MK2 inhibitors, synthesis thereof, and intermediates thereto

Abstract

The present invention provides methods of preparing a MK2 inhibitor, and intermediates related thereto.

Claims

1. A compound selected from the group consisting of: ##STR00178## ##STR00179## or a salt thereof.

2. The compound of claim 1, selected from the group consisting of: ##STR00180## or a salt thereof.

3. The compound of claim 2, wherein the compound is: ##STR00181## or a salt thereof.

4. The compound of claim 2, wherein the compound is: ##STR00182## or a salt thereof.

5. The compound of claim 2, wherein the compound is: ##STR00183## or a salt thereof.

6. The compound of claim 2, wherein the compound is: ##STR00184## or a salt thereof.

7. The compound of claim 2, wherein the compound is: ##STR00185## or a salt thereof.

8. The compound of claim 1, selected from the group consisting of: ##STR00186## and ##STR00187## and or a salt thereof.

9. The compound of claim 8, wherein the compound is: ##STR00188## or a salt thereof.

10. The compound of claim 8, wherein the compound is: ##STR00189## or a salt thereof.

Description

EXEMPLIFICATION

Example 1

Synthesis of Compound 1-2

(1) ##STR00147##

(2) A mixture of 6-nitroquinoline 1-1(450 g, 2.6 mol) and DBU (1.16 L, 7.8 mol) in DMSO (1.8 L) was warmed to 40 to 45° C. and ethyl cyanoacetate (690 mL, 6.5 mol) was added at a rate sufficient to maintain the batch temp. in the same range. At the end of the addition, the batch is cooled to 20-25° C. After 16 h, the batch was sampled by HPLC for full consumption of the starting material. Then, concentrated HCl (1.13 L, 13.5 mol) was added at a rate sufficient to maintain the batch temp. at 20-25° C. The batch was warmed to 80-90° C. and agitated for 4 h and then sampled for completion by HPLC. The batch was cooled to 20-30° C., acetonitrile (4.5 L) was added and the batch was further cooled to 0-5° C. and held for 2 h. The batch was filtered and the cake is rinsed with acetonitrile (2×900 mL) and dried under vacuum. The cake was transferred to a clean vessel and combined with THF (4.5 L) and water (1.8 L). Then, 10N aqueous NaOH solution was added at a rate sufficient to maintain the batch temperature less than 25° C. The batch was agitated, settled and split, and the upper organic phase was retained in the reactor. A 10% Aqueous NaCl solution (2.25 L) was charged to the vessel. The batch was agitated, settled and split, and the upper organic phase was retained in the reactor. The batch was then heated to reflux and continuously distilled at atmospheric pressure with the addition of water (4.5 L) to maintain a constant volume. The batch was cooled to 20-25° C. and the product was filtered. The cake was washed with water (2×900 mL) and dried under vacuum at 30-40° C. to afford compound 1-2, 440 g, in 65% yield.

(3) .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 6.93 (s, 2H) 7.20-7.33 (m, 1H) 7.52 (dd, J=8.44, 4.31 Hz, 1H) 7.93 (s, 4H) 7.95-8.09 (m, 1H) 8.61 (dd, J=4.31, 1.56 Hz, 14H).

(4) .sup.13C NMR (75 MHz, DMSO-d.sub.6) δ 82.9, 117.1, 122.0, 123.9, 129.4, 130.1, 135.7, 141.8, 146.8, 153.0.

(5) MS: M+1 Calc: 170.2, Found: 170.0.

Example 2

Synthesis of Compound 1-3

(6) ##STR00148##

(7) A mixture of compound 1-2 (80 g, 470 mmol) and copper (II) bromide (137 g, 620 mmol), acetonitrile (1.28 L) and water (320 mL) was warmed to 30-35° C. and agitated for 30-60 min. Tert-butyl nitrite (147 mL, 1.4 mol) was then added over 60 min. After the addition was completed, the mixture was stirred for 20 h and then sampled for completion by HPLC. The mixture was then warmed to 55-60° C. and held at this temperature for 1 h. Then, conc. ammonium hydroxide (240 mL) was added over 1 h, taking care to maintain the batch temperature under 60° C. The batch was stirred for 2 h and then cooled to 20-25° C., held for an additional 2 h, and the product was filtered. The cake was washed with water (3×400 mL) and heptane (400 mL), and the product was dried under vacuum at 30-40° C. to afford compound 1-3, 99 g, in 89% yield.

(8) .sup.1H NMR (300 MHz, CDCl.sub.3-d) δ ppm 7.65 (dd, J=8.25, 3.85 Hz, 1H) 7.94 (d, J=8.99 Hz, 1H) 8.21 (d, J=9.08 Hz, 1H) 8.52 (d, J=8.53 Hz, 1H).

(9) MS: M+1 Calc: 233.0/235.0, Found: 233.0/235.0.

