMS (ESI): m/z 368.0733 (M+H)+; calc. for C20H16N3Cl2: 368.0721.
1H NMR (200 MHz, CDCl3) δ 7.71-7.53 (m, 1H), 7.52-7.39 (m, 1H), 7.39-7.20 (m, 2H), 7.14 (s, 1H), 6.29 (s, 1H), 2.91 (s, 3H), 2.54 (m, 1H), 2.31 (s, 3H), 1.58 (m, 5H), 1.11-0.68 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 143.77, 138.20, 135.88, 134.77, 134.58, 132.74, 132.57, 129.31, 128.86, 127.69, 126.79, 116.02, 114.18, 58.77, 33.16, 25.80, 24.76, 20.87, 19.72.
HRMS (ESI): m/z 354.1715 (M+H)+; calc. for C21H25N3Cl: 354.1737.
1H NMR (200 MHz, CDCl3) δ 7.68-7.61 (m, 1H), 7.56-7.41 (m, 3H), 7.39-7.28 (m, 3H), 7.28-7.19 (m, 3H), 7.08-6.89 (m, 1H), 5.91 (d, J=7.2, 1H), 2.89-2.80 (m, 1H), 1.78-1.41 (m, 6H), 1.11-0.81 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 156.34, 149.94, 143.46, 138.28, 134.05, 133.85, 131.01, 129.96, 129.24, 128.01, 127.34, 124.91, 120.04, 113.84, 97.02, 57.96, 33.95, 25.74, 25.07.
HRMS (ESI): m/z 418.1635 (M+H)+; calc. for C25H25N3OCl: 418.1686.
1H NMR (200 MHz, CDCl3) δ 7.57 (dd, J=3.3, 6.0, 1H), 7.51-7.39 (m, 1H), 7.38-7.19 (m, 2H), 7.13 (d, J=8.9, 1H), 7.04-6.88 (m, 1H), 5.89 (d, J=7.3, 1H), 4.26 (q, J=7.0, 2H), 4.11 (s, 1H), 2.74 (s, 1H), 1.83-1.63 (m, 2H), 1.63-1.31 (m, 6H), 1.21-0.75 (m, 5H).
13C NMR (50 MHz, CDCl3) δ 150.94, 142.66, 134.48, 134.05, 132.58, 129.41, 128.73, 128.48, 126.29, 123.89, 110.70, 88.54, 65.45, 57.15, 33.42, 25.88, 24.57, 14.46.
HRMS (ESI): m/z 370.1658 (M+H)+; calc. for C21H25N3OCl: 370.1686.
1H NMR (400 MHz, CDCl3) δ 8.24 (dd, J=1.7, 8.5, 2H), 8.05 (dt, J=1.0, 6.9, 1H), 7.69 (dd, J=1.7, 8.5, 2H), 7.53 (dt, J=1.0, 9.1, 1H), 7.17 (ddd, J=1.2, 6.7, 9.1, 1H), 6.81 (td, J=1.0, 6.8, 1H), 3.06 (d, J=4.9, 1H), 2.95 (ddd, J=4.6, 10.0, 14.4, 1H), 1.87-1.76 (m, 2H), 1.76-1.64 (m, 2H), 1.64-1.51 (m, 1H), 1.33-1.03 (m, 5H).
13C NMR (101 MHz, CDCl3) δ 141.94, 139.17, 134.70, 132.16, 127.17, 126.06, 124.61, 122.63, 119.18, 117.75, 112.04, 110.20, 56.96, 34.22, 25.59, 24.77.
HRMS (ESI): m/z 317.1765 (M+H)+; calc. for C20H21N4: 317.1766.
1H NMR (400 MHz, CDCl3) δ 8.48 (t, J=1.6, 1H), 8.37 (dt, J=1.5, 7.6, 1H), 8.14-7.94 (m, 1H), 7.62-7.45 (m, 3H), 7.16 (ddd, J=1.1, 6.7, 9.0, 1H), 6.81 (td, J=1.0, 6.8, 1H), 3.04 (d, J=4.7, 1H), 2.94 (ddd, J=4.4, 10.0, 14.3, 1H), 1.88-1.75 (m, 2H), 1.75-1.63 (m, 2H), 1.63-1.49 (m, 1H), 1.42-0.92 (m, 5H).
13C NMR (101 MHz, CDCl3) δ 141.85, 135.91, 134.59, 130.95, 130.44, 130.33, 129.11, 125.29, 124.46, 122.58, 118.98, 117.64, 112.48, 111.96, 56.91, 34.21, 25.58, 24.76.
