PI3K-α inhibitors and methods of use thereof

Abstract

The present disclosure relates to novel compounds and pharmaceutical compositions thereof, and methods for inhibiting the activity of PI3K-α enzymes with the compounds and compositions of the disclosure. The present disclosure further relates to, but is not limited to, methods for treating disorders associated with PI3K-α signaling with the compounds and compositions of the disclosure.

Description

[0931] Characterization data for methyl 2-(4-methoxybenzyl)-7-((methoxycarbonyl)amino)-3-oxo-l-(o-tolyl)isoindoline-5-carboxylate: MS: m / z = 475.3 [M+H]+; ’H NMR (400 MHz, DMSO- / 6) 5 9.17 (d, J= 16.4 Hz, 1H), 8.13 (dd, / =23.6, 1.2 Hz, 1H), 7.94 (d, J= 1.2 Hz, 1H), 7.60 (d, J= 19.4 Hz, 1H), 6.93 - 6.83 (d, J= 19.4 Hz, 1H), 7.45 (d, J= 24 Hz, 1H), 7.28 - 7.22 (m, 5H), 7.07 - 7.00 (m, 6H), 6.91 - 6.87 (m, 4H), 6.46 (d, J= 7.6 Hz, 1H), 6.29 (d, J= 7.6 Hz, 1H), 5.97 (s, 1H), 5.73 (s, 1H), 5.63 (s, 1H), 5.50 (s, 1H), 5.01 - 4.91 (m, 2H), 4.77 (s, 1H), 3.92 (d, J= 4.8 Hz, 4H), 3.87 (d, J= 4.8 Hz, 2H), 3.74 (d, J= 8.0 Hz, 6H), 3.62(d, J= 14.8 Hz, 1H), 3.49 (d, J= 9.6 Hz, 5H), 2.25 (d, J= 18.4 Hz, 3H), 1.48 (s, 1H), 1.34 (s, 2H). 4-Amino-6-(hydroxymethyl)-2-[(4-methoxyphenyl)methyl]-3-(2-methylphenyl)-2,3-dihydro-lZZ-isoindol-l-one

[0932] Step 2: A solution of methyl 7-amino-2-(4-methoxybenzyl)-3-oxo-l-(o-tolyl)isoindoline-5-carboxylate (516 mg, 1.24 mmol) in THF (6.19 mL) was stirred under nitrogen atmosphere and cooled to 0 °C using an ice bath. Then a solution of borane lithium hydride (930 pL, 1.86 mmol, 2 M in THF) was added, and the mixture was warmed to room temperature overnight. The reaction mixture was quenched with water (20 mL), extracted with DCM (3 x 20 mL), and the combined organic phases were concentrated under reduced pressure. The resulting residue was purified by reverse-phase chromatography (60g column Cl8, 10 to 100% ACN / AmF lOmM) to afford after lyophilisation 4-amino-6-(hydroxymethyl)-2-[(4-methoxyphenyl)methyl]-3-(2-methylphenyl)-2,3-dihydro-l / / -isoindol-l-one (188 mg, 0.484 mmol, 39% yield) as a white powder. MS: m / z = 389.3 [M+H]+. A-[6-(Hydroxymethyl)-2-[(4-methoxyphenyl)methyl]-3-(2-methylphenyl)-l-oxo-2,3-dihydro-l / Z-isomdol-4-yl]-l,2-benzothiazole-3-carboxamide O

[0933] Step 3: To a solution of 4-amino-6-(hydroxymethyl)-2-[(4-methoxyphenyl)methyl]-3-(2-methylphenyl)-2,3-dihydro-l / f-isoindol-l-one (150 mg, 0.3861 mmol) in DCM (1.93 mL) was added 177-imidazole (65.7 mg, 0.9652 mmol), and the reaction mixture was cooled to 0°C using an ice bath. Then ter / -butyl(chloro)dimethylsilane (69.8 mg, 0.4633 mmol) was added, and the reaction mixture was stirred for 2h at room temperature.

[0934] To the reaction mixture was added l,2-benzothiazole-3-carbonyl chloride (76.3 mg, 0.3861 mmol), and the reaction mixture was stirred for 3 days at room temperature. The reaction mixture was concentrated to dryness and purified by reverse phase chromatography (60g Cl8 column, 10 to 100% ACN / AmF lOmM) to afford after lyophilisation A-[6-(hydroxymethyl)-2-[(4-methoxyphenyl)methyl]-3-(2-methylphenyl)-l -oxo-2,3-dihydro- \H-isoindol-4-yl]-l,2-benzothiazole-3-carboxamide (80.5 mg, 0.1466 mmol, 38% yield) as an orange powder. MS: m / z = 550.3 [M+H]+; ^NMR (400 MHz, DMSO-t / 6) 5 10.18 (s, 0.31H), 10.06 (s, 0.48H), 8.58 (d, J= 8.2 Hz, 0.32H), 8.52 (d, J= 8.2 Hz, 0.53H), 8.29 (d, J= 8.3 Hz, 1H), 7.72 (d, J= 4.5 Hz, 1H), 7.71 - 7.67 (m, 1H), 7.67 - 7.63 (m, 1H), 7.60 - 7.52 (m, 1H), 7.27 (d, J= 7.0 Hz, 0.38H), 7.11 - 6.81 (m, 7H), 6.74 (t, J= 6.7 Hz, 0.36H), 6.42 -6.35 (m, 0.57H), 5.96 (s, 0.51H), 5.76 (s, 0.33H), 5.45 (td, J= 5.8, 2.9 Hz, 1H), 5.00 (dd, J= 15.0, 11.1 Hz, 1H), 4.65 (t, J =52 Hz, 2H), 3.73 (s, 3H), 3.61 (d, J= 14.9 Hz, 0.40H), 3.47 (d, J= 15.5 Hz, 0.71H), 2.10 (s, 2H), 1.44 (s, 1H). The compound appears to exist as noninterconverting rotamers in DMSO solution at ambient temperature. A-[6-(Hydroxymethyl)-3-(2-methylphenyl)-l-oxo-2,3-dihydro-lZZ-isoindol-4-yl]-l,2-benzothiazole-3-carboxamide

[0935] Step 4: In a sealed tube A-[6-(hydroxymethyl)-2-[(4-methoxyphenyl)methyl]-3-(2-methylphenyl)-l-oxo-2,3-dihydro-l / / -isoindol-4-yl]-l,2-benzothiazole-3-carboxamide (231 mg, 0.420 mmol) was dissolved in trifluoroacetic acid (6.42 mL, 84.0 mmol). The resulting mixture was heated at 90°C for 24 h. The reaction was diluted with DCM (50 mL), the organic layer was washed with water (2x5 mL), and the organic phase was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (60g C18 cartridge, 10 to 100%ACN / AmF 10mM)toaffordA-[6-(hydroxymethyl)-3-(2-methylphenyl)-l-oxo-2,3-dihydro-l / / -isoindol-4-yl]-l,2-benzothiazole-3-carboxamide (123 mg, 0.288 mmol, 68% yield) as a brown powder after lyophilisation.

[0936] Additional compounds prepared according to the methods of Example 44 are listed in Table 18 below. Certain compounds in Table 18 below were prepared with other compounds whose preparation is described elsewhere in the Examples. Table 18. Additional Exemplary Compounds Compound 1-154 1-185 1-224 Compound 1-306 1-307 Compound 1-314 1-373 Example 45 7V-(6-((Methylsulfonyl)methyl)-l-oxo-3-(o-tolyl)isomdolm-4-yl)benzo[< / ]isothiazole-3-carboxamide (1-202) 0 A-(6-(Bromomethyl)-l-oxo-3-(o-tolyl)isomdolm-4-yl)benzo[<Z]isothiazole-3-carboxamide O

[0937] Step 1: A flask was charged with A-(6-(hydroxymethyl)-l-oxo-3-(o-tolyl)isoindolin-4-yl)benzo[t / ]isothiazole-3-carboxamide (7 mg, 0.0163 mmol), dichloromethane (0.13 mL) triphenylphosphine (4.69 mg, 0.0179 mmol), and tetrabromomethane (5.93 mg, 0.0179 mmol). The reaction mixture was stirred for 1.5 h at room temperature. The reaction mixture was concentrated under reduced pressure and purified by reverse phase chromatography (30 g Cl8 cartridge, 10 to 100% ACN / AmF lOmM) to afford A-(6-(bromomethy 1)-1 -oxo-3-(o-tolyl)isoindolin-4-yl)benzo[t / ]isothiazole-3-carboxamide (9.00 mg, 0.0183 mmol) as a beige powder. MS: m / z = 492.2 [M+H]+. A-(6-((Methylsulfonyl)methyl)-l-oxo-3-(o-tolyl)isoindolm-4-yl)benzo[< / ]isothiazole-3-carboxamide O

[0938] Step 2: A sealed tube was charged with A-(6-(bromomethyl)-l-oxo-3-(o-tolyl)isoindolin-4-yl)benzo[< / ]isothiazole-3-carboxamide (9.00 mg, 0.01827 mmol), DMF (0.09 mL), and sodium methanesulfmate (4.66 mg, 0.04567 mmol). The reaction mixture was heated to 70°C for 6 h. The reaction mixture was cooled to room temperature then directly purified on reverse phase chromatography (30 g C18 cartridge, 10 to 100% ACN / AmF 10 mM) to afford after lyophilisation ,V-(6-((mcthy I sulfonyl (methyl )-1-oxo-3-(o-tolyl)isoindolin-4-yl)benzo[t / ]isothiazole-3-carboxamide (5.44 mg, 0.0111 mmol, 60% yield) as a white powder. MS: m / z = 492.3 [M+H]+; ' H NMR (400 MHz, CDCh) 5 8.90 (d, J= 7.7 Hz, 1H), 8.87 (s, 1H), 8.59 (s, 1H), 7.94 (d, J= 7.8 Hz, 1H), 7.79 (d, J= 1.2 Hz, 1H), 7.72 -7.62 (m, 1H), 7.60 - 7.50 (m, 3H), 7.46 (td, J= 7.4, 3.0 Hz, 1H), 7.17 (br s, 1H), 6.65 (s, 1H), 6.00 (br s, 1H), 4.41 (s, 2H), 2.89 (s, 3H), 2.16 (s, 1H), 1.24 (br s, 3H).

[0939] Additional compounds prepared according to the methods of Example 45 are listed in Table 19 below. Certain compounds in Table 19 below were prepared with other compounds whose preparation is described elsewhere in the Examples. Table 19. Additional Exemplary Compounds Compound 1-231 1-310 Example 46 A-(6-(Methoxymethyl)-l-oxo-3-(o-tolyl)isoindolin-4-yl)-A-methylbenzo[<Z]isothiazole-3-carboxamide (1-134) O 7V-(2-(4-Methoxybenzyl)-6-(methoxymethyl)-l-oxo-3-(o-tolyl)isoindolm-4-yl)-7V-methylbenzo[< / ]isothiazole-3-carboxamide

[0940] Step 1: To a solution of ^-^-(hydroxymethyl^-^-methoxybenzy^-l-oxo-S^o-toly^isoindolin-d-y^benzofaQisothiazole-S-carboxamide (20 mg, 0.036 mmol) in DMF (0.18 mL) cooled to 0°C using an ice bath, was added sodium hydride (3.05 mg, 0.0764 mmol) and the mixture was stirred for 30 minutes. lodomethane (2.71 pL, 0.0437 mmol) was added, and the reaction mixture was warmed to room temperature for 2 h. The reaction was quenched with water (10 mL), the aqueous layer was extracted with DCM (3 x 10mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by reverse phase chromatography (30 g C18 Biotage, 10 to 100% ACN / AmF lOmM) to afford after lyophilisation A-(2-(4-methoxybenzyl)-6-(methoxymethyl)-l-oxo-3-(o-tolyl)isoindolin-4-yl)-A-methylbenzo[t / ]isothiazole-3-carboxamide (10.5 mg, 0.0183 mmol, 50% yield) as a beige powder. MS: m / z = 578.4 [M+H]+. A-(6-(Methoxymethyl)-l-oxo-3-(°-tolyl)isoindolin-4-yl)-A-methylbenzo[<Z]isothiazole-3-carboxamide O

[0941] Step 2 : A sealed tube was charged with A-(2-(4-methoxybenzyl)-6-(methoxymethyl)-l-oxo-3-(o-tolyl)isoindolin-4-yl)-A-methylbenzo[t / ]isothiazole-3-carboxamide (10.5 mg, 0.0183 mmol) and trifluoroacetic acid (317 pL, 4.15 mmol), and the reaction mixture was heated to 90°C for 24 h. The resulting mixture was diluted with DCM (20 mL), washed with water (2 x 50 mL), and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (30 g Cl8 cartridge, 10 to 100% ACN / AmF lOmM) affording after lyophilisation A-(6-(methoxymethy 1)-1 -oxo-3-(o-tolyl)isoindolin-4-yl)-A-methylbenzo[t / ]isothiazole-3-carboxamide (3.84 mg, 0.00839 mmol, 40% yield) as a beige powder. Example 47 A-(6-(Methoxymethyl)-l-oxo-3-(o-tolyl)isoindolm-4-yl)benzo[<Z]isothiazole-3-carboxamide (1-146) (7-(Benzo[J]isothiazole-3-carboxamido)-2-(4-methoxybenzyl)-3-oxo-l-(<9-tolyl)isoindolm-5-yl)methyl methanesulfonate

[0942] Step 1: To a solution of A-(6-(hydroxymethyl)-2-(4-methoxybenzyl)-l-oxo-3-(o-tolyl)isoindolin-4-yl)benzo[t / ]isothiazole-3-carboxamide (25 mg, 0.036 mmol) in anhydrous DCM (0.23 mL) was added triethylamine (19.0 pL, 0.14 mmol), and the mixture was cooled to 0°C using an ice bath. Methanesulfonyl methanesulfonate (11.8 mg, 0.0682 mmol) was added, and the reaction mixture was stirred for 30 minutes at room temperature. The mixture was quenched with water (20 mL). The layers were separated, and the aqueous layer was further extracted with DCM (3 x 20 mL). The combined organics were washed with brine, dried over sodium sulfate, and concentrated to provide (7-(benzo[t / ]isothiazole-3-carboxamido)-2-(4-methoxybenzyl)-3-oxo-l-(o-tolyl)isoindolin-5-yl)methyl methanesulfonate which was used directly in the next step. MS: m / z = 628.2 [M+H]+. A-(2-(4-Methoxybenzyl)-6-(methoxymethyl)-l-oxo-3-(o-tolyl)isoindolm-4-yl)benzo[<Z]isothiazole-3-carboxamide

[0943] Step 2: To a solution of (7-(benzo[t / ]isothiazole-3-carboxamido)-2-(4-methoxybenzyl)-3-oxo-l-(o-tolyl)isoindolin-5-yl)methyl methanesulfonate in methanol (1 mL) was added sodium methanolate (1.0 mL, 4.36 mmol, 25% w / w in MeOH), and the mixture was stirred for 18 h at room temperature. The mixture was concentrated under reduced pressure, and the crude was purified by reverse-phase chromatography (30 g C18 cartridge, 10 to 100% ACN / AmF lOmM) to afford after lyophilisation 77-(2-(4-mcthoxybcnzyl)-6-(mcthoxymcthyl)-l-oxo-3-(o-tolyl)isoindolin-4-yl)bcnzo[<7]isothiazolc-3-carboxamide (13.0 mg, 0.0231 mmol, 50% yield over two steps) as a beige powder. MS: m / z = 564.3 [M+H]+. A-(6-(Methoxymethyl)-l-oxo-3-(o-tolyl)isoindolin-4-yl)benzo[< / ]isothiazole-3-carboxamide O

[0944] Step 3 : A sealed tube was charged with A-(2-(4-methoxybenzyl)-6-(methoxymethyl)-l-oxo-3-(o-tolyl)isoindolin-4-yl)benzo[t / ]isothiazole-3-carboxamide (13.0 mg, 0.0231 mmol) and trifluoroacetic acid (352 pL, 4.61 mmol), and the reaction mixture was heated to 90°C for 24 h. The resulting mixture was diluted with DCM (20 mL), washed with water (2 x 50 mL), and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (30 g C18 cartridge, 10 to 100% ACN / AmF lOmM) affording after lyophilisation 7V-(6-(methoxymethyl)-l-oxo-3-(o-tolyl)isoindolin-4-yl)benzo[< / |isothiazole-3-carboxamide (6 mg, 0.013 mmol, 55% yield) as a beige powder. Example 48 7-(Benzo[6]thiophene-3-carboxamido)-7V-methyl-3-oxo-l-(o-tolyl)isomdolme-5-carboxamide (1-6), (l?)-7-(Benzo[6]thiophene-3-carboxamido)-7V-methyl-3-oxo-l-(o-tolyl)isoindolme-5-carboxamide (1-75), and (5)-7-(Benzo[6]thiophene-3-carboxamido)-7V-methyl-3-oxo-l-(o-tolyl)isoindolme-5-carboxamide (1-76) 7-Amino-2-(4-methoxybenzyl)-3-oxo-l-(o-tolyl)isomdolme-5-carboxylic acid

[0945] Step 1 : To a mixture of methyl 2-(4-methoxybenzyl)-7-((methoxycarbonyl)amino)-3-oxo-l-(o-tolyl)isoindoline-5-carboxylate (10.0 g, 19.9 mmol, 1.00 equiv.) in MeOH (200 mL) was added NaOH (2 M, 99.6 mL, 10.0 equiv.) at 25°C. Then the mixture was heated to 60°C and stirred at 60°C for 4 h. The mixture was concentrated in vacuum to afford a residue. The residue was diluted with water (200 mL), and washed with ethyl acetate (3 x 200 mL). The aqueous layer was adjusted to pH = 3, then extracted with ethyl acetate (3 x 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (SiO2, 0 to 5% MeOH in DCM) to afford 7-amino-2-(4-methoxybenzyl)-3-oxo-l-(o-tolyl)isoindoline-5-carboxylic acid (3.50 g, 7.89 mmol, 39.6% yield, 90.7% purity) as a yellow solid. MS:m / z = 401.1 [M-H]’; ’HNMR (400 MHz, DMSO-t / 6) 5 12.93 (s, 1H), 7.60 -7.54 (m, 3H), 7.44 - 7.39 (m, 2H), 7.31 - 7.21(m, 4H), 7.03 - 6.99 (m, 6H), 6.88 - 6.86 (m, 4H), 6.46 (d, J= 8.0 Hz, 1H), 5.60 (s, 1H), 5.48 (s, 1H), 4.99 - 4.93 (m, 1H), 4.85 (s, 1H), 4.71 (s, 2H), 3.73 (s, 6H), 3.65 (d, J= 8.0 Hz, 1H), 3.60 (d, J= 14.8 Hz, 1H), 3.51 (d, J= 15.6 Hz, 1H), 2.26 (s, 3H), 1.48 (s, 2H). 7-Ammo-2-(4-methoxybenzyl)-A-methyl-3-oxo-l-(o-tolyl)isomdolme-5-carboxamide