Example 3

Synthesis of Compound 1-4

(10) ##STR00149##

(11) To a well agitated slurry of 6-bromoquinoline-5-carbonitrile 1-3 (50 g, 215 mmol) in dichloromethane (750 mL) at room temperature was charged a solution of mCPBA (69.1 g, 300 mmol of 77% mCPBA) in dichloromethane (350 mL) at a rate sufficiently slow to maintain the batch temperature under 25° C. The mixture was stirred at 20-25° C. for 24 h. The batch was sampled by HPLC for reaction completion. The mixture was warmed to 35° C. and distilled at 80-100 Torr to reduce the batch volume to ˜500 mL. Then acetonitrile was slowly added while continuing to distill under reduced pressure, maintaining a constant batch volume at ˜500 mL. After 1.1 L of acetonitrile was added, the batch was sampled by .sup.1H NMR to ensure that the solvent mixture contained less than 7.5 mol % of dichloromethane. The batch was cooled to 20-25° C. and an aqueous solution of 10% Na.sub.2S203 (350 mL) was charged to the batch and the mixture was agitated for a minimum of 2 h at 20-25° C. An aqueous solution of 5% NaHCO.sub.3 (350 mL) was then added over 10-15 min and the mixture was agitated for a minimum of 4 h at 20-25° C. The batch was filtered and washed with MeCN:water (1:1) (350 mL) followed by water (350 mL) and then heptane (350 mL). The cake was dried at 40-45° C. under vacuum to afford the product compound 1-4, (41.5 g, 78% yield).

(12) .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 7.73 (dd, J=8.62, 6.14 Hz, 0H) 7.96 (d, J=8.71 Hz, 0H) 8.19 (d, J=9.44 Hz, 0H) 8.57-8.84 (m, 2H).

(13) MS: M+1 Calc: 249.0/251.0, Found: 248.8/250.8.

Example 4

Synthesis of Compound 1-5

(14) ##STR00150##

(15) A mixture of 6-bromo-5-cyanoquinoline 1-oxide 1-4 (102 g, 411 mmol) and BnOH (1.0 L, 9.6 mol) was cooled to 3-7° C. and DIEA (215 mL, 1.25 mol) was added at a rate sufficient to maintain the batch temp. in the same range. Then, a solution of p-toluenesulfonic anhydride (201 g, 620 mmol) in THF (1.0 L) was added over a period of 2 h. At the end of the addition, the batch was warmed to 20-25° C. After 30 min, the batch was sampled by HPLC for reaction completion. Additional DIEA (215 mL, 1.25 mol) was added to the mixture, which was then warmed to 40-45° C. and 10% aq. NH.sub.4OH solution (IL of a 10% NH.sub.3 in water) was added. The batch was stirred at 40-45° C. for 45 min, and was then settled and the phases were split, retaining the upper organic phase in the reactor. 20% aqueous NaCl solution (510 mL) was charged to the reactor. The batch was agitated, settled and split, and the upper organic phase was retained in the reactor. The batch was heated to 70-75° C. and distilled at atmospheric pressure until THF stops distilling over. The batch was cooled to 40-45° C. and agitated until a thin slurry forms. Methanol (510 mL) was added over a period of 2 h and the slurry was agitated for 1 h. Water (510 mL) was added over a period of 2 h and the slurry was agitated for 1 h. The batch was cooled to 20-25° C., stirred for an additional 1 h and then filtered. The cake was washed with 1:1 MeOH/water (510 mL) and dried under vacuum at 30-40° C. to provide 104 g of compound 1-5, in 75% yield.

(16) .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 5.52 (s, 2H) 7.28-7.45 (m, 4H) 7.49-7.60 (m, 2H) 7.95-8.08 (m, 2H) 8.31 (d, J=9.08 Hz, 1H).

(17) MS: M+1 Calc: 339.0/341.0, Found: 339.1/341.0.

Example 5

Synthesis of Compound 1-7

(18) ##STR00151##

(19) To a mixture of compound 1-5 (20 g, 59 mmol) and methyl 2-mercaptoacetate (9.9 g, 88 mmol) in THF (160 mL) was charged 25% sodium methoxide solution in methanol (17.5 mL, 77 mmol) slowly to maintain the reaction temperature of 20-25° C. The mixture was then heated to reflux for 2-4 hours and the batch was sampled for reaction completion by HPLC. The reaction mixture was cooled to 20-25° C. over 1 hour. Acetic acid (1.7 mL, 29.5 mmol) was added to quench the reaction. Then water (160 mL) was added over 2 h. The batch was stirred at 20-25° C. for 16 hours and the product was filtered. The cake was washed with THF:water (1:2) (2×40 mL) and dried under vacuum at 30-40° C. to provide compound 1-7, 18.9 g, in 89% yield.

(20) .sup.1H NMR (300 MHz, DMSO-d.sub.6) ppm 3.85 (s, 3H) 5.53 (s, 2H) 7.07 (br, 2H) 7.24 (d, J=9.08 Hz, 1H) 7.29-7.47 (m, 3H) 7.56 (d, J=6.97 Hz, 2H) 7.89 (d, J=8.89 Hz, 1H) 8.12 (d, J=8.89 Hz, 1H) 9.07 (d, J=9.17 Hz, 1H).

(21) MS: M+1 Calc: 365.1, Found: 365.1.

Example 6

Version 1 Synthesis of Compound 1-9

(22) ##STR00152##

(23) A mixture of compound 7 (100 g, 274 mmol) and compound 1-8 (73 g, 302 mmol) in NMP (400 mL) was cooled to −10-−15° C. Then, 2.2M t-BuOLi solution in THF (160 mL, 0.340 mmol) was charged over 90 min. The mixture was stirred for additional 30 min at the same temperature and was then sampled for conversion by HPLC. The reaction was quenched with acetic acid (20 mL, 340 mmol) and warmed to 20-25° C. The mixture was partitioned between 2-MeTHF (1 L) and 2% aqueous NaCl (500 mL), and the organic phase was washed with 5% aqueous NaCl (2×500 mL) and water (500 mL). The batch was heated to reflux and distilled at atmospheric pressure until the batch volume is reduced to 500 mL. The batch was then distilled at constant volume with addition of acetonitrile (1 L) and then sampled by .sup.1H NMR to ensure that the solvent composition contains less than 5 mol % 2-MeTHF. Additional acetonitrile (1.5 L) was added to bring the total batch volume to 2.0 L. The batch was cooled to 60-65° C. and seeded with compound 1-8 seed (2.0 g, 4.0 mmol). The batch was held at 60-65° C. for 1 h and cooled to 20-25° C. over 6 h. The batch was heated back to 60-65° C. and held for 2 h and then cooled to 20-25° C. over 6 h. The batch was filtered, washed with acetonitrile (2×00 mL) and dried in vacuo at 35-40° C. for 16-18 to provide compound 1-9, 122.3 g, in 85% yield.