HRMS (ESI): m/z 317.1775 (M+H)+; calc. for C20H21N4: 317.1766.
1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=7.3, 1H), 7.64 (d, J=5.5, 1H), 7.52 (s, 1H), 7.47 (d, J=6.3, 1H), 7.35 (dd, J=7.1, 12.4, 2H), 6.79 (d, J=7.2, 1H), 3.26 (s, 1H), 2.64 (s, 1H), 1.75-1.61 (m, 2H), 1.56 (s, 2H), 1.47 (s, 1H), 1.15-0.91 (m, 5H).
13C NMR (101 MHz, CDCl3) δ 141.08, 135.68, 133.40, 132.41, 132.35, 130.20, 129.44, 129.28, 126.93, 126.56, 123.19, 116.16, 113.23, 56.41, 33.71, 25.49, 24.46.
1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.70 (dd, J=1.9, 7.5, 1H), 7.60 (dd, J=0.7, 9.3, 1H), 7.54 (d, J=8.8, 2H), 7.48 (dd, J=1.5, 7.7, 1H), 7.43-7.29 (m, 3H), 7.03 (d, J=8.8, 2H), 3.86 (s, 3H), 3.31 (d, J=6.8, 1H), 2.80-2.59 (m, 1H), 1.78-1.63 (m, 2H), 1.63-1.51 (m, 2H), 1.51-1.40 (m, 1H), 1.17-0.89 (m, 5H).
13C NMR (101 MHz, CDCl3) δ 159.32, 140.83, 135.58, 133.97, 132.48, 130.28, 129.41, 129.07, 127.99, 126.88, 126.56, 125.70, 124.48, 119.32, 117.26, 114.43, 56.42, 55.32, 33.79, 25.55, 24.53.
1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J=2.1, 7.3, 1H), 7.60-7.53 (m, 1H), 7.46 (d+m, J=8.7, 3H), 7.37-7.26 (m, 2H), 7.14 (dd, J=6.8, 8.9, 1H), 6.98 (d, J=8.6, 2H), 6.61 (dd, J=1.0, 6.8, 1H), 3.88 (s, 3H), 2.64 (s, 1H), 2.00 (m, 1H), 0.82 (m, 8H), 0.37 (m, 2H).
13C NMR (101 MHz, CDCl3) δ 159.88, 142.70, 138.01, 135.45, 134.19, 133.32, 132.69, 130.78, 129.40, 128.92, 127.99, 127.08, 126.62, 122.99, 116.73, 115.26, 112.64, 56.36, 55.50, 32.47, 25.59, 24.34.
1H NMR (400 MHz, CDCl3) δ 7.65-7.60 (m, 1H), 7.58 (dd, J=1.2, 9.0, 1H), 7.46-7.19 (m, 7H), 7.15 (dd, J=6.8, 9.0, 1H), 6.57 (dd, J=1.2, 6.8, 1H), 2.45 (d, J=7.8, 1H), 2.07 (s, 3H), 2.01 (ddd, J=3.6, 8.5, 10.1, 1H), 1.41-0.98 (m, 5H), 0.89-0.65 (m, 2H), 0.58 (d, J=12.4, 1H), 0.41-0.27 (m, 1H), 0.27-0.11 (m, 1H).
13C NMR (101 MHz, CDCl3) δ 142.26, 138.77, 137.87, 134.92, 134.19, 133.22, 132.68, 129.34, 129.24, 129.00, 128.97, 128.94, 128.53, 127.75, 127.34, 126.66, 125.06, 122.97, 116.94, 114.82, 56.76, 32.63, 32.50, 25.55, 19.77.
1H NMR (400 MHz, CDCl3) δ 8.53 (dd, J=2.1, 4.1, 1H), 8.46 (dd, J=2.1, 6.8, 1H), 7.81-7.70 (m, 1H), 7.55-7.43 (m, 1H), 7.38 (dqd, J=1.8, 7.4, 14.8, 2H), 6.90 (dd, J=4.1, 6.8, 1H) 3.34 (d, J=6.9, 1H), 2.64 (dd, J=3.4, 6.7, 1H), 1.73-1.61 (m, 2H), 1.61-1.52 (m, 2H), 1.47 (s, 1H), 1.19-0.91 (m, 5H).
13C NMR (101 MHz, CDCl3) δ 149.13, 144.56, 136.60, 133.27, 132.79, 132.24, 130.42, 129.45, 129.42, 127.01, 124.75, 108.09, 56.60, 33.72, 25.47, 24.46.