[0946] Step 2: To a solution of 7-amino-2-(4-methoxybenzyl)-3-oxo-l-(o-tolyl)isoindoline-5-carboxylic acid (844 mg, 2.10 mmol, 1.00 equiv.) in DMF (10 mL) was added DIPEA (2.17 g, 16.8 mmol, 2.92 mL, 8.00 equiv.) at 25°C. The mixture was cooled to 0°C, then HOBt (567 mg, 4.19 mmol, 2.00 equiv.) and EDCI (804 mg, 4.19 mmol, 2.00 equiv.) were added at 0°C. The mixture was warmed to 25°C and stirred at 25°C for 0.5 hr. Then MeNH2-HCl (708 mg, 10.5 mmol, 5.00 equiv.) was added to the reaction mixture, and the mixture was stirred at 25°C for 4 hrs. The mixture was poured into water (40.0 mL) and extracted with ethyl acetate (3 x 40.0 mL). The combined organic layer was washed with brine (40.0 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 0:1) to afford compound 7-amino-2-(4-methoxybenzyl)-7V-methyl-3-oxo-l-(o-tolyl)isoindoline-5-carboxamide (340 mg) as a light yellow solid. MS: m / z = 414.3 [M+H]+; 1H NMR (400 MHz, DMSO-de) 5 8.50 - 8.47 (m, 2H), 7.57 - 7.52 (m, 2H), 7.44 (d, J= 1.2 Hz, 1H), 7.37 -7.20 (m, 7H), 7.10 - 7.00 (m, 4H), 6.90 - 6.85 (m, 7H), 6.62 (d, J= 8.4 Hz, 2H), 6.46 (d, J= 8.0 Hz, 1H), 5.58 (s, 1H), 5.45 (s, 1H), 5.00 - 4.94 (m, 1H), 4.68 (t, J= 19.2 Hz, 4H), 3.72 (s, 3H), 3.65 (s, 3H), 3.59 (d, J= 14.8 Hz, 1H), 3.51 (d, J= 15.2 Hz, 1H), 2.78 - 2.75 (m, 6H), 2.26 (s, 2H), 1.30 (s, 2H). 7-(Benzo[ / >]thiophene-3-carboxamido)-2-(4-methoxybenzyl)-V-methyl-3-oxo-l-(<9-tolyl)isoindolme-5-carboxamide

[0947] Step 3: To a mixture of 7-amino-2-(4-methoxybenzyl)-7V-methyl-3-oxo-l-(o-tolyl)isoindoline-5-carboxamide (340 mg, 818 pmol, 1.00 equiv.) and benzo[6]thiophene-3-carbonyl chloride (241 mg, 1.23 mmol, 1.50 equiv.) in THF (8.00 mL) was added EtsN (248.42 mg, 2.45 mmol, 342 pL, 3.00 equiv.). The mixture was stirred at 50°C for 8 hrs. The mixture was concentrated in vacuum to afford the crude product. The crude product was purified by prep-HPLC (Column: Waters X bridge BEH C18 250*50mm*10pm; Mobile phase: 42%-72% ACN in water (lOmM NH4HCO3)) to afford 7-(benzo[6]thiophene-3-carboxamido)-2-(4-methoxybenzyl)-X-methyl-3-oxo-l-(o-tolyl)isoindoline-5-carboxamide (130 mg, 224 pmol, 99.2% purity) as a white solid. MS: m / z = 576.4 [M+H]+; 1H NMR (400 MHz, DMSO-de) 5 10.18 (d, J= 43.2 Hz, 1H), 8.80 - 8.77 (m, 1H), 8.24 (d, J= 21.2 Hz, 1H), 8.16 - 8.13 (m, 1H), 8.07 - 7.96 (m, 3H), 7.79 (d, J= 20.0 Hz, 7H), 6.62 (d, J= 8.4 Hz, 2H), 6.46 (d, J= 8.0 Hz, 1H), 5.58 (s, 1H), 5.45 (s, 1H), 5.00 - 4.94 (m, 1H), 7.42 - 7.36 (m, 2H), 7.18 - 7.00 (m, 5H), 6.92 - 6.86 (m, 3H), 6.34 (d, J= 12 Hz, 1H), 5.94 (s, 1H), 5.71 (s, 1H), 5.00 (dd, J= 14.8, 3.6 Hz, 1H), 3.73 (s, 3H), 3.63 (d, J= 15.2 Hz, 1H), 3.53 (d, J= 15.6 Hz, 1H), 2.83 (t, J= 4.8 Hz, 3H), 1.94 (s, 2H), 1.39 (s, 1H). 7-(Benzo[6]thiophene-3-carboxamido)-A-methyl-3-oxo-l-(o-tolyl)isomdolme-5-carboxamide

[0948] Step 4: A solution of 7-(benzo[6]thiophene-3-carboxamido)-2-(4-methoxybenzyl)-A-methyl-3-oxo-l-(o-tolyl)isoindoline-5-carboxamide (130 mg, 226 pmol, 1.00 equiv.) in TFA (4.00 g, 35.1 mmol, 2.60 mL, 156 equiv.) was stirred at 100°C for 75 hrs. The mixture was concentrated in vacuum to afford the residue. The residue was dissolved in ethyl acetate (20.0 mL), poured into saturated aqueous solution of NaHCCL (20.0 mL), extracted with ethyl acetate (3 x 20.0 mL). The combined organic layer was washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by prep-HPLC (Column: Waters Xbridge 150*25mm* 5pm; Mobile phase: 28%-58% ACN in water (lOmM NH4HCO3)) to afford 7-(benzo[6]thiophene-3-carboxamido)-X-methyl-3-oxo-l-(o-tolyl)isoindoline-5-carboxamide (76.0 mg, 167 pmol, 73.8% yield, 100% purity) as a white solid. MS: m / z = 456.2 [M+H]+; HKMR (400 MHz, CD3OD) 5 8.18 (d, J= 1.2 Hz, 1H), 8.13 (t, J= 5.6 Hz, 1H), 8.02 (d, J= 1.6 Hz, 1H), 7.92 -7.89 (m, 1H), 7.42 -7.39 (m, 3H), 7.16 - 7.12 (m, 1H), 7.03 - 7.00 (m, 2H), 6.15 (s, 1H), 2.98(s, 3H), 2.21 - 2.18 (m, 3H). (l?)-7-(Benzo[ / >]thiophene-3-carboxamido)-W-methyl-3-oxo-l-(o-tolyl)isomdolme-5-carboxamide and (5)-7-(Benzo[6]thiophene-3-carboxamido)-W-methyl-3-oxo-l-(o-tolyl)isoindolme-5-carboxamide

[0949] Step 5: The enantiomers of 7-(benzo[6]thiophene-3-carboxamido)-X-methyl-3-oxo-l-(o-tolyl)isoindoline-5-carboxamide were resolved by SFC (Column: REGIS (S^-WHELK-01 (250 mm*50 mm, 10 pm); Mobile phase: 50% [0.1%NH3H2O in MeOH]) to afford (5)-7-(benzo[6]thiophene-3-carboxamido)-X-methyl-3-oxo-l-(o-tolyl)isoindoline-5-carboxamide (27.7 mg, 60.2 pmol, 36.0% yield, 99.0% purity, 99.6% ee) as a white solid and (5)-7-(benzo[6]thiophene-3-carboxamido)-X-methyl-3-oxo-l-(o-tolyl)isoindoline-5-carboxamide (25.8 mg, 55.9 pmol, 33.4% yield, 98.5% purity, 99.8% ee) as an off-white solid.

[0950] Additional compounds prepared according to the methods of Example 48 are listed in Table 20 below. Certain compounds in Table 20 below were prepared with other compounds whose preparation is described elsewhere in the Examples. Table 20. Additional Exemplary Compounds Compound Compound Compound 1-121 1-163 1-166 1-123 1-164 1-211 1-156 1-165 1-212 Example 49 V-|6-(l-hydro\vevelopropvl)-3-(2-niethvlphenvl)-l-o\o-2,3-dihvdro-l / / -isoindol-4-vl|-1,2-benzothiazole-3-carboxamide (1-315) Methyl 7-(1,2-benzothiazole-3-amido)-2-[(4-methoxyphenyl)methyl]-l-(2- methylphenyl)-3-oxo-2,3-dihydro-lZZ-isoindole-5-carboxylate

[0951] Step 1: A solution of 1,2-benzothiazole-3-carbonyl chloride (110 mg, 0.56 mmol) in DCM (2.0 mL) was added to a solution of methyl 7-amino-2-(4-methoxybenzyl)-3-oxo-l-(o-tolyl)isoindoline-5-carboxylate (154 mg, 0.372 mmol) in DCM (2.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10-15 min, then allowed to reach room temperature overnight. The reaction mixture was quenched with saturated sodium bicarbonate (1.0 mL), and stirred for 30 minutes. The reaction mixture was diluted with DCM (10 mL), and washed with saturated sodium bicarbonate (15 mL x 3), water (15 mL), and then brine (15 mL). The organic layer was dried with Na2SO4, and filtered. The filtrate was evaporated under reduced pressure to afford methyl 7-(1,2-benzothiazole-3-amido)-2-[(4-methoxyphenyl)methyl]-l-(2-mcthylphcnyl)-3-oxo-2,3-dihydro-l / / -isoindolc-5-carboxylatc, which was used in the next step without further purification. MS: m / z = 578.2 [M+H]+. Methyl 7-(benzo[< / ]isothiazole-3-carboxamido)-3-oxo-l-(o-tolyl)isomdolme-5-carboxylate

[0952] Step 2: Methyl 7-(1,2-benzothiazole-3-amido)-2-[(4-methoxyphenyl)methyl]-l-(2-methylphenyl)-3-oxo-2,3-dihydro-l / / -isoindole-5-carboxylate was dissolved in trifluoroacetic acid (2.0 mL, 17.5 pmol) at room temperature in a screw-top glass reaction vial equipped with a stir bar and septum under nitrogen atmosphere. Excess triethylsilane (100 pL, 625 pmol) was added, and the solution was stirred at room temperature for 30 min. The septa was quickly replaced with a plastic cap, and the reaction mixture was sealed from the oxygen atmosphere. The reaction mixture was placed in a pre-heated oil bath (105 °C, external) and stirred overnight. The reaction mixture was diluted with DCM (10 mL), and then all volatiles were evaporated to furnish a crude residue. To the crude residue was added diethyl ether (3 mL) and MeOH (10 mL). The resulting suspension was shaken, and the insoluble fraction was allowed to settle. The supernatant was slowly fdtered followed by the solid, and the remaining solid was washed with MeOH (3 mL x 3). The washing and filtration steps were repeated two more times to afford 93 mg of methyl 7-(benzo[t / ]isothiazole-3-carboxamido)-3-oxo-l-(o-tolyl)isoindoline-5-carboxylate as a light brown solid, which was used in the next step without further purification. MS: m / z = 458.1 [M+H]+. A-[6-(l-hydroxycyclopropyl)-3-(2-methylphenyl)-l-oxo-2,3-dihydro-lZZ-isoindol-4-yl]-1,2 -benzothiazole-3-carb oxamide

[0953] Step 3 : A flame-dried, round-bottom flask equipped with a stir bar was charged with methyl 7-(benzo[t / ]isothiazole-3-carboxamido)-3-oxo-1 -(o-tolyl)isoindoline-5-carboxylate (30 mg, 65.5 pmol). The solid was suspended in THF (5.0 mL), and stirrred vigorously at room temperature for 10 minutes. Titanium tetraisopropoxide (50 pL, 168 pmol) was added, and the mixture was stirred for 10 minutes at room temperature. To the resulting solution was added dropwise over 3 hours ethylmagnesium bromide (0.8 mL, 3.0 M, 2.40 mmol). The solution was quenched with dropwise addition of IM HC1 (1 mL), then diluted with DCM (20 mL). The mixture was washed with water (20 mL x 3), then with brine (20 mL x 3). The solvent was evaporated. The resulting residue was purified by reverse-phase flash column chromatography (eluting with 0 to 100% acetonitrile in 10 mM AmF in water) to afford after lyophilization A-[6-(l-hydroxycyclopropyl)-3-(2-methylphenyl)- l-oxo-2,3-dihydro-1 / 7-isoindol-4-yl]-l,2-benzothiazole-3-carboxamide (13 mg) as a white powder. Example 50 A^-(7-Cyano-l-oxo-3-(o-tolyl)isoindolin-4-yl)benzo[6]thiophene-3-carboxamide (1-132) 6-Bromo-2-methyl-3-nitrobenzoic acid Br O no2

[0954] Step 1: To a solution of 2-bromo-6-methylbenzoic acid (240 g, 1.12 mol, 1.00 equiv.) in H2SO4 (1.20 L) at 0°C was added dropwise a mixture of HNO3 (76.5 g, 1.21 mol, 54.7 mL, 1.09 equiv.) in H2SO4 (100 mL). The mixture was stirred at 0°C for 45 min. The mixture was poured into ice water (5.00 L), and solids precipitated. The suspension was filtered. The filter cake was dried under reduced pressure to afford an approximately equimolar mixture of 6-bromo-2-methyl-3-nitrobenzoic acid and a regioisomer (339 g, crude) as a light yellow solid. MS: m / z = 261.9 [M+H]+; 1H NMR (400 MHz, CDCh) 5 7.84 (d, J= 8.8 Hz, 1H), 7.81 (d, J= 8.0 Hz, 0.5H), 7.65 (d, J= 8.8 Hz, 1H), 7.37 (d, J= 8.4 Hz, 0.9H), 2.61 (s, 3H), 2.52 (s, 1.5H). 4-Amino-7-bromo-2-(4-methoxybenzyl)-3-(o-tolyl)isomdolm-l-one

[0955] Steps 2 through 7: Using the procedures described in Example 10, Steps 1 through 6, 6-bromo-2-methyl-3-nitrobenzoic acid was converted to 4-amino-7-bromo-2-(4-methoxybenzyl)-3-(o-tolyl)isoindolin-l-one in 2% yield over the six steps. (The undesired regioisomer generated in Step 1 was removed by reverse-phase chromatography after the iron-mediated nitro-group reduction of Step 5.) The 4-amino-7-bromo-2-(4-methoxybenzyl)-3-(o-tolyl)isoindolin-l-one product was isolated as a white solid following purification by reverse-phase HPLC. MS: m / z = 439.2 [M+H]+; 1H NMR (400 MHz, DMSO-de) 5 7.57 -7.55 (m, 0.5H), 7.39 - 7.34 (m, 1H), 7.30 - 7.20 (m, 2H), 7.11 - 6.99 (m, 3H), 6.88 - 6.85(m, 2H) 6.76 - 6.68(m, 1H), 6.49 (d, J= 7.6 Hz, 0.5H), 5.50 (s, 0.5H), 5.38 (s, 0.5H), 4.96 - 4.90 (m, 1H), 4.72 (s, 1H), 4.57 (s, 1H), 3.72 (s, 3H), 3.58 (d, J= 14.8 Hz, 0.5H), 3.48 (d, J= 15.2 Hz, 0.5H), 2.25 (s, 1.7H), 1.52 (s, 1.3H). A-(7-Bromo-l-oxo-3-(o-tolyl)isomdolm-4-yl)benzo[ / >]thiophene-3-carboxamide

[0956] Steps 8 and 9: According to the procedures of Example 1, Steps 5 and 6, 4-amino-7-bromo-2-(4-methoxybenzyl)-3-(o-tolyl)isoindolin-l-one was converted to A-(7-bromo-l-oxo-3-(o-tolyl)isoindolin-4-yl)benzo[6]thiophene-3-carboxamide. A-(7-Cyano-l-oxo-3-(o-tolyl)isoindolm-4-yl)benzo[6]thiophene-3-carboxamide

[0957] Step 10: A microwave vial equipped with a Teflon-coated stir bar and rubber septum was charged with A-(7-bromo-l-oxo-3-(o-tolyl)isoindolin-4-yl)benzo[6]thiophene-3-carboxamide (30 mg, 0.0628 mmol), followed by Pd2(dba)3 (11.5 mg, 0.0126 mmol), dppf (6.96 mg, 0.0126 mmol), Zn(CN)2 (14.7 mg, 0.126 mmol), zinc (821 pg, 0.0126 mmol), DMF (1.9 mL), and water (0.1 mL). The dark turbid solution, under moderate stirring, at room temperature, was degassed by bubbling with nitrogen gas for about 5 minutes. The vial was then placed in a pre-heated oil bath (105 °C, external), and vigorously stirred for 3 hours. The mixture was cooled to room temperature and directly loaded onto a Cl8 column (24 g), which was eluted with 10-60% acetonitrile in 10 mM aq. AmF. Fractions containing pure product were combined, acetonitrile was removed under reduced pressure, and the remaining aqueous solution was lyophilized to afford A-(7-cyano-l-oxo-3-(o-tolyl)isoindolin-4-yl)benzo[6]thiophene-3-carboxamide as a tan, amorphous solid (18 mg).

[0958] Additional compounds prepared according to the methods of Example 50 are listed in Table 21 below. Certain compounds in Table 21 below were prepared with other compounds whose preparation is described elsewhere in the Examples. Table 21. Additional Exemplary Compounds Example 51 A-[7-Ethenyl-3-(2-methylphenyl)-l-oxo-2,3-dihydro-lZf-isomdol-4-yl]-l-benzothiophene-3-carboxamide (1-2157)

[0959] A 50 mL round-bottomed flask equipped with a Teflon-coated stir bar and rubber septum was charged with 7V-(7-bromo-l-oxo-3-(o-tolyl)isoindolin-4-yl)benzo[h]thiophene-3-carboxamide (100 mg, 0.209 mmol), followed by potassium vinyltrifluoroborate (139 mg, 1.04 mmol), K2CO3 (201 mg, 1.46 mmol), and THF:water (10 mL, 9:1). The brown color turbid solution, under slow stirring, was degassed by bubbling with nitrogen gas for about five minutes. Then Pd(dppf)Ch (29 mg, 0.042 mmol) was added, and the rubber septum was quickly exchanged for a reflux condenser. The system was evacuated under house vacuum, and back-filled with nitrogen gas. The flask was then placed in a pre-heated oil bath (63 °C, external), and the mixture stirred for 40 hours. The mixture was diluted with ethyl acetate (20 mL), and washed with water (2 x 20 mL). The combined aqueous layers were extracted with ethyl acetate (20 mL). The combined organics were washed with brine (20 mL), dried over sodium sulfate, filtered, and solvents removed under reduced pressure to afford a tan paste. The residue was purified by silica gel flash chromatography (ethyl acetate / hexanes) to afford A-[7-ethenyl-3-(2-methylphenyl)-l-oxo-2,3-dihydro-l / f-isoindol-4-yl]-l-benzothiophene-3-carboxamide (65 mg) as a tan powder. MS: m / z = 425.3 [M+H]+.

[0960] Additional compounds prepared according to the methods of Example 51 are listed in Table 22 below. Certain compounds in Table 22 below were prepared with other compounds whose preparation is described elsewhere in the Examples. Table 22. Additional Exemplary Compounds Compound 1-205 Example 52 7-(Benzo[6]thiophene-3-carboxamido)-3-oxo-l-(o-tolyl)isoindolme-4-carboxamide CI- 149)

[0961] A microwave vial equipped with a Teflon-coated stir bar and rubber septum was charged with A-(7-bromo-l-oxo-3-(o-tolyl)isoindolin-4-yl)benzo[h]thiophene-3-carboxamide (20 mg, 0.0419 mmol), followed by Pd(OAc)2 (1.88 mg, 0.00838 mmol), Xantphos (4.84 mg, 0.00838 mmol), 4-dimethylaminopyridine (10.2 mg, 0.0838 mmol), Co2(CO)s (3.6 mg, 0.010 mmol), and dioxane (2 mL). This dark color turbid solution, under moderate stirring, was degassed by bubbling with nitrogen gas for five minutes, and then a 2M solution of ammonia in isopropanol (0.1 mL, 0.20 mmol) was added. The rubber septum was quickly exchanged for a microwave vial cap and sealed. The vial was then placed in a Biotage microwave reactor and irradiated at 90°C for one hour. The mixture was directly loaded onto a C18 column (24 g, 1 mL of DMF was used to rinse the vial), and the column was eluted with 1060% acetonitrile in lOmM aq. AmF. The fractions containing pure product were lyophilized to afford 7-(benzo[6]thiophene-3-carboxamido)-3-oxo-l-(o-tolyl)isoindoline-4-carboxamide as an off-white amorphous solid (9 mg).