(24) .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 1.00 (d, J=6.51 Hz, 3H) 1.06-1.51 (m, 9H) 3.10 (t, J=6.42 Hz, 2H) 3.54-3.74 (m, 1H) 3.89 (s, 3H), 5.54 (s, 2H) 6.52 (t, J=6.56 Hz, 1H) 6.80 (d, J=8.25 Hz, 1H) 7.24 (d, J=9.08 Hz, 1H) 7.29-7.47 (m, 3H) 7.50-7.64 (m, 2H) 7.89 (d, J=8.99 Hz, 1H) 8.16 (d, J=8.89 Hz, 1H) 8.99 (d, J=9.17 Hz, 1H)

(25) MS: M+1 Calc: 522.2, Found: 522.2.

Example 7

Version 1 Synthesis of Compound 1-10-1

(26) ##STR00153##

(27) To a mixture of compound 1-9 (100 g, 192 mmol) in methanol (1.0 L) was charged 5-6 N HCl in isopropanol (128 mL, 767 mmol) at ambient temperature. The mixture was stirred for 15 min and then heated to reflux and held with stirring for 20 h. The batch was sampled for conversion by HPLC and was then cooled to 20-25° C. The mixture was filtered and the cake was washed with methanol (2×200 mL) and dried under vacuum at 35-40° C. for 16 h to afford 68.1 g of compound 1-10-1, in 97% yield.

(28) .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 1.21 (d, J=6.51 Hz, 3H) 2.98 (dd, J=12.75, 7.52 Hz, 1H) 3.10-3.25 (m, 1H) 3.25-3.40 (m, 1H) 3.82 (s, 3H) 6.53-6.82 (m, 1H) 7.36-7.57 (m, 1H) 7.83-8.01 (m, 1H) 8.65 (d, J=9.81 Hz, 1H).

(29) MS: M+1 Calc: 332.1, Found: 332.1.

Example 8

Version 1 Synthesis of Compound 1-11

(30) ##STR00154##

(31) A mixture of compound 1-10-1 (4.0 g, 10.9 mmol) in methanol (100 mL) was stirred at 20-25° C. and DBU (8.20 mL, 54.4 mmol) was added dropwise at a rate sufficient to maintain the batch temp. within the same range. Then the batch was heated to 60-70° C. and stirred at this temperature for 40 h. The batch was cooled to 35-40° C. and distilled under reduced pressure until the batch volume was reduced to 16-20 mL. Then acetonitrile (90 mL) was added slowly and the batch was heated to 70-75° C. for 20 h. The mixture was cooled to 20-25° C., aged for 1 h, and was then filtered. The cake was washed with water (2 mL) and 1:1 acetonitrile-methanol (2 mL) and dried under vacuum at 40-50° C. for 30 h to afford compound 1-11, 3.0 g as a yellow solid, in 92% yield.

(32) .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 1.16 (d, J=6.79 Hz, 3H) 3.39 (br. s., 2H) 3.50-3.60 (m, 1H) 6.60 (d, J=9.90 Hz, 1H) 6.85 (t, J=5.27 Hz, 1H) 7.43 (d, J=8.80 Hz, 1H) 7.92 (d, J=8.71 Hz, 1H) 8.07 (d, J=4.22 Hz, 1H) 8.80 (d, J=10.00 Hz, 1H), 12.02 (br, 1H).

(33) MS: M+1 Calc: 300.1, Found: 300.0.

Example 9

Version 2 Synthesis of Compound 1-10-2

(34) ##STR00155##

(35) A mixture of compound 1-7 (100 g, 274 mmol) and compound 1-8 (71.6 g, 302 mmol) in NMP (400 mL) was cooled to −10-−15° C. Then, 2.2 M t-BuOLi solution in THF (156 mL, 343 mmol) was charged over 90 min maintaining a temperature between −10-−15° C. The reaction was sampled by HPLC for completion and then quenched with 1:1 v/v acetic acid-THF (38.8 mL, 343 mmol) and warmed to 0-5° C. The mixture was partitioned between 2-MeTHF (1.0 L) and 2.5% aqueous LiCl (500 mL). The aqueous phase was back extracted with 100 mL vol 2-MeTHF. The organic phases were combined and washed with 5% aqueous LiCl (500 mL Vol.) two times and once with water (500 mL). The batch was heated to reflux and distilled at atmospheric pressure until the batch volume was reduced to 500 mL. Acetonitrile (500 mL) was added and the batch was distilled at constant volume with addition of acetonitrile (1.2 L) and then sampled by NMR to ensure that the 2-MeTHF content in the solvent composition is less than 2.5 mol %. Additional acetonitrile (200 mL) was added to bring the total batch volume to 1.2 L. The batch was cooled to 65-70° C. and a solution of BSA (78 g, 494 mmol) in MeOH (200 mL) was added dropwise. Additional MeOH (200 mL) was then added dropwise as a rinse and to bring the total batch volume to 1.6 L. The reaction was stirred at 65 to 70° C. for 16 h and was then monitored by HPLC for completion of reaction. Once complete, the reaction was cooled to 20-25° C. over 2 h, held for 1 h and then filtered. The yellow filter cake was then washed with 3:2 MeCN/MeOH (2×200 mL). The final wet cake was then dried under vacuum at 40-45° C. to provide 109 g of compound 1-10-2, in 81% yield.

(36) .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 1.25 (d, J=6.33 Hz, 3H) 3.00-3.18 (m, 1H) 3.28 (d, J=7.34 Hz, 1H) 3.34-3.37 (m, 1H), 3.90 (s, 3H) 6.24 (t, J=6.92 Hz, 1H) 6.70 (d, J=9.90 Hz, 1H) 7.19-7.36 (m, 3H) 7.51-7.64 (m, 3H) 7.85 (br. s., 3H) 8.09 (d, J=8.89 Hz, 1H) 8.68 (d, J=9.90 Hz, 1H) 12.14 (s, 1H).

(37) MS: M+1 Calc: 332.1, Found: 332.1.

Example 10

Version 2 Synthesis of Compound 1-11

(38) ##STR00156##

(39) A mixture of compound 1-10-2 (1.5 kg, 3.1 mol) in methanol (30 L) was stirred at 20-30° C. and DBU (2.25 L, 15.4 mol), was added slowly, maintaining the batch temperature under 35° C. The resulting suspension was heated to 60-65° C. for 24-30 h under nitrogen. The reaction was sampled by HPLC to ensure that less than 2% starting material remains. The reaction was then cooled to 20-30° C. and filtered. The cake was washed with MeOH (7.5×L) and deliquored. The wet cake was transferred to a visually clean reactor, and then acetonitrile (30 L) and MeOH (7.5 L were added) and the batch was stirred at 20-30° C. were added while DBU (0.45 L, 3.0 mol). Heat the suspension, with overhead agitation to reflux (65-70° C.) for 18-24 h. The mixture is sampled by HPLC to ensure that less than 0.5% starting material remains. The reaction is cooled to 20-30° C. and filtered. The cake is washed with water (7.5 L), MeOH:MeCN (1.1 v/v, 7.5 L), deliquored and dried in oven under vacuum at 45-55° C. for 18-24 h to afford compound 1-11, 820 g as a yellow solid in 89% yield.

(40) .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 1.16 (d, J=6.79 Hz, 3H) 3.39 (br. s., 2H) 3.50-3.60 (m, 1H) 6.60 (d, J=9.90 Hz, 1H) 6.85 (t, J=5.27 Hz, 1H) 7.43 (d, J=8.80 Hz, 1H) 7.92 (d, J=8.71 Hz, 1H) 8.07 (d, J=4.22 Hz, 1H) 8.80 (d, J=10.00 Hz, 1H), 12.02 (br, 1H).

(41) MS: M+1 Calc: 300.1, Found. 300.0.

Example 11

Synthesis of Compound I

(42) ##STR00157##

(43) A mixture of compound 1-11 (55 g, 184 mmol), compound 1-12 (45.7 g, 220 mmol), potassium carbonate (30.5 g, 220 mmol) and DMSO (550 mL) was stirred at ambient temperature for 15 min and then warmed to 40-45° C. for 7 h. The mixture was cooled to 20-25° C. and stirred for 10 h. The mixture was sampled by HPLC for completion of reaction. The batch was then warmed to 40-45° C. and water (550 mL) and THF were added, maintaining the batch temperature in the same range. The biphasic mixture was agitated for 15 then allowed to settle and the phases were split. The lower aqueous phase was transferred back to the vessel and was back-extracted with THF (550 mL). The combined organic phases were washed with a 10% aqueous NaCl solution (2×550 mL) and filtered to remove suspended solids. The filtrate was transferred to a clean reactor and distilled under atmospheric pressure until the batch volume was reduced to 440 mL. The batch was seeded with compound 1 (1.1 g, 2.3 mmol). Then the batch was distilled under atmospheric pressure with addition of isopropanol (1.1 L) to maintain the batch at constant volume. The batch was sampled by NMR to ensure that the THF content was less than 3 mol % of the solvent composition. Then the batch was agitated at 80-85° C. for 1 h, cooled to 20-25° C. over 3 h, and agitated at 20-25° C. for 16 h. The batch was filtered and the cake was washed with isopropanol (2×110 mL) and dried under vacuum at 40-45° C. for 16 h to provide 69.8 g of compound I, in 81% yield.

(44) .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 1.12-1.25 (m, 6H) 3.42-3.50 (m, 2H) 3.61 (q, J=6.97 Hz, 3H) 4.65 (s, 2H) 7.17 (t, J=5.18 Hz, 1H) 7.63 (d, J=9.08 Hz, 1H) 7.86 (d, J=8.89 Hz, 1H) 8.15 (d, J=4.40 Hz, 1H) 8.18 (d, J=8.90 Hz, 1H) 8.71 (s, 1H) 9.36 (d, J=9.08 Hz, 1H).

(45) MS: M+1 Calc: 470.10/472.10, Found: 470.10/472.20.

Example 12

Alternative Synthesis of Compound I

(46) ##STR00158##

(47) A mixture of compound 1-11 (100 g, 334 mmol), compound 1-12 (83 g, 401 mmol), potassium carbonate (55 g, 401 mmol), DMSO (500 mL) and THF (500 mL) was stirred at ambient temperature for 15 min and then warmed to 40-45° C. for 22 h. The mixture was sampled by HPLC for completion of reaction. The mixture was cooled to 20-25° C. and filtered through a bed a Celite (10 g). The reactor was washed with 100 mL of (8:2) THF/DMSO and filtered. Finally the Celite cake was washed with 100 mL (8:2) THF/DMSO followed by 100 mL of THF. The filtrate was transferred to a clean reactor, followed by THF (700 mL). The batch was then warmed to 40-45° C. and 10% aqueous NaCl (500 mL) was added, maintaining the batch temperature in the same range. The biphasic mixture was agitated for 15 min then allowed to settle and the phases were split, leaving the upper organic phase in the reactor. Then THF (500 mL) and 10% aqueous NaCl (500 mL) were added, maintaining the batch temperature in the same range. The biphasic mixture was agitated for 15 min then allowed to settle and the phases were split, leaving the upper organic phase in the reactor. THF (500 mL) and 10% aqueous NaCl (200 mL) were added, maintaining the batch temperature in the same range. The biphasic mixture was agitated for 15 min then allowed to settle and the phases were split, leaving the upper organic phase in the reactor. The batch was then distilled under atmospheric pressure until the batch volume was reduced to 800 mL. The batch was seeded with compound I (2.0 g, 4.3 mmol). Then the batch was distilled under atmospheric pressure with addition of isopropanol (2.0 L) to maintain the batch at constant volume. The batch was sampled by GC to ensure that the THF content was less than 6 wt % of the solvent composition. Then the batch was agitated at 80-85° C. for 1 h, cooled to 20-25° C. over 3 h, and agitated at 20-25° C. for 16 h. The batch was filtered and the cake was washed with isopropanol (200 mL) and then water (200 mL), and dried under vacuum at 40-45° C. for 16 h to provide 134.7 g of the crude product, in 86% yield.

(48) A mixture of crude compound 1(75 g, 160 mmol), THF (675 mL) and water (75 mL) was heated to 55-65° C. and agitated until formation of a clear solution. The batch was cooled to 4° C. and seeded with the THF solvate form of compound 1(1.5 g, 2.7 mmol). After 20 min, the batch was cooled to 20° C. over 2 h and held at 20° C. for 30 min. Then the mixture was heated to 40° C. over 30 min and held at this temperature for 30 min and then cooled to 20° C. over 2 h and held for 14 h. The batch was warmed back to 40° C. over 30 min and water (938 mL) was charged over 8 h. The batch was cooled to 20° C. over 2 h and filtered. The reactor was washed with water:THF (2:1 by vol, 150 mL) and this wash was used to rinse the cake. The cake was then washed with water (2×150 mL) and dried under vacuum at 50-55° C. to afford 75.6 g of the THF solvate, in 88% yield.

(49) A mixture of THF solvate (29.0 g, 54.6 mmol) and acetone (290 mL) was agitated in the presence of the anhydrate form of compound 1(250 mg, 0.5 mmol) and the resulting mixture was heated to 50-55° C. and agitated at this temperature for 48 h. The mixture was sampled by XRPD to assess conversion to the anhydrate form. Then the batch was cooled to 20-25° C. over 2 h and held at that temperature for 16 h. The batch was filtered and the cake was rinsed with acetone (2×60 mL). The cake was dried under vacuum at 45-55° C. to afford 24.0 g of the anhydrate form of compound I as a yellow solid, in 94% yield.

(50) .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 1.12-1.25 (m, 6H) 3.42-3.50 (m, 2H) 3.61 (q, J=6.97 Hz, 3H) 4.65 (s, 2H) 7.17 (t, J=5.18 Hz, 1H) 7.63 (d, J=9.08 Hz, 1H) 7.86 (d, J=8.89 Hz, 1H) 8.15 (d, J=4.40 Hz, 1H) 8.18 (d, J=8.90 Hz, 1H) 8.71 (s, 1H) 9.36 (d, J=9.08 Hz, 1H).

(51) MS: M+1 Calc: 470.10/472.10, Found: 470.10/472.20.

Example 13

(S)-3-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one

(52) ##STR00159##

Step 1: Preparation of (S)-methyl 1-((2-aminopropyl)amino)-7-hydroxythieno[3,2-f]quinoline-2-carboxylate benzenesulfonate

(53) ##STR00160##

(54) A hazy brown mixture of methyl 1-amino-7-(benzyloxy)thieno[3,2-f]quinoline-2-carboxylate (100 g, 274 mmol), (S)-tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (73.0 g, 302 mmol) in anhydrous NMP (400 ml, 4127 mmol) was stirred at ambient temperature for 30 minutes, followed by cooling the mixture to −15° C. to −20° C. Then a cloudy mixture of lithium tert-butoxide (27.4 g, 343 mmol) in anhydrous THF (135 ml) was charged over 90 min while keeping the reaction mixture less than −10° C. The reaction was kept at −10° C. for additional one hour and then quenched with acetic acid (19.6 ml, 343 mmol) over 10 minutes and then warmed to 20-25° C. over 30 minutes. The mixture was partitioned between 2-MeTHF (1000 ml) and 2.5% aqueous LiCl (500 ml). The aqueous phase was back extracted with 100 ml of 2-MeTHF. The organic phases were combined and washed two times with 5% aqueous LiCl (500 ml) and once with water (500 ml). The batch was heated to reflux and distilled at ˜85° C. under atmospheric pressure until the batch volume was reduced to ˜500 ml, followed by distillation at constant volume with addition of acetonitrile (1200 ml). Additional acetonitrile (200 ml) was added to bring the total batch volume to ˜700 ml. The batch was cooled to 60-65° C. and a solution of benzenesulfonic acid (82 g, 494 mmol) in MeOH (200 ml) was added dropwise over 30 minutes. Additional MeOH (100 ml) was then added dropwise as a rinse and to bring the total batch volume to ˜1000 ml. The reaction was held at 65-70° C. for at least 16 hours then cooled to 20-25° C. over 2 hours, held for 1 h and then filtered. The yellow filter cake was then washed twice with (200 ml) 3:2 MeCN/MeOH. The final wet cake was then dried in a vacuum oven at 40° C. with a slow bleed of nitrogen for 12-16 hours to give a yellow solid (115.8 g, 86% yield); mp 283-285° C.; HPLC: Waters Ascentis Express C-18 HPLC column, 10 cm×4.6 μm, 1 mL/min, 234 nm, gradient at 100% 0.1% H.sub.3PO.sub.4 to 100% CH.sub.3CN in 10 min, then hold at 100% CH.sub.3CN for 5 min): t.sub.R=3.65 min (99.4%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 1.25 (d, J=6.33 Hz, 3H) 3.02-3.19 (m, 1H) 3.22-3.44 (m, 2H) 3.90 (s, 3H) 6.25 (t, J=6.97 Hz, 1H) 6.71 (d, J=9.90 Hz, 1H) 7.25-7.40 (m, 3H) 7.51-7.66 (m, 3H) 7.85 (br s, 3H) 8.10 (d, J=8.80 Hz, 1H) 8.69 (d, J=9.90 Hz, 1H) 12.15 (s, 1H). .sup.13C NMR (DMSO-d.sub.6) δ 16.90, 47.28, 52.63, 52.85, 114.71, 114.95, 118.15, 122.45, 125.91, 126.29, 128.09, 128.58, 128.86, 134.24, 136.05, 138.54, 148.71, 151.46, 161.61, 164.53. LC/MS m/e.sup.+=332. Anal. Calcd. for C.sub.22H.sub.23N.sub.3O.sub.6S.sub.2: C, 53.98; H, 4.74; N, 8.58; S, 13.10. Found: C, 53.97; H, 4.92; N, 8.52; S, 12.96.

Step 2: Preparation of (S)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one

(55) ##STR00161##

(56) To a stirred yellow slurry of (S)-methyl 1-((2-aminopropyl)amino)-7-hydroxythieno[3,2-f]quinoline-2-carboxylate benzenesulfonate (110.3 g, 225 mmol) in methanol (2200 ml, 225 mmol) at ambient temperature under nitrogen was charged 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (“DBU”, 158 ml, 1127 mmol) slowly over 5 minutes with rapid agitation (300-400 rpm) while keeping temperature less than 35° C. The mixture was then heated to reflux (65-70° C.) for 24-36 hours until the benzenesulfonate was no more than 2% area by HPLC. If not met, heat for additional 18-24 hours. The batch was cooled to 20-30° C. over one hour and filtered. The cake was washed with MeOH (550 ml) and deliquored. The wet cake was transferred to a visually clean reactor and charged with MeCN (2200 ml), MeOH (550 ml) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (33 ml). The mixture was heated to reflux (65-70° C.) for 18-24 hours until the benzenesulfonate was not more than 0.5% area by HPLC. The batch was cooled to 20-30° C. and filtered. The cake was washed with water (550 ml), MeOH:MeCN (1:1 v/v, 550 vol), deliquored and dried oven under vacuum at 45-55° C. for 18-24 hours to afford a yellow solid (62.6 g, 93% yield); HPLC: Waters Ascentis Express C-18 HPLC column, 10 cm×4.6 μm, 1 mL/min, 254 nm, gradient at 100% 0.1% H.sub.3PO.sub.4 to 100% CH.sub.3CN in 10 min, then hold at 100% CH.sub.3CN for 5 min): t.sub.R=2.87 min (98.9%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 1.16 (d, J=6.79 Hz, 3H) 3.33 (s, 3H) 3.38 (br d, J=4.68 Hz, 2H) 3.56 (br dd, J=6.60, 3.48 Hz, 1H) 6.60 (d, J=9.90 Hz, 1H) 6.86 (t, J=5.41 Hz, 1H) 7.43 (d, J=8.71 Hz, 1H) 7.93 (d, J=8.80 Hz, 1H) 8.08 (d, J=4.22 Hz, 1H) 8.80 (d, J=10.00 Hz, 1H) 12.05 (s, 1H); .sup.13C NMR (DMSO-d.sub.6) δ 19.11, 48.50, 52.39, 115.08, 116.57, 121.35, 125.90, 128.02, 134.45, 135.97, 138.41, 143.91, 161.42, 164.50. LC/MS m/e.sup.+=300. Anal. Calcd. for C.sub.15H.sub.13N.sub.3O.sub.2S: C, 60.19; H, 4.38; N, 14.04; S, 10.71. Found: C, 59.60; H, 4.07; N, 13.69; S, 10.38.

Step 3: Preparation of (S)-3-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one (I′)

(57) ##STR00162##

(58) A yellow slurry mixture of (S)-3-hydroxy-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one (30 g, 100 mmol), 2,4-dichloro-5-(ethoxymethyl)pyrimidine (24.90 g, 120 mmol), and potassium carbonate (325 mesh) (16.96 g, 120 mmol) in DMSO (150 ml, 2114 mmol) and THF (150 ml, 1831 mmol) was stirred at ambient temperature for 5-10 minutes, followed by heating at 40-45° C. for at least 16 hours with sufficient agitation (350-400 rpm). The yellow/tan slurry mixture was then cooled to 20-25° C., and filtered over 9 g of Celite (prewetted with 15 mL of THF). The yellow filtrate (˜400 ml) was transferred back to the visually clean jacketed flask along with 240 mL of THF, and was heated to 40-45° C. over 30 minutes. To the mixture was charged 150 mL of 10 wt % aqueous NaCl, stirred for 5 minutes and settled for phase split. After the bottom aqueous phase was removed, 150 mL of THF and 150 mL of 10 wt % aqueous NaCl were charged and stirred at 40-45° C. for 5 minutes. The aqueous phase was removed again. Then, 90 mL of THF and 50 mL of 10 wt % aqueous NaCl were charged, maintaining the batch temp at 40-45° C. (lower temp will make product crystallize out). The aqueous phase was removed and the remaining organic portion was distilled under atmospheric pressure at 65-70° C. to ˜300 ml. The batch was seeded with 200 mg of the product and the resulting mixture was aged for one hour. Then the batch was distilled with addition of isopropanol (600 ml) at a rate sufficient to maintain a constant batch volume. The slurry was cooled from ˜70° C. to 22° C. over 4 hours, hold at 22° C. for 16 hours and filtered, washed with 3×30 mL of IPA, and dried in a vacuum oven at 40-45° C. for 12-16 hours to afford compound I′ as a yellow solid (41.1 g, 87% yield); HPLC: Waters Ascentis Express C-18 HPLC column, 10 cm×4.6 μm, 1 mL/min, 234 nm, gradient at 100% 0.1% H.sub.3PO.sub.4 to 100% CH.sub.3CN in 10 min, then hold at 100% CH.sub.3CN for 5 min): t.sub.R=6.40 min (99.0%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ ppm 1.13-1.27 (m, 6H) 3.42-3.54 (m, 2H) 3.57-3.70 (m, 3H) 4.66 (s, 2H) 7.18 (br t, J=5.18 Hz, 1H) 7.64 (d, J=9.08 Hz, 1H) 7.87 (d, J=8.89 Hz, 1H) 8.12-8.23 (m, 2H) 8.72 (s, 1H) 9.37 (d, J=9.17 Hz, 1H); .sup.13C NMR (75 MHz, DMSO-d.sub.6) δ ppm 15.47, 19.12, 48.46, 52.39, 64.02, 66.28, 114.87, 115.10, 119.60, 124.30, 126.49, 126.75, 127.7, 135.77, 139.30, 145.00, 145.84, 156.32, 158.02, 160.48, 164.52, 167.37. LC/MS m/e*=470. Anal. Calcd. for C.sub.22H.sub.20N.sub.5O.sub.3SCl: C, 56.23; H, 4.29; N, 14.90; S, 6.82; Cl, 7.54. Found: C, 55.87; H, 4.33; N, 14.61; S, 6.60.

ENUMERATED EMBODIMENTS

(59) 1. A method for preparing compound I:

(60) ##STR00163##

(61) or a pharmaceutically acceptable salt thereof, comprising the steps of: reacting a compound of formula 1-11:

(62) ##STR00164##

(63) or a pharmaceutically acceptable salt thereof;

(64) with a compound of formula 1-12,

(65) ##STR00165##

(66) wherein LG.sup.3 is a suitable leaving group;

(67) under suitable reaction conditions to provide compound I, or a pharmaceutically acceptable salt thereof.

(68) 2. The method according to embodiment 1, wherein LG.sup.3 is halogen. 3. The method according to embodiment 2, wherein LG.sup.3 is chloro. 4. The method according to any of embodiments 1-3, wherein the reaction conditions comprise a base. 5. The method according to embodiment 4, wherein the base is K.sub.2CO.sub.3. 6. The method according to any one of embodiments 1-5, wherein a compound of formula 1-11 is prepared by a process comprising:
reacting a compound of formula 1-10:

(69) ##STR00166##

(70) or a salt thereof, wherein

(71) R′ is hydrogen or optionally substituted C.sub.1-6 aliphatic or aryl;

(72) under suitable reaction conditions to provide a compound of formula 1-11, or a salt thereof.

(73) 7. The method according to embodiment 6, wherein R′ is C.sub.1-6 aliphatic. 8. The method according to embodiment 7, wherein R′ is methyl. 9. The method according any one of embodiments 6-8, wherein the reaction conditions comprise a base. 10. The method according to embodiment 9, wherein the base is DBU. 11. The method according any one of embodiments 6-10, wherein a compound of formula 1-10 is prepared by a process comprising:
reacting a compound of formula 1-9:

(74) ##STR00167##

(75) or a salt thereof, wherein

(76) R.sup.1 is a suitable oxygen protecting group; and

(77) PG.sup.1 is a suitable nitrogen protecting group;

(78) under suitable reaction conditions to provide a compound of formula 1-10, or a salt thereof.

(79) 12. The method according to embodiment 11, wherein R′ is C.sub.1-6 aliphatic. 13. The method according to embodiment 12, wherein R′ is methyl. 14. The method according to any one of embodiments 11-13, wherein PG.sup.1 is Boc. 15. The method according to any one of embodiments 11-14, wherein R.sup.1 is benzyl. 16. The method according to any one of embodiments 11-15, wherein the reaction conditions comprise an acid. 17. The method according to embodiment 16, wherein the acid is HCl. 18. The method according to embodiment 16, wherein the acid is BSA. 19. The method according to any one of embodiments 11-17, wherein a compound of formula 1-10 is provided as an HCl salt. 20. The method according to claim any one of embodiments 11-16 and 18, wherein a compound of formula 1-10 is provided as a BSA salt 21 The method according to any one of embodiments 11-20, wherein a compound of formula 1-9 is prepared by a process comprising:
reacting a compound of formula 1-7:

(80) ##STR00168##

(81) or a salt thereof;

(82) with a compound of formula 1-8:

(83) ##STR00169##

(84) or salt thereof, wherein,

(85) LG.sup.2 is a suitable leaving group;

(86) under suitable reaction conditions to provide a compound of formula 1-9, or a salt thereof.

(87) 22. The method according to embodiment 21, wherein R′ is C.sub.1-6 aliphatic. 23. The method according to embodiment 22, wherein R′ is methyl. 24. The method according to any one of embodiments 21-23, wherein R.sup.1 is benzyl. 25. The method according to any one of embodiments 21-24, wherein a compound of formula 1-8 is:

(88) ##STR00170## 26. The method according to any one of embodiments 21-25, wherein PG.sup.1 is Boc. 27. The method according to any one of embodiments 21-26, wherein the reaction conditions comprise a base. 28. The method according to embodiment 27, wherein the base is LiOtBu. 29. The method according to any one of embodiments 21-28, wherein a compound of formula 1-7 is prepared by a process comprising:
reacting a compound of formula 1-5:

(89) ##STR00171##

(90) or a salt thereof, wherein:

(91) LG.sup.1 is a suitable leaving group; and

(92) R.sup.1 is a suitable oxygen protecting group;

(93) with a compound of formula 1-6:

(94) ##STR00172##
under suitable reaction conditions to provide a compound of formula 1-7. 30. The method according to embodiment 29, wherein LG.sup.1 is halogen. 31. The method according to embodiment 30, wherein LG.sup.1 is bromide. 32. The method according to any one of embodiments 29-31, wherein R.sup.1 is benzyl. 33. The method according to any one of embodiments 29-32, wherein R′ is C.sub.1-6 aliphatic. 34. The method according to embodiment 33, wherein R′ is methyl. 35. The method according any one of embodiments 29-34, wherein the reaction conditions comprise a base. 36. The method according to embodiment 35, wherein the base is NaOMe. 37. The method according to any one of embodiments 29-36, wherein a compound of formula 1-5 is prepared by a process comprising:
reacting a compound of formula 1-4:

(95) ##STR00173##

(96) or a salt thereof;

(97) with a compound of formula R.sup.1OH under suitable reaction conditions to provide a compound of formula 1-5, or a salt thereof.

(98) 38. The method according to embodiment 37, wherein LG.sup.1 is halogen. 39. The method according to embodiment 38, wherein LG.sup.1 is bromide. 40. The method according to any one of embodiments 37-39, wherein R.sup.1 is benzyl. 41. The method according to any one of embodiments 37-40, wherein the reaction conditions comprise a base. 42. The method according to embodiment 41, wherein the base is DIEA. 43. The method according to any one of embodiments 36-42, wherein the reaction conditions comprise an activating compound. 44. The method according to embodiment 43, wherein the activating compound is p-toluenesulfonic anhydride. 45. The method according to any one of embodiments 37-44, wherein a compound of formula 1-4 is prepared by a process comprising:
reacting a compound of formula 1-3:

(99) ##STR00174##

(100) or a pharmaceutically acceptable salt thereof;

(101) under suitable reaction conditions to provide a compound of formula 1-4, or a salt thereof

(102) 46. The method according to embodiment 45, wherein LG.sup.1 is halogen. 47. The method according to embodiment 46, wherein LG.sup.1 is bromide. 48. The method according to any one of embodiments 45-47, wherein the reaction conditions comprise a peroxide reagent. 49. The method according to embodiment 48, wherein the peroxide reagent is mCPBA. 50. The method according to any one of embodiments 45-49, wherein a compound of formula 1-3 is prepared by a process comprising:
reacting a compound of formula 1-2:

(103) ##STR00175##

(104) or a salt thereof;

(105) under suitable reaction conditions to provide a compound of formula 1-3, or a salt thereof.

(106) 51. The method according to embodiment 50, wherein the reaction conditions comprise a nitrite compound. 52. The method according to embodiment 51, wherein the nitrite compound is tert-butyl nitrite. 53. The method according to any one of embodiments 50-52, wherein the reaction conditions further comprise a bromide source. 54. The method according to embodiment 53, wherein the bromide source is CuBr.sub.2. 55. The method according to claims any one of embodiments 50-54, wherein the reaction conditions comprise in situ formation of a diazonium intermediate of formula 1-2a:

(107) ##STR00176##

(108) wherein X″ is a counterion. 56. The method according to any one of embodiments 50-55, wherein a compound of formula 1-2 is prepared by a process comprising:
reacting a compound of formula 1-1:

(109) ##STR00177##

(110) or a salt thereof;

(111) under suitable reaction conditions to provide a compound of formula 1-2, or a pharmaceutically acceptable salt thereof.

(112) 57. The method according to embodiment 56, wherein the reaction conditions comprise a cyanating agent. 58. The method according to embodiment 57, wherein the cyanating agent is ethyl cyanoacetate. 59. The method according to any one of embodiments 56-58, wherein the reaction conditions further comprise a base. 60. The method according to embodiment 59, wherein the base is DBU. 61. The method according to claim any one of embodiments 56-60, wherein the reaction conditions further comprise an acid. 62. The method according to embodiment 61, wherein the acid is HCl.