HRMS (ESI): m/z 327.1380 (M+H)+; calc. for C18H20N4Cl: 327.1376.
1H NMR (400 MHz, CDCl3) δ 8.66 (d, J=8.0, 1H), 8.00 (d, J=7.3, 1H), 7.75 (dd, J=1.6, 7.5, 1H), 7.71 (d, J=7.0, 1H), 7.62-7.57 (m, 1H), 7.57-7.51 (m, 1H), 7.48 (dd, J=1.2, 7.9, 1H), 7.39 (td, J=1.4, 7.5, 1H), 7.36-7.30 (m, 1H), 7.07 (d, J=7.2, 1 H), 3.29 (d, J=7.1, 1H), 2.78-2.62 (m, 1H), 1.77-1.66 (m, 2H), 1.63-1.51 (m, 2H), 1.51-1.44 (m, 1H), 1.16-0.98 (m, 5H).
13C NMR (101 MHz, CDCl3) δ 139.07, 134.03, 132.69, 132.61, 129.61, 129.43, 129.38, 128.97, 128.12, 127.88, 127.78, 127.05, 126.89, 123.95, 122.72, 120.44, 112.30, 56.93, 33.80, 25.62, 24.60.
HRMS (ESI): m/z 376.1587 (M+H)+; calc. for C23H23N3Cl: 376.1581.
Biological Activity
Table 1 gives selected results for the compounds of the invention against HIV-1 reverse transcriptase in an enzymatic assay and/or whole cell anti-HIV assay.
96
82
81
99
118
43
74
89
42
48
97
170
104
163
165
8
166
171
116
Enzymatic Method for Determining Activity Against Reverse Transcriptase
The assay is based on a sandwich-ELISA protocol employing the ROCHE colorimetric reverse transcriptase kit (cat#11468120910). Biotin and DIG-labelled nucleotides are incorporated into cDNA strands polymerized on an RNA template by the action of HIV-1 reverse transcriptase. The cDNA products are bound to streptavidin-coated wells of 96-well plate inserts, and their associated DIG-moieties detected by incubation with anti-DIG antibodies conjugated to horseradish peroxidase (HRP). The amount of bound antibody is quantitated by incubation with a colorimetric HRP substrate, followed by absorbance reading at 405 nm using a multiwell spectrophotometer.
To assess the inhibitory activity of test compounds, a single concentration screen (usually 50 μM) or IC50 determination may be carried out. In the single concentration screen, compounds are incubated with HIV-1 reverse trancriptase and substrate and the residual enzyme activity expressed as a percentage relative to a control without inhibitor. For IC50 determinations, 4-fold serial dilutions of the compounds are incubated with HIV-1 reverse trancriptase and substrate and the enzyme activity, expressed as a percentage relative to a control without inhibitor, plotted against inhibitor concentration to derive the concentration at which 50% enzyme inhibition (IC50) is obtained.
Cellular Methods for Determining Anti-HIV Activity
PBMC
Fresh human PBMCs, seronegative for HIV and HBV, were isolated from screened donors (Interstate Blood Bank, Inc. Memphis, Tenn.). Cells were pelleted/washed 2-3 times by low speed centrifugation and re-suspension in PBS to remove contaminating platelets. The Leukophoresed blood was then diluted 1:1 with Dulbecco's Phosphate Buffered Saline (DPBS) and layered over 14 mL of Lymphocyte Separation Medium (LSM; Cellgro® by Mediatech, Inc.; density 1.078+/−0.002 g/ml; Cat.#85-072-CL) in a 50 mL centrifuge tube and then centrifuged for 30 minutes at 600×g. Banded PBMCs were gently aspirated from the resulting interface and subsequently washed 2× with PBS by low speed centrifugation. After the final wash, cells were enumerated by trypan blue exclusion and re-suspended at 1×107 cells/ml in RPMI 1640 supplemented with 15% Fetal Bovine Serum (FBS), and 2 mM L-glutamine, 4 μg/ml Phytohemagglutinin (PHA-P, Sigma). The cells were allowed to incubate for 48-72 hours at 37° C. After incubation, PBMCs were centrifuged and resuspended in RPMI 1640 with 15% FBS, 2 mM L-glutamine, 100 U/ml penicillin, 100 μg/ml streptomycin, 10 μg/ml gentamycin, and 20 U/ml recombinant human IL-2 (R&D Systems, Inc). IL-2 is included in the culture medium to maintain the cell division initiated by the PHA mitogenic stimulation. PBMCs were maintained in this medium at a concentration of 1−2×106 cells/mL with biweekly medium changes until used in the assay protocol. Cells were kept in culture for a maximum of two weeks before being deemed too old for use in assays and discarded. Monocytes were depleted from the culture as the result of adherence to the tissue culture flask.