[0962] Additional compounds prepared according to the methods of Example 52 are listed in Table 23 below. Certain compounds in Table 23 below were prepared with other compounds whose preparation is described elsewhere in the Examples. Table 23. Additional Exemplary Compounds Compound Compound Compound 1-150 1-261 1-278 1-219 1-276 1-339 1-225 Example 53 A-(7-Methyl-l-oxo-3-(o-tolyl)isoindolin-4-yl)benzo[6]thiophene-3-carboxamide (1-153)

[0963] A microwave vial equipped with a Teflon-coated stir bar and rubber septum was charged with A-(7-bromo-l-oxo-3-(o-tolyl)isoindolin-4-yl)benzo[h]thiophene-3-carboxamide (20 mg, 0.0419 mmol), followed by Pd2(dba)3 (3.83 mg, 0.00419 mmol), DABAL-Me3 (10.7 mg, 0.0419 mmol), Xphos (3.99 mg, 0.00838 mmol), and THF (2 mL). The dark color reaction mixture was then heated to reflux and vigorously stirred for 9 hours. The mixture was cooled to RT, and additional DABAL-Me3 (5 mg) was added. The mixture was again heated to reflux and vigorously stirred for 18 hours. The mixture was cooled to RT, diluted with ethyl acetate (20 mL), and washed with water (2 x 20 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL). The combined organics were dried over sodium sulfate, fdtered, and solvents removed under reduced pressure. The resulting residue was purified by reverse phase chromatography (load in DMF, C18 column, 24 g, 10-50% Acetonitrile in lOmM aq. AmF). The fractions containing pure product were lyophilized to afford X-(7-methyl-l-oxo-3-(o-tolyl)isoindolin-4-yl)benzo[h]thiophene-3-carboxamide (2.6 mg) as a white amorphous solid. Example 54 A-(6-Acetyl-3-(2-chloro-5-fluorophenyl)-l-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1-127)

[0964] A-[6-Bromo-3 -(2-chloro-5 -fluorophenyl)-1 -oxo-2,3 -dihydro- l / f-isoindol-4-yl] -3 -fluoro-5-(trifluoromethyl)benzamide (600 mg, 1.09 mmol), tributyl(l-ethoxy ethenyl)stannane (787 mg, 2.18 mmol) and bis(triphenylphosphine)palladium(II) dichloride (153 mg, 0.218 mmol) were combined and evacuated / purged with nitrogen. Dioxane (4 mL) was added, and the mixture was heated to 90 °C for 4 hrs. The mixture was diluted with EtOAc, filtered through a plug of silica, and the filtrate was concentrated to provide A-(3-(2-chloro-5-fluoropheny 1)-6-( 1 -ethoxy vinyl)-1 -oxoisoindolin-4-yl)-3-fluoro-5 -(trifluoromethyl)benzamide.

[0965] The resulting residue was stirred in TFA (2.5 mL) and water (0.5 mL) for 2 hr, then concentrated and purified by reverse phase HPLC to provide A-(6-acetyl-3-(2-chloro-5-fluorophenyl)-l-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (0.42 g, 72%). Example 55 A-(3-(2-chloro-5-fluorophenyl)-6-(2-hydroxypropan-2-yl)-l-oxoisomdolm-4-yl)-3-fhioro-5-(trifluoromethyl)benzamide (1-128)

[0966] To a solution of A-(6-acetyl-3-(2-chloro-5-fluorophenyl)-l-oxoisoindolin-4-yl)-3- fluoro-5-(trifluoromethyl)benzamide (400 mg, 0.7 mmol) in THF (5 mL) at 0 °C was dropwise added MeMgBr, 3.0 M in Et20 (3.5 mmol, 1.16 mL). After completion of the reaction, the reaction was quenched with aq NH4CI, and the mixture was extracted with EtOAc. The organics were washed with brine, dried, and concentrated. The residue was purified by reverse phase HPLC using a gradient of water (0.1 % FA) and acetonitrile (0.1 % FA) 70 / 30 to 35 / 65 in 13 minutes then 5 / 95. Product-containing fractions were combined and lyophilized to provide A-(3-(2-chloro-5-fluorophenyl)-6-(2-hydroxypropan-2-yl)-l-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (0.25 g, 67%).

[0967] Additional compounds prepared according to the methods of Examples 54 and 55 are listed in Table 24 below. Table 24. Additional Exemplary Compounds Compound Compound Compound 1-135 1-238 1-272 1-136 1-239 1-280 1-189 1-242 1-290 1-190 1-250 1-298 1-191 1-263 1-299 1-192 1-264 1-308 1-214 1-267 1-355 1-215 1-271 1-356 Example 56 A-(3-(2-chloro-5-fluorophenyl)-l-oxo-6-(2,2,2-trifluoro-l-hydroxyethyl)isoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1-270)

[0968] To A-[3-(2-chloro-5-fluorophenyl)-6-formyl-l-oxo-2,3-dihydro-l / f-isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (110 mg, 0.2223 mmol) in 0.5 mL of DMF was added K2CO3 (28 mg, 0.2 mmol) and trimethyl(trifluoromethyl)silane (80 mg, 0.5626 mmol). The mixture was stirred at RT for 16 hrs. The mixture was then taken in 1 mL of MeOH and added 50 pL of cone. HC1 and stirred for 1 hr. The mixture was taken in 2 mL of DMSO and purified by reverse-phase HPLC using a gradient of water (0.1% FA) and acetonitrile (0.1% FA) 70 / 30 to 35 / 65 in 13 minutes, then 5 / 95. Product-containing fractions were combined and lyophilized to provide A-(3-(2-chloro-5-fluorophenyl)-l-oxo-6-(2,2,2-trifluoro-l-hydroxyethyl)isoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (35 mg, 27%).

[0969] Additional compounds prepared according to the method of Example 56 are listed in Table 25 below. Table 25. Additional Exemplary Compounds Compound 1-297 1-334 Example 57 A-(3-(2-Chloro-5-fluorophenyl)-6-((3,3-difluoroazetidin-l-yl)methyl)-l-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1-348) O

[0970] A solution of A-[3-(2-chloro-5-fluorophenyl)-6-formyl-l-oxo-2,3-dihydro-17f-isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (15 mg, 0.030 mmol) inTHF (1 mL) was treated with 3,3-difluoroazetidine hydrochloride (8 mg, 0.061 mmol) and polymer-bound Biotage® MP-Triacetoxyborohydride (2 mmol / g, 40 mg). The mixture was stirred at 45 °C for 12 h and then diluted with EtOAc. It was filtered and then concentrated by rotary evaporation. The residue was subjected to reverse-phase HPLC purification (15-60% acetonitrile / water) to afford A-(3-(2-chloro-5-fluorophenyl)-6-((3,3-difluoroazetidin-l-yl)methyl)-l-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (5 mg, 29% yield) as an off-white powder.

[0971] Additional compounds prepared according to the method of Example 57 are listed in Table 26 below. Table 26. Additional Exemplary Compounds Example 58 A-[3-(2-chloro-5-fluorophenyl)-6-(l-hydroxycyclopropyl)-l-oxo-2,3-dihydro-lH-isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (1-374) Methyl l-(2-chloro-5-fluorophenyl)-7-[3-fluoro-5-(trifluoromethyl)benzamido]-3-oxo- 2,3-dihydro-lZZ-isoindole-5-carboxylate

[0972] Step 1 : A screw-top glass reaction vial equipped with a stir bar and a rubber septa was charged with X-[6-bromo-3-(2-chloro-5-fluorophenyl)-l-oxo-2,3-dihydro-17 / -isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (90 mg, 164 pmol), palladium(II) acetate (7.36 mg, 32.8 pmol), methanol (1.58 g, 49.3 mmol), Co2(CO)s (16.6 mg, 48.8 pmol), Xantphos (18.8 mg, 32.6 pmol), and 4-dimethylaminopyridine (20 mg, 164 pmol). The reaction mixture was degassed by bubbling with nitrogen gas (balloon) under vigorous stirring for two minutes, the rubber septa was quickly replaced with a plastic cap, and the reaction mixture was sealed from the atmosphere. The vial was then placed in a pre-heated oil bath (85 °C, external), and the mixture was vigorously stirred for 7 h. The volatiles were evaporated under reduced pressure to afford a residue, which was purified by normal-phase flash column chromatography (eluted with 0-100% EtOAc / heptanes in gradient) to furnish methyl 1-(2-chloro-5 -fluorophenyl)-7-[3 -fluoro-5 -(trifluoro methyl)benzamido]-3 -oxo-2,3 -dihydro-1H-isoindole-5-carboxylate (73 mg) as an off-white solid. MS: m / z = 525.3 [M+H]+; 1H NMR (400 MHz, DMSO-t / 6) 5 10.66 (s, 1H), 9.35 (br s, 1H), 8.13 (dd, J= 16.4, 1.2 Hz, 2H), 7.96 (d, J= 8.3 Hz, 1H), 7.76 (d, J= 8.8 Hz, 1H), 7.68 (s, 1H), 7.33 (dd, J= 8.9, 5.2 Hz, 1H), 7.10 (td, J= 8.5, 3.1 Hz, 1H), 6.04 (br s, 1H), 3.93 (s, 3H). One proton expected at ca. 6.8 ppm was not observed. A-[3-(2-chloro-5-fluorophenyl)-6-(l-hydroxycyclopropyl)-l-oxo-2,3-dihydro-lZZ-isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide

[0973] Step 2: According to the procedure of Example 49, Step 3, methyl l-(2-chloro-5-fluorophenyl)-7-[3-fluoro-5-(trifluoromethyl)benzamido]-3-oxo-2,3-dihydro-l / / -isoindole-5-carboxylate was converted to A-[3-(2-chloro-5-fluorophenyl)-6-(l-hydroxycyclopropyl)-l-oxo-2,3-dihydro-lZf-isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide, which was isolated as an off-white solid following reverse-phase chromatography (10 mM AmF in a gradient of 0-100% CH3CN in water). Example 59 7V-(3-Cyclohexyl-l-oxoisomdolm-4-yl)benzo[<Z]isothiazole-3-carboxamide (1-204) 4-Amino-3-cyclohexylisomdolm-l-one

[0974] Step 1: To a solution of 4-amino-3-methoxyisoindolin-l-one (50 mg, 0.28 mmol) in dry THF (0.35 mL) at 0 °C under a nitrogen atmosphere was added a IM solution of bromo(cyclohexyl)magnesium (841 pL, 0.841 mmol) in THF. The mixture was stirred at R.T. for 15 min. Another portion of IM solution of bromo(cyclohexyl)magnesium (560 uL, 0.56 mmol) was added and stirring was continuied at R.T. for 15 min. A sat. aq solution of NH4CI was then added, and the mixture was extracted with EtOAct (3x). The combined organic layers were washed with brine, dried over Na2SO4, fdtered, and concentrated under reduced pressure. The resulting 4-amino-3-cyclohexylisoindolin-l-one, as a brown oil, was used in the next step without further purification. .V-(3-Cyclohexyl-l-oxoisoindolin-4-yl)benzo[< / ]isothiazole-3-carboxamide

[0975] Step 2: The 4-amino-3-cyclohexylisoindolin-l-one from the previous step was dissolved in dry DMF (0.94 mL) at room temperature under a nitrogen atmosphere, and 1,2- benzothiazole-3-carboxylic acid (60.3 mg, 0.337 mmol) was added, followed by HATU (159 mg, 0.421 mmol) and finally DIPEA (197 pL, 1.12 mmol). The mixture was stirred at room temperature for 12h. The mixture was then diluted with water and extracted with AcOEt (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by reverse phase chromatography (5 to 70% ACN / aqueous AmF 10 mM) followed by purification by normal phase chromatography (0 to 60% acetone / hexanes) afforded A-(3-cyclohexyl- l-oxoisoindolin-4-yl)benzo[t / ]isothiazole-3-carboxamide (10 mg, 10%) as a yellow powder after lyophilisation.

[0976] Additional compounds prepared according to the methods of Example 59 are listed in Table 27 below. Table 27. Additional Exemplary Compounds Compound 1-8 1-18 1-106 Compound 1-259 1-327 Example 60 A-(7-oxo-5-(o-tolyl)-6,7-dihydro-5Zf-pyrrolo[3,4-6]pyridin-4-yl)indoline-l-carboxamide (1-147) 4-Chloro-A-(2,4-dimethoxybenzyl)picolinamide

[0977] Step 1: To a solution of 4-chloropicolinic acid (200 g, 1.27 mol, 1.00 eq) in DCM (2.00 L) was added CDI (216 g, 1.33 mol, 1.05 eq) and DMAP (4.65 g, 38.1 mmol, 0.03 eq) at 15 °C for 0.5 h. Then a solution of (2,4-dimethoxyphenyl)methanamine (212 g, 1.27 mol, 191 mL, 1.00 eq) in DCM (400 mL) was added, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated. The residue was purified by fast flash column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1), to obtain 4-chloro- / V-(2,4-dimethoxybenzyl)picolinamide (316 g, 1.03 mol, 81.1% yield) as a white solid. 4-Chloro-6-(2,4-dimethoxybenzyl)-5-hydroxy-5-(o-tolyl)-5,6-dihydro-7Zf-pyrrolo[3,4-6]pyridin-7-one

[0978] Step 2: To a solution ofn-BuLi (2.50 M, 391 mL, 3.00 eq) in THF (1.20 L) at -78 °C was added a solution of 4-chloro- / V-(2,4-dimcthoxybcnzyl)picolinamide (100 g, 326 mmol, 1.00 eq) in THF (200 mL). The mixture was stirred at -40 to -50 °C for nearly 3 h. The reaction was then cooled back to -78 °C. To the reaction was added dropwise over 15 minutes a solution of 2-methylbenzoyl chloride (101 g, 652 mmol, 84.7 mL, 2.00 eq) in THF (200 mL). The reaction was stirred for 1 h at -78 °C, before removal of the dry ice / ethyl acetate bath. The reaction was then stirred at 25 °C for 2 h. The mixture was poured into water (2.00 L) and extracted with ethyl acetate (3 x 500 mL). The combined organic layer was washed with brine (500 mL), dried over Na2SO4, and concentrated. The resulting yellow oil was purified once by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) and twice by column chromatography (SiO2, DCM / MeOH = 1 / 0 to 50 / 1), to obtain 4-chloro-6-(2,4-dimethoxybenzyl)-5-hydroxy-5-(o-tolyl)-5,6-dihydro-77f-pyrrolo[3,4-6]pyridin-7-one (125 g) as a white solid. MS: m / z = 425.0 [M+H]+; 1H NMR (400 MHz, DMSO-de) 5 9.02 (t, J= 6.4 Hz, 1H), 8.73 (d, J= 5.2 Hz, 1H), 7.94 (d, J= 5.2 Hz, 1H), 7.44 - 7.47 (m, 1H), 7.36 (d, J= 12 Hz, 1H), 7.21 (d, J= 4.0 Hz, 1H), 6.91 (d, J= 8.4 Hz, 1H), 6.52 (d, J= 2.4 Hz, 1H), 6.39 (dd, / =2.4, 8.4 Hz, 1H), 4.25 (d, J= 6.0 Hz, 2H), 3.76 (s, 3H), 3.72 (s, 3H), 2.65 (s, 3H). 4-Chloro-6-(2,4-dimethoxybenzyl)-5-(o-tolyl)-5,6-dihydro-7ZZ-pyrrolo[3,4-6]pyridin-7-one OMe

[0979] Step 3: To a stirred solution of 4-chloro-6-(2,4-dimethoxybenzyl)-5-hydroxy-5-(o-tolyl)-5,6-dihydro-7 / f-pyrrolo[3,4-6]pyridin-7-one (75.0 g, 177 mmol, 1.00 eq) in DCM (1.10 L) was added TFA (503 g, 4.41 mol, 327 mL, 25.0 eq) at 25 °C. The mixture was cooled to 0 °C, then triethylsilane (205 g, 1.77 mol, 282 mL, 10.0 eq) was added. The mixture was warmed to 25 °C, stirred at 25 °C for 12 h, and then concentrated. The residue was purified by reverse-phase HPLC (0.1% FA condition) to afford 4-chloro-6-(2,4-dimethoxybenzyl)-5-(o-tolyl)-5,6-dihydro-7 / f-pyrrolo[3,4-h]pyridin-7-one (62.0 g, 152 mmol, 85.9% yield) as a white solid. MS: m / z = 409.1 [M+H]+; 1H NMR (400 MHz, DMSO-A) 5 8.73 (d, J= 5.2 Hz, 1H), 7.66 (d, J= 5.6 Hz, 1H), 7.20 - 7.28 (m, 2H), 7.04 - 7.08 (m, 1H), 6.95 (d, J= 8.4 Hz, 1H), 6.45 - 6.50 (m, 4H), 5.78 (s, 1H), 4.82 (dd, ^=3.6, 14.8 Hz, 1H), 3.73 (s, 3H), 3.64 (s, 3H), 2.24 (s, 3H). 6-(2,4-Dimethoxybenzyl)-4-((2,4-dimethoxybenzyl)amino)-5-(o-tolyl)-5,6-dihydro-7ZZ-pyrrolo [3,4-6] pyridin-7-one OMe

[0980] Step 4: A mixture of 4-chloro-6-(2,4-dimethoxybenzyl)-5-(o-tolyl)-5,6-dihydro-77f-pyrrolo[3,4-6]pyridin-7-one (70.0 g, 171 mmol, 1.00 eq), (2,4-dimethoxyphenyl) methanamine (42.9 g, 256 mmol, 38.6 mL, 1.50 eq), CS2CO3 (55.7 g, 171 mmol, 1.00 eq), Pd2(dba)3 (15.6 g, 17.1 mmol, 0.10 eq), and BRETTPHOS (18.3 g, 34.2 mmol, 0.20 eq) in dioxane (700 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90 °C for 12 h under N2 atmosphere. Additional (2,4-dimethoxyphenyl) methanamine (14.3 g, 85.6 mmol, 12.8 mL, 0.50 eq) was added, the mixture was purged with N2 three times, and then the mixture was stirred at 90 °C for 18 h under N2 atmosphere. The reaction mixture was diluted with H2O (600 mL) and extracted with ethyl acetate (3 x 400 mL). The combined organic layers were washed with satd. aq. NaCl (800 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1, ethyl acetate / methanol = 20 / 1) to afford 6-(2,4-dimethoxybenzyl)-4-((2,4-dimethoxybenzyl) amino)-5-(o-tolyl)-5,6-dihydro-7 / / -pyrrolo[3,4-6]pyridin-7-one (60.0 g, 94.1 mmol, 55.0% yield, 84.7% purity) as a brown oil. MS: m / z = 540.0 [M+H]+; 1H NMR (400 MHz, CDCh) 5 8.39 - 8.42 (m, 1H), 7.29 - 7.30 (m, 1H), 7.21-7.23 (m, 1H), 7.17 - 7.18 (m, 1H), 7.14 (s, 1H), 7.12 (s, 1H), 7.07 - 7.09 (m, 1H), 6.91 - 6.94 (m, 1H), 6.78 - 6.80 (m, 1H), 6.70 (d, J= 8.4 Hz, 1H), 6.54 (d, J= 6.0 Hz, 1H), 6.29 - 6.32 (m, 2H), 5.36 (s, 1H), 3.76 - 3.80 (m, 12H), 3.66 (s, 2H), 3.63 (s, 2H), 2.08 (s, 3H). 4-Amin 0-6-(2,4-dimethoxybenzyl)-5-(o-tolyl)-5,6-dihydro-7Z / -pyrrolo[3,4- / >]pyridin-7-one OMe

[0981] Step 5: A solution of 6-(2,4-dimethoxybenzyl)-4-((2,4-dimethoxybenzyl) amino)-5-(o-tolyl)-5,6-dihydro-7 / f-pyrrolo[3,4-6]pyridin-7-one (60.0 g, 111 mmol, 1.00 eq) in HCl / MeOH (4.00 M, 600 mL, 21.6 eq) was stirred at 35 °C for 7 h. Additional HCl / MeOH (4.00 M, 600 mL, 21.6 eq) was added to the mixture, then the mixture was stirred at 35 °C for 16 h. Additional HCl / MeOH (4.00 M, 600 mL, 21.6 eq) was added to the mixture, then the mixture was stirred at 35 °C for 22 h. The reaction mixture was concentrated under vacuum, and the residue was dissolved in DCM (2.00 L). The mixture was adjusted to pH = 8 with saturated NaHCO? (1.00 L) and stirred at 25 °C for 0.5 h. The mixture was extracted with DCM (2 x 2.00 L). The combined organic layers were washed with brine (2 x 200 mL), dried over Na2SO4, filtered, and concentrated. The resulting brown gum was purified by reversed-phase HPLC (0.1% FA condition) to afford 4-amino-6-(2,4-dimethoxybenzyl)-5-(o-tolyl)-5,6-dihydro-77f-pyrrolo[3,4-6]pyridin-7-one (20.4 g, 50.4 mmol, 45.3% yield, 96.0% purity) as a white solid. MS: m / z = 390.2 [M+H]+; NMR (400 MHz, DMSO-A) 5 8.17 - 8.23 (m, 1H), 7.52 - 7.54 (m, 1H), 7.18 - 7.27 (m, 2H), 7.06 - 7.09 (m, 1H), 6.97 (d, J= 8.4 Hz, 1H), 6.84 (d, J= 8.4 Hz, 1H), 6.59 - 6.65 (m, 1H), 6.44 - 6.53 (m, 3H), 5.39 - 5.48 (m, 2H), 4.69 - 4.82 (m, 1H), 3.69 - 3.78 (m, 6H), 2.25 (s, 2H), 1.15 (s, 1H). A-(6-(2,4-Dimethoxybenzyl)-7-oxo-5-(o-tolyl)-6,7-dihydro-5ZZ-pyrrolo[3,4- / >]pyridm-4-yl)indoline-l-carboxamide NH

[0982] Step 6: 4-Amino-6-(2,4-dimethoxybenzyl)-5-(o-tolyl)-5 / / -pyrrolo[3,4-6]pyridine-7(6Z / )-one (1.00 g, 1.87 mmol) and carbonyldiimidazole (457 mg, 2.82 mmol) were dissolved in DCM (25 mL). To the resulting mixture were added A,A-diisopropylethylamine (0.54 mL, 3.08 mmol) and 4-dimethylaminopyridine (2.5 mg, 0.020 mmol). The resulting mixture was stirred at 40 °C. After 24 h, the reaction mixture was cooled to 22 °C, and indoline (457 mg, 3.84 mmol) was added to the solution. The resulting mixture was stirred at 22 °C for 1 h and then diluted with a saturated aqueous NH4CI solution and extracted with DCM. The organic layer was dried over sodium sulfate, fdtered, and concentrated by rotary evaporation. The resulting A-(6-(2,4-dimethoxybenzyl)-7-oxo-5-(o-tolyl)-6,7-dihydro-5 / / -pyrrolo[3,4-6]pyridin-4-yl)indoline-1-carboxamide was directly subjected to the subsequent reaction without further purification. A-(7-Oxo-5-(o-tolyl)-6,7-dihydro-5ZZ-pyrrolo[3,4- / >]pyridm-4-yl)mdolme-l-carboxamide O^NH

[0983] Step 7: The A-(6-(2,4-dimethoxybenzyl)-7-oxo-5-(o-tolyl)-6,7-dihydro-5 / / -pyrrolo [3,4-6]pyridin-4-yl)indoline-1 -carboxamide (ca. 1.00 mmol) from the preceding step was treated with trifluoroacetic acid (14.2 mL) and trifluoromethanesulfonic acid (0.41 mL, 4.67 mmol). The resulting mixture was stirred at 40 °C. After 1 h, the reaction mixture was concentrated, diluted with saturated aqueous NaHCOs, and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting mixture was purified by C18 silica gel column chromatography (20% to 100% MeCN / 10 mM AmF (aq)). The product-containing fractions were combined and lyophilized to obtain A-(7-oxo-5-(o-tolyl)-6,7-dihydro-5 / / -pyrrolo[3,4-6]pyridin-4-yl)indoline-l-carboxamide (38 mg, 5.3% over two steps) as a white powder.

[0984] Additional compounds prepared according to the methods of Example 60 are listed in Table 28 below. Table 28. Additional Exemplary Compounds Example 61 A-(5-(2,3-Difluorophenyl)-7-oxo-6,7-dihydro-5ZZ-pyrrolo[3,4-6]pyridin-4-yl)benzo[6]thiophene-3-carboxamide (1-15) O 4-Amin 0-5-(2,3-difluorophenyl)-6-(2,4-dimethoxybenzyl)-5,6-dihydro-7ZZ-pyrrolo[3,4-£>]pyridm-7-one

[0985] Steps 1 to 5: According to the procedures of Example 60, Steps 1 to 5, 4-amino-5-(2,3-difluorophenyl)-6-(2,4-dimethoxybenzyl)-5,6-dihydro-7Zf-pyrrolo[3,4-6]pyridin-7-one was synthesized. A-(5-(2,3-Dinuorophenvl)-6-(2,4-dinietho\vbenzvl)-7-o\o-6,7-dihvdro-5 / / -pvrrolo|3,4-6]pyridin-4-yl)benzo[6]thiophene-3-carboxamide OMe

[0986] Step 6: To a stirred solution of (l-chloro-2-methylprop-l-en-l-yl)dimethylamine (257 mg, 1.93 mmol, 4 eq) in toluene (1.6 mL) was added 1-benzothiophene-3-carboxylic acid (343 mg, 1.93 mmol, 4 eq). The suspension quickly turned into a clear, light pink solution, which was stirred for 30 minutes. About 0.4 mL of this solution was added to a stirred solution of 4-amino-5-(2,3-difluorophenyl)-6-(2,4-dimethoxybenzyl)-5,6-dihydro-77 / -pyrrolo[3,4-6]pyridin-7-one (200 mg, 0.483 mmol) in pyridine (1 mL). To this solution was added catalytic DMAP (24 mg, 0.19 mmol, 0.4 eq). The mixture was stirred at room temperature for 5 minutes and then at 75-80 °C for 5 hours. Every hour an additional 0.4 mL of the preformed acid chloride solution in toluene was added to the mixture until the reaction was nearly completed. The mixture was cooled to room temperature and quenched with methanol (2 mL). The mixture was stirred 10 minutes after quenching and was then concentrated. The residue was eluted on 12 g column eluted with a gradient of 10:90:1 MeOH / DCM / NH4OH in DCM, to afford A-(5-(2,3-difluorophenyl)-6-(2,4-dimcthoxybcnzyl)-7-oxo-6,7-dihydro-5 / / -pyrrolo[3,4- / )]pyridin-4-yl)bcnzo[ / )]thiophcnc-3-carboxamide (214 mg, -95% purity, 73.5% yield) as a light yellow, foamy solid. A small amount of residual pyridine was still present after purification. MS: m / z = 572.5 [M+H]+. A-(5-(2,3-Difluorophenyl)-7-oxo-6,7-dihydro-5Zf-pyrrolo[3,4-6]pyridin-4-yl)benzo[6] thiophene-3-carboxamide O

[0987] Step 7: To a solution of / 7-(5-(2,3-difluorophcnyl )-6-(2,4-dimcthoxybcnzyl)-7-oxo-6,7-dihydro-5 / f-pyrrolo[3,4-6]pyridin-4-yl)benzo[6]thiophene-3-carboxamide (197 mg, 0.342 mmol) in acetonitrile (6.8 mL) was added a solution of ammonium cerium (IV) nitrate (559 mg, 1.02 mmol, 3.0 eq). The mixture was stirred for 15 minutes at RT. The mixture was carefully treated with saturated aqueous NaHCOs (25 mL). The resulting solid was isolated by filtration, dried, and loaded as a silica gel slurry onto a 24 gram silica gel column, which was eluted with a gradient of 10:90:1 MeOH / DCM / NH4OH in DCM. Productcontaining fractions (eluting between 6.7% and 7.5% MeOH / DCM) were combined, concentrated, and dried. The resulting yellow solid (93 mg) was then treated with dichloromethane (2 mL). A light yellow solid was isolated by filtration and dried to yield V-(5-(2,3-difluorophenyl)-7-oxo-6,7-dihydro-5 / / -pyrrolo[3,4-6]pyridin-4-yl)benzo[6] thiophene-3-carboxamide (84.5 mg, 58% yield).

[0988] Additional compounds prepared according to the methods of Example 60 and 61 are listed in Table 29 below. Table 29. Additional Exemplary Compounds Example 62 3-Fluoro-7V-(4-methyl-3-oxo-l-(o-tolyl)-2,3-dihydro-lZf-pyrrolo[3,4-c]pyridin-7-yl)-5-(trifluoromethyl)benzamide (1-244) 7V-(2-(2,4-Dimethoxybenzyl)-4-methyl-3-oxo-l-(o-tolyl)-2,3-dihydro-lZZ-pyrrolo[3,4-c]pyridm-7-yl)-3-fluoro-5-(trifhioromethyl)benzamide OMe

[0989] Step 1: To a solution of / V-(4-chloro-2-(2,4-dimethoxybenzyl)-3-oxo-l-(o-tolyl)-2,3-dihydro-17 / -pyrrolo[3,4-c]pyridin-7-yl)-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 0.0814 mmol) in dioxane (500 pL) and water (50 pL) was added potassium carbonate (33.7 mg, 0.2442 mmol), trimethyl-l,3,5,2,4,6-trioxatriborinane (12.4 pL, 0.0896 mmol), and tetrakis(triphenylphosphine) palladium (4.70 mg, 0.00407 mmol). The mixture was stirred at 100 °C for 16 h, then quenched with IN HC1 (100 pL), then diluted with water. The resulting mixture was extracted with EtOAc three times. The combined organics were dried over Na2SO4, filtered, and concentrated. The resulting residue was used directly in the next step without further purification. 3-Fluoro-A-(4-methyl-3-oxo-l-(o-tolyl)-2,3-dihydro-lZZ-pyrrolo[3,4-c]pyridm-7-yl)-5-(trifluoromethyl)benzamide

[0990] Step 2: According to the procedures of Example 13, Step 6, 77-(2-(2,4-dimethoxybenzyl)-4-methyl-3-oxo-l-(o-tolyl)-2,3-dihydro-17 / -pyrrolo[3,4-c]pyridin-7-yl)-3-fluoro-5-(trifluoromethyl)benzamide was converted to 3-fluoro-A-(4-methyl-3-oxo-l-(o-tolyl)-2,3-dihydro-17 / -pyrrolo[3,4-c]pyridin-7-yl)-5-(trifluoromethyl)benzamide. Example 63 A-(l-Chloro-l-(2-chloro-5-fluorophcnyi)-4-(3,3-difluoroazctidin-l-yl)-3-oxo-2,3-dihydro-lZZ-pyrrolo[3,4-c]pyridm-7-yl)-3-fluoro-5-(trifhioromethyl)benzamide (1-274) O. f^^cf3 A-[4-Chloro-l-(2-chloro-5-fluorophenyl)-3-oxo-lZZ,2Zf,3#-pyrrolo[3,4-c]pyridm-7-yl]-3-fluoro-5-(trifhioromethyl)benzamide

[0991] Steps 1-6: By analogy to the procedures of Example 13, Steps 1-6,A-[4-chl oro-1-(2-chloro-5-fluoropheny 1)-3-oxo-3 / / -pyrrolo[3,4-c]pyridin-7-yl]-3-fluoro-5-(trifluoromethyl)benzamide was prepared. A-(l-Chloro-l-(2-chloro-5-fluorophenyl)-4-(3,3-difluoroazetidin-l-yl)-3-oxo-2,3-dihydro-1 / / -pyrrolo[3,4-c|pyridin-7-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0992] Step 7: A conical microwave reaction tube was charged with A-[4-chloro-l-(2-chloro-5-fluorophenyl)-3-oxo-l / f,2 / f,3 / f-pyrrolo[3,4-c]pyridin-7-yl]-3-fluoro-5-(trifhioromethyl)benzamide (11 mg, 21.9 pmol, 1.0 eq.), 3,3-difluoroazetidine hydrochloride (3.65 mg, 28.4 pmol, 1.3 eq.), and cesium carbonate (17.8 mg, 54.7 pmol, 2.5 eq.) and purged with nitrogen for 5 minutes. Dry DMF (0.5 mL) was then added to the reaction media, which was sealed and stirred at 85 °C for 2 h. The reaction media was allowed to cool to room temperature, diluted with EtOAc (4 mL), and the organic phase was washed 4 times with half-saturated NaHCOs (aq). The organic layer was then dried over anhydrous MgSO4 and concentrated under vacuum. The crude mixture was purified over C18 column, eluting with water (lOmM formate): acetonitrile 95:5 to 0:100. The pure fractions were lyophilized to afford A-(l-chloro-l-(2-chloro-5-fluorophenyl)-4-(3,3-difluoroazetidin-l-yl)-3-oxo-2,3-dihydro-l / f-pyrrolo[3,4-c]pyridin-7-yl)-3-fluoro-5-(trifluoromethyl)benzamide (3.2 mg). MS: m / z = 593.1 [M+H]+; NMR (400 MHz, CD3OD) 5 8.71 (s, 1H), 7.87 (s, 1H), 7.77 (d, J= 8.6 Hz, 1H), 7.68 - 7.58 (m, 2H), 7.49 - 7.32 (m, 1H), 7.14 - 6.97 (m, 1H), 3.82 - 3.56 (m, 4H).

[0993] Additional compounds prepared by analogy to the methods of Examples 13, 14, 62, 63, and other Examples herein, are listed in Table 30 below. Table 30. Additional Exemplary Compounds Compound Compound Compound 1-143 1-253 1-265 1-233 1-254 1-287 1-236 1-255 1-320 1-243 Example 64 A-(3-(2-(Difluoromethyl)-5-fluorophenyl)-5-fluoro-l-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1-283) 2-[l-(3-Bromo-2,4-difluorophenyl)-V-[(2,4-dimethoxyphenyl)methyl|formamido|-V-tert-butyl-2-[2-(difluoromethyl)-5-fluorophenyl]acetamide Br

[0994] Step 1 : To a solution of 2-(difluoromethyl)-5-fluorobenzaldehyde (405 mg, 2.33 mmol) in methanol (5 mL) was added l-(2,4-dimethoxyphenyl)methanamine (350 pL, 2.33 mmol), followed by 3-bromo-2,4-difluorobenzoic acid (500 mg, 2.10 mmol), and 2-isocyano-2-methylpropane (193 mg, 2.33 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to obtain a yellow solid. The resulting 2-[l-(3-bromo-2,4-difluorophenyl)-A-[(2,4-dimethoxyphenyl)methyl]formamido]-A-ter / -butyl-2-[2-(difluoromethyl)-5-fluorophenyl]acetamide was used in the next step without further purification. LC-MS (Method 1): 1.62 min, m / z = 644.2 [M+H]+. 4-Bromo-3-[2-(difluoromethyl)-5-fluorophenyl]-2-[(2,4-dimethoxyphenyl)methyl]-5-fluoro-2,3-dihydro-LH-isoindol-l-one F

[0995] Step 2: A solution of 2-[l-(3-bromo-2,4-difluorophenyl)-A-[(2,4-dimethoxyphenyl)methyl]formamido]-A-tert-butyl-2-[2-(difluoromethyl)-5-fluorophenyl]acetamide (1.0 g, 1.55 mmol) in DMF (6.2 mL) was evacuated and purged with nitrogen three times, and the reaction mixture was stirred at -78 °C for 5 minutes. Then NaH (92.8 mg, 3.87 mmol) was added under nitrogen atmosphere, and the reaction was stirred overnight from -78 °C to 22 °C. The reaction mixture was neutralized with sat. NH4CI and then extracted with EtOAc (10 mL). The aqueous phase was extracted with EtOAc (3x5 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue contained both 4-bromo-3-[2-(difluoromethyl)-5-fluorophenyl]-2-[(2,4-dimethoxyphenyl)methyl]-5-fhioro-2,3-dihydro-17f-isoindol-l-one and oxidized product 4-bromo-3-[2-(difluoromethyl)-5-fluorophenyl]-2-[(2,4-dimethoxyphenyl)methyl]-5-fluoro-3-hydroxy-2,3-dihydro-lH-isoindol-l-one. The mixture was purified by normal phase chromatography (50 g column, hexane / acetone). The purified desired 4-bromo-3-[2-(difluoromethyl)-5-fluorophenyl]-2-[(2,4-dimcthoxyphcnyl)mcthyl]-5-fluoro-2,3-dihydro-l / / -isoindol-l -one was used in Step 3.

[0996] The purified oxidized product was subjected to a reduction reaction: A solution of 4-bromo-3-[2-(difhioromethyl)-5-fluorophenyl]-2-[(2,4-dimethoxyphenyl)methyl]-5-fluoro-3- hydroxy-2,3-dihydro-l / f-isoindol-l-one (500 mg, 0.9253 mmol) in DCM (2 mL) was cooled to -78 °C and BF3’OEt2 (182 pL, 1.48 mmol) was added. After 15 min, triethylsilane (1.46 mL, 9.25 mmol) was added. The mixture was stirred at - 78 °C for additional 15 minutes and then warmed to 22 °C and stirred for 3 h. The mixture was diluted with aq. NaHCOs and extracted with DCM. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting 4-bromo-3-[2-(difluoromethyl)-5-fluorophenyl]-2-[(2,4-dimethoxyphenyl)methyl]-5-fluoro-2,3-dihydro-l / / -isoindol-l-one was combined with the previous portion and used in the next step without further purification. 4-Amino-3-[2-(difluoromethyl)-5-fluorophenyl]-2-[(2,4-dimethoxyphenyl)methyl]-5-fluoro-2,3-dihydro-lZf-isoindol-l-one F

[0997] Step 3: To a solution of4-bromo-3-[2-(difluoromethyl)-5-fluorophenyl]-2-[(2,4-dimethoxyphenyl)methyl]-5-fluoro-2,3-dihydro-l / / -isoindol-l-one (20 mg, 0.03814 mmol) in toluene (0.4 mL) was added diphenylmethanimine (8.29 mg, 0.04576 mmol), followed by (5)-BINAP (7.12 mg, 0.01144 mmol), Pd2(dba)3 (3.49 mg, 0.003814 mmol), and NaO / Bu (5.49 mg, 0.05721 mmol). The mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with 1 M HC1 and stirred at 22 °C overnight. Then, the reaction mixture was diluted with DCM (10 mL) and NaHCOs (15 mL), and the aqueous phase was extracted with DCM (3x5 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase chromatography (30 g column, water / ACN; water solvent is lOmM ammonium formate) to afford 4-amino-3-[2-(difluoromethyl)-5-fluorophenyl]-2-[(2,4-dimethoxyphenyl)methyl]-5-fluoro-2,3-dihydro-l / / -isoindol-l-one. LC-MS (Method 1): 1.30 min, m / z = 461.3 [M+H]+. A-{3-[2-(difluoromethyl)-5-fluorophenyl]-2-[(2,4-dimethoxyphenyl)methyl]-5-fluoro-l-oxo-2,3-dihydro-lZZ-isomdol-4-yl}-3-fluoro-5-(trifluoromethyl)benzamide

[0998] Step 4: To a solution of4-amino-3-[2-(difluoromethyl)-5-fluorophenyl]-2-[(2,4-dimethoxyphenyl)methyl]-5-fluoro-2,3-dihydro-17 / -isoindol-l-one (10 mg, 0.0217 mmol) in DCM (1 mL) was added 3-fluoro-5-(trifluoromethyl)benzoyl chloride (7.37 mg, 0.0326 mmol) and K2CO3 (15 mg, 0.108 mmol). The reaction mixture was stirred for 3 hrs at 50 °C. The reaction mixture was diluted with EtOAc (10 mL) and NaHCOs (15 mL), and the aqueous phase was extracted with EtOAc (3x5 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by reverse-phase chromatography (30 g column, water / ACN; water solvent is lOmM ammonium formate). LC-MS (Method 1): 1.52 min, m / z = 651.7 [M+H]+. A-(3-(2-(Difluoromethyl)-5-fluorophenyl)-5-fluoro-l-oxoisomdolm-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0999] Step 5: A mixture of A-{3-[2-(difluoromethyl)-5-fhiorophenyl]-2-[(2,4-dimethoxyphenyl)methyl]-5-fluoro-l-oxo-2,3-dihydro-lH-isoindol-4-yl}-3-fluoro-5-(trifluoromethyl)benzamide (10 mg, 0.01537 mmol) in TFA (2 mL) was heated to 40 °C in a sealed tube for 1 hour. The reaction mixture was then cooled to ambient temperature and concentrated in vacuo. The resulting residue was purified by reverse-phase chromatography (30 g column, water / ACN; water solvent is lOmM ammonium formate) to afford A-(3-(2- (difluoromethyl)-5-fluorophenyl)-5-fluoro-l-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (0.79 mg, 5 % yield over 2 steps). Example 65 7V-(3-Methyl-l-oxo-3-(o-tolyl)isomdolm-4-yl)benzo[6]thiophene-3-carboxamide (1-80) 4-Ammo-2-(4-methoxybenzyl)-3-methyl-3-(o-tolyl)isoindolm-l-one

[1000] Step 1 : To a solution of 4-amino-3-hydroxy-2-(4-methoxybenzyl)-3-(o-tolyl)isoindolin-l-one (300 mg, 0.801 mmol) in dry THF (3 mL) at room temperature under a nitrogen atmosphere was added BF3-OEt2 (295 pL, 2.40 mmol). The purple solution was then stirred at room temperature for 12h, then a solution of chloro(methyl)magnesium (4.8 mL, 3M in THF, 14.3 mmol) was added. The mixture was stirred for another 1 h, and then a saturated (aq) solution of NH4CI (20 mL) was added slowly. The mixture was diluted with EtOAc and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, fdtered, and concentrated under reduced pressure to yield an orange foam. The resulting 4-amino-2-(4-methoxybenzyl)-3-methyl-3-(o-tolyl)isoindolin-l-one was used without further purification. LC-MS (Method 1): 1.24 min, m / z = 373.3 [M+H]+. 4-Amino-3-methyl-3-(o-tolyl)isomdolm-l-one

[1001] Step 2: A solution of 4-amino-2-(4-methoxybenzyl)-3-methyl-3-(o-tolyl)isoindolin-l-one (150 mg, 0.282 mmol) in TFA (15 mL) was heated at 170°C for 80 min under microwave irradiation. Analysis indicated the major product was 2,2,2-trifluoro-7V-(3-methyl-l-oxo-3-(o-tolyl)isoindolin-4-yl)acetamide. The mixture was then concentrated under reduced pressure and dissolved in MeOH (10 mL). Potassium carbonate (500 mg, 3.56 mmol) was added, and the mixture was heated at 60°C for 12 h. The mixture was then diluted with a satd. (aq) solution of NH4CI and extracted with DCM (4x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 4-amino-3-methyl-3-(o-tolyl)isoindolin-l-one, which was used in the next step without further purification. 7V-(3-Methyl-l-oxo-3-(o-tolyl)isoindolm-4-yl)benzo[6]thiophene-3-carboxamide

[1002] Step 3: The 4-amino-3-methyl-3-(o-tolyl)isoindolin-l-one from the previous step was dissolved in pyridine (6 mL) and 1-benzothiophene-3-carbonyl chloride (110 mg, 0.563 mmol) was added. The mixture was stirred at room temperature for 12 h. The mixture was then diluted with a satd. (aq) solution of CuSO4 and extracted with EtOAc (3x). The combined organic layers were washed with water, then satd. NaHCOs (aq), and finally with brine, then dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by reverse phase chromatography (5 to 70% ACN / Water [AmF 10 mM]) followed by purification by normal phase chromatography (0 to 60% acetone / heptanes) afforded A-(3- methyl-l-oxo-3-(o-tolyl)isoindolin-4-yl)benzo[6]thiophene-3-carboxamide (43 mg, 37% over two steps) as a white powder after lyophilisation.

[1003] Additional compounds prepared by analogy to the methods of Example 65, and other Examples herein, are listed in Table 31 below. Table 31. Additional Exemplary Compounds Compound 1-130 Example 66 V-(l-(2-ehlorophenvl)-6-metho\v-3-o\o-2,3-dihvdro-l / / -pvrrolo|3,4-c]pvridin-7-vl)-3-fluoro-5-(trifluoromethyl)benzamide (1-335) O 2-Chloro-V-(2,4-dimethoxybenzyl)benzamide Cl O OMe OMe

[1004] Step 1: To a solution of 1-(2,4-dimethoxyphenyl)methanamine (4.76 g, 28.5 mmol) in DCM (30 mL) was added DIPEA (9.91 mL, 57.0 mmol). The solution was cooled to 0-5 °C, then 2-chlorobenzoyl chloride (3.61 mL, 28.5 mmol) was added dropwise. The mixture was warmed to RT and stirred for 2 h. The mixture was diluted with DCM and washed with water. The organic layer was dried and concentrated. Heptane was added, and the mixture was sonicated until solid separated. The mixture was fdtered and air dried to afford 2-chloro-A-(2,4-dimethoxybenzyl)benzamide (7.89 g, 25.8 mmol, 90.5% yield) as a white solid. MS: m / z = 306.3 [M+H]+. l-(2-Chlorophenyl)-2-(2,4-dimethoxybenzyl)-6-methoxy-7-nitro-l,2-dihydro-3ZZ-pyrrolo[3,4-c]pyridin-3-one OMe

[1005] Step 2: To a solution of 2-chloro-A-(2,4-dimethoxybenzyl)benzamide (1.51 g, 4.97 mmol) in THF (25 mL) at -50 °C was added LHMDS (4.97 mL, 4.97 mmol) dropwise over 15 min, keeping temperature at -50 °C. The mixture was stirred at -50 °C for 15 min, then 6-chloro-5-nitropyridine-3-carbonyl chloride (1.1 g, 4.97 mmol) was added dropwise over 15 min. Upon completion of addition, the mixture was warmed to -20 °C over 30 min. After 30 min, the mixture was cooled to -50 °C and a second equivalent of LHMDS (4.97 mL, 4.97 mmol) was added dropwise over 15 min. The mixture was warmed to room temperature over 45 min. The reaction mixture was quenched at room temperature with MeOH (25 mL). The solution was concentrated onto SiO2 and purified by normal phase chromatography (0-100% ethyl acetate in heptanes) to afford l-(2-chlorophenyl)-2-(2,4-dimethoxybenzyl)-6-methoxy-7-nitro-l,2-dihydro-3 / f-pyrrolo[3,4-c]pyridin-3-one (1.24 g, 0.638 mmol, 12.8%, 30% pure by HPLC). MS: m / z = 486.12 [M+H]+. 7-Amino-l-(2-chlorophenyl)-2-(2,4-dimethoxybenzyl)-l-hydroxy-6-methoxy-l,2-dihydro-3ZZ-pyrrolo [3,4-c ] pyridin-3-one OMe

[1006] Step 3: A solution of l-(2-chlorophenyl)-2-(2,4-dimethoxybenzyl)-6-methoxy-7-nitro-l,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one as prepared in the previous step (300 mg, 0.6174 mmol) in MeOH (4 mL) and AcOH (2 mL) was cooled to 0 °C, and iron (172 mg, 3.08 mmol) was added. The mixture was warmed to RT, then heated at 80 °C for 1 h. The mixture was partitioned between EtOAc and water, then filtered through a pad of celite to remove any solids. The layers were separated layers, and the organic layer was washed with brine, dried overNa2SO4, fdtered, and concentrated. The resulting 7-amino-l-(2-chlorophenyl)-2-(2,4-dimethoxybenzyl)-l-hydroxy-6-methoxy-l,2-dihydro-3 / / -pyrrolo[3,4-c]pyridin-3-one (35% pure by LCMS) was used directly in the next step without further purification. A-(l-(2-Chlorophenyl)-2-(2,4-dimethoxybenzyl)-l-hydroxy-6-methoxy-3-oxo-2,3-dihydro-lZf-pyrrolo[3,4-c]pyi‘idin-7-yl)-3-fluoro-5-(trifluoromethyl)benzamide ,N—'   OMe .Cl I HO NH <

[1007] Step 4: A suspension of 3-fluoro-5-(trifluoromethyl)benzoic acid (94.6 mg, 0.4546 mmol) in DCE (5 mL) was treated with (l-chloro-2-methylprop-l-en-l-yl)dimethylamine (60.7 mg, 0.4546 mmol). The mixture was stirred at RT for 15 min, before it was transferred to a solution of 7-amino-l-(2-chlorophenyl)-2-(2,4-dimethoxybenzyl)-l-hydroxy-6-methoxy-l,2-dihydro-3 / / -pyrrolo[3,4-c]pyridin-3-one as prepared in the previous step (100 mg, 0.2273 mmol), DMAP (8.74 mg, 0.0227 mmol), and pyridine (90.9 pL, 1.13 mmol) in DCE (5 mL). The mixture was stirred at 60 °C for 16 h. The mixture was concentrated and the resulting N-(1 -(2-chlorophenyl)-2-(2,4-dimethoxybenzyl)-1 -hydroxy-6-methoxy-3-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin-7-yl)-3-fluoro-5-(trifluoromethyl)benzamide was used in the next step without further purification. A-(l-(2-chlorophenyl)-6-methoxy-3-oxo-2,3-dihydro-LH-pyrrolo[3,4-c]pyridm-7-yl)-3-fluoro-5-(trifluoromethyl)benzamide MeO O.

[1008] Step 5: A-(l-(2-chlorophenyl)-2-(2,4-dimethoxybenzyl)-l-hydroxy-6-methoxy-3-oxo-2,3-dihydro-17 / -pyrrolo[3,4-c]pyridin-7-yl)-3-fluoro-5-(trifluoromethyl)benzamide as prepared in the previous step was dissolved in TFA (1 mL) and stirred at 80 °C for 30 min. The mixture was cooled to room temperature, triethylsilane (108 pL, 0.682 mmol) was added, and the mixture was heated at 80 °C for 30 min. The mixture was concentrated, and the residue was purified by reverse phase purification to give A-(l-(2-chlorophenyl)-6-methoxy-3-oxo-2,3-dihydro-l / / -pyrrolo[3,4-c]pyridin-7-yl)-3-fluoro-5-(trifhioromethyl)benzamide (6 mg, 0.01250 mmol, 5.50 % from step 2) as a white solid. Example 67 6-([l,2,4]triazolo[l,5-a]pyridm-6-yl)-3-(2-chloro-5-fluorophenyl)-4-(piperidm-3-ylamino)isomdolin-l-one (1-2158) tert-butyl 3-((6-( [1,2,4] triazolo [1,5-a] pyridin-6-yl)-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-l-oxoisoindolm-4-yl)amino)piperidme-l-carboxylate

[1009] Step 1 : .A 25 mL microwave vial equipped with a stir bar was charged with 4-bromo-3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-6-{[l,2,4]triazolo[l,5-a]pyridin-6-yl}-2,3-dihydro-lH-isoindol-l-one (300 mg, 0.5191 mmol), Pd2dba3 (47.5 mg, 0.05191 mmol), DavePhos (40.8 mg, 0.1038 mmol), sodium tert-butoxide (148 mg, 1.55 mmol) and tert-butyl 3-aminopiperidine-1-carboxylate (187 pL, 2 eq) before diluting with toluene (4 mL). The mixture was sparged with nitrogen before sealing and heating at 110 °C for 1 h. After concentration in vacuo, the mixture was subjected to reverse phase C18 chromotography and lyophilized to afford tert-butyl 3-((6-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-l-oxoisoindolin-4-yl)amino)piperidine-l-carboxylate (150 mg, 0.22 mmol, 41.5% yield). 6-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-3-(2-chloro-5-fluorophenyl)-4-(piperidin-3-ylamino)isoindolin-l-one

[1010] Step 2: A 20 mL sealed tube equipped with a stir bar was charged with tert-butyl 3-{[3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-l -oxo-6-{ [ 1,2,4]triazolo[ 1,5-a]pyridin-6-yl}-2,3-dihydro-lH-isoindol-4-yl]amino}piperidine-l-carboxylate (150 mg, 0.2151 mmol) followed by dilution in trifluoroacetic acid (20 mL) and addition of trifluoromethanesulfonic acid (28.4 pL, 1.5 eq). The vial was sealed and heated at 90°C for 1 h. The mixture was diluted with DCM and concentrated, subjected to reverse-phase chromotography (C18-30g), and lyophilized to afford 6-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-3-(2-chloro-5-fluorophenyl)-4-(piperidin-3-ylamino)isoindolin-l-one (20 mg, 0.042 mmol, 19.6% yield). MS: m / z = 477.0 [M+H]+. Example 68 (S)-N-[3-(2-chloro-5-fluorophenyl)-l-oxo-6-{[l,2,4]triazolo[l,5-a]pyridin-6-yl}-2,3-dihydro-lH-isomdol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (1-943) and (R)- N-[3- (2-chloro-5-fluorophenyl)-l-oxo-6-{[l,2,4]triazolo[l,5-a]pyridin-6-yl}-2,3-dihydro-lH-isomdol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (1-945) N-[3-(2-chloro-5-fluorophenyl)-l-oxo-6-{[l,2,4]triazolo[l,5-a]pyridin-6-yl}-2,3-dihydro-lH-isoindol-4-yl]-3-fluoro-5-(trifhioromethyl)benzamide F F—I—F

[1011] Stepl: AN2-degassed mixture of N-[6-bromo-3-(2-chloro-5-fluorophenyl)-l-oxo-2,3-dihydro-lH-isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (32.1 mg), 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-[l,2,4]triazolo[l,5-a]pyridine (23.0 mg), palladium(II) bis(triphenylphosphane) dichloride (6.18 mg), disodium carbonate (18.6 mg) in acetonitrile (1.17 mL) / water (0.4 mL) was stirred in a sealed tube for 40 minutes at 110°C. The mixture was cooled, diluted with THF (10 mL) and brine (8 mL), and the layers were separated. The organic layer was concentrated. The crude was loaded as a silica gel slurry onto a 12 g silica gel column, which was eluted with DCM to 10:90:1 MeOH / DCM / NH4OH gradient over 25 minutes. The product eluted between 5.5% and 6.2% MeOH / DCM. The fractions containing product were combined, concentrated in vacuo, and dried to yield a foamy, white solid (25.0 mg). MS: m / z = 584.0 [M+H]+. HKMR (400 MHz, DMSO-d6) 5 10.65 (s, 1H), 9.48 (s, 1H), 9.34 - 9.26 (br s, 1H), 8.58 (s, 2H), 8.34 (s, 2H), 8.00 (m, 3H), 7.97 (m, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.59 (s, 1H), 7.42(t, J = 7.7 Hz, 1H), 6.04 (br s, 1H). (S)-N-[3-(2-chloro-5-fluorophenyl)-l-oxo-6-{[l,2,4]triazolo[l,5-a]pyridin-6-yl}-2,3-dihydro-lH-isomdol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (1-943) and (R)- N-[3- (2-chloro-5-fluorophenyl)-l-oxo-6-{[l,2,4]triazolo[l,5-a]pyridin-6-yl}-2,3-dihydro-lH-isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (1-945)

[1012] Step 2: 90.3 mg of the racemate from step 1 (combined over multiple reaction runs) was subjected to chiral separation by SFC (method: Column: ChiralPak AS-H 30 x 250 mm Mobile Phase: 55% methanol in CO2; Flow Rate: 80 mL / min; Sample: 90.3 mg of sample was dissolved in 10 mL methanol + 10 mL dichloromethane; Injection: 2.5 mL; Detection: 220 nm). Separation yielded two peaks.

[1013] Peakl (retention time: 0.66 min): (S)-N-[3-(2-chloro-5-fluorophenyl)-l-oxo-6-{[l,2,4]triazolo[l,5-a]pyridin-6-yl}-2,3-dihydro-lH-isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide was isolated as a white solid in 100% LC purity and 100% in chiral purity (38.8 mg). MS: m / z = 584.3 [M+H]+. 1H NMR (DMSO-d6, 400 MHz): 5 = 10.64 (s, 1H), 9.48 (s, 1H), 9.26 (br s, 1H), 8.58 (s, 1H), 8.10-8.19 (m, 2H), 7.99 (br d, J = 9.9 Hz, 3H), 7.75-7.83 (m, 1H), 7.73 (s, 1H), 7.35 (dd, J = 8.8, 5.3 Hz, 1H), 7.12 (td, J = 8.3, 3.0 Hz, 1H), 6.51-6.97 (m, 1H), 6.07 (br s, 1H).

[1014] Peak 2 (retention time: 2.48 min): (R)-N-[3-(2-chloro-5-fluorophenyl)-l-oxo-6-{[l,2,4]triazolo[l,5-a]pyridin-6-yl}-2,3-dihydro-lH-isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide was isolated as a white solid in 100% LC purity and 99.89% in chiral purity (37.6 mg). MS: m / z = 584.3 [M+H]+. 1H NMR (DMSO-d6, 400 MHz): 5 = 10.64 (s, 1H), 9.48 (s, 1H), 9.26 (br s, 1H), 8.58 (s, 1H), 8.10-8.19 (m, 2H), 7.99 (br d, J = 9.9 Hz, 3H), 7.75-7.83 (m, 1H), 7.73 (s, 1H), 7.35 (dd, J = 8.8, 5.3 Hz, 1H), 7.12 (td, J = 8.3, 3.0 Hz, 1H), 6.51-6.97 (m, 1H), 6.07 ppm (br s, 1H). Example 69 (S)-N-(3-(2-chloro-5-fluorophenyl)-6-(5-cyano-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-oxoisomdolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1-1647) and (R)-N-(3-(2-chloro-5-fluorophenyl)-6-(5-cyano-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-oxoisomdolm-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1-1648) N-(3-(2-chloro-5-fluorophenyl)-6-(5-cyano-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-oxoisomdolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[1015] Stepl: To a sealed tube fitted with stir bar were added [l-(2-chloro-5-fluorophenyl)-7-[3-fluoro-5-(trifluoromethyl)benzamido]-3-oxo-2,3-dihydro-lH-isoindol5-yl]boronic acid (50 mg, 0.09792 mmol), 6-bromo-[l,2,4]triazolo[l,5-a]pyridine-5-carbonitrile (21.8 mg, 0.09792 mmol), palladium(II) bis(triphenylphosphane) dichloride (10.3 mg, 0.01468 mmol), acetonitrile (2 mL, 0.05M), and a solution of disodium carbonate (31.1 mg, 0.2937 mmol) in water (0.65 mL). The mixture was degassed with nitrogen for 30 seconds, and the tube was sealed. The reaction was heated at 90°C for 45 min. The reaction was cooled to RT, filtered through a pad of Celite®, and concentrated. The residue was purified on prep-HPLC (AccQ Prep; eluting with 30-60% acetonitrile in water w / 0.1% formic acid). Combined fractions containing product were concentrated in vacuo to yield a solid (10 mg, 15.9 % yield). MS: m / z = 609.08 [M+H]+. HKMR (500 MHz, DMSO-d6) 5 10.71 (s, 1H), 9.33 (s, 1H), 8.79 (s, 1H), 8.33 (d, J = 9.2 Hz, 1H), 8.06 (s, 1H), 7.98 (d, J = 9.3 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.83 (s, 1H), 7.75 (d, J = 9.1 Hz, 1H), 7.68 (s, 1H), 7.35 (dd, J = 8.9, 5.1 Hz, 1H), 7.12 (td, J = 8.4, 3.1 Hz, 1H), 6.54 (s, 1H), 6.08 (s, 1H). (S)-N-(3-(2-chloro-5-fluorophenyl)-6-(5-cyano-[l,2,4]triazolo[l,5-a]pyridm-6-yl)-l-oxoisomdolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1-1647) and (R)-N-(3-(2-chloro-5-fluorophenyl)-6-(5-cyano-[l,2,4]triazolo[l,5-a]pyridm-6-yl)-l-oxoisomdolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1-1648)

[1016] Step 2: 100.0 mg of the racemate from step 1 (combined over multiple reaction runs) was subjected to chiral separation by SFC (method: UniChiral AS-5H 21 x 250 mm; Mobile Phase: 60% ethanol in CO2; Flow Rate: 70 mL / min; Sample: 100.0 mg of sample was dissolved in 5 mL methanol + 5 mL dichloromethane; Injection: 2.5 mL; Detection: 254 nm). Separation yielded two peaks.

[1017] Peak 1 (retention time: 0.83 min): (S)-N-(3-(2-chloro-5-fluorophenyl)-6-(5-cyano-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide was isolated as a solid (40 mg). MS: m / z = 609.1 [M+H]+. ’H NMR (500 MHz, DMSO-d6) 5 10.71 (s, 1H), 9.33 (s, 1H), 8.80 (s, 1H), 8.34 (d, J = 9.2 Hz, 1H), 8.07 (s, 1H), 7.97 (t, J = 9.9 Hz, 2H), 7.83 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.68 (s, 1H), 7.35 (dd, J = 8.8, 5.1 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H).

[1018] Peak 2 (retention time: 3.11 min): (R)-N-(3-(2-chloro-5-fluorophenyl)-6-(5-cyano-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide was isolated as a solid (43 mg). MS: m / z = 609.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 5 10.71 (s, 1H), 9.33 (s, 1H), 8.80 (s, 1H), 8.34 (d, J = 9.2 Hz, 1H), 8.07 (s, 1H), 7.97 (t, J = 9.9 Hz, 2H), 7.83 (s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.68 (s, 1H), 7.35 (dd, J = 8.8, 5.1 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H). Example 70 (S)-N-(3-(2-chloro-5-fluorophenyl)-6-(l-(difluoromethyl)-lH-pyrazol-4-yl)-l-oxoisomdolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1-1739) and (R)-N-(3-(2-chloro-5-fluorophenyl)-6-(l-(difluoromethyl)-lH-pyrazol-4-yl)-l-oxoisoindolm-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1-1740) F                                F F—|—F                  F-kF N-(3-(2-chloro-5-fluorophenyl)-6-(5-cyano-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-oxoisomdolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[1019] Stepl: To a sealed tube fitted with stir bar were added N-[6-bromo-3-(2-chloro-5-fluorophenyl)-l-oxo-2,3-dihydro-lH-isoindol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (350 mg, 0.641 mmol, 1 eq), l-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (211 mg, 0.865 mmol, 1.35 eq), bis(triphenylphosphine)palladium (II) dichloride (67.4 mg, 0.096 mmol, 0.15 eq), dioxane (4.3 mL, 0.15M), and a solution of sodium carbonate (203 mg, 1.92 mmol, 3.0 eq) in water (1.4 mL). The mixture was degassed with nitrogen for 30 seconds, and the tube was sealed. The reaction was stirred at 100 °C for a total of 55 minutes. The reaction was cooled to R.T. and treated with water (30 mL). A dark brown solid was isolated by filtration. The crude (>400 mg) was loaded as a silica gel slurry on a 24 g silica gel column, which was eluted with DCM to 10:90:1 MeOH / DCM / NH4OH gradient over 25 minutes. The product eluted at ~3.8% MeOH / DCM. The fractions containing desired product were combined, concentrated, and dried to yield a tan solid (94.0 mg). MS: m / z = 583.4 [M+H]+. HKMR (400 MHz, DMSO-d6) 5 10.56 (s, 1H), 9.18 (s, 1H), 8.94 (s, 1H), 8.43 (s, 1H), 8.06 (d, J = 1.6 Hz, 1H), 8.02 - 7.79 (m, 3H), 7.75 (d, J = 9.1 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.31 (dd, J = 8.9, 5.1 Hz, 1H), 7.09 (td, J = 8.3, 3.1 Hz, 1H), 6.86 - 6.58 (m, 1H), 5.98 (s, 1H). (S)-N-(3-(2-chloro-5-fluorophenyl)-6-(l-(difluoromethyl)-lH-pyrazol-4-yl)-l-oxoisomdolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1-1739) and (R)-N-(3-(2-chIoro-5-fluorophenyl)-6-(l-(difluoromethyl)-lH-pyrazol-4-yl)-l-oxoisoindolm-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1-1740)

[1020] Step 2: 85.1 mg of the racemate from step 1 was subjected to chiral separation by SFC (Column: UniChiral AS-5H 21 x 250 mm; Mobile Phase: 45% methanol in CO2; Flow Rate: 70 mL / min; Sample: 85.1 mg of sample was dissolved in 10 mL methanol + 5 mL dichloromethane; Injection: 2.5 mL; Detection: 254 nm). Separation yielded two peaks.

[1021] Peak 1 (retention time: 0.45 min): (S)-N-(3-(2-chloro-5-fluorophenyl)-6-(l-(difluoromethyl)-lH-pyrazol-4-yl)-l-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide was isolated as a solid (42.8 mg). MS: m / z = 583.4 [M+H]+. JH NMR (500 MHz, DMSO-d6) 5 10.55 (s, 1H), 9.17 (s, 1H), 8.94 (s, 1H), 8.44 (s, 1H), 8.06 (d, J = 1.5 Hz, 1H), 7.99 - 7.69 (m, 5H), 7.32 (dd, J = 8.9, 5.1 Hz, 1H), 7.09 (td, J = 8.4, 3.1 Hz, 1H), 6.92 - 6.41 (m, 1H), 5.99 (s, 1H).

[1022] Peak 2 (retention time: 0.74 min): (R)-N-(3-(2-chloro-5-fluorophenyl)-6-(l-(difluoromethyl)-lH-pyrazol-4-yl)-l-oxoisoindolin-4-yl)-3-fluoro-5- (trifluoromethyl)benzamide as a solid (23.4 mg). MS: m / z = 583.4 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 5 10.55 (s, 1H), 9.17 (s, 1H), 8.94 (s, 1H), 8.44 (s, 1H), 8.06 (d, J = 1.5 Hz, 1H), 7.99 - 7.69 (m, 5H), 7.32 (dd, J = 8.9, 5.1 Hz, 1H), 7.09 (td, J = 8.4, 3.1 Hz, 1H), 6.92 -6.41 (m, 1H), 5.99 (s, 1H). Example 71 (5)-N-(3-(2-chloro-5-fhiorophenyl)-6-(l-methyl-6-oxo-l,6-dihydropyridm-3-yl)-l-oxoisoindolin-4-yl)-3-fluoro-5-(trifhioromethyl)benzamide (1-701) and ( / ?)-N-(3-(2-chloro-5-fluorophenyl)-6-(l-methyl-6-oxo-l,6-dihydropyridm-3-yl)-l-oxoisomdolm-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1-702) N-[3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-6-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-l-oxo-2,3-dihydro-lH-isomdol-4- yl]-3-fluoro-5-(trifluoro methyl)benzamide

[1023] Step 1: A Nz-degassed mixture ofN-[6-bromo-3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-l-oxo-2,3-dihydro-lH-isoindol-4-yl]-3-fluoro-5- (trifluoromethyl)benzamide (140 mg), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2-dihydropyridin-2-one (83.6 mg), palladium(II) bis(triphenylphosphane) dichloride (22.0 mg), disodium carbonate (66.7 mg) in acetonitrile (4.19 mL) / water (1.40 mL) was stirred in a sealed tube for 40 minutes at 105 °C. The mixture was cooled, diluted with THF (7-8 mL) and brine (10 mL), and the layers were separated. The organic layer was concentrated . The crude was loaded as a silica gel slurry onto a 24 g silica gel column, which was eluted with DCM to 10:90:1 MeOHyDCM / NH4OH gradient over 20 minutes. The product eluted between 4.7% and 5.2% MeOH / DCM. The combined fractions were concentrated in vacuo and dried to yield an off-white / light gray-green, foamy solid weighing 114.1 mg. MS: m / z = 694.7 [M+H]+. N-[3-(2-chloro-5-fluorophenyl)-6-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-l-oxo-2,3-dihydro-lH-isomdol-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide O

[1024] Step 2: A mixture ofN-[3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-6-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-l-oxo-2,3-dihydro-lH-isoindol-4-yl]-3-fluoro-5-(trifluor methyl)benzamide (114.1 mg) and 10% TFA in DCM (5.5 mL) was heated for 14 hours at 100 °C in microwave. After cooling, the mixture was concentrated and eluted on 12 gram silica gel column with DCM to 10:90:1 MeOH / DCM / NH4OH. The product eluted between 6.1% and 6.7% MeOH / DCM, which was concentrated in vacuo and dried to yield 61.6 mg. MS: m / z = 574.5 [M+H]+; HKMR (400 MHz, DMSO-d6) 5 10.90 (s, 1H), 9.52 (s, 1H), 8.62 (d, / = 1.5 Hz, 1H), 8.18 (dd, J= 8.6, 1.6 Hz, 1H), 7.98 (d, / =8.7, 1H), 7.87 (s, 1H), 7.75 (d, J= 8.5, 1H), 7.67 (s, 1H), 7.35 (m, 1H), 7.10 (td, 8.6, 1.6 Hz, 1H), 6.57 (d, J= 8.8 Hz, 1H), 6.02 (s, 1H), 3.59 (s, 3H). (5)-N-(3-(2-chloro-5-fluorophenyl)-6-(l-methyl-6-oxo-l,6-dihydropyridm-3-yl)-l-oxoisomdolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1-701) and ( / ?)-N-(3-(2-chloro-5-fluorophenyl)-6-(l-methyl-6-oxo-l,6-dihydropyridm-3-yl)-l-oxoisoindolm-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1-702)

[1025] Step 3: 55 mg of the racemate from step 2 was subjected to chiral separation by SFC (method: Column: ChiralPak IC-H 21 x 250 mm; Mobile Phase: 40% methanol in CO2; Flow Rate: 70 mL / min; Sample: 54.8 mg of sample was dissolved in 4 mL methanol + 4 mL dichloromethane; Injection: 1 mL; Detection: 220 nm). Separation yielded two peaks.

[1026] Peakl (retention time: 2.4 min): (5)-N-(3-(2-chloro-5-fluorophenyl)-6-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-l-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide was isolated as a white solid in 100% LC purity and 100% in chiral purity (20.2 mg). MS: m / z = 574.3 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 5 10.90 (s, 1H), 9.52 (s, 1H), 8.62 (d, J = 1.5 Hz, 1H), 8.18 (dd, J= 8.6, 1.6 Hz, 1H), 7.98 (d, J= 8.7, 1H), 7.87 (s, 1H), 7.75 (d, J= 8.5, 1H), 7.67 (s, 1H), 7.35 (m, 1H), 7.10 (td, 8.6, 1.6 Hz, 1H), 6.57 (d, J= 8.8 Hz, 1H), 6.02 (s, 1H), 3.59 (s, 3H).

[1027] Peak2 (retention time: 3.72 min): (R)-N-(3-(2-chloro-5-fluorophenyl)-6-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-l-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide was isolated as a white solid in 100% LC purity and 100% in chiral purity (20.1 mg ). MS: m / z = 574.2 [M+H]+; *HNMR (400 MHz, DMSO-d6) 5 10.90 (s, 1H), 9.52 (s, 1H), 8.62 (d, J = 1.5 Hz, 1H), 8.18 (dd, J= 8.6, 1.6 Hz, 1H), 7.98 (d, J= 8.7, 1H), 7.87 (s, 1H), 7.75 (d, J= 8.5, 1H), 7.67 (s, 1H), 7.35 (m, 1H), 7.10 (td, 8.6, 1.6 Hz, 1H), 6.57 (d, J= 8.8 Hz, 1H), 6.02 (s, 1H), 3.59 (s, 3H). Example 72 4-Ammo-2-chloro-6-(2,4-dimethoxybenzyl)-5-(o-tolyl)-5,6-dihydro-7ZZ-pyrrolo[3,4-6]pyridin-7-one OMe 4,6-Dichloro-A-(2,4-dimethoxybenzyl)picolinamide O OMe Cl

[1028] Step 1: To a solution of 4,6-dichloropicolinic acid (50.0 g, 260 mmol, 1.00 eq) in DCM (250 mL) was added CDI (44.3 g, 273 mmol, 1.05 eq) and DMAP (1.59 g, 13.02 mmol, 0.05 eq), and the mixture was stirred at 45 °C for 2 h. Then the mixture was cooled to 15 °C, and a solution of 2,4-dimethoxybenzylamine (43.5 g, 260 mmol, 39.2 mL, 1.00 eq) in DCM (50 mL) was added. The mixture was stirred at 15 °C for 5 h. Water (700 mL) was added, and the mixture was extracted with DCM (3 x 300 mL). The organic phase was adjusted to pH = 4 with IM HC1, and extracted with DCM (300 mL). The combined organic layers were washed with satd. NaCl (50 mL), dried over Na2SO4, fdtered, and concentrated under reduced pressure to afford 4,6-dichloro-7V-(2,4-dimethoxybenzyl)picolinamide (68.0 g, 165 mmol, 63.5% yield, 83.0% purity) as a white solid. MS: m / z = 341.0 [M+H]+; 1H NMR (400 MHz, CDCL) 5 8.15 (s, 1H), 8.14 (s, 1H), 7.45 (d, J= 0.8 Hz, 1H), 7.26 (t, J= 12 Hz, 1H), 6.50 - 6.42 (m, 2H), 3.88 (s, 3H), 3.80 (s, 3H). 4,6-Dichloro-V-(2,4-dimethoxybenzyl)-V-(2-methylbenzoyl)picolinamide OMe

[1029] Step 2: To a suspension ofNaH (10.6 g, 264 mmol, 60% purity, 1.50 eq) in THF (300 mL) at 0 °C under N2 was added 4,6-dichloro-7V-(2,4-dimethoxybenzyl)picolinamide (60.0 g, 176 mmol, 1.00 eq) in THF (100 mL). The mixture was stirred at 0 °C for 0.5 h. Then, 2-methylbenzoyl chloride (28.8 g, 186 mmol, 24.2 mL, 1.06 eq) was added dropwise at 0 °C, and the mixture was stirred at 0 °C for 2 h. The mixture was quenched with 1.0 L of NH4CI and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:0 to 100:6) to afford 4,6-dichloro-A / -(2,4-dimethoxybenzyl)-A / -(2-methylbenzoyl)picolinamide (35.0 g, 64.7 mmol, 36.8 yield, 84.9% purity) as a brown oil. MS: m / z = 483.1 [M+Na]+; 1H NMR (400 MHz, CDCL) 5 7.40 (d, J= 4.2 Hz, 1H), 7.37 (d, J= 0.8 Hz, 1H), 7.18 - 7.16 (m, 3H), 7.02 - 7.00 (m, 2H), 6.48 (d, / =4.2 Hz, 1H), 6.41 (d, J= 1.2 Hz, 1H), 5.12 (s, 2 H), 3.80 (s, 3H), 3.66 (s, 3H), 2.44 (s, 3H). 2,4-Dichloro-6-(2,4-dimethoxybenzyl)-5-hydroxy-5-(o-tolyl)-5,6-dihydro-7ZZ-pyrrolo [3,4-6] pyridin-7-one OMe

[1030] Step 3: To a solution of 4,6-dichloro-A-(2,4-dimethoxybenzyl)-A-(2-methylbenzoyl)picolinamide (44.8 g, 97.4 mmol, 1.00 eq) in THF (450 mL) at -50 °C was added LiHMDS (1 M, 146 mL, 1.50 eq). The solution was stirred at -50 °C for 3 h. The mixture was quenched with saturated NH4CI solution (1.0 L) and extracted with ethyl acetate (2 x 500 mL). The organic layers were combined, washed with brine (500 mL), dried, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 100:11) to afford 2,4-dichloro-6-(2,4-dimethoxybenzyl)-5-hydroxy-5-(o-tolyl)-5,6-dihydro-7 / f-pyrrolo[3,4-6]pyridin-7-one (29.0 g, 33.5 mmol, 34.3% yield, 53.0% purity) as a yellow oil. MS: m / z = 459.0 [M+H]+; 1H NMR (400 MHz, DMSO-dd) 5 8.99 (t, J=62 Hz, 1H), 8.21 (s, 1H), 7.35 (s, 1H), 7.23 (d, .7 = 3.6 Hz, 1H), 7.16 (d,J = 4.0 Hz, 1H) 6.88 (d, J= 4.0 Hz, 1H), 6.55 (d, J= 1.2 Hz, 1H), 6.53 - 6.50 (m, 3H), 4.24 (d, J = 3.2 Hz, 2H), 3.80 (s, 3H), 3.70 (s, 3H), 2.64 (s, 3H). 2,4-Dichloro-6-(2,4-dimethoxybenzyl)-5-(o-tolyl)-5,6-dihydro-7ZZ-pyrrolo[3,4-6]pyridin-7-one OMe

[1031] Step 4: To a solution of 2,4-dichloro-6-(2,4-dimethoxybenzyl)-5-hydroxy-5-(o-tolyl)-5,6-dihydro-7 / f-pyrrolo[3,4-6]pyridin-7-one (28.0 g, 32.3 mmol, 1.00 eq) and TFA (92.1 g, 808 mmol, 59.8 mL, 25.0 eq) in DCM (280 mL) was added EtsSiH (37.6 g, 323 mmol, 51.6 mL, 10.0 eq) at 20 °C. The solution was stirred at 25 °C for 12 h. The mixture was concentrated. The crude product was purified by prep-HPLC (TFA condition) to give 2,4- dichloro-6-(2,4-dimethoxybenzyl)-5-(o-tolyl)-5,6-dihydro-7 / / -pyrrolo[3,4-6]pyridin-7-one (7.85 g, 17.5 mmol, 54.3% yield, 99.0% purity) as a brown solid. MS: m / z = 443.0 [M+H]+; 1H NMR (400 MHz, DMSO-t / 6) 5 7.95 (s, 1H), 7.23, (s, 1H), 7.09 - 7.08 (m, 1H), 6.95 (d, J= 4.2 Hz, 1H), 6.57 (d, J= 5.8 Hz, 1H) 6.51 (s, 1H), 6.50 - 6.44 (m, 1H), 5.78 (s, 1H), 4.80 (d, J= 7.6 Hz, 1H), 3.77 (s, 1H), 3.74 (s, 3H), 3.65 (s, 3H), 2.22 (s, 3H). 2-Chloro-6-(2,4-dimethoxybenzyl)-4-((2,4-dimethoxybenzyl)amino)-5-(o-tolyl)-5,6-dihvdro-7 / / -pvrrolo|3,4-6]pvridin-7-one and 4-Chloro-6-(2,4-dimethoxybenzyl)-2-((2,4-dimethoxybenzyl)amino)-5-(o-tolyl)-5,6-dihydro-7ZZ-pyrrolo[3,4- / >]pyridm-7-one

[1032] Step 5: To a solution of 2,4-dichloro-6-(2,4-dimethoxybenzyl)-5-(o-tolyl)-5,6-dihydro-7 / f-pyrrolo[3,4-6]pyridin-7-one (3.92 g, 8.84 mmol, 1.00 eq) in i-PrOH (25.0 mL) was added compound 2,4-dimethoxybenzylamine (2.22 g, 13.3 mmol, 2.00 mL, 1.50 eq) and DIPEA (3.43 g, 26.5 mmol, 4.62 mL, 3.00 eq) in a sealed tube. The mixture was stirred at 160 °C for 5 h. The mixture was concentrated. The residue was purified by prep-HPLC (Column: Phenomenex Luna C18 (250*80 mm* 15 pm); Mobile phase: 56% - 86% CH3CN in water (0.1% TFA) over 20 min) to afford 2-chloro-6-(2,4-dimethoxybenzyl)-4-((2,4-dimethoxybenzyl)amino)-5-(o-tolyl)-5,6-dihydro-7 / / -pyrrolo[3,4-6]pyridin-7-one (4.79 g, 8.20 mmol, 46.4% yield, 98.24% purity) as a light yellow solid and 4-chloro-6-(2,4-dimethoxybenzyl)-2-((2,4-dimethoxybenzyl)amino)-5-(o-tolyl)-5,6-dihydro-7 / / -pyrrolo[3,4-6]pyridin-7-one (1.35 g, 2.28 mmol, 12.9% yield, 97.0% purity) as a yellow solid.

[1033] 2-Chloro-6-(2,4-dimethoxybenzyl)-4-((2,4-dimethoxybenzyl)amino)-5-(o-tolyl)-5,6-dihydro-7 / f-pyrrolo[3,4-6]pyridin-7-one: MS: m / z = 574.2 [M+H]+; 1H NMR (400 MHz, DMSO-t / e) 5 7.50 (d, J= 3.4 Hz, 1H), 7.29 - 7.25 (m, 2H), 7.14 - 7.10 (m, 1H), 7.00 - 6.84 (m, 1H), 6.70 - 6.63 (m, 2H) 6.52 - 6.43 (m, 4H), 5.76 - 5.38 (m, 2H), 4.79 - 4.67 (m, 1H), 4.16 - 4.14 (m,2H), 3.74 (s, 3H), 3.70 (s, 3H), 3.69 (s, 3H), 3.66 (s, 3H), 2.21 (s, 2H), 1.55 (s, 1H).

[1034] 4-Chloro-6-(2,4-dimethoxybenzyl)-2-((2,4-dimethoxybenzyl)amino)-5-(o-tolyl)-5,6-dihydro-7 / f-pyrrolo[3,4-6]pyridin-7-one: MS: m / z = 574.4 [M+H]+; 1H NMR (400 MHz, DMSO- / ,) 5 7.41 (s, 1H), 8.21 (s, 1H), 7.20-7.18 (m, 3H), 7.11 - 7.07 (m, 1H), 6.78 (d, / = 3.2 Hz, 1H), 6.58 (s, 1H), 6.54 (s, 1H), 6.52 - 6.50 (m, 4H), 5.52 (s, 1H), 4.75 (d„ J= 7.6 Hz, 3H), 4.43 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 3.73 (s, 3H), 3.65 (s, 3H), 2.19 (s, 2H), 1.61 (s, 1H). 4-Ammo-2-chloro-6-(2,4-dimethoxybenzyl)-5-(o-tolyl)-5,6-dihydro-7ZZ-pyrrolo[3,4-6]pyridin-7-one OMe

[1035] Step 6: A solution of 2-chloro-6-(2,4-dimethoxybenzyl)-4-((2,4-dimethoxybenzyl)amino)-5-(o-tolyl)-5,6-dihydro-7 / / -pyrrolo[3,4-6]pyridin-7-one (3.60 g, 6.27 mmol, 1.00 eq) and TFA (17.9 g, 157 mmol, 11.6 mL, 25.0 eq) was stirred at 25 °C for 2 h. The mixture was poured into satd. Na2CO3 (200 mL) and fdtered. The fdtrate was extracted with ethyl acetate (2 x 150 mL). The combined organics were dried over Na2SO4 and concentrated. The residue was purified by reversed-phase HPLC (0.1% NH3 H2O) to afford 4-amino-2-chloro-6-(2,4-dimcthoxybcnzyl)-5-(o-tolyl)-5,6-dihydro-7 / / -pyrrolo[3,4-6]pyridin-7-one (1.18 g, 2.76 mmol, 43.9% yield, 99.1% purity) as a white solid. MS: m / z = 424.3 [M+H]+; *HNMR (400 MHz, DMSO- / ,) 5 7.51 (t, / = 2.6 Hz, 1H), 7.28 - 7.20 (m, 2H), 7.11-7.08 (s, 1H), 6.98 -6.84 (m, 1H), 6.86 (d, / =9.0 Hz, 1H) 6.53-6.51 (m, 1H), 6.46 - 6.44 (m, 1H), 5.87 - 5.80 (m, 2H), 5.48 (d, J= 10.8 Hz, 1H), 4.80 - 4.66 (m, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 2.24 (s, 2H), 1.59 (s, 1H). Example 73 7V-(5-(2-Chlorophenyl)-7-oxo-2-(EH-pyrazol-4-yl)-6,7-dihydro-5ZZ-pyrrolo[3,4-6]pyridm-4-yl)benzo[< / |isothiazole-3-carboxamide (1-94) 4-Ammo-2-chloro-5-(2-chlorophenyl)-6-(4-methoxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one OMe

[1036] Step 1 to 6: According to the procedures of Example 68, Steps 1 to 6, 4,6-dichloropicolinic acid, 4-methoxybenzylamine, and 2-chlorobenzoyl chloride were converted to 4-amino-2-chloro-5-(2-chlorophenyl)-6-(4-methoxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one. MS: m / z = 414.3 [M+H]+. N-[2-Chloro-5-(2-chlorophenyl)-6-[(4-methoxyphenyl)methyl]-7-oxo-5H,6H,7H-pyrrolo [3,4-b] pyridin-4-yl] -1,2-benzothiazole-3- carboxamide OMe

[1037] Step 7: To a stirred solution of (l-chloro-2-methylprop-l-en-l-yl)dimethylamine (624 mg, 4.67 mmol) in toluene (3.89 mL) was added l,2-benzothiazole-3-carboxylic acid (836 mg, 4.67 mmol). The suspension very quickly turned into a clear, light pink solution, which was stirred for 30 minutes before addition of 1.3 mL to a solution of 4-amino-2-chloro-5-(2-chlorophenyl)-6-[(4- methoxyphenyl)methyl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-7-one (323 mg, 0.779 mmol) in pyridine (2.6 mL). To this reaction solution was added catalytic DMAP. The solution was stirred at room temperature for 5 minutes and then at 65°C for 30 minutes. A total of 6 equivalents of acid chloride was added in several portions. The reaction was eventually cooled to R.T. and quenched with MeOH (3 mL), then concentrated and loaded onto a 12 g silica gel column eluted with DCM to 10:90:1 MeOH / DCM / NH4OH gradient over 25 minutes. The product eluted between 3% and 3.5% MeOH / DCM to yield a light yellow, foamy solid (316 mg, 70.5% yield). MS: m / z = 575.5 [M+H]+. A-[2-Chloro-5-(2-chlorophenyl)-7-oxo-5Zf,6ZZ,7ZZ-pyrrolo[3,4- / >]pyridm-4-yl]-l,2-benzothiazole-3-carboxamide (1-93) O

[1038] Step 8: To a solution ofN-[2-chloro-5-(2-chlorophenyl)-6-[(4-methoxyphenyl)methyl]-7-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-4-yl]-l,2-benzothiazole-3-carboxamide (251 mg, 0.436 mmol) in acetonitrile (8.7 mL) was added a solution of cerium ammonium nitrate (712 mg, 1.30 mmol) in water (0.87 mL). The mixture was stirred 1 hour at RT. The reaction was treated with saturated aqueous NaHCOs (25 mL). A yellow precipitate was isolated by fdtration, dried, and eluted on a 12 g silica gel column with a DCM to 10:90:1 MeOH / DCM / NH4OH gradient over 25 minutes. The major product peak eluted between 5.5% and 6.7% MeOH / DCM. The fractions containing pure product were combined, concentrated, and dried to yield N-[2-chloro-5-(2-chlorophenyl)-7-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-4-yl]-l,2-benzothiazole-3-carboxamide (44 mg, 21.8% yield). MS: m / z = 455.3 [M+H]+; *HNMR (400 MHz, DMSO-rfc) 5 10.53 (s, 1H), 9.65 (s, 1H), 8.67 (d, 1H), 8.32 (d, 1H), 7.98 (s, 1H), 7.69 (t, 1H), 7.62 (t, 1H), 7.33 (d, 1H), 7.22 (t, 1H), 7.14 (t, 1H). A-(5-(2-Chlorophenyl)-7-oxo-2-(LH-pyrazol-4-yl)-6,7-dihydro-5ZZ-pyrrolo[3,4- / >]pyridm- 4-yl)benzo[< / ]isothiazole-3-carboxamide (1-94)

[1039] Step 9: To a mixture ofN-[2-chloro-5-(2-chlorophenyl)-7-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-4-yl]-l,2-benzothiazole-3-carboxamide (18.3 mg, 0.04 mmol), tertbutyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (17.6 mg, 0.06 mmol, 1.5 eq), bis(triphenylphosphine) palladium (II) dichloride (4.2 mg, 0.006 mmol, 0.15 eq) in a sealed tube were added acetonitrile (0.8 mL) and a solution of sodium carbonate (12.7 mg, 0.12 mmol, 3 eq) in water (0.27 mL). The reaction mixture was briefly degassed with nitrogen before sealing the tube. The reaction mixture was then stirred at 115°C for 20 minutes before cooling back to RT. The reaction mixture was diluted with THF (5 mL) and brine (3 mL), and the layers were separated. The organic layer was dried over sodium sulfate, fdtered, and concentrated. The crude was loaded as a silica gel slurry onto a 12 gram silica gel column and eluted with a gradient of DCM to 10:90:1 MeOH / DCM / NH4OH over 20 minutes. The fractions eluting between 7% and 9% MeOH / DCM were combined, concentrated, and dried to yield racemic N-[5-(2-chlorophenyl)-7-oxo-2-(lH-pyrazol-4-yl)-5H,6H,7Hpyrrolo[3,4-b]pyridin-4-yl]-l,2-benzothiazole-3-carboxamide as a light yellow solid (6.8 mg, 35% yield). MS: m / z = 487.3 [M+H]+; 1H NMR (400 MHz, DMSO-A) 5 13.20 (br s, 1H), 10.48 (s, 1H), 9.46 (s, 1H), 8.69 (d, J= 8.1 Hz, 1H), 8.41 (br s, 1H), 8.33 (d, / =8.1 Hz, 1H), 8.10 (brs, 1H), 8.07 (s, 1H), 7.60-7.73 (m, 3H), 7.30 (d, J= 7.8 Hz, 1H), 7.15-7.21 (m, 1H), 7.09-7.14 (m, 1H), 6.29 ppm (brs, 1H).

[1040] Additional compounds prepared according to the method of Examples 68 and 69 are listed in Table 32 below. Table 32. Additional Exemplary Compounds Example 74 A-[5-(2-Chloro-5-fluorophenyl)-2-(3,3-difluoroazetidin-l-yl)-7-oxo-5 / / ,6 / / ,7 / / -pyrrolo[3,4-6]pyridin-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (1-286) 4-Amino-2-chloro-5-(2-chloro-5-fluorophenyl)-6-(2,4-dimethoxybenzyl)-5,6-dihydro-7 / / -pyrrolo [3,4-6] pyridin-7-one OMe F

[1041] Step 1 to 6: According to the procedures of Example 68, Steps 1 to 6, 4,6-dichloropicolinic acid, 2,4-dimethoxybenzylamine, and 2-chloro-5-fluorobenzoyl chloride were converted to 4-amino-2-chloro-5-(2-chloro-5-fluorophenyl)-6-(2,4-dimethoxybenzyl)-5,6-dihydro-7 / / -pyrrolo[3,4-6]pyridin-7-one. / V-(2-Chloro-5-(2-chloro-5-fluorophenyl)-6-(2,4-dimethoxybenzyl)-7-oxo-6,7-dihydro-5Z7-pyrrolo[3,4- / >]pyridm-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide N—'   OMe Cl

[1042] Step 7: To a mixture of 4-amino-2-chloro-5-(2-chloro-5-fluorophenyl)-6-(2,4-dimethoxybenzyl)-5,6-dihydro-7 / f-pyrrolo[3,4-6]pyridin-7-one (1.00 g, 2.31 mmol) in dry pyridine (14.7 mL) under nitrogen was added dropwise 3-fluoro-5-(trifluoromethyl)benzoyl chloride (530.4 pL, 3.47 mmol). Then 4-dimethylaminopyridine (14 mg, 0.115 mmol) was added, and the mixture was stirred at ambient temperature for 6 h. The mixture was quenched with water, and the pH was adjusted with a saturated aqueous NaHCOs solution. The product was extracted with DCM. The organic phase was then dried over sodium sulfate, fdtered, and concentrated by rotary evaporation. Purification by normal-phase silica chromatography (0% to 70% EtOAc / hexanes) furnished A-(2-chloro-5-(2-chloro-5-fluorophenyl)-6-(2,4-dimethoxybenzyl)-7-oxo-6,7-dihydro-5 / / -pyrrolo[3,4-6]pyridin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide as a white solid (67% yield). A-(5-(2-Chloro-5-fluorophenyl)-2-(3,3-difluoroazetidin-l-yl)-6-(2,4-dimethoxybenzyl)-7-oxo-6,7-dihydro-5 / / -pyrrolo[3,4- / >|pyridin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide N—'   OMe .Cl

[1043] Step 8: A vial containing A-(2-chloro-5-(2-chloro-5-fluorophenyl)-6-(2,4-dimethoxybenzyl)-7-oxo-6,7-dihydro-5 / f-pyrrolo[3,4-6]pyridin-4-yl)-3-fluoro-5- (trifluoromethyl)benzamide (1.00 g, 1.61 mmol), 3,3-difluoroazetidine hydrochloride (416.24 mg, 3.21 mmol), and BrettPhos Pd Gen.4 (728.3 mg, 0.803 mmol) was evacuated under vacuum and purged with nitrogen. Toluene (10.7 mL, 0.15 M) was added, and the mixture was purged once more with nitrogen. Then LiHMDS (IM in THF, 8.03 mL, 8.03 mmol) was added to the mixture, and the mixture was stirred at 105 °C for 2 h. The mixture was cooled to 22 °C and quenched with DCM and water under inert atmosphere. The bi-phasic solution was then diluted with a saturated aqueous NH4CI solution and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting product mixture was directly subjected to the subsequent reaction without further purification. / V-|5-(2-Chloro-5-fluorophenyl)-2-(3,3-difluoroazetidin-l-yl)-7-oxo-5 / / ,6 / / ,7 / / -pyrrolo[3,4-6]pyridin-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide (1-286)

[1044] Step 9: The product mixture from the previous step containing A-(5-(2-Chloro-5-fluoropheny 1)-2-(3,3-difluoroazetidin-1 -yl)-6-(2,4-dimethoxybenzyl)-7-oxo-6,7-dihydro-5 / f-pyrrolo[3,4-6]pyridin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (ca. 1.00 mmol) was treated with trifluoroacetic acid (22 mL) and trifluoromethanesulfonic acid (0.1 mL, 1 mmol). The resulting mixture was stirred at 90 °C for 1 h. The mixture was cooled to room temperature and concentrated. The residue was purified by C18 silica gel column chromatography (30% to 80% MeCN / 10 mM Ammonium Bicarbonate aq.). The productcontaining fractions were combined and lyophilized to obtain A-[5-(2-chloro-5-fluorophenyl)-2-(3,3-difluoroazetidin-l-yl)-7-oxo-5 / / ,6Z / ,7 / 7-pyrrolo[3,4-6]pyridin-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide as a white powder (64.8 mg, 11.5% over two steps). MS: m / z = 559.3 [M+H]+; 1H NMR (400 MHz, DMSO-r / 6) 5 10.72 (br s, 1H), 9.30 (br s, 1H), 7.94 (d, J= 6.5 Hz, 1H), 7.71 (d, J= 9.0 Hz, 1H), 7.62 (s, 1H), 7.34 (dd, J= 8.9, 5.2 Hz, 1H), 7.17 - 6.97 (m, 1H), 6.94 - 6.56 (m, 2H), 5.91 (br s, 1H), 4.65 - 4.33 (m, 4H).

[1045] Additional compounds prepared according to the method of Examples 68-70 are listed in Table 33 below. Table 33. Additional Exemplary Compounds Example 75 Methyl 4-(l,2-benzothiazole-3-amido)-5-(2-chlorophenyl)-7-oxo-5 / / ,6 / / ,7 / / -pyrrolo[3,4-6]pyridine-2-carboxylate (1-222) 4-Chloro-6-(methoxycarbonyl)pyridine-2-carboxylic acid

[1046] Step 1: 4-Chloropyridine-2,6-dicarboxylic acid (8.15 g, 40.4 mmol) was mixed with thionyl chloride (58.8 mL, 807 mmol) and warmed to reflux. After 5 hours of stirring, the mixture was cooled to room temperature and stirred for 16 hours. The excess thionyl chloride was removed by rotary evaporation. The residue was dissolved with anhydrous dichloroethane (161 mL) and then cooled to 0-5 °C. Methanol (1.87 mL, 46.4 mmol) and DIPEA (8.07 mL, 46.4 mmol) were added dropwise to the mixture (exothermic). The mixture was stirred for 2.5 hours at room temperature. The volatiles were removed by rotary evaporation. The residue containing a mixture of monomethyl ester, dimethyl ester, and starting material was purified by normal phase chromatography (0-50% acetonitrile / DCM). The pure fractions were combined, concentrated, and dried under vacuum to afford 4-chloro-6-(methoxycarbonyl)pyridine-2-carboxylic acid as an off-white solid (2.28 g, 26% yield, 90% purity by LC / MS). Methyl 4-chloro-6-{[(4-methoxyphenyl)methyl]carbamoyl}pyridine-2-carboxylate

[1047] Step 2: Thionyl chloride (15.2 mL, 10 mmol) was added dropwise to a stirred suspension of 4-chloro-6-(methoxycarbonyl)pyridine-2-carboxylic acid (2.28 g, 10.5 mmol) in DMF (10 mL) at room temperature. After 25 mins and following gas evolution, the mixture was warmed to 40 °C for 20 mins. The excess of thionyl chloride was removed by rotary evaporation, and the residue was dissolved in dry dichloroethane (42.0 mL) and cooled to 0°C. Triethylamine (3.12 mL, 22.5 mmol) and 1 -(4-methoxyphenyl)methanamine (2.04 mL, 15.7 mmol) were added to the solution. The mixture was stirred at room temperature for 1 hour. The mixture was slowly quenched with water. The layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, and the solvents were evaporated. The residue was purified through normal phase silica gel chromatography (20-75% EtOAc / hexanes) to afford methyl 4-chloro-6-{[(4-methoxyphenyl)methyl]carbamoyl}pyridine-2-carboxylate as a yellow solid (2.56 g, 73% yield). Methyl 4-chloro-5-(2-chlorophenyl)-5-hydroxy-6-[(4-methoxyphenyl)methyl]-7-oxo-5ZL,6Zf,7ZZ-pyrrolo[3,4-6]pyridine-2-carboxylate OMe

[1048] Step 3: To a stirred -50 °C solution of methyl 4-chloro-6-{[(4-methoxyphenyl) methyl]carbamoyl}pyridine-2-carboxylate (1.53 g, 4.57 mmol) in THF (22.8 mL) under nitrogen atmosphere was slowly added LiHMDS (1.0 M solution in THF, 5.0 mL, 5.0 mmol). The solution was stirred at -78°C for 1 hour. To the mixture was added dropwise 2-chlorobenzoyl chloride (635 pL, 5.02 mmol) over 2 minutes. The mixture was stirred 0.5 hour at -78°C and then 2.5 hours at room temperature. The mixture was cooled back between -50°C and -78°C, and then LiHMDS (IM in THF, 5.0 mL, 5.0 mmol) was slowly added. The mixture was stirred between -50°C and -78°C for 1 hour. The mixture was slowly quenched with a solution of AcOH (0.6 mL) in MeOH (25 mL). The solution was then diluted in water and EtOAc. The layers were separated, and the aqueous layer was extracted three times with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, fdtered, and concentrated. The residue was purified by normal phase silica chromatography (0-60% acetone / heptanes) to afford methyl 4-chloro-5-(2-chlorophenyl)-5-hydroxy-6-[(4-methoxyphenyl)methyl]-7-oxo-5 / f,6 / f,7 / f-pyrrolo[3,4-6]pyridine-2-carboxylate as an off-white solid (1.03 g, 38% yield). Methyl 4-chloro-5-(2-chlorophenyl)-6-[(4-methoxyphenyl)methyl]-7-oxo-5Zf,6Zf,7ZZ-pyrrolo [3,4-6] pyridine-2-carboxylate OMe

[1049] Step 4: To a stirred 0°C solution of methyl 4-chloro-5-(2-chlorophenyl)-5-hydroxy-6-[(4-methoxyphenyl)methyl]-7-oxo-5 / f,6 / f,7 / f-pyrrolo[3,4-6]pyridine-2-carboxylate (1.03 g, 2.17 mmol) in DCM (10.8 mL) under nitrogen was added TFA (3.31 mL, 43.4 mmol) followed by triethylsilane (3.46 mL, 21.7 mmol). The mixture was then allowed to warm to room temperature and stirred for 16 hours. The mixture was cooled to 0°C and a second portion of TFA (1.65 mL, 21.7 mmol) and triethylsilane (1.73 mL, 10.9 mmol) were added. The mixture was warmed to room temperature and stirred for 16 hours. The mixture was diluted with DCM and quenched with saturated aqueous solution of NaHCCL until pH 6-7 was obtained. The layers were separated, and the aqueous layer was extracted once with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by normal phase silica gel column (30-100% acetone / hexanes) to afford methyl 4-chloro-5-(2-chlorophenyl)-6-[(4-methoxyphenyl) methyl]-7-oxo-57f,67f,77f-pyrrolo[3,4-6]pyridine-2-carboxylate as a yellow solid (684.8 mg, 69% yield). Methyl 4-azido-5-(2-chlorophenyl)-5-hydroxy-6-[(4-methoxyphenyl)methyl]-7-oxo-5ZL,6Zf,7ZZ-pyrrolo[3,4-6]pyridine-2-carboxylate OMe

[1050] Step 5: To a round bottom flask was added methyl 4-chloro-5-(2-chlorophenyl)-6-[(4-methoxyphenyl)methyl]-7-oxo-57f,67f,77f-pyrrolo[3,4-6]pyridine-2-carboxylate (500 mg, 1.09 mmol) in DMF (5.7 mL). Sodium azide (105 mg, 1.63 mmol) was added, and the mixture was stirred at 70°C for 1.5 hours. The mixture was cooled to room temperature, then diluted with water and extracted with DCM. The aqueous layer was extracted once more with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting methyl 4-azido-5-(2-chlorophenyl)-5-hydroxy-6-[(4-methoxyphenyl)methyl]-7-oxo-5 / f,6Zf,7 / f-pyrrolo[3,4-6]pyridine-2-carboxylate was directly subjected to the subsequent reaction without further purification. Methyl 4-amino-5-(2-chlorophenyl)-5-hydroxy-6-[(4-methoxyphenyl)methyl]-7-oxo-5ZL,6Zf,7ZZ-pyrrolo[3,4-6]pyridine-2-carboxylate OMe

[1051] Step 6: To a solution of methyl 4-azido-5-(2-chlorophenyl)-5-hydroxy-6-[(4-methoxyphenyl)methyl]-7-oxo-5 / f,6Zf,7 / f-pyrrolo[3,4-6]pyridine-2-carboxylate (505 mg, 1.05 mmol) in THF (10.5 mL) and water (2.10 mL) was added triphenylphosphine (826 mg, 3.15 mmol). The mixture was heated at 60°C for 2 hours. The mixture was cooled to room temperature and concentrated hydrochloric acid (2.62 mL, 31.5 mmol) was added dropwise (exothermic addition). The mixture was heated at 60°C for 2 hours and then cooled to room temperature. The volatiles were concentrated by rotary evaporation, and the residue was diluted in DCM and water. The aqueous layer was basified with a saturated aqueous solution of NaHCOv The layers were separated, and the aqueous layer was extracted twice with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by normal-phase silica chromatography (0-15% MeOH / DCM) follow by a second purification by normal phase silica chromatography (080% acetone / heptanes) to afford methyl 4-amino-5-(2-chloropheny 1)-5 -hydroxy-6-[(4-methoxyphenyl)methyl]-7-oxo-5 / f,6Zf,7 / f-pyrrolo[3,4-6]pyridine-2-carboxylate as a yellow solid (100.7 mg, 21% yield over 2 steps). Methyl 4-amino-5-(2-chlorophenyl)-6-[(4-methoxyphenyl)methyl]-7-oxo-5Zf,6Zf,7Zf-pyrrolo [3,4-6] pyridine-2-carboxylate OMe

[1052] Step 7: To a stirred solution of methyl 4-amino-5-(2-chlorophenyl)-5-hydroxy-6-[(4-methoxyphenyl)methyl]-7-oxo-5 / f,6Zf,7 / f-pyrrolo[3,4-6]pyridine-2-carboxylate (87.6 mg, 0.193 mmol) in DCE (2.57 mL) under nitrogen was added trifluoroborane diethyl etherate (76.1 pL, 0.618 mmol) followed by triethylsilane (307 pL, 1.93 mmol). The mixture was heated to 80°C, stirred for 15 hours, and then cooled to room temperature. A second portion of trifluoroborane diethyl etherate (76.1 pL, 0.618 mmol) and triethylsilane (307 pL, 1.93 mmol) was added, and the mixture was heated to 80°C and stirred 15 hours. The mixture was cooled to room temperature and diluted with DCM and water. The pH was adjusted to 8-9 with a saturated aqueous solution of NaHCOs. The layers were separated, and the aqueous layer was extracted with DCM twice. The organic layers were combined, washed with brine, dried over Na2SO4, fdtered, and concentrated. The residue was directly used for the next step without any further purification. Methyl 4-(l,2-benzothiazole-3-amido)-5-(2-chlorophenyl)-6-[(4-methoxyphenyl)methyl]- 7-oxo-5Zf,6Zf,7ZZ-pyrrolo[3,4-6]pyridine-2-carboxylate

[1053] Step 8: The residue from the previous step containing methyl 4-amino-5-(2-chlorophcnyl)-6-[(4-mcthoxyphcnyl)mcthyl]-7-oxo-5 / / ,6 / / ,7 / / -pyrrolo[3,4- / )]pyridinc-2-carboxylate (84.5 mg, 0.193 mmol) and l,2-benzothiazole-3-carboxylic acid (44.9 mg, 0.251 mmol) were dissolved in DCM (0.96mL). A-Methylimidazole (53.7 uL, 0.675 mmol) was added, followed by tetramethylchloroformamidinium hexafluorophosphate (64.9 mg, 0.231 mmol). The mixture was stirred at room temperature for 16 hours and then diluted with DCM and water. The pH was adjusted to 7-8 with a saturated aqueous solution of NaHCCh. The layers were separated, and the aqueous layer was extracted with DCM. The combined organics were washed with brine, dried with Na2SO4, fdtered, and concentrated. The resulting residue was directly subjected to the subsequent reaction without further purification. Methyl 4-(l,2-benzothiazole-3-amido)-5-(2-chlorophenyl)-7-oxo-5 / / ,6 / / ,7 / / -pyrrolo[3,4-6]pyridine-2-carboxylate (1-222)

[1054] Step 9: According to the procedures of Example 37, Step 7, methyl 4-(1,2-benzothiazole-3-amido)-5-(2-chlorophenyl)-6-[(4-methoxyphenyl)methyl]-7-oxo-57 / ,6Zf,7 / f-pyrrolo[3,4-6]pyridine-2-carboxylate was converted to methyl 4-(l,2-benzothiazole-3-amido)-5-(2-chlorophenyl)-7-oxo-57 / ,6Zf,77 / -pyrrolo[3,4-6]pyridine-2-carboxylate. The residue was purified by normal-phase silica chromatography (0% to 10% MeOH / DCM). The residue was suspended in water and the precipitate filtered. The solid was then dissolved with a mixture of acetonitrile / water and lyophilized to obtain methyl 4-(l,2-benzothiazole-3-amido)-5-(2-chlorophenyl)-7-oxo-5 / f,6Zf,7 / f-pyrrolo[3,4-6]pyridine-2-carboxylate as an off-white powder (4.62 mg, 13% yield over 3 steps). MS: m / z = 479.2 [M+H]+; 1H NMR (400 MHz, DMSO-de) 5 10.61 (br s, 1H), 9.70 (br s, 1H), 8.70 (d, J= 7.9 Hz, 1H), 8.60 (s, 1H), 8.33 (d, J= 8.2 Hz, 1H), 7.70 (ddd, J= 8.3, 7.0, 1.2 Hz, 1H), 7.67 - 7.52 (m, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.23 (td, / =7.9, 1.6 Hz, 1H), 7.15 (td, J= 7.4, 1.1 Hz, 1H), 6.40 (brs, 1H), 3.97 (s, 3H). Example 76

[1055] Selected compounds of the present invention were tested in an ADP-Glo Biochemical PIK3CA Kinase Assay. Compounds to be assayed were plated in 16 doses of 1:2 serial dilutions (20 nL volume each well) on a 1536-well plate, and the plate warmed to room temperature. PIK3CA enzyme (e.g. H1047R, E542K, E545K, or wild-type) (1 pL of 2 nM solution in Enzyme Assay Buffer (comprising 50 mM HEPES pH 7.4, 50mM NaCl, 6mM MgCh, 5mM DTT and 0.03% CHAPS)) was added and shaken for 10 seconds and preincubated for 30 minutes. To the well was added 1 pL of 200 pM ATP and 20 pM of diC8-PIP2 in Substrate Assay Buffer (50 mM HEPES pH7.4, 50mM NaCl, 5mM DTT and 0.03% CHAPS) to start the reaction, and the plate was shaken for 10 seconds, then spun briefly at 1500 rpm, and then incubated for 60 minutes at room temperature. The reaction was stopped by adding 2 pL of ADP-Glo reagent (Promega), and spinning briefly at 1500 rpm, and then incubating for 40 minutes. ADP-Glo Detection reagent (Promega) was added and the plate spun briefly at 1500 rpm, then incubated for 30 minutes. The plate was read on an Envision 2105 (Perkin Elmer), and the ICso values were calculated using Genedata software.

[1056] Results of the ADP-Glo Biochemical PIK3CA Kinase Assay using Hl 047R PIK3CA enzyme are presented in Table 1. Compounds having an ICso less than or equal to 100 nM are represented as “A”; compounds having an IC50 greater than 100 nM but less than or equal to 500 nM are represented as “B”; compounds having an IC50 greater than 500 nM but less than or equal tol pM are represented as “C”; compounds having an IC50 greater than 1 pM but less than or equal to 10 pM are represented as “D”; and compounds having an ICso greater than 10 uM but less than or equal to 100 pM are represented as “E”. Example 77

[1057] Selected compounds of the present invention were tested in a MCF10A Cell-Based PIK3CA Kinase Assay, namely the CisBio Phospho-AKT (Ser473) HTRF assay, to measure the degree of PIK3CA-mediated AKT phosphorylation. MCF10A cells (immortalized nontransformed breast cell line) overexpressing hotspot PIK3CA mutations (including H1047R, E542K, and E545K mutations) were used. Cells were seeded at 5,000 cells per well in DMEM / F12 (Thermo Fisher Scientific) supplemented with 0.5 mg / mL hydrocortisone, lOOng / mL Cholera Toxin, lOpg / mL insulin, and 0.5% horse serum. Once plated, cells were placed in a 5% CO2, 37 °C incubator to adhere overnight.

[1058] The following day, compounds were added to the cell plates in 12 doses of 1:3 serial dilutions. The dose response curves were run in duplicate. Compound addition was carried out utilizing an Echo 55 Liquid Handler acoustic dispenser (Labcyte). The cell plates were incubated for 2 hours in a 5% CO2, 37 °C incubator. Following compound incubation, the cells were lysed for 60 min at room temperature. Finally, a 4-hour incubation with the HTRF antibodies was performed at room temperature. All reagents, both lysis buffer and antibodies, were used from the CisBio pAKT S473 HTRF assay kit, as per the manufacturers protocol. Plates were read on an Envision 2105 (Perkin Elmer), and the IC50 values were calculated using Genedata software.

[1059] Results of the MCF10A Cell- Based PIK3CA Kinase Assay are presented in Table 1. Compounds having an IC50 less than or equal to 1 pM are represented as “A”; compounds having an IC50 greater than 1 pM but less than or equal to 5 pM are represented as “B”; compounds having an IC50 greater than 5 pM but less than or equal tol 0 pM are represented as “C”; compounds having an IC50 greater than 10 pM but less than or equal to36 pM are represented as “D”; and compounds having an IC50 greater than 36 pM but less than or equal to 100 pM are represented as “E”. INCORPORATION BY REFERENCE

[1060] All publications and patents mentioned herein are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS

[1061] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[1062] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

1. A compound, which is:or a pharmaceutically acceptable salt thereof.

2. A compound, which is:or a pharmaceutically acceptable salt thereof.

3. A compound, which is:or a pharmaceutically acceptable salt thereof.2021263914   18 Jun 20264.     A pharmaceutical composition comprising a pharmaceutically acceptable carrier,adjuvant, or vehicle and the compound of claim 1, or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier,adjuvant, or vehicle and the compound of claim 2, or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier,adjuvant, or vehicle and the compound of claim 3, or a pharmaceutically acceptable salt thereof.

7. A method of inhibiting PI3Ka signaling activity in a subject, comprisingadministering a therapeutically effective amount of the compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 4-6, to a subject in need thereof.

8. A method of treating a PI3Ka-mediated disease or disorder in a subject, comprisingadministering a therapeutically effective amount of the compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 4-6, to a subject in need thereof.

9. A method of treating a cellular proliferative disease mediated by PI3Ka, in asubject, comprising administering a therapeutically effective amount of the compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 4-6, to a subject in need thereof.

10. The method of claim 9, wherein the cellular proliferative disease is cancer.

11. Use of the compound according to any one of claims 1-3, or a pharmaceuticallyacceptable salt thereof, or the pharmaceutical composition according to any one of claims 4-6, in the manufacture of a medicament for inhibiting PI3Ka signaling activity in a subject in need thereof.

12. Use of the compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 4-6, in the manufacture of a medicament for treating a PI3Ka-mediated disease or disorder in a subject in need thereof.2021263914   18 Jun 202613. Use of the compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 4-6, in the manufacture of a medicament for the treatment of a cellular proliferative disorder mediated by PI3Ka, in a subject in need thereof.

14. The use of claim 16, wherein the cellular proliferative disease is cancer.

15. The method of claim 10, or the use of claim 14, wherein the cancer is selected from sarcoma; lung; bronchus; prostate; breast including sporadic breast cancers and sufferers of Cowden disease; pancreas; gastrointestinal; colon; rectum; carcinoma; colon carcinoma; adenoma; colorectal adenoma; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; glioma; glioblastoma; endometrial; melanoma; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary including clear cell ovarian cancer; multiple myeloma; esophagus; leukemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; carcinoma of the brain; oral cavity and pharynx; larynx; small intestine; non-Hodgkin lymphoma; villous colon adenoma; neoplasia; neoplasia of epithelial character; lymphoma; mammary carcinoma; basal cell carcinoma; squamous cell carcinoma; actinic keratosis; neck; head; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Waldenstrom macroglobulinemia.

16. The method of claim 10, or the use of claim 14, wherein the cancer is breast cancer.

17. The method of claim 10, or the use of claim 14, wherein the cancer is ovarian cancer.

18. The method or use of claim 17, wherein the ovarian cancer is clear cell ovariancancer.

19. The method of claim 8, or the use of claim 12, wherein the PI3Ka-mediated disease or disorder is selected from the group consisting of polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, asthma, COPD, ARDS, PROS, PI3K-related overgrowth syndrome, venous malformation, Loffler's syndrome, eosinophilic pneumonia, parasitic in particular metazoan infestation including tropical eosinophilia, bronchopulmonary aspergillosis, polyarteritis nodosa including Churg-Strauss syndrome, eosinophilic granuloma, eosinophil-related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia greata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo,2021263914   30 Jun 2026hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, autoimmune haematogical disorders, haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia, systemic lupus erythematosus, polychondritis, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease, ulcerative colitis and Crohn's disease, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis such as anterior and posterior, interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis, cardiovascular diseases, atherosclerosis, hypertension, deep venous thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic occlusions, coronary artery disease, reperfusion injuries, retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma.

20. The method or use of any one of claims 7-19, wherein the subject has PI3Ka containing at least one of the following mutations: H1047R, E542K, and E545K.Relay Therapeutics, Inc.D.E. Shaw Research, LLCPatent Attorneys for the Applicant / Nominated Person SPRUSON & FERGUSON