For the standard PBMC assay, PHA-P stimulated cells from at least two normal donors were pooled (mixed together), diluted in fresh medium to a final concentration of 1×106 cells/mL, and plated in the interior wells of a 96 well round bottom microplate at 50 μl/well (5×104 cells/well) in a standard format developed by the Infectious Disease Research department of Southern Research Institute. Pooling (mixing) of mononuclear cells from more than one donor is used to minimize the variability observed between individual donors, which results from quantitative and qualitative differences in HIV infection and overall response to the PHA and IL-2 of primary lymphocyte populations. Each plate contains virus/cell control wells (cells plus virus), experimental wells (drug plus cells plus virus) and compound control wells (drug plus media without cells, necessary for MTS monitoring of cytotoxicity). Since HIV-1 is not cytopathic to PBMCs, this allows the use of the same assay plate for both antiviral activity and cytotoxicity measurements. Test drug dilutions were prepared at a 2× concentration in microtiter tubes and 100 μl of each concentration was placed in appropriate wells using the standard format. 50 μl of a predetermined dilution of virus stock was placed in each test well (final MOI≈0.1). The PBMC cultures were maintained for seven days following infection at 37° C., 5% CO2. After this period, cell-free supernatant samples were collected for analysis of reverse transcriptase activity. Following removal of supernatant samples, compound cytotoxicity was measured by addition of MTS to the plates for determination of cell viability. Wells were also examined microscopically and any abnormalities were noted.
MAGI
MAGI-R5 cells naturally express the CXCR4 co-receptor and are engineered to express CD4 (HIV-1 cell surface receptor), the CCR5 co-receptor and also to contain an LTR-β-galactosidase reporter construct. The MAGI Antiviral Assay is designed to identify compounds that block HIV-1 replication via targets in the viral life cycle up to and including Tat transactivation (e.g. virus attachment/fusion/entry, uncoating, reverse transcription, nuclear import, integration, LTR transactivation). MAGI cells are treated with compound for 15 to 30 min prior to addition of virus. HIV-1 is then added to the cells/compounds and the cultures are incubated for 48 hours. If the virus is able to infect the cells it will proceed through reverse transcription and integration and begin transcription from the integrated provirus. One of the first virus proteins produced is HIV 1 Tat, which transactivates the HIV-1 LTR promoter driving expression of β-galactosidase. As a result, infected cells begin to overproduce the β-galactosidase enzyme. Forty-eight hours post infection, the cells are lysed and β-galactosidase enzyme activity is measured using a chemiluminescence detection method (Perkin Elmer Applied Biosystems). Compound toxicity is monitored on replicate plates using MTS dye reduction (CellTiter 96® Reagent, Promega, Madison, Wis.).
The invention accordingly shows that compounds of the general structure A and B inhibit the enzyme HIV-1 reverse transcriptase and thus have application as anti-HIV agents.
PCT/US2008/082531 claims the priority of U.S. Ser. No. 60/986,990. However, at the time of filing this application, the priority document was not available from the US Patent Office. If the priority date of any compounds disclosed in PCT/US2008/082531 is later than the priority date of the compounds disclosed in this specification it will be necessary to amend the provisos. The following has therefore been included in this specification to provide for this eventuality.
The invention also provides the use of a compound selected from compounds of the formula A and B in the manufacture of a medicament for the treatment of a subject infected with HIV, a composition for use in treating a subject who has been infected with HIV, the composition including a compound selected from compounds of formula A or B, for use in the treatment of a subject suffering from an HIV infection, a method of treating a subject suffering from an HIV infection by administration of a compound selected from compounds of formula A or B and compounds of formula A or B in which, for formula A
R2-R5 are independently selected from H, halogen, cyano, alkyl and substituted alkyl, or R2 and R3 together form a carbocyclic ring or, independently, R4 and R5 together form a carbocyclic ring,
R6 is H, alkyl or alkanoyl,
and in which for formula B,
| Number | Date | Country | Kind |
|---|---|---|---|
| 2008/07954 | Sep 2008 | ZA | national |
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|---|---|---|---|---|
| PCT/IB2009/054021 | 9/16/2009 | WO | 00 | 8/30/2011 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2010/032195 | 3/25/2010 | WO | A |